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Sample records for development neurotoxicity implications

  1. Ethanol Neurotoxicity in the Developing Cerebellum: Underlying Mechanisms and Implications

    Directory of Open Access Journals (Sweden)

    Ambrish Kumar

    2013-06-01

    Full Text Available Ethanol is the main constituent of alcoholic beverages that exerts toxicity to neuronal development. Ethanol affects synaptogenesis and prevents proper brain development. In humans, synaptogenesis takes place during the third trimester of pregnancy, and in rodents this period corresponds to the initial few weeks of postnatal development. In this period neuronal maturation and differentiation begin and neuronal cells start migrating to their ultimate destinations. Although the neuronal development of all areas of the brain is affected, the cerebellum and cerebellar neurons are more susceptible to the damaging effects of ethanol. Ethanol’s harmful effects include neuronal cell death, impaired differentiation, reduction of neuronal numbers, and weakening of neuronal plasticity. Neuronal development requires many hormones and growth factors such as retinoic acid, nerve growth factors, and cytokines. These factors regulate development and differentiation of neurons by acting through various receptors and their signaling pathways. Ethanol exposure during development impairs neuronal signaling mechanisms mediated by the N-methyl-d-aspartate (NMDA receptors, the retinoic acid receptors, and by growth factors such as brain-derived neurotrophic factor (BDNF, insulin-like growth factor 1 (IGF-I, and basic fibroblast growth factor (bFGF. In combination, these ethanol effects disrupt cellular homeostasis, reduce the survival and migration of neurons, and lead to various developmental defects in the brain. Here we review the signaling mechanisms that are required for proper neuronal development, and how these processes are impaired by ethanol resulting in harmful consequences to brain development.

  2. Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: implications for developmental neurotoxicity.

    Science.gov (United States)

    Seegal, Richard F; Brosch, Karl O; Okoniewski, Richard J

    2005-07-01

    We show that developmental exposure of the laboratory rat to the coplanar polychlorinated biphenyl (PCB) congener 3,4,3',4'-tetrachlorobiphenyl (TCB) and the structurally similar congener 3,4,5,3',4'-pentachlorobiphenyl (PtCB) elevates dopamine (DA) concentrations in the prefrontal cortex (PFC). To determine whether these coplanar congeners are estrogenic, and may thus contribute to the elevations in PFC DA, we measured uterine wet weight (UWW) in prepubertal rats exposed to TCB or PtCB. For comparison, additional animals were exposed to either the ortho-substituted congener 2,4,2',4'-tetrachlorobiphenyl (o-TCB) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), a coplanar congener highly resistant to metabolism. Both TCB and PtCB increased UWW, but this effect was blocked after exposure to the anti-estrogen ICI 182,780. Neither o-TCB nor HCB altered UWW. These results demonstrate that certain coplanar PCB congeners and/or their metabolites, are estrogenic, and suggest that exposure during critical periods of neuronal development may increase central DA concentrations, and by inference, alter behavior.

  3. Molecular, Behavioral, and Physiological Consequences of Methamphetamine Neurotoxicity: Implications for Treatment.

    Science.gov (United States)

    Moszczynska, Anna; Callan, Sean Patrick

    2017-09-01

    Understanding the relationship between the molecular mechanisms underlying neurotoxicity of high-dose methamphetamine (METH) and related clinical manifestations is imperative for providing more effective treatments for human METH users. This article provides an overview of clinical manifestations of METH neurotoxicity to the central nervous system and neurobiology underlying the consequences of administration of neurotoxic METH doses, and discusses implications of METH neurotoxicity for treatment of human abusers of the drug. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  4. Recent Insights Into Molecular Mechanisms of Propofol-Induced Developmental Neurotoxicity: Implications for the Protective Strategies.

    Science.gov (United States)

    Bosnjak, Zeljko J; Logan, Sarah; Liu, Yanan; Bai, Xiaowen

    2016-11-01

    Mounting evidence has demonstrated that general anesthetics could induce developmental neurotoxicity, including acute widespread neuronal cell death, followed by long-term memory and learning abnormalities. Propofol is a commonly used intravenous anesthetic agent for the induction and maintenance of anesthesia and procedural and critical care sedation in children. Compared with other anesthetic drugs, little information is available on its potential contributions to neurotoxicity. Growing evidence from multiple experimental models showed a similar neurotoxic effect of propofol as observed in other anesthetic drugs, raising serious concerns regarding pediatric propofol anesthesia. The aim of this review is to summarize the current findings of propofol-induced developmental neurotoxicity. We first present the evidence of neurotoxicity from animal models, animal cell culture, and human stem cell-derived neuron culture studies. We then discuss the mechanism of propofol-induced developmental neurotoxicity, such as increased cell death in neurons and oligodendrocytes, dysregulation of neurogenesis, abnormal dendritic development, and decreases in neurotrophic factor expression. Recent findings of complex mechanisms of propofol action, including alterations in microRNAs and mitochondrial fission, are discussed as well. An understanding of the toxic effect of propofol and the underlying mechanisms may help to develop effective novel protective or therapeutic strategies for avoiding the neurotoxicity in the developing human brain.

  5. Neurotoxicity of PBDEs and metabolites : concern for the developing brain?

    NARCIS (Netherlands)

    Dingemans, M.M.L.

    2010-01-01

    Increasing human exposure to brominated flame retardants (BFRs), including the widely used polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD), raises concern about possible neurotoxicity in humans, particularly through developmental exposure. Recently, also several hydroxylated

  6. Rechallenging With Intrathecal Methotrexate After Developing Subacute Neurotoxicity in Children With Hematologic Malignancies.

    Science.gov (United States)

    Badke, Colleen; Fleming, Amy; Iqbal, Asneha; Khilji, Ohmed; Parhas, Sophia; Weinstein, Joanna; Morgan, Elaine; Hijiya, Nobuko

    2016-04-01

    Methotrexate is associated with neurologic side effects. It is recommended that patients who developed neurotoxicity be rechallenged with methotrexate, but little is known about the safety of this approach. We performed a chart review to identify patients who received high-dose or intrathecal (IT) methotrexate. Twenty-one of 298 patients (7%) experienced neurologic symptoms attributed to methotrexate treatment in the premaintenance phase. Seventeen of these patients were rechallenged with IT methotrexate and 13 (76%) had no further neurotoxic events. No patients rechallenged during maintenance (n = 9) experienced recurrence of neurotoxic events. It is safe to rechallenge with IT methotrexate in maintenance.

  7. Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans

    DEFF Research Database (Denmark)

    Grandjean, Philippe; Herz, Katherine T

    2011-01-01

    Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan, a few years later. Whereas the infant...

  8. Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence

    Directory of Open Access Journals (Sweden)

    Zhaowei Zhou

    2014-03-01

    Full Text Available Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies.

  9. Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development

    Science.gov (United States)

    Dubovický, Michal; Kovačovský, Pavel; Ujházy, Eduard; Navarová, Jana; Brucknerová, Ingrid; Mach, Mojmír

    2008-01-01

    Exposure of the developing organism to industrial chemicals and physical factors represents a serious risk factor for the development of neurobehavioral disorders, such as attention-deficit hyperactivity disorder, autism and mental retardation. Appropriate animal models are needed to test potentially harmful effects and mechanisms of developmental neurotoxicity of various chemical substances. However, there are significant human vs. rat differences in the brain developmental profile which should be taken into account in neurotoxicity studies. Subtle behavioral alterations are hard to detect by traditional developmental toxicity and teratogenicity studies, and in many cases they remain hidden. They can however be revealed by using special behavioral, endocrine and/or pharmacological challenges, such as repeated behavioral testing, exposure to single stressful stimulus or drugs. Further, current neurobehavioral test protocols recommend to test animals up to their adulthood. However some behavioral alterations, such as anxiety-like behavior or mental deficiency, may become manifest in later periods of development. Our experimental and scientific experiences are highly suggestive for a complex approach in testing potential developmental neurotoxicity. Strong emphasis should be given on repeated behavioral testing of animals up to senescence and on using proper pharmacological and/or stressful challenges. PMID:21218116

  10. Evaluation of developmental neurotoxicity: some important issues focused on neurobehavioral development.

    Science.gov (United States)

    Dubovický, Michal; Kovačovský, Pavel; Ujházy, Eduard; Navarová, Jana; Brucknerová, Ingrid; Mach, Mojmír

    2008-12-01

    Exposure of the developing organism to industrial chemicals and physical factors represents a serious risk factor for the development of neurobehavioral disorders, such as attention-deficit hyperactivity disorder, autism and mental retardation. Appropriate animal models are needed to test potentially harmful effects and mechanisms of developmental neurotoxicity of various chemical substances. However, there are significant human vs. rat differences in the brain developmental profile which should be taken into account in neurotoxicity studies. Subtle behavioral alterations are hard to detect by traditional developmental toxicity and teratogenicity studies, and in many cases they remain hidden. They can however be revealed by using special behavioral, endocrine and/or pharmacological challenges, such as repeated behavioral testing, exposure to single stressful stimulus or drugs. Further, current neurobehavioral test protocols recommend to test animals up to their adulthood. However some behavioral alterations, such as anxiety-like behavior or mental deficiency, may become manifest in later periods of development. Our experimental and scientific experiences are highly suggestive for a complex approach in testing potential developmental neurotoxicity. Strong emphasis should be given on repeated behavioral testing of animals up to senescence and on using proper pharmacological and/or stressful challenges.

  11. Vulnerability of children and the developing brain to neurotoxic hazards.

    OpenAIRE

    Weiss, B

    2000-01-01

    For much of the history of toxicology, the sensitivity of the developing organism to chemical perturbation attracted limited attention. Several tragic episodes and new insights finally taught us that the course of early brain development incurs unique risks. Although the process is exquisitely controlled, its lability renders it highly susceptible to damage from environmental chemicals. Such disturbances, as recognized by current testing protocols and legislation such as the Food Quality Prot...

  12. Etanercept, an inhibitor of TNF-a, prevents propofol-induced neurotoxicity in the developing brain.

    Science.gov (United States)

    Chen, Bo; Deng, Xiaoyuan; Wang, Bin; Liu, Hongliang

    2016-12-01

    Propofol can induce acute neuronal apoptosis, neuronal loss or long-term cognitive impairment when exposed in neonatal rodents, but the mechanisms by which propofol induces developmental neurotoxicity are unclear. Recent studies have demonstrated that propofol can increase the TNF-α level in the developing brain, but there is a lack of direct evidence to show whether TNF-α is partially or fully involved in propofol-induced neurotoxicity. The present study shows that propofol exposure in neonatal rats induces an increase of TNF-α in the cerebral spinal fluid, hippocampus and prefrontal cortex (PFC). Etanercept, a TNF-α inhibitor, prevents propofol-induced short- or long-term neuronal apoptosis, neuronal loss, synaptic loss and long-term cognitive impairment. Furthermore, mTNF-α (precursor of TNF-α) expression in microglia cells is increased after propofol anaesthesia in either the hippocampus or PFC, but mTNF-α expression in neurons is only increased in the PFC. These findings suggest that TNF-α may mediate propofol-induced developmental neurotoxicity, and etanercept can provide neural protection. Microglia are the main cellular source of TNF-α after propofol exposure, while the synthesis of TNF-α in neurons is brain-region selective. Copyright © 2016 ISDN. Published by Elsevier Ltd. All rights reserved.

  13. Vulnerability of children and the developing brain to neurotoxic hazards.

    Science.gov (United States)

    Weiss, B

    2000-06-01

    For much of the history of toxicology, the sensitivity of the developing organism to chemical perturbation attracted limited attention. Several tragic episodes and new insights finally taught us that the course of early brain development incurs unique risks. Although the process is exquisitely controlled, its lability renders it highly susceptible to damage from environmental chemicals. Such disturbances, as recognized by current testing protocols and legislation such as the Food Quality Protection Act, can result in outcomes ranging from death to malformations to functional impairment. The latter are the most difficult to determine. First, they require a variety of measures to assay their extent. Second, adult responses may prove an inadequate guide to the response of the developing brain, which is part of the reason for proposing additional safety factors for children. Third, neuropsychological tests are deployed in complex circumstances in which many factors, including economic status, combine to produce a particular effect such as lowered intelligence quotient score. Fourth, the magnitude of the effect, for most environmental exposure levels, may be relatively small but extremely significant for public health. Fifth, changes in brain function occur throughout life, and some consequences of early damage may not even emerge until advanced age. Such factors need to be addressed in estimating the influence of a particular agent or group of agents on brain development and its functional expression. It is especially important to consider ways of dealing with multiple risks and their combinations in addition to the prevailing practice of estimating risks in isolation.

  14. Neurotoxic effects of MDMA (ecstasy) on the developing rodent brain.

    Science.gov (United States)

    Dzietko, M; Sifringer, M; Klaus, J; Endesfelder, S; Brait, D; Hansen, H H; Bendix, I; Felderhoff-Mueser, U

    2010-08-01

    The incidence of methamphetamine abuse is particularly high in adolescents and is a common problem among women of childbearing age, leading to an increasing number of children with prenatal exposure. MDMA (3,4-methylenedioxymethamphetamine, ecstasy) is an amphetamine-like stimulant and is known to induce apoptotic damage to fine serotonergic fibers in the adult rat brain. Little is known about toxic effects of MDMA and potential underlying molecular mechanisms in the developing brain. Here, we investigated whether MDMA exposure during the period of rapid brain growth causes neurodegeneration in the developing rat brain. MDMA significantly enhanced neuronal death in the brains of 6-day-old rat pups at a dose of 60 mg/kg, but no significant toxicity was detected at the ages of 14 and 21 days. Brain regions mainly affected were the cortex, septum, thalamus, hypothalamus and the cornu ammonis 1 region. To explore possible molecular mechanisms involved in this neurodegenerative process, we investigated the impact of MDMA on the expression of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor. Neonatal exposure of 6-day-old rats to MDMA triggered a considerable increase in cortical BDNF and NT-3 levels. Moreover, P7 CD1/BDNF knockout mice were noticeably more sensitive to MDMA exposure as compared to their wild-type age-matched littermates. These data suggest that a single injection of MDMA causes neurodegeneration in the neonatal rat brain. The upregulation of BDNF and NT-3 expression may indicate an important compensatory mechanism leading to the survival of neuronal cells in the developing brain.

  15. NEUROTOXIC EFFECTS OF AZT ON DEVELOPING AND ADULT NEUROGENESIS

    Directory of Open Access Journals (Sweden)

    Meryem eDemir

    2015-03-01

    Full Text Available Azidothymidine (AZT is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions. We employed in vitro and in vivo models of mouse neurogenesis in order to assess the effects of AZT on developing and adult neurogenesis. Using in vitro assays we show that AZT reduces the population expansion potential of neural stem/progenitor cells by inducing senescence. Additionally, in a model of in vitro neurogenesis AZT severely attenuates neuroblast production. These effects are mirrored in vivo by clinically-relevant animal models. We show that in utero AZT exposure perturbs both population expansion and neurogenesis among neural stem/progenitor cells. Additionally, a short-term AZT regimen in adult mice suppresses subependymal zone neurogenesis. These data reveal novel negative effects of AZT on neural stem cell biology. Given that the sequelae of HIV infection often include neurologic deficits –subsumed under AIDS Dementia Complex (Brew, 1999 - it is important to determine to what extent AZT negatively affects neurological function in ways that contribute to, or exacerbate, ADC in order to avoid attributing iatrogenic drug effects to the underlying disease process, and thereby skewing the risk/benefit analysis of AZT therapy.

  16. Comprehensive neurotoxicity assessment

    NARCIS (Netherlands)

    Kulig, B.M.

    1996-01-01

    Significant progress has been made in recent years in terms of both the conceptualization of neurotoxicity assessment strategies as well as in the development of behavioral techniques for evaluating neurotoxic exposures. A tiered approach, for example, has been advocated as an assessment strategy in

  17. Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

    Science.gov (United States)

    Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

    2002-09-01

    The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

  18. Developmental neurotoxicity testing: recommendations for developing alternative methods for the screening and prioritization of chemicals.

    Science.gov (United States)

    Crofton, Kevin M; Mundy, William R; Lein, Pamela J; Bal-Price, Anna; Coecke, Sandra; Seiler, Andrea E M; Knaut, Holger; Buzanska, Leonora; Goldberg, Alan

    2011-01-01

    Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternative methods to current animal testing protocols and guidelines. An immediate goal is to develop test methods that are capable of screening large numbers of chemicals. This document provides recommendations for developing alternative DNT approaches that will generate the type of data required for evaluating and comparing predictive capacity and efficiency across test methods and laboratories. These recommendations were originally drafted to stimulate and focus discussions of alternative testing methods and models for DNT at the TestSmart DNT II meeting (http://caat.jhsph.edu/programs/workshops/dnt2.html) and this document reflects critical feedback from all stakeholders that participated in this meeting. The intent of this document is to serve as a catalyst for engaging the research community in the development of DNT alternatives and it is expected that these recommendations will continue to evolve with the science.

  19. Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children

    DEFF Research Database (Denmark)

    Hansen, Tom G

    2015-01-01

    A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice possibly during a vulnerable period of brain development (i.e., brain growth spurt, peak of synaptogenesis) may lead to neurodegeneration (particularly apoptosis) and abnormal synaptic...... no such association. Prospective studies are underway, but the result will not be available for several years. This paper reviews some of the preclinical background behind anesthesia-related neurotoxicity but focuses mainly on the human studies so far. It is concluded that although disturbing, the animal data lack...... verification in humans. Fortunately, the humans studies performed so far have been unable to confirm these animal data. A single brief anesthetic seems safe in infants. Multiple anesthetic and surgical exposures on the other hand are different. But there may be other reasons for this than merely...

  20. Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity.

    Directory of Open Access Journals (Sweden)

    Susanna B Park

    Full Text Available BACKGROUND: Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+ channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+ channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Specifically the function of transient and persistent Na(+ currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+ channel inactivation was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001 and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05, strength-duration time constant (marker of persistent Na(+ conductances was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS. However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05. CONCLUSIONS/SIGNIFICANCE: It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+ conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies.

  1. Development of An ICR Mouse Bioassay for Toxicity Evaluatition in Neurotoxic Poistioning Toxins-Ctiontaminated Shellfish

    Institute of Scientific and Technical Information of China (English)

    WONG Chun Kwan; HUNG Patricia; KAM Kai Man

    2013-01-01

    Objective To develop an ICR (female) mouse bioassay (MBA) for toxicity ctionfirmatition and evaluatition of neurotoxins (brevetoxins)-ctiontaminated shellfish. Methods Brevetoxins (BTX-B) as a causative agent of neurotoxic shellfish poistioning (NSP) under different shellfish matrices were intraperittioneally injected at different doses into mice to study their toxic effects and to differentiate the range of lethal and sublethal dosages. Their sensitivity and specificity were analyzed with 2 competitive ELISA kits for quantitative determinatition of standard BTX-B and dihydroBTX-B under different shellfish matrix-diluent combinatitions. Detectition rates of MBA and two antibody-based assays for BTX-B from field NSP-positive shellfish samples were compared. Results BTX-B could be detected in shellfish tissues at ctioncentratition of 50-400 μg/100 g under shellfish matrix-Tween-saline media, which were appropriate to identify toxic shellfish at or above the regulatory limit (80 μg/100 g shellfish tissues). The LD50 identified was 455 μg/kg for BTX-B under general shellfish matrices (excluding oyster matrices) dissolved in Tween-saline. The presence of shellfish matrices, of oyster matrices in particular, retarded the occurrence of death and toxicity presentatition in mice. Two antibody-based assays, even in the presence of different shellfish matrix-diluent combinatitions, showed acceptable results in quantifying BTX-B and dihydroBTX-B well below the regulatory limit. Ctionclusition The two ELISA analyses agree favorably (correlatition coefficient, r≥0.96;Student's t-tests, P>0.05) with the developed bioassay.

  2. Thalidomide neurotoxicity

    DEFF Research Database (Denmark)

    Clemmensen, O J; Olsen, P Z; Andersen, Klaus Ejner

    1984-01-01

    therapy. Since reports on thalidomide neurotoxicity have shown that the neurological symptoms are long standing and possibly irreversible, it is obviously important to inform patients of this possible side effect and to evaluate them closely for the symptoms and electrophysiological signs of evolving...

  3. A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats.

    Science.gov (United States)

    Kassa, Jirí; Kunesova, Gabriela

    2006-01-01

    The neuroprotective effects of newly developed oximes (K027, K048) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (170 microg kg(-1) i.m.; 80% of LD(50) value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 h and 7 days following tabun challenge. The results indicate that the oxime HI-6 in combination with atropine was not able to protect the rats from the lethal effects of tabun. Two non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine combined with HI-6 died within 2 h. On the other hand, all other tested oximes combined with atropine allowed all the tabun-poisoned rats to survive 7 days following tabun challenge. Both newly developed oximes combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The neuroprotective efficacy of obidoxime in combination with atropine approached the potency of newly developed oximes but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity was significantly lower, especially at 24 h after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisoning.

  4. Neurotoxic Weapons and Syndromes.

    Science.gov (United States)

    Carota, Antonio; Calabrese, Pasquale; Bogousslavsky, Julien

    2016-01-01

    The modern era of chemical and biological warfare began in World War I with the large-scale production and use of blistering and choking agents (chlorine, phosgene and mustard gases) in the battlefield. International treaties (the 1925 Geneva Protocol, the 1975 Biological and Toxin Weapons Convention and the 1993 Chemical Weapons Convention) banned biological and chemical weapons. However, several countries are probably still engaged in their development. Hence, there is risk of these weapons being used in the future. This chapter will focus on neurotoxic weapons (e.g. nerve agents, chemical and biological neurotoxins, psychostimulants), which act specifically or preeminently on the central nervous system and/or the neuromuscular junction. Deeply affecting the function of the nervous system, these agents either have incapacitating effects or cause clusters of casualties who manifest primary symptoms of encephalopathy, seizures, muscle paralysis and respiratory failure. The neurologist should be prepared both to notice patterns of symptoms and signs that are sufficiently consistent to raise the alarm of neurotoxic attacks and to define specific therapeutic interventions. Additionally, extensive knowledge on neurotoxic syndromes should stimulate scientific research to produce more effective antidotes and antibodies (which are still lacking for most neurotoxic weapons) for rapid administration in aerosolized forms in the case of terrorist or warfare scenarios. © 2016 S. Karger AG, Basel.

  5. Organophosphate induced chronic neurotoxicity: Health ...

    African Journals Online (AJOL)

    Organophosphate induced chronic neurotoxicity: Health, environmental and risk exposure issues in developing nations of the world. ... show that many agents considered toxic and banned in many parts of the industrialized world are still in ...

  6. The Evaluation of the Potency of Newly Developed Oximes (K727, K733 and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats

    Directory of Open Access Journals (Sweden)

    Jiří Kassa

    2016-03-01

    Full Text Available Aim: The ability of two newly developed oximes (K727, K733 to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. Methods: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 μg/kg i.m.; 90% of LD50 value were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sensory, motor and autonomic nervous functions at 2 hours following tabun challenge. Results: All tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K727, K733 combined with atropine were able to decrease tabun-induced neurotoxicity in the case of lethal poisoning although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Conclusion: The ability of both novel bispyridinium oximes to decrease tabun-induced acute neurotoxicity was slightly lower than that of trimedoxime. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes such as trimedoxime in the treatment of acute tabun poisonings.

  7. Development of a direct exposure system for studying the mechanisms of central neurotoxicity caused by volatile organic compounds.

    Science.gov (United States)

    Kanemitsu, Masanari; Fueta, Yukiko; Ishidao, Toru; Aou, Shuji; Hori, Hajime

    2016-01-01

    Many volatile organic compounds (VOCs) used in work places are neurotoxic. However, it has been difficult to study the cellular mechanisms induced by a direct exposure to neurons because of their high volatility. The objective of this study was to establish a stable system for exposing brain slices to VOCs. With a conventional recording system for brain slices, it is not possible to keep a constant bath concentration of relatively highly volatile solvents, e.g. 1-bromopropane (1-BP). Here we report a new exposure system for VOCs that we developed in which a high concentration of oxygen is dissolved to a perfused medium applying a gas-liquid equilibrium, and in which the tubing is made of Teflon, non adsorptive material. Using our system, the bath concentration of the perfused 1-BP remained stable for at least 2 h in the slice chamber. Both 6.4 and 2.2 mM of 1-BP did not change the paired-pulse response, but fully suppressed long-term potentiation in the dentate gyrus (DG) of hippocampal slices obtained from rats, suggesting that 1-BP decreases synaptic plasticity in the DG at the concentrations tested. Our new system can be applicable for investigating the underlying mechanisms of the neurotoxicity of VOCs at the cellular level.

  8. Development of a direct exposure system for studying the mechanisms of central neurotoxicity caused by volatile organic compounds

    Science.gov (United States)

    KANEMITSU, Masanari; FUETA, Yukiko; ISHIDAO, Toru; AOU, Shuji; HORI, Hajime

    2015-01-01

    Many volatile organic compounds (VOCs) used in work places are neurotoxic. However, it has been difficult to study the cellular mechanisms induced by a direct exposure to neurons because of their high volatility. The objective of this study was to establish a stable system for exposing brain slices to VOCs. With a conventional recording system for brain slices, it is not possible to keep a constant bath concentration of relatively highly volatile solvents, e.g. 1-bromopropane (1-BP). Here we report a new exposure system for VOCs that we developed in which a high concentration of oxygen is dissolved to a perfused medium applying a gas-liquid equilibrium, and in which the tubing is made of Teflon, non adsorptive material. Using our system, the bath concentration of the perfused 1-BP remained stable for at least 2 h in the slice chamber. Both 6.4 and 2.2 mM of 1-BP did not change the paired-pulse response, but fully suppressed long-term potentiation in the dentate gyrus (DG) of hippocampal slices obtained from rats, suggesting that 1-BP decreases synaptic plasticity in the DG at the concentrations tested. Our new system can be applicable for investigating the underlying mechanisms of the neurotoxicity of VOCs at the cellular level. PMID:26320726

  9. Propofol-Induced Neurotoxicity in the Fetal Animal Brain and Developments in Modifying These Effects—An Updated Review of Propofol Fetal Exposure in Laboratory Animal Studies

    Directory of Open Access Journals (Sweden)

    Ming Xiong

    2016-03-01

    Full Text Available In the past twenty years, evidence of neurotoxicity in the developing brain in animal studies from exposure to several general anesthetics has been accumulating. Propofol, a commonly used general anesthetic medication, administered during synaptogenesis, may trigger widespread apoptotic neurodegeneration in the developing brain and long-term neurobehavioral disturbances in both rodents and non-human primates. Despite the growing evidence of the potential neurotoxicity of different anesthetic agents in animal studies, there is no concrete evidence that humans may be similarly affected. However, given the growing evidence of the neurotoxic effects of anesthetics in laboratory studies, it is prudent to further investigate the mechanisms causing these effects and potential ways to mitigate them. Here, we review multiple studies that investigate the effects of in utero propofol exposure and the developmental agents that may modify these deleterious effects.

  10. A comparison of the potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats.

    Science.gov (United States)

    Kassa, Jiri; Karasova, Jana

    2007-01-05

    The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 micro g/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.

  11. The Evaluation of the Potency of Newly Developed Oximes (K727, K733) and Trimedoxime to Counteract Acute Neurotoxic Effects of Tabun in Rats

    OpenAIRE

    Jiří Kassa; Jana Hatlapatková; Jana Žďárová Karasová

    2016-01-01

    Aim: The ability of two newly developed oximes (K727, K733) to reduce tabun-induced acute neurotoxic signs and symptoms was evaluated and compared with currently available trimedoxime in rats. Methods: The neuroprotective effects of the oximes studied combined with atropine on Wistar rats poisoned with tabun at a lethal dose (380 μg/kg i.m.; 90% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery consisting of 38 measurements of sen...

  12. Computational Analysis of Axonal Transport: A Novel Assessment of Neurotoxicity, Neuronal Development and Functions

    Directory of Open Access Journals (Sweden)

    Toshiyuki Gotoh

    2012-03-01

    Full Text Available Axonal transport plays a crucial role in neuronal morphogenesis, survival and function. Despite its importance, however, the molecular mechanisms of axonal transport remain mostly unknown because a simple and quantitative assay system for monitoring this cellular process has been lacking. In order to better characterize the mechanisms involved in axonal transport, we formulate a novel computer-assisted monitoring system of axonal transport. Potential uses of this system and implications for future studies will be discussed.

  13. Developmental neurotoxicity of Propylthiouracil (PTU) in rats: Relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes

    DEFF Research Database (Denmark)

    Petersen, Marta Axelstad; Hansen, Pernille Reimer; Boberg, Julie

    2008-01-01

    Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent Studies, indicating that even small changes in the mother's thyroid hormone Status early in pregnancy may Cause adverse effects on her child, have lead to increas....... This supports the hypothesis that decreased T-4 may be a relevant predictor for long-lasting developmental neurotoxicity. (C) 2008 Elsevier Inc. All rights reserved....

  14. [Neurotoxicity of intrathecally administrated agents].

    Science.gov (United States)

    Malinovsky, J M; Pinaud, M

    1996-01-01

    Spinal anaesthetics can induce histopathologic lesions and regional haemodynamic alterations in the spinal cord. There are numerous causes of neurologic lesions, including direct trauma of the spinal cord and nerve roots during puncture or catheter insertion, compromised spinal cord perfusion and direct neurotoxic effect. Histopathologic lesions are localized either in meninges (meningitis or arachnoiditis) or in neuraxis (myelitis or axonal degeneration). Neurotoxicity can result from decrease in neuronal blood supply, elicited by high concentrations of the solutions, long duration exposure to local anaesthetics, and the use of adjuvants. They have been implicated in the occurrence of cauda equina syndrome after continuous spinal anaesthesia using hyperbaric solution of lidocaine and tetracaine given through small diameter catheters. Selective spinal analgesia is induced by spinal opioids without motor blockade except for meperidine. Complications occurred in patients after high doses of morphine, which were related to one of its metabolites, morphine-3-glucuronide. Preservative-free opioid solutions are to be preferred for spinal anaesthesia. There is no report of neurotoxicity neither in animal studies, nor in humans, using spinal clonidine. In order to reduce the incidence of neurotoxicity, some safety rules should be followed. The lowest efficient dose of local anaesthetics must be given. Incomplete blockade should not necessarily lead to a reinjection. Large volume of hyperbaric lidocaine or repeated injections of such solutions must be avoided as well as preservative-containing solutions. The administration of new compounds by the spinal route must be supported by data of spinal neuropharmacology and the lack of neurotoxicity must have been previously checked with animal studies.

  15. Neurotoxicity versus Neuroprotection of Anesthetics: Young Children on the Ropes?

    Science.gov (United States)

    Eizaga Rebollar, Ramón; García Palacios, María V; Morales Guerrero, Javier; Torres Morera, Luis M

    2017-08-01

    Normal brain development in young children depends on a balance between excitation and inhibition of neurons, and alterations to this balance may cause apoptosis. During the perioperative period, both surgical stimuli and anesthetics can induce neurotoxicity. This article attempts to expand the perspective of a topical issue-anesthetic-induced neurotoxicity-by also considering the protective effect of general anesthetics against surgery-induced neurotoxicity, all of which may generate some controversy in the current literature. The "new" major factor influencing neurotoxicity-nociceptive stimulus-is discussed together with other factors to develop clinical and research strategies to obtain a balance between neurotoxicity and neuroprotection.

  16. Development and characterization of a nonprimate animal model of methanol-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Eells, J.T.; Salzman, M.M.; Lewandowski, M.F. [Medical Coll. of Wisconsin, Milwaukee, WI (United States); Murray, T.G. [Univ. of Miami School of Medicine, Miami, FL (United States). Bascom Palmer Eye Inst.

    1996-12-31

    Humans and nonhuman primates are uniquely sensitive to the toxic effects of methanol. The toxic syndrome in these species is characterized by formic acidemia, metabolic acidosis and blindness or serious visual impairment. Nonprimate species are normally resistant to the accumulation of formate and associated metabolic and visual toxicity. The authors have developed a nonprimate model of methanol toxicity using rates in which formate oxidation has been selectively inhibited. Methanol-intoxicated rats developed formic acidemia, metabolic acidosis and visual toxicity analogous to the human methanol poisoning syndrome. Visual dysfunction was manifested as reductions in the flash evoked cortical potential and electroretinogram which occurred coincident with blood formate accumulation. Histopathologic studies revealed mitochondrial disruption and vacuolation in the retinal pigment epithelium, photoreceptor inner segments and optic nerve. The establishment of this nonprimate animal model of methanol intoxication will facilitate research into the mechanistic aspects of methanol toxicity as well as the development and testing of treatments for human methanol poisoning.

  17. Phenotypic screening for developmental neurotoxicity ...

    Science.gov (United States)

    There are large numbers of environmental chemicals with little or no available information on their toxicity, including developmental neurotoxicity. Because of the resource-intensive nature of traditional animal tests, high-throughput (HTP) methods that can rapidly evaluate chemicals for the potential to affect the developing brain are being explored. Typically, HTP screening uses biochemical and molecular assays to detect the interaction of a chemical with a known target or molecular initiating event (e.g., the mechanism of action). For developmental neurotoxicity, however, the mechanism(s) is often unknown. Thus, we have developed assays for detecting chemical effects on the key events of neurodevelopment at the cellular level (e.g., proliferation, differentiation, neurite growth, synaptogenesis, network formation). Cell-based assays provide a test system at a level of biological complexity that encompasses many potential neurotoxic mechanisms. For example, phenotypic assessment of neurite outgrowth at the cellular level can detect chemicals that target kinases, ion channels, or esterases at the molecular level. The results from cell-based assays can be placed in a conceptual framework using an Adverse Outcome Pathway (AOP) which links molecular, cellular, and organ level effects with apical measures of developmental neurotoxicity. Testing a wide range of concentrations allows for the distinction between selective effects on neurodevelopmental and non-specific

  18. Anaesthesia associated developmental neurotoxicity (AADN) 2015

    African Journals Online (AJOL)

    'An estimated 6 million children (including 1.5 million infants) undergo ... that anaesthesia is neurotoxic to the developing brain after ... injury is worse when younger animals are exposed to larger .... Older perspectives that postoperative.

  19. Neurotoxicity of Folic Acid

    NARCIS (Netherlands)

    Amsterdam van JGC; Jansen EHJM; A Opperhuizen; TOX

    2004-01-01

    The present review summarises the neurotoxicological effects of folic acid. Some studies in animals have shown that folic acid is neurotoxic and epileptogenic when applied directly to the brain. One poorly controlled and not further reproduced study from 1970 reported neurotoxic symptoms like

  20. Multiple mechanisms of PCB neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, D.O.; Stoner, C.T.; Lawrence, D.A. [Univ. of New York, Albany, NY (United States)] [and others

    1996-12-31

    Polychlorinated biphenyls (PCBs) have been implicated in cancer, but many of the symptoms in humans exposed to PCBs are related to the nervous system and behavior. We demonstrated three different direct mechanisms whereby PCBs are neurotoxic in rats. By using flow cytometry, we demonstrated that the orthosubstituted PCB congener 2,4,4{prime}, but neither TCDD nor the coplanar PCB congener 3,4,5,3{prime},4{prime}, causes rapid death of cerebellar granule cells. The ortho-substituted congener 2,4,4{prime} reduced long-term potentiation, an indicator of cognitive potential, in hippocampal brain slices, but a similar effect was observed for the coplanar congener 3,4,3{prime},4{prime}, indicating that this effect may be caused by both ortho- and coplanar congeners by mechanisms presumably not mediated via the Ah receptor. It was previously shown that some ortho-substituted PCB congeners cause a reduction in levels of the neurotransmitter dopamine, and we present in vitro and in vivo evidence that this is due to reduction of synthesis of dopamine via inhibition of the enzyme tyrosine hydroxylase. Thus, PCBs have a variety of mechanisms of primary neurotoxicity, and neurotoxicity is a characteristic of ortho-substituted, non-dioxin-like congeners as well as some coplanar congeners. The relative contribution of each of these mechanisms to the loss of cognitive function in humans exposed to PCBs remains to be determined. 42 refs., 3 figs., 1 tab.

  1. Neurotoxic and teratogenic effects of an organophosphorus insecticide (phenyl phosphonothioic acid-O-ethyl -O-[4-nitrophenyl] ester) on mallard development

    Science.gov (United States)

    Hoffman, D.J.; Sileo, L.

    1984-01-01

    Phenyl phosphonothioic acid-O-ethyl-O-[4-nitrophenyl] ester (EPN) is one of the 10 most frequently used organophosphorus insecticides and causes delayed neurotoxicity in adult chickens and mallards. Small amounts of organophosphorus insecticides placed on birds' eggs are embryotoxic and teratogenic. For this reason, the effects of topical egg application on EPN were examined on mallard (Anas platyrhynchos) embryo development. Mallard eggs were treated topically at 72 hr of incubation with 25 microliter of a nontoxic oil vehicle or with EPN in the vehicle at concentrations of approximately 12, 36, or 108 micrograms/g egg, equivalent to one, three, and nine times the agricultural level of application used to spray crops. Treatment with EPN resulted in 22 to 44% mortality over this dose range by 18 days of development compared with 4 and 5% for untreated and vehicle-treated controls. EPN impaired embryonic growth and was highly teratogenic: 37-42% of the surviving embryos at 18 days were abnormal with cervical and axial scoliosis as well as severe edema. Brain weights were significantly lower in EPN-treated groups at different stages of development including hatchlings. Brain neurotoxic esterase (NTE) activity was inhibited by as much as 91% at 11 days, 81% at 18 days, and 79% in hatchlings. Examination of brain NTE activity during the course of normal development revealed an increase of nearly sixfold from Day 11 through hatching. The most rapid increase occurred between Day 20 and hatching. Brain acetylcholinesterase (AChE) activity was inhibited by as much as 41% at 11 days, 47% at 18 days, and 20% in hatchlings. Plasma cholinesterase and alkaline phosphatase activities were inhibited and plasma aspartate aminotransferase activity was increased at one or more stages of development. Hatchlings from EPN-treated eggs were weaker and slower to right themselves. Histopathological examination did not reveal demyelination and axonopathy of the spinal cord that was

  2. Development of a direct exposure system for studying the mechanisms of central neurotoxicity caused by volatile organic compounds

    OpenAIRE

    2015-01-01

    Many volatile organic compounds (VOCs) used in work places are neurotoxic. However, it has been difficult to study the cellular mechanisms induced by a direct exposure to neurons because of their high volatility. The objective of this study was to establish a stable system for exposing brain slices to VOCs. With a conventional recording system for brain slices, it is not possible to keep a constant bath concentration of relatively highly volatile solvents, e.g. 1-bromopropane (1-BP). Here we ...

  3. Neurotoxic Shellfish Poisoning

    Directory of Open Access Journals (Sweden)

    Roberta Hammond

    2008-07-01

    Full Text Available Neurotoxic shellfish poisoning (NSP is caused by consumption of molluscan shellfish contaminated with brevetoxins primarily produced by the dinoflagellate, Karenia brevis. Blooms of K. brevis, called Florida red tide, occur frequently along the Gulf of Mexico. Many shellfish beds in the US (and other nations are routinely monitored for presence of K. brevis and other brevetoxin-producing organisms. As a result, few NSP cases are reported annually from the US. However, infrequent larger outbreaks do occur. Cases are usually associated with recreationally-harvested shellfish collected during or post red tide blooms. Brevetoxins are neurotoxins which activate voltage-sensitive sodium channels causing sodium influx and nerve membrane depolarization. No fatalities have been reported, but hospitalizations occur. NSP involves a cluster of gastrointestinal and neurological symptoms: nausea and vomiting, paresthesias of the mouth, lips and tongue as well as distal paresthesias, ataxia, slurred speech and dizziness. Neurological symptoms can progress to partial paralysis; respiratory distress has been recorded. Recent research has implicated new species of harmful algal bloom organisms which produce brevetoxins, identified additional marine species which accumulate brevetoxins, and has provided additional information on the toxicity and analysis of brevetoxins. A review of the known epidemiology and recommendations for improved NSP prevention are presented.

  4. [Neurotoxicity of intrathecal lidocaine].

    Science.gov (United States)

    Pavón, A; Anadón Senac, P

    2001-01-01

    Lidocaine is a local anesthetic belonging to the amide group and has been administered intrathecally for over 40 years. Although no serious complications had been attributed to lidocaine before the 1990s, subarachnoid administration is now the subject of controversy following its implication in numerous cases of neurological complication. The clinical pictures described in the literature are cauda equina syndrome, which is mainly associated with continuous subarachnoid anesthesia through microcatheters, and transitory neurological symptoms, also termed radicular irritation syndrome and associated with single injections. The literature reveals a clearly higher incidence of transitory neurological symptoms with lidocaine than with other local anesthetics. Although the underlying mechanism remains unclear, the main hypotheses being the neurotoxicity of lidocaine itself or the malpositioning of the paravertebral musculature due to extreme relaxation. The various factors that can lead to neuropathy have been widely described in the many articles reporting complications. Arthroscopy and lithotomy positions are significantly related to the appearance of symptoms, as are early ambulation or the use of small-gauge needles or pencil-point needles. Further clinical studies should be undertaken. No consensus on subarachnoid administration of lidocaine has emerged, yet no alternative has been demonstrated to be safe and to offer similar pharmacological features (short latency, short duration of action and good muscle relaxation). Prilocaine, mepivacaine, articaine and bupivacaine at low doses have been suggested as alternatives.

  5. A comparison of the potency of newly developed oximes (K347, K628) and currently available oximes (obidoxime, HI-6) to counteract acute neurotoxic effects of Tabun in rats.

    Science.gov (United States)

    Kassa, Jirí; Karasová, Jana Zdarová; Tesarová, Sandra; Musílek, Kamil; Kuca, Kamil

    2010-01-01

    The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 microg/kg i.m.; 80% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings.

  6. Taxane-Induced Peripheral Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Roser Velasco

    2015-04-01

    Full Text Available Taxane-derived agents are chemotherapy drugs widely employed in cancer treatment. Among them, paclitaxel and docetaxel are most commonly administered, but newer formulations are being investigated. Taxane antineoplastic activity is mainly based on the ability of the drugs to promote microtubule assembly, leading to mitotic arrest and apoptosis in cancer cells. Peripheral neurotoxicity is the major non-hematological adverse effect of taxane, often manifested as painful neuropathy experienced during treatment, and it is sometimes irreversible. Unfortunately, taxane-induced neurotoxicity is an uncertainty prior to the initiation of treatment. The present review aims to dissect current knowledge on real incidence, underlying pathophysiology, clinical features and predisposing factors related with the development of taxane-induced neuropathy.

  7. Occupational Neurotoxic Diseases in Taiwan

    Directory of Open Access Journals (Sweden)

    Chi-Hung Liu

    2012-12-01

    Full Text Available Occupational neurotoxic diseases have become increasingly common in Taiwan due to industrialization. Over the past 40 years, Taiwan has transformed from an agricultural society to an industrial society. The most common neurotoxic diseases also changed from organophosphate poisoning to heavy metal intoxication, and then to organic solvent and semiconductor agent poisoning. The nervous system is particularly vulnerable to toxic agents because of its high metabolic rate. Neurological manifestations may be transient or permanent, and may range from cognitive dysfunction, cerebellar ataxia, Parkinsonism, sensorimotor neuropathy and autonomic dysfunction to neuromuscular junction disorders. This study attempts to provide a review of the major outbreaks of occupational neurotoxins from 1968 to 2012. A total of 16 occupational neurotoxins, including organophosphates, toxic gases, heavy metals, organic solvents, and other toxic chemicals, were reviewed. Peer-reviewed articles related to the electrophysiology, neuroimaging, treatment and long-term follow up of these neurotoxic diseases were also obtained. The heavy metals involved consisted of lead, manganese, organic tin, mercury, arsenic, and thallium. The organic solvents included n-hexane, toluene, mixed solvents and carbon disulfide. Toxic gases such as carbon monoxide, and hydrogen sulfide were also included, along with toxic chemicals including polychlorinated biphenyls, tetramethylammonium hydroxide, organophosphates, and dimethylamine borane. In addition we attempted to correlate these events to the timeline of industrial development in Taiwan. By researching this topic, the hope is that it may help other developing countries to improve industrial hygiene and promote occupational safety and health care during the process of industrialization.

  8. Autophagy and ethanol neurotoxicity.

    Science.gov (United States)

    Luo, Jia

    2014-01-01

    Excessive ethanol exposure is detrimental to the brain. The developing brain is particularly vulnerable to ethanol such that prenatal ethanol exposure causes fetal alcohol spectrum disorders (FASD). Neuronal loss in the brain is the most devastating consequence and is associated with mental retardation and other behavioral deficits observed in FASD. Since alcohol consumption during pregnancy has not declined, it is imperative to elucidate the underlying mechanisms and develop effective therapeutic strategies. One cellular mechanism that acts as a protective response for the central nervous system (CNS) is autophagy. Autophagy regulates lysosomal turnover of organelles and proteins within cells, and is involved in cell differentiation, survival, metabolism, and immunity. We have recently shown that ethanol activates autophagy in the developing brain. The autophagic preconditioning alleviates ethanol-induced neuron apoptosis, whereas inhibition of autophagy potentiates ethanol-stimulated reactive oxygen species (ROS) and exacerbates ethanol-induced neuroapoptosis. The expression of genes encoding proteins required for autophagy in the CNS is developmentally regulated; their levels are much lower during an ethanol-sensitive period than during an ethanol-resistant period. Ethanol may stimulate autophagy through multiple mechanisms; these include induction of oxidative stress and endoplasmic reticulum stress, modulation of MTOR and AMPK signaling, alterations in BCL2 family proteins, and disruption of intracellular calcium (Ca2+) homeostasis. This review discusses the most recent evidence regarding the involvement of autophagy in ethanol-mediated neurotoxicity as well as the potential therapeutic approach of targeting autophagic pathways.

  9. Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA: regulation by CB2 receptors and implications for neurotoxicity

    Directory of Open Access Journals (Sweden)

    O'Shea Esther

    2011-05-01

    Full Text Available Abstract Background 3,4-Methylenedioxymethamphetamine (MDMA produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL-1β and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra levels and IL-1 receptor type I (IL-1RI expression and the effects of JWH-015. The cellular location of IL-1β and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI and neurotoxic effects examined. Methods Dark Agouti rats received MDMA (12.5 mg/kg, i.p. and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p. was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1β or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 μg/animal; i.c.v. was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection. Results MDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1β expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain-barrier permeability was compromised. Conclusions In summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1β may play a partial role in MDMA-induced neurotoxicity.

  10. Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA): regulation by CB2 receptors and implications for neurotoxicity

    Science.gov (United States)

    2011-01-01

    Background 3,4-Methylenedioxymethamphetamine (MDMA) produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL-1β) and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra) levels and IL-1 receptor type I (IL-1RI) expression and the effects of JWH-015. The cellular location of IL-1β and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI) and neurotoxic effects examined. Methods Dark Agouti rats received MDMA (12.5 mg/kg, i.p.) and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p.) was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1β or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 μg/animal; i.c.v.) was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection. Results MDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1β expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain-barrier permeability was compromised. Conclusions In summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1β may play a partial role in MDMA-induced neurotoxicity. PMID:21595923

  11. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Accordi, Benedetta; Basso, Giuseppe [Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova (Italy); Gaspar, John Antonydas [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Sachinidis, Agapios [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Bremer-Hoffmann, Susanne, E-mail: susanne.bremer@jrc.ec.europa.eu [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy)

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  12. Toxicologic evidence of developmental neurotoxicity of environmental chemicals

    DEFF Research Database (Denmark)

    Andersen, H R; Nielsen, J B; Grandjean, P

    2000-01-01

    , exposure to neurotoxic chemicals during critical periods of brain development has induced permanent functional disturbances in the CNS. Although available data suggest that proper animal models exist, only few chemicals have been tested. Neurotoxicity testing is not required by national authorities...... will be essential in establishing a scientifically based hazard evaluation and risk assessment....

  13. In Vitro Studies of Neurotoxic Substances

    Science.gov (United States)

    1985-12-31

    less neurotoxic to mammals and, in the case of pesticides, more toxic to insects . Validated in vitro test systems developed specifically for the...1974, Johnson (11) reported that phosphinates behaved like carbamates and sulphonates against NTE, inhibiting it but not causing OPIDN. p It has been

  14. Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase.

    Science.gov (United States)

    Milatovic, Dejan; Jenkins, Jerry W; Hood, Jonathan E; Yu, Yingchun; Rongzhu, Lu; Aschner, Michael

    2011-10-01

    Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A(2A) receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology-centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects.

  15. Developmental neurotoxicity of propylthiouracil (PTU) in rats: relationship between transient hypothyroxinemia during development and long-lasting behavioural and functional changes.

    Science.gov (United States)

    Axelstad, Marta; Hansen, Pernille Reimar; Boberg, Julie; Bonnichsen, Mia; Nellemann, Christine; Lund, Søren Peter; Hougaard, Karin Sørig; Hass, Ulla

    2008-10-01

    Markedly lowered thyroid hormone levels during development may influence a child's behaviour, intellect, and auditory function. Recent studies, indicating that even small changes in the mother's thyroid hormone status early in pregnancy may cause adverse effects on her child, have lead to increased concern for thyroid hormone disrupting chemicals in the environment. The overall aim of the study was therefore to provide a detailed knowledge on the relationship between thyroid hormone levels during development and long-lasting effects on behaviour and hearing. Groups of 16-17 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/kg/day) from gestation day (GD) 7 to postnatal day (PND) 17, and the physiological and behavioural development of rat offspring was assessed. Both dams and pups in the higher dose groups had markedly decreased thyroxine (T(4)) levels during the dosing period, and the weight and histology of the thyroid glands were severely affected. PTU exposure caused motor activity levels to decrease on PND 14, and to increase on PND 23 and in adulthood. In the adult offspring, learning and memory was impaired in the two highest dose groups when tested in the radial arm maze, and auditory function was impaired in the highest dose group. Generally, the results showed that PTU-induced hypothyroxinemia influenced the developing rat brain, and that all effects on behaviour and loss of hearing in the adult offspring were significantly correlated to reductions in T(4) during development. This supports the hypothesis that decreased T(4) may be a relevant predictor for long-lasting developmental neurotoxicity.

  16. Exocytosis: using amperometry to study presynaptic mechanisms of neurotoxicity

    NARCIS (Netherlands)

    Westerink, R.H.S.

    2004-01-01

    The development of carbon fiber microelectrode amperometry enabled detailed investigation of the presynaptic response at the single cell level with single vesicle resolution. Consequently, amperometry allowed for detailed studies into the presynaptic mechanisms underlying neurotoxicity. This review

  17. Iron and Mechanisms of Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Gabriela A. Salvador

    2011-01-01

    Full Text Available The accumulation of transition metals (e.g., copper, zinc, and iron and the dysregulation of their metabolism are a hallmark in the pathogenesis of several neurodegenerative diseases. This paper will be focused on the mechanism of neurotoxicity mediated by iron. This metal progressively accumulates in the brain both during normal aging and neurodegenerative processes. High iron concentrations in the brain have been consistently observed in Alzheimer's (AD and Parkinson's (PD diseases. In this connection, metalloneurobiology has become extremely important in establishing the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them, the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms mediating the effects of iron-induced increase in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders.

  18. Pain in chemotherapy-induced peripheral neurotoxicity.

    Science.gov (United States)

    Marmiroli, Paola; Scuteri, Arianna; Cornblath, David R; Cavaletti, Guido

    2017-09-01

    Chemotherapy-induced peripheral neurotoxicity (CIPN) is a potentially dose-limiting side effect of the treatment of several cancers. CIPN is predominantly or exclusively sensory, and it is frequently associated with unpleasant symptoms, overall referred to as "pain." However, given the markedly different clinical presentation and course of CIPN depending on the antineoplastic drug used, the broad term "pain" in the specific context of CIPN needs to be reconsidered and refined. In fact, a precise identification of the features of CIPN has relevant implication in the design of rational-based clinical trials and in the selection of possible active drugs. © 2017 Peripheral Nerve Society.

  19. Phonological development in young bilinguals: clinical implications.

    Science.gov (United States)

    Core, Cynthia; Scarpelli, Chiara

    2015-05-01

    This article reviews recent research on bilingual phonological development and describes the nature of bilingual phonology, focusing on characteristics of cross-linguistic influence on bilingual phonological abilities. There is evidence of positive and negative transfer (acceleration and deceleration) on children's phonological abilities. Several methodological issues limit the ability to generalize findings from previous research to larger groups of bilingual children (e.g., small sample size, lack of consideration of age of acquisition of each language, and language abilities of the participants). Sources of heterogeneity in language development are presented and discussed. Phonological abilities are related to language abilities in bilingual first language learners of English and Spanish. Empirical evidence from research in our laboratory supports this claim. We discuss implications of research findings and limitations for future research and clinical practice. We provide specific recommendations for bilingual research and for clinical assessment of young bilingual children.

  20. Potential developmental neurotoxicity of pesticides used in Europe

    Directory of Open Access Journals (Sweden)

    Grandjean Philippe

    2008-10-01

    Full Text Available Abstract Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.

  1. MODE OF ACTION: NEUROTOXICITY INDUCED BY THYROID HORMONE DISRUPTION DURING DEVELOPMENT - HEARING LOSS RESULTING FROM EXPOSURE TO PHAHS.

    Science.gov (United States)

    A manuscript summarizes a workshop aimed at developing a framework to determine the relevancy of animal modes-of-action for extrapolation to humans. This specific report used animal data on the neurodevelopmental effects of hypothyroidism to test the framework. Propylthiouracil,...

  2. Current techniques for assessing developmental neurotoxicity of pesticides

    Institute of Scientific and Technical Information of China (English)

    Yu GAO; Ying TIAN; Xiaoming SHEN

    2008-01-01

    Organophosphates (OPs) and Pyrethroids (PRY) have been widely used in agriculture and in the home as broad spectrum insecticides, but may produce considerable risk to human health, especially to children. Children are more susceptible to environmental exposure, and concern about the neurotoxic effects of pesticide exposure on children is increasing. There is a need for better understanding of the potential developmental neu-rotoxicity of pesticides. Techniques for assessing devel-opmental neurotoxicity of pesticides will continue to be developed, rendering a need for flexibility of testing para-digms. Current techniques used in evaluating the devel-opmental neurotoxicity of OPs and PRY are presented in this review. These include: (1) In vitro techniques (PC12 cells, C6 cells and other cell models); (2) Non-mammalian models (sea urchins, zebrafish and other non-mammalian models); and (3) In vivo mammalian models (morpho-logical techniques, neurobehavioral assessments and biomarkers).

  3. Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson's disease.

    Science.gov (United States)

    Zhang, Xiao-Feng; Thompson, Mark; Xu, Yi-Hua

    2016-05-01

    Laboratory studies involving repeated exposure to paraquat (PQ) in different animal models can induce many of the pathological features of Parkinson's disease (PD), such as the loss of dopaminergic neurons in the nigrostriatal dopamine system. Epidemiological studies identify an increased risk of developing PD in human populations living in areas where PQ exposure is likely to occur and among workers lacking appropriate protective equipment. The mechanisms involved in developing PD may not be due to any single cause, but rather a multifactorial situation may exist where PQ exposure may cause PD in some circumstances. Multifactorial theory is adopted into this review that includes a number of sub-cellular mechanisms to explain the pathogenesis of PD. The theory is placed into an environmental context of chronic low-dose exposure to PQ that consequently acts as an oxidative stress inducer. Oxidative stress and the metabolic processes of PQ-inducing excitotoxicity, α-synuclein aggregate formation, autophagy, alteration of dopamine catabolism, and inactivation of tyrosine hydroxylase are positioned as causes for the loss of dopaminergic cells. The environmental context and biochemistry of PQ in soils, water, and organisms is also reviewed to identify potential routes that can lead to chronic rates of low-dose exposure that would replicate the type of response that is observed in animal models, epidemiological studies, and other types of laboratory investigations involving PQ exposure. The purpose of this review is to synthesize key relations and summarize hypotheses linking PD to PQ exposure by using the multifactorial approach. Recommendations are given to integrate laboratory methods to the environmental context as a means to improve on experimental design. The multifactorial approach is necessary for conducting valid tests of causal relations, for understanding of potential relations between PD and PQ exposure, and may prevent further delay in solving what has

  4. Manganese and 1-methyl-4-phenylpyridinium (MPP(+) ) induced neurotoxicity indicate differences in morphological, electrophysiological and genome-wide alterations: Implications for idiopathic Parkinson's disease.

    Science.gov (United States)

    Mythri, Rajeswara Babu; Raghunath, Narayana Reddy; Narwade, Santosh Chandrakant; Pandareesh, Mirazkar DasharathaRao; Sabitha, Kollarkandi Rajesh; Aiyaz, Mohamad; Chand, Bipin; Sule, Manas; Ghosh, Krittika; Kumar, Senthil; Shankarappa, Bhagyalakshmi; Soundararajan, Soundarya; Alladi, Phalguni Anand; Purushottam, Meera; Gayathri, Narayanappa; Deobagkar, Deepti Dileep; Laxmi, Thenkanidiyoor Rao; Muchukunte Mukunda, Srinivas Bharath

    2017-08-12

    Idiopathic Parkinson's disease (iPD) and manganese-induced atypical Parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the PD toxin 1-methyl-4-phenylpyridinium ion (MPP(+) ) and manganese (Mn) followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP(+) and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~93%) with slow discharge rates (0-5Hz). While MPP(+) exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP(+) and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the JAK-STAT pathway. We conclude that iPD and atypical Parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. This article is protected by copyright. All rights

  5. Neurotoxic shellfish poisoning: A review

    NARCIS (Netherlands)

    Apeldoorn ME van; Egmond HP van; Speijers GJA; CSR; ARO

    2001-01-01

    This review contains information on the neurotoxic shellfish poisoning (NSP) syndrome and the provoking toxins called brevetoxins, produced by the dinoflagellate Gymnodinium breve. Data on chemical structures and detection methods for brevetoxins, sources for brevetoxins, marine organisms associated

  6. Hypothalamic-pituitary adrenal (HPAA) axis function in adult Fischer-344 rats exposed during development to neurotoxic chemicals perinatally.

    Science.gov (United States)

    Rosecrans, J A; Johnson, J H; Tilson, H A; Hong, J S

    1984-01-01

    The major objective of these experiments was to determine long-term effects on the hypothalamic-pituitary adrenal axis (HPAA) of adult rats exposed during development to chlordecone, an organochlorine insecticide. Chlordecone was administered to mothers prenatally plus the first 12 days of the neonatal period (6 ppm in the diet) or neonatally via a single subcutaneous injection to rats at 4 days of age (1 mg/pup in 20 micrograms of DMSO). DMSO (20 microliters/pup) and dexamethasone (100 micrograms/pup in 20 microliters saline) were also injected on day 4. HPAA function was evaluated at 70-80 days of age. Responsiveness of the HPAA to a repeated stressor was evaluated by exposing rats of each treatment group to a 7-day stress-induced analgesia (SIA) paradigm consisting of a daily 15 sec foot-shock (0.9 mA) exposure which was preceded by a 15 sec white noise conditioned stimulus. The behavioral response to daily stress was evaluated by measuring tail-flick latencies immediately before and/or after each stress exposure. The conditioned response to stress was evaluated 24 hours after the last of 7 daily foot-shock sessions in which rats of each treatment and experimental group were exposed to the shock chamber only. All rats were killed 15 minutes after the final session and tissue (serum and adrenals) were removed and frozen for later chemical analysis; serum and adrenal corticosterone (CS) and serum prolactin (Prl) levels were measured. Perinatal exposure to chlordecone did not significantly alter the behavioral and/or neuroendocrine responses to stress. Ambient hormone levels (both CS and Prl), however, were uniformly attenuated by chlordecone.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Putative adverse outcome pathways relevant to neurotoxicity

    Science.gov (United States)

    Bal-Price, Anna; Crofton, Kevin M.; Sachana, Magdalini; Shafer, Timothy J.; Behl, Mamta; Forsby, Anna; Hargreaves, Alan; Landesmann, Brigitte; Lein, Pamela J.; Louisse, Jochem; Monnet-Tschudi, Florianne; Paini, Alicia; Rolaki, Alexandra; Schrattenholz, André; Suñol, Cristina; van Thriel, Christoph; Whelan, Maurice; Fritsche, Ellen

    2016-01-01

    The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways. PMID:25605028

  8. Contrast-Induced Neurotoxicity following Cardiac Catheterization

    Directory of Open Access Journals (Sweden)

    Susan Law

    2012-01-01

    Full Text Available We report a case of probable contrast-induced neurotoxicity that followed a technically challenging cardiac catheterization in a 69-year-old woman. The procedure had involved the administration of a large cumulative dose of an iodinated, nonionic contrast medium into the innominate artery: twelve hours following the catheterization, the patient developed a seizure followed by a left hemiplegia, and an initial computed tomography (CT scan showed sulcal effacement in the right cerebral hemisphere due to cerebral swelling. The patient’s clinical symptoms resolved within 24 hours, and magnetic resonance imaging at 32 hours showed resolution of swelling. Contrast-induced neurotoxicity should be found in the differential diagnosis of acute neurological deficits occurring after radiological procedures involving iodinated contrast media, whether ionic or nonionic.

  9. Clinical and imaging features of fludarabine neurotoxicity.

    Science.gov (United States)

    Lee, Michael S; McKinney, Alexander M; Brace, Jeffrey R; Santacruz, Karen

    2010-03-01

    Neurotoxicity from intravenous fludarabine is a rare but recognized clinical entity. Its brain imaging features have not been extensively described. Three patients received 38.5 mg or 40 mg/m per day fludarabine in a 5-day intravenous infusion before bone marrow transplantation in treatment of hematopoietic malignancies. Several weeks later, each patient developed progressive neurologic decline, including retrogeniculate blindness, leading to coma and death. Brain MRI showed progressively enlarging but mild T2/FLAIR hyperintensities in the periventricular white matter. The lesions demonstrated restricted diffusion but did not enhance. Because the neurotoxicity of fludarabine appears long after exposure, neurologic decline in this setting is likely to be attributed to opportunistic disease. However, the imaging features are distinctive in their latency and in being mild relative to the profound clinical features. The safe dose of fludarabine in this context remains controversial.

  10. [Hyperhomocysteinemia: atherothrombosis and neurotoxicity].

    Science.gov (United States)

    Fridman, O

    1999-01-01

    The positive correlation existing between hyperhomocyst(e)inemia [HH(e)] and vascular disease has firmly been established through data derived from numerous epidemiological and experimental observations. Clinical data corroborate that homocysteine (Hcy) is an independent risk factor for coronary, cerebral and peripheral arterial occlusive disease or peripheral venous thrombosis. Hcy is a sulfhydryl-containing amino acid that is formed by the demethylation of methionine. It is normally catalyzed to cystathionine by cystathionine beta-synthase a pyridoxal phosphate-dependent enzyme. Hcy is also remethylated to methionine by 5-methyltetrahydrofolate-Hcy methyltransferase (methionine synthase), a vitamin B12 dependent enzyme and by betaine-Hcy methyltransferase. Nutritional status such as vitamin B12, or vitamin B6, or folate deficiencies and genetic defects such as cystathionine beta-synthase or methylene-tetrahydrofolate reductase may contribute to increasing plasma homocysteine levels. The pathogenesis of Hcy-induced vascular damage may be multifactorial, including direct Hcy damage to the endothelium, stimulation of proliferation of smooth muscle cells, enhanced low-density lipoprotein peroxidation, increase of platelet aggregation, and effects on the coagulation system. Besides adverse effects on the endothelium and vessel wall, Hcy exert a toxic action on neuronal cells trough the stimulation of N-methyl-D-aspartate (NMDA) receptors. Under these conditions, neuronal damage derives from excessive calcium influx and reactive oxygen generation. This mechanism may contribute to the cognitive changes and markedly increased risk of cerebrovascular disease in children and young adults with homocystunuria. Moreover, during stroke, in hiperhomocysteinemic patients, disruption of the blood-brain barrier results in exposure of the brain to near plasma levels of Hcy. The brain is exposed to 15-50 microM H(e). Thus, the neurotoxicity of Hcy acting through the overstimulation

  11. Clinical Neurotoxic Disorders : Past, Present and Future

    Directory of Open Access Journals (Sweden)

    Nag Devika

    2001-01-01

    Full Text Available Neurotoxins have existed on the earth from times immemorial. Old neurotoxic disorders were due to ingestion/ exposure of heavy metals and food like lathyrus sativus over a long period of time. The 20th Century with rapid industrialsation and expanding chemical and drug industry has spawned several new, hitherto unknown disorders. Old disorders continue to exist e.g. fluorosis, arsenicosis, lathyrism, manganism and lead neuropathy, along with new diseases like Minamata disease, subacute myelo optic neuropathy (SMON, MPTP-Parkinsonian syndorme, triorthcresyl phosphate (TOCP neuroparalytic disease, pesticide induced seizures, tremor and neuropathy, solvent encephalopthy, antipileptic drug foetal syndrome and excitotoxin induced behavioural disorders. Studies on pesticides Organochlorine and organophosphates, synthetic pyrethrins, solvents, heavy metals and substances abuse in the Indian context confirm the neurotoxic nature of many synthetic substances. Future problems envisaged are of concern to clinical neurologists as many of these neurotoxic disorders mimic syndromes of well known neurological disease. The new millenium poses a challenge to the clinician as newer compounds in industry, food, drugs and chemical war agents are being developed. Molecular genetics has advanced rapidly with release of the human genome map. Animal cloning and genetically modified plant products have entered the food chain. How safe are these new inventions for the central nervous system is a big question? India cannot afford disasters like Union Carbide′s Bhopal gas leak nor be a silent spectator to manipulative biotechnology. Unless it is proven beyond all doubt to be a safe innovation, Chemicals have to be cautiously introduced in our environment. To Study, ascertain and confirm safety or neurotoxicity is an exciting challenge for the neuroscientists of the 21st century.

  12. Molecular pathways of pannexin1-mediated neurotoxicity

    Directory of Open Access Journals (Sweden)

    Valery I. Shestopalov

    2014-02-01

    Full Text Available Pannexin1 (Panx1 forms nonselective membrane channels, structurally similar to gap junction hemichannels, that is permeable to ions, nucleotides and other small molecules below 900 Da. Panx1 activity is implicated in paracrine signaling and inflammasome regulation. Recent studies in different animal models showed that Panx1 overactivation correlates with a selective demise of several types of neurons, including retinal ganglion cells, brain pyramidal and enteric neurons. The list of Panx1 activators includes extracellular ATP, glutamate, high K+, Zn2+, fibroblast growth factors (FGFs, pro-inflammatory cytokines and elevation of intracellular Ca2+. Most of these molecules are released following mechanical, ischemic or inflammatory injury of the CNS, and rapidly activate this channel. As a result, prolonged opening of Panx1 channel induced by these danger signals trigger a cascade of neurotoxic events capable of killing cells. The most vulnerable cell type are neurons that express high levels of Panx1. Experimental evidence suggests that Panx1 channels mediate at least two distinct neurotoxic processes: increased permeability of the plasma membrane and activation of the inflammasome in neurons and glia. Importantly, either pharmacological or genetic inactivation of Panx1 suppresses both these processes, providing a marked protection in several disease and injury models. These findings indicate that external danger signals generated after diverse types of injuries converge to activate Panx1. In this review we discuss molecular mechanisms associated with Panx1 toxicity and the crosstalk between different pathways.

  13. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

    OpenAIRE

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-01-01

    Topical application of benzalkonium chloride (BAK) to the eye causes dose-related corneal neurotoxicity. Corneal inflammation and reduction in aqueous tear production accompany neurotoxicity. Cessation of BAK treatment leads to recovery of corneal nerve density.

  14. What is microglia neurotoxicity (Not)?

    DEFF Research Database (Denmark)

    Biber, Knut; Owens, Trevor; Boddeke, Erik

    2014-01-01

    not replaced by peripheral myeloid cells. These phylogenic and ontogenic features suggest that microglia serve vital functions. Yet, microglia often are described as neurotoxic cells, that actively kill (healthy) neurons. Since it is from an evolutionary point of view difficult to understand why an important...... and vulnerable organ like the brain should host numerous potential killers, we here review the concept of microglia neurotoxicity. On one hand it is discussed that most of our understanding about how microglia kill neurons is based on in vitro experiments or correlative staining studies that suffer from...... are normally important protective elements in the brain. This might change in chronic disease or the aged brain, where; however, it remains to be established whether microglia simply lose their protective capacities or whether microglia become truly neurotoxic cells. GLIA 2014....

  15. Relative contribution of CTR1 and DMT1 in copper transport by the blood–CSF barrier: Implication in manganese-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Gang [School of Health Sciences, Purdue University, West Lafayette, Indiana 47907 (United States); Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an, Shanxi 710032 (China); Chen, Jingyuan [Department of Occupational and Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi' an, Shanxi 710032 (China); Zheng, Wei, E-mail: wzheng@purdue.edu [School of Health Sciences, Purdue University, West Lafayette, Indiana 47907 (United States)

    2012-05-01

    The homeostasis of copper (Cu) in the cerebrospinal fluid (CSF) is partially regulated by the Cu transporter-1 (CTR1) and divalent metal transporter-1 (DMT1) at the blood–CSF barrier (BCB) in the choroid plexus. Data from human and animal studies suggest an increased Cu concentration in blood, CSF, and brains following in vivo manganese (Mn) exposure. This study was designed to investigate the relative role of CTR1 and DMT1 in Cu transport under normal or Mn-exposed conditions using an immortalized choroidal Z310 cell line. Mn exposure in vitro resulted in an increased cellular {sup 64}Cu uptake and the up-regulation of both CTR1 and DMT1. Knocking down CTR1 by siRNA counteracted the Mn-induced increase of {sup 64}Cu uptake, while knocking down DMT1 siRNA resulted in an increased cellular {sup 64}Cu uptake in Mn-exposed cells. To distinguish the roles of CTR1 and DMT1 in Cu transport, the Z310 cell-based tetracycline (Tet)-inducible CTR1 and DMT1 expression cell lines were developed, namely iZCTR1 and iZDMT1 cells, respectively. In iZCTR1 cells, Tet induction led to a robust increase (25 fold) of {sup 64}Cu uptake with the time course corresponding to the increased CTR1. Induction of DMT1 by Tet in iZDMT1 cells, however, resulted in only a slight increase of {sup 64}Cu uptake in contrast to a substantial increase in DMT1 mRNA and protein expression. These data indicate that CTR1, but not DMT1, plays an essential role in transporting Cu by the BCB in the choroid plexus. Mn-induced cellular overload of Cu at the BCB is due, primarily, to Mn-induced over-expression of CTR1. -- Highlights: ► This study compares the relative role of CTR1 and DMT1 in Cu transport by the BCB. ► Two novel tetracycline-inducible CTR1 and DMT1 expression cell lines are created. ► CTR1, but not DMT1, plays an essential role in transporting Cu by the BCB. ► Mn-induced cellular Cu overload is due to its induction of CTR1 rather than DMT1. ► Induction of CTR1 by Mn in the BCB

  16. Is Neurotoxicity of Metallic Nanoparticles the Cascades of Oxidative Stress?

    Science.gov (United States)

    Song, Bin; Zhang, YanLi; Liu, Jia; Feng, XiaoLi; Zhou, Ting; Shao, LongQuan

    2016-06-01

    With the rapid development of nanotechnology, metallic (metal or metal oxide) nanoparticles (NPs) are widely used in many fields such as cosmetics, the food and building industries, and bio-medical instruments. Widespread applications of metallic NP-based products increase the health risk associated with human exposures. Studies revealed that the brain, a critical organ that consumes substantial amounts of oxygen, is a primary target of metallic NPs once they are absorbed into the body. Oxidative stress (OS), apoptosis, and the inflammatory response are believed to be the main mechanisms underlying the neurotoxicity of metallic NPs. Other studies have disclosed that antioxidant pretreatment or co-treatment can reverse the neurotoxicity of metallic NPs by decreasing the level of reactive oxygen species, up-regulating the activities of antioxidant enzymes, decreasing the proportion of apoptotic cells, and suppressing the inflammatory response. These findings suggest that the neurotoxicity of metallic NPs might involve a cascade of events following NP-induced OS. However, additional research is needed to determine whether NP-induced OS plays a central role in the neurotoxicity of metallic NPs, to develop a comprehensive understanding of the correlations among neurotoxic mechanisms and to improve the bio-safety of metallic NP-based products.

  17. Acrylamide neurotoxicity on the cerebrum of weaning rats

    Institute of Scientific and Technical Information of China (English)

    Su-min Tian; Yu-xin Ma; Jing Shi; Ting-ye Lou; Shuai-shuai Liu; Guo-ying Li

    2015-01-01

    The mechanism underlying acrylamide-induced neurotoxicity remains controversial. Previ-ous studies have focused on acrylamide-induced toxicity in adult rodents, but neurotoxicity in weaning rats has not been investigated. To explore the neurotoxic effect of acrylamide on the developing brain, weaning rats were gavaged with 0, 5, 15, and 30 mg/kg acrylamide for 4 consecutive weeks. No obvious neurotoxicity was observed in weaning rats in the low-dose acrylamide group (5 mg/kg). However, rats from the moderate- and high-dose acrylamide groups (15 and 30 mg/kg) had an abnormal gait. Furthermore, biochemical tests in these rats demonstrated that glutamate concentration was significantly reduced, and γ-aminobutyric acid content was signiifcantly increased and was dependent on acrylamide dose. Immunohis-tochemical staining showed that in the cerebral cortex,γ-aminobutyric acid, glutamic acid decarboxylase and glial ifbrillary acidic protein expression increased remarkably in the moder-ate-and high-dose acrylamide groups. These results indicate that in weaning rats, acrylamide is positively associated with neurotoxicity in a dose-dependent manner, which may correlate with upregulation of γ-aminobutyric acid and subsequent neuronal degeneration after the initial acrylamide exposure.

  18. Acrylamide neurotoxicity on the cerebrum of weaning rats

    Directory of Open Access Journals (Sweden)

    Su-min Tian

    2015-01-01

    Full Text Available The mechanism underlying acrylamide-induced neurotoxicity remains controversial. Previous studies have focused on acrylamide-induced toxicity in adult rodents, but neurotoxicity in weaning rats has not been investigated. To explore the neurotoxic effect of acrylamide on the developing brain, weaning rats were gavaged with 0, 5, 15, and 30 mg/kg acrylamide for 4 consecutive weeks. No obvious neurotoxicity was observed in weaning rats in the low-dose acrylamide group (5 mg/kg. However, rats from the moderate- and high-dose acrylamide groups (15 and 30 mg/kg had an abnormal gait. Furthermore, biochemical tests in these rats demonstrated that glutamate concentration was significantly reduced, and γ-aminobutyric acid content was significantly increased and was dependent on acrylamide dose. Immunohistochemical staining showed that in the cerebral cortex, γ-aminobutyric acid, glutamic acid decarboxylase and glial fibrillary acidic protein expression increased remarkably in the moderate- and high-dose acrylamide groups. These results indicate that in weaning rats, acrylamide is positively associated with neurotoxicity in a dose-dependent manner, which may correlate with upregulation of γ-aminobutyric acid and subsequent neuronal degeneration after the initial acrylamide exposure.

  19. Expertise development in the professions; Implications for teaching and assessment

    NARCIS (Netherlands)

    Boshuizen, Els

    2011-01-01

    Boshuizen, H. P. A. (2011, 30 August - 3 September). Expertise development in the professions; Implications for teaching and assessment. Paper presented at the bi-annual EARLI conferences, Exeter, UK.

  20. Inhibitors of Microglial Neurotoxicity: Focus on Natural Products

    Directory of Open Access Journals (Sweden)

    Kyoungho Suk

    2011-01-01

    Full Text Available Microglial cells play a dual role in the central nervous system as they have both neurotoxic and neuroprotective effects. Uncontrolled and excessive activation of microglia often contributes to inflammation-mediated neurodegeneration. Recently, much attention has been paid to therapeutic strategies aimed at inhibiting neurotoxic microglial activation. Pharmacological inhibitors of microglial activation are emerging as a result of such endeavors. In this review, natural products-based inhibitors of microglial activation will be reviewed. Potential neuroprotective activity of these compounds will also be discussed. Future works should focus on the discovery of novel drug targets that specifically mediate microglial neurotoxicity rather than neuroprotection. Development of new drugs based on these targets may require a better understanding of microglial biology and neuroinflammation at the molecular, cellular, and systems levels.

  1. Platinum-induced neurotoxicity: A review of possible mechanisms.

    Science.gov (United States)

    Kanat, Ozkan; Ertas, Hulya; Caner, Burcu

    2017-08-10

    Patients treated with platinum-based chemotherapy frequently experience neurotoxic symptoms, which may lead to premature discontinuation of therapy. Despite discontinuation of platinum drugs, these symptoms can persist over a long period of time. Cisplatin and oxaliplatin, among all platinum drugs, have significant neurotoxic potential. A distal dose-dependent symmetrical sensory neuropathy is the most common presentation of platinum neurotoxicity. DNA damage-induced apoptosis of dorsal root ganglion (DRG) neurons seems to be the principal cause of neurological symptoms. However, DRG injury alone cannot explain some unique symptoms such as cold-aggravated burning pain affecting distal extremities that is observed with oxaliplatin administration. In this article, we briefly reviewed potential mechanisms for the development of platinum drugs-associated neurological manifestations.

  2. Destination image: Origins, Developments and Implications

    Directory of Open Access Journals (Sweden)

    Sérgio Dominique Ferreira Lopes

    2011-04-01

    Full Text Available Over the last few decades, tourism has become one of the main sectors of the global economy, not only because of its contribution to the Gross Domestic Product (GDP of different countries, but also because of the employment it generates. Since 2009, however, the results of tourism have been severely affected by the economic and financial crisis and it is now essential to analyze the key elements of tourist consumer behavior. In this context, the image that a destination transmits to the market becomes one of the elements which influence tourists the most when choosing a tourist destination. The authors therefore aim to identify the main elements that characterize the image of a tourist destination, as well as their implications for the management of tourist destinations.

  3. Destination image: Origins, Developments and Implications

    Directory of Open Access Journals (Sweden)

    Sérgio Dominique Ferreira Lopes

    2011-01-01

    Full Text Available Over the last few decades, tourism has become one of the main sectors of the global economy, not only because of its contribution to the Gross Domestic Product (GDP of different countries, but also because of the employment it generates. Since 2009, however, the results of tourism have been severely affected by the economic and financial crisis and it is now essential to analyze the key elements of tourist consumer behavior. In this context, the image that a destination transmits to the market becomes one of the elements which influence tourists the most when choosing a tourist destination. The authors therefore aim to identify the main elements that characterize the image of a tourist destination, as well as their implications for the management of tourist destinations.

  4. Practical implications of rapid development methodologies

    CSIR Research Space (South Africa)

    Gerber, A

    2007-11-01

    Full Text Available Rapid development methodologies are popular approaches for the development of modern software systems. The goals of these methodologies are the inclusion of the client into the analysis, design and implementation activities, as well...

  5. Potential Role of Epigenetic Mechanism in Manganese Induced Neurotoxicity

    Science.gov (United States)

    Tarale, Prashant; Chakrabarti, Tapan; Sivanesan, Saravanadevi; Naoghare, Pravin; Bafana, Amit; Krishnamurthi, Kannan

    2016-01-01

    Manganese is a vital nutrient and is maintained at an optimal level (2.5–5 mg/day) in human body. Chronic exposure to manganese is associated with neurotoxicity and correlated with the development of various neurological disorders such as Parkinson's disease. Oxidative stress mediated apoptotic cell death has been well established mechanism in manganese induced toxicity. Oxidative stress has a potential to alter the epigenetic mechanism of gene regulation. Epigenetic insight of manganese neurotoxicity in context of its correlation with the development of parkinsonism is poorly understood. Parkinson's disease is characterized by the α-synuclein aggregation in the form of Lewy bodies in neuronal cells. Recent findings illustrate that manganese can cause overexpression of α-synuclein. α-Synuclein acts epigenetically via interaction with histone proteins in regulating apoptosis. α-Synuclein also causes global DNA hypomethylation through sequestration of DNA methyltransferase in cytoplasm. An individual genetic difference may also have an influence on epigenetic susceptibility to manganese neurotoxicity and the development of Parkinson's disease. This review presents the current state of findings in relation to role of epigenetic mechanism in manganese induced neurotoxicity, with a special emphasis on the development of Parkinson's disease. PMID:27314012

  6. Enterprise level implications of heifer development

    Science.gov (United States)

    Research emphasis has been placed on heifer development strategies in recent years, comparing traditional, more intensive systems to more extensive systems using less feed and relying on compensatory gain to reach a target BW. Recent research has suggested that developing heifers to a lighter target...

  7. A novel antibody-based biomarker for chronic algal toxin exposure and sub-acute neurotoxicity

    Science.gov (United States)

    Lefebvre, Kathi A.; Frame, Elizabeth R.; Gulland, Frances; Hansen, John D.; Kendrick, Preston S.; Beyer, Richard P.; Bammler, Theo K.; Farin, Frederico M.; Hiolski, Emma M.; Smith, Donald R.; Marcinek, David J.

    2012-01-01

    The neurotoxic amino acid, domoic acid (DA), is naturally produced by marine phytoplankton and presents a significant threat to the health of marine mammals, seabirds and humans via transfer of the toxin through the foodweb. In humans, acute exposure causes a neurotoxic illness known as amnesic shellfish poisoning characterized by seizures, memory loss, coma and death. Regular monitoring for high DA levels in edible shellfish tissues has been effective in protecting human consumers from acute DA exposure. However, chronic low-level DA exposure remains a concern, particularly in coastal and tribal communities that subsistence harvest shellfish known to contain low levels of the toxin. Domoic acid exposure via consumption of planktivorous fish also has a profound health impact on California sea lions (Zalophus californianus) affecting hundreds of animals yearly. Due to increasing algal toxin exposure threats globally, there is a critical need for reliable diagnostic tests for assessing chronic DA exposure in humans and wildlife. Here we report the discovery of a novel DA-specific antibody response that is a signature of chronic low-level exposure identified initially in a zebrafish exposure model and confirmed in naturally exposed wild sea lions. Additionally, we found that chronic exposure in zebrafish caused increased neurologic sensitivity to DA, revealing that repetitive exposure to DA well below the threshold for acute behavioral toxicity has underlying neurotoxic consequences. The discovery that chronic exposure to low levels of a small, water-soluble single amino acid triggers a detectable antibody response is surprising and has profound implications for the development of diagnostic tests for exposure to other pervasive environmental toxins.

  8. Lithium-mediated protection against ethanol neurotoxicity

    Directory of Open Access Journals (Sweden)

    Jia Luo

    2010-06-01

    Full Text Available Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke–Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3 which has recently been identified as a mediator of ethanol neurotoxicity. Lithium’s neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms.

  9. Asymmetry of the Brain: Development and Implications.

    Science.gov (United States)

    Duboc, Véronique; Dufourcq, Pascale; Blader, Patrick; Roussigné, Myriam

    2015-01-01

    Although the left and right hemispheres of our brains develop with a high degree of symmetry at both the anatomical and functional levels, it has become clear that subtle structural differences exist between the two sides and that each is dominant in processing specific cognitive tasks. As the result of evolutionary conservation or convergence, lateralization of the brain is found in both vertebrates and invertebrates, suggesting that it provides significant fitness for animal life. This widespread feature of hemispheric specialization has allowed the emergence of model systems to study its development and, in some cases, to link anatomical asymmetries to brain function and behavior. Here, we present some of what is known about brain asymmetry in humans and model organisms as well as what is known about the impact of environmental and genetic factors on brain asymmetry development. We specifically highlight the progress made in understanding the development of epithalamic asymmetries in zebrafish and how this model provides an exciting opportunity to address brain asymmetry at different levels of complexity.

  10. Revenue Generation Capacity in Developing Countries: Implications ...

    African Journals Online (AJOL)

    physical and human capital development in Tanzania, Kenya, and Uganda using time-series ... education, reversing the spread of HIV/AIDS, reducing child and maternal mortality, ... human capital investment in order to maintain social cohesion and political legitimacy. ...... European Economy Group-UCM and FUNCAS.

  11. BMAA neurotoxicity in Drosophila.

    Science.gov (United States)

    Zhou, Xianchong; Escala, Wilfredo; Papapetropoulos, Spyridon; Bradley, Walter G; Zhai, R Grace

    2009-01-01

    We report the establishment of an in vivo model using the fruit fly Drosophila melanogaster to investigate the toxic effects of L-BMAA. We found that dietary intake of BMAA reduced the lifespan as well as the neurological functions of flies. Furthermore, we have developed an HPLC method to reliably detect both free and protein-bound BMAA in fly tissue extracts.

  12. Platform development: implications for portfolio management

    DEFF Research Database (Denmark)

    Hsuan, Juliana; Hansen, Poul H. Kyvsgård

    2007-01-01

    complex, possibly increasing the strategic risks for the firm. This paper reports preliminary findings on platform management process at LEGO, a Danish toy company. Specifically, we report the process of applying games combined with simulations and workshops in the platform development. We also propose...... a framework, based on the portfolio management thinking to evaluate the degree of modularity embedded in a given platform and to which extent it is aligned with other platforms."...

  13. Predicting the acute neurotoxicity of diverse organic solvents using probabilistic neural networks based QSTR modeling approaches.

    Science.gov (United States)

    Basant, Nikita; Gupta, Shikha; Singh, Kunwar P

    2016-03-01

    Organic solvents are widely used chemicals and the neurotoxic properties of some are well established. In this study, we established nonlinear qualitative and quantitative structure-toxicity relationship (STR) models for predicting neurotoxic classes and neurotoxicity of structurally diverse solvents in rodent test species following OECD guideline principles for model development. Probabilistic neural network (PNN) based qualitative and generalized regression neural network (GRNN) based quantitative STR models were constructed using neurotoxicity data from rat and mouse studies. Further, interspecies correlation based quantitative activity-activity relationship (QAAR) and global QSTR models were also developed using the combined data set of both rodent species for predicting the neurotoxicity of solvents. The constructed models were validated through deriving several statistical coefficients for the test data and the prediction and generalization abilities of these models were evaluated. The qualitative STR models (rat and mouse) yielded classification accuracies of 92.86% in the test data sets, whereas, the quantitative STRs yielded correlation (R(2)) of >0.93 between the measured and model predicted toxicity values in both the test data (rat and mouse). The prediction accuracies of the QAAR (R(2) 0.859) and global STR (R(2) 0.945) models were comparable to those of the independent local STR models. The results suggest the ability of the developed QSTR models to reliably predict binary neurotoxicity classes and the endpoint neurotoxicities of the structurally diverse organic solvents.

  14. Neurotoxicity of cancer chemotherapy

    Institute of Scientific and Technical Information of China (English)

    Miyoung Yang; Changjong Moon

    2013-01-01

    There is accumulating clinical evidence that chemotherapeutic agents induce neurological side effects, including memory deficits and mood disorders, in cancer patients who have undergone chemotherapeutic treatments. This review focuses on chemotherapy-induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches. These investigations are helpful in determining how best to further explore the causal mechanisms of chemotherapy-induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents.

  15. Neurotoxicity of the Cyanotoxin BMAA Through Axonal Degeneration and Intercellular Spreading.

    Science.gov (United States)

    Tan, Vanessa X; Lassus, Benjamin; Lim, Chai K; Tixador, Philippe; Courte, Josquin; Bessede, Alban; Guillemin, Gilles J; Peyrin, Jean-Michel

    2017-08-25

    β-Methylamino-L-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments-(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons-creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 μM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis.

  16. Platform development: implications for portfolio management

    DEFF Research Database (Denmark)

    Hsuan, Juliana; Hansen, Poul H. Kyvsgård

    2007-01-01

    " The challenge of implementing industrial platforms in practice can be described as a configuration problem caused by a considerable number of variables, which often have contradictory influences on the total performance of the firm. Consequently, the specific platform decisions become extremely...... a framework, based on the portfolio management thinking to evaluate the degree of modularity embedded in a given platform and to which extent it is aligned with other platforms."...... complex, possibly increasing the strategic risks for the firm. This paper reports preliminary findings on platform management process at LEGO, a Danish toy company. Specifically, we report the process of applying games combined with simulations and workshops in the platform development. We also propose...

  17. Anesthetic-Induced Developmental Neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    Jia-RenLiu; Qian Liu; Jing Li; Sulpicio G. Soriano

    2011-01-01

    1 IntroductionMillions of newborn and infants receive anesthetic,sedative and analgesic drugs for surgery and painful procedures on a daily basis.Recent laboratory reports clearly demonstrate that anesthetic and sedative drugs induced both neuroapoptosis and neurocognitive deficits in laboratory models.This issue is of paramount interest to pediatric anesthesiologists and intensivists because it questions the safety of anesthetics used for fetal and neonatal anesthesia[1-2].In an attempt to summarize the rapidly expanding laboratorybased literature on anesthetic-induced developmental neurotoxicity (AIDN),this review will examine published reports on the characterization,mechanisms and alleviation of this phenomenon.

  18. Problems of neurotoxicity assessment with using of electroretinography

    Directory of Open Access Journals (Sweden)

    R. A. Tkachuk

    2015-06-01

    Full Text Available Introduction. An actual problem of detection neurotoxication from getting nanoparticles into the human body in its initial stage, the identification of toxicant, determine its amount (dose is considered. Formulation of the problem. The solving of the basic problems which encountered during improving electroretinography means and methods in its application to risk assessment person neurotoxication are considered in this article. Directions of retinographia improvement. We propose a method to improve of the standard electroretinography tools for assessment of risk of neurotoxicity. On the basis of the concept of applying with low intense pulsed light exposure on to the retina leads to a large resolution and less recovery time of the retina. A negative effect of reducing the intensity of the light obtained in the form of decrease of ratio energies of electroretino - signal to noise (ER-SNR. The application of the optimal Kalman filter to estimate the electroretinosignal in the selected from the retina its mixture with noise is based. The main results cited as simulation, and the field experiment. The statistical test of whether the alternative hypothesis achieves the predetermined significance level in order to be accepted in preference to the null hypothesis was applied. The formulas for entropy expressions in stationary and periodical correlated models of ERS are proposed. Conclusion. The results are used in development of an expert system for detecting of neurotoxicity, identification of nanoparticle type, and estimation of their dose in the nervous system of an organism, including at cases of a priori unknown particle.

  19. Alternative Test Methods for Developmental Neurotoxicity: A History and Path Forward (OECD EFSA workshop)

    Science.gov (United States)

    Exposure to environmental contaminants is well documented to adversely impact the development of the nervous system. However, the time, animal and resource intensive EPA and OECD testing guideline methods for developmental neurotoxicity (DNT) are not a viable solution to characte...

  20. Transformation of Developmental Neurotoxicity Data into a Structure-Searchable Relational Database

    Science.gov (United States)

    A database of neurotoxicants is critical to support the development and validation of animal alternatives for neurotoxicity. Validation of in vitro test methods can only be done using known animal and human neurotoxicants producing defined responses for neurochemical, neuropatho...

  1. Population Explosion in Africa and its Implications for Economic Development

    Science.gov (United States)

    Akinbode, Ade

    1977-01-01

    Analyzes patterns of population growth in Africa, accounts for the population explosion in certain parts of the continent, and discusses implications of the population growth for economic development. Seven tables and two maps are included in the article. (Author/DB)

  2. Some Implications of Career Theory for Adult Development and Aging.

    Science.gov (United States)

    Holland, John L.

    Structural-interactive vocational theory shows that both aspirational and work histories have continuity over the life span and provide useful explanations of stability and change. This paper suggests some implications of structural-interactive theory for the study of adult development. Common principles of structural-interactive theories are…

  3. Some Instructional Implications from a Mathematical Model of Cognitive Development.

    Science.gov (United States)

    Mierkiewicz, Diane B.

    Cognitive development and various educational implications are discussed in terms of Donald Saari's model of the interaction of a learner and the enviroment and the constraints imposed by the inefficiency of the learner's cognitive system. Saari proposed a hierarchical system of cognitive structures such that the relationships between structures…

  4. Neurotoxic effects of ecstasy on the thalamus

    NARCIS (Netherlands)

    de Win, Maartje M. L.; Jager, Gerry; Booij, Jan; Reneman, Liesbeth; Schilt, Thelma; Lavini, Cristina; Olabarriaga, Silvia D.; Ramsey, Nick F.; den Heeten, Gerard J.; van den Brink, Wim

    2008-01-01

    Background Neurotoxic effects of ecstasy have been reported, although it remains unclear whether effects can be attributed to ecstasy, other recreational drugs or a combination of these. Aims To assess specific/independent neurotoxic effects of heavy ecstasy use and contributions of amphetamine, coc

  5. The Family Medicine Curriculum Resource Project: implications for faculty development.

    Science.gov (United States)

    Sheets, Kent J; Quirk, Mark E; Davis, Ardis K

    2007-01-01

    Faculty development implications related to implementing the Family Medicine Curriculum Resource (FMCR) Project provide an opportunity to look at the recommendations of the Society of Teachers of Family Medicine's federally funded Faculty Futures Initiative (FFI) and the recent Future of Family Medicine (FFM) project. Implications for faculty development include the importance of the clerkship setting, originally defined in 1991, with new features added in today's practice environment as outlined by the FFM and the changing assumptions in approaching faculty development. Previously, faculty development focused on teaching learners to master current knowledge. Now, faculty must teach learners how to master new competencies throughout their lives; learners need to learn how they and others learn now. Teaching must focus on how to learn in the future as well as what to learn for the present. Competence ("what individuals know or are able to do in terms of knowledge, skills, and attitudes") has become the focus of curriculum development efforts over the last few years and most appropriately serves as the focus of curriculum development in the FMCR Project. Implications for developing teachers and preceptors focus on the skills and circumstances required to teach and evaluate all types (cognitive, metacognitive, and affective) of competence. In the new culture, novel teaching methods will serve as the focus of faculty development in teaching and of educational ("best practices") research.

  6. Endoplasmic Reticulum Stress and Ethanol Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Fanmuyi Yang

    2015-10-01

    Full Text Available Ethanol abuse affects virtually all organ systems and the central nervous system (CNS is particularly vulnerable to excessive ethanol exposure. Ethanol exposure causes profound damages to both the adult and developing brain. Prenatal ethanol exposure induces fetal alcohol spectrum disorders (FASD which is associated with mental retardation and other behavioral deficits. A number of potential mechanisms have been proposed for ethanol-induced brain damage; these include the promotion of neuroinflammation, interference with signaling by neurotrophic factors, induction of oxidative stress, modulation of retinoid acid signaling, and thiamine deficiency. The endoplasmic reticulum (ER regulates posttranslational protein processing and transport. The accumulation of unfolded or misfolded proteins in the ER lumen triggers ER stress and induces unfolded protein response (UPR which are mediated by three transmembrane ER signaling proteins: pancreatic endoplasmic reticulum kinase (PERK, inositol-requiring enzyme 1 (IRE1, and activating transcription factor 6 (ATF6. UPR is initiated to protect cells from overwhelming ER protein loading. However, sustained ER stress may result in cell death. ER stress has been implied in various CNS injuries, including brain ischemia, traumatic brain injury, and aging-associated neurodegeneration, such as Alzheimer’s disease (AD, Huntington’s disease (HD, Amyotrophic lateral sclerosis (ALS, and Parkinson’s disease (PD. However, effects of ethanol on ER stress in the CNS receive less attention. In this review, we discuss recent progress in the study of ER stress in ethanol-induced neurotoxicity. We also examine the potential mechanisms underlying ethanol-mediated ER stress and the interaction among ER stress, oxidative stress and autophagy in the context of ethanol neurotoxicity.

  7. Fumonisin B(1): a neurotoxic mycotoxin.

    Science.gov (United States)

    Domijan, Ana-Marija

    2012-12-01

    Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

  8. Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong, E-mail: dayongw@seu.edu.cn

    2015-02-11

    Graphical abstract: - Highlights: • We investigated in vivo neurotoxicity of CdTe QDs on RMEs motor neurons in C. elegans. • CdTe QDs in the range of μg/L caused neurotoxicity on RMEs motor neurons. • Bioavailability of CdTe QDs may be the primary inducer for CdTe QDs neurotoxicity. • Both oxidative stress and cell identity regulate the CdTe QDs neurotoxicity. • CdTe QDs were translocated and deposited into RMEs motor neurons. - Abstract: We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1–1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd{sup 2+}. Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals.

  9. MR findings of cyclosporine neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Po Song; Ahn, Kook Jin; Ahn, Bo Young; Jung, Hae An; Kim, Hee Je; Lee, Jae Mun [The Catholic Univ. St Mary' s Hospital, Seoul (Korea, Republic of)

    1998-12-01

    To analyze the MR findings of cyclosporine-induced neurotoxicity in patients receiving high dose of cyclosporine and to suggest the possible pathogenetic mechanism. The cases of seven patients (2 males, 5 females;18-36 years old) who suffered seizures after receiving high-dose cyclosporine for bone marrow transplantation due to diseases such as aplastic anemia or leukemia were retrospectively reviewed. We evaluated the location and pattern of abnormal signal intensity seen on T2 weighted images, the presence of contrast enhancement, and the changes seen on follow-up MR performed at intervals of 12-30 days after initial MR in five of seven patients. We analyzed levels of blood cyclosporine and magnesium, and investigated the presence of hypertension at the sity of the seizure. Locations of the lesions were bilateral(n=3D5), unilateral(n=3D2), parietal(n=3D6), occipital(n=3D6), temporal(n=3D4), and in the frontal lobe(n=3D3). Frontal lesions showed high signal intensities in the borderline ischemic zone of the frontal lobe between the territory of the anterior and middle cerebral arteries. In six of the seven patients, cortical and subcortical areas including subcortical U-fibers were seen on T2-weighted images to be involved in the parietooccipital lobes. Only one of the seven showed high signal intensity in the left basal ganglia. All lesions showed high signal intensity on T2-weighted images, and iso to low signal intensity on T1-weighted. In five of seven patients there was no definite enhancement, but in the other two, enhancement was slight. In four of seven patients seizures occurred within high therapeutic ranges(250-450ng/ml), while others suffered such attacks at levels below the therapeutic range. After cyclospirine was administered at a reduced dosage or stopped, follow-up MR images showed the complete or near-total disappearance of the abnormal findings previously described. Only two patients had hypertension, and the others normotension. Five of the

  10. Neurotoxicity of manganese oxide nanomaterials

    Science.gov (United States)

    Stefanescu, Diana M.; Khoshnan, Ali; Patterson, Paul H.; Hering, Janet G.

    2009-11-01

    Manganese (Mn) toxicity in humans has been observed as manganism, a disease that resembles Parkinson's disease. The mechanism of Mn toxicity and the chemical forms that may be responsible for its neurotoxicity are not well understood. We examined the toxicity of Mn oxide nanomaterials in a neuronal precursor cell model, using the MTS assay to evaluate mitochondrial function in living cells and the LDH assay to quantify the release of the enzyme lactate dehydrogenase as a result of damage to the cell membrane. Both assays show that the toxicity of Mn is dependent on the type of Mn oxide nanomaterial and its concentration as well as on the state of cell differentiation. Following exposure to Mn oxide nanomaterials, reactive oxygen species (ROS) are generated, and flow cytometry experiments suggest that cell death occurred through apoptosis. During exposure to Mn oxide nanomaterials, increased levels of the transcription factor NF-κB (which mediates the cellular inflammatory response) were observed.

  11. New Developments in Mast Cell Biology: Clinical Implications.

    Science.gov (United States)

    Arthur, Greer; Bradding, Peter

    2016-09-01

    Mast cells (MCs) are present in connective tissue and at mucosal surfaces in all classes of vertebrates. In health, they contribute to tissue homeostasis, host defense, and tissue repair via multiple receptors regulating the release of a vast stockpile of proinflammatory mediators, proteases, and cytokines. However, these potentially protective cells are a double-edged sword. When there is a repeated or long-term stimulus, MC activation leads to tissue damage and dysfunction. Accordingly, MCs are implicated in the pathophysiologic aspects of numerous diseases covering all organs. Understanding the biology of MCs, their heterogeneity, mechanisms of activation, and signaling cascades may lead to the development of novel therapies for many diseases for which current treatments are lacking or are of poor efficacy. This review will focus on updates and developments in MC biology and their clinical implications, with a particular focus on their role in respiratory diseases.

  12. Immunosuppressant-Associated Neurotoxicity Responding to Olanzapine

    Directory of Open Access Journals (Sweden)

    James A. Bourgeois

    2014-01-01

    Full Text Available Immunosuppressants, particularly tacrolimus, can induce neurotoxicity in solid organ transplantation cases. A lower clinical threshold to switch from tacrolimus to another immunosuppressant agent has been a common approach to reverse this neurotoxicity. However, immunosuppressant switch may place the graft at risk, and, in some cases, continuation of the same treatment protocol may be necessary. We report a case of immunosuppressant-associated neurotoxicity with prominent neuropsychiatric manifestation and describe psychiatric intervention with olanzapine that led to clinical improvement while continuing tacrolimus maintenance.

  13. Women Education and Economic Development in Kenya: Implications for Curriculum Development and Implementation Processes

    Science.gov (United States)

    Syomwene, Anne; Kindiki, Jonah Nyaga

    2015-01-01

    This paper is a discussion of the relationship between women education and sustainable economic development in Kenya and its implications for curriculum development and implementation processes. The argument advanced in this paper is that the solution to the development problems in Kenya and other developing nations lies on women education.…

  14. Recovered Alcoholics and Career Development: Implications for Human Resource Development

    Science.gov (United States)

    Gedro, Julie; Mercer, Frances; Iodice, Jody D.

    2012-01-01

    This article presents three issues regarding alcoholism, recovery, and career development. First, alcoholism is a disease that creates health and wellness problems for those it afflicts. It also impacts individual and workplace productivity. Second, alcoholism has a persistent stigmatization. As a result, those alcoholics who are in recovery face…

  15. Recovered Alcoholics and Career Development: Implications for Human Resource Development

    Science.gov (United States)

    Gedro, Julie; Mercer, Frances; Iodice, Jody D.

    2012-01-01

    This article presents three issues regarding alcoholism, recovery, and career development. First, alcoholism is a disease that creates health and wellness problems for those it afflicts. It also impacts individual and workplace productivity. Second, alcoholism has a persistent stigmatization. As a result, those alcoholics who are in recovery face…

  16. Mechanism involved in the UCB neurotoxicity on cellular models

    OpenAIRE

    Giraudi, Pablo Jose'

    2009-01-01

    Summary This doctoral thesis covers three years period (2006-2008) during which I have investigated the bilirubin neurotoxicity in the neuroblastoma SH-SY5Y cell line, a neuronal cell model widely used in the study of the pathogenesis and in the development of new therapeutic compounds for neurodegenerative diseases. In the first chapter is summarized the current knowledge about bilirubin chemistry and metabolism including disorders of bilirubin metabolism and the neuronal disturbanc...

  17. Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Bhojwani, Deepa; Sabin, Noah D.; Pei, Deqing; Yang, Jun J.; Khan, Raja B.; Panetta, John C.; Krull, Kevin R.; Inaba, Hiroto; Rubnitz, Jeffrey E.; Metzger, Monika L.; Howard, Scott C.; Ribeiro, Raul C.; Cheng, Cheng; Reddick, Wilburn E.; Jeha, Sima; Sandlund, John T.; Evans, William E.; Pui, Ching-Hon; Relling, Mary V.

    2014-01-01

    Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity. PMID:24550419

  18. Short and long-term effects of three neurotoxic insecticides on biological and behavioural attributes of the orb-web spider Alpaida veniliae (Araneae, Araneidae): implications for IPM programs.

    Science.gov (United States)

    Benamú, Marco A; Schneider, Marcela I; González, Alda; Sánchez, Norma E

    2013-09-01

    Soybean pest control in Argentina is done just by chemical control using broad-spectrum pesticides. Alpaida veniliae (Araneae, Araneidae) is one of the most abundant spider species of the orb web weaver guild in soybean, and it is considered a very important polyphagous predator, attacking different insects' families. The objective of this study was to determine if neurotoxic insecticides commonly used in soybean crops and a new active ingredient registered in Argentina (spinosad) adversely affected survival, prey consumption, mating behaviour, web building and reproductive capacity of A. veniliae females, under standard laboratory conditions. Spinosad was the most harmful insecticide due to high acute toxicity, even at lower concentrations than those registered for its field use and for its sublethal effects also. Cypermethrin caused several sublethal effects although its acute toxicity on spider was lower than other insecticides. It reduced prey consumption, affected web building, caused abnormalities in eggs sacs and decreased drastically the fecundity and fertility at sublethal concentrations. Endosulfan did not reduce prey consumption but it affected web building, caused abnormalities in eggs sacs and egg masses, and decreased the fecundity and fertility. Spinosad was also the compound with the most drastic effect on web building, it did not reduce prey consumption and fecundity, but fertility was reduced and abnormalities in egg sacs and egg masses were observed. The use of these insecticides in IPM programs according to their potential toxicity on spider communities is discussed.

  19. Developmental neurotoxicity of propylthiouracil in rats

    DEFF Research Database (Denmark)

    Petersen, Marta Axelstad; Hansen, Pernille Reimer; Christiansen, Sofie

    2007-01-01

    . The overall aim was to provide detailed knowledge on the relationship between effects on thyroid hormone levels and long-lasting developmental neurotoxicity effects. Groups of 16–18 pregnant rats (HanTac:WH) were dosed with PTU (0, 0.8, 1.6 or 2.4 mg/(kg day)) from gestation day 7 to postnatal day (PND) 16...... behaviour and hearing function. This supports that exposure to TDC's in general may cause long-lasting developmental neurotoxicity....

  20. alpha7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not beta-amyloid-induced neurotoxicity.

    Science.gov (United States)

    de Fiebre, Nancyellen C; de Fiebre, Christopher M

    2005-01-03

    The alpha7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, beta-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from alpha7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, "binge" ethanol and beta-amyloid. Knockout of the alpha7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to beta-amyloid induced toxicity, however, was unaffected by alpha7 nAChR gene null mutation. Further, beta-amyloid did not inhibit the binding of the highly alpha7-selective radioligand, [(125)I]alpha-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited alpha7 nAChR function. These data suggest that alpha7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by beta-amyloid. It is hypothesized that inhibition of alpha7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.

  1. Phthalates and neurotoxic effects on hippocampal network plasticity.

    Science.gov (United States)

    Holahan, Matthew R; Smith, Catherine A

    2015-05-01

    Phthalates are synthetically derived chemicals used as plasticizers in a variety of common household products. They are not chemically bound to plastic polymers and over time, easily migrate out of these products and into the environment. Experimental investigations evaluating the biological impact of phthalate exposure on developing organisms are critical given that estimates of phthalate exposure are considerably higher in infants and children compared to adults. Extensive growth and re-organization of neurocircuitry occurs during development leaving the brain highly susceptible to environmental insults. This review summarizes the effects of phthalate exposure on brain structure and function with particular emphasis on developmental aspects of hippocampal structural and functional plasticity. In general, it appears that widespread disruptions in hippocampal functional and structural plasticity occur following developmental (pre-, peri- and post-natal) exposure to phthalates. Whether these changes occur as a direct neurotoxic effect of phthalates or an indirect effect through disruption of endogenous endocrine functions is not fully understood. Comprehensive investigations that simultaneously assess the neurodevelopmental, neurotoxic, neuroendocrine and behavioral correlates of phthalate exposure are needed to provide an opportunity to thoroughly evaluate the neurotoxic potential of phthalates throughout the lifespan.

  2. Tourism and Sustainable Development. Implications at Local Community Level

    Directory of Open Access Journals (Sweden)

    Catalin Ioan Nechifor

    2014-10-01

    Full Text Available Tourism represents an economic activity with a special growth potential and rate that, managed in a proper way, can represent an important means for ensuring a sustainable development and to promote and sustain local communities. During the past period, the development of tourism raised awareness among policy makers, local governments, tourists, etc. about the effect of tourism on the environment, this way the development of a sustainable tourism being a necessity. The present paper aims to outline a series of implications at communities' level that the relationship between tourism and sustainable development may generate, focusing on one of the most representative and important components of sustainable tourism, respectively ecotourism and its particular forms of rural and agrotourism.

  3. Implications of plant glycans in the development of innovative vaccines.

    Science.gov (United States)

    Rosales-Mendoza, Sergio; Salazar-González, Jorge A; Decker, Eva L; Reski, Ralf

    2016-07-01

    Plant glycans play a central role in vaccinology: they can serve as adjuvants and/or delivery vehicles or backbones for the synthesis of conjugated vaccines. In addition, genetic engineering is leading to the development of platforms for the production of novel polysaccharides in plant cells, an approach with relevant implications for the design of new types of vaccines. This review contains an updated outlook on this topic and provides key perspectives including a discussion on how the molecular pharming field can be linked to the production of innovative glycan-based and conjugate vaccines.

  4. Lead Neurotoxicity and Socioeconomic Status: Conceptual and Analytical Issues

    Science.gov (United States)

    Bellinger, David C.

    2008-01-01

    Socioeconomic status (SES) is usually considered to be a potential confounder of the association between lead exposure and children’s neurodevelopment, but experimental and epidemiological data suggest that SES might also modify lead neurotoxicity. The basis of this effect modification is uncertain, but might include differences among SES strata in co-exposures to other neurotoxicants, genetic susceptibilities, environmental enrichment, and stress. The role of SES in the causal nexus is likely to include other dimensions, however. It conveys information about lead exposure opportunities as well as about predictors of child outcome that are correlated with but causally independent of lead. Failure to distinguish these aspects of SES will lead to an underestimate of lead’s contribution, and might even result in attributing to SES health effects that should be attributed to lead. Conventional models, which treat SES and SES-related factors solely as potential confounders, do not capture the possibility that a child’s early lead exposure alters the behaviors that the child elicits from others. Failure to model lead’s contribution to such time-varying covariates will also tend to bias estimates of lead neurotoxicity toward the null. On a transgenerational level, low SES might be a proxy for vulnerability to lead. To estimate the burden of lead-associated neurotoxicity on a population level, we need to apply analytical approaches that model a child’s development and its context as a complex system of interdependent relationships that change over time. PMID:18501967

  5. Death adder envenoming causes neurotoxicity not reversed by antivenom--Australian Snakebite Project (ASP-16.

    Directory of Open Access Journals (Sweden)

    Christopher I Johnston

    Full Text Available BACKGROUND: Death adders (Acanthophis spp are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. METHODOLOGY/PRINCIPAL FINDINGS: Definite death adder bites were recruited from the Australian Snakebite Project (ASP as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5-74 yr; 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12, diplopia (9, bulbar weakness (7, intercostal muscle weakness (2 and limb weakness (2. Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5-15.5 hr. One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5-168. The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4-245 ng/mL. In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. CONCLUSIONS/SIGNIFICANCE: Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom

  6. Death Adder Envenoming Causes Neurotoxicity Not Reversed by Antivenom - Australian Snakebite Project (ASP-16)

    Science.gov (United States)

    Johnston, Christopher I.; O'Leary, Margaret A.; Brown, Simon G. A.; Currie, Bart J.; Halkidis, Lambros; Whitaker, Richard; Close, Benjamin; Isbister, Geoffrey K.

    2012-01-01

    Background Death adders (Acanthophis spp) are found in Australia, Papua New Guinea and parts of eastern Indonesia. This study aimed to investigate the clinical syndrome of death adder envenoming and response to antivenom treatment. Methodology/Principal Findings Definite death adder bites were recruited from the Australian Snakebite Project (ASP) as defined by expert identification or detection of death adder venom in blood. Clinical effects and laboratory results were collected prospectively, including the time course of neurotoxicity and response to treatment. Enzyme immunoassay was used to measure venom concentrations. Twenty nine patients had definite death adder bites; median age 45 yr (5–74 yr); 25 were male. Envenoming occurred in 14 patients. Two further patients had allergic reactions without envenoming, both snake handlers with previous death adder bites. Of 14 envenomed patients, 12 developed neurotoxicity characterised by ptosis (12), diplopia (9), bulbar weakness (7), intercostal muscle weakness (2) and limb weakness (2). Intubation and mechanical ventilation were required for two patients for 17 and 83 hours. The median time to onset of neurotoxicity was 4 hours (0.5–15.5 hr). One patient bitten by a northern death adder developed myotoxicity and one patient only developed systemic symptoms without neurotoxicity. No patient developed venom induced consumption coagulopathy. Antivenom was administered to 13 patients, all receiving one vial initially. The median time for resolution of neurotoxicity post-antivenom was 21 hours (5–168). The median peak venom concentration in 13 envenomed patients with blood samples was 22 ng/mL (4.4–245 ng/mL). In eight patients where post-antivenom bloods were available, no venom was detected after one vial of antivenom. Conclusions/Significance Death adder envenoming is characterised by neurotoxicity, which is mild in most cases. One vial of death adder antivenom was sufficient to bind all circulating venom. The

  7. Endocytic pathways mediating oligomeric Aβ42 neurotoxicity

    Directory of Open Access Journals (Sweden)

    Laxton Kevin

    2010-05-01

    Full Text Available Abstract Background One pathological hallmark of Alzheimer's disease (AD is amyloid plaques, composed primarily of amyloid-β peptide (Aβ. Over-production or diminished clearance of the 42 amino acid form of Aβ (Aβ42 in the brain leads to accumulation of soluble Aβ and plaque formation. Soluble oligomeric Aβ (oAβ has recently emerged to be as a likely proximal cause of AD. Results Here we demonstrate that endocytosis is critical in mediating oAβ42-induced neurotoxicity and intraneuronal accumulation of Aβ. Inhibition of clathrin function either with a pharmacological inhibitor, knock-down of clathrin heavy chain expression, or expression of the dominant-negative mutant of clathrin-assembly protein AP180 did not block oAβ42-induced neurotoxicity or intraneuronal accumulation of Aβ. However, inhibition of dynamin and RhoA by expression of dominant negative mutants reduced neurotoxicity and intraneuronal Aβ accumulation. Pharmacologic inhibition of the dynamin-mediated endocytic pathway by genistein also reduced neurotoxicity. Conclusions These data suggest that dynamin-mediated and RhoA-regulated endocytosis are integral steps for oligomeric Aβ42-induced neurotoxicity and intraneuronal Aβ accumulation.

  8. Neurotoxic Alkaloids: Saxitoxin and Its Analogs

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    Troco K. Mihali

    2010-07-01

    Full Text Available Saxitoxin (STX and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs. PSTs are the causative agents of paralytic shellfish poisoning (PSP and are mostly associated with marine dinoflagellates (eukaryotes and freshwater cyanobacteria (prokaryotes, which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified in several cyanobacterial genera including Anabaena, Cylindrospermopsis, Aphanizomenon Planktothrix and Lyngbya. STX and its analogs can be structurally classified into several classes such as non-sulfated, mono-sulfated, di-sulfated, decarbamoylated and the recently discovered hydrophobic analogs—each with varying levels of toxicity. Biotransformation of the PSTs into other PST analogs has been identified within marine invertebrates, humans and bacteria. An improved understanding of PST transformation into less toxic analogs and degradation, both chemically or enzymatically, will be important for the development of methods for the detoxification of contaminated water supplies and of shellfish destined for consumption. Some PSTs also have demonstrated pharmaceutical potential as a long-term anesthetic in the treatment of anal fissures and for chronic tension-type headache. The recent elucidation of the saxitoxin biosynthetic gene cluster in cyanobacteria and the identification of new PST analogs will present opportunities to further explore the pharmaceutical potential of these intriguing alkaloids.

  9. Neophyte facilitator experiences of interprofessional education: implications for faculty development.

    Science.gov (United States)

    Egan-Lee, Eileen; Baker, Lindsay; Tobin, Stasey; Hollenberg, Elisa; Dematteo, Dale; Reeves, Scott

    2011-09-01

    The facilitation of learners from different professional groups requires a range of interprofessional knowledge and skills (e.g. an understanding of possible sources of tension between professions) in addition to those that are more generic, such as how to manage a small group of learners. The development and delivery of interprofessional education (IPE) programs tends to rely on a small cohort of facilitators who have typically gained expertise through 'hands-on' involvement in facilitating IPE and through mentorship from more experienced colleagues. To avoid burn-out and to meet a growing demand for IPE, a larger number of facilitators are needed. However, empirical evidence regarding effective approaches to prepare for this type of work is limited. This article draws on data from a multiple case study of four IPE programs based in an urban setting in North America with a sample of neophyte facilitators and provides insight into their perceptions and experiences in preparing for and delivering IPE. Forty-one semi-structured interviews were conducted before (n = 20) and after (n = 21) program delivery with 21 facilitators. Findings indicated that despite participating in a three-fold faculty development strategy designed to support them in their IPE facilitation work, many felt unprepared and continued to have a poor conceptual understanding of core IPE and interprofessional collaboration principles, resulting in problematic implications (e.g. 'missed teachable moments') within their IPE programs. Findings from this study are discussed in relation to the IPE, faculty development and wider educational literature before implications are offered for the future delivery of interprofessional faculty development activities.

  10. Features of Microglia and Neuroinflammation Relevant to Environmental Exposure and Neurotoxicity

    Directory of Open Access Journals (Sweden)

    G. Jean Harry

    2011-07-01

    Full Text Available Microglia are resident cells of the brain involved in regulatory processes critical for development, maintenance of the neural environment, injury and repair. They belong to the monocytic-macrophage lineage and serve as brain immune cells to orchestrate innate immune responses; however, they are distinct from other tissue macrophages due to their relatively quiescent phenotype and tight regulation by the CNS microenvironment. Microglia actively survey the surrounding parenchyma and respond rapidly to changes such that any disruption to neural architecture or function can contribute to the loss in regulation of the microglia phenotype. In many models of neurodegeneration and neurotoxicity, early events of synaptic degeneration and neuronal loss are accompanied by an inflammatory response including activation of microglia, perivascular monocytes, and recruitment of leukocytes. In culture, microglia have been shown to be capable of releasing several potentially cytotoxic substances, such as reactive oxygen intermediates, nitric oxide, proteases, arachidonic acid derivatives, excitatory amino acids, and cytokines; however, they also produce various neurotrophic factors and quench damage from free radicals and excitotoxins. As the primary source for pro-inflammatory cytokines, microglia are implicated as pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Neuroinflammation should be considered as a balanced network of processes whereby subtle modifications can shift the cells toward disparate outcomes. For any evaluation of neuroinflammation and microglial responses, within the framework of neurotoxicity or degeneration, one key question in determining the consequence of neuroinflammation is whether the response is an initiating event or the consequence of tissue damage. As examples of environmental exposure-related neuroinflammation in the literature, we provide an evaluation of data on manganese

  11. Translocation and neurotoxicity of CdTe quantum dots in RMEs motor neurons in nematode Caenorhabditis elegans.

    Science.gov (United States)

    Zhao, Yunli; Wang, Xiong; Wu, Qiuli; Li, Yiping; Wang, Dayong

    2015-01-01

    We employed Caenorhabditis elegans assay system to investigate in vivo neurotoxicity of CdTe quantum dots (QDs) on RMEs motor neurons, which are involved in controlling foraging behavior, and the underlying mechanism of such neurotoxicity. After prolonged exposure to 0.1-1 μg/L of CdTe QDs, abnormal foraging behavior and deficits in development of RMEs motor neurons were observed. The observed neurotoxicity from CdTe QDs on RMEs motor neurons might be not due to released Cd(2+). Overexpression of genes encoding Mn-SODs or unc-30 gene controlling cell identity of RMEs neurons prevented neurotoxic effects of CdTe QDs on RMEs motor neurons, suggesting the crucial roles of oxidative stress and cell identity in regulating CdTe QDs neurotoxicity. In nematodes, CdTe QDs could be translocated through intestinal barrier and be deposited in RMEs motor neurons. In contrast, CdTe@ZnS QDs could not be translocated into RMEs motor neurons and therefore, could only moderately accumulated in intestinal cells, suggesting that ZnS coating might reduce neurotoxicity of CdTe QDs on RMEs motor neurons. Therefore, the combinational effects of oxidative stress, cell identity, and bioavailability may contribute greatly to the mechanism of CdTe QDs neurotoxicity on RMEs motor neurons. Our results provide insights into understanding the potential risks of CdTe QDs on the development and function of nervous systems in animals.

  12. Can Zebrafish be used to Identify Developmentally Neurotoxic Chemicals

    Science.gov (United States)

    Can Zebrafish be Used to Identify Developmentally Neurotoxic Chemicals? The U.S. Environmental Protection Agency is evaluating methods to screen and prioritize large numbers of chemicals for developmental neurotoxicity. We are exploring behavioral methods using zebrafish by desig...

  13. Current status of developmental neurotoxicity: regulatory view

    DEFF Research Database (Denmark)

    Hass, Ulla

    2003-01-01

    . Until recently, however, developmental neurotoxicity testing of industrial chemicals has not been a clear regulatory requirement in EU, probably due to the lack of an accepted OECD TG. The revised EU Technical Guidance Document for Risk Assessment (EU-TGD) has now included the OECD draft TG 426...... in the testing strategy for new and existing substances, and biocides. Hopefully, this will lead to an improved database for risk assessment of potential developmental neurotoxicants. However, the regulatory authorities and toxicologists will also be faced with the challenge that decisions have to be made......The need for developmental neurotoxicity testing has been recognized for decades and guidelines are available, as the USEPA guideline and the OECD draft TG 426. Regulatory testing of industrial chemicals for developmental neurotoxicity is required to some extent, especially for pesticides in the US...

  14. Developmental neurotoxic effects of two pesticides: Behavior and biomolecular studies on chlorpyrifos and carbaryl.

    Science.gov (United States)

    Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik

    2015-11-01

    In recent times, an increased occurrence of neurodevelopmental disorders, such as neurodevelopmental delays and cognitive abnormalities has been recognized. Exposure to pesticides has been suspected to be a possible cause of these disorders, as these compounds target the nervous system of pests. Due to the similarities of brain development and composition, these pesticides may also be neurotoxic to humans. We studied two different pesticides, chlorpyrifos and carbaryl, which specifically inhibit acetylcholinesterase (AChE) in the nervous system. The aim of the study was to investigate if the pesticides can induce neurotoxic effects, when exposure occurs during a period of rapid brain growth and maturation. The results from the present study show that both compounds can affect protein levels in the developing brain and induce persistent adult behavior and cognitive impairments, in mice neonatally exposed to a single oral dose of chlorpyrifos (0.1, 1.0 or 5mg/kg body weight) or carbaryl (0.5, 5.0 or 20.0mg/kg body weight) on postnatal day 10. The results also indicate that the developmental neurotoxic effects induced are not related to the classical mechanism of acute cholinergic hyperstimulation, as the AChE inhibition level (8-12%) remained below the threshold for causing systemic toxicity. The neurotoxic effects are more likely caused by a disturbed neurodevelopment, as similar behavioral neurotoxic effects have been reported in studies with pesticides such as organochlorines, organophosphates, pyrethroids and POPs, when exposed during a critical window of neonatal brain development.

  15. Developmental origins of adult diseases and neurotoxicity: epidemiological and experimental studies.

    Science.gov (United States)

    Fox, Donald A; Grandjean, Philippe; de Groot, Didima; Paule, Merle G

    2012-08-01

    To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data on children exposed to inorganic mercury and methylmercury, and discussed the behavioral outcome measures as they relate to age and stage of brain development. Donald A. Fox presented data that low-dose human equivalent gestational lead exposure produces late-onset obesity only in male mice that is associated with neurodegeneration. Didima de Groot presented results on prenatal exposure of rats to methylazoxymethanol and discussed the results in light of the etiology of western Pacific amyotrophic lateral sclerosis and Parkinson-dementia complex. Merle G. Paule addressed the long-term changes in learning, motivation and short-term memory in aged Rhesus monkeys following acute 24 h exposure to ketamine during early development. Overall, these presentations addressed fundamental issues in the emerging areas of lifetime neurotoxicity testing, differential vulnerable periods of exposure, nonmonotonic dose-response effects and neurotoxic risk assessment. The results indicate that developmental neurotoxicity results in permanent changes, thus emphasizing the need to prevent such toxicity. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Pb Neurotoxicity: Neuropsychological Effects of Lead Toxicity

    Directory of Open Access Journals (Sweden)

    Lisa H. Mason

    2014-01-01

    Full Text Available Neurotoxicity is a term used to describe neurophysiological changes caused by exposure to toxic agents. Such exposure can result in neurocognitive symptoms and/or psychiatric disturbances. Common toxic agents include heavy metals, drugs, organophosphates, bacterial, and animal neurotoxins. Among heavy metal exposures, lead exposure is one of the most common exposures that can lead to significant neuropsychological and functional decline in humans. In this review, neurotoxic lead exposure's pathophysiology, etiology, and epidemiology are explored. In addition, commonly associated neuropsychological difficulties in intelligence, memory, executive functioning, attention, processing speed, language, visuospatial skills, motor skills, and affect/mood are explored.

  17. Poverty in Eritrea: challenges and implications for development.

    Science.gov (United States)

    Rena, Ravinder

    2009-01-01

    Poverty, one of the world's most serious problems, is particularly severe in Africa. Eritrea is a 16-year-old nation that gained its independence from Ethiopia in 1993. The country's economy was doing relatively well between 1993 and 1997. Eritrea was then exposed to numerous challenges such as drought, famines and recurrent war. As a result, poverty has become more rampant in a country where over 66 per cent of people live below the poverty line. Some families live on remittances. The government has taken some poverty alleviation measures. However, it has not mitigated poverty due to a lack of resources and a poorly implemented poverty alleviation programme. This article attempts to explore the incidence of poverty. It also provides details of poverty surveys that have been conducted since independence. It discusses various poverty challenges and provides some policy implications for development.

  18. Slip of the tongue: Implications for evolution and language development.

    Science.gov (United States)

    Forrester, Gillian S; Rodriguez, Alina

    2015-08-01

    A prevailing theory regarding the evolution of language implicates a gestural stage prior to the emergence of speech. In support of a transition of human language from a gestural to a vocal system, articulation of the hands and the tongue are underpinned by overlapping left hemisphere dominant neural regions. Behavioral studies demonstrate that human adults perform sympathetic mouth actions in imitative synchrony with manual actions. Additionally, right-handedness for precision manual actions in children has been correlated with the typical development of language, while a lack of hand bias has been associated with psychopathology. It therefore stands to reason that sympathetic mouth actions during fine precision motor action of the hands may be lateralized. We employed a fine-grained behavioral coding paradigm to provide the first investigation of tongue protrusions in typically developing 4-year old children. Tongue protrusions were investigated across a range of cognitive tasks that required varying degrees of manual action: precision motor action, gross motor action and no motor actions. The rate of tongue protrusions was influenced by the motor requirements of the task and tongue protrusions were significantly right-biased for only precision manual motor action (p<.001). From an evolutionary perspective, tongue protrusions can drive new investigations regarding how an early human communication system transitioned from hand to mouth. From a developmental perspective, the present study may serve to reveal patterns of tongue protrusions during the motor development of typically developing children.

  19. Downregulation of miR-210 protected bupivacaine-induced neurotoxicity in dorsal root ganglion.

    Science.gov (United States)

    Wang, Yiheng; Ni, Hongxia; Zhang, Wenrui; Wang, Xiu; Zhang, Haishan

    2016-04-01

    Local anesthetic may cause neurotoxicity in developing neurons. In this study, we examined the molecular mechanisms of microRNA-210 (miR-210) in regulating bupivacaine-induced dorsal root ganglia (DRG) neurotoxicity in vitro. Young mouse (P30) DRG explants were cultured in vitro and treated with 5 mM bupivacaine to induce neurotoxicity. QRT-PCR was used to evaluate the expression profiles of miRNAs within 24 h after bupivacaine treatment. MiR-210 was downregulated in DRG, and its effects on bupivacaine-induced neurotoxicity were evaluated by apoptosis and neurite growth assays, respectively. Putative downstream target of miR-210 in DRG, BDNF, was evaluated by dual-luciferase assay, qRT-PCR, and western blot, respectively. BDNF was then knocked down by siRNA to assess its associated effects in regulating DRG neurotoxicity. Within the initial 24 h after bupivacaine treatment, various patterns of miRNA expression were observed, whereas miR-210 was constantly upregulated. Application of miR-210 inhibitor efficiently downregulated endogenous miR-210, protected apoptosis and neurite retraction in bupivacaine damaged DRG neurons. Using dual-luciferase assay, qRT-PCR, and western blot, BDNF was confirmed to the downstream target of miR-210 in DRG. SiRNA-mediated BDNF downregulation reversed the effect of miR-210 downregulation in DRG neurotoxicity. MiR-210, through the regulation of BDNF, plays important role in anesthetics-induced DRG neurotoxicity.

  20. Innovations in coaching and mentoring: implications for nurse leadership development.

    Science.gov (United States)

    Fielden, Sandra L; Davidson, Marilyn J; Sutherland, Valerie J

    2009-05-01

    This longitudinal study sought to examine ways in which coaching and mentoring relationships impact on the professional development of nurses in terms of career and leadership behaviours, and evaluating the differences and similarities between those coaching and mentoring relationships. According to the UK government, leadership in nursing is essential to the improvement of service delivery, and the development and training of all nurses is vital in achieving effective change. A coaching and mentoring programme was used to explore the comparative advantages of these two approaches for the leadership development of nurses in acute, primary care and mental health settings. A longitudinal in-depth study was conducted to measure differences and similarities between the mentoring and coaching process as a result of a six-month coaching/mentoring programme. Five nurses from six UK Health Care Trusts were allocated to a coaching group (n = 15) or a mentoring group (n = 15), these were coached or mentored by a member of the senior directorate from their own Trust. Qualitative and quantitative data were collected at three time points (T1 = baseline, T2 = 4 months and T3 = 9 months) using semi-structured interviews and questionnaires. While mentoring was perceived to be 'support' and coaching was described as 'action', descriptions of the actual process and content were quite similar. However, while both groups reported significant development in terms of career development, leadership skills and capabilities, mentees reported the highest level of development with significantly higher scores in eight areas of leadership and management and in three areas of career impact. Implications for nurses and health services are discussed.

  1. A logo-leadership intervention: Implications for leadership development

    Directory of Open Access Journals (Sweden)

    Frances Scholtz

    2015-02-01

    Full Text Available Orientation: Logo-leadership development challenges leaders to move beyond financial or individual gain to accepting leadership as a calling.Research purpose: The objective of the study was to ascertain whether an intervention embedded in the life and teachings of logo-therapist Viktor Frankl affects the way aspiring leaders construct leadership in terms of meaning (logo-leadership.Motivation for the study: A consideration of Frankl’s life gives rise to the question of whether aspiring leaders can learn from and use his life teachings as an inspiration in the discovery of meaning for themselves as leaders.Research approach, design and method: Participants comprised 20 students registered for an MCom degree at a South African metropolitan university. The research process involved three phases: (1 a pre-intervention questionnaire, (2 an appreciative inquiry intervention and (3 a post-intervention questionnaire. Framework analysis and a comparative method were used to analyse the data.Main findings: A meaning-centred leadership development intervention may impact the leadership role orientation of aspiring leaders, changing it from a predominantly career orientation to a calling. However, this effect largely occurred on an explicit (extrinsic level.Managerial implications: Organisations that wish to develop logo-leadership may consider using the life teachings and work of Frankl as a development tool.Contribution/value-add: This study contributes theoretically to a relatively new development within the field of Frankl’s logotherapy, leadership with meaning (logo-leadership. On apractical level, this study introduced the concept of logo-leadership for leadership development and suggests that leadership may be influenced by exposure to a leadership intervention.

  2. Neurotoxicity of isoniazid and its metabolites in cultures of mouse dorsal root ganglion neurons and hybrid neuronal cell line.

    Science.gov (United States)

    Sanfeliu, C; Wright, J M; Kim, S U

    1999-12-01

    Isoniazid (INH) is one of the anti-tuberculosis drugs widely prescribed for patients since the early 1950s. It is relatively nontoxic but some patients develop peripheral neuropathy attributed to a disturbance of vitamin B6 metabolism. Some isoniazid metabolites are hepatotoxic but little is known about their neurotoxic property. Isoniazid and its metabolites including acetylisoniazid, acetylhydrazine, diacetylhydrazine, isonicotinic acid and hydrazine were examined for their potential neurotoxic effects in cultured mouse dorsal root ganglion (DRG) neurons and mouse neuroblastoma x DRG neuron hybrid cell line N18D3. Isoniazid did not cause neurotoxicity at exposures up to 7 days. Hydrazine was found to be the most toxic metabolite with LC50 values of 2.7 mM and 0.3 mM after 7 days of exposure in DRG neurons and N18D3 hybrid neurons, respectively. Other metabolites including acetylisoniazid, acetylhydrazine, diacetylhydrazine and isonicotinic acid had moderate to minor neurotoxic effects on N18D3 hybrid neurons. Pyridoxine, which is used in clinical practice to prevent or ameliorate the isoniazid-induced neuropathy, did not consistently reverse the neurotoxicity of any of the metabolites in the cell cultures, but some interaction with hydrazine cannot be ruled out. Pyridoxine itself was found to be neurotoxic both in DRG neurons and N18D3 hybrid neurons, in agreement with human peripheral sensory neuropathy caused by prolonged overdosage. The enzymes catalase and superoxide dismutase and the antioxidant agent selenium showed some protection against hydrazine neurotoxicity, suggesting an involvement of the generation of reactive oxygen species in the pathogenesis of isoniazid neuropathy. Both mouse DRG neurons and N18D3 mouse hybrid neurons were shown to be useful culture systems for elucidating the neurotoxicity mechanisms of agents causing sensory neuropathies and general neurotoxic effects in the nervous system.

  3. NEUROTOXICITY OF TETRACHLOROETHYLENE (PERCHLOROETHYLENE): DISCUSSION PAPER

    Science.gov (United States)

    This paper is a background document for a meeting of neurotoxicity experts to discuss the central nervous system effects of exposure to perchloroethylene (perc). The document reviews the literature on neurological testing of people exposed to perc occupationally in dry cleanin...

  4. Neurotoxicity of ecstasy (MDMA): an overview.

    Science.gov (United States)

    Sarkar, Sumit; Schmued, Larry

    2010-08-01

    "Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.

  5. Neurotoxic effect of maneb in rats as studied by neurochemical and immunohistochemical parameters

    DEFF Research Database (Denmark)

    Nielsen, Brian Svend; Larsen, Erik Huusfeldt; Ladefoged, Ole;

    2006-01-01

    Epidemiological investigations document that workers in agriculture, horticulture and people living near areas with frequent use of pesticides have increased risk of developing symptoms of Parkinson's disease. This study investigated the neurotoxic effect of the fungicide maneb by morphological, ......-synuclein and synaptophysin in corpus striatum and the rest of the brain were not changed. No histological parameter was affected when studied in corpus striatum, and substantia nigra.......Epidemiological investigations document that workers in agriculture, horticulture and people living near areas with frequent use of pesticides have increased risk of developing symptoms of Parkinson's disease. This study investigated the neurotoxic effect of the fungicide maneb by morphological......) increased in a dose-related manner, as did the 5-HT concentrations in the rest of the brain indicating early sign of neurotoxicity. Striatal acetylcholinesterase activity was not affected. The concentrations of noradrenaline, dopamine, neurotransmitter amino acids and the levels of the proteins alpha...

  6. Genetic regulation of heart valve development: Clinical implications

    Directory of Open Access Journals (Sweden)

    Marc-Phillip Hitz

    2011-12-01

    Full Text Available Cardiac malformations, most commonly valve defects, are some of the predominant causes of cardiovascular morbidity and mortality worldwide. Up to a third of all patients with complex congenital heart defects and numerous syndromic conditions, as well as a significant amount of the general population, exhibit valve defects. These observations have not only major implications in infancy; they also have a major impact on the adult population and the growing number of adults with congenital malformations. Over recent years, a large number of Mendelian inheritance patterns and syndromic causes have been identified, shedding light on the importance of genes encoding components of the extracelluar matrix in valve disease. Nevertheless, we still know little about the genetic origin of sporadic and more complex family traits. It is unclear to what extent genetic variations play a role in disease pathogenesis and influences phenotypes rooted in early development. Such knowledge would be greatly beneficial for counseling and treatment of patients. Therefore, this review summarizes the findings in human non-syndromic and syndromic valve disease with a special focus on extracellular matrix proteins, and discusses them in the context of vertebrate valve development.

  7. Methadone-Induced Neurotoxicity in Advanced Cancer: A Case Report.

    Science.gov (United States)

    Hoff, Ann M; Hartwig, Kristopher N; Rosielle, Drew A

    2017-09-01

    Methadone use as a second-line agent for severe cancer-related pain is increasing in the field of hospice and palliative care. It has a number of qualities that make its use favorable, including lack of known active metabolites and presumed relative safety from adverse effects such as opioid-induced neurotoxicity (OIN). This article describes a case of a patient undergoing treatment of severe cancer-related pain who developed OIN in the setting of oral methadone use. As the use of methadone increases, more research into its pharmacologic and pharmacokinetic properties will be necessary.

  8. L-DOPA neurotoxicity is mediated by up-regulation of DMT1-IRE expression.

    Directory of Open Access Journals (Sweden)

    Fang Du

    Full Text Available BACKGROUND: The mechanisms underlying neurotoxicity caused by L-DOPA are not yet completely known. Based on recent findings, we speculated that the increased expression of divalent metal transporter 1 without iron-response element (DMT1-IRE induced by L-DOPA might play a critical role in the development of L-DOPA neurotoxicity. To test this hypothesis, we investigated the effects of astrocyte-conditioned medium (ACM and siRNA DMT-IRE on L-DOPA neurotoxicity in cortical neurons. METHODS AND FINDINGS: We demonstrated that neurons treated with L-DOPA have a significant dose-dependent decrease in neuronal viability (MTT Assay and increase in iron content (using a graphite furnace atomic absorption spectrophotometer, DMT1-IRE expression (Western blot analysis and ferrous iron (55Fe(II uptake. Neurons incubated in ACM with or without L-DOPA had no significant differences in their morphology, Hoechst-33342 staining or viability. Also, ACM significantly inhibited the effects of L-DOPA on neuronal iron content as well as DMT1-IRE expression. In addition, we demonstrated that infection of neurons with siRNA DMT-IRE led to a significant decrease in DMT1-IRE expression as well as L-DOPA neurotoxicity. CONCLUSION: The up-regulation of DMT1-IRE and the increase in DMT1-IRE-mediated iron influx play a key role in L-DOPA neurotoxicity in cortical neurons.

  9. GRIN2A polymorphisms and expression levels are associated with lead-induced neurotoxicity.

    Science.gov (United States)

    Wu, Yu; Wang, Yiqing; Wang, Miaomiao; Sun, Na; Li, Chunping

    2017-04-01

    Lead acts as an antagonist of the N-methyl-d-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in lead-induced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells ( p lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls ( p lead level ( p lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01-2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity.

  10. THC Prevents MDMA Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Clara Touriño

    Full Text Available The majority of MDMA (ecstasy recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4 were pretreated with THC (3 mg/kg x 4 at room (21 degrees C and at warm (26 degrees C temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1 receptor antagonist AM251 and the CB(2 receptor antagonist AM630, as well as in CB(1, CB(2 and CB(1/CB(2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1 receptor antagonist AM251, neither in CB(1 and CB(1/CB(2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2 cannabinoid antagonist and in CB(2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1 receptor, although CB(2 receptors may also contribute to

  11. Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

    Science.gov (United States)

    Sarkar, Joy; Chaudhary, Shweta; Namavari, Abed; Ozturk, Okan; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Hallak, Joelle; Jain, Sandeep

    2012-01-01

    Purpose. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro. Methods. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Wide-field stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth. Results. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001). Conclusion. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous

  12. Bifurcation in epigenetics: Implications in development, proliferation, and diseases

    Science.gov (United States)

    Jost, Daniel

    2014-01-01

    Cells often exhibit different and stable phenotypes from the same DNA sequence. Robustness and plasticity of such cellular states are controlled by diverse transcriptional and epigenetic mechanisms, among them the modification of biochemical marks on chromatin. Here, we develop a stochastic model that describes the dynamics of epigenetic marks along a given DNA region. Through mathematical analysis, we show the emergence of bistable and persistent epigenetic states from the cooperative recruitment of modifying enzymes. We also find that the dynamical system exhibits a critical point and displays, in the presence of asymmetries in recruitment, a bifurcation diagram with hysteresis. These results have deep implications for our understanding of epigenetic regulation. In particular, our study allows one to reconcile within the same formalism the robust maintenance of epigenetic identity observed in differentiated cells, the epigenetic plasticity of pluripotent cells during differentiation, and the effects of epigenetic misregulation in diseases. Moreover, it suggests a possible mechanism for developmental transitions where the system is shifted close to the critical point to benefit from high susceptibility to developmental cues.

  13. Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms.

    Science.gov (United States)

    Moratalla, Rosario; Khairnar, Amit; Simola, Nicola; Granado, Noelia; García-Montes, Jose Ruben; Porceddu, Pier Francesca; Tizabi, Yousef; Costa, Giulia; Morelli, Micaela

    2017-08-01

    Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

    Directory of Open Access Journals (Sweden)

    Yan Long

    Full Text Available Perfluorooctane sulfonate (PFOS is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA and 3,4-dihydrophenylacetic acid (DOPAC in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase, Herc5 (hect domain and RLD 5 isoform 2 and Tyro3 (TYRO3 protein tyrosine kinase 3 were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit, Gzma (Isoform HF1 of Granzyme A precursor, Plau (Urokinase-type plasminogen activator precursor and Lig4 (DNA ligase 4 were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

  15. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  16. A Neuronal and Astrocyte Co-Culture Assay for High Content Analysis of Neurotoxicity

    Science.gov (United States)

    Anderl, Janet L; Redpath, Stella; Ball, Andrew J

    2009-01-01

    High Content Analysis (HCA) assays combine cells and detection reagents with automated imaging and powerful image analysis algorithms, allowing measurement of multiple cellular phenotypes within a single assay. In this study, we utilized HCA to develop a novel assay for neurotoxicity. Neurotoxicity assessment represents an important part of drug safety evaluation, as well as being a significant focus of environmental protection efforts. Additionally, neurotoxicity is also a well-accepted in vitro marker of the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Recently, the application of HCA to neuronal screening has been reported. By labeling neuronal cells with βIII-tubulin, HCA assays can provide high-throughput, non-subjective, quantitative measurements of parameters such as neuronal number, neurite count and neurite length, all of which can indicate neurotoxic effects. However, the role of astrocytes remains unexplored in these models. Astrocytes have an integral role in the maintenance of central nervous system (CNS) homeostasis, and are associated with both neuroprotection and neurodegradation when they are activated in response to toxic substances or disease states. GFAP is an intermediate filament protein expressed predominantly in the astrocytes of the CNS. Astrocytic activation (gliosis) leads to the upregulation of GFAP, commonly accompanied by astrocyte proliferation and hypertrophy. This process of reactive gliosis has been proposed as an early marker of damage to the nervous system. The traditional method for GFAP quantitation is by immunoassay. This approach is limited by an inability to provide information on cellular localization, morphology and cell number. We determined that HCA could be used to overcome these limitations and to simultaneously measure multiple features associated with gliosis - changes in GFAP expression, astrocyte hypertrophy, and astrocyte proliferation - within a single assay. In co

  17. A neuronal and astrocyte co-culture assay for high content analysis of neurotoxicity.

    Science.gov (United States)

    Anderl, Janet L; Redpath, Stella; Ball, Andrew J

    2009-05-05

    High Content Analysis (HCA) assays combine cells and detection reagents with automated imaging and powerful image analysis algorithms, allowing measurement of multiple cellular phenotypes within a single assay. In this study, we utilized HCA to develop a novel assay for neurotoxicity. Neurotoxicity assessment represents an important part of drug safety evaluation, as well as being a significant focus of environmental protection efforts. Additionally, neurotoxicity is also a well-accepted in vitro marker of the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Recently, the application of HCA to neuronal screening has been reported. By labeling neuronal cells with betaIII-tubulin, HCA assays can provide high-throughput, non-subjective, quantitative measurements of parameters such as neuronal number, neurite count and neurite length, all of which can indicate neurotoxic effects. However, the role of astrocytes remains unexplored in these models. Astrocytes have an integral role in the maintenance of central nervous system (CNS) homeostasis, and are associated with both neuroprotection and neurodegradation when they are activated in response to toxic substances or disease states. GFAP is an intermediate filament protein expressed predominantly in the astrocytes of the CNS. Astrocytic activation (gliosis) leads to the upregulation of GFAP, commonly accompanied by astrocyte proliferation and hypertrophy. This process of reactive gliosis has been proposed as an early marker of damage to the nervous system. The traditional method for GFAP quantitation is by immunoassay. This approach is limited by an inability to provide information on cellular localization, morphology and cell number. We determined that HCA could be used to overcome these limitations and to simultaneously measure multiple features associated with gliosis - changes in GFAP expression, astrocyte hypertrophy, and astrocyte proliferation - within a single assay. In co

  18. Developmental origins of adult diseases and neurotoxicity: Epidemiological and experimental studies

    DEFF Research Database (Denmark)

    Fox, Donald A; Grandjean, Philippe; de Groot, Didima

    2012-01-01

    and the development of metabolic-related diseases and neurotoxicity later in life. The four speakers at this symposium presented their research results on different neurotoxic chemicals relating to the developmental origins of health and adult disease (DOHaD). Philippe Grandjean presented epidemiological data......To date, only a small number of commercial chemicals have been tested and documented as developmental neurotoxicants. Moreover, an increasing number of epidemiological, clinical and experimental studies suggest an association between toxicant or drug exposure during the perinatal period...

  19. Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

    Science.gov (United States)

    Hettmer, Simone; Li, Zhizhong; Billin, Andrew N.; Barr, Frederic G.; Cornelison, D.D.W.; Ehrlich, Alan R.; Guttridge, Denis C.; Hayes-Jordan, Andrea; Helman, Lee J.; Houghton, Peter J.; Khan, Javed; Langenau, David M.; Linardic, Corinne M.; Pal, Ranadip; Partridge, Terence A.; Pavlath, Grace K.; Rota, Rossella; Schäfer, Beat W.; Shipley, Janet; Stillman, Bruce; Wexler, Leonard H.; Wagers, Amy J.; Keller, Charles

    2014-01-01

    Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called “fusion-positive” tumors) carries exclusive chromosomal translocations that join the DNA-binding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in <30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusion-positive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate

  20. The International Implications of the Development of Microelectronics.

    Science.gov (United States)

    Sieghart, Paul

    1981-01-01

    Synthesizes issues covered at a conference on microelectronics: production, productivity, and employment; social implications; market mechanisms v government intervention; the role of national governments; data protection laws; and cultural pollution. (SW)

  1. Developments of global capital markets and implications to China

    Institute of Scientific and Technical Information of China (English)

    Mr.KevanWatts

    2004-01-01

    Great changes are happening to global capital markets. Those changes will have extensive influences to China. Therefore, China needs to understand their implications and to reflect those trends in setting a framework of policy to deal with this environment.

  2. Neurotoxic Alkaloids: Saxitoxin and Its Analogs

    OpenAIRE

    Mihali, Troco K; Moffitt, Michelle C.; Neilan, Brett A.; Maria Wiese; D’Agostino, Paul M.

    2010-01-01

    Saxitoxin (STX) and its 57 analogs are a broad group of natural neurotoxic alkaloids, commonly known as the paralytic shellfish toxins (PSTs). PSTs are the causative agents of paralytic shellfish poisoning (PSP) and are mostly associated with marine dinoflagellates (eukaryotes) and freshwater cyanobacteria (prokaryotes), which form extensive blooms around the world. PST producing dinoflagellates belong to the genera Alexandrium, Gymnodinium and Pyrodinium whilst production has been identified...

  3. Role of endolysosomes in HIV-1 Tat-induced neurotoxicity

    Directory of Open Access Journals (Sweden)

    Liang Hui

    2012-06-01

    Full Text Available Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder. Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND.

  4. Molecular Mechanism of Acrylamide Neurotoxicity: Lessons Learned from Organic Chemistry

    Science.gov (United States)

    Gavin, Terrence

    2012-01-01

    Background: Acrylamide (ACR) produces cumulative neurotoxicity in exposed humans and laboratory animals through a direct inhibitory effect on presynaptic function. Objectives: In this review, we delineate how knowledge of chemistry provided an unprecedented understanding of the ACR neurotoxic mechanism. We also show how application of the hard and soft, acids and bases (HSAB) theory led to the recognition that the α,β-unsaturated carbonyl structure of ACR is a soft electrophile that preferentially forms covalent bonds with soft nucleophiles. Methods: In vivo proteomic and in chemico studies demonstrated that ACR formed covalent adducts with highly nucleophilic cysteine thiolate groups located within active sites of presynaptic proteins. Additional research showed that resulting protein inactivation disrupted nerve terminal processes and impaired neurotransmission. Discussion: ACR is a type-2 alkene, a chemical class that includes structurally related electrophilic environmental pollutants (e.g., acrolein) and endogenous mediators of cellular oxidative stress (e.g., 4-hydroxy-2-nonenal). Members of this chemical family produce toxicity via a common molecular mechanism. Although individual environmental concentrations might not be toxicologically relevant, exposure to an ambient mixture of type-2 alkene pollutants could pose a significant risk to human health. Furthermore, environmentally derived type-2 alkenes might act synergistically with endogenously generated unsaturated aldehydes to amplify cellular damage and thereby accelerate human disease/injury processes that involve oxidative stress. Conclusions: These possibilities have substantial implications for environmental risk assessment and were realized through an understanding of ACR adduct chemistry. The approach delineated here can be broadly applied because many toxicants of different chemical classes are electrophiles that produce toxicity by interacting with cellular proteins. PMID:23060388

  5. Role of Endolysosomes in HIV-1 Tat-Induced Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Liang Hui

    2012-05-01

    Full Text Available Combined anti-retroviral therapeutic drugs effectively increase the lifespan of HIV-1-infected individuals who then have a higher prevalence of HAND (HIV-1 associated neurocognitive disorder. Soluble factors including HIV-1 proteins released from HIV-1-infected cells have been implicated in the pathogenesis of HAND, and particular attention has been paid to the HIV-1 Tat (transactivator of transcription protein because of its ability to directly excite neurons and cause neuronal cell death. Since HIV-1 Tat enters cells by receptor-mediated endocytosis and since endolysosomes play an important role in neuronal cell life and death, we tested here the hypothesis that HIV-1 Tat neurotoxicity is associated with changes in the endolysosome structure and function and also autophagy. Following the treatment of primary cultured rat hippocampal neurons with HIV-1 Tat or as controls mutant-Tat or PBS, neuronal viability was determined using a triple staining method. Preceding observations of HIV-1 Tat-induced neuronal cell death, we observed statistically significant changes in the structure and membrane integrity of endolysosomes, endolysosome pH and autophagy. As early as 24 h after HIV-1 Tat was applied to neurons, HIV-1 Tat accumulated in endolysosomes, endolysosome morphology was affected and their size increased, endolysosome membrane integrity was disrupted, endolysosome pH increased, specific activities of endolysosome enzymes decreased and autophagy was inhibited, as indicated by the significant changes in three markers for autophagy. In contrast, statistically significant levels of HIV-1 Tat-induced neuronal cell death were observed only after 48 h of HIV-1 Tat treatment. Our findings suggest that endolysosomes are involved in HIV-1 Tat-induced neurotoxicity and may represent a target for therapeutic intervention against HAND.

  6. Neurotoxicity of Acrylamide in Exposed Workers

    Science.gov (United States)

    Pennisi, Manuela; Malaguarnera, Giulia; Puglisi, Valentina; Vinciguerra, Luisa; Vacante, Marco; Malaguarnera, Mariano

    2013-01-01

    Acrylamide (ACR) is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies. PMID:23985770

  7. Neurotoxicity of Acrylamide in Exposed Workers

    Directory of Open Access Journals (Sweden)

    Mariano Malaguarnera

    2013-08-01

    Full Text Available Acrylamide (ACR is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies.

  8. Current View in Platinum Drug Mechanisms of Peripheral Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Alessia Chiorazzi

    2015-08-01

    Full Text Available Peripheral neurotoxicity is the dose-limiting factor for clinical use of platinum derivatives, a class of anticancer drugs which includes cisplatin, carboplatin, and oxaliplatin. In particular cisplatin and oxaliplatin induce a severe peripheral neurotoxicity while carboplatin is less neurotoxic. The mechanisms proposed to explain these drugs’ neurotoxicity are dorsal root ganglia alteration, oxidative stress involvement, and mitochondrial dysfunction. Oxaliplatin also causes an acute and reversible neuropathy, supposed to be due by transient dysfunction of the voltage-gated sodium channels of sensory neurons. Recent studies suggest that individual genetic variation may play a role in the pathogenesis of platinum drug neurotoxicity. Even though all these mechanisms have been investigated, the pathogenesis is far from clearly defined. In this review we will summarize the current knowledge and the most up-to-date hypotheses on the mechanisms of platinum drug-induced peripheral neurotoxicity.

  9. Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria.

    Science.gov (United States)

    Xu, Shangcheng; Pi, Huifeng; Zhang, Lei; Zhang, Nixian; Li, YuMing; Zhang, Huiliang; Tang, Ju; Li, Huijuan; Feng, Min; Deng, Ping; Guo, Pan; Tian, Li; Xie, Jia; He, Mindi; Lu, Yonghui; Zhong, Min; Zhang, Yanwen; Wang, Wang; Reiter, Russel J; Yu, Zhengping; Zhou, Zhou

    2016-04-01

    Cadmium (Cd) is a persistent environmental toxin and occupational pollutant that is considered to be a potential risk factor in the development of neurodegenerative diseases. Abnormal mitochondrial dynamics are increasingly implicated in mitochondrial damage in various neurological pathologies. The aim of this study was to investigate whether the disturbance of mitochondrial dynamics contributed to Cd-induced neurotoxicity and whether melatonin has any neuroprotective properties. After cortical neurons were exposed to 10 μM cadmium chloride (CdCl2 ) for various periods (0, 3, 6, 12, and 24 hr), the morphology of their mitochondria significantly changed from the normal tubular networks into punctuated structures within 3 hr. Following this pronounced mitochondrial fragmentation, Cd treatment led to signs of mitochondrial dysfunction, including excess reactive oxygen species (ROS) production, decreased ATP content, and mitochondrial membrane potential (▵Ψm) loss. However, 1 mM melatonin pretreatment efficiently attenuated the Cd-induced mitochondrial fragmentation, which improved the turnover of mitochondrial function. In the brain tissues of rats that were intraperitoneally given 1 mg/kg CdCl2 for 7 days, melatonin also ameliorated excessive mitochondrial fragmentation and mitochondrial damage in vivo. Melatonin's protective effects were attributed to its roles in preventing cytosolic calcium ([Ca(2+) ]i ) overload, which blocked the recruitment of Drp1 from the cytoplasm to the mitochondria. Taken together, our results are the first to demonstrate that abnormal mitochondrial dynamics is involved in cadmium-induced neurotoxicity. Melatonin has significant pharmacological potential in protecting against the neurotoxicity of Cd by blocking the disbalance of mitochondrial fusion and fission.

  10. A holistic view of anesthesia-related neurotoxicity in children

    Directory of Open Access Journals (Sweden)

    Clausen NG

    2015-11-01

    Full Text Available Nicola G Clausen, Tom G Hansen Department of Anesthesia and Intensive Care, Odense University Hospital, Odense, Denmark Introduction: Animal studies (including in nonhuman primates have shown that most general anesthetics cause enhanced neuroapoptosis in the immature brain with subsequent long-term neurocognitive deficits later in life. Whether human neurons are equally affected is yet unknown, but a final answer to this issue is still pending. To date, most human studies within the field are of observational nature and the results are conflicting. Some studies indicate an association between exposure to anesthesia and surgery while others do not. Objective: This review summarizes results from preclinical and observational studies. Controversies and challenges regarding the interpretation of these results are presented. Crucial aspects of neurocognitive safety during pediatric anesthesia and surgery are highlighted. International initiatives aiming to improve the safe conductance of pediatric anesthesia are introduced. Conclusion: So far, anesthesia-related neurotoxicity in humans remains an area of concern but it cannot be completely excluded. Clinical practice should not be changed until there are definite proofs that anesthetic exposure causes neurocognitive impairment later in life. Withholding necessary and timely surgeries as a consequence of any such concerns could result in worse harm. Focus of current research should also be redirected to include other factors, than merely anesthetics and surgery, that influence the neurocognitive safety of children perioperatively. Keywords: pediatric anesthesia, neurotoxicity, anesthesia safety, neurocognitive development 

  11. Mitochondria: key players in the neurotoxic effects of amphetamines.

    Science.gov (United States)

    Barbosa, Daniel José; Capela, João Paulo; Feio-Azevedo, Rita; Teixeira-Gomes, Armanda; Bastos, Maria de Lourdes; Carvalho, Félix

    2015-10-01

    Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.

  12. A Case of Neurotoxicity Following 5-Fluorouracil-based Chemotherapy

    Science.gov (United States)

    Ki, Seung Seog; Jeong, Jin Mo; Kim, Seong Ho; Jeong, Sook Hyang; Lee, Jin Hyuk; Han, Chul Ju; Kim, You Cheol; Lee, Jhin Oh; Hong, Young Joon

    2002-01-01

    5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy. PMID:12014219

  13. Cognitive Moral Development and Clinical Performance: Implications for Pharmacy Education.

    Science.gov (United States)

    Latif, David A.; Berger, Bruce A.

    1999-01-01

    A study explored the notion that moral reasoning skills are important to the provision of pharmaceutical care. It compared the moral reasoning skills of two classes of pharmacy students with those of practitioners who scored high on measures of pharmaceutical care and clinical decision making. Implications for pharmacy school admissions and…

  14. Local Citation Analysis of Graduate Biology Theses: Collection Development Implications

    Science.gov (United States)

    Miller, Laura Newton

    2011-01-01

    This paper will focus on the citation analysis of graduate masters theses from Carleton University's Biology Department with implications for library collection management decisions. Twenty-five masters theses were studied to determine citation types and percentages, ranking of journals by frequency of citation and by number of authors citing, and…

  15. Cognitive Moral Development and Clinical Performance: Implications for Pharmacy Education.

    Science.gov (United States)

    Latif, David A.; Berger, Bruce A.

    1999-01-01

    A study explored the notion that moral reasoning skills are important to the provision of pharmaceutical care. It compared the moral reasoning skills of two classes of pharmacy students with those of practitioners who scored high on measures of pharmaceutical care and clinical decision making. Implications for pharmacy school admissions and…

  16. Behavioral Momentum: Implications and Development from Reinforcement Theories.

    Science.gov (United States)

    Plaud, Joseph J.; Gaither, George A.

    1996-01-01

    Analyzes historical and contemporary theories of reinforcement and clinical application of reinforcement principles to behavior and modification therapy. Presents a behavioral momentum model that studies the allocation of behavior under changed environmental constraints and discusses the implications of this model on behavior modification and…

  17. Neurotoxicity of Thyroid Disrupting Contaminants

    Science.gov (United States)

    Thyroid hormones playa critical role in the normal development ofthe mammalian brain. Thyroid disrupting chemicals (TDCs) are environmental contaminants that alter the structure or function ofthe thyroid gland, alter regulatory enzymes associated with thyroid hormone (TH) homeost...

  18. Exploring Writing In The Workplace: Implications For Human Resource Development

    OpenAIRE

    AKDERE, Dr. Mesut; AZEVEDO, Dr.Ross E.

    2010-01-01

    Writing in the workplace is among the understudied business topics in the field of HRD. Yet, the impacts of writing in today's workplace are significant, and organizations making it a priority benefit from it. Furthermore, writing is related to the issue of workplace literacy which is the umbrella term for basic communication skills. This literature review provides a general view on workplace writing and discusses implications to HRD within a model research proposal

  19. Ecological network analysis for economic systems: growth and development and implications for sustainable development.

    Science.gov (United States)

    Huang, Jiali; Ulanowicz, Robert E

    2014-01-01

    The quantification of growth and development is an important issue in economics, because these phenomena are closely related to sustainability. We address growth and development from a network perspective in which economic systems are represented as flow networks and analyzed using ecological network analysis (ENA). The Beijing economic system is used as a case study and 11 input-output (I-O) tables for 1985-2010 are converted into currency networks. ENA is used to calculate system-level indices to quantify the growth and development of Beijing. The contributions of each direct flow toward growth and development in 2010 are calculated and their implications for sustainable development are discussed. The results show that during 1985-2010, growth was the main attribute of the Beijing economic system. Although the system grew exponentially, its development fluctuated within only a small range. The results suggest that system ascendency should be increased in order to favor more sustainable development. Ascendency can be augmented in two ways: (1) strengthen those pathways with positive contributions to increasing ascendency and (2) weaken those with negative effects.

  20. Perspectives on the Present State and Future of Higher Education Faculty Development in Kazakhstan: Implications for National Human Resource Development

    Science.gov (United States)

    Seitova, Dinara

    2016-01-01

    The article aims at examining the present state of higher education faculty development in Kazakhstan in the context of multidimensional nationwide development reforms and exploring implications for the National Human Resource Development of the country. For the purpose of this research, theoretical human resource development (HRD) and…

  1. Charge Nurses' Experiences With Horizontal Violence: Implications for Leadership Development.

    Science.gov (United States)

    Longo, Joy; Cassidy, Linda; Sherman, Rose

    2016-11-01

    HOW TO OBTAIN CONTACT HOURS BY READING THIS ISSUE Instructions: 1.2 contact hours will be awarded by Villanova University College of Nursing upon successful completion of this activity. A contact hour is a unit of measurement that denotes 60 minutes of an organized learning activity. This is a learner-based activity. Villanova University College of Nursing does not require submission of your answers to the quiz. A contact hour certificate will be awarded after you register, pay the registration fee, and complete the evaluation form online at http://goo.gl/gMfXaf. In order to obtain contact hours you must: 1. Read the article, "Charge Nurses' Experiences With Horizontal Violence: Implications for Leadership Development," found on pages 493-499, carefully noting any tables and other illustrative materials that are included to enhance your knowledge and understanding of the content. Be sure to keep track of the amount of time (number of minutes) you spend reading the article and completing the quiz. 2. Read and answer each question on the quiz. After completing all of the questions, compare your answers to those provided within this issue. If you have incorrect answers, return to the article for further study. 3. Go to the Villanova website to register for contact hour credit. You will be asked to provide your name, contact information, and a VISA, MasterCard, or Discover card number for payment of the $20.00 fee. Once you complete the online evaluation, a certificate will be automatically generated. This activity is valid for continuing education credit until October 31, 2019. CONTACT HOURS This activity is co-provided by Villanova University College of Nursing and SLACK Incorporated. Villanova University College of Nursing is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. OBJECTIVES Describe types of horizontal violence experienced by charge nurses. Identify the skills needed for

  2. Implications of research on infant development for psychodynamic theory and practice.

    Science.gov (United States)

    Zeanah, C H; Anders, T F; Seifer, R; Stern, D N

    1989-09-01

    Recent research on infant development is reviewed to consider its implications for psychodynamic theory and practice. To address the question of the importance of early experiences for development, research on continuities and discontinuities in development, temperament, motivational systems in infancy, affect development and regulation, development of the sense of self, and infant-caregiver attachment are reviewed. Two major implications emerge, both emphasizing the need for more complexities in our conceptualizations. First, research on infant development underscores the importance of context in development and cautions about the limits of reductionistic thinking and theories. Second a major paradigmatic shift away from the fixation-regression model of psychopathology and development is indicated. A new model that better fits available data is proposed instead. In this continuous construction model, there is no need for regression, and ontogenetic origins of psychopathology are no longer necessarily tied to specific critical or sensitive periods in development. Implications for psychodynamic treatment are also described.

  3. Reappraisal of Vipera aspis venom neurotoxicity.

    Directory of Open Access Journals (Sweden)

    Elisabeth Ferquel

    Full Text Available BACKGROUND: The variation of venom composition with geography is an important aspect of intraspecific variability in the Vipera genus, although causes of this variability remain unclear. The diversity of snake venom is important both for our understanding of venomous snake evolution and for the preparation of relevant antivenoms to treat envenomations. A geographic intraspecific variation in snake venom composition was recently reported for Vipera aspis aspis venom in France. Since 1992, cases of human envenomation after Vipera aspis aspis bites in south-east France involving unexpected neurological signs were regularly reported. The presence of genes encoding PLA(2 neurotoxins in the Vaa snake genome led us to investigate any neurological symptom associated with snake bites in other regions of France and in neighboring countries. In parallel, we used several approaches to characterize the venom PLA(2 composition of the snakes captured in the same areas. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an epidemiological survey of snake bites in various regions of France. In parallel, we carried out the analysis of the genes and the transcripts encoding venom PLA(2s. We used SELDI technology to study the diversity of PLA(2 in various venom samples. Neurological signs (mainly cranial nerve disturbances were reported after snake bites in three regions of France: Languedoc-Roussillon, Midi-Pyrénées and Provence-Alpes-Côte d'Azur. Genomes of Vipera aspis snakes from south-east France were shown to contain ammodytoxin isoforms never described in the genome of Vipera aspis from other French regions. Surprisingly, transcripts encoding venom neurotoxic PLA(2s were found in snakes of Massif Central region. Accordingly, SELDI analysis of PLA(2 venom composition confirmed the existence of population of neurotoxic Vipera aspis snakes in the west part of the Massif Central mountains. CONCLUSIONS/SIGNIFICANCE: The association of epidemiological studies to

  4. Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

    Directory of Open Access Journals (Sweden)

    Mayado Andrea

    2011-11-01

    Full Text Available Abstract Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p. 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.. IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v. prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA.

  5. Involvement of Programmed Cell Death in Neurotoxicity of Metallic Nanoparticles: Recent Advances and Future Perspectives

    Science.gov (United States)

    Song, Bin; Zhou, Ting; Liu, Jia; Shao, LongQuan

    2016-11-01

    The widespread application of metallic nanoparticles (NPs) or NP-based products has increased the risk of exposure to NPs in humans. The brain is an important organ that is more susceptible to exogenous stimuli. Moreover, any impairment to the brain is irreversible. Recently, several in vivo studies have found that metallic NPs can be absorbed into the animal body and then translocated into the brain, mainly through the blood-brain barrier and olfactory pathway after systemic administration. Furthermore, metallic NPs can cross the placental barrier to accumulate in the fetal brain, causing developmental neurotoxicity on exposure during pregnancy. Therefore, metallic NPs become a big threat to the brain. However, the mechanisms underlying the neurotoxicity of metallic NPs remain unclear. Programmed cell death (PCD), which is different from necrosis, is defined as active cell death and is regulated by certain genes. PCD can be mainly classified into apoptosis, autophagy, necroptosis, and pyroptosis. It is involved in brain development, neurodegenerative disorders, psychiatric disorders, and brain injury. Given the pivotal role of PCD in neurological functions, we reviewed relevant articles and tried to summarize the recent advances and future perspectives of PCD involvement in the neurotoxicity of metallic NPs, with the purpose of comprehensively understanding the neurotoxic mechanisms of NPs.

  6. Copper in Alzheimer's disease: Implications in amyloid aggregation and neurotoxicity

    Science.gov (United States)

    Gamez, Patrick; Caballero, Ana B.

    2015-09-01

    The relationship of copper dyshomeostasis with neurodegenerative diseases has become evident in the last years. Because of the major role that this metal ion plays in biological processes, most of which being located in the brain, it is not surprising that changes in its distribution are closely related with the advent of neurodegenerative disorders such as Alzheimer's disease (AD). An increasing number of works have dealt with this subject in the last years, and opened an intense debate in some points while raising new questions that still remain unanswered. This revision work puts together and discusses the latest findings and insights on how copper ions are involved in AD progression, including its interaction with Aβ and its consequently induced aggregation.

  7. Environmental Compliance Costs in Developed Country Agricultures: Implications for Trade and Competitiveness

    NARCIS (Netherlands)

    Fox, G.; Brouwer, F.M.

    2012-01-01

    This chapter reflects on the costs of compliance with environmental regulations and standards in agriculture in developed countries, and its implications for trade and competitiveness. It highlights the importance of enforcement mechanisms and implementation, subjects which often have been undervalu

  8. 40 CFR 799.9620 - TSCA neurotoxicity screening battery.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true TSCA neurotoxicity screening battery... REQUIREMENTS Health Effects Test Guidelines § 799.9620 TSCA neurotoxicity screening battery. (a) Scope. This... battery consists of a functional observational battery, motor activity, and neuropathology. The functional...

  9. Modifying welding process parameters can reduce the neurotoxic potential of manganese-containing welding fumes.

    Science.gov (United States)

    Sriram, Krishnan; Lin, Gary X; Jefferson, Amy M; Stone, Samuel; Afshari, Aliakbar; Keane, Michael J; McKinney, Walter; Jackson, Mark; Chen, Bean T; Schwegler-Berry, Diane; Cumpston, Amy; Cumpston, Jared L; Roberts, Jenny R; Frazer, David G; Antonini, James M

    2015-02-03

    Welding fumes (WF) are a complex mixture of toxic metals and gases, inhalation of which can lead to adverse health effects among welders. The presence of manganese (Mn) in welding electrodes is cause for concern about the potential development of Parkinson's disease (PD)-like neurological disorder. Consequently, from an occupational safety perspective, there is a critical need to prevent adverse exposures to WF. As the fume generation rate and physicochemical characteristics of welding aerosols are influenced by welding process parameters like voltage, current or shielding gas, we sought to determine if changing such parameters can alter the fume profile and consequently its neurotoxic potential. Specifically, we evaluated the influence of voltage on fume composition and neurotoxic outcome. Rats were exposed by whole-body inhalation (40 mg/m(3); 3h/day × 5 d/week × 2 weeks) to fumes generated by gas-metal arc welding using stainless steel electrodes (GMA-SS) at standard/regular voltage (25 V; RVSS) or high voltage (30 V; HVSS). Fumes generated under these conditions exhibited similar particulate morphology, appearing as chain-like aggregates; however, HVSS fumes comprised of a larger fraction of ultrafine particulates that are generally considered to be more toxic than their fine counterparts. Paradoxically, exposure to HVSS fumes did not elicit dopaminergic neurotoxicity, as monitored by the expression of dopaminergic and PD-related markers. We show that the lack of neurotoxicity is due to reduced solubility of Mn in HVSS fumes. Our findings show promise for process control procedures in developing prevention strategies for Mn-related neurotoxicity during welding; however, it warrants additional investigations to determine if such modifications can be suitably adapted at the workplace to avert or reduce adverse neurological risks.

  10. Post-Deployment Reintegration Experiences of AF Personnel: Implications for Scale Development

    Science.gov (United States)

    2006-09-01

    Post-deployment reintegration experiences of AF personnel: Implications for scale development Ann-Renée Blais Wendy Sullivan-Kwantes Donald...la défense Canada DEFENCE DÉFENSE & Post-deployment reintegration experiences of AF personnel: Implications for scale development Ann...ministre de la Défense nationale, 2006 DRDC Toronto TR 2006-304 i Abstract The process of post-deployment reintegration can lead to

  11. Teacher frustration and professional development: Causes, consequences and practical implications

    DEFF Research Database (Denmark)

    Noesgaard, Signe Schack

    2017-01-01

    The influence of frustration on the effectiveness of teacher professional development has previously been overlooked. This study of in-service teachers who become frustrated during professional development interventions considers the development of two Danish science teachers. Frustration theory...

  12. Effects of potential neurotoxic pesticides on hearing loss: a review.

    Science.gov (United States)

    Gatto, M P; Fioretti, M; Fabrizi, G; Gherardi, M; Strafella, E; Santarelli, L

    2014-05-01

    Several pesticides are supposed to be neurotoxic for humans, consequently, they may also affect the auditory system. This review analyzes human and experimental animal studies testing the hypothesis that exposure to pesticides is associated with hearing loss. The literature on this topic is still sparse and methodological limitations of some papers evaluated are identified. As a whole, available data indicate a possible ototoxic action of pesticides, but alternative hypotheses could not be ruled out, also considering some confounders, such as the co-exposure to noise. Therefore, further studies are necessary in order to clarify the association between pesticides exposure and hearing loss. While awaiting more evidence, for precautionary action we recommend considering pesticides as possible ototoxic agents, in particular for vulnerable targets, such as pregnant women and children during early development.

  13. Neurotoxicity of general anesthetics: A modern view of the problem

    Directory of Open Access Journals (Sweden)

    A. M. Ovezov

    2015-01-01

    Full Text Available All general anesthetics routinely used in clinical practice are noted to have a neurotoxic effect on the brain in different animal species including primates. The negative effects observed both in young and sexually mature animals include apoptotic neuronal cell death, suppression of neurogenesis and gliogenesis, neuroinflammation, as well as learning and memory impairments. A number of epidemiologic surveys have established an association between anesthesia in patients younger than 3 to 4 years and subsequent learning disabilities and language disorders whereas others have not found this link. In middle-aged and elderly patients, anesthesia is frequently associated with the development of postoperative cognitive dysfunction. The key component of its pathogenesis (general anesthesia itself or other factors, such as operative injury, an inflammatory response, pain syndrome, intraoperative complications, underlying disease in a patient remains unelucidated. It is concluded that there is a need for additional experimental and clinical studies of the pathogenesis of these undesirable phenomena to be prevented and corrected.

  14. Prion protein oligomer and its neurotoxicity

    Institute of Scientific and Technical Information of China (English)

    Pei Huang; Fulin Lian; Yi Wen; Chenyun Guo; Donghai Lin

    2013-01-01

    The prion diseases,also known as transmissible spongiform encephalopathies,are fatal neurodegenerative disorders.According to the 'protein only' hypothesis,the key molecular event in the pathogenesis of prion disease is the conformational conversion of the host-derived cellular prion protein (PrPC) into a misfolded form (scrapie PrP,prpSc).Increasing evidence has shown that the most infectious factor is the smaller subfibrillar oligomers formed by prion proteins.Both the prion oligomer and PrPSc are rich in β-sheet structure and resistant to the proteolysis of proteinase K.The prion oligomer is soluble in physiologic environments whereas PrPSc is insoluble.Various prion oligomers are formed in different conditions.Prion oligomers exhibited more neurotoxicity both in vitro and in vivo than the fibrillar forms of PrPSc,implying that prion oligomers could be potential drug targets for attacking prion diseases.In this article,we describe recent experimental evidence regarding prion oligomers,with a special focus on prion oligomer formation and its neurotoxicity.

  15. Neurotoxicity of Dietary Supplements from Annonaceae Species.

    Science.gov (United States)

    Höllerhage, Matthias; Rösler, Thomas W; Berjas, Magda; Luo, Rensheng; Tran, Kevin; Richards, Kristy M; Sabaa-Srur, Armando U; Maia, José Guilherme S; Moraes, Maria Rosa de; Godoy, Helena T; Höglinger, Günter U; Smith, Robert E

    2015-01-01

    Dietary supplements containing plant materials of Annonaceae species (Annona muricata L., A. squamosa L., A. mucosa JACQ., A. squamosa × cherimola Mabb.) were extracted by hot, pressurized ethyl acetate and analyzed for their effect in vitro on Lund human mesencephalic neurons. Cell viability was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell death was determined by lactate dehydrogenase levels. Three supplements strongly decreased the cell viability at extract concentrations of 1 µg/mL, of which 1 decreased cell viability at 0.1 µg/µL. Also, strong neuronal toxicities of these supplements were found. Cell death was observed at concentrations of 10 µg/mL. The degree of toxicity was comparable to the ones found in Annonaceous fruit extracts. Two fruit pulps of Annonaceae (A. muricata and A. squamosa) showed a reduction in cell viability at lower concentrations. The fruit pulp extract of A. muricata revealed the strongest neurotoxic effect, with 67% cell death at a concentration of 1 µg/mL. A high reduction in cell viability coupled with pronounced cell death was found at 0.1 µg/mL for an Annonaceous seed extract. These results demonstrate that the intake of dietary supplements containing plant material from Annonaceae may be hazardous to health in terms of neurotoxicity.

  16. Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity.

    Directory of Open Access Journals (Sweden)

    James P O'Callaghan

    Full Text Available Astrogliosis, a cellular response characterized by astrocytic hypertrophy and accumulation of GFAP, is a hallmark of all types of central nervous system (CNS injuries. Potential signaling mechanisms driving the conversion of astrocytes into "reactive" phenotypes differ with respect to the injury models employed and can be complicated by factors such as disruption of the blood-brain barrier (BBB. As denervation tools, neurotoxicants have the advantage of selective targeting of brain regions and cell types, often with sparing of the BBB. Previously, we found that neuroinflammation and activation of the JAK2-STAT3 pathway in astrocytes precedes up regulation of GFAP in the MPTP mouse model of dopaminergic neurotoxicity. Here we show that multiple mechanistically distinct mouse models of neurotoxicity (MPTP, AMP, METH, MDA, MDMA, KA, TMT engender the same neuroinflammatory and STAT3 activation responses in specific regions of the brain targeted by each neurotoxicant. The STAT3 effects seen for TMT in the mouse could be generalized to the rat, demonstrating cross-species validity for STAT3 activation. Pharmacological antagonists of the neurotoxic effects blocked neuroinflammatory responses, pSTAT3tyr705 and GFAP induction, indicating that damage to neuronal targets instigated astrogliosis. Selective deletion of STAT3 from astrocytes in STAT3 conditional knockout mice markedly attenuated MPTP-induced astrogliosis. Monitoring STAT3 translocation in GFAP-positive cells indicated that effects of MPTP, METH and KA on pSTAT3tyr705 were localized to astrocytes. These findings strongly implicate the STAT3 pathway in astrocytes as a broadly triggered signaling pathway for astrogliosis. We also observed, however, that the acute neuroinflammatory response to the known inflammogen, LPS, can activate STAT3 in CNS tissue without inducing classical signs of astrogliosis. Thus, acute phase neuroinflammatory responses and neurotoxicity-induced astrogliosis both

  17. The Portland Neurotoxicity Scale: Validation of a Brief Self-Report Measure of Antiepileptic-Drug-Related Neurotoxicity

    Science.gov (United States)

    Salinsky, Martin C.; Storzbach, Daniel

    2005-01-01

    The Portland Neurotoxicity Scale (PNS) is a brief patient-based survey of neurotoxicity complaints commonly encountered with the use of antiepileptic drugs (AEDs). The authors present data on the validity of this scale, particularly when used in longitudinal studies. Participants included 55 healthy controls, 23 epilepsy patient controls, and 86…

  18. A review on potential neurotoxicity of titanium dioxide nanoparticles

    Science.gov (United States)

    Song, Bin; Liu, Jia; Feng, Xiaoli; Wei, Limin; Shao, Longquan

    2015-08-01

    As the rapid development of nanotechnology in the past three decades, titanium dioxide nanoparticles (TiO2 NPs), for their peculiar physicochemical properties, are widely applied in consumer products, food additives, cosmetics, drug carriers, and so on. However, little is known about their potential exposure and neurotoxic effects. Once NPs are unintentionally exposed to human beings, they could be absorbed, and then accumulated in the brain regions by passing through the blood-brain barrier (BBB) or through the nose-to-brain pathway, potentially leading to dysfunctions of central nerve system (CNS). Besides, NPs may affect the brain development of embryo by crossing the placental barrier. A few in vivo and in vitro researches have demonstrated that the morphology and function of neuronal or glial cells could be impaired by TiO2 NPs which might induce cell necrosis. Cellular components, such as mitochondrial, lysosome, and cytoskeleton, could also be influenced as well. The recognition ability, spatial memory, and learning ability of TiO2 NPs-treated rodents were significantly impaired, which meant that accumulation of TiO2 NPs in the brain could lead to neurodegeneration. However, conclusions obtained from those studies were not consistent with each other as researchers may choose different experimental parameters, including administration ways, dosage, size, and crystal structure of TiO2 NPs. Therefore, in order to fully understand the potential risks of TiO2 NPs to brain health, figure out research areas where further studies are required, and improve its bio-safety for applications in the near future, how TiO2 NPs interact with the brain is investigated in this review by summarizing the current researches on neurotoxicity induced by TiO2 NPs.

  19. Cognitive competence as a positive youth development construct: conceptual bases and implications for curriculum development.

    Science.gov (United States)

    Sun, Rachel C F; Hui, Eadaoin K P

    2006-01-01

    This paper outlines the conceptual bases of "cognitive competence" as a positive youth development construct and the implications for curriculum development. Cognitive competence refers to the cognitive processes that comprise (i) creative thinking, which includes various creative thinking styles, such as legislative, global, and local thinking styles; and (ii) critical thinking, which includes reasoning, making inferences, self-reflection, and coordination of multiple views. Based on the adolescent development progression on cognitive competence, and with reference to Hong Kong Chinese context, six units are designed to promote creative and critical thinking for Secondary 1-3 students in the Project P.A.T.H.S., supported by the Hong Kong Jockey Club Charities Trust. In the Secondary 1 curriculum, the goals of the units are to enable students to recognize different but inter-related thinking styles and to apply these thinking skills to deal with daily life issues. The goal in the Secondary 2 curriculum is to enhance students' creative thinking skills to solve problems, whereas the goal in the Secondary 3 curriculum is to enhance students' critical thinking skills to accept beliefs and make decisions.

  20. The extended trajectory of hippocampal development: Implications for early memory development and disorder.

    Science.gov (United States)

    Gómez, Rebecca L; Edgin, Jamie O

    2016-04-01

    Hippocampus has an extended developmental trajectory, with refinements occurring in the trisynaptic circuit until adolescence. While structural change should suggest a protracted course in behavior, some studies find evidence of precocious hippocampal development in the first postnatal year and continuity in memory processes beyond. However, a number of memory functions, including binding and relational inference, can be cortically supported. Evidence from the animal literature suggests that tasks often associated with hippocampus (visual paired comparison, binding of a visuomotor response) can be mediated by structures external to hippocampus. Thus, a complete examination of memory development will have to rule out cortex as a source of early memory competency. We propose that early memory must show properties associated with full function of the trisynaptic circuit to reflect "adult-like" memory function, mainly (1) rapid encoding of contextual details of overlapping patterns, and (2) retention of these details over sleep-dependent delays. A wealth of evidence suggests that these functions are not apparent until 18-24 months, with behavioral discontinuities reflecting shifts in the neural structures subserving memory beginning approximately at this point in development. We discuss the implications of these observations for theories of memory and for identifying and measuring memory function in populations with typical and atypical hippocampal function.

  1. Theories of Equity in Health Care, Implications for Developed and Developing Countries

    Directory of Open Access Journals (Sweden)

    AR Olyaee Manesh

    2005-10-01

    Full Text Available Objective: This abstract focuses on theoretical background for the notion of “equity in health care” and on the implications of applying these theories to the health care of developed and developing countries. Equity Principals and the Implications: There are different theories about the principle of Equity or Justice such as Altruism, Utilitarians, Marxists, Rawls’ theory and Nazick’s entitlement. Among these theories, some of them are applicable to health care such as Libertarianism and Egalitarianism. The focus of the Libertarians is on the extent to which people are free to purchase the health care that they want. The Libertarians’ principle is the main equity base for private health systems. In contrast, Egalitarians suggest that finance of the health care should be according to the ability to pay and distribution of health care should be according to the need (ill health. It seems that policy makers in most developed countries such as European countries accept the Egalitarians’ principle and application of this equity principle by their health systems has significantly reduced health inequities and inequalities in these countries. There are a limited number of studies to look at equity in the health care of developing countries. A common equity principle for these countries is “equal access for everyone” and different mechanisms are applied to attain this target. Despite the overall improvements in health care in recent years, evidence indicates that many of developing countries have failed to provide equal access to health care for all in need. The financial limitations of the governments, spending about 70% of the health care resources on hospital-based care, unequal access to hospital services in favour of urban population, income inequalities among population, and lack of consistent and up-to-date information of inequalities, make developing countries unable to monitor and prevent inequities and inequalities of health

  2. Implications of Climate Change for Children in Developing Countries

    Science.gov (United States)

    Hanna, Rema; Oliva, Paulina

    2016-01-01

    Climate change may be particularly dangerous for children in developing countries. Even today, many developing countries experience a disproportionate share of extreme weather, and they are predicted to suffer disproportionately from the effects of climate change in the future. Moreover, developing countries often have limited social safety nets,…

  3. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity.

    Science.gov (United States)

    Vilela, Luciano R; Gobira, Pedro H; Viana, Thercia G; Medeiros, Daniel C; Ferreira-Vieira, Talita H; Doria, Juliana G; Rodrigues, Flávia; Aguiar, Daniele C; Pereira, Grace S; Massessini, André R; Ribeiro, Fabíola M; de Oliveira, Antonio Carlos P; Moraes, Marcio F D; Moreira, Fabricio A

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity.

  4. When Research Meets Development: Antecedents and Implications of Transfer Speed

    OpenAIRE

    Du, Jingshu; Leten, Bart; Vanhaverbeke, Wim; Lopez-Vega, Henry

    2014-01-01

    This paper focuses on the organization of new product development in large, R&D-intensive firms. In these firms, research and development activities are often separated. Research is conducted in dedicated research projects at specialized research labs. Once research results are achieved by research projects, they are transferred to business units for further development and commercialization. We investigate the speed whereby research projects transfer their first research results to busin...

  5. Men's Identity Development: Issues and Implications for Residence Life

    Science.gov (United States)

    Scott, David A.; Livingston, Wade G.; Havice, Pamela A.; Cawthon, Tony W.

    2012-01-01

    Young men struggle with privilege and oppression in college and university residence halls just as they do in other educational and social contexts. While discussions and research about adolescent and adult identity development continue, little attention has focused on how a male student's identity development can impact residence life cultures on…

  6. Implications of Bilingual Development for Specific Language Impairments in Turkey

    Science.gov (United States)

    Topbas, Seyhun

    2011-01-01

    The potential impact of bilingualism on children's language development has emerged as a crucial concern for Turkey, but so far it has not been addressed from the point of view of language disorders. This short review examines the potential impact of bilingual language development for language impairments in Turkey, with special emphasis on the…

  7. Men's Identity Development: Issues and Implications for Residence Life

    Science.gov (United States)

    Scott, David A.; Livingston, Wade G.; Havice, Pamela A.; Cawthon, Tony W.

    2012-01-01

    Young men struggle with privilege and oppression in college and university residence halls just as they do in other educational and social contexts. While discussions and research about adolescent and adult identity development continue, little attention has focused on how a male student's identity development can impact residence life cultures on…

  8. Toward an Integrated Approach to Positive Development: Implications for Intervention

    Science.gov (United States)

    Tolan, Patrick; Ross, Katherine; Arkin, Nora; Godine, Nikki; Clark, Erin

    2016-01-01

    Positive development models shift focus for intervention from avoiding problems, deficits, or psychopathology to promoting skills, assets, and psychological well-being as the critical interests in development and intervention. The field can be characterized as multiple parallel lines of empirical inquiry from four frameworks: Social Competence,…

  9. Macroeconomic pressures and their implications for business development in Africa

    DEFF Research Database (Denmark)

    Kuada, John

    2011-01-01

    The paper discusses the complex relationships between macroeconomic pressures, savings, investments and business development in Sub-Sahara African countries......The paper discusses the complex relationships between macroeconomic pressures, savings, investments and business development in Sub-Sahara African countries...

  10. Implications for a Green Curriculum Application toward Sustainable Development

    Science.gov (United States)

    Sahin, Elvan; Ertepinar, Hamide; Teksoz, Gaye

    2009-01-01

    The aim of present study was two-fold: (1) to determine university students' familiarity and understandings of "sustainable development", (2) to examine their attitudes toward sustainable development, environmental values, and their behaviors toward sustainable life styles. The data collected by on-line administration of a questionnaire…

  11. The neurotoxicity of pyridinium metabolites of haloperidol

    Directory of Open Access Journals (Sweden)

    Agnieszka Górska

    2015-10-01

    Full Text Available Haloperydol is a butyrophenone, typical neuroleptic agent characterized as a high antipsychotics effects in the treatment of schizophrenia and in palliative care to alleviation many syndromes, such as naursea, vomiting and delirium. Clinical problems occurs during and after administration of the drug are side effects, particularly extrapyrramidal symptoms (EPS. The neurotoxicity of haloperydol may be initiated by the cationic metabolites of haloperydol, HPP+, RHPP+, formed by oxidation and reduction pathways. These metabolites are transported by human organic cation transporters (hOCT to several brain structures for exapmle, in substantia nigra, striatum, caudate nucleus, hippocampus. After reaching the dopaminergic neurons inhibits mitochondrial complex I, evidence for free radical involvement, thus leading to neurodegeneration.

  12. [Link between aluminum neurotoxicity and neurodegenerative disorders].

    Science.gov (United States)

    Kawahara, Masahiro

    2016-07-01

    Aluminum is an old element that has been known for a long time, but some of its properties are only now being discovered. Although environmentally abundant, aluminum is not essential for life; in fact, because of its specific chemical properties, aluminum inhibits more than 200 biologically important functions and exerts various adverse effects in plants, animals, and humans. Aluminum is a widely recognized neurotoxin. It has been suggested that there is a relationship between exposure to aluminum and neurodegenerative diseases, including dialysis encephalopathy, amyotrophic lateral sclerosis and parkinsonism dementia in the Kii Peninsula and Guam, as well as Alzheimer' s disease: however, this claim remains to be verified. In this chapter, we review the detailed characteristics of aluminum neurotoxicity and the link between Alzheimer' s disease and other neurodegenerative diseases, based on recent findings on metal-metal interactions and the functions of metalloproteins in synapses.

  13. Policy Change Implication Toward Integrated Wonorejo Zone as A Strategic Economic Development Zone

    Directory of Open Access Journals (Sweden)

    Akbar Pandu Dwinugraha

    2014-04-01

    Full Text Available Integrated Wonorejo Zone is one of the development zone in Lumajang Regency with significant goals to improve potensial condition in three aspect namely tourism, agriculture and SMEs. Based on RTRW in 2008-2028, which was established in 2008, the development strategy of this zone is change. Integrated Wonorejo Zone was mentioned as a Strategic Economic Development Zone. This research describe and analyse about how the implication of policy change toward Integrated Wonorejo Zone. This research using method of descriptive research with qualitative approach as well as analysis of data by John Seidel about QDA (qualitative data analysis. The result of this research explain that the policy change implication, from description, implementation and implication point of view did not give significant expectation. Key Words: Policy Change, Integrated Wonorejo Zone, Strategic Economic Development Zone.

  14. Some technical implications of Klein's concept of 'premature ego development'.

    Science.gov (United States)

    Mitrani, Judith L

    2007-08-01

    In this paper, the author revisits the problem of 'premature ego development' first introduced by Melanie Klein in 1930. She also highlights several developments in post-Kleinian thinking since the publication of that paper, which can be seen as offshoots of or complements to Klein's work. The author proposes a link between this category of precocious development and the absence of the experience of what Bion termed the 'containing object.' She puts forward several technical considerations relevant to analytic work with patients who suffer as a result of early developmental failures and presents various clinical vignettes in order to demonstrate the ways in which these considerations take shape in the analytic setting.

  15. Academic libraries and collection development implications for grey literature

    OpenAIRE

    Gelfand, Julia; GreyNet, Grey Literature Network Service

    1994-01-01

    The proliferation of grey literature (GL) in all subject areas poses great challenges, concerns and responsibilities for libraries. This paper examines the major issues most germane to the acquisition and collection development aspects of grey literature and providing access to it in library collections. With increasing academic and scholarly value placed in the grey literature and it being an original and primary source for information, many collection development policies are beginning to i...

  16. Implication of epigenetics in pancreas development and disease

    OpenAIRE

    Quilichini, Evans; Haumaitre, Cécile

    2015-01-01

    International audience; Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model o...

  17. On the Welfare Implications of Financial Globalization without Financial Development

    OpenAIRE

    Enrique G. Mendoza; Vincenzo Quadrini; José-Víctor Ríos-Rull

    2007-01-01

    It is widely argued that countries can reap large gains from liberalizing their capital accounts if financial globalization is accompanied by the development of domestic institutions and financial markets. However, if liberalization does not lead to financial development, globalization can result in adverse effects on social welfare and the distribution of wealth. We use a multi-country model with non-insurable idiosyncratic risk to show that, if countries differ in the degree of asset market...

  18. Development of a structured undergraduate research experience: Framework and implications.

    Science.gov (United States)

    Brown, Anne M; Lewis, Stephanie N; Bevan, David R

    2016-09-10

    Participating in undergraduate research can be a pivotal experience for students in life science disciplines. Development of critical thinking skills, in addition to conveying scientific ideas in oral and written formats, is essential to ensuring that students develop a greater understanding of basic scientific knowledge and the research process. Modernizing the current life sciences research environment to accommodate the growing demand by students for experiential learning is needed. By developing and implementing a structured, theory-based approach to undergraduate research in the life sciences, specifically biochemistry, it has been successfully shown that more students can be provided with a high-quality, high-impact research experience. The structure of this approach allowed students to develop novel, independent projects in a computational molecular modeling lab. Students engaged in an experience in which career goals, problem-solving skills, time management skills, and independence in a research lab were developed. After experiencing this approach to undergraduate research, students reported feeling challenged to think critically and prepared for future career paths. The approach allowed for a progressive learning environment where more undergraduate students could participate in publishable research. Future areas for development include implementation in a bench-top lab and extension to disciplines beyond biochemistry. In this study, it has been shown that utilizing the structured approach to undergraduate research could allow for more students to experience undergraduate research and develop into more confident, independent life scientists well prepared for graduate schools and professional research environments. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(5):463-474, 2016.

  19. Multiparametric High Content Analysis for assessment of neurotoxicity in differentiated neuronal cell lines and human embryonic stem cell-derived neurons.

    Science.gov (United States)

    Wilson, Melinda S; Graham, James R; Ball, Andrew J

    2014-05-01

    The potential for adverse neurotoxic reactions in response to therapeutics and environmental hazards continues to prompt development of novel cell-based assays to determine neurotoxic risk. A challenge remains to characterize and understand differences between assays and between neuronal cellular models in their responses to neurotoxicants if scientists are to determine the optimal model, or combination of models, for neurotoxicity screening. Most studies to date have focused on developmental neurotoxicity applications. This study reports the development of a robust multiparameter High Content Analysis (HCA) assay for neurotoxicity screening in three differentiated neuronal cell models - SH-SY5Y, PC12 and human embryonic stem cell-derived hN2™ cells. Using a multiplexed detection reagent panel (Hoechst nuclear stain; antibodies against βIII-Tubulin and phosphorylated neurofilament subunit H, and Mitotracker(®) Red CMXRos), a multiparametric HCA assay was developed and used to characterize a test set of 36 chemicals. HCA data generated were compared to data generated using MTT and LDH assays under the same assay conditions. Data showed that multiparametric High Content Analysis of differentiated neuronal cells is feasible, and represents a highly effective method for obtaining large quantities of robust data on the neurotoxic effects of compounds compared with cytotoxicity assays like MTT and LDH. Significant differences were observed between the responses to compounds across the three cellular models tested, illustrating the heterogeneity in responses to neurotoxicants across different cell types. This study provides data strongly supporting the use of cellular imaging as a tool for neurotoxicity assessment in differentiated neuronal cells, and provides novel insights into the neurotoxic effects of a test set of compounds upon differentiated neuronal cell lines and human embryonic stem cell-derived neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Racial Identity Development and Academic Achievement of Academically Gifted African American Students: Implications for School Counselors

    Science.gov (United States)

    Spencer, Natalie F.; Dowden, Angel Riddick

    2014-01-01

    Gifted African American students are underrepresented and underserved in gifted education. The current article provides an overview of proper identification, racial identity development implications, psycho-social concerns and the importance of family involvement in the development of gifted African American students. A case study is presented to…

  1. The Legacy of Lawrence Kohlberg: Implications for Counseling and Human Development.

    Science.gov (United States)

    Hayes, Richard L.

    1994-01-01

    Notes that, despite great contributions by Lawrence Kohlberg to understanding of moral development, counselors are only beginning to appreciate fully implications of his developmental psychology for practice of counseling and human development. Draws on collective body of Kohlberg's work to show how seven assumptions have direct relevance for…

  2. Development of the Adolescent Brain: Implications for Executive Function and Social Cognition

    Science.gov (United States)

    Blakemore, Sarah-Jayne; Choudhury, Suparna

    2006-01-01

    Adolescence is a time of considerable development at the level of behaviour, cognition and the brain. This article reviews histological and brain imaging studies that have demonstrated specific changes in neural architecture during puberty and adolescence, outlining trajectories of grey and white matter development. The implications of brain…

  3. Observations of a Working Class Family: Implications for Self-Regulated Learning Development

    Science.gov (United States)

    Vassallo, Stephen

    2012-01-01

    Guardians have been implicated in the development of children's academic self-regulation. In this case study, which involved naturalistic observations and interviews, the everyday practices of a working class family were considered in the context of self-regulated learning development. The family's practices, beliefs, dispositions and home…

  4. Parallel distributed processing: Implications for cognition and development. Technical report

    Energy Technology Data Exchange (ETDEWEB)

    McClelland, J.L.

    1988-07-11

    This paper provides a brief overview of the connectionist or parallel distributed processing framework for modeling cognitive processes, and considers the application of the connectionist framework to problems of cognitive development. Several aspects of cognitive development might result from the process of learning as it occurs in multi-layer networks. This learning process has the characteristic that it reduces the discrepancy between expected and observed events. As it does this, representations develop on hidden units which dramatically change both the way in which the network represents the environment from which it learns and the expectations that the network generates about environmental events. The learning process exhibits relatively abrupt transitions corresponding to stage shifts in cognitive development. These points are illustrated using a network that learns to anticipate which side of a balance beam will go down, based on the number of weights on each side of the fulcrum and their distance from the fulcrum on each side of the beam. The network is trained in an environment in which weight more frequently governs which side will go down. It recapitulates the states of development seen in children, as well as the stage transitions, as it learns to represent weight and distance information.

  5. Developmental neurotoxic effects of two pesticides: Behavior and neuroprotein studies on endosulfan and cypermethrin.

    Science.gov (United States)

    Lee, Iwa; Eriksson, Per; Fredriksson, Anders; Buratovic, Sonja; Viberg, Henrik

    2015-09-01

    Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. Exposure to these substances during early development may lead to adverse behavior effects manifested at a later phase of life. Pesticides are a wide group of chemicals which are still actively used and residues are found in the environment and in food products. The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5 mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.

  6. Product Configuration Systems - Implications for Product Innovation and Development

    DEFF Research Database (Denmark)

    Edwards, Kasper; Pedersen, Jørgen Lindgaard

    2004-01-01

    configurations. However, costs are but one parameter on which firms compete and firms must continually innovate new and develop existing products. This paper presents original empirical insights on implementation and use of product configuration systems in a number of Danish industrial firms. The paper discusses...... the organisational changes associated with PCS and how this affects product innovation and development. The paper begins by introducing product configuration systems, which are then placed in context to the firm as a process technology which coordinate different processes: product development, order acquisition......Product Configuration Systems (PCS) is a step in the direction of mass customization in the sense that PCS allows a firm to significantly lower the unit cost of configuration. Thus PCS is a valuable technology for lowering operating costs while retaining a high number of possible product...

  7. Recurrent Intrathecal Methotrexate Induced Neurotoxicity in an Adolescent with Acute Lymphoblastic Leukemia: Serial Clinical and Radiologic Findings

    Science.gov (United States)

    Brugnoletti, Fulvia; Morris, E. Brannon; Laningham, Fred H.; Patay, Zoltán; Pauley, Jennifer L; Pui, Ching-Hon; Jeha, Sima; Inaba, Hiroto

    2008-01-01

    Systemic and intrathecal methotrexate (MTX) are integral components of acute lymphoblastic leukemia (ALL) therapy, but can be associated with neurotoxicity. We describe here the case of an adolescent male with T-cell ALL who developed recurrent episodes of subacute neurotoxicity characterized by slurred speech, emotional lability, and hemiparesis after intrathecal MTX administration. Serial magnetic resonance imaging with diffusion-weighted imaging showed recurrent areas of restricted diffusion within cerebral hemispheric white matter, which correlated chronologically with the administration of intrathecal therapy and severity of clinical symptoms. Resolution of diffusion abnormalities did not preclude further toxicity and a large lesion could cause persisting symptoms. PMID:18831032

  8. Neurotoxicity of the Parkinson Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos

    OpenAIRE

    Lulla, A.; Barnhill, L; Bitan, G.; Ivanova, MI; Nguyen, B; O'Donnell, K.; Stahl, MC; Yamashiro, C.; Klaerner, F-G; Schrader, T; Sagasti, A; Bronstein, JM

    2016-01-01

    Background: Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood. Objective: We studied the mechanisms of ziram’s (a DTC fungicide) neurotoxicity in vivo. Methods: Zebrafish (ZF) embryos were utilized to determine ziram’s effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity. Results: Nanomolar...

  9. Relational Aggression in School Settings: Definition, Development, Strategies, and Implications

    Science.gov (United States)

    Dailey, Alicia L.; Frey, Andy J.; Walker, Hill M.

    2015-01-01

    Relational aggression (RA) is a nonphysical form of aggression whereby the perpetrator's goal is to inflict or threaten damage to relationships, including harm to the target child's social standing or reputation. This form of aggression may result in long-term psychological harm to victims. This article defines RA, summarizes its development, and…

  10. Public Understanding of Sustainable Development: Some Implications for Education

    Science.gov (United States)

    Scott, William

    2015-01-01

    A number of recent surveys of public opinion claim that there is now widespread acceptance of the need for sustainable development, and that the general public, through its social and consumer activity is already successfully engaged. However, in all this, the focus has primarily been on individual and family behaviours such as recycling and…

  11. Business development - the function, research propositions, and managerial implications

    DEFF Research Database (Denmark)

    Sørensen, Hans Eibe

    and executives from high-tech firms and venture capitalists in North America, Asia, and Europe to provide a foundation for future research. Business development is an emerging staff function providing an added level of sophistication to the firms' overall strategic management with interesting performance...

  12. Fatherhood in Kenyan Ethnic Communities: Implication for Child Development

    Science.gov (United States)

    Lasser, Jon; Fite, Kathleen; Wadende, Akinyi P.

    2011-01-01

    This article reviews the traditional and evolving constructions of fatherhood in Kenyan society, with an emphasis on fatherhood's impact on child development outcomes. Western influence and increased access to technology have changed the role of the Kenyan father, and in turn affected his role in the family. Special attention is given to…

  13. Sexual abuse prevention training for preschoolers: Implications for moral development

    OpenAIRE

    Berrick, JD

    1991-01-01

    Child sexual abuse prevention education is taught to children of all ages. The youngest students are preschool age children. Many programs focus on the moral ramifications of a sexual assault. The limitations of children's moral development, however, may hinder their ability to understand the concepts presented. In some instances, education may unwittingly foster sentiments of guilt in these very young children. © 1991.

  14. Creating World-Class Universities: Implications for Developing Countries

    Science.gov (United States)

    Lee, Jeongwoo

    2013-01-01

    Many countries are now creating world-class universities (WCUs) as essential parts of their higher education reform agendas, and as national goals. It is legitimate to ask whether every country that aspires to build a WCU can do so--especially developing countries. To answer this question, this paper provides a three-step framework. The first step…

  15. The Educational Implications of Introducing a NQF for Developing Countries

    Science.gov (United States)

    Young, Michael

    2011-01-01

    The one-year research project on the implementation of NQFs in developing countries was launched by the ILO 2009 in collaboration with the ETF. This article reviews some of the educational issues that arose from the project. The findings of the case studies raise issues that are important for how future research and policy on NQFs is taken…

  16. Plasticity in the Developing Brain: Implications for Rehabilitation

    Science.gov (United States)

    Johnston, Michael V.

    2009-01-01

    Neuronal plasticity allows the central nervous system to learn skills and remember information, to reorganize neuronal networks in response to environmental stimulation, and to recover from brain and spinal cord injuries. Neuronal plasticity is enhanced in the developing brain and it is usually adaptive and beneficial but can also be maladaptive…

  17. Mexican Industrial Development Plans: Implications for United States Policy.

    Science.gov (United States)

    1981-04-01

    strategy and developed serious problems. Is Mexico avoiding the errors of its predecessors and, if so, will it continue to do so? Abel Beltran del...menting the exchange controls necessary to administer periodic exchange rate adjustments efficiently.* * See: Ortiz, G. and Solis, L., " Tipos de Cambio

  18. Organisational Learning in International Joint Ventures: Implications for Management Development.

    Science.gov (United States)

    Berrell, Mike; Gloet, Marianne; Wright, Phil

    2002-01-01

    Malaysian and Australian managers enrolled in a training program exhibited differences attributed to national culture in their approaches to learning, influences on management behavior, and ways of knowing. National culture had greater influence on management development and organizational learning than did organizational or systems cultures.…

  19. Fatherhood in Kenyan Ethnic Communities: Implication for Child Development

    Science.gov (United States)

    Lasser, Jon; Fite, Kathleen; Wadende, Akinyi P.

    2011-01-01

    This article reviews the traditional and evolving constructions of fatherhood in Kenyan society, with an emphasis on fatherhood's impact on child development outcomes. Western influence and increased access to technology have changed the role of the Kenyan father, and in turn affected his role in the family. Special attention is given to…

  20. Plasticity in the Developing Brain: Implications for Rehabilitation

    Science.gov (United States)

    Johnston, Michael V.

    2009-01-01

    Neuronal plasticity allows the central nervous system to learn skills and remember information, to reorganize neuronal networks in response to environmental stimulation, and to recover from brain and spinal cord injuries. Neuronal plasticity is enhanced in the developing brain and it is usually adaptive and beneficial but can also be maladaptive…

  1. Implications of climate change mitigation for sustainable development

    Science.gov (United States)

    Jakob, Michael; Steckel, Jan Christoph

    2016-10-01

    Evaluating the trade-offs between the risks related to climate change, climate change mitigation as well as co-benefits requires an integrated scenarios approach to sustainable development. We outline a conceptual multi-objective framework to assess climate policies that takes into account climate impacts, mitigation costs, water and food availability, technological risks of nuclear energy and carbon capture and sequestration as well as co-benefits of reducing local air pollution and increasing energy security. This framework is then employed as an example to different climate change mitigation scenarios generated with integrated assessment models. Even though some scenarios encompass considerable challenges for sustainability, no scenario performs better or worse than others in all dimensions, pointing to trade-offs between different dimensions of sustainable development. For this reason, we argue that these trade-offs need to be evaluated in a process of public deliberation that includes all relevant social actors.

  2. Implication of epigenetics in pancreas development and disease.

    Science.gov (United States)

    Quilichini, Evans; Haumaitre, Cécile

    2015-12-01

    Pancreas development is controlled by a complex interaction of signaling pathways and transcription factor networks that determine pancreatic specification and differentiation of exocrine and endocrine cells. Epigenetics adds a new layer of gene regulation. DNA methylation, histone modifications and non-coding RNAs recently appeared as important epigenetic factors regulating pancreas development. In this review, we report recent findings obtained by analyses in model organisms as well as genome-wide approaches that demonstrate the role of these epigenetic regulators in the control of exocrine and endocrine cell differentiation, identity, function, proliferation and regeneration. We also highlight how altered epigenetic processes contribute to pancreatic disorders: diabetes and pancreatic cancer. Uncovering these epigenetic events can help to better understand these diseases, provide novel therapeutical targets for their treatment, and improve cell-based therapies for diabetes.

  3. Trimethyltin (TMT) neurotoxicity in organotypic rat hippocampal slice cultures

    DEFF Research Database (Denmark)

    Noraberg, J; Gramsbergen, J B; Fonnum, F

    1998-01-01

    The neurotoxic effects of trimethyltin (TMT) on the hippocampus have been extensively studied in vivo. In this study, we examined whether the toxicity of TMT to hippocampal neurons could be reproduced in organotypic brain slice cultures in order to test the potential of this model for neurotoxico......The neurotoxic effects of trimethyltin (TMT) on the hippocampus have been extensively studied in vivo. In this study, we examined whether the toxicity of TMT to hippocampal neurons could be reproduced in organotypic brain slice cultures in order to test the potential of this model...... for neurotoxicological studies, including further studies of neurotoxic mechanisms of TMT. Four-week-old cultures, derived from 7-day-old donor rats and grown in serum-free medium, were exposed to TMT (0.5-100 microM) for 24 h followed by 24 h in normal medium. TMT-induced neurodegeneration was then monitored by (a...... of TMT neurotoxicity....

  4. Implications of Energy Efficiency and Economic Growth in Developing Countries

    OpenAIRE

    2012-01-01

    It is essential that society shift toward more efficient energy consumption patterns. A sector basis analysis of energy consumption provides some suggestions regarding this view. In the residential sector, energy resources change with the advancement of development stages. The industrial sector is characterized by a diverse range of energy intensity in each subsector. Relevant policies and measures are considered based on the relevant sector information.

  5. Implications of China’s Aircraft Carrier Development

    Science.gov (United States)

    2012-03-16

    Taiwanese” instead of “Chinese” and want to release from China’s fetters. Former President Chen Shui -bian (2000-2008), the chairman of the...For instance, the Hsiung Feng III Anti-ship missile is in development by the Chungshan Institute of Science and Technology (CSIST) in Taiwan. After...weapon against the ex-Varyag.37 Another missile system that contributes to Taiwan security is the Hsiung Feng IIE surface-to-surface cruise missiles

  6. Policy implications in developing a land use management information systems

    Science.gov (United States)

    Landini, A. J.

    1975-01-01

    The current land use map for the city of Los Angeles was developed by the guesstimation process and provides single stage information for each level in the critical geographical hierarchy for land use planning management. Processing and incorporation of LANDSAT data in the land use information system requires special funding; however, computergraphic maps are able to provide a viable information system for city planning and management.

  7. The Development of Metacognition in Musicians: Implication for Education

    OpenAIRE

    Hallam, S.

    2001-01-01

    Recent research on musical practice has focused on metacognition and the strategies that musicians adopt in their preparations for performance. This study explored the development of metacognition and performance planning strategies in musicians from novice to professional level. 22 professional musicians and 55 novices were interviewed about their practising. The novices were also tape recorded learning and performing a short piece. The professional musicians demonstrated extensive metacogni...

  8. Leadership theory: implications for developing dental surgeons in primary care?

    Science.gov (United States)

    Willcocks, S

    2011-02-12

    The development of leadership in healthcare has been seen as important in recent years, particularly at the clinical level. There have been various specific initiatives focusing on the development of leadership for doctors, nurses and other health care professions: for example, a leadership competency framework for doctors, the LEO programme and the RCN clinical leadership programme for nurses. The NHS has set up a Leadership Council to coordinate further developments. However, there has not been the same focus in dentistry, although the recent review of NHS dental services (Steele review) has proposed a need for leadership initiatives in NHS dentistry as a medium-term action. Central to this will be a need to focus on the leadership role for dental surgeons. Leadership is all the more important in dentistry, given the change of government and the policy of retrenchment, major public sector reform, the emergence of new organisations such as new commissioning consortia, possible changes to the dental contract, new ways of working, and changes to the profession such as the requirements for the revalidation of dental surgeons. The question is: which leadership theory or approach is best for dental surgeons working in primary care? This paper builds on earlier work exploring this question in relation to doctors generally, and GPs, in particular, and planned work on nurses. It will seek to address this question in relation to dental surgeons working in primary care.

  9. Autophagy activation is involved in 3,4-methylenedioxymethamphetamine ('ecstasy'--induced neurotoxicity in cultured cortical neurons.

    Directory of Open Access Journals (Sweden)

    I-Hsun Li

    Full Text Available Autophagic (type II cell death, characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells, has been suggested to play pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy is an illicit drug causing long-term neurotoxicity in the brain. Apoptotic (type I and necrotic (type III cell death have been implicated in MDMA-induced neurotoxicity, while the role of autophagy in MDMA-elicited neurotoxicity has not been investigated. The present study aimed to evaluate the occurrence and contribution of autophagy to neurotoxicity in cultured rat cortical neurons challenged with MDMA. Autophagy activation was monitored by expression of microtubule-associated protein 1 light chain 3 (LC3; an autophagic marker using immunofluorescence and western blot analysis. Here, we demonstrate that MDMA exposure induced monodansylcadaverine (MDC- and LC3B-densely stained autophagosome formation and increased conversion of LC3B-I to LC3B-II, coinciding with the neurodegenerative phase of MDMA challenge. Autophagy inhibitor 3-methyladenine (3-MA pretreatment significantly attenuated MDMA-induced autophagosome accumulation, LC3B-II expression, and ameliorated MDMA-triggered neurite damage and neuronal death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in neurons and aggravated neurite degeneration, indicating that excessive autophagosome accumulation contributes to MDMA-induced neurotoxicity. Furthermore, MDMA induced phosphorylation of AMP-activated protein kinase (AMPK and its downstream unc-51-like kinase 1 (ULK1, suggesting the AMPK/ULK1 signaling pathway might be involved in MDMA-induced autophagy activation.

  10. Neurotoxicity in long-term survivors of small cell lung cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.S.; Umsawasdi, T.; Lee, Y.Y.; Barkley, H.T. Jr.; Murphy, W.K.; Welch, S.; Valdivieso, M.

    1986-03-01

    Chronic central nervous system neurotoxicity was studied in 38 long-term survivors (greater than or equal to 3 years) of small cell lung cancer who were treated at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1971 and 1980. All but one patient received combination chemotherapy with or without chest irradiation. Twenty-four patients received whole brain irradiation (Group I), 22 for elective and two for therapeutic purposes, while 14 did not (Group II). Abnormalities in computed tomographic (CT) scans of the brain were more frequently observed in Group I than in Group II (70% vs. 0%, p less than 0.01). Clinical central nervous system neurotoxicity developed in three patients in Group I, while none developed in patients in Group II (p less than 0.05). Patients who received methotrexate and procarbazine after whole brain irradiation were at a higher risk for clinical central nervous system neurotoxicity (p less than 0.05), and for development of periventricular white matter changes in CT brain scans (p less than 0.05) than were patients in Group II. Impaired methylation of the myelin sheath is proposed as a possible underlying pathogenic mechanism.

  11. L-Ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Ya-Ni [Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan (China); Wang, Jiz-Yuh [Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (China); Lee, Ching-Tien [Department of Nursing, Hsin Sheng College of Medical Care and Management, Taoyuan, Taiwan (China); Lin, Chih-Hung [Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China); Lai, Chien-Cheng [Far Eastern Memorial Hospital, Department of Surgery, Taipei, Taiwan (China); Wang, Jia-Yi, E-mail: jywang2010@tmu.edu.tw [Graduate Institute of Medical Sciences and Department of Physiology, College of Medicine, Taipei Medical University, Taipei, Taiwan (China)

    2012-12-01

    Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of L-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2′,7′-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO-1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity. -- Highlights: ► Besides the anti-oxidant effect, Vit. C also induces HO-1 expression in brain cells. ► Vit. C reduces METH neurotoxicity and ROS production by

  12. Alcohol-Mediated Missplicing of Mcl-1 Pre-mRNA is Involved in Neurotoxicity.

    Science.gov (United States)

    Sariyer, Rahsan; De-Simone, Francesca I; Donadoni, Martina; Hoek, Jan B; Chang, Sulie L; Sariyer, Ilker Kudret

    2017-08-11

    Heavy and chronic ethanol (EtOH) exposure can cause significant structural and functional damage to the adult brain. The most devastating consequence of EtOH exposure is the neurotoxicity associated with the depletion of neurons. Regulation of splice variants in the brain can modulate protein functions, which may ultimately affect behaviors associated with alcohol dependence and EtOH-mediated neurotoxicity. As alcohol consumption is associated with neurotoxicity, it is possible that altered splicing of survival and pro-survival factors during the development of alcoholism may contribute to the neurotoxicity. Primary human neurons and a neuroblastoma cell line were exposed to different concentrations of EtOH for various time periods. Cell viability and neuronal marker expression were analyzed by MTT assay and immunoblotting, respectively. Effect of EtOH exposure on splicing regulatory protein expression and alternative splicing of candidate genes was analyzed by a biochemical approach. Transcriptional activity of serine/arginine-rich splicing factor 1 (SRSF1) gene was determined by reporter gene analysis. Our results suggest that EtOH exposure to neuronal cells at 25 mM and higher concentrations are detrimental. In addition, EtOH exposure caused a dramatic reduction in SRSF1 expression levels. Furthermore, EtOH exposure led to pre-mRNA missplicing of Mcl-1, a pro-survival member of the Bcl-2 family, by down-regulating the expression levels of SRSF1. Moreover, ectopic expression of both SRSF1 and Mcl-1L isoform was able to recover EtOH-mediated neurotoxicity. Our results suggest that EtOH exposure can lead to pre-mRNA missplicing of Mcl-1 in neuronal cells. Our results indicate that EtOH exposure of neurons leads to a decrease in the ratio of Mcl-1L/Mcl-1S by favoring pro-apoptotic Mcl-1S splicing over anti-apoptotic Mcl-1L isoform suggesting that Mcl-1S may play a crucial role in neurotoxicity associated with alcohol consumption. Copyright © 2017 by the Research

  13. Comparative developmental neurotoxicity of flame-retardants, polybrominated flame-retardants and organophosphorous compounds, in mice

    Energy Technology Data Exchange (ETDEWEB)

    Eriksson, P.; Johansson, N.; Viberg, H.; Fischer, C.; Fredriksson, A. [Dept. of Environmental Toxicology, Uppsala Univ. (Sweden)

    2004-09-15

    Recently we have reported that certain PBDEs, such as 2,2',4,4'-tetrabromodiphenyl ether (PBDE 47), 2,2',4,4',5- pentabromodiphenyl ether (PBDE 99), 2,2',4,4',5,5'-hexabromodiphenyl ether (PBDE153) and 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (PBDE 209) can cause developmental neurotoxic effects when given to neonatal mice. The developmental neurotoxic effects after neonatal exposure to PBDE 209 are suggested to be caused by a metabolite (possible de-brominated one). Neonatal exposure HBCDD has also been shown to cause developmental neurotoxic effects. Neonatal exposure to PBDE 99, PBDE 153 and HBCDD was also found to affect learning and memory in the adult animal. The induction of permanent aberration in spontaneous behaviour was induced during limited period of the neonatal brain development. The altered spontaneous behaviour was also seen to worsen with age. In these studies we have also found that the cholinergic system is one target that is affected, observed as changes in the response of the cholinergic system and a decrease in cholinergic receptors, and is one of the mechanisms underlying the observed behavioural changes. BFRs so far studied TBBPA appears not to cause developmental neurotoxic effects when administered at the same dose levels to neonatal mice. In the present studies we have investigated whether neonatal exposure to three highly brominated dipehenyl ethers, 2,2',3,4,4',5',6'-heptabromodiphenyl ether (PBDE183), 2,2',3'4'4',5,5',6- octabromodiphenyl ether (PBDE 203) and 2,2',3,3',4,4',5',6'-nonabromodiphenyl ether (PBDE 206) can induce developmental neurotoxic effects, such as aberrations in spontaneous behaviour and in learning and memory. Furthermore, neonatal developmental neurotoxicity effects were also studied for two OPs used as FR, triphenyl phosphate and tris(2-chloro-ethyl)phosphate.

  14. Glial Reactivity in Resistance to Methamphetamine-Induced Neurotoxicity

    OpenAIRE

    Friend, Danielle M.; Keefe, Kristen A

    2013-01-01

    Neurotoxic regimens of methamphetamine (METH) result in reactive microglia and astrocytes in striatum. Prior data indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. Such resistant animals also do not show an activated microglia phenotype, suggesting a relation between microglial activation and METH-induced neurotoxicity. To date, the astrocyte response in such resista...

  15. Metabolic costs and evolutionary implications of human brain development.

    Science.gov (United States)

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-09

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

  16. Increased Screen Time: Implications for Early Childhood Development and Behavior.

    Science.gov (United States)

    Radesky, Jenny S; Christakis, Dimitri A

    2016-10-01

    The authors review trends in adoption of new digital technologies (eg, mobile and interactive media) by families with young children (ages 0-8 years), continued use of television and video games, and the evidence for learning from digital versus hands-on play. The authors also discuss continued concerns about health and developmental/behavioral risks of excessive media use for child cognitive, language, literacy, and social-emotional development. This evidence is then applied to clinical care in terms of the screening questions providers can use, tools available to providers and parents, and changes in anticipatory guidance. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Near field communication recent developments and library implications

    CERN Document Server

    McHugh, Sheli

    2014-01-01

    Near Field Communication is a radio frequency technology that allows objects, such as mobile phones, computers, tags, or posters, to exchange information wirelessly across a small distance. This report on the progress of Near Field Communication reviews the features and functionality of the technology and summarizes the broad spectrum of its current and anticipated applications. We explore the development of NFC technology in recent years, introduce the major stakeholders in the NFC ecosystem, and project its movement toward mainstream adoption. Several examples of early implementation of NFC

  18. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors.

    Science.gov (United States)

    Chao, C C; Hu, S; Ehrlich, L; Peterson, P K

    1995-12-01

    The cytokines interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, produced by glial cells within the brain, appear to contribute to the neuropathogenesis of several inflammatory neurodegenerative diseases; however, little is known about the mechanism underlying cytokine-induced neurotoxicity. Using human fetal brain cell cultures composed of neurons and glial cells, we investigated the injurious effects of IL-1beta and TNF-alpha, cytokines which are known to induce nitric oxide (NO) production by astrocytes. Although neither cytokine alone was toxic, IL-1beta and TNF-alpha in combination caused marked neuronal injury. Brain cell cultures treated with IL-1beta plus TNF-alpha generated substantial amounts of NO. Blockade of NO production with a NO synthase inhibitor was accompanied by a marked reduction (about 45%) of neuronal injury, suggesting that NO production by astrocytes plays a role in cytokine-induced neurotoxicity. Addition of N-methly-D-aspartate (NMDA) receptor antagonists to brain cell cultures also blocked IL-1beta plus TNF-alpha-induced neurotoxicity (by 55%), implicating the involvement of NMDA receptors in cytokine-induced neurotoxicity. Treatment of brain cell cultures with IL-1beta plus TNF-alpha was found to inhibit [3H]-glutamate uptake and astrocyte glutamine synthetase activity, two major pathways involved in NMDA receptor-related neurotoxicity. These in vitro findings suggest that agents which suppress NO production or inhibit NMDA receptors may protect against neuronal damage in cytokine-induced neurodegenerative diseases.

  19. The Neurotoxicity of Nitrous Oxide: The Facts and “Putative” Mechanisms

    Directory of Open Access Journals (Sweden)

    Sinead Savage

    2014-01-01

    Full Text Available Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects.

  20. The neurotoxicity of amphetamines during the adolescent period.

    Science.gov (United States)

    Teixeira-Gomes, Armanda; Costa, Vera Marisa; Feio-Azevedo, Rita; Bastos, Maria de Lourdes; Carvalho, Félix; Capela, João Paulo

    2015-04-01

    Amphetamine-type psychostimulants (ATS), such as amphetamine (AMPH), 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) are psychoactive substances widely abused, due to their powerful central nervous system (CNS) stimulation ability. Young people particularly use ATS as recreational drugs. Moreover, AMPH is used clinically, particularly for attention deficit hyperactivity disorder, and has the ability to cause structural and functional brain alterations. ATS are known to interact with monoamine transporter sites and easily diffuse across cellular membranes, attaining high levels in several tissues, particularly the brain. Strong evidence suggests that ATS induce neurotoxic effects, raising concerns about the consequences of drug abuse. Considering that many teenagers and young adults commonly use ATS, our main aim was to review the neurotoxic effects of amphetamines, namely AMPH, MDMA, and METH, in the adolescence period of experimental animals. Reports agree that adolescent animals are less susceptible than adult animals to the neurotoxic effects of amphetamines. The susceptibility to the neurotoxic effects of ATS seems roughly located in the early adolescent period of animals. Many authors report that the age of exposure to ATS is crucial for the neurotoxic outcome, showing that the stage of brain maturity has a strong importance. Moreover, recent studies have been undertaken in young adults and/or consumers during adolescence that clearly indicate brain or behavioural damage, arguing for long-term neurotoxic effects in humans. There is an urgent need for more studies during the adolescence period, in order to unveil the mechanisms and the brain dysfunctions promoted by ATS.

  1. Auxin metabolism rates and implications for plant development

    Directory of Open Access Journals (Sweden)

    Eric M Kramer

    2015-03-01

    Full Text Available Studies of auxin metabolism rarely express their results as a metabolic rate, although the data obtained would often permit such a calculation to be made. We analyze data from 31 previously published papers to quantify the rates of auxin biosynthesis, conjugation, conjugate hydrolysis, and catabolism in seed plants. Most metabolic pathways have rates in the range 10 nM/h to 1 μM/h, with the exception of auxin conjugation, which has rates as high as ~100 μM/h. The highest rates of auxin conjugation suggests that auxin metabolic sinks may be very small, perhaps as small as a single cell. By contrast, the relatively low rate of auxin biosynthesis requires plants to conserve and recycle auxin during long-distance transport. The consequences for plant development are discussed.

  2. EVOLUTION OF MYCOBACTERIUM TUBERCULOSIS AND IMPLICATIONS FOR VACCINE DEVELOPMENT.

    Science.gov (United States)

    Gagneux, Sebastien

    2016-04-01

    Tuberculosis (TB) is a growing public health threat, particularly in the face of the global epidemics of multidrug resistance. Given the limited efficacy of the current TB vaccine and the recent clinical failure of the most advanced new TB vaccine candidate, novel concepts for vaccine design should be explored. Most T cell antigens in the human-adapted Mycobacterium tuberculosis complex (MTBC) are evolutionarily conserved and under strong purifying selection, indicating that host immune responses targeting these antigens might not be protective. By contrast, a few highly variable T cell epitopes have recently been discovered, which could serve as alternative vaccine antigens. Moreover, there is increasing evidence that the human-adapted MTBC has been co-evolving with the human host for a long time. Hence, studying the interaction between bacterial and human genetic diversity might help identify additional targets that could be exploited for TB vaccine development.

  3. Public health implications of urban air pollution in developing countries

    Energy Technology Data Exchange (ETDEWEB)

    Schwela, D.H. [World Health Organisation, Geneva (Switzerland)

    1995-12-31

    Exposure to air pollution is an almost inescapable part of urban life throughout the world. Ambient air pollutant levels in urban areas are generally a reflection of emissions. For sulphur dioxide, total suspended particulate matter and lead, ambient concentrations are declining in the industrialized western countries. For nitrogen dioxide, ambient levels in cities are generally constant, or slightly increasing. For carbon dioxide, they are variable, declining where controls are being applied. In a substantial number of cities, particularly in developing countries, WHO guidelines are being often exceeded for the compounds mentioned. Given the rate at which these cities are growing, the air pollution situation will probably worsen if environmental control measures are not implemented. As a consequence, the health and well-being of urban residents will further deteriorate with high ambient air pollutant concentrations causing increased mortality, morbidity, deficits on pulmonary functions and cardiovascular and neurobehavioural effects. (author)

  4. Determinants of breastfeeding in developing countries: overview and policy implications.

    Science.gov (United States)

    Huffman, S L

    1984-01-01

    Breastfeeding can play a major role in fertility regulation in developing countries. The effect of breastfeeding is enhanced when the incidence of breastfeeding is high and the duration extended. These factors are more likely to occur when suckling at the breast is frequent. Sociological and behavioral factors can also influence a woman's decision to initiate and terminate breastfeeding. The effects of urbanization, maternal education, and socioeconomic status act through the intervening variables of sociocultural factors, health services, employment status of women, and availability of breastmilk substitutes. Strategies to alter these intervening variables include educational campaigns and support groups for lactating women, changes in health services, availability of child care facilities near employment centers, and enforcement of the international code of marketing of breastmilk substitutes.

  5. The Development of Bimodal Bilingualism: Implications for Linguistic Theory.

    Science.gov (United States)

    Lillo-Martin, Diane; de Quadros, Ronice Müller; Pichler, Deborah Chen

    2016-01-01

    A wide range of linguistic phenomena contribute to our understanding of the architecture of the human linguistic system. In this paper we present a proposal dubbed Language Synthesis to capture bilingual phenomena including code-switching and 'transfer' as automatic consequences of the addition of a second language, using basic concepts of Minimalism and Distributed Morphology. Bimodal bilinguals, who use a sign language and a spoken language, provide a new type of evidence regarding possible bilingual phenomena, namely code-blending, the simultaneous production of (aspects of) a message in both speech and sign. We argue that code-blending also follows naturally once a second articulatory interface is added to the model. Several different types of code-blending are discussed in connection to the predictions of the Synthesis model. Our primary data come from children developing as bimodal bilinguals, but our proposal is intended to capture a wide range of bilingual effects across any language pair.

  6. The Learning Object Economy: Implications For Developing Faculty Expertise

    Directory of Open Access Journals (Sweden)

    The COHERE Group

    2002-10-01

    Full Text Available The evolving use of learning technologies and systems, such as learning object systems, to support more social learning environments in which learners have more agency than ever before to construct their own learning experiences is an innovation that involves both faculty and learners in a process of difficult sociocultural change. Programs of faculty support that acknowledge that faculty’s learning needs extend beyond the development of technical skills to the development of new pedagogical skills are indicated. This paper argues that the evolving concept of learning objects systems, and the "economy" that is emerging around the idea of sharable, reusable learning objects managed by repositories, presents new challenges and opportunities for our community. Faculty working with these systems may need to be supported through a personal process of reconceptualizing the nature of teaching and learning within these environments. This process of personal transformation has the potential for change in institutional policy and practice, the institutional cultural change of which Tony Bates (2000 and others speak (cf. Advisory Committee for Online Learning, 2000. The Collaboration for Online Higher Education Research (COHERE is an alliance of eight research-intensive Canadian universities that is examining these challenges through a multi-pronged research program, one focus of which is supporting faculty as they research their own practice related to technology-enhanced teaching innovations. More specifically, this paper is itself a collaboration among the COHERE partners to share our collective belief about the potential for faculty and institutional transformation through participation in these "e-learning evolutions".

  7. AN APROACH OF LOCAL FINANCIAL AUTONOMY AND IMPLICATION OVER SUSTAINABLE DEVELOPMENT IN THE KNOWLEDGE SOCIETY

    Directory of Open Access Journals (Sweden)

    Elena CIGU

    2014-12-01

    Full Text Available Local governments play an important role in sustainable development processes based on their administrative and financial autonomy. Policies and programs undertaken to assure sustainable development by local governments produce benefits for persistence of the knowledge society. This paper will try to highlight the implication of local financial autonomy over sustainable development of local communities in a knowledge society, based especially on local financial autonomy theory approach.

  8. Transboundary air pollution in Asia: Model development and policy implications

    Science.gov (United States)

    Holloway, Tracey

    2001-12-01

    This work investigates transboundary air pollution in Asia through atmospheric modeling and public policy analysis. As an example of models actively shaping environmental policy, the Convention on Long-Range Transboundary Air Pollution in Europe (LRTAP) is selected as a case study. The LRTAP Convention is the only mulit- lateral air pollution agreement to date, and results from the RAINS integrated assessment model were heavily used to calculate nationally differentiated emission ceilings. Atmospheric chemistry and transport are included in RAINS through the use of transfer coefficients (or ``source-receptor relationships'') relating pollutant transfer among European nations. Following past work with ATMOS to simulate sulfur species in Asia, here ATMOS is developed to include odd-nitrogen. Fitting with the linear structure of ATMOS and the emphasis on computational efficiency, a simplified chemical scheme developed for use in the NOAA Geophysical Fluid Dynamics Laboratory Global Chemical Transport Model (GFDL GCTM) is adopted. The method solves for the interconversions between NOx, HNO3, and PAN based on five reaction rates stored in look-up tables. ATMOS is used to calculate source-receptor relationships for Asia. Significant exchange of NOy occurs among China, North and South Korea, and Japan. On an annual average basis, China contributes 18% to Japan's total nitrate deposition, 46% to North Korea, and 26% to South Korea. Nitrate deposition is an important component of acidification (along with sulfate deposition), contributing 30-50% to the acid burden over most of Japan, and more than 50% to acid deposition in southeast Asia, where biomass burning emits high levels of NOx. In evaluating the policy-relevance of results from the ATMOS model, four factors are taken into account: the uncertainty and limitations of ATMOS, the environmental concerns facing Asia, the current status of the scientific community in relation to regional air pollution in the region, and

  9. Development and implication of a human-volcano system model

    Science.gov (United States)

    Bachri, Syamsul; Stötter, Johann; Monreal, Matthias; Sartohadi, Junun

    2014-05-01

    In an attempt to understand the complexity of human-environment systems, models help to define, quantify, describe, or simulate complex interactions. With regards to the human-volcano system, we develop a conceptual model in order to assist analysis of its two basic elements, the physical and the social environment. A field survey of the human environment interaction of two of the most active volcanic areas in Indonesia (Mt. Merapi and Mt. Bromo) and a corresponding literature review from other case studies was carried out. A differentiated understanding of human interaction with hazard potential elements within the human-volcano system is the main focus of the model development. We classified volcanic processes and effects as three pairs of dichotomies: positive or negative impacts, on society or environment in an indirect or direct way. Each volcanically induced process or effect characterized accordingly leads to eight distinct process/effect classes. They are positive direct effects on society (PDS); positive direct effects on natural resources (PDN); positive indirect effects on society (PIS); positive indirect effects on natural resources (PIN); negative direct effects on society (NDS); negative direct effects on natural resources (NDN); negative indirect effects on society (NIS) and lastly negative indirect effects on natural resources (NIN). Such differentiated view of volcanic process/effects bears several advantages. First, whereas volcanic processes have hitherto been viewed as hazards only, it becomes possible now to describe a particular process/effect in a particular context as negative or positive. Secondly, such a categorization makes it possible to account for processes of the human-volcano system that do not have a direct physical expression but are of socio-cultural relevance. Thirdly, the greater degree of differentiation that is made possible when evaluating volcanic processes has significant repercussions on the way volcanic risk must be

  10. The classification of motor neuron defects in the zebrafish embryo toxicity test (ZFET) as an animal alternative approach to assess developmental neurotoxicity.

    Science.gov (United States)

    Muth-Köhne, Elke; Wichmann, Arne; Delov, Vera; Fenske, Martina

    2012-07-01

    Rodents are widely used to test the developmental neurotoxicity potential of chemical substances. The regulatory test procedures are elaborate and the requirement of numerous animals is ethically disputable. Therefore, non-animal alternatives are highly desirable, but appropriate test systems that meet regulatory demands are not yet available. Hence, we have developed a new developmental neurotoxicity assay based on specific whole-mount immunostainings of primary and secondary motor neurons (using the monoclonal antibodies znp1 and zn8) in zebrafish embryos. By classifying the motor neuron defects, we evaluated the severity of the neurotoxic damage to individual primary and secondary motor neurons caused by chemical exposure and determined the corresponding effect concentration values (EC₅₀). In a proof-of-principle study, we investigated the effects of three model compounds thiocyclam, cartap and disulfiram, which show some neurotoxicity-indicating effects in vertebrates, and the positive controls ethanol and nicotine and the negative controls 3,4-dichloroaniline (3,4-DCA) and triclosan. As a quantitative measure of the neurotoxic potential of the test compounds, we calculated the ratios of the EC₅₀ values for motor neuron defects and the cumulative malformations, as determined in a zebrafish embryo toxicity test (zFET). Based on this index, disulfiram was classified as the most potent and thiocyclam as the least potent developmental neurotoxin. The index also confirmed the control compounds as positive and negative neurotoxicants. Our findings demonstrate that this index can be used to reliably distinguish between neurotoxic and non-neurotoxic chemicals and provide a sound estimate for the neurodevelopmental hazard potential of a chemical. The demonstrated method can be a feasible approach to reduce the number of animals used in developmental neurotoxicity evaluation procedures.

  11. The Bali Agreement: Implications for Development and the WTO

    Directory of Open Access Journals (Sweden)

    Christophe Bellmann

    2014-05-01

    Full Text Available At the most recent World Trade Organisation (WTO ministerial conference, in December 2013, in Bali, Indonesia, ministers from 160 countries concluded the first multilateral agreement ever negotiated under the auspices of the WTO. After five years of impasse in the moribund Doha Round of trade negotiations, the so-called “Bali package” was enthusiastically welcomed by the world’s governments and international press alike as a critical step towards restoring the credibility of the WTO as a negotiating forum. The centrepiece of the package is without doubt a new agreement on trade facilitation aimed at reducing red tape, and facilitating customs procedures in an effort to cut down the cost of doing business. Other — less far reaching — aspects of the deal focused on food security and a set of issues of particular interest to least developed countries including trade preferences or cotton subsidies. As the dust from the heated Bali negotiations settles, the main challenge for the WTO will now consist in building on this success to re-energise multilateral negotiations and ultimately close the Doha Round. In a world increasingly dominated by regional and bilateral free-trade agreements, members will have to confront the core issues that have divided them for nearly 15 years and find creative solutions to rehabilitate the WTO’s centrality in global trade governance.

  12. Developing Biological ISRU: Implications for Life Support and Space Exploration

    Science.gov (United States)

    Brown, I. I.; Allen, C. C.; Garrison, D. H.; Sarkisova, S. A.; Galindo, C.; Mckay, David S.

    2010-01-01

    Main findings: 1) supplementing very dilute media for cultivation of CB with analogs of lunar or Martian regolith effectively supported the proliferation of CB; 2) O2 evolution by siderophilic cyanobacteria cultivated in diluted media but supplemented with iron-rich rocks was higher than O2 evolution by same strain in undiluted medium; 3) preliminary data suggest that organic acids produced by CB are involved in iron-rich mineral dissolution; 4) the CB studied can accumulate iron on and in their cells; 4) sequencing of the cyanobacterium JSC-1 genome revealed that this strain possesses molecular features which make it applicable for the cultivation in special photoreactors on Moon and Mars. Conclusion: As a result of pilot studies, we propose, to develop a concept for semi-closed integrated system that uses CB to extract useful elements to revitalize air and produce valuable biomolecules. Such a system could be the foundation of a self-sustaining extraterrestrial outpost (Hendrickx, De Wever et al., 2005; Handford, 2006). A potential advantage of a cyanobacterial photoreactor placed between LSS and ISRU loops is the possibility of supplying these systems with extracted elements and compounds from the regolith. In addition, waste regolith may be transformed into additional products such as methane, biomass, and organic and inorganic soil enrichment for the cultivation of higher plants.

  13. Fertilizer Reduction Policies in Developed Countries: Suitability and Implications

    Directory of Open Access Journals (Sweden)

    LI Fang

    2017-01-01

    Full Text Available This study reviewed and analyzed the specific practices, implementation effects and applicable conditions of fertilizer reduction policies in the EU, US and Japan, explored the common laws and general conditions in the formulation of environmental orientation, and pro vided feasible policy recommendations for the formulation of fertilizer reduction policies in China. This study showed that fertilizer reduction policies in each country had their own advantages and disadvantages, and the applicable conditions were different. The EU's command and control policy was applicable to the situation of less farm households and the same agricultural planting type or farm type. The economic in centive policy in the US was applicable to the situation of more farm households, relatively perfect agricultural market system and sensitive price formation mechanism, while the public participation policy in Japan was applicable to regions with more relevant agricultural groups and strong economy. China should learn from each of these policies and make a comprehensive choice in the formulation of fertilizer reduc tion policies. Therefore, China should proceed from improving the agricultural price mechanism and the pollution-free agricultural products certification system as well as encouraging and supporting the development of large scale production units, and then promote the adoption of environmentally friendly technology through the guidance of market mechanism, ensure the effective implementation of environmental stan dards through farmers' integration and improve farmers' environmental awareness through propaganda guidance, so as to ensure the effective implementation of different types(command and control policy, economic incentive policy and public participation policyof fertilizer reduc tion policies.

  14. Commodification of human tissue: implications for feminist and development ethics.

    Science.gov (United States)

    Dickenson, Donna

    2002-05-01

    One effect of late capitalism--the commodification of practically everything--is to knock down the Chinese walls between the natural and productive realms, to use a Marxist framework. Women's labour in egg extraction and 'surrogate' motherhood might then be seen as what it is, labour which produces something of value. But this does not necessarily mean that women will benefit from the commodification of practically everything, in either North or South. In the newly developing biotechnologies involving stem cells, the reverse is more likely, particular given the the shortage in the North of the egg donors who will be increasingly necessary to therapeutic cloning. Although most of the ethical debate has focused on the status of the embryo, this is to define ethics with no reference to global or gender justice. There has been little or no debate about possible exploitation of women, particularly of ovum donors from the South. Countries of the South without national ethics committees or guidelines may be particularly vulnerable: although there is increasing awareness of the susceptibility of poorer countries to abuses in research ethics, very little has been written about how they might be affected by the enormously profitable new technologies exploiting human tissue. Even in the UK, although the new Medical Research Council guidelines make a good deal of the 'gift relationship', what they are actually about is commodification. If donors believe they are demonstrating altruism, but biotechnology firms and researchers use the discourse of commodity and profit, we have not 'incomplete commodification' but complete commodification with a plausibly human face.

  15. Monitoring and Evaluation of an Early Childhood Development Programme: Implications for Leadership and Management

    Science.gov (United States)

    Hodgson, Sarah; Papatheodorou, Theodora; James, Mary

    2014-01-01

    The article aims to discuss preliminary findings from a participatory monitoring and evaluation (M&E) framework, used in a community-based early childhood development (ECD) programme in KwaZulu-Natal South Africa, and their implications for leadership and management. The purposes of the M&E were for LETCEE, the implementing organization,…

  16. Implications of the International Classification of Functioning, Disability and Health (ICF) for Test Development and Use

    Science.gov (United States)

    Carlson, Janet F.; Benson, Nicholas; Oakland, Thomas

    2010-01-01

    Implications of the International Classification of Functioning, Disability and Health (ICF) on the development and use of tests in school settings are enumerated. We predict increased demand for behavioural assessments that consider a person's activities, participation and person-environment interactions, including measures that: (a) address…

  17. Theory Development and Convergence of Human Resource Fields: Implications for Human Performance Technology

    Science.gov (United States)

    Cho, Yonjoo; Yoon, Seung Won

    2010-01-01

    This study examines major theory developments in human resource (HR) fields and discusses implications for human performance technology (HPT). Differentiated HR fields are converging to improve organizational performance through knowledge-based innovations. Ruona and Gibson (2004) made a similar observation and analyzed the historical evolution…

  18. Implications for Students Role Character Development When the Teacher Becomes an Actor in the Production.

    Science.gov (United States)

    Buckner, Debi

    A case study explored the implications for secondary school acting students in developing character in a role when the theater teacher assumes the role of actor in a student production. Two of Albuquerque, New Mexico's 11 public high schools co-produced "Romeo and Juliet." Pre- and posttests of student perceptions of acting and character…

  19. Theory Development and Convergence of Human Resource Fields: Implications for Human Performance Technology

    Science.gov (United States)

    Cho, Yonjoo; Yoon, Seung Won

    2010-01-01

    This study examines major theory developments in human resource (HR) fields and discusses implications for human performance technology (HPT). Differentiated HR fields are converging to improve organizational performance through knowledge-based innovations. Ruona and Gibson (2004) made a similar observation and analyzed the historical evolution…

  20. Airline network development in Europe and its implications for airport planning

    NARCIS (Netherlands)

    Burghouwt, G.

    2007-01-01

    Order by Fax Printer Friendly PDF Brochure Send to Friend Enquire before Buying Hard Copy Airline Network Development in Europe and its Implications for Airport Planning Ashgate Publishing, March 2007, Pages: 300 Description Table of Contents Enquire before Buying Send to a Friend The ongoing deregu

  1. Water Supply Deficiency and Implications for Rural Development in the Niger-Delta Region of Nigeria

    Science.gov (United States)

    Nkwocha, E. E.

    2009-01-01

    There is a growing concern about the marginalization of the Niger Delta region of Nigeria in terms of infrastructural and social services provision. This study examined the water supply deficiency and its general implications for rural development within the region. Data and other study characteristics were extracted from 501 subjects drawn from…

  2. Learning-Inhibiting Problems Experienced by Middle School Teachers: Implications for Staff Development

    OpenAIRE

    Dillard, Patricia Hutcherson

    2000-01-01

    Learning-Inhibiting Problems Experienced by Middle School Teachers: Implications for Staff Development Patricia H. Dillard (ABSTRACT) This study sought to determine if there were statistically significant differences between years of teaching experience and education relative to learning-inhibiting problems in the classroom. These differences were measured by responses on surveys, classroom observations, review of summative teacher appraisal instruments and focus group...

  3. Functional groups show distinct differences in nitrogen cycling during early stand development: implications for forest management

    Science.gov (United States)

    Doug P. Aubrey; David R. Coyle; Mark D. Coleman

    2012-01-01

    Background and aims Nutrient acquisition of forest stands is controlled by soil resource availability and belowground production, but tree species are rarely compared in this regard. Here, we examine ecological and management implications of nitrogen (N) dynamics during early forest stand development in productive commercial tree species with narrow (Populus...

  4. Oxidative and nitrosative stress in ammonia neurotoxicity.

    Science.gov (United States)

    Skowrońska, Marta; Albrecht, Jan

    2013-04-01

    Increased ammonia accumulation in the brain due to liver dysfunction is a major contributor to the pathogenesis of hepatic encephalopathy (HE). Fatal outcome of rapidly progressing (acute) HE is mainly related to cytotoxic brain edema associated with astrocytic swelling. An increase of brain ammonia in experimental animals or treatment of cultured astrocytes with ammonia generates reactive oxygen and nitrogen species in the target tissues, leading to oxidative/nitrosative stress (ONS). In cultured astrocytes, ammonia-induced ONS is invariably associated with the increase of the astrocytic cell volume. Interrelated mechanisms underlying this response include increased nitric oxide (NO) synthesis which is partly coupled to the activation of NMDA receptors and increased generation of reactive oxygen species by NADPH oxidase. ONS and astrocytic swelling are further augmented by excessive synthesis of glutamine (Gln) which impairs mitochondrial function following its accumulation in there and degradation back to ammonia ("the Trojan horse" hypothesis). Ammonia also induces ONS in other cell types of the CNS: neurons, microglia and the brain capillary endothelial cells (BCEC). ONS in microglia contributes to the central inflammatory response, while its metabolic and pathophysiological consequences in the BCEC evolve to the vasogenic brain edema associated with HE. Ammonia-induced ONS results in the oxidation of mRNA and nitration/nitrosylation of proteins which impact intracellular metabolism and potentiate the neurotoxic effects. Simultaneously, ammonia facilitates the antioxidant response of the brain, by activating astrocytic transport and export of glutathione, in this way increasing the availability of precursors of neuronal glutathione synthesis.

  5. Role of Prion Protein Aggregation in Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Tullio Florio

    2012-07-01

    Full Text Available In several neurodegenerative diseases, such as Parkinson, Alzheimer’s, Huntington, and prion diseases, the deposition of aggregated misfolded proteins is believed to be responsible for the neurotoxicity that characterizes these diseases. Prion protein (PrP, the protein responsible of prion diseases, has been deeply studied for the peculiar feature of its misfolded oligomers that are able to propagate within affected brains, inducing the conversion of the natively folded PrP into the pathological conformation. In this review, we summarize the available experimental evidence concerning the relationship between aggregation status of misfolded PrP and neuronal death in the course of prion diseases. In particular, we describe the main findings resulting from the use of different synthetic (mainly PrP106-126 and recombinant PrP-derived peptides, as far as mechanisms of aggregation and amyloid formation, and how these different spatial conformations can affect neuronal death. In particular, most data support the involvement of non-fibrillar oligomers rather than actual amyloid fibers as the determinant of neuronal death.

  6. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  7. Protection against neurotoxicity by an autophagic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Kangyong; Huang, Jiankang; Chen, Rongfu; Zhang, Ting [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Shen, Liwei [Department of Neurology, Fifth People' s Hospital, Fudan University, Shanghai (China); Yang, Jiajun; Sun, Xiaojiang [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China)

    2012-03-23

    The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP{sup +})-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP{sup +} (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP{sup +}-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP{sup +}-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP{sup +}-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  8. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  9. Neurotoxicity of traffic-related air pollution.

    Science.gov (United States)

    Costa, Lucio G; Cole, Toby B; Coburn, Jacki; Chang, Yu-Chi; Dao, Khoi; Roqué, Pamela J

    2017-03-01

    The central nervous system is emerging as an important target for adverse health effects of air pollution, where it may contribute to neurodevelopmental and neurodegenerative disorders. Air pollution comprises several components, including particulate matter (PM) and ultrafine particulate matter (UFPM), gases, organic compounds, and metals. An important source of ambient PM and UFPM is represented by traffic-related air pollution, primarily diesel exhaust (DE). Human epidemiological studies and controlled animal studies have shown that exposure to air pollution, and to traffic-related air pollution or DE in particular, may lead to neurotoxicity. In particular, air pollution is emerging as a possible etiological factor in neurodevelopmental (e.g. autism spectrum disorders) and neurodegenerative (e.g. Alzheimer's disease) disorders. The most prominent effects caused by air pollution in both humans and animals are oxidative stress and neuro-inflammation. Studies in mice acutely exposed to DE (250-300μg/m(3) for 6h) have shown microglia activation, increased lipid peroxidation, and neuro-inflammation in various brain regions, particularly the hippocampus and the olfactory bulb. An impairment of adult neurogenesis was also found. In most cases, the effects of DE were more pronounced in male mice, possibly because of lower antioxidant abilities due to lower expression of paraoxonase 2.

  10. Selenium protects neonates against neurotoxicity from prenatal exposure to manganese.

    Directory of Open Access Journals (Sweden)

    Xin Yang

    Full Text Available Manganese (Mn exposure can affect brain development. Whether Selenium (Se can protect neonates against neurotoxicity from Mn exposure remains unclear. We investigated this issue in 933 mother-newborn pairs in Shanghai, China, from 2008 through 2009. Umbilical cord serum concentrations of Mn and Se were measured and Neonatal Behavioral Neurological Assessment (NBNA tests were conducted. The scores <37 were defined as the low NBNA. The median concentrations of cord serum Mn and Se were 4.0 µg/L and 63.1 µg/L, respectively. After adjusting for potential confounders, the interaction between Se and Mn was observed. Cord blood Mn levels had different effects on NBNA scores stratified by different cord blood Se levels. With Sedevelopment against neurotoxicity from prenatal exposure to Mn. Se supplementation should be considered during pregnancy, especially in areas with low natural Se.

  11. Adiponectin is protective against oxidative stress induced cytotoxicity in amyloid-beta neurotoxicity.

    Directory of Open Access Journals (Sweden)

    Koon-Ho Chan

    Full Text Available Beta-amyloid (Aβ neurotoxicity is important in Alzheimer's disease (AD pathogenesis. Aβ neurotoxicity causes oxidative stress, inflammation and mitochondrial damage resulting in neuronal degeneration and death. Oxidative stress, inflammation and mitochondrial failure are also pathophysiological mechanisms of type 2 diabetes (T(2DM which is characterized by insulin resistance. Interestingly, T(2DM increases risk to develop AD which is associated with reduced neuronal insulin sensitivity (central insulin resistance. We studied the potential protective effect of adiponectin (an adipokine with insulin-sensitizing, anti-inflammatory and anti-oxidant properties against Aβ neurotoxicity in human neuroblastoma cells (SH-SY5Y transfected with the Swedish amyloid precursor protein (Sw-APP mutant, which overproduced Aβ with abnormal intracellular Aβ accumulation. Cytotoxicity was measured by assay for lactate dehydrogenase (LDH released upon cell death and lysis. Our results revealed that Sw-APP transfected SH-SY5Y cells expressed both adiponectin receptor 1 and 2, and had increased AMP-activated protein kinase (AMPK activation and enhanced nuclear factor-kappa B (NF-κB activation compared to control empty-vector transfected SH-SY5Y cells. Importantly, adiponectin at physiological concentration of 10 µg/ml protected Sw-APP transfected SH-SY5Y cells against cytotoxicity under oxidative stress induced by hydrogen peroxide. This neuroprotective action of adiponectin against Aβ neurotoxicity-induced cytotoxicity under oxidative stress involved 1 AMPK activation mediated via the endosomal adaptor protein APPL1 (adaptor protein with phosphotyrosine binding, pleckstrin homology domains and leucine zipper motif and possibly 2 suppression of NF-κB activation. This raises the possibility of novel therapies for AD such as adiponectin receptor agonists.

  12. Molecular Mechanisms of Allosteric Inhibition of Brain Glycogen Phosphorylase by Neurotoxic Dithiocarbamate Chemicals.

    Science.gov (United States)

    Mathieu, Cécile; Bui, Linh-Chi; Petit, Emile; Haddad, Iman; Agbulut, Onnik; Vinh, Joelle; Dupret, Jean-Marie; Rodrigues-Lima, Fernando

    2017-02-03

    Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (kinact = 1.4 × 10(5) m(-1) s(-1)). Using cysteine chemical labeling, mass spectrometry, and site-directed mutagenesis approaches, we show that thiram (and certain of its metabolites) alters the activity of bGP through the formation of an intramolecular disulfide bond (Cys(318)-Cys(326)), known to act as a redox switch that precludes the allosteric activation of bGP by AMP. Given the key role of glycogen metabolism in brain functions and neurodegeneration, impairment of the glycogenolytic activity of bGP by DTCs such as thiram may be a new mechanism by which certain DTCs exert their neurotoxic effects.

  13. Overexpression cdc42 attenuates isoflurane-induced neurotoxicity in developmental brain of rats.

    Science.gov (United States)

    Fang, Xi; Li, Shiyong; Han, Qiang; Zhao, Yilin; Gao, Jie; Yan, Jing; Luo, Ailin

    2017-08-26

    Nowadays many children receive operations with general anesthesia. Isoflurane is a commonly-used general anesthetic. Numbers of studies demonstrated that isoflurane induced neurotoxicity and neurobehavioral deficiency in young rats, however, the underlying mechanism remained unknown. Cell division cycle 42 (cdc42) played an important role in regulating synaptic vesicle trafficking and actin dynamics in neuron, which closely linked to synaptic plasticity and dendritic spine formation. Meanwhile, cdc42 also involved in many neurodegenerative diseases. However, whether cdc42 provided a protective role in isoflurane induced synaptogenesis dysfunction still unknown. As the upstream of cdc42, calcium/Calmodulin-dependent protein kinase II (CaMKII) interacts with ion channels such as VDCCs and N-methyl-d-aspartate receptors (NMDARs), which closely associated with neuroapoptosis and cognitive deficiency in developing brain. The phosphorylation of CaMKIIα at Thr 286 plays an important role in introduction and maintenance of long-term potentiation (LTP). Therefore, we investigated the effect of isoflurane on cdc42 and its upstream Calcium/Calmodulin-dependent protein kinase II (CaMKII) and its downstream p21 activated kinase 3 (PAK3), then determined whether CaMKIIα/cdc42/PAK3 signaling pathway was involved in neurotoxicity and cognitive deficiency induced by isoflurane. Our study found that isoflurane induced neurotoxicity and resulted in cognitive impairment in young rats through suppressed CaMKIIα/cdc42/PAK3 signaling pathway. Cdc42 over-expression could reverse neurotoxicity and improve cognitive impairment induced by isoflurane. Copyright © 2017. Published by Elsevier Inc.

  14. Oxaliplatin neurotoxicity involves peroxisome alterations. PPARγ agonism as preventive pharmacological approach.

    Directory of Open Access Journals (Sweden)

    Matteo Zanardelli

    Full Text Available The development of neuropathic syndromes is an important, dose limiting side effect of anticancer agents like platinum derivates, taxanes and vinca alkaloids. The causes of neurotoxicity are still unclear but the impairment of the oxidative equilibrium is strictly related to pain. Two intracellular organelles, mitochondria and peroxisomes cooperate to the maintaining of the redox cellular state. Whereas a relationship between chemotherapy-dependent mitochondrial alteration and neuropathy has been established, the role of peroxisome is poor explored. In order to study the mechanisms of oxaliplatin-induced neurotoxicity, peroxisomal involvement was evaluated in vitro and in vivo. In primary rat astrocyte cell culture, oxaliplatin (10 µM for 48 h or 1 µM for 5 days increased the number of peroxisomes, nevertheless expression and functionality of catalase, the most important antioxidant defense enzyme in mammalian peroxisomes, were significantly reduced. Five day incubation with the selective Peroxisome Proliferator Activated Receptor-γ (PPAR-γ antagonist G3335 (30 µM induced a similar peroxisomal impairment suggesting a relationship between PPARγ signaling and oxaliplatin neurotoxicity. The PPARγ agonist rosiglitazone (10 µM reduced the harmful effects induced both by G3335 and oxaliplatin. In vivo, in a rat model of oxaliplatin induced neuropathy, a repeated treatment with rosiglitazone (3 and 10 mg kg(-1 per os significantly reduced neuropathic pain evoked by noxious (Paw pressure test and non-noxious (Cold plate test stimuli. The behavioral effect paralleled with the prevention of catalase impairment induced by oxaliplatin in dorsal root ganglia. In the spinal cord, catalase protection was showed by the lower rosiglitazone dosage without effect on the astrocyte density increase induced by oxaliplatin. Rosiglitazone did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. These results highlight the role

  15. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy.

    Science.gov (United States)

    Melli, Giorgia; Taiana, Michela; Camozzi, Francesca; Triolo, Daniela; Podini, Paola; Quattrini, Angelo; Taroni, Franco; Lauria, Giuseppe

    2008-12-01

    The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.

  16. An autophagic mechanism is involved in the 6-hydroxydopamine-induced neurotoxicity in vivo.

    Science.gov (United States)

    He, Xin; Yuan, Wei; Li, Zijian; Feng, Juan

    2017-08-09

    6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied. We found that both 3-MA and Z-FA-fmk could not only exert immediate protection against 6-OHDA-induced neuronal apoptosis, but also prevent dopaminergic neuron loss in the long-term, which was related to reduced autophagosome formation. Furthermore, by monitoring the sequential changes of mTOR-related signaling pathways, we found that reactive oxygen species (ROS)-mediated AKT/AMPK-mTOR signaling pathway participated in but was not the initial cause of autophagy activation by 6-OHDA. Collectively, our data suggest that 6-OHDA-induced autophagy activation contributes to its neurotoxicity and targeting autophagy activation or cysteine proteases could be promising for developing neuroprotective agents for PD. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. ASEAN Open Skies and Its Implications on Airport Development Strategy in Malaysia

    OpenAIRE

    Siew Yean Tham

    2008-01-01

    This paper seeks to examine the implication of open skies in ASEAN on the airport development strategy in Malaysia. "Open Skies," in general, refers to the liberalization of aviation markets that can be pursued on a bilateral, regional, or multilateral basis. The findings show that although Malaysia has invested substantially in overall infrastructure development, including airports, other member countries within ASEAN, notably Singapore and Thailand, have also followed a similar investment-i...

  18. Neurosciences of infant mental health development: recent findings and implications for counseling psychology.

    Science.gov (United States)

    Sampaio, Adriana; Lifter, Karin

    2014-10-01

    This article is about the neural correlates of infant mental health and their correspondences to social emotional development. These correspondences are organized in terms of the definition of infant mental provided by Zero to Three (2001), centered on infants' capacities regarding the experience and expression of emotions, interpersonal relationships, and learning. We conclude with implications of these correspondences for counseling psychology-namely, working with children's caregivers to maximize children's healthy social and emotional development.

  19. Corticosterone and Exogenous Glucose Alter Blood Glucose levels, Neurotoxicity, and Vascular Toxicity Produced by Methamphetamine.

    Science.gov (United States)

    Bowyer, John F; Tranter, Karen M; Sarkar, Sumit; George, Nysia I; Hanig, Joseph P; Kelly, Kimberly A; Michalovicz, Lindsay T; Miller, Diane B; O'Callaghan, James P

    2017-08-09

    Our previous studies have raised the possibility that altered blood glucose levels may influence and/or be predictive of methamphetamine (METH) neurotoxicity. This study evaluated the effects of exogenous glucose and corticosterone (CORT) pretreatment alone or in combination with METH on blood glucose levels and the neural and vascular toxicity produced. METH exposure consisted of four sequential injections of 5, 7.5, 10, and 10 mg/kg (2h between injections) D-METH. The three groups given METH in combination with saline, glucose (METH+Glucose), or CORT (METH+CORT) had significantly higher glucose levels compared to the corresponding treatment groups without METH except at 3 h after the last injection. At this last time point, the METH and METH+Glucose groups had lower levels than the non-METH groups, while the METH+CORT group did not. CORT alone or glucose alone did not significantly increase blood glucose. Mortality rates for the METH+CORT (40%) and METH+Glucose (44%) groups were substantially higher than the METH (< 10%) group. Additionally, METH+CORT significantly increased neurodegeneration above all other treatments (≈ 2.5-fold in the parietal cortex). Thus, maintaining elevated levels of glucose during METH exposure increases lethality and may exacerbate neurodegeneration. Neuroinflammation, specifically microglial activation, was associated with degenerating neurons in the parietal cortex and thalamus after METH exposure. The activated microglia in the parietal cortex were surrounding vasculature in most cases and the extent of microglial activation was exacerbated by CORT pretreatment. Our findings implicate elevated blood levels of glucose and hyperthermia in METH-induced neurotoxicity, neurovascular damage, and lethality, and that acute elevation of CORT exacerbates both neurotoxicity and neuroinflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  20. Enzymatic activity and inhibition of the neurotoxic complex vipoxin from the venom of Vipera ammodytes meridionalis.

    Science.gov (United States)

    Noetzel, Corinna; Chandra, Vikas; Perbandt, Markus; Rajashankar, Kanagalaghatta; Singh, Tej; Aleksiev, Boris; Kalkura, Narayana; Genov, Nicolay; Betzel, Christian

    2002-01-01

    Vipoxin from the venom of Vipera ammodytes meridionalis is an unique neurotoxic complex between a toxic phospholipase A2 and a highly homologous non-toxic protein inhibitor. It is an example of evolution of a catalytic and toxic function into inhibitory and non-toxic one. The activity of the V. ammodytes meridionalis toxin is 1.7 times higher than that of the closely related (92% sequence identity) neurotoxic complex RV4/RV7 from the venom of Vipera russelli formosensis The enhanced enzymatic activity of vipoxin is attributed to limited structural changes, in particular to the substitutions G54R and Q78K in the PLA2 subunit of the complex and to the T54R substitution in the inhibitor. Oleyloxyethylphosphocholine, aristolochic acid and vitamin E suppressed the enzymatic activity of vipoxin and its isolated PLA2 subunit. These compounds influence inflammatory processes in which PLA2 is implicated. The peptide Lys-Ala-Ile-Tyr-Ser, which is an integral part of the PLA2 components of the two neurotoxic complexes from V. ammodytes meridionalis and V. russelli formosensis (sequence 70-74) activated vipoxin increasing its PLA2 activity by 23%. This is in contrast to the inhibitory effect of the respective pentapeptides with 70-74 sequences on other group II PLA2s. Surprisingly, the same peptide inhibited 46% of the V. russelli formosensis PLA2 activity. The limited changes in the structure of the two highly homologous neurotoxins lead to considerable differences in their interaction with native peptides.

  1. [Neurotoxicity of organic solvents--recent findings].

    Science.gov (United States)

    Matsuoka, Masato

    2007-06-01

    In this review, the recent findings of central nervous system (CNS) or peripheral nervous system (PNS) dysfunction induced by occupational exposure to organic solvents are described. While acute, high-level exposure to almost all organic solvents causes the general, nonspecific depression of CNS, it is still not clear whether chronic, low-level occupational exposure causes the chronic neurological dysfunction which has been called "organic solvent syndrome", "painters syndrome", "psycho-organic syndrome" or "chronic solvent encephalopathy". At least at lower than occupational exposure limits, chronic and low-level organic solvent exposure does not appear to cause the "sy mptomatic" neurological dysfunction. The chronic, moderate- to high-level exposure to a few organic solvents (such as carbon disulfide, n-hexane and methyl n-butyl ketone) affects CNS or PNS specifically. The substitutes for chlorofluorocarbons, 2-bromopropane and 1-bromopropane were shown to have the peripheral nerve toxicity in the experimental animals. Shortly after these observations, human cases of 1-bromopropane intoxication with the dysfunction of CNS and PNS were reported in the United States. Neurological abnormalities in workers of a 1-bromopropane factory in China were also reported. Thus, the possible neurotoxicity of newly introduced substitutes for ozone-depleting solvents into the workplace must be considered. Enough evidences indicate that some common solvents (such as toluene and styrene) induce sensorineural hearing loss and acquired color vision disturbances in workers. In some studies using magnetic resonance imaging (MRI), cerebral atrophy, patchy periventricular hyperintensities and hypointensities in the basal ganglia were found in solvent-exposed workers as have been shown in toluene abusers (toluene leukoencephalopathy). Further studies using the neurobehavioral test batteries, neurophysiological measurements and advanced neuroimaging techniques are required to detect the

  2. Geochemical Implication of Rare Earth Elements in Process of Soil Development

    Institute of Scientific and Technical Information of China (English)

    黄成敏; 龚子同

    2001-01-01

    The geochemical characteristics and behavior of rare earth elements (REE) in soils developed on the basalts in the northern part of Hainan Island erupted in different time were studied as well as the REE partition in the soil-formation process and its implication on soil development degree. The results show that the total REE content in soils is correlative with soil age significantly and can be selected as the index to show soil evolution. With the soil developing intensively, light rare earth elements (LREE) gain and heavy rare earth elements (HREE) lose. The trends of positive Ce-anomaly and negative Eu-anomaly are remarkable with soil development.

  3. Neurotoxicity Caused by the Treatment with Platinum Analogues

    Directory of Open Access Journals (Sweden)

    Sousana Amptoulach

    2011-01-01

    Full Text Available Platinum agents (cisplatin, carboplatin, and oxaliplatin are a class of chemotherapy agents that have a broad spectrum of activity against several solid tumors. Toxicity to the peripheral nervous system is the major dose-limiting toxicity of at least some of the platinum drugs of clinical interest. Among the platinum compounds in clinical use, cisplatin is the most neurotoxic, inducing mainly sensory neuropathy of the upper and lower extremities. Carboplatin is generally considered to be less neurotoxic than cisplatin, but it is associated with a higher risk of neurological dysfunction if administered at high dose or in combination with agents considered to be neurotoxic. Oxaliplatin induces two types of peripheral neuropathy, acute and chronic. The incidence of oxaliplatin-induced neuropathy is related to various risk factors such as treatment schedule, cumulative dose, and time of infusion. To date, several neuroprotective agents including thiol compounds, vitamin E, various anticonvulsants, calcium-magnesium infusions, and other nonpharmacological strategies have been tested for their ability to prevent platinum-induced neurotoxicity with controversial results. Further studies on the prevention and treatment of neurotoxicity of platinum analogues are warranted.

  4. Neurotoxicity of propofol on rat hypoglossal motoneurons in vitro.

    Science.gov (United States)

    Monni, Laura; Ghezzi, Filippo; Corsini, Silvia; Nistri, Andrea

    2017-08-10

    Although propofol is a widely used intravenous general anaesthetic, many studies report its toxic potential, particularly on the developing central nervous system. We investigated its action on hypoglossal motoneurons (HMs) that control two critical functions in neonates, namely tongue muscle activity and airway patency. Thus, clinically relevant concentrations of propofol (1 and 5μM) were applied (4h) to neonatal rat brainstem slices to evaluate the expression of apoptosis-inducing factor (AIF) as biomarker of toxicity. This anaesthetic strongly increased AIF in the cytoplasm and the nucleus, without early loss of HMs. Electrophysiological recordings from HMs showed that propofol (5μM) enhanced GABA- and glycine-evoked current amplitude and lengthened GABAergic current decay time. Propofol also depressed NMDA receptor-mediated responses without affecting AMPA receptors. Since GABA and glycine depolarize neonatal HMs, we propose that the damaging action by propofol on these motoneurons might arise from the facilitated action of these transmitters with subsequent cytoplasmic Ca(2+) overload. This phenomenon, in turn, may trigger cell death mechanisms manifested as increased expression of AIF and its translocation into the nucleus. Since propofol is also employed for induction and maintenance of paediatric surgery, caution is needed because its potential neurotoxicity might negatively impact neurodevelopment. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. miR-137 attenuates Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in Neuro2a cells.

    Science.gov (United States)

    He, Dan; Tan, Jun; Zhang, Jiewen

    2017-08-26

    Accumulation of β-amyloid (Aβ) and neuroinflammation are implicated in the pathogenesis and development of Alzheimer's disease (AD). Neuron-enriched miR-137 was aberrantly downregulated and may be associated with the pathogenesis of AD. However, the detailed function of miR-137 in AD pathogenesis and the molecular mechanism have not been elucidated. The expressions of miR-137 and tumor necrosis factor alpha (TNFα)-induced protein 1 (TNFAIP1) at mRNA and protein levels in primary mouse cortical neurons and Neuro2a (N2a) cells exposed to different concentrations of Aβ25-35 were examined by qRT-PCR and western blot. Luciferase reporter assay was used to confirm the potential target of miR-137. MTT assay, flow cytometry analysis, caspase-3 activity assay, Enzyme-linked immunosorbent assay (ELISA), and western blot were used to detect cell viability, apoptosis, caspase-3 activity, Nuclear factor-kappa B (NF-κB) activity and level, respectively. Aβ25-35 downregulated miR-137 and upregulated TNFAIP1 in primary mouse cortical neurons and N2a cells. In addition, miR-137 was found to directly target TNFAIP1 and suppress its mRNA and protein levels. Moreover, miR-137 restoration and TNFAIP1 knockdown facilitate Aβ25-35-induced cell toxicity, apoptosis, caspase-3 activity, and activated NF-κB in N2a cells, which was partially abolished by TNFAIP1 overexpression. miR-137 attenuated Aβ-induced neurotoxicity through inactivation of NF-κB pathway by targeting TNFAIP1 in N2a cells, shedding light on the molecular mechanism of miR-137 underlying Aβ-induced neurotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Attenuation of Oxidative Damage by Boerhaavia diffusa L. Against Different Neurotoxic Agents in Rat Brain Homogenate.

    Science.gov (United States)

    Ayyappan, Prathapan; Palayyan, Salin Raj; Kozhiparambil Gopalan, Raghu

    2016-01-01

    Due to a high rate of oxidative metabolic activity in the brain, intense production of reactive oxygen metabolite occurs, and the subsequent generation of free radicals is implicated in the pathogenesis of traumatic brain injury, epilepsy, and ischemia as well as chronic neurodegenerative diseases. In the present study, protective effects of polyphenol rich ethanolic extract of Boerhaavia diffusa (BDE), a neuroprotective edible medicinal plant against oxidative stress induced by different neurotoxic agents, were evaluated. BDE was tested against quinolinic acid (QA), 3-nitropropionic acid (NPA), sodium nitroprusside (SNP), and Fe (II)/EDTA complex induced oxidative stress in rat brain homogenates. QA, NPA, SNP, and Fe (II)/EDTA treatment caused an increased level of thiobarbituric acid reactive substances (TBARS) in brain homogenates along with a decline in the activities of antioxidant enzymes. BDE treatment significantly decreased the production of TBARS (p tissues. Therefore, B. diffusa had high antioxidant potential that could inhibit the oxidative stress induced by different neurotoxic agents in brain. Since many of the neurological disorders are associated with free radical injury, these data may imply that B. diffusa, functioning as an antioxidant agent, may be beneficial for reducing various neurodegenerative complications.

  7. Lithium prevents acrolein-induced neurotoxicity in HT22 mouse hippocampal cells.

    Science.gov (United States)

    Huang, Yingjuan; Qin, Jian; Chen, Meihui; Chao, Xiaojuan; Chen, Ziwei; Ramassamy, Charles; Pi, Rongbiao; Jin, Minghua

    2014-04-01

    Acrolein is a highly electrophilic alpha, beta-unsaturated aldehyde to which humans are exposed in many situations and has been implicated in neurodegenerative diseases, such as Alzheimer's disease. Lithium is demonstrated to have neuroprotective and neurotrophic effects in brain ischemia, trauma, neurodegenerative disorders, and psychiatric disorders. Previously we have found that acrolein induced neuronal death in HT22 mouse hippocampal cells. In this study, the effects of lithium on the acrolein-induced neurotoxicity in HT22 cells as well as its mechanism(s) were investigated. We found that lithium protected HT22 cells against acrolein-induced damage by the attenuation of reactive oxygen species and the enhancement of the glutathione level. Lithium also attenuated the mitochondrial dysfunction caused by acrolein. Furthermore, lithium significantly increased the level of phospho-glycogen synthase kinase-3 beta (GSK-3β), the non-activated GSK-3β. Taken together, our findings suggest that lithium is a protective agent for acrolein-related neurotoxicity.

  8. Studies with neuronal cells: From basic studies of mechanisms of neurotoxicity to the prediction of chemical toxicity.

    Science.gov (United States)

    Suñol, C; Babot, Z; Fonfría, E; Galofré, M; García, D; Herrera, N; Iraola, S; Vendrell, I

    2008-08-01

    Neurotoxicology considers that chemicals perturb neurological functions by interfering with the structure or function of neural pathways, circuits and systems. Using in vitro methods for neurotoxicity studies should include evaluation of specific targets for the functionalism of the nervous system and general cellular targets. In this review we present the neuronal characteristics of primary cultures of cortical neurons and of cerebellar granule cells and their use in neurotoxicity studies. Primary cultures of cortical neurons are constituted by around 40% of GABAergic neurons, whereas primary cultures of cerebellar granule cells are mainly constituted by glutamatergic neurons. Both cultures express functional GABAA and ionotropic glutamate receptors. We present neurotoxicity studies performed in these cell cultures, where specific neural targets related to GABA and glutamate neurotransmission are evaluated. The effects of convulsant polychlorocycloalkane pesticides on the GABAA, glycine and NMDA receptors points to the GABAA receptor as the neural target that accounts for their in vivo acute toxicity, whereas NMDA disturbance might be relevant for long-term toxicity. Several compounds from a list of reference compounds, whose severe human poisoning result in convulsions, inhibited the GABAA receptor. We also present cell proteomic studies showing that the neurotoxic contaminant methylmercury affect mitochondrial proteins. We conclude that the in vitro assays that have been developed can be useful for their inclusion in an in vitro test battery to predict human toxicity.

  9. Non-fibrillar amyloid-{beta} peptide reduces NMDA-induced neurotoxicity, but not AMPA-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Niidome, Tetsuhiro, E-mail: tniidome@pharm.kyoto-u.ac.jp [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goto, Yasuaki; Kato, Masaru; Wang, Pi-Lin [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Goh, Saori; Tanaka, Naoki [Department of Biomolecular Engineering, Kyoto Institute of Technology, Kyoto 606-8585 (Japan); Akaike, Akinori [Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan); Kihara, Takeshi; Sugimoto, Hachiro [Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501 (Japan)

    2009-09-04

    Amyloid-{beta} peptide (A{beta}) is thought to be linked to the pathogenesis of Alzheimer's disease. Recent studies suggest that A{beta} has important physiological roles in addition to its pathological roles. We recently demonstrated that A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity, but the relationship between A{beta}42 assemblies and their neuroprotective effects remains largely unknown. In this study, we prepared non-fibrillar and fibrillar A{beta}42 based on the results of the thioflavin T assay, Western blot analysis, and atomic force microscopy, and examined the effects of non-fibrillar and fibrillar A{beta}42 on glutamate-induced neurotoxicity. Non-fibrillar A{beta}42, but not fibrillar A{beta}42, protected hippocampal neurons from glutamate-induced neurotoxicity. Furthermore, non-fibrillar A{beta}42 decreased both neurotoxicity and increases in the intracellular Ca{sup 2+} concentration induced by N-methyl-D-aspartate (NMDA), but not by {alpha}-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA). Our results suggest that non-fibrillar A{beta}42 protects hippocampal neurons from glutamate-induced neurotoxicity through regulation of the NMDA receptor.

  10. Co-exposure to an ortho-substituted PCB (PCB 153) and methylmercury enhances developmental neurotoxic effects

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, C.; Fredriksson, A.; Eriksson, P. [Dept. Environment. Toxicol., Uppsala Univ. (Sweden)

    2004-09-15

    In our environment there are innumerable hazardous contaminants. Many of these compounds are the well-known persistent organic pollutants (POPs) like PCB and DDT. Another persistent agent in our environment is methylmercury (MeHg). These agents are known to be neurotoxic in laboratory animals and humans. Fetuses and neonates are known to be high-risk groups for exposure to these agents. A naturally occurring circumstance is the exposure to a combination of different persistent compounds. The knowledge of interaction between different toxic agents during development is sparse. In several studies we have shown that low-dose exposure of environmental toxic agents such as PCBs, DDT, BFRs (brominated flame retardants) as well as well-known neurotoxic agents such as nicotine, organophosphorous compounds and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), during the ''BGS'', in neonatal mice can lead to disruption of the adult brain function, and to an increased susceptibility to toxic agents as adults. Our studies concerning developmental neurotoxic effects after neonatal exposure to single PCB congeners have shown that some orthosubstituted PCBs (such as PCB 28, PCB 52, PCB 153) and some co-planar PCBs (such as PCB 77, PCB 126, PCB 169) cause derangement of adult behaviour that can worsen with age. Furthermore, the cholinergic receptors in the brain were also found to be affected8. Just recently we have seen that neonatal co-exposure to an ortho-substituted PCB, 2,2',5,5'-tetrachlorobiphenyl (PCB 52), together with a brominated flame retardant, 2,2',4,4',5-pentabromodiphenylether (PBDE 99), can enhance developmental neurotoxic effects when the exposure occurs during a critical stage of neonatal brain development. The present study was carried out in order to see whether PCB and MeHg could interact to cause enhanced developmental neurotoxic effects on spontaneous behaviour and habituation capability when given to neonatal mice.

  11. Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes

    Science.gov (United States)

    Gonzalez-Carter, Daniel A.; Leo, Bey Fen; Ruenraroengsak, Pakatip; Chen, Shu; Goode, Angela E.; Theodorou, Ioannis G.; Chung, Kian Fan; Carzaniga, Raffaella; Shaffer, Milo S. P.; Dexter, David T.; Ryan, Mary P.; Porter, Alexandra E.

    2017-03-01

    Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity.

  12. Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes

    Science.gov (United States)

    Gonzalez-Carter, Daniel A.; Leo, Bey Fen; Ruenraroengsak, Pakatip; Chen, Shu; Goode, Angela E.; Theodorou, Ioannis G.; Chung, Kian Fan; Carzaniga, Raffaella; Shaffer, Milo S. P.; Dexter, David T.; Ryan, Mary P.; Porter, Alexandra E.

    2017-01-01

    Silver nanoparticles (AgNP) are known to penetrate into the brain and cause neuronal death. However, there is a paucity in studies examining the effect of AgNP on the resident immune cells of the brain, microglia. Given microglia are implicated in neurodegenerative disorders such as Parkinson’s disease (PD), it is important to examine how AgNPs affect microglial inflammation to fully assess AgNP neurotoxicity. In addition, understanding AgNP processing by microglia will allow better prediction of their long term bioreactivity. In the present study, the in vitro uptake and intracellular transformation of citrate-capped AgNPs by microglia, as well as their effects on microglial inflammation and related neurotoxicity were examined. Analytical microscopy demonstrated internalization and dissolution of AgNPs within microglia and formation of non-reactive silver sulphide (Ag2S) on the surface of AgNPs. Furthermore, AgNP-treatment up-regulated microglial expression of the hydrogen sulphide (H2S)-synthesizing enzyme cystathionine-γ-lyase (CSE). In addition, AgNPs showed significant anti-inflammatory effects, reducing lipopolysaccharide (LPS)-stimulated ROS, nitric oxide and TNFα production, which translated into reduced microglial toxicity towards dopaminergic neurons. Hence, the present results indicate that intracellular Ag2S formation, resulting from CSE-mediated H2S production in microglia, sequesters Ag+ ions released from AgNPs, significantly limiting their toxicity, concomitantly reducing microglial inflammation and related neurotoxicity. PMID:28251989

  13. Perceived environmental uncertainty : understanding the implications for strategy development processes across Barclays Plc

    OpenAIRE

    Ryder, Jansen

    2005-01-01

    The managerial issue being addressed in this research is perceived environmental uncertainty (experienced by corporate strategists) and its implications for strategy development processes at the strategic business unit level (or business-level strategy) across Barclays Bank PLC. The objectives of the research are achieved through: an extensive review of the strategy and uncertainty literature (Project 1); a series of semi-structured interviews with fifteen members of the Group ...

  14. ASEAN open skies and the implications for airport development strategy in Malaysia

    OpenAIRE

    Tham, Siew Yean

    2008-01-01

    Open Skies, in general, refers to the liberalization of aviation markets that can be pursued on a bilateral, regional, or multilateral basis. At the Association of Southeast Asian Nations (ASEAN) level, liberalization of airfreight and passenger services is targeted by December 2008. This paper seeks to examine the implication of open skies in ASEAN on the airport development strategy in Malaysia. The findings show that although Malaysia has invested substantially in overall infrastructure de...

  15. The rise of supermarkets in developing countries: Implications for credit markets

    OpenAIRE

    Luc, Veyssiere

    2007-01-01

    The rise of supermarket in developing countries has important implications for the agricultural system in these countries. To lessen the intense price competition in retail markets, supermarkets have introduced private food standards. While the literature has pointed out the additional financial burden for producers, associated with the introduction of supermarket standards, it has ignored its positive demand effect. This paper examines the relationship between downstream product competition ...

  16. Phantom limb pain as a manifestation of paclitaxel neurotoxicity.

    Science.gov (United States)

    Khattab, J; Terebelo, H R; Dabas, B

    2000-07-01

    Paclitaxel is a chemotherapeutic agent with activity directed against several malignancies. It has multiple adverse effects including neurotoxicity. We describe 2 patients with prior amputation who experienced phantom limb pain (PLP) after receiving paclitaxel therapy. A third patient experienced disabling neurotoxicity in the extremity of a prior ulnar nerve and tendon transposition after receiving paclitaxel. This unique syndrome should be identified as a direct causal effect of paclitaxel. In this report, we review the pathophysiology of PLP and treatment options. Physicians should be aware that PLP can occur after initiation of paclitaxel.

  17. [Neurotoxicity of 1-bromopropane in rats].

    Science.gov (United States)

    Ohnishi, A; Ishidao, T; Kasai, T; Arashidani, K; Hori, H

    1999-03-01

    Neurotoxicity of 1-bromopropane (1-BP) used as an alternative solvent of fluorocarbons was experimentally studied. Eight rats in the experimental group were exposed to 1-BP at 1500 ppm for six hours a day, five days a week for four weeks in an exposure chamber. Another eight rats in the control group were exposed to room air in a similar exposure chamber as those in the experimental group. During the latter half of the fourth week of exposure, all the rats in the experimental group showed a loss of body weight and ataxic gait compared with control rats. At the end of the fourth week, the rats in both groups were perfused through the ascending aorta and fixed. The cerebellum, medulla oblongata, spinal cord and peripheral nerve were processed for histopathological studies. No statistically significant difference in the frequency of axonal degeneration in both peroneal and sural nerves was found between the experimental and control groups. In the cerebellum, the frequency of degeneration of Purkinje cells in both the vermis and hemisphere was higher in the experimental group than in the control group (P < 0.05). There was no significant difference in the frequency of myelin ovoids in the fifth thoracic and in the third cervical posterior columns of the spinal cord between control and experimental groups. There was also no significant difference in the frequency of axonal swelling in the nucleus gracilis of the medulla oblongata between control and experimental groups. Ataxic gait was considered to be induced by degeneration of Purkinje cells in the cerebellum due to 1-BP exposure. However, degenerative findings of nerve fibers in the peripheral nerve, spinal posterior column and nucleus gracilis of the medulla oblongata due to 1-BP exposure were not evident. At the end of the fourth week of exposure, rats in the experimental group showed loss of body weight and markedly decreased motor activities, and it was considered that they would die if we continued the exposure

  18. Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age

    Science.gov (United States)

    Graham, Alice M.; Buss, Claudia; Rasmussen, Jerod M.; Rudolph, Marc D.; Demeter, Damion V.; Gilmore, John H.; Styner, Martin; Entringer, Sonja; Wadhwa, Pathik D.; Fair, Damien A.

    2015-01-01

    The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M=3.65 weeks, SD=1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health. PMID:26499255

  19. Implications of newborn amygdala connectivity for fear and cognitive development at 6-months-of-age.

    Science.gov (United States)

    Graham, Alice M; Buss, Claudia; Rasmussen, Jerod M; Rudolph, Marc D; Demeter, Damion V; Gilmore, John H; Styner, Martin; Entringer, Sonja; Wadhwa, Pathik D; Fair, Damien A

    2016-04-01

    The first year of life is an important period for emergence of fear in humans. While animal models have revealed developmental changes in amygdala circuitry accompanying emerging fear, human neural systems involved in early fear development remain poorly understood. To increase understanding of the neural foundations of human fear, it is important to consider parallel cognitive development, which may modulate associations between typical development of early fear and subsequent risk for fear-related psychopathology. We, therefore, examined amygdala functional connectivity with rs-fcMRI in 48 neonates (M=3.65 weeks, SD=1.72), and measured fear and cognitive development at 6-months-of-age. Stronger, positive neonatal amygdala connectivity to several regions, including bilateral anterior insula and ventral striatum, was prospectively associated with higher fear at 6-months. Stronger amygdala connectivity to ventral anterior cingulate/anterior medial prefrontal cortex predicted a specific phenotype of higher fear combined with more advanced cognitive development. Overall, findings demonstrate unique profiles of neonatal amygdala functional connectivity related to emerging fear and cognitive development, which may have implications for normative and pathological fear in later years. Consideration of infant fear in the context of cognitive development will likely contribute to a more nuanced understanding of fear, its neural bases, and its implications for future mental health.

  20. The role of endogenous serotonin in methamphetamine-induced neurotoxicity to dopamine nerve endings of the striatum.

    Science.gov (United States)

    Thomas, David M; Angoa Pérez, Mariana; Francescutti-Verbeem, Dina M; Shah, Mrudang M; Kuhn, Donald M

    2010-11-01

    Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the striatum where long-term DA depletion and microglial activation are maximal. Endogenous DA has been implicated as a critical participant in METH-induced neurotoxicity, most likely as a substrate for non-enzymatic oxidation by METH-generated reactive oxygen species. The striatum is also extensively innervated by serotonin (5HT) nerve endings and this neurochemical system is modified by METH in much the same manner as seen in DA nerve endings (i.e., increased release of 5HT, loss of function in tryptophan hydroxylase and the serotonin transporter, long-term depletion of 5HT stores). 5HT can also be modified by reactive oxygen species to form highly reactive species that damage neurons but its role in METH neurotoxicity has not been assessed. Increases in 5HT levels with 5-hydroxytryptophan do not change METH-induced neurotoxicity to the DA nerve endings as revealed by reductions in DA, tyrosine hydroxylase and dopamine transporter levels. Partial reductions in 5HT with p-chlorophenylalanine are without effect on METH toxicity, despite the fact that p-chlorophenylalanine largely prevents METH-induced hyperthermia. Mice lacking the gene for brain tryptophan hydroxylase 2 are devoid of brain 5HT and respond to METH in the same manner as wild-type controls, despite showing enhanced drug-induced hyperthermia. Taken together, the present results indicate that endogenous 5HT does not appear to play a role in METH-induced damage to DA nerve endings of the striatum.

  1. Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells.

    Science.gov (United States)

    Popova, Dina; Forsblad, Andréas; Hashemian, Sanaz; Jacobsson, Stig O P

    2016-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

  2. Spatial Analysis on Future Housing Markets: Economic Development and Housing Implications

    Directory of Open Access Journals (Sweden)

    Xin Liu

    2014-01-01

    Full Text Available A coupled projection method combining formal modelling and other statistical techniques was developed to delineate the relationship between economic and social drivers for net new housing allocations. Using the example of employment growth in Tyne and Wear, UK, until 2016, the empirical analysis yields housing projections at the macro- and microspatial levels (e.g., region to subregion to elected ward levels. The results have important implications for the strategic planning of locations for housing and employment, demonstrating both intuitively and quantitatively how local economic developments affect housing demand.

  3. The Quality of Relationships in International Development: Institutional and Personal Implications

    Directory of Open Access Journals (Sweden)

    Leslie Groves

    2006-01-01

    Full Text Available In this article, the authors explore some of the personal and organisational implications entailed in satisfying the new demands for greater transparency and accountability in development aid. This calls for changes in the relationships among the different actors inthe international development system. The first part of the article focuses on how the groups of people conceive each other and behave, that is, the “personal” dimension of the construction of the relationship. In this sense, one can observe the role that can be played by the individual development agent to support the change in relationships called for by the new development agenda. In the second part, it examines how the people are connected through their organisations, as well as the institutional mechanisms that can hinder the development of quality relationships, and also how they can be transformed in order to better satisfy the needs of the new poverty reduction agenda.

  4. Time Windows of Interneuron Development: Implications to Our Understanding of the Aetiology and Treatment of Schizophrenia

    Directory of Open Access Journals (Sweden)

    Zarina Greenberg

    2015-11-01

    Full Text Available Schizophrenia is a devastating neuropsychiatric disorder widely believed to arise from defects during brain development. Indeed, dysfunction in the formation and function of GABAergic cortical interneurons has been implicated as a central pathogenic mechanism in this, and other, neurodevelopmental disorders. Understanding the coordination and timing of interneuron development including the complex processes of specification, proliferation, migration and their incorporation into finely tuned cortical networks is therefore essential in determining their role in neurodevelopmental disease. Studies using mouse models have highlighted the functional relevance of transcription factor networks and common signalling pathways in interneuron development but have faced challenges in identifying clear time windows where these factors are essential. Here we discuss recent developments highlighting critical time frames in the specification and migration of cortical interneurons and the impact of aberrant development to aetiology and treatments of schizophrenia.

  5. In vitro neurotoxic hazard characterisation of dinitrophenolic herbicides

    NARCIS (Netherlands)

    Heusinkveld, Harm J; van Vliet, Arie C; Nijssen, Peter C G; Westerink, Remco H S

    2016-01-01

    Dinitrophenolic compounds are powerful toxicants with a long history of use in agriculture and industry. While (high) human exposure levels are not uncommon, in particular for agricultural workers during the spraying season, the neurotoxic mechanism(s) that underlie the human health effects are larg

  6. The use of glial data in neurotoxicity risk assessment

    Science.gov (United States)

    Central nervous system (CNS) glia (i.e., astrocytes, microglia, and oligodendrocytes) are essential for normal brain function, and they orchestrate the CNS response to injury. While effects on glia are important to consider when evaluating the neurotoxicity risk of exposure to xe...

  7. Teriflunomide and monomethylfumarate target HIV-induced neuroinflammation and neurotoxicity.

    Science.gov (United States)

    Ambrosius, Björn; Faissner, Simon; Guse, Kirsten; von Lehe, Marec; Grunwald, Thomas; Gold, Ralf; Grewe, Bastian; Chan, Andrew

    2017-03-11

    HIV-associated neurocognitive disorders (HAND) affect about 50% of infected patients despite combined antiretroviral therapy (cART). Ongoing compartmentalized inflammation mediated by microglia which are activated by HIV-infected monocytes has been postulated to contribute to neurotoxicity independent from viral replication. Here, we investigated effects of teriflunomide and monomethylfumarate on monocyte/microglial activation and neurotoxicity. Human monocytoid cells (U937) transduced with a minimal HIV-Vector were co-cultured with human microglial cells (HMC3). Secretion of pro-inflammatory/neurotoxic cytokines (CXCL10, CCL5, and CCL2: p < 0.001; IL-6: p < 0.01) by co-cultures was strongly increased compared to microglia in contact with HIV-particles alone. Upon treatment with teriflunomide, cytokine secretion was decreased (CXCL10, 3-fold; CCL2, 2.5-fold; IL-6, 2.2-fold; p < 0.001) and monomethylfumarate treatment led to 2.9-fold lower CXCL10 secretion (p < 0.001). Reduced toxicity of co-culture conditioned media on human fetal neurons by teriflunomide (29%, p < 0.01) and monomethylfumarate (27%, p < 0.05) indicated functional relevance. Modulation of innate immune functions by teriflunomide and monomethylfumarate may target neurotoxic inflammation in the context of HAND.

  8. Berberine Reduces Neurotoxicity Related to Nonalcoholic Steatohepatitis in Rats

    Directory of Open Access Journals (Sweden)

    Doaa A. Ghareeb

    2015-01-01

    Full Text Available Berberine is a plant alkaloid that has several pharmacological effects such as antioxidant, antilipidemic, and anti-inflammatory effects. Nonalcoholic steatohepatitis (NASH triggers different aspects of disorders such as impaired endogenous lipid metabolism, hypercholesterolemia, oxidative stress, and neurotoxicity. In this study, we examined the mechanism by which NASH induces neurotoxicity and the protective effect of berberine against both NASH and its associated neurotoxicity. NASH induced rats showed significant impairments in lipid metabolism with increased serum triglycerides, cholesterol, and low-density lipoprotein (LDL. The NASH induced group also demonstrated a significant oxidative stress which is characterized by increased TBARs level and decreased antioxidant capacity such as GSH and SOD levels. Moreover, the NASH induction was associated with inflammation which was demonstrated by increased TNFα and nitric oxide levels. Hyperglycemia and hyperinsulinemia were observed in the NASH induced group. Also, our results showed a significant increase in the expression of the acetylcholine esterase (AChE and amyloid beta precursor protein (AβPP. These changes were significantly correlated with decreased insulin degrading enzyme (IDE and beta-amyloid40 (Aβ40 and increased beta-amyloid42 (Aβ42 in the hippocampal region. Daily administration of berberine (50 mg/kg for three weeks ameliorated oxidative stress, inflammation, hyperlipidemia, hyperglycemia, hyperinsulinemia, and the observed neurotoxicity.

  9. Paeonol attenuates inflammation-mediated neurotoxicity and microglial activation

    Institute of Scientific and Technical Information of China (English)

    Kyong Nyon Nam; Byung-Cheol Woo; Sang-Kwan Moon; Seong-Uk Park; Joo-young Park; Jae-Woong Hwang; Hyung-Sup Bae; Chang-Nam Ko; Eunjoo Hwang Lee

    2013-01-01

    Chronic activation of microglial cells endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. The root of Paeonia lactiflora Pall has been considered useful for the treatment of various disorders in traditional oriental medicine. Paeonol, found in the root of Paeonia lactiflora Pall, has a wide range of pharmacological functions, including anti-oxidative, anti-inflammatory and neuroprotective activities. The objective of this study was to examine the efficacy of paeonol in the repression of inflammation-induced neurotoxicity and microglial cell activation. Organotypic hippocampal slice cultures and primary microglial cells from rat brain were stimulated with bacterial lipopolysaccharide. Paeonol pretreatment was performed for 30 minutes prior to lipopolysaccharide addition. Cell viability and nitrite (the production of nitric oxide), tumor necrosis factor-alpha and interleukin-1beta products were measured after lipopolysaccharide treatment. In organotypic hippocampal slice cultures, paeonol blocked lipopolysaccharide-related hippocampal cell death and inhibited the release of nitrite and interleukin-1beta. Paeonol was effective in inhibiting nitric oxide release from primary microglial cells. It also reduced the lipopolysaccharide-stimulated release of tumor necrosis factor-alpha and interleukin-1β from microglial cells. Paeonol possesses neuroprotective activity in a model of inflammation-induced neurotoxicity and reduces the release of neurotoxic and proinflammatory factors in activated microglial cells.

  10. Studies into the mechanism of arsenic-induced neurotoxicity

    NARCIS (Netherlands)

    Vahidnia, Ali

    2008-01-01

    Arsenic (As) is a notoriously poisonous metalloid with known hazardous effects to human health. The project described in this thesis was aimed at elucidating the probable mechanism of As-induced neurotoxicity in vivo and in vitro. The animal studies in this thesis were designed to answer questions a

  11. Investigating Climate Compatible Development Outcomes and their Implications for Distributive Justice: Evidence from Malawi

    Science.gov (United States)

    Wood, Benjamin T.; Quinn, Claire H.; Stringer, Lindsay C.; Dougill, Andrew J.

    2017-09-01

    Governments and donors are investing in climate compatible development in order to reduce climate and development vulnerabilities. However, the rate at which climate compatible development is being operationalised has outpaced academic enquiry into the concept. Interventions aiming to achieve climate compatible development "wins" (for development, mitigation, adaptation) can also create negative side-effects. Moreover, benefits and negative side-effects may differ across time and space and have diverse consequences for individuals and groups. Assessments of the full range of outcomes created by climate compatible development projects and their implications for distributive justice are scarce. This article develops a framework using a systematic literature review that enables holistic climate compatible development outcome evaluation over seven parameters identified. Thereafter, we explore the outcomes of two donor-funded projects that pursue climate compatible development triple-wins in Malawi using this framework. Household surveys, semi-structured interviews and documentary material are analysed. Results reveal that uneven outcomes are experienced between stakeholder groups and change over time. Although climate compatible development triple-wins can be achieved through projects, they do not represent the full range of outcomes. Ecosystem—and community-based activities are becoming popularised as approaches for achieving climate compatible development goals. However, findings suggest that a strengthened evidence base is required to ensure that these approaches are able to meet climate compatible development goals and further distributive justice.

  12. Diffusion abnormalities of the globi pallidi in manganese neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    McKinney, Alexander M.; Filice, Ross W.; Teksam, Mehmet; Casey, Sean; Truwit, Charles; Clark, H. Brent; Woon, Carolyn; Liu, Hai Ying [Department of Radiology, Medical School, Box 292, 420 Delaware Street S.E., 55455, Minneapolis, MN (United States)

    2004-04-01

    Manganese is an essential trace metal required for normal central nervous system function, which is toxic when in excess amounts in serum. Manganese neurotoxicity has been demonstrated in patients with chronic liver/biliary failure where an inability to excrete manganese via the biliary system causes increased serum levels, and in patients on total parenteral nutrition (TPN), occupational/inhalational exposure, or other source of excess exogenous manganese. Manganese has been well described in the literature to deposit selectively in the globi pallidi and to induce focal neurotoxicity. We present a case of a 53-year-old woman who presented for a brain MR 3 weeks after liver transplant due to progressively decreasing level of consciousness. The patient had severe liver failure by liver function tests and bilirubin levels, and had also been receiving TPN since the transplant. The MR demonstrated symmetric hyperintensity on T1-weighted images in the globi pallidi. Apparent diffusion coefficient (ADC) map indicated restricted diffusion in the globi pallidi bilaterally. The patient eventually succumbed to systemic aspergillosis 3 days after the MR. The serum manganese level was 195 mcg/l (micrograms per liter) on postmortem exam (over 20 times the upper limits of normal). The patient was presumed to have suffered from manganese neurotoxicity since elevated serum manganese levels have been shown in the literature to correlate with hyperintensity on T1-weighted images, neurotoxicity symptoms, and focal concentration of manganese in the globi pallidi. Neuropathologic sectioning of the globi pallidi at autopsy was also consistent with manganese neurotoxicity. (orig.)

  13. Developmental neurotoxicity of pyrethroid insecticides in zebrafish embryos.

    Science.gov (United States)

    DeMicco, Amy; Cooper, Keith R; Richardson, Jason R; White, Lori A

    2010-01-01

    Pyrethroid insecticides are one of the most commonly used residential and agricultural insecticides. Based on the increased use of pyrethroids and recent studies showing that pregnant women and children are exposed to pyrethroids, there are concerns over the potential for developmental neurotoxicity. However, there have been relatively few studies on the developmental neurotoxicity of pyrethroids. In this study, we sought to investigate the developmental toxicity of six common pyrethroids, three type I compounds (permethrin, resmethrin, and bifenthrin) and three type II compounds (deltamethrin, cypermethrin, and lambda-cyhalothrin), and to determine whether zebrafish embryos may be an appropriate model for studying the developmental neurotoxicity of pyrethroids. Exposure of zebrafish embryos to pyrethroids caused a dose-dependent increase in mortality and pericardial edema, with type II compounds being the most potent. At doses approaching the LC(50), permethrin and deltamethrin caused craniofacial abnormalities. These findings are consistent with mammalian studies demonstrating that pyrethroids are mildly teratogenic at very high doses. However, at lower doses, body axis curvature and spasms were observed, which were reminiscent of the classic syndromes observed with pyrethroid toxicity. Treatment with diazepam ameliorated the spasms, while treatment with the sodium channel antagonist MS-222 ameliorated both spasms and body curvature, suggesting that pyrethroid-induced neurotoxicity is similar in zebrafish and mammals. Taken in concert, these data suggest that zebrafish may be an appropriate alternative model to study the mechanism(s) responsible for the developmental neurotoxicity of pyrethroid insecticides and aid in identification of compounds that should be further tested in mammalian systems.

  14. Identification of Genetic Modifiers of TDP-43 Neurotoxicity in Drosophila

    Science.gov (United States)

    Kim, Sang Hwa; Tare, Apeksha; Tibbetts, Randal S.

    2013-01-01

    Cytosolic aggregation of the nuclear RNA-binding protein TDP-43 is a histopathologic signature of degenerating neurons in amyotrophic lateral sclerosis (ALS), and mutations in the TARDBP gene encoding TDP-43 cause dominantly inherited forms of this condition. To understand the relationship between TDP-43 misregulation and neurotoxicity, we and others have used Drosophila as a model system, in which overexpression of either wild-type TDP-43 or its ALS-associated mutants in neurons is sufficient to induce neurotoxicity, paralysis, and early death. Using microarrays, we have examined gene expression patterns that accompany TDP-43-induced neurotoxicity in the fly system. Constitutive expression of TDP-43 in the Drosophila compound eye elicited widespread gene expression changes, with strong upregulation of cell cycle regulatory genes and genes functioning in the Notch intercellular communication pathway. Inducible expression of TDP-43 specifically in neurons elicited significant expression differences in a more restricted set of genes. Genes that were upregulated in both paradigms included SpindleB and the Notch target Hey, which appeared to be a direct TDP-43 target. Mutations that diminished activity of Notch or disrupted the function of downstream Notch target genes extended the lifespan of TDP-43 transgenic flies, suggesting that Notch activation was deleterious in this model. Finally, we showed that mutation of the nucleoporin Nup50 increased the lifespan of TDP-43 transgenic flies, suggesting that nuclear events contribute to TDP-43-dependent neurotoxicity. The combined findings identified pathways whose deregulation might contribute to TDP-43-induced neurotoxicity in Drosophila. PMID:23468938

  15. A critical review of neonicotinoid insecticides for developmental neurotoxicity.

    Science.gov (United States)

    Sheets, Larry P; Li, Abby A; Minnema, Daniel J; Collier, Richard H; Creek, Moire R; Peffer, Richard C

    2016-02-01

    A comprehensive review of published and previously unpublished studies was performed to evaluate the neonicotinoid insecticides for evidence of developmental neurotoxicity (DNT). These insecticides have favorable safety profiles, due to their preferential affinity for nicotinic receptor (nAChR) subtypes in insects, poor penetration of the mammalian blood-brain barrier, and low application rates. Nevertheless, examination of this issue is warranted, due to their insecticidal mode of action and potential exposure with agricultural and residential uses. This review identified in vitro, in vivo, and epidemiology studies in the literature and studies performed in rats in accordance with GLP standards and EPA guidelines with imidacloprid, acetamiprid, thiacloprid, clothianidin, thiamethoxam, and dinotefuran, which are all the neonicotinoids currently registered in major markets. For the guideline-based studies, treatment was administered via the diet or gavage to primiparous female rats at three dose levels, plus a vehicle control (≥20/dose level), from gestation day 0 or 6 to lactation day 21. F1 males and females were evaluated using measures of motor activity, acoustic startle response, cognition, brain morphometry, and neuropathology. The principal effects in F1 animals were associated with decreased body weight (delayed sexual maturation, decreased brain weight, and morphometric measurements) and acute toxicity (decreased activity during exposure) at high doses, without neuropathology or impaired cognition. No common effects were identified among the neonicotinoids that were consistent with DNT or the neurodevelopmental effects associated with nicotine. Findings at high doses were associated with evidence of systemic toxicity, which indicates that these insecticides do not selectively affect the developing nervous system.

  16. X-ray fluorescence imaging: a new tool for studying manganese neurotoxicity.

    Directory of Open Access Journals (Sweden)

    Gregory Robison

    Full Text Available The neurotoxic effect of manganese (Mn establishes itself in a condition known as manganism or Mn induced parkinsonism. While this condition was first diagnosed about 170 years ago, the mechanism of the neurotoxic action of Mn remains unknown. Moreover, the possibility that Mn exposure combined with other genetic and environmental factors can contribute to the development of Parkinson's disease has been discussed in the literature and several epidemiological studies have demonstrated a correlation between Mn exposure and an elevated risk of Parkinson's disease. Here, we introduce X-ray fluorescence imaging as a new quantitative tool for analysis of the Mn distribution in the brain with high spatial resolution. The animal model employed mimics deficits observed in affected human subjects. The obtained maps of Mn distribution in the brain demonstrate the highest Mn content in the globus pallidus, the thalamus, and the substantia nigra pars compacta. To test the hypothesis that Mn transport into/distribution within brain cells mimics that of other biologically relevant metal ions, such as iron, copper, or zinc, their distributions were compared. It was demonstrated that the Mn distribution does not follow the distributions of any of these metals in the brain. The majority of Mn in the brain was shown to occur in the mobile state, confirming the relevance of the chelation therapy currently used to treat Mn intoxication. In cells with accumulated Mn, it can cause neurotoxic action by affecting the mitochondrial respiratory chain. This can result in increased susceptibility of the neurons of the globus pallidus, thalamus, and substantia nigra pars compacta to various environmental or genetic insults. The obtained data is the first demonstration of Mn accumulation in the substantia nigra pars compacta, and thus, can represent a link between Mn exposure and its potential effects for development of Parkinson's disease.

  17. Parental transfer of microcystin-LR induced transgenerational effects of developmental neurotoxicity in zebrafish offspring.

    Science.gov (United States)

    Wu, Qin; Yan, Wei; Cheng, Houcheng; Liu, Chunsheng; Hung, Tien-Chieh; Guo, Xiaochun; Li, Guangyu

    2017-08-21

    Microcystin-LR (MCLR) has been reported to cause developmental neurotoxicity in zebrafish, but there are few studies on the mechanisms of MCLR-induced transgenerational effects of developmental neurotoxicity. In this study, zebrafish were exposed to 0, 1, 5, and 25 μg/L MCLR for 60 days. The F1 zebrafish embryos from the above-mentioned parents were collected and incubated in clean water for 120 h for hatching. After examining the parental zebrafish and F1 embryos, MCLR was detected in the gonad of adults and F1 embryos, indicating MCLR could potentially be transferred from parents to offspring. The larvae also showed a serious hypoactivity. The contents of dopamine, dihydroxyphenylacetic acid (DOPAC), serotonin, gamma-aminobutyric acid (GABA) and acetylcholine (ACh) were further detected, but only the first three neurotransmitters showed significant reduction in the 5 and 25 μg/L MCLR parental exposure groups. In addition, the acetylcholinesterase (AChE) activity was remarkably decreased in MCLR parental exposure groups, while the expression levels of manf, bdnf, ache, htr1ab, htr1b, htr2a, htr1aa, htr5a, DAT, TH1 and TH2 genes coincided with the decreased content of neurotransmitters (dopamine, DOPAC and serotonin) and the activity of AChE. Neuronal development related genes, α1-tubulin, syn2a, mbp, gfap, elavl3, shha and gap43 were also measured, but gap43 was the gene only up-regulated. Our results demonstrated MCLR could be transferred to offspring, and subsequently induce developmental neurotoxicity in F1 zebrafish larvae by disturbing the neurotransmitter systems and neuronal development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. A Panel of Autoantibodies Against Neural Proteins as Peripheral Biomarker for Pesticide-Induced Neurotoxicity.

    Science.gov (United States)

    El Rahman, Heba Allah Abd; Salama, Mohamed; Gad El-Hak, Seham A; El-Harouny, Mona A; ElKafrawy, Passent; Abou-Donia, Mohamed B

    2017-09-05

    In the present study, we screened the sera of subjects chronically exposed to mixtures of pesticides (composed mainly of organophosphorus compounds (OPs) and others) and developed neurological symptoms for the presence of autoantibodies against cytoskeletal neural proteins. OPs have a well-characterized clinical profile resulting from acute cholinergic crisis. However, some of these compounds cause neuronal degeneration and demyelination known as organophosphorus compound-induced delayed neurotoxicity (OPIDN) and/or organophosphorus compound-induced chronic neurotoxicity (OPICN). Studies from our group have demonstrated the presence of autoantibodies to essential neuronal and glial proteins against cytoskeletal neural proteins in patients with chemical-induced brain injury. In this study, we screened the serum of 50 pesticide-exposed subjects and 25 non-exposed controls, using Western blot analysis against the following proteins: neurofilament triplet proteins (NFPs), tubulin, microtubule-associated tau proteins (Tau), microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), myelin-associated glycoprotein (MAG), glial fibrillary acidic protein (GFAP), calcium-calmodulin kinase II (CaMKII), glial S100-B protein, and alpha-synuclein (SNCA). Serum reactivity was measured as arbitrary chemiluminescence units. As a group, exposed subjects had significantly higher levels of autoantibody reactivity in all cases examined. The folds of increase in of autoantibodies against neural proteins of the subjects compared to healthy humans in descending order were as follows: MBP, 7.67, MAG 5.89, CaMKII 5.50, GFAP 5.1, TAU 4.96, MAP2 4.83, SNCA 4.55, NFP 4.55, S-100B 2.43, and tubulin 1.78. This study has demonstrated the presence of serum autoantibodies to central nervous system-specific proteins in a group of farmers chronically exposed to pesticides who developed neurological signs and symptoms of neural injury. These autoantibodies can be used as future diagnostic

  19. Integrating Youth into Community Development: Implications for Policy Planning and Program Evaluation

    Directory of Open Access Journals (Sweden)

    Rosemary V. Barnett

    2006-09-01

    Full Text Available As non-profits, volunteer groups, and nongovernmental organizations take on increasingly larger roles in contributing to local well-being, the active collaboration between youth and adults is vital to the long-term success of community development efforts. Similarly, as service activities become standardized components of high-school programs, youth are empowered to becoming long-term contributors to local development efforts. Through this process youth engage in shared citizenship, leading to greater investment in their communities. This research was based on the premise that youth, acting as central parts of the community development process, have the capacity to improve local well-being. It reflects input from 12 key informants and 418 youth who participated in a survey conducted on the development issues contributing to their involvement. The findings of this study provide insights into the factors most directly shaping youth attitudes and involvement in their communities, as well as presenting direct implications for applied use.

  20. Communication for Development: A Personal Experience with Implications for Development Policy

    Science.gov (United States)

    Agunga, Robert

    2012-01-01

    Purpose: Communication for Development (C4D) is a new academic discipline and profession for addressing human dimension concerns in development, such as local participation, integration and capacity building, which are the main issues limiting aid effectiveness. However, my experience in Malawi, one of the poorest countries in Africa and where a…

  1. Science Teachers' Conceptualizations and Implications for the Development of the Professional Development Programs

    Science.gov (United States)

    Kaymakamoglu, Sibel Ersel

    2017-01-01

    This study aimed to investigate the two primary school science teachers' conceptions of professional development, their perceptions of self-improvement and the factors influencing their professional development. In this investigation, a case study approach was adopted. The participant teachers were given a semi-structured interview and the data…

  2. The Development of English to Englishes and their Implications in EFL Teaching and Learning

    Institute of Scientific and Technical Information of China (English)

    刘思齐

    2014-01-01

    English, for various reasons, has expanded from local through national to international domains.Thus, it is now acquiring itself a new identity of the global language.However, along with its thriving development, new variants of English emerged and now are referred as“Englishes”, which shoulder not only cultural, economic, political, but also, most importantly, educational responsibilities.This paper discusses the process that English went through to become Englishs, makes a list of several ways that Englishes have been catergorized, and finally reveals the implications of teaching and learning Englishes in EFL contexts.

  3. The Development of English to Englishes and their Implications in EFL Teaching and Learning

    Institute of Scientific and Technical Information of China (English)

    刘思齐

    2014-01-01

    English, for various reasons, has expanded from local through national to international domains.Thus, it is now acquiring itself a new identity of the global language.However, along with its thriving development, new variants of English emerged and now are referred as "Englishes", which shoulder not only cultural, economic, political, but also, most importantly, educational responsibilities.This paper discusses the process that English went through to become Englishs, makes a list of several ways that Englishes have been catergorized, and finally reveals the implications of teaching and learning Englishes in EFL contexts.

  4. ORGANISATIONAL DETERMINANTS INFLUENCING INFORMATION SYSTEMS REIMPLEMENTATION: SOME IMPLICATIONS TO THE DEVELOPING COUNTRIES

    Directory of Open Access Journals (Sweden)

    Sayyen Teoh

    2010-01-01

    Full Text Available This article presents an in-depth study of global Web-based Marketing Decision Support System reimplementation, in a British-based Fast Moving Consumer Goods (FMCG manufacturer. The paper shows that the success of a system implementation can still be marginal even if the organisation understands the key organisational determinants of success and has influence over them. The paper concludes with a discussion of how implementation planning, user need analysis and communication problems could be overcomed and also some implications to the companies in the developing nations.

  5. Implications of MMPI/MMPI--a findings for understanding adolescent development and psychopathology.

    Science.gov (United States)

    Archer, Robert P

    2005-12-01

    The MMPI (Hathaway & McKinley, 1943) and the MMPI-Adolescent (MMPI-A; Butcher et al., 1992) have been used in the evaluation of adolescents for over 60 years, resulting in over 200 studies involving tens of thousands of adolescents. This literature not only informs us concerning characteristics of this test instrument but also holds important implications for our understanding of adolescent development and psychopathology. In this article, based on an invited master lecture at the 2005 Annual Meeting of the Society for Personality Assessment, I present several points illustrating the relevance of MMPI and MMPI--A research in enriching our understanding of adolescence.

  6. Implications for Development Needs and Managing Students’Expecta-tion in EAP

    Institute of Scientific and Technical Information of China (English)

    LI Dan

    2016-01-01

    English for academic purpose (EAP), as one of branches of English for specific purpose (ESP), is special because it is organized in academic contexts and decides the academic behavior of individuals in future. However, there is no standard or course for college students about EAP in China, so they tend to learn it autonomously, which is limited to a small group. To pro-mote the significance and implementation of EAP, it is essential to design EAP according to students’needs. Therefore, this pa-per focuses on offering implications based on students’development needs and expectation in EAP.

  7. Towards energy sustainability in the world: the implications of energy subsidy for developing countries

    Energy Technology Data Exchange (ETDEWEB)

    Iwaro, Joseph; Mwasha, Abraham [University of West Indies, W. Department of Civil and Environmental Engineering, St. Augustine Campus (Trinidad and Tobago)

    2010-07-01

    Energy subsidies are widespread around the world but they vary greatly in importance and type of fuel and country. The fossil fuel consumption rate is growing every year and in about 50 years we will have depleted most of our fossil fuel reserves, so it is necessary to find alternative sources of energy before that happens. However, the only solution to this challenge is through investment on energy conservation programmes and renewable energy source. In line with this challenge and confusion on fund appropriate for energy. This paper is aimed at examining the effect of energy subsidy on energy conservation and renewable energy in developing countries. The study intends to quantify and analysis a case study of Trinidad and Tobago energy subsidy and its implications for developing countries and energy sustainability in the world. Findings show that huge amount investments and government intervention were being expended on energy subsidy in order to lower the price of energy products for consumers. The study further identified implication of this growing subsidy for developing countries and that the funds could be used for creating renewable energy technology and energy conservation programmes.

  8. Interplay between progesterone and prolactin in mammary development and implications for breast cancer.

    Science.gov (United States)

    Lee, Heather J; Ormandy, Christopher J

    2012-06-24

    Progesterone and prolactin remodel mammary morphology during pregnancy by acting on the mammary epithelial cell hierarchy. The roles of each hormone in mammary development have been well studied, but evidence of signalling cross-talk between progesterone and prolactin is still emerging. Factors such as receptor activator of NFkB ligand (RANKL) may integrate signals from both hormones to orchestrate their joint actions on the epithelial cell hierarchy. Common targets of progesterone and prolactin signalling are also likely to integrate their pro-proliferative actions in breast cancer. Therefore, a thorough understanding of the interplay between progesterone and prolactin in mammary development may reveal therapeutic targets for breast cancer. This review summarises our understanding of Pg and PRL action in mammary gland development before focusing on molecular mechanisms of signalling cross-talk and the implications for breast cancer. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  9. Exploring the implications of social change for human development: perspectives, issues and future directions.

    Science.gov (United States)

    Chen, Xinyin

    2015-02-01

    Researchers have investigated the implications of social change for human development from different perspectives. The studies published in this special section were conducted within Greenfield's theoretical framework (2009). The findings concerning links between specific sociodemographic features (e.g., commercial activities, schooling) and individual cognition and social behaviour are particularly interesting because they tap the underlying forces that drive human development. To further understand the issues in these studies and in the field, a pluralist-constructive perspective is discussed, which emphasises the integration of diverse values and practices in both Western and non-Western societies and its effects on the development of sophisticated competencies in individual adaptation to the changing global community. In addition, several issues are highlighted and some suggestions are provided for future explorations in this field.

  10. Contemporary Issues in Building Collapse and Its Implications for Sustainable Development

    Directory of Open Access Journals (Sweden)

    James O. Rotimi

    2012-07-01

    Full Text Available This paper examines contemporary issues in building collapse and its implications for sustainable development in Nigeria. It explores whether the approach to construction by industry stakeholders is in line with the principles of sustainable development following the spate of building collapses in Nigeria. The rationale for the investigation stems from the view by scholars that construction industry stakeholders’ do not seem to consider the future in their current activities. The study establishes that the approach to construction by industry stakeholders do not match sustainable principles, and contributes to general under perforxmance of buildings. The paper recommends an overhaul of planning and implementation policies for building development regulations (e.g., building codes. The Nigerian government, as a major construction stakeholder should initiate sustainable construction measures and enforce this as best practice for the construction industry.

  11. Growth, maturation and development during childhood and adolescence: Implications for sports practice

    Directory of Open Access Journals (Sweden)

    Alessandro H. Nicolai Ré

    2011-09-01

    Full Text Available Human development emerges from the interactions between environmental and biological factors. This review focuses on the relationship between biological development and environmental experiences during infancy and adolescence and their implications for motor skill acquisition. During infancy, as a consequence of the accelerated development of the central nervous system, it is fundamental that a vast and adequate variation in environmental stimuli is supplied, favoring motor, cognitive and affective-social domains. In adolescence, biological alterations are associated with peaking testosterone and estradiol hormone production in males and females respectively and it is necessary to adjust motor stimulation to biological maturation and previous experiences. Motor skill acquisition during infancy has an important relation to continuity of physical activity in later years and the practice of sports in adolescence and adulthood, favoring both the blossoming of athletes and promotion of health in general population.

  12. Growth, maturation and development during childhood and adolescence: Implications for sports practice

    Directory of Open Access Journals (Sweden)

    A.H.N. Ré

    2011-01-01

    Full Text Available Human development emerges from the interactions between environmental and biological factors. This review focuses on the relationship between biological development and environmental experiences during infancy and adolescence and their implications for motor skill acquisition. During infancy, as a consequence of the accelerated development of the central nervous system, it is fundamental that a vast and adequate variation in environmental stimuli is supplied, favoring motor, cognitive and affective-social domains. In adolescence, biological alterations are associated with peaking testosterone and estradiol hormone production in males and females respectively and it is necessary to adjust motor stimulation to biological maturation and previous experiences. Motor skill acquisition during infancy has an important relation to continuity of physical activity in later years and the practice of sports in adolescence and adulthood, favoring both the blossoming of athletes and promotion of health in general population.

  13. The regulation of apoptosis in kidney development: implications for nephron number and pattern?

    Directory of Open Access Journals (Sweden)

    Jacqueline eHo

    2014-11-01

    Full Text Available Apoptosis is essential to remodel developing structures and eliminate superfluous cells in a controlled manner during normal development, and continues to be an important component of tissue remodeling and regeneration during an organism’s lifespan, or as a response to injury. This mini-review will discuss recent studies that have provided insights into the roles of apoptosis in the determination of nephron number and pattern, during normal and abnormal kidney development. The regulation of congenital nephron endowment has implications for risk of chronic kidney disease in later life, whereas abnormalities in nephron pattern are associated with congenital anomalies of the kidney and urinary tract (the leading cause of renal disease in children. Tight regulation of apoptosis is required in normal renal morphogenesis, although many questions remain regarding the regulation of apoptosis by genetic, epigenetic and environmental factors, in addition to the functional requirement of different components of the apoptotic pathway.

  14. Lhermitte sign and urinary retention: atypical presentation of oxaliplatin neurotoxicity in four patients.

    Science.gov (United States)

    Taieb, Sarah; Trillet-Lenoir, Véronique; Rambaud, Loïc; Descos, Louis; Freyer, Gilles

    2002-05-01

    Regimens combining oxaliplatin with fluorouracil and folinic acid are standard therapeutic options for patients with metastatic colorectal carcinoma. Oxaliplatin has a good safety profile, although it is responsible for dose-limiting neurotoxicity typically consisting of two distinct clusters of symptoms. Cold-induced distal paresthesiae occur during or shortly after infusion in most patients and are usually transient and mild. A persistent sensory peripheral neuropathy may develop with prolonged treatment, eventually causing superficial and deep sensory loss, sensory ataxia and functional impairment. The authors report four cases of atypical neurotoxicity induced by oxaliplatin in patients treated for metastatic colorectal carcinoma. Two patients were male and two were female, with an age range of 52-59 years. Three patients experienced Lhermitte sign and two experienced urinary retention. In all cases, the cumulative dose of oxaliplatin was higher than 1000 mg (range, 1248-2040 mg). Brain and spinal magnetic resonance imaging was performed in two patients and was normal. Somatosensory evoked potentials were recorded in two patients and suggested cervical dorsal column dysfunction. Symptoms resolved a few weeks after discontinuation of oxaliplatin. Lhermitte sign may be induced via a neurotoxic effect on the ascending axons of these T-shaped neurons. An atonic bladder may be the result of damage to the sensory portion of the sacral reflex arc, either in the dorsal roots, as for example in diabetic neuropathy, or in the posterior columns, as in tabes dorsalis. Alternatively, it may result from a paralysis of the parasympathetic fibers that control the bladder musculature. It is unclear at present whether the micturition difficulties observed in patients in the current series are due to sensory neuropathy or to autonomic neuropathy, event if the former hypothesis seems more likely, as autonomic neuropathy has not been previously observed with oxaliplatin, and its

  15. Recognition for Positive Behavior as a Critical Youth Development Construct: Conceptual Bases and Implications on Youth Service Development

    Directory of Open Access Journals (Sweden)

    Ben M. F. Law

    2012-01-01

    Full Text Available Recognition for positive behavior is an appropriate response of the social environment to elicit desirable external behavior among the youth. Such positive responses, rendered from various social systems, include tangible and intangible reinforcements. The following theories are used to explain the importance of recognizing positive behavior: operational conditioning, observational learning, self-determination, and humanistic perspective. In the current work, culturally and socially desirable behaviors are discussed in detail with reference to Chinese adolescents. Positive behavior recognition is especially important to adolescent development because it promotes identity formation as well as cultivates moral reasoning and social perspective thinking from various social systems. The significance of recognizing positive behavior is illustrated through the support, tutorage, invitation, and subsidy provided by Hong Kong’s social systems in recognition of adolescent volunteerism. The practical implications of positive behavior recognition on youth development programs are also discussed in this work.

  16. Millennium Development Goals (MDGs and the UN Post-2015 Global Development Agenda: Implications for Africa

    Directory of Open Access Journals (Sweden)

    Mmaduabuchi G. S. Okeke

    2013-05-01

    Full Text Available 800x600 The United Nations declared the Millennium Development Goals (MDGs in the year 2000 with the aim of reducing to the barest minimum, by 2015, global poverty and hunger; illiteracy; gender inequality; child and maternal mortality; HIV/AIDS and other world development challenges. Unfortunately, available evidence shows that most, if not all countries in Africa will not achieve the MDGs by 2015, hence the setting up of the UN System Task Team to design a post-2015 Global Development agenda. This response serves as a clarion call for African political leaders who, for too long, have failed to take Africa’s development seriously. The paper examines these deficiencies and also explains why the MGDs are failing in Africa. It adapts qualitative methodology and deploys data from secondary sources. We state that while devising a post-MDG Agenda is a lofty idea, the failure of African leadership to be at the forefront in shaping and determining its contents will create the opportunity for the emergence of a global development paradigm that only satisfies the politico-economic whims and caprices of the donor nations and their institutions for global hegemony. Using a symbiotic development paradigm as the analytical tool, we contend that for UN post-2015 Global Development Agenda to be successful and achievable, it must be comprehensive, inclusive and symbiotic for all nations. We recommend that African leadership should try and become an active participant in the post-2015 global development debate. Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Calibri","sans-serif";}

  17. Leakage Implications for European Timber Markets from Reducing Deforestation in Developing Countries

    Directory of Open Access Journals (Sweden)

    Mattias Boman

    2012-08-01

    Full Text Available Forest management strategies and policies such as REDD (reduced emissions from deforestation and forest degradation may have unintentional implications for forest sectors in countries not targeted by such policies. The success of a policy effort like REDD would result in a significant reduction in deforestation and forest degradation and an ensuing reduction in the supply of natural forest timber production within participating countries. This could in turn result in price increases, inducing a supply response outside project boundaries with possible implications for forest management as well as global carbon emissions. This paper reviews the literature to discern potential timber market implications for countries sourcing wood products from developing countries affected by REDD related conservation efforts. The literature reviewed shows varying degrees of market effects leakage—policy actions in one place creating incentives for third parties to increase timber harvesting elsewhere through the price mechanism—ranging from negligible to substantial. However, wood products in the studies reviewed are dealt with on quite an aggregated scale and are assumed to be more or less perfect substitutes for wood products outside conservation effort boundaries. The review suggests that a thorough mapping of the end-uses of tropical timber is needed to comprehensively analyze impacts on wood-product markets in regions such as Europe from conservation efforts in tropical developing countries. The types of tropical timber expected to be affected, in which applications they are used, which are the most likely substitutes and where they would be sourced, are issues that, along with empirical analysis of supply and demand price elasticities and degree of substitutability, should be investigated when assessing the overall effectiveness of REDD.

  18. Molecular dynamics of the interaction of pralidoxime and deazapralidoxime with acetylcholinesterase inhibited by the neurotoxic agent tabun

    OpenAIRE

    Gonçalves,Arlan da S.; França,Tanos C. C.; Wilter,Alan; Figueroa-Villar,José D.

    2006-01-01

    Efficient acetylcholinesterase reactivators are fundamental for the development of antidotes against poisoning by neurotoxic pesticides and chemical warfare agents. However, the mechanism of the reactivation reaction and the structural characteristics of the known reactivators are poorly understood. In order to study the dynamic behavior and the effect of the antidote net charge in the reactivation of this enzyme, we carried out a molecular dynamics study of human acetylcholinesterase inhibit...

  19. International Comparison and Implications of Agricultural Development in Foreign Low Latitude Plateau Regions for Yunnan Province

    Institute of Scientific and Technical Information of China (English)

    Yan; LUO; Yan; YANG; Rui; CHEN; Wei; WU; Ziyun; PENG; Liangzheng; CHEN; Xuelin; LI

    2013-01-01

    Climatic characteristics of foreign low latitude plateau regions are firstly introduced.Then,experience and lessons of major foreign low latitude plateau countries in developing modern agriculture are analyzed,including Indian three agricultural revolutions and agricultural informationization development,application of agricultural biotechnology in Brazil,trade liberalization and economic de-agriculture of Mexico,and Argentina,Saudi Arabia and South Africa attaching great importance to developing modern agriculture relying on science and technology and paying close attention to resource conservation and environmental protection.Combining natural and social resource characteristics of Yunnan plateau agriculture,pertinent implications and recommendations for modern agricultural development in Yunnan are put forward.Specifically,these include strengthening agricultural sci-tech research and development,and extension and application;transforming agricultural development model;enhancing agricultural resource conservation and environmental protection;accelerating developing mountain organic ecological agriculture and autumn agriculture;reinforcing urban and rural integration to develop plateau characteristic agriculture on the basis of local actual conditions.

  20. Mapping Gray Matter Development: Implications for Typical Development and Vulnerability to Psychopathology

    Science.gov (United States)

    Gogtay, Nitin; Thompson, Paul M.

    2010-01-01

    Recent studies with brain magnetic resonance imaging (MRI) have scanned large numbers of children and adolescents repeatedly over time, as their brains develop, tracking volumetric changes in gray and white matter in remarkable detail. Focusing on gray matter changes specifically, here we explain how earlier studies using lobar volumes of specific…

  1. The implications of future building scenarios for long-term building energy research and development

    Energy Technology Data Exchange (ETDEWEB)

    Flynn, W.T.

    1986-12-01

    This report presents a discussion of alternative future scenarios of the building environment to the year 2010 and assesses the implications these scenarios present for long-term building energy R and D. The scenarios and energy R and D implications derived from them are intended to serve as the basis from which a strategic plan can be developed for the management of R and D programs conducted by the Office of Buildings and Community Systems, US Department of Energy. The scenarios and analysis presented here have relevance not only for government R and D programs; on the contrary, it is hoped that the results of this effort will be of interest and useful to researchers in both private and public sector organizations that deal with building energy R and D. Making R and D decisions today based on an analysis that attempts to delineate the nexus of events 25 years in the future are clearly decisions made in the face of uncertainty. Yet, the effective management of R and D programs requires a future-directed understanding of markets, technological developments, and environmental factors, as well as their interactions. The analysis presented in this report is designed to serve that need. Although the probability of any particular scenario actually occurring is uncertain, the scenarios to be presented are sufficiently robust to set bounds within which to examine the interaction of forces that will shape the future building environment.

  2. Selective processes in development: implications for the costs and benefits of phenotypic plasticity.

    Science.gov (United States)

    Snell-Rood, Emilie C

    2012-07-01

    Adaptive phenotypic plasticity, the ability of a genotype to develop a phenotype appropriate to the local environment, allows organisms to cope with environmental variation and has implications for predicting how organisms will respond to rapid, human-induced environmental change. This review focuses on the importance of developmental selection, broadly defined as a developmental process that involves the sampling of a range of phenotypes and feedback from the environment reinforcing high-performing phenotypes. I hypothesize that understanding the degree to which developmental selection underlies plasticity is key to predicting the costs, benefits, and consequences of plasticity. First, I review examples that illustrate that elements of developmental selection are common across the development of many different traits, from physiology and immunity to circulation and behavior. Second, I argue that developmental selection, relative to a fixed strategy or determinate (switch) mechanisms of plasticity, increases the probability that an individual will develop a phenotype best matched to the local environment. However, the exploration and environmental feedback associated with developmental selection is costly in terms of time, energy, and predation risk, resulting in major changes in life history such as increased duration of development and greater investment in individual offspring. Third, I discuss implications of developmental selection as a mechanism of plasticity, from predicting adaptive responses to novel environments to understanding conditions under which genetic assimilation may fuel diversification. Finally, I outline exciting areas of future research, in particular exploring costs of selective processes in the development of traits outside of behavior and modeling developmental selection and evolution in novel environments.

  3. Development of the carapacial ridge: implications for the evolution of genetic networks in turtle shell development.

    Science.gov (United States)

    Moustakas, Jacqueline E

    2008-01-01

    Paleontologists and neontologists have long looked to development to understand the homologies of the dermal bones that form the "armor" of turtles, crocodiles, armadillos, and other vertebrates. This study shows molecular evidence supporting a dermomyotomal identity for the mesenchyme of the turtle carapacial ridge. The mesenchyme of the carapace primordium expresses Pax3, Twist1, Dermo1, En1, Sim1, and Gremlin at early stages and before overt ossification expresses Pax1. A hypothesis is proposed that this mesenchyme forms dermal bone in the turtle carapace. A comparison of regulatory gene expression in the primordia of the turtle carapace, the vertebrate limb, and the vertebral column implies the exaptation of key genetic networks in the development of the turtle shell. This work establishes a new role for this mesodermal compartment and highlights the importance of changes in genetic regulation in the evolution of morphology.

  4. Conceptual Development in Festival Quality Management: Implications for Product Development and Marketing

    OpenAIRE

    Bassey Benjamin Esu

    2015-01-01

    This paper seeks to explore the trends in the conceptual development of knowledge relevant in festival quality management. There is plethora of literature on festival quality that spans over three decades. However, researchers and practitioners have continued to grapple with trying to understand the why and what of festival quality study in special event tourism management. This taxonomical problem exist probably because of the historical antecedent of service quality research. This paper the...

  5. Parkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity

    Directory of Open Access Journals (Sweden)

    Palmiter Richard D

    2005-12-01

    Full Text Available Abstract Background Autosomal recessive juvenile parkinsonism (AR-JP is caused by mutations in the parkin gene which encodes an E3 ubiquitin-protein ligase. Parkin is thought to be critical for protecting dopaminergic neurons from toxic insults by targeting misfolded or oxidatively damaged proteins for proteasomal degradation. Surprisingly, mice with targeted deletions of parkin do not recapitulate robust behavioral or pathological signs of parkinsonism. Since Parkin is thought to protect against neurotoxic insults, we hypothesized that the reason Parkin-deficient mice do not develop parkinsonism is because they are not exposed to appropriate environmental triggers. To test this possibility, we challenged Parkin-deficient mice with neurotoxic regimens of either methamphetamine (METH or 6-hydroxydopamine (6-OHDA. Because Parkin function has been linked to many of the pathways involved in METH and 6-OHDA toxicity, we predicted that Parkin-deficient mice would be more sensitive to the neurotoxic effects of these agents. Results We found no signs consistent with oxidative stress, ubiquitin dysfunction, or degeneration of striatal dopamine neuron terminals in aged Parkin-deficient mice. Moreover, results from behavioral, neurochemical, and immunoblot analyses indicate that Parkin-deficient mice are not more sensitive to dopaminergic neurotoxicity following treatment with METH or 6-OHDA. Conclusion Our results suggest that the absence of a robust parkinsonian phenotype in Parkin-deficient mice is not due to the lack of exposure to environmental triggers with mechanisms of action similar to METH or 6-OHDA. Nevertheless, Parkin-deficient mice could be more sensitive to other neurotoxins, such as rotenone or MPTP, which have different mechanisms of action; therefore, identifying conditions that precipitate parkinsonism specifically in Parkin-deficient mice would increase the utility of this model and could provide insight into the mechanism of AR

  6. Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder

    Science.gov (United States)

    Birner, Armin; Platzer, Martina; Bengesser, Susanne Astrid; Dalkner, Nina; Fellendorf, Frederike T.; Queissner, Robert; Pilz, Rene; Rauch, Philipp; Maget, Alexander; Hamm, Carlo; Herzog-Eberhard, Simone; Mangge, Harald; Fuchs, Dietmar; Moll, Natalie; Zelzer, Sieglinde; Schütze, Gregor; Schwarz, Markus; Reininghaus, Bernd; Kapfhammer, Hans-Peter; Reininghaus, Eva Z.

    2017-01-01

    which should be capable to produce an even greater imbalance due to activation of key enzymes in the neurotoxic direction of KYN -conversion. These processes could finally be involved in the development of unspecific brain structural changes and cognitive deficits which are prevalent in BD. Further research should focus on state dependent changes in TRYCATs and its relation to cognition, brain structure and staging parameters. PMID:28241062

  7. INCOME AND ENERGY SOURCES AMONG AGRARIAN HOUSEHOLDS IN NIGERIA: IMPLICATIONS FOR LOW CARBON ENERGY DEVELOPMENT IN LESS DEVELOPED COUNTRIES

    Directory of Open Access Journals (Sweden)

    M. Mkpado

    2012-07-01

    Full Text Available Low-carbon power comes from sources that produce fewer greenhouse gases than do traditional means of power generation. It includes zero carbon power generation sources, such as wind power, solar power, geothermal power and (except for fuel preparation nuclear power, as well as sources with lower-level emissions such as natural and petroleum gas, and also technologies that prevent carbon dioxide from being emitted into the atmosphere, such as carbon capture and storage. This article correlated value of income from different sources to energy sources used by agrarian households in Nigeria and drew implications for low carbon development in Africa. It analysis included use of wind power for irrigation purposes, harnessing solar energy for lightening and possible cost implications. Secondary data were collected from Community Based Monitoring System Nigeria Project. Descriptive statistics, correlation and qualitative analysis were employed. The average annual income of agrarian households from different sources such as crop farming, livestock farming, petty trading, forest exploitation, remittance and labour per day was below the poverty line of $1 per day. The source of energy that had the highest number of significant correlation was electrical energy (low carbon electrical energy. It showed the possibility of pooling resources as farmers group to attract grants or equity financing to build wind mills for irrigation. The study recommended use of energy efficient bulbs to reduce CO2 emissions. This requires creating awareness among rural dwellers of the need to make such change.

  8. An Overview of Models of Speaking Performance and Its Implications for the Development of Procedural Framework for Diagnostic Speaking Tests

    Science.gov (United States)

    Zhao, Zhongbao

    2013-01-01

    This paper aims at developing a procedural framework for the development and validation of diagnostic speaking tests. The researcher reviews the current available models of speaking performance, analyzes the distinctive features and then points out the implications for the development of a procedural framework for diagnostic speaking tests. On…

  9. Differential effects of amphetamines-induced neurotoxicity on appetitive and aversive Pavlovian conditioning in mice.

    Science.gov (United States)

    Achat-Mendes, Cindy; Ali, Syed F; Itzhak, Yossef

    2005-06-01

    The abuse of substituted amphetamines such as methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA/Ecstasy) can result in neurotoxicity, manifested as the depletion of dopamine (DA) and 5-hydroxytriptamine (5-HT; serotonin) axon terminal markers in humans and animal models. Human METH and MDMA users exhibit impairments in memory and executive functions, which may be a direct consequence of the neurotoxic potential of amphetamines. The objective of this study was to investigate the influence of amphetamines-induced neurotoxicity on Pavlovian learning. Using mouse models of selective DA neurotoxicity (METH; 5 mg/kg x 3), selective 5-HT neurotoxicity (fenfluramine /FEN; 25 mg/kg x 4) and dual DA and 5-HT neurotoxicity (MDMA; 15 mg/kg x 4), appetitive and aversive conditioning were investigated. Dopaminergic neurotoxicity significantly impaired METH and cocaine conditioned place preference (CPP), but had no effect on LiCl-induced conditioned place aversion (CPA). In contrast, serotonergic neurotoxicity significantly enhanced CPP, and had no effect on CPA. Dual dopaminergic/serotonergic neurotoxicity had no apparent effect on CPP; however, CPA was significantly attenuated. Postmortem analysis revealed that significantly diminished levels of DA and 5-HT markers persisted in the striatum, frontal cortex, hippocampus, and amygdala. These findings suggest that amphetamines-induced dopaminergic and serotonergic neurotoxicity exert opposing influences on the affective state produced by subsequent drug reward, while dual dopaminergic/serotonergic neurotoxicity impairs associative learning of aversive conditioning. Furthermore, results revealed that amphetamines-induced DA and 5-HT neurotoxicity modulates appetitive Pavlovian conditioning similar to other DA and 5-HT neurotoxins. Modulation of Pavlovian conditioning by amphetamines-induced neurotoxicity may be relevant to compulsive drug-seeking behavior in METH and MDMA abusers.

  10. Implications of climate change for economic development in northern Canada: energy, resource, and transportation sectors.

    Science.gov (United States)

    Prowse, Terry D; Furgal, Chris; Chouinard, Rebecca; Melling, Humfrey; Milburn, David; Smith, Sharon L

    2009-07-01

    Northern Canada is projected to experience major changes to its climate, which will have major implications for northern economic development. Some of these, such as mining and oil and gas development, have experienced rapid expansion in recent years and are likely to expand further, partly as the result of indirect effects of changing climate. This article reviews how a changing climate will affect several economic sectors including the hydroelectric, oil and gas, and mining industries as well as infrastructure and transportation, both marine and freshwater. Of particular importance to all sectors are projected changes in the cryosphere, which will create both problems and opportunities. Potential adaptation strategies that could be used to minimize the negative impacts created by a climate change are also reviewed.

  11. Recent Advances in Developing Inhibitors for Hypoxia-Inducible Factor Prolyl Hydroxylases and Their Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    So Yeon Kim

    2015-11-01

    Full Text Available Hypoxia-inducible factor (HIF prolyl hydroxylases (PHDs are members of the 2-oxoglutarate dependent non-heme iron dioxygenases. Due to their physiological roles in regulation of HIF-1α stability, many efforts have been focused on searching for selective PHD inhibitors to control HIF-1α levels for therapeutic applications. In this review, we first describe the structure of PHD2 as a molecular basis for structure-based drug design (SBDD and various experimental methods developed for measuring PHD activity. We further discuss the current status of the development of PHD inhibitors enabled by combining SBDD approaches with high-throughput screening. Finally, we highlight the clinical implications of small molecule PHD inhibitors.

  12. The investment development path in a globalised world: implications for Eastern Europe

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    José Guimón

    2010-12-01

    Full Text Available This article summarises recent revisions to the investment development path(IDP as postulated by Narula and Dunning (2010. The IDP provides a framework to understand the dynamic interaction between foreign direct investment (FDI and economic development. The revisions take into account some recent changes in the global economic environment. This paper argues that studies based on the IDP should adopt a broader perspective, encompassing the idiosyncratic economic structure of countries as well as the heterogeneous nature of FDI. It is critical to understand the complex forces and interactions that determine the turning points in a country’s IDP, and to more explicitly acknowledge the role of historical, social and political circumstances in hindering or promoting FDI. We discuss some of the implications for EasternEuropean countries and provide some guidelines for future research.

  13. Implications Of Foreign Direct Investment, Financial Development And Real Exchange Rate For Economic Growth In Cameroon

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    Victalice Ngimanang Achamoh

    2016-05-01

    Full Text Available This paper assesses the effects of foreign direct investment (FDI, financial development and real exchange rate (RER on economic growth in Cameroon using Cameroon’s annual time series data spanning the period 1977 - 2010. To address these objectives, residual based Engle-Granger test, the OLS based Autoregressive Distributive Lag (ARDL bound testing and maximum likelihood based Johansen cointegration techniques are employed. Results of Unit roots tests show that all the series possessed unit roots at level or first difference form. The ARDL model and VECM results reveal that the RER has a significant negative effect on economic growth, while FDI and Financial Development relate positively to economic growth. These findings have implications for stimulating economic growth by increasing efficiency of the financial sector in allocating credit to the private sector and preventing real exchange rate appreciation in the shortrun.

  14. Functional, Structural, and Neurotoxicity Biomarkers in Integrative Assessment of Concussions

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    Svetlana A Dambinova

    2016-10-01

    Full Text Available Concussion is a complex, heterogenous process affecting the brain. Accurate assessment and diagnosis and appropriate management of concussion are essential to ensure athletes do not prematurely return to play or others to work or active military duty, risking re-injury. To date, clinical diagnosis relies primarily on evaluating subjects for functional impairment using instruments that include neurocognitive testing, subjective symptom report, and neurobehavioral assessments, such as balance and vestibular-ocular reflex testing. Structural biomarkers, defined as advanced neuroimaging techniques and biomarkers assessing neurotoxicity and immunoexcitotoxicity may complement the use of functional biomarkers. We hypothesize that neurotoxicity AMPA, NMDA, and kainite receptor biomarkers might be utilized as a part of comprehensive approach to concussion evaluations, with the goal of increasing diagnostic accuracy and facilitating treatment planning and prognostic assessment.

  15. China's CDM Policies and Their Development Implications: Major Concerns for CDM Implementation

    Institute of Scientific and Technical Information of China (English)

    Zhu Xianli; Pan Jiahua

    2006-01-01

    Most CDM (Clean Development Mechanism)opportunities exist in some large industrializing developing countries. For instance, China is estimated to take 48% of the world potential for CDM project activities. In reality, however, the share by China over the CDM projects registered and CDM projects in the pipeline is less than 10% as of Auguest 2005. This paper will examine the reasons behind, as reflected in China's CDM policies. Further investigation will be made into the use of these policies to boost the country's sustainable development, the sustainable development implications and effects of these policies. In addition, it is noted that incompatibility of some other Chinese laws and policies can be responsible for the low level and slow pace of CDM implementation in China and some suggestions are offered for promoting CDM project activities in China. There also exist barriers at the international level that impedes implementation of CDM project activities. A conclusion is drawn that CDM policies in a developing country like China aim mainly at promotion of sustainable development and to a lesser extent the generation of CERs.

  16. Adverse prenatal environment and kidney development: implications for programing of adult disease.

    Science.gov (United States)

    Dorey, Emily S; Pantaleon, Marie; Weir, Kristy A; Moritz, Karen M

    2014-06-01

    The 'developmental origins of health and disease' hypothesis suggests that many adult-onset diseases can be attributed to altered growth and development during early life. Perturbations during gestation can be detrimental and lead to an increased risk of developing renal, cardiovascular, metabolic, and neurocognitive dysfunction in adulthood. The kidney has emerged as being especially vulnerable to insult at almost any stage of development resulting in a reduction in nephron endowment. In both humans and animal models, a reduction in nephron endowment is strongly associated with an increased risk of hypertension. The focus of this review is twofold: i) to determine the importance of specific periods during development on long-term programing and ii) to examine the effects of maternal perturbations on the developing kidney and how this may program adult-onset disease. Recent evidence has suggested that insults occurring around the time of conception also have the capacity to influence long-term health. Although epigenetic mechanisms are implicated in mediating these outcomes, it is unclear as to how these may impact on kidney development. This presents exciting new challenges and areas for research. © 2014 Society for Reproduction and Fertility.

  17. Study of neurotoxic intracellular calcium signalling triggered by amyloids.

    Science.gov (United States)

    Villalobos, Carlos; Caballero, Erica; Sanz-Blasco, Sara; Núñez, Lucía

    2012-01-01

    Neurotoxicity in Alzheimer's disease (AD) is associated to dishomeostasis of intracellular Ca(2+) induced by amyloid β peptide (Aβ) species. Understanding of the effects of Aβ on intracellular Ca(2+) homeostasis requires preparation of the different Aβ assemblies including oligomers and fibrils and the testing of their effects on cytosolic and mitochondrial Ca(2+) in neurons. Procedures for cerebellar granule cell culture, preparation of Aβ species as well as fluorescence and bioluminescence imaging of cytosolic and mitochondrial Ca(2+) in neurons are described.

  18. Syndrome of Irreversible Lithium-Effectuated NeuroToxicity

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    Ana Luísa Silva

    2017-02-01

    Full Text Available Lithium has a narrow therapeutic window. Frequent monitoring of both serum levels and clinical signs of toxicity is warranted because toxicity may be present even when concentrations are within the therapeutic range. We report the case of a man with lithium poisoning, with persistent neurologic signs and symptoms even after removal of lithium from circulation – a diagnosis of syndrome of irreversible lithium-effectuated neurotoxicity (SILENT was made.

  19. Dopaminergic Neuron-Specific Deletion of p53 Gene Attenuates Methamphetamine Neurotoxicity.

    Science.gov (United States)

    Lu, Tao; Kim, Paul P; Greig, Nigel H; Luo, Yu

    2017-08-01

    p53 plays an essential role in the regulation of cell death in dopaminergic (DA) neurons and its activation has been implicated in the neurotoxic effects of methamphetamine (MA). However, how p53 mediates MA neurotoxicity remains largely unknown. In this study, we examined the effect of DA-specific p53 gene deletion in DAT-p53KO mice. Whereas in vivo MA binge exposure reduced locomotor activity in wild-type (WT) mice, this was significantly attenuated in DAT-p53KO mice and associated with significant differences in the levels of the p53 target genes BAX and p21 between WT and DAT-p53KO. Notably, DA-specific deletion of p53 provided protection of substantia nigra pars reticulata (SNpr) tyrosine hydroxylase (TH) positive fibers following binge MA, with DAT-p53KO mice having less decline of TH protein levels in striatum versus WT mice. Whereas DAT-p53KO mice demonstrated a consistently higher density of TH fibers in striatum compared to WT mice at 10 days after MA exposure, DA neuron counts within the substantia nigra pars compacta (SNpc) were similar. Finally, supportive of these results, administration of a p53-specific inhibitor (PFT-α) provided a similarly protective effect on MA binge-induced behavioral deficits. Neither DA specific p53 deletion nor p53 pharmacological inhibition affected hyperthermia induced by MA binge. These findings demonstrate a specific contribution of p53 activation in behavioral deficits and DA neuronal terminal loss by MA binge exposure.

  20. Comparison of Cannabidiol, Antioxidants, and Diuretics in Reversing Binge Ethanol-Induced Neurotoxicity

    Science.gov (United States)

    Hamelink, Carol; Hampson, Aidan; Wink, David A.; Eiden, Lee E.; Eskay, Robert L.

    2014-01-01

    Binge alcohol consumption in the rat induces substantial neurodegeneration in the hippocampus and entorhinal cortex. Oxidative stress and cytotoxic edema have both been shown to be involved in such neurotoxicity, whereas N-methyl-D-aspartate (NMDA) receptor activity has been implicated in alcohol withdrawal and excitoxic injury. Because the nonpsychoactive cannabinoid cannabidiol (CBD) was previously shown in vitro to prevent glutamate toxicity through its ability to reduce oxidative stress, we evaluated CBD as a neuroprotectant in a rat binge ethanol model. When administered concurrently with binge ethanol exposure, CBD protected against hippocampal and entorhinal cortical neurodegeneration in a dose-dependent manner. Similarly, the common antioxidants butylated hydroxytoluene and α-tocopherol also afforded significant protection. In contrast, the NMDA receptor antagonists dizocilpine (MK-801) and memantine did not prevent cell death. Of the diuretics tested, furosemide was protective, whereas the other two anion exchanger inhibitors, L-644,711 [(R)-(+)-(5,6-dichloro2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy acetic acid] and bumetanide, were ineffective. In vitro comparison of these diuretics indicated that furosemide is also a potent antioxidant, whereas the nonprotective diuretics are not. The lack of efficacy of L-644,711 and bumetanide suggests that the antioxidant rather than the diuretic properties of furosemide contribute most critically to its efficacy in reversing ethanol-induced neurotoxicity in vitro, in our model. This study provides the first demonstration of CBD as an in vivo neuroprotectant and shows the efficacy of lipophilic antioxidants in preventing binge ethanol-induced brain injury. PMID:15878999

  1. Evaluation of drug-induced neurotoxicity based on metabolomics, proteomics and electrical activity measurements in complementary CNS in vitro models.

    Science.gov (United States)

    Schultz, Luise; Zurich, Marie-Gabrielle; Culot, Maxime; da Costa, Anaelle; Landry, Christophe; Bellwon, Patricia; Kristl, Theresa; Hörmann, Katrin; Ruzek, Silke; Aiche, Stephan; Reinert, Knut; Bielow, Chris; Gosselet, Fabien; Cecchelli, Romeo; Huber, Christian G; Schroeder, Olaf H-U; Gramowski-Voss, Alexandra; Weiss, Dieter G; Bal-Price, Anna

    2015-12-25

    The present study was performed in an attempt to develop an in vitro integrated testing strategy (ITS) to evaluate drug-induced neurotoxicity. A number of endpoints were analyzed using two complementary brain cell culture models and an in vitro blood-brain barrier (BBB) model after single and repeated exposure treatments with selected drugs that covered the major biological, pharmacological and neuro-toxicological responses. Furthermore, four drugs (diazepam, cyclosporine A, chlorpromazine and amiodarone) were tested more in depth as representatives of different classes of neurotoxicants, inducing toxicity through different pathways of toxicity. The developed in vitro BBB model allowed detection of toxic effects at the level of BBB and evaluation of drug transport through the barrier for predicting free brain concentrations of the studied drugs. The measurement of neuronal electrical activity was found to be a sensitive tool to predict the neuroactivity and neurotoxicity of drugs after acute exposure. The histotypic 3D re-aggregating brain cell cultures, containing all brain cell types, were found to be well suited for OMICs analyses after both acute and long term treatment. The obtained data suggest that an in vitro ITS based on the information obtained from BBB studies and combined with metabolomics, proteomics and neuronal electrical activity measurements performed in stable in vitro neuronal cell culture systems, has high potential to improve current in vitro drug-induced neurotoxicity evaluation.

  2. N-Acetylcysteine in Combination with IGF-1 Enhances Neuroprotection against Proteasome Dysfunction-Induced Neurotoxicity in SH-SY5Y Cells

    Science.gov (United States)

    Anand, Pinki; Kuang, Anxiu; Akhtar, Feroz; Scofield, Virginia L.

    2016-01-01

    Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration. PMID:27774335

  3. Using protein misfolding cyclic amplification generates a highly neurotoxic PrP dimer causing neurodegeneration.

    Science.gov (United States)

    Yang, XiuJin; Yang, LiFeng; Zhou, XiangMei; Khan, Sher Hayat; Wang, HuiNuan; Yin, XiaoMin; Yuan, Zhen; Song, ZhiQi; Wu, WenYu; Zhao, DeMing

    2013-11-01

    Under the "protein-only" hypothesis, prion-based diseases are proposed to result from an infectious agent that is an abnormal isoform of the prion protein in the scrapie form, PrP(Sc). However, since PrP(Sc) is highly insoluble and easily aggregates in vivo, this view appears to be overly simplistic, implying that the presence of PrP(Sc) may indirectly cause neurodegeneration through its intermediate soluble form. We generated a neurotoxic PrP dimer with partial pathogenic characteristics of PrP(Sc) by protein misfolding cyclic amplification in the presence of 1-palmitoyl-2-oleoylphosphatidylglycerol consisting of recombinant hamster PrP (23-231). After intracerebral injection of the PrP dimer, wild-type hamsters developed signs of neurodegeneration. Clinical symptoms, necropsy findings, and histopathological changes were very similar to those of transmissible spongiform encephalopathies. Additional investigation showed that the toxicity is primarily related to cellular apoptosis. All results suggested that we generated a new neurotoxic form of PrP, PrP dimer, which can cause neurodegeneration. Thus, our study introduces a useful model for investigating PrP-linked neurodegenerative mechanisms.

  4. Advanced Pre-clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity

    Directory of Open Access Journals (Sweden)

    Cheng eWang

    2012-10-01

    Full Text Available Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cell and nonhuman primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticaled research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey models (in vivo, when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course and developmental stage at time of exposure (in vivo studies, serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

  5. Developmental neurotoxicity: methylmercury and prenatal exposure protection in the context of the Minamata Convention.

    Science.gov (United States)

    Boischio, Ana

    2015-09-01

    Mercury is a global pollutant of public environmental health concern due to its long-range atmospheric distribution, environmental distribution, and neurotoxic effects. Following biological methylation, methylmercury (MeHg) can be un-evenly bioaccumulated within aquatic food chains. Fish consumption can be a significant route of human exposure to MeHg. MeHg exposure in the prenatal stage, at relatively low levels, has recently been established as harmful during neurological development, potentially leading to intellectual disability. The Minamata Convention on Mercury is a global agreement, currently under ratification, to protect human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds. The resolution regarding the role of the World Health Organization and ministries of health in the implementation of the Convention includes protection of human health from critical exposures to MeHg. Riverside populations living in areas with artisanal small-scale gold mining, and relying heavily on fish consumption, have been identified as the most vulnerable population in terms of MeHg exposure and developmental neurotoxicity. This article focuses on the proper design and dissemination of fish advisories within the context of implementation of the Convention.

  6. Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity.

    Science.gov (United States)

    Xu, Jin-Chong; Fan, Jing; Wang, Xueqing; Eacker, Stephen M; Kam, Tae-In; Chen, Li; Yin, Xiling; Zhu, Juehua; Chi, Zhikai; Jiang, Haisong; Chen, Rong; Dawson, Ted M; Dawson, Valina L

    2016-04-06

    Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable. In human cortical neuronal cultures, excitotoxicity or ischemia due to oxygen and glucose deprivation led to cell death that was dependent on N-methyl-D-aspartate (NMDA) receptors, nitric oxide (NO), and poly(ADP-ribose) polymerase (PARP) (a cell death pathway called parthanatos that is distinct from apoptosis, necroptosis, and other forms of cell death). Neuronal cell death was attenuated by PARP inhibitors that are currently in clinical trials for cancer treatment. This culture system provides a new platform for the study of human cortical neurotoxicity and suggests that PARP inhibitors may be useful for ameliorating excitotoxic and ischemic cell death in human neurons.

  7. Developmental Neurotoxicity of Methamidophos in the Embryo-Larval Stages of Zebrafish

    Directory of Open Access Journals (Sweden)

    Xiaowei He

    2016-12-01

    Full Text Available Methamidophos is a representative organophosphate insecticide. The knowledge of its developmental neurotoxicity is limited, especially for zebrafish in the early stages of their life. Four hour post-fertilization (hpf zebrafish embryos were exposed to several environmentally relevant concentrations of methamidophos (0, 25, and 500 μg/L for up to 72 hpf. Locomotor behavior was then studied in the zebrafish larvae at this timepoint. Acridine orange (AO staining was carried out in the zebrafish larvae, and the mRNA levels of genes associated with neural development (mbp and syn2a were analyzed by reverse transcription-polymerase chain reaction (RT-PCR. The number of escape responders for mechanical stimulation was significantly decreased in exposed groups. AO staining showed noticeable signs of apoptosis mainly in the brain. In addition, the mRNA levels of mbp and syn2a were both significantly down-regulated in exposed groups. Our study provides the first evidence that methamidophos exposure can cause developmental neurotoxicity in the early stages of zebrafish life, which may be caused by the effect of methamidophos on neurodevelopmental genes and the activation of cell apoptosis in the brain.

  8. Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: a pharmacodynamic interaction?

    Science.gov (United States)

    Novy, Jan; Patsalos, Philip N; Sander, Josemir W; Sisodiya, Sanjay M

    2011-01-01

    Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.

  9. Developmental Neurotoxicity of Traffic-Related Air Pollution: Focus on Autism.

    Science.gov (United States)

    Costa, Lucio G; Chang, Yu-Chi; Cole, Toby B

    2017-06-01

    Epidemiological and animal studies suggest that air pollution may negatively affect the central nervous system (CNS) and contribute to CNS diseases. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component. Several studies suggest that young individuals may be particularly susceptible to air pollution-induced neurotoxicity and that perinatal exposure may cause or contribute to developmental disabilities and behavioral abnormalities. In particular, a number of recent studies have found associations between exposures to traffic-related air pollution and autism spectrum disorders (ASD), which are characterized by impairment in socialization and in communication and by the presence of repetitive and unusual behaviors. The cause(s) of ASD are unknown, and while it may have a hereditary component, environmental factors are increasingly suspected as playing a pivotal role in its etiology, particularly in genetically susceptible individuals. Autistic children present higher levels of neuroinflammation and systemic inflammation, which are also hallmarks of exposure to traffic-related air pollution. Gene-environment interactions may play a relevant role in determining individual susceptibility to air pollution developmental neurotoxicity. Given the worldwide presence of elevated air pollution, studies on its effects and mechanisms on the developing brain, genetic susceptibility, role in neurodevelopmental disorders, and possible therapeutic interventions are certainly warranted.

  10. Neuroprotective Role of a Novel Copper Chelator against Aβ42 Induced Neurotoxicity

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    Sandeep Kumar Singh

    2013-01-01

    Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative disease and associated with the extracellular deposits of amyloid-β peptide in hippocampus region. Metal ions like Cu, Fe and Zn are known to associate with the amyloid beta (Aβ at high concentration and interaction of these ions with soluble and aggregated forms of Aβ peptide help in development of AD. Here we showed Cu mediated neurotoxicity in the eye tissues of transgenic Drosophila expressing human amyloid β and its rescue through a novel Cu chelator. In this context, we have synthesised and characterized the compound L 2,6-Pyridinedicarboxylic acid, 2,6-bis[2-[(4-carboxyphenyl methylene] hydrazide] by Mass spectra (MS and Elemental analysis (EA. The Cu chelation potential of the compound L is tested in vivo in Drosophila. Oral administration of Copper to the transgenic larvae resulted in severe degeneration in eye tissues, which was rescued by the supplementation of compound L. The levels of anti-oxidant markers like SOD and MDA were measured in compound L treated flies and found a significant rescue (P<0.001. Further rescue of the eye degeneration phenotypes as revealed by SEM affirm the role of copper in Aβ toxicity. Hence, use of compound L, an amidoamine derivative, could be a possible therapeutic measure for Aβ induced neurotoxicity.

  11. Phosphorylation promotes neurotoxicity in a C. elegans model of TDP-43 proteinopathy

    Science.gov (United States)

    Liachko, Nicole F.; Guthrie, Chris R.; Kraemer, Brian C.

    2010-01-01

    Neurodegenerative disorders characterized by neuronal and glial lesions containing aggregated pathological TDP-43 protein in the cytoplasm, nucleus, or neurites are collectively referred to as TDP-43 proteinopathies. Lesions containing aggregated TDP-43 protein are a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In addition, mutations in human TDP-43 cause ALS. We have developed a C. elegans model of TDP-43 proteinopathies to study the cellular, molecular, and genetic underpinnings of TDP-43 mediated neurotoxicity. Expression of normal human TDP-43 in all C. elegans neurons causes moderate motor defects, while ALS-mutant G290A, A315T, or M337V TDP-43 transgenes cause severe motor dysfunction. The model recapitulates some characteristic features of ALS and FTLD-U including age-induced decline in motor function, decreased lifespan, and degeneration of motor neurons accompanied by hyperphosphorylation, truncation, and ubiquitination of TDP-43 protein that accumulates in detergent insoluble protein deposits. In C. elegans, TDP-43 neurotoxicity is independent of activity of the cell death caspase CED-3. Furthermore, phosphorylation of TDP-43 at serine residues 409/410 drives mutant TDP-43 toxicity. This model provides a tractable system for further dissection of the cellular and molecular mechanisms underlying TDP-43 neuropathology. PMID:21123567

  12. Central and peripheral neurotoxicity induced by the Jack Bean Urease (JBU) in Nauphoeta cinerea cockroaches.

    Science.gov (United States)

    Carrazoni, Thiago; de Avila Heberle, Marines; Perin, Ana Paula Artusi; Zanatta, Ana Paula; Rodrigues, Polyana Veloso; Dos Santos, Fabiola Duarte Machado; de Almeida, Carlos Gabriel Moreira; Vaz Breda, Ricardo; Dos Santos, Douglas Silva; Pinto, Paulo Marcos; da Costa, Jaderson Costa; Carlini, Celia Regina; Dal Belo, Cháriston André

    2016-08-10

    Ureases of Canavalia ensiformis are natural insecticides with a still elusive entomotoxic mode of action. We have investigated the mechanisms involved in the neurotoxicity induced by Jack Bean Urease (JBU) in Nauphoeta cinerea (Olivier). To carry out this study we have employed biochemical and neurophysiological analysis of different cockroach organ systems. The injection of the insects with JBU (0.75-6μg/g animal), although not lethal within 24h, caused significant inhibition of the brain acetylcholinesterase activity (60±5%, pcockroaches (pcockroaches, an effect prevented by bicuculline (5μg/g) (pcockroaches probably by interfering with the cholinergic neurotransmission. The neuromuscular blocking activity of JBU suggests an interplay between acetylcholine and GABA signaling. The search for novel natural molecules with insecticide potential has become a necessity more than an alternative. Understanding the mode of action of candidate molecules is a crucial step towards the development of new bioinsecticides. The present study focused on the neurotoxicity of Canavalia ensiformis urease, a natural insecticide, in cockroaches and revealed interferences on the cholinergic, octopaminergic and GABA-ergic pathways as part of its entomotoxic mode of action. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Developmental neurotoxicity of monocrotophos and lead is linked to thyroid disruption

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    B. Kala Kumar

    2016-02-01

    Full Text Available Aim: A role of thyroid disruption in developmental neurotoxicity of monocrotophos (MCP and lead is studied. Materials and Methods: A total of 24 female rats after conception were randomized into four groups of six each and treated as follows: Group I - Sham was administered distilled water orally. Group II - A positive control was administered methyl methimazole at 0.02% orally in drinking water. Group III - MCP orally at 0.3 mg/kg and Group IV - Lead acetate at 0.2% orally in drinking water. The drug was administered from gestation day 3 through post-natal day 21 in all the groups. Acetylcholinesterase (AChE inhibition, thyroid profile (thyroid stimulating hormone, T3 and T4, neurodevelopment (brain wet weights, DNA, RNA and protein, and neurobehavioral (elevated plus maze, photoactometry, and Morris water maze parameters were assessed in pups. A histopathology of thyroid of dams and brain of progeny was conducted. Results: Inhibition of AChE was <20%. Thyroid profile decreased in the treatment groups. Neurodevelopmental and neurobehavioral parameters did not reveal any significant changes. Thyroid architecture was affected significantly with MCP and lead. Cortical layers too were affected. The three layers of cerebellum either had abnormal arrangement or decreased cellularity in all treated groups relating to thyroid disruption. Conclusion: MCP and lead might have affected the development of cerebrum and cerebellum via thyroid disruption leading to developmental neurotoxicity.

  14. LIS1 and DCX: Implications for Brain Development and Human Disease in Relation to Microtubules

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    Orly Reiner

    2013-01-01

    Full Text Available Proper lamination of the cerebral cortex requires the orchestrated motility of neurons from their place of birth to their final destination. Improper neuronal migration may result in a wide range of diseases, including brain malformations, such as lissencephaly, mental retardation, schizophrenia, and autism. Ours and other studies have implicated that microtubules and microtubule-associated proteins play an important role in the regulation of neuronal polarization and neuronal migration. Here, we will review normal processes of brain development and neuronal migration, describe neuronal migration diseases, and will focus on the microtubule-associated functions of LIS1 and DCX, which participate in the regulation of neuronal migration and are involved in the human developmental brain disease, lissencephaly.

  15. Principles of crop modelling and simulation: II. the implications of the objective in model development

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    Dourado-Neto D.

    1998-01-01

    Full Text Available With the purpose of presenting to scientists the implications of the objective in model development and a basic vision of modeling, with its potential applications and limitations in agriculture, an integration of crop modeling professionals with agricultural professionals is suggested. Models mean modernization of the information, of the measurement process and of an efficient way to learn more about complex systems. They are one of the best mechanisms of transforming information in useful knowledge and of transferring this knowledge to others. One of the problems that impede a larger progress in modeling is the lack of communication between modelers and a frequent appearance of modelers without a global vision of reality.

  16. Stability and instability of childhood traits: implications for personality development of animals.

    Science.gov (United States)

    Putnam, Samuel P

    2011-09-01

    Concepts of animal personality and human temperament are nearly identical, both emphasizing overt behaviors rather than conscious processes, and assuming a primary role of biology in shaping individual differences. A point of divergence is emphasis on development among temperament scholars. Whereas most definitions of personality and temperament emphasize differential continuity-the maintenance of individual differences in behavioral tendencies over time-several behaviors demonstrate absolute discontinuity-age-related changes in mean levels. Attention to species-wide changes in behaviors may generate insight regarding the forces that govern individual differences. Differential continuity may also be heterotypic, with an inferred genotypic attribute being manifest in different behaviors at different ages. Structural continuity-persistence of correlational patterns among variables at different ages-represents a tool for identifying coherence in the common underpinnings of these diverse behaviors. This article describes research exemplifying these forms of continuity in humans, and suggests potential implications for animal personality investigations. Copyright © 2011 Wiley Periodicals, Inc.

  17. Experience as Knowledge in a New Product Development Team: Implications for Knowledge Management

    Science.gov (United States)

    Cooper, Lynne P.

    2009-01-01

    This study was conducted to better understand how New Product Development (NPD) team members apply their experiences to meet the task needs of their project. Although "experience" is highly valued in team members, little research has looked specifically at experiences as a type of knowledge, and how this knowledge is used in work settings. This research evaluated nearly 200 instances where team members referenced past experiences during team meetings. During these experience exchanges, team members structured the sharing of their experiences to include three common elements: the source of the experience, the nature of the experience, and the degree of relevance to the current work of the team. The experiences fell into four categories: people (relationships), process, product, and politics. This paper describes how team members structured, applied, and integrated their individual experiences and presents the resulting implications for knowledge management systems that wish to exploit experience knowledge.

  18. White matter development in adolescence: the influence of puberty and implications for affective disorders.

    Science.gov (United States)

    Ladouceur, Cecile D; Peper, Jiska S; Crone, Eveline A; Dahl, Ronald E

    2012-01-01

    There have been rapid advances in understanding a broad range of changes in brain structure and function during adolescence, and a growing interest in identifying which of these neurodevelopmental changes are directly linked with pubertal maturation—at least in part because of their potential to provide insights into the numerous emotional and behavioral health problems that emerge during this developmental period. This review focuses on what is known about the influence of puberty on white matter development in adolescence.We focus on white matter because of its role in providing the structural architectural organization of the brain and as a structural correlate of communication within complex neural systems. We begin with a review of studies that report sex differences or sex by age interactions in white matter development as these findings can provide, although indirectly,information relevant to puberty-related changes. Studies are also critically reviewed based on methodological procedures used to assess pubertal maturation and relations with white matter changes. Findings are discussed in light of their implications for the development of neural systems underlying the regulation of emotion and behavior and how alterations in the development of these systems may mediate risk for affective disorders in vulnerable adolescents.

  19. The Water Demand of Energy: Implications for Sustainable Energy Policy Development

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    Kaveh Madani

    2013-11-01

    Full Text Available With energy security, climate change mitigation, and sustainable development as three main motives, global energy policies have evolved, now asking for higher shares of renewable energies, shale oil and gas resources in the global energy supply portfolios. Yet, concerns have recently been raised about the environmental impacts of the renewable energy development, supported by many governments around the world. For example, governmental ethanol subsidies and mandates in the U.S. are aimed to increase the biofuel supply while the water footprint of this type of energy might be 70–400 times higher than the water footprint of conventional fossil energy sources. Hydrofracking, as another example, has been recognized as a high water-intensive procedure that impacts the surface and ground water in both quality and quantity. Hence, monitoring the water footprint of the energy mix is significantly important and could have implications for energy policy development. This paper estimates the water footprint of current and projected global energy policies, based on the energy production and consumption scenarios, developed by the International Energy Outlook of the U.S. Energy Information Administration. The outcomes reveal the amount of water required for total energy production in the world will increase by 37%–66% during the next two decades, requiring extensive improvements in water use efficiency of the existing energy production technologies, especially renewables.

  20. Biologic interactions between HSV-2 and HIV-1 and possible implications for HSV vaccine development.

    Science.gov (United States)

    Schiffer, Joshua T; Gottlieb, Sami L

    2017-09-25

    Development of a safe and effective vaccine against herpes simplex virus type 2 (HSV-2) has the potential to limit the global burden of HSV-2 infection and disease, including genital ulcer disease and neonatal herpes, and is a global sexual and reproductive health priority. Another important potential benefit of an HSV-2 vaccine would be to decrease HIV infections, as HSV-2 increases the risk of HIV-1 acquisition several-fold. Acute and chronic HSV-2 infection creates ulcerations and draws dendritic cells and activated CD4+ T cells into genital mucosa. These cells are targets for HIV entry and replication. Prophylactic HSV-2 vaccines (to prevent infection) and therapeutic vaccines (to modify or treat existing infections) are currently under development. By preventing or modifying infection, an effective HSV-2 vaccine could limit HSV-associated genital mucosal inflammation and thus HIV risk. However, a vaccine might have competing effects on HIV risk depending on its mechanism of action and cell populations generated in the genital mucosa. In this article, we review biologic interactions between HSV-2 and HIV-1, consider HSV-2 vaccine development in the context of HIV risk, and discuss implications and research needs for future HSV vaccine development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Sustainable development, demography and sexual and reproductive health: inseparable linkages and their policy implications.

    Science.gov (United States)

    Herrmann, Michael

    2014-05-01

    The greatest challenge today is to meet the needs of current and future generations, of a large and growing world population, without imposing catastrophic pressures on the natural environment. Meeting this challenge depends on decisive policy changes in three areas: more inclusive economic growth, greener economic growth, and population policies. This article focuses on efforts to address and harness demographic changes for sustainable development, which are largely outside the purview of the current debate. Efforts to this end must be based on the recognition that demographic changes are the cumulative result of individual choices and opportunities, and that demographic changes are best addressed through policies that enlarge these choices and opportunities, with a focus on ensuring unrestricted and universal access to sexual and reproductive health information and services, empowering women to fully participate in social, economic and political life, and investing in the education of the younger generation beyond the primary level. The article provides a strong argument for why the Programme of Action that was agreed at the International Conference on Population and Development (ICPD) 20 years ago continues to hold important implications and lessons for the formulation of the post-2015 development agenda, which is expected to supersede the Millennium Development Goals (MDGs).

  2. Brain-derived neurotrophic factor as an indicator of chemical neurotoxicity: an animal-free CNS cell culture model.

    Science.gov (United States)

    Woehrling, Elizabeth K; Hill, Eric J; Nagel, David; Coleman, Michael D

    2013-12-01

    Recent changes to the legislation on chemicals and cosmetics testing call for a change in the paradigm regarding the current 'whole animal' approach for identifying chemical hazards, including the assessment of potential neurotoxins. Accordingly, since 2004, we have worked on the development of the integrated co-culture of post-mitotic, human-derived neurons and astrocytes (NT2.N/A), for use as an in vitro functional central nervous system (CNS) model. We have used it successfully to investigate indicators of neurotoxicity. For this purpose, we used NT2.N/A cells to examine the effects of acute exposure to a range of test chemicals on the cellular release of brain-derived neurotrophic factor (BDNF). It was demonstrated that the release of this protective neurotrophin into the culture medium (above that of control levels) occurred consistently in response to sub-cytotoxic levels of known neurotoxic, but not non-neurotoxic, chemicals. These increases in BDNF release were quantifiable, statistically significant, and occurred at concentrations below those at which cell death was measureable, which potentially indicates specific neurotoxicity, as opposed to general cytotoxicity. The fact that the BDNF immunoassay is non-invasive, and that NT2.N/A cells retain their functionality for a period of months, may make this system useful for repeated-dose toxicity testing, which is of particular relevance to cosmetics testing without the use of laboratory animals. In addition, the production of NT2.N/A cells without the use of animal products, such as fetal bovine serum, is being explored, to produce a fully-humanised cellular model.

  3. Current Developments in Public Relations and a Review of their Implications on Public Relations Curriculum in Canada.

    Science.gov (United States)

    Wills, Sandra Judith Abiola

    Intended to review the recent professional developments in public relations as they are documented in the literature and to explore the implications of these developments for public relations education in Canada at the university level, this thesis is in six chapters, as follows: (1) Introduction; (2) Defining Public Relations; (3) Current Public…

  4. Copper inducing Aβ42 rather than Aβ40 nanoscale oligomer formation is the key process for Aβ neurotoxicity.

    Science.gov (United States)

    Jin, Lu; Wu, Wei-Hui; Li, Qiu-Ye; Zhao, Yu-Fen; Li, Yan-Mei

    2011-11-01

    Copper is known to be a critical factor in Alzheimer's disease (AD) pathogenesis, as it is involved in amyloid-β (Aβ) peptide related toxicity. However, the relationship between neurotoxicity and Aβ peptide in the presence of copper remains unclear. The effect of copper has not been clearly differentiated between Aβ42 and Aβ40, and it is still debated whether copper-mediated neurotoxicity is due to reactive oxygen species (ROS) accumulation or other molecular mechanisms. Here, we describe that copper dramatically affects Aβ42 aggregation and enhances Aβ42 cytotoxicity while it shows no significant effects on Aβ40. These phenomena are mainly because that the strong interactions between copper and Aβ42 lead to great conformation changes, and stabilize Aβ42 aggregates at highly toxic nanoscale oligomer stage, whereas copper shows no similar impact on Aβ40. We also propose a possible molecular mechanism that copper enhances Aβ42 cytotoxicity via perturbing membrane structure. Moreover, we test the effect of an analogue of copper, nickel, on Aβ aggregation and cytotoxicity, finding that nickel also enhances cytotoxicity via Aβ42 nanoscale oligomer formation. These results clarify that the copper-induced Aβ42 nanoscale oligomer formation is the key process for Aβ neurotoxicity, and suggest that disrupting the interactions between copper and Aβ42 peptide to inhibit nanoscale oligomerization process, deserves more attention in AD drug development.

  5. Neurotoxicity, anticoagulant activity and evidence of rhabdomyolysis in patients bitten by death adders (Acanthophis sp.) in southern Papua New Guinea.

    Science.gov (United States)

    Lalloo, D G; Trevett, A J; Black, J; Mapao, J; Saweri, A; Naraqi, S; Owens, D; Kamiguti, A S; Hutton, R A; Theakston, R D; Warrell, D A

    1996-01-01

    Thirty-two patients with enzyme-immunoassay-proven death adder (Acanthophis sp.) bites were studied in Port Moresby, Papua New Guinea. Eighteen were envenomed; local signs were rare and none had incoagulable blood, but all except one had signs of neurotoxicity. Five (27.7%) envenomed patients required intubation and ventilation. One patient developed renal failure, previously undescribed following death adder bites. Laboratory investigations showed mild prolongation of prothrombin and partial thromboplastin times in some patients. In vitro studies showed that the venom contains anticoagulant activity, but does not cause fibrinogenolysis. In contrast to taipan envenoming, neurotoxicity did not progress after antivenom administration, and there was reversal of neurotoxicity, evident within 6 h, in three severely envenomed patients treated less than 12 h after the bite. One patient treated with antivenom and anticholinesterases had the most dramatic response to treatment; the optimum management of bites by this species may include prompt treatment with both antivenom and anticholinesterases in addition to effective first aid.

  6. Multi-Parametric Profiling Network Based on Gene Expression and Phenotype Data: A Novel Approach to Developmental Neurotoxicity Testing

    Directory of Open Access Journals (Sweden)

    Hideko Sone

    2011-12-01

    Full Text Available The establishment of more efficient approaches for developmental neurotoxicity testing (DNT has been an emerging issue for children’s environmental health. Here we describe a systematic approach for DNT using the neuronal differentiation of mouse embryonic stem cells (mESCs as a model of fetal programming. During embryoid body (EB formation, mESCs were exposed to 12 chemicals for 24 h and then global gene expression profiling was performed using whole genome microarray analysis. Gene expression signatures for seven kinds of gene sets related to neuronal development and neuronal diseases were selected for further analysis. At the later stages of neuronal cell differentiation from EBs, neuronal phenotypic parameters were determined using a high-content image analyzer. Bayesian network analysis was then performed based on global gene expression and neuronal phenotypic data to generate comprehensive networks with a linkage between early events and later effects. Furthermore, the probability distribution values for the strength of the linkage between parameters in each network was calculated and then used in principal component analysis. The characterization of chemicals according to their neurotoxic potential reveals that the multi-parametric analysis based on phenotype and gene expression profiling during neuronal differentiation of mESCs can provide a useful tool to monitor fetal programming and to predict developmentally neurotoxic compounds.

  7. Multi-parametric profiling network based on gene expression and phenotype data: a novel approach to developmental neurotoxicity testing.

    Science.gov (United States)

    Nagano, Reiko; Akanuma, Hiromi; Qin, Xian-Yang; Imanishi, Satoshi; Toyoshiba, Hiroyoshi; Yoshinaga, Jun; Ohsako, Seiichiroh; Sone, Hideko

    2012-01-01

    The establishment of more efficient approaches for developmental neurotoxicity testing (DNT) has been an emerging issue for children's environmental health. Here we describe a systematic approach for DNT using the neuronal differentiation of mouse embryonic stem cells (mESCs) as a model of fetal programming. During embryoid body (EB) formation, mESCs were exposed to 12 chemicals for 24 h and then global gene expression profiling was performed using whole genome microarray analysis. Gene expression signatures for seven kinds of gene sets related to neuronal development and neuronal diseases were selected for further analysis. At the later stages of neuronal cell differentiation from EBs, neuronal phenotypic parameters were determined using a high-content image analyzer. Bayesian network analysis was then performed based on global gene expression and neuronal phenotypic data to generate comprehensive networks with a linkage between early events and later effects. Furthermore, the probability distribution values for the strength of the linkage between parameters in each network was calculated and then used in principal component analysis. The characterization of chemicals according to their neurotoxic potential reveals that the multi-parametric analysis based on phenotype and gene expression profiling during neuronal differentiation of mESCs can provide a useful tool to monitor fetal programming and to predict developmentally neurotoxic compounds.

  8. Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Marreilha dos Santos, A.P., E-mail: apsantos@ff.ul.pt [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal); Lucas, Rui L.; Andrade, Vanda; Mateus, M. Luísa [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal); Milatovic, Dejan; Aschner, Michael [Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232 (United States); Batoreu, M. Camila [I-Med.UL, Department of Toxicology and Food Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon (Portugal)

    2012-02-01

    Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E{sub 2} prostaglandin (PGE{sub 2}) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity. -- Highlights: ► The manuscript is unique in its approach to the neurotoxicity of Mn. ► The manuscript incorporates molecular, cellular and functional (behavioral) analyses. ► Both PAS and Ebs are effective in restoring Mn behavioral function. ► Both PAS and Ebs are effective in reducing Mn-induced oxidative stress. ► Both PAS and Ebs led to a decrease in Mn-induced neuro-inflammation.

  9. Oxidative and excitatory mechanisms of developmental neurotoxicity: transcriptional profiles for chlorpyrifos, diazinon, dieldrin, and divalent nickel in PC12 cells.

    Science.gov (United States)

    Slotkin, Theodore A; Seidler, Frederic J

    2009-04-01

    Oxidative stress and excitotoxicity underlie the developmental neurotoxicity of numerous chemicals. We compared the effects of organophosphates (chlorpyrifos and diazinon), an organo-chlorine (dieldrin), and a metal [divalent nickel (Ni2+)] to determine how these mechanisms contribute to similar or dissimilar neurotoxic outcomes. We used PC12 cells as a model of developing neurons and evaluated transcriptional profiles for genes for oxidative stress responses and glutamate receptors. Chlorpyrifos had a greater effect on oxidative-stress-related genes in differentiating cells compared with the undifferentiated state. Chlorpyrifos and diazinon showed significant concordance in their effects on glutathione-related genes, but they were negatively correlated for effects on catalase and superoxide dismutase isoforms and had no concordance for effects on ionotropic glutamate receptors. Surprisingly, the correlations were stronger between diazinon and dieldrin than between the two organophosphates. The effects of Ni2+ were the least similar for genes related to oxidative stress but had significant concordance with dieldrin for effects on glutamate receptors. Our results point to underlying mechanisms by which different organophosphates produce disparate neurotoxic outcomes despite their shared property as cholinesterase inhibitors. Further, apparently unrelated neurotoxicants may produce similar outcomes because of convergence on oxidative stress and excitotoxicity. The combined use of cell cultures and microarrays points to specific end points that can distinguish similarities and disparities in the effects of diverse developmental neurotoxicants.

  10. Gonadal steroids differentially modulate neurotoxicity of HIV and cocaine: testosterone and ICI 182,780 sensitive mechanism

    Directory of Open Access Journals (Sweden)

    Mactutus Charles F

    2005-06-01

    Full Text Available Abstract Background HIV Associated Dementia (HAD is a common complication of human immunodeficiency virus (HIV infection that erodes the quality of life for patients and burdens health care providers. Intravenous drug use is a major route of HIV transmission, and drug use is associated with increased HAD. Specific proteins released as a consequence of HIV infection (e.g., gp120, the HIV envelope protein and Tat, the nuclear transactivating protein have been implicated in the pathogenesis of HAD. In primary cultures of human fetal brain tissue, subtoxic doses of gp120 and Tat are capable of interacting with a physiologically relevant dose of cocaine, to produce a significant synergistic neurotoxicity. Using this model system, the neuroprotective potential of gonadal steroids was investigated. Results 17β-Estradiol (17β-E2, but not 17α-estradiol (17α-E2, was protective against this combined neurotoxicity. Progesterone (PROG afforded limited neuroprotection, as did dihydrotestosterone (DHT. The efficacy of 5α-testosterone (T-mediated neuroprotection was robust, similar to that provided by 17β-E2. In the presence of the specific estrogen receptor (ER antagonist, ICI-182,780, T's neuroprotection was completely blocked. Thus, T acts through the ER to provide neuroprotection against HIV proteins and cocaine. Interestingly, cholesterol also demonstrated concentration-dependent neuroprotection, possibly attributable to cholesterol's serving as a steroid hormone precursor in neurons. Conclusion Collectively, the present data indicate that cocaine has a robust interaction with the HIV proteins gp120 and Tat that produces severe neurotoxicity, and this toxicity can be blocked through pretreatment with ER agonists.

  11. PET and SPECT imaging of neurotoxicity

    NARCIS (Netherlands)

    Vries, E.F.J. de; Dierckx, R.A.J.O.

    2014-01-01

    From conception until death, we are exposed to neurotoxins that can potentially induce toxic encephalopathy. Neurotoxins can cause acute adverse effects or show delayed symptoms. They can even induce impaired brain development in the offspring of exposed pregnant females. Both in patients and in ani

  12. Accelerated Urban Expansion in Lhasa City and the Implications for Sustainable Development in a Plateau City

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    Wei Tang

    2017-08-01

    Full Text Available Urbanization challenges regional sustainable development, but a slight expansion mechanism was revealed in a plateau city. We have integrated the urban expansion process and analyzed its determinants in Lhasa (Tibet, and we provide insightful suggestions for urban management and planning for Lhasa. The full continuum of the urban expansion process has been captured using time-series of high-resolution remote sensing data (1990–2015. Four categories of potential determinants involved in economic, demographic, social, and government policy factors were selected, and redundancy analysis was employed to define the contribution rates of these determinants. The results illustrate that considerable urban expansion occurred from 1990 to 2015 in Lhasa, with the area of construction land and transportation land increasing at rates of 117.2% and 564.7%, respectively. The urban expansion in the center of Lhasa can be characterized as temperate sprawl from 1990 through 2008, primarily explained by governmental policies and investment, economic development, tourist growth, and increased governmental investment resulting in faster urban expansion from 2008 to 2015, mainly occurring in the east, south, and west of Lhasa. In contrast with other cities of China, central government investment and “pairing-up support” projects have played an important role in infrastructure construction in Lhasa. The miraculous development of the tourism industry had prominent effects on this economic development and urbanization after 2006, due to the running of the Tibetan Railway. An integrative and proactive policy framework, the “Lhasa development model”, having important theoretical, methodological, and management implications for urban planning and development, has been proposed.

  13. Social problems and social work in Ghana: Implications for sustainable development

    Directory of Open Access Journals (Sweden)

    Baffoe M.

    2013-03-01

    Full Text Available Social Work practice is a helping profession that provides services aimed at assisting societies work better for their people. It is designed to support people burdened with varying degrees of social problems to function better within society. Meaningful and sustainable development cannot take place in societies afflicted with a host of social problems which receive no meaningful interventions. Ghana is beset with a myriad of social problems that call for professional social work interventions. Using Social work education and practice as a backdrop, this article highlights some of the key and emerging social problems in Ghana. It examines the constraints and unique challenges that the profession face in its efforts to help people develop their full potential and improve their lives. Furthermore, the authors discuss social work education and practice interventions that would bring about social change and help people, especially the poor and the marginalized, to appropriately play their part in society. This article concludes with highlights on the implications of social problems and social work interventions for sustainable development in Ghanaian society.

  14. Regulation of liver development: implications for liver biology across the lifespan.

    Science.gov (United States)

    Gruppuso, Philip A; Sanders, Jennifer A

    2016-04-01

    The liver serves a spectrum of essential metabolic and synthetic functions that are required for the transition from fetal to postnatal life. Processes essential to the attainment of adequate liver mass and function during fetal life include cell lineage specification early in development, enzymic and other functional modes of differentiation throughout gestation, and ongoing cell proliferation to achieve adequate liver mass. Available data in laboratory rodents indicate that the signaling networks governing these processes in the fetus differ from those that can sustain liver function and mass in the adult. More specifically, fetal hepatocytes may develop independent of key mitogenic signaling pathways, including those involving the Erk mitogen-activated protein kinases MAPK1/3 and the mechanistic target of rapamycin (mTOR). In addition, the fetal liver is subject to environmental influences that, through epigenetic mechanisms, can have sustained effects on function and, by extension, contribute to the developmental origin of adult metabolic disease. Finally, the mitogen-independent phenotype of rat fetal hepatocytes in late gestation makes these cells suitable for cell-based therapy of liver injury. In the aggregate, studies on the mechanisms governing fetal liver development have implications not only for the perinatal metabolic transition but also for the prevention and treatment of liver disorders throughout the lifespan.

  15. Loss of Panx1 Impairs Mammary Gland Development at Lactation: Implications for Breast Tumorigenesis

    Science.gov (United States)

    Stewart, Michael K. G.; Plante, Isabelle; Penuela, Silvia; Laird, Dale W.

    2016-01-01

    Pannexin1 (Panx1) subunits oligomerize to form large-pore channels between the intracellular and extracellular milieu that have been shown to regulate proliferation, differentiation and cell death mechanisms. These key cellular responses are ultimately necessary for normal tissue development and function but the role of Panx1 in development, differentiation and function in many tissues remains unexplored, including that of the breast. Panx1 was identified to be expressed in the mammary gland through western blot and immunofluorescent analysis and is dynamically upregulated during pregnancy and lactation. In order to evaluate the role of Panx1 in the context of mammary gland development and function, Panx1-/- mice were evaluated in comparison to wild-type mice in the mammary glands of virgin, lactating and involuting mice. Our results revealed that Panx1 ablation did not affect virgin or involuting mammary glands following histological and whole mount analysis. Panx1 was necessary for timely alveolar development during early lactation based on a decreased number of alveolar lumen following histological analysis and reduced proliferation following Ki67 immunofluorescent labelling. Importantly, the loss of Panx1 in lactating mammary glands did not overtly affect epithelial or secretory differentiation of the mammary gland suggesting that Panx1 is not critical in normal mammary gland function. In addition, PANX1 mRNA expression was correlated with negative clinical outcomes in patients with breast cancer using in silico arrays. Together, our results suggest that Panx1 is necessary for timely alveolar development following the transition from pregnancy to lactation, which may have implications extending to patients with breast cancer. PMID:27099931

  16. Occupational exposure to neurotoxic substances in Asian countries - Challenges and approaches

    Science.gov (United States)

    Meyer-Baron, Monika; Kim, Eun A; Nuwayhid, Iman; Ichihara, Gaku; Kang, Seong-Kyu

    2012-01-01

    The fact that a conference on neurotoxicity was held in China triggered the idea to provide an insight into occupational diseases, their development and the approaches to investigate them in Asian countries. A historical review, a meta-analysis, and studies on humans and animals provide impressions on past and current problems. The Korean example showed that each newly introduced industry is accompanied by its own problems as regards occupational diseases. Mercury and carbon disulfide were of importance in the beginning, whereas solvents and manganese became important later. Outbreaks of diseases were important reasons to guide both the public and the governmental attention to prevention and allowed within a relatively short time considerable progress. As the example on the replacement of 2-bromopropane by 1-bromopropane showed, also the introduction of chemicals that are more beneficial for the environment may result in additional occupational risks. A lower mutagenicity of 1-bromopopane was shown to be associated with a greater neurotoxicity in Japanese studies. Although occupational health and diseases are commonly related to adults, child workers exposed to solvents were examined in a Lebanese study. The study started outlining the health hazards in young workers because they might be at a much greater risk due to the not yet completed maturation of their nervous system. That some occupational diseases are not yet a focus of prevention was shown by the study on pesticides. If at all, the serious health consequences resulting from excessive exposure were investigated. Research enabling precautionary actions was not available from the international literature. Despite globalization the knowledge on occupational diseases is not yet “globalized” and each country obviously undergoes its own development triggered by local experiences. Economic development that requires a healthy workforce, but also public interest that challenges governmental regulations further

  17. Project-Based Market Competition and Policy Implications for Sustainable Developments in Building and Construction Sectors

    Directory of Open Access Journals (Sweden)

    Min-Ren Yan

    2015-11-01

    Full Text Available Building and construction sectors are significant contributors to the global economy, but their energy consumption necessitates greater commitment to sustainable developments. There is therefore a growing demand for green innovation in the form of cleaner production and policies to meet the modern requirements of sustainability. However, the nature in which public work is undertaken is in an environment of project-based market competition, whereby contractors routinely bid for contracts under specific project awarding systems, and variations are accompanied with the unique scope of individual projects before the final goods or services are delivered. A comprehensive understanding of the characteristics and contractors’ behavior in systems could help to identify the leverage points of policies. This paper proposes a system dynamics model, with quantitative analysis and simulations, to demonstrate the problems of a system with different project awarding systems and ineffective market performance. The framework of market efficiency and performance measures has been proposed to evaluate the project-based competition mechanism. Managerial policy implications for market efficiency and sustainable developments can thus be systematically discussed and compared through iterative computer simulations and scenario analysis.

  18. Private sector participation in secondary education in Nigeria: Implications for national development

    Directory of Open Access Journals (Sweden)

    Uyi Kizito Ehigiamusoe

    2012-12-01

    Full Text Available The study examines private sector participation in secondary education in Nigeria and its implications for national development. The population consisted all the providers and recipients of private secondary education in the Federal Capital Territory (FCT. Simple random sampling was used to select 200 providers and recipients of private secondary education across the six Area Councils in the FCT. An instrument designated Private Sector Participation in Secondary Education (PSPSE was used to collect data. The data were analysed using Chi-Square method to test for the acceptance or rejection of the study hypotheses. The findings revealed that the academic performance of students in private secondary schools is better than the academic performance of students in public secondary schools. The study further revealed that private secondary schools have better infrastructure than public secondary schools in Nigeria, but private secondary schools contribute less to the development of human resources than public schools in Nigeria. Recommendations are proffered to make private secondary education more viable and responsive to the needs of the society.

  19. Making poverty reduction irreversible: development implications of the Millennium Ecosystem Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Bass, Steve

    2006-07-15

    Development is achieved through growing and managing the 'portfolio of assets' available to a household or a nation. Soils, water, plants and animals often make up the biggest chunk of poor people's assets. The Millennium Ecosystem Assessment (MA) has taken stock of these environmental assets worldwide. It reveals that fully sixty percent are being degraded – with poor people disproportionately suffering the consequences such as shortage of clean water, floods and droughts. Yet the MA also identified instances of effective asset management – proven 'Response Options' that deserve scaling up. This briefing note identifies the major developmental implications of the MA, and calls for action in four areas: Information – getting information on environmental assets and hazards to the heart of development planning; Institutional reform – encouraging ecosystem management by poor people and local organisations, and enabling better oversight by national authorities; International cooperation – increasing aid and benchmarking it against just how far off-track we are on MDG7 (the 'environmental sustainability' goal); Investment vehicles and budgets – to support long-term environmental management in key environmentally-sensitive sectors. Action on these is so urgently required that we can no longer avoid asking what it will cost. We propose 'Millennium Ecosystem Budgets', globally and nationally.

  20. Carboxypeptidase A6 in zebrafish development and implications for VIth cranial nerve pathfinding.

    Directory of Open Access Journals (Sweden)

    Peter J Lyons

    Full Text Available Carboxypeptidase A6 (CPA6 is an extracellular protease that cleaves carboxy-terminal hydrophobic amino acids and has been implicated in the defective innervation of the lateral rectus muscle by the VIth cranial nerve in Duane syndrome. In order to investigate the role of CPA6 in development, in particular its potential role in axon guidance, the zebrafish ortholog was identified and cloned. Zebrafish CPA6 was secreted and interacted with the extracellular matrix where it had a neutral pH optimum and specificity for C-terminal hydrophobic amino acids. Transient mRNA expression was found in newly formed somites, pectoral fin buds, the stomodeum and a conspicuous condensation posterior to the eye. Markers showed this tissue was not myogenic in nature. Rather, the CPA6 localization overlapped with a chondrogenic site which subsequently forms the walls of a myodome surrounding the lateral rectus muscle. No other zebrafish CPA gene exhibited a similar expression profile. Morpholino-mediated knockdown of CPA6 combined with retrograde labeling and horizontal eye movement analyses demonstrated that deficiency of CPA6 alone did not affect either VIth nerve development or function in the zebrafish. We suggest that mutations in other genes and/or enhancer elements, together with defective CPA6 expression, may be required for altered VIth nerve pathfinding. If mutations in CPA6 contribute to Duane syndrome, our results also suggest that Duane syndrome can be a chondrogenic rather than a myogenic or neurogenic developmental disorder.

  1. Nature of Technology: Implications for design, development, and enactment of technological tools in school science classrooms

    Science.gov (United States)

    Waight, Noemi; Abd-El-Khalick, Fouad

    2012-12-01

    This position paper provides a theory-based explanation informed by philosophy of technology (PoT) of the recurrent documented patterns often associated with attempts to enact technology-supported, inquiry-based approaches in precollege science classrooms. Understandings derived from the history of technological development in other domains (e.g. medicine, transportation, and warfare) reveal numerous parallels that help to explain these recurrent patterns. Historical analyses of major technologies reveal a conglomerate of factors that interact to produce benefits, as well as intended and unintended consequences. On a macro-scale, PoT facilitates understandings of how technologies interact and are impacted by individuals, society, institutions, economy, politics, and culture. At the micro-level, and most relevant to science education, PoT engages the inherent nature of technology along a number of key dimensions: role of culture and values, notions of technological progression, technology as part of systems, technological diffusion, technology as a fix, and the notions of expertise. Overall, the present analysis has implications for the design, development, implementation, and adoption of technological tools for use in precollege science education, and highlights the role of technology as both artifact and process.

  2. Perspectives on the rhythm-grammar link and its implications for typical and atypical language development.

    Science.gov (United States)

    Gordon, Reyna L; Jacobs, Magdalene S; Schuele, C Melanie; McAuley, J Devin

    2015-03-01

    This paper reviews the mounting evidence for shared cognitive mechanisms and neural resources for rhythm and grammar. Evidence for a role of rhythm skills in language development and language comprehension is reviewed here in three lines of research: (1) behavioral and brain data from adults and children, showing that prosody and other aspects of timing of sentences influence online morpho-syntactic processing; (2) comorbidity of impaired rhythm with grammatical deficits in children with language impairment; and (3) our recent work showing a strong positive association between rhythm perception skills and expressive grammatical skills in young school-age children with typical development. Our preliminary follow-up study presented here revealed that musical rhythm perception predicted variance in 6-year-old children's production of complex syntax, as well as online reorganization of grammatical information (transformation); these data provide an additional perspective on the hierarchical relations potentially shared by rhythm and grammar. A theoretical framework for shared cognitive resources for the role of rhythm in perceiving and learning grammatical structure is elaborated on in light of potential implications for using rhythm-emphasized musical training to improve language skills in children.

  3. Meis1 coordinates a network of genes implicated in eye development and microphthalmia.

    Science.gov (United States)

    Marcos, Séverine; González-Lázaro, Monica; Beccari, Leonardo; Carramolino, Laura; Martin-Bermejo, Maria Jesus; Amarie, Oana; Mateos-San Martín, Daniel; Torroja, Carlos; Bogdanović, Ozren; Doohan, Roisin; Puk, Oliver; Hrabě de Angelis, Martin; Graw, Jochen; Gomez-Skarmeta, Jose Luis; Casares, Fernando; Torres, Miguel; Bovolenta, Paola

    2015-09-01

    Microphthalmos is a rare congenital anomaly characterized by reduced eye size and visual deficits of variable degree. Sporadic and hereditary microphthalmos have been associated with heterozygous mutations in genes fundamental for eye development. Yet, many cases are idiopathic or await the identification of molecular causes. Here we show that haploinsufficiency of Meis1, which encodes a transcription factor with evolutionarily conserved expression in the embryonic trunk, brain and sensory organs, including the eye, causes microphthalmic traits and visual impairment in adult mice. By combining analysis of Meis1 loss-of-function and conditional Meis1 functional rescue with ChIP-seq and RNA-seq approaches we show that, in contrast to its preferential association with Hox-Pbx BSs in the trunk, Meis1 binds to Hox/Pbx-independent sites during optic cup development. In the eye primordium, Meis1 coordinates, in a dose-dependent manner, retinal proliferation and differentiation by regulating genes responsible for human microphthalmia and components of the Notch signaling pathway. In addition, Meis1 is required for eye patterning by controlling a set of eye territory-specific transcription factors, so that in Meis1(-/-) embryos boundaries among the different eye territories are shifted or blurred. We propose that Meis1 is at the core of a genetic network implicated in eye patterning/microphthalmia, and represents an additional candidate for syndromic cases of these ocular malformations.

  4. Emerging diseases and implications for Millennium Development Goals in Africa by 2015 - an overview

    Directory of Open Access Journals (Sweden)

    Mohammed Bello

    2010-06-01

    Full Text Available Emerging zoonotic diseases have assumed increasing fundamental importance in both public and animal health, as the last few years have seen a steady increase of new cases, each emerging from an unsuspected geographic area and causing serious problems, often leading to mortalities among animals and humans. The reasons for disease emergence or re-emergence are multiple and include certain major factors, such as expansion of the human population, climate change and globalisation of trade. Further contributing issues, such as the increased movement of animal species, microbial evolution, ecological disruption, changes in human behaviour, all imply that emerging diseases will not only continue to occur, but the rate of their emergence will also increase. These will constitute constraints for the attainment of the Millennium Development Goals by African Governments by 2015. There is no doubt that the current trend calls for more and stronger partnerships between national and international organisations, veterinary and medical communities, environmentalists, academics and policy-makers of various governments on the continent within the context of the global ‘One Health’ movement. This article attempts to analyse the impact of emerging diseases and the implications for the achievement of the Millennium Development Goals in Africa by the year 2015.

  5. Sustainable development of cement and concrete: Two practical examples of typical implication for the future

    Energy Technology Data Exchange (ETDEWEB)

    Jahren, P. [P. J. Consult A/S, Hvalstad (Norway)

    1998-12-31

    Two practical examples of challenges to the environment by the cement and concrete industry and their implications for sustainable development are discussed. The first example involves alternative uses for 70,000 to 100,000 tons per annum of residual filter-cake, a by-product of calcium-carbide production, which up till now mostly have been discarded and deposited in sanitary landfills. With the dwindling of landfill sites in many countries of the world, the cement and concrete industry is currently exploring ways of making use of this material. The second example is drawn from the the increasing interest in producing artificial fish reefs to improve the seafood supply. Some 61 countries around the world are involved in various projects related to this endeavour. Recently, concrete has become the materials of choice to construct these reefs. Use of materials like fly ash and quarry dust in concrete mixtures has given rise to concerns of possible pollution of the food chain, leading to requests for standards and specifications and testing for cementitious materials. Details of both these problems and efforts to respond to the challenges are described against the background of increasing recognition, at the same time, of the need for sustainable development. 8 refs., 1 tab., 2 figs.

  6. Fatty acid amide hydrolase inhibition by neurotoxic organophosphorus pesticides.

    Science.gov (United States)

    Quistad, G B; Sparks, S E; Casida, J E

    2001-05-15

    Organophosphorus (OP) compound-induced inhibition of acetylcholinesterase (AChE) and neuropathy target esterase explains the rapid onset and delayed neurotoxic effects, respectively, for OP insecticides and related compounds but apparently not a third or intermediate syndrome with delayed onset and reduced limb mobility. This investigation tests the hypothesis that fatty acid amide hydrolase (FAAH), a modulator of endogenous signaling compounds affecting sleep (oleamide) and analgesia (anandamide), is a sensitive target for OP pesticides with possible secondary neurotoxicity. Chlorpyrifos oxon inhibits 50% of the FAAH activity (IC50 at 15 min, 25 degrees C, pH 9.0) in vitro at 40--56 nM for mouse brain and liver, whereas methyl arachidonyl phosphonofluoridate, ethyl octylphosphonofluoridate (EOPF), oleyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (oleyl-BDPO), and dodecyl-BDPO give IC50s of 0.08--1.1 nM. These BDPOs and EOPF inhibit mouse brain FAAH in vitro with > or =200-fold higher potency than for AChE. Five OP pesticides inhibit 50% of the brain FAAH activity (ED50) at diazinon, and methamidophos occurs near acutely toxic levels, profenofos and tribufos are effective at asymptomatic doses. Two BDPOs (dodecyl and phenyl) and EOPF are potent inhibitors of FAAH in vivo (ED50 0.5--6 mg/kg). FAAH inhibition of > or =76% in brain depresses movement of mice administered anandamide at 30 mg/kg ip, often leading to limb recumbency. Thus, OP pesticides and related inhibitors of FAAH potentiate the cannabinoid activity of anandamide in mice. More generally, OP compound-induced FAAH inhibition and the associated anandamide accumulation may lead to reduced limb mobility as a secondary neurotoxic effect.

  7. Neurotoxicity induced by mephedrone: An up-to-date review.

    Science.gov (United States)

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Pacifici, Roberta; di Luca, Alessandro; Busardò, Francesco Paolo; Marinelli, Enrico

    2016-11-30

    Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.

  8. NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.

    Directory of Open Access Journals (Sweden)

    Miriam Aza-Carmona

    Full Text Available SHOX and SHOX2 transcription factors are highly homologous, with even identical homeodomains. Genetic alterations in SHOX result in two skeletal dysplasias; Léri-Weill dyschondrosteosis (LWD and Langer mesomelic dysplasia (LMD, while no human genetic disease has been linked to date with SHOX2. SHOX2 is, though, involved in skeletal development, as shown by different knockout mice models. Due to the high homology between SHOX and SHOX2, and their functional redundancy during heart development, we postulated that SHOX2 might have the same transcriptional targets and cofactors as SHOX in limb development. We selected two SHOX transcription targets regulated by different mechanisms: 1 the natriuretic peptide precursor B gene (NPPB involved in the endochondral ossification signalling and directly activated by SHOX; and 2 Aggrecan (ACAN, a major component of cartilage extracellular matrix, regulated by the cooperation of SHOX with the SOX trio (SOX5, SOX6 and SOX9 via the protein interaction between SOX5/SOX6 and SHOX. Using the luciferase assay we have demonstrated that SHOX2, like SHOX, regulates NPPB directly whilst activates ACAN via its cooperation with the SOX trio. Subsequently, we have identified and characterized the protein domains implicated in the SHOX2 dimerization and also its protein interaction with SOX5/SOX6 and SHOX using the yeast-two hybrid and co-immunoprecipitation assays. Immunohistochemistry of human fetal growth plates from different time points demonstrated that SHOX2 is coexpressed with SHOX and the members of the SOX trio. Despite these findings, no mutation was identified in SHOX2 in a cohort of 83 LWD patients with no known molecular defect, suggesting that SHOX2 alterations do not cause LWD. In conclusion, our work has identified the first cofactors and two new transcription targets of SHOX2 in limb development, and we hypothesize a time- and tissue-specific functional redundancy between SHOX and SHOX2.

  9. Marijuana, Spice 'herbal high', and early neural development: implications for rescheduling and legalization.

    Science.gov (United States)

    Psychoyos, Delphine; Vinod, K Yaragudri

    2013-01-01

    Marijuana is the most widely used illicit drug by pregnant women in the world. In utero exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), a major psychoactive component of marijuana, is associated with an increased risk for anencephaly and neurobehavioural deficiencies in the offspring, including attention deficit hyperactivity disorder (ADHD), learning disabilities, and memory impairment. Recent studies demonstrate that the developing central nervous system (CNS) is susceptible to the effects of Δ⁹-THC and other cannabimimetics, including the psychoactive ingredients of the branded product 'Spice' branded products. These exocannabinoids interfere with the function of an endocannabinoid (eCB) system, present in the developing CNS from E12.5 (week 5 of gestation in humans), and required for proliferation, migration, and differentiation of neurons. Until recently, it was not known whether the eCB system is also present in the developing CNS during the initial stages of its ontogeny, i.e. from E7.0 onwards (week 2 of gestation in humans), and if so, whether this system is also susceptible to the action of exocannabinoids. Here, we review current data, in which the presence of an eCB system during the initial stage of development of the CNS is demonstrated. Furthermore, we focus on recent advances on the effect of canabimimetics on early gestation. The relevance of these findings and potential adverse developmental consequences of in utero exposure to 'high potency' marijuana, Spice branded products and/or cannabinoid research chemicals during this period is discussed. Finally, we address the implication of these findings in terms of the potential dangers of synthetic cannabinoid use during pregnancy, and the ongoing debate over legalization of marijuana.

  10. Amantadine neurotoxicity in a pediatric patient with renal insufficiency.

    Science.gov (United States)

    Strong, D K; Eisenstat, D D; Bryson, S M; Sitar, D S; Arbus, G S

    1991-11-01

    Amantadine hydrochloride, a dopamine agonist with antiviral and antiparkinsonism properties, is used for the prevention and treatment of influenza A respiratory infections in high-risk populations. The occurrence of amantadine-induced hallucinations and tremors is described in a young, renal transplant patient with declining renal function. Following discontinuation of amantadine, plasma amantadine concentrations were correlated with central nervous system toxicity. In view of the usage of amantadine in renal transplant recipients and the elderly, clinicians must be alert to the possibility of amantadine-induced neurotoxicity in patients with changing renal function.

  11. The unfolded protein response protects from tau neurotoxicity in vivo.

    Directory of Open Access Journals (Sweden)

    Carin A Loewen

    Full Text Available The unfolded protein response is a critical system by which the cell handles excess misfolded protein in the secretory pathway. The role of the system in modulating the effects of aggregation prone cytosolic proteins has received less attention. We use genetic reporters to demonstrate activation of the unfolded protein response in a transgenic Drosophila model of Alzheimer's disease and related tauopathies. We then use loss of function genetic reagents to support a role for the unfolded protein response in protecting from tau neurotoxicity. Our findings suggest that the unfolded protein response can ameliorate the toxicity of tau in vivo.

  12. Neurotoxicity from prenatal and postnatal exposure to methylmercury

    DEFF Research Database (Denmark)

    Grandjean, Philippe; Weihe, Pal; Debes, Frodi;

    2014-01-01

    , but visuospatial memory revealed a significant negative association. Mutual adjustment caused decreases of the apparent effect of the prenatal exposure. However, such adjustment may lead to underestimations due to the presence of correlated, error-prone exposure variables. In structural equation models, all...... exposure appeared to contribute to neurotoxic effects, in particular in regard to visuospatial processing and memory. Thus, addition in the regression analysis of exposure information obtained at a different point in time was not informative and should be avoided. Further studies with better information...

  13. Neurotoxicity of Quinolinic Acid to Spiral Ganglion Cells in Rats

    Institute of Scientific and Technical Information of China (English)

    肖红俊; 杨琛; 何圆圆; 郑娜

    2010-01-01

    Our study investigated the neurotoxicity of quinolinic acid(QA) to spiral ganglion cells(SGCs),observed the protective effects of N-methyl-D-aspartate(NMDA) receptor antagonist MK-801 and magnesium ions on the QA-induced injury to SGCs,and analyzed the role of QA in otitis media with effusion(OME)-induced sensorineural hearing loss(SNHL).After culture in vitro for 72 h,SGCs were exposed to different media and divided into 4 groups:the blank control group,the QA injury group,the MK-801 treatment group,and th...

  14. Assessing the neurotoxic potential of methyl ethyl ketoxime in rats.

    Science.gov (United States)

    Schulze, G E; Derelanko, M J

    1993-11-01

    The potential of methyl ethyl ketoxime (MEKO) to produce neurotoxicity following acute and subchronic exposure was studied in rats. A Functional Observational Battery, assessment of motor activity, and neuropathology evaluations were conducted in the context of acute and subchronic toxicity studies. Three independent studies are reported: a pilot time-effect study designed to determine the time course and time to peak effect following a single high dose of MEKO, a single-dose neurotoxicity study, and a subchronic (13-week) repeated-dose neurotoxicity study in rats. An acrylamide-positive control group was included in the acute and subchronic studies for comparison with MEKO. Following an acute oral exposure of MEKO at a dose level of 900 mg/kg, locomotor activity was decreased compared to control with maximum decreases occurring between 30 and 60 min following oral administration. In the acute study, transient treatment-related changes in ease of cage removal, ease of handling, and in posture and gait were observed 1 hr after dosing with 900 mg/kg MEKO, as were significant depressions in motor activity. Following a single 300 mg/kg dose, transient MEKO-related changes in gait and aerial righting reflex were noted 1 hr after dosing. All effects were reversible within 24 hr of dosing. The single 100 mg/kg dose of MEKO was without observable effects. No acrylamide-related behavioral effects were noted following a single 50 mg/kg dose. In the subchronic study, transient treatment-related changes in ease of cage removal, ease of handling, and in posture, gait, and aerial righting were observed at the 400 mg/kg/day dose level when assessments were conducted immediately after dose administration. No consistent behavioral effects were observed prior to daily dose administration even after 13 weeks of exposure, indicating a lack of cumulative behavioral effect. No consistent behavioral changes were noted at doses of 125 mg/kg/day and below. Significant dose

  15. Exploring the notion of a 'capability for uncertainty' and the implications for leader development

    Directory of Open Access Journals (Sweden)

    Kathy Bennett

    2016-04-01

    Full Text Available Orientation: With uncertainty increasingly defining organisational contexts, executive leaders need to develop their ‘capability for uncertainty’ – the ability to engage with uncertainty in their organisational context and to lead others, while simultaneously managing their own experience of uncertainty. However, what constitutes such a holistic ‘capability for uncertainty’ is not clear.Research purpose: The purpose was to gain an understanding of what constitutes a capability for uncertainty.Motivation for the study: Gaining an understanding of what components constitute leaders’ capability for uncertainty would provide a basis for determining what interventions would be relevant for developing leaders towards achieving such a capability.Research approach, design and method: An interpretive qualitative approach was adopted, using interpretative phenomenological analysis to gain an understanding of what capability executive leaders developed through their lived experience of uncertainty. Two purposive samples of six executive leaders from two different South African companies (a private company and a state-owned company, which had both been experiencing long-term organisational uncertainty prior to and up to the time of the study, were used. Data were collected through semi-structured interviews.Main findings: The executives all developed their capability for uncertainty through lived experiences of uncertainty, to a greater or lesser extent. Five components were identified as constituting a holistic capability for uncertainty, as follows: a sense of positive identity, an acceptance of uncertainty, effective sense-making, learning agility and relevant leadership practices during organisational uncertainty.Practical/managerial implications: Organisations need to target and design leader development interventions to specifically develop these components of a holistic capability for uncertainty in executives and leaders, enabling them

  16. Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats.

    Science.gov (United States)

    Shi, Yiwei; Wang, Gang; Li, Jinyuan; Yu, Wenli

    2017-09-18

    Anesthesia neurotoxicity in developing brain has gained increasing attention. However, knowledge regarding its mitigating strategies remains scant. Sevoflurane, a commonly used anesthetic, is responsible for learning and memory deficits in neonates. Molecular hydrogen is reported to be a potential neuroprotective agent because of its antioxidative and anti-inflammatory activities. This study aimed to investigate the effect of hydrogen gas on sevoflurane neurotoxicity. The newborn rats were treated with sevoflurane and/or hydrogen gas for 2 h. Spatial recognition memory and fear memory were determined by Y-maze and fear conditioning tests at 10 weeks of age. Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and proinflammatory cytokine levels were detected using western blot analysis. The data showed that the spatial recognition memory and fear memory of the rats treated with sevoflurane decreased compared with the control, and the cognitive function of the rats treated with sevoflurane and hydrogen gas significantly increased in comparison with treatment with sevoflurane alone. Moreover, hydrogen gas suppressed NF-κB phosphorylation and nuclear translocation and reduced the production of interleukin-1β, interleukin-6, and tumor necrosis factor-α following sevoflurane administration. Thus, the results proposed that hydrogen gas might protect against sevoflurane neurotoxicity by inhibiting NF-κB activation and proinflammatory cytokine release, providing a novel therapeutic strategy for anesthesia neurotoxicity.

  17. Clinical drugs that interact with St. John's wort and implication in drug development.

    Science.gov (United States)

    Di, Yuan Ming; Li, Chun Guang; Xue, Charlie Changli; Zhou, Shu-Feng

    2008-01-01

    St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and

  18. Evolutionary development of embryonic cerebrospinal fluid composition and regulation: an open research field with implications for brain development and function.

    Science.gov (United States)

    Bueno, David; Garcia-Fernàndez, Jordi

    2016-03-15

    Within the consolidated field of evolutionary development, there is emerging research on evolutionary aspects of central nervous system development and its implications for adult brain structure and function, including behaviour. The central nervous system is one of the most intriguing systems in complex metazoans, as it controls all body and mind functions. Its failure is responsible for a number of severe and largely incurable diseases, including neurological and neurodegenerative ones. Moreover, the evolution of the nervous system is thought to be a critical step in the adaptive radiation of vertebrates. Brain formation is initiated early during development. Most embryological, genetic and evolutionary studies have focused on brain neurogenesis and regionalisation, including the formation and function of organising centres, and the comparison of homolog gene expression and function among model organisms from different taxa. The architecture of the vertebrate brain primordium also reveals the existence of connected internal cavities, the cephalic vesicles, which in fetuses and adults become the ventricular system of the brain. During embryonic and fetal development, brain cavities and ventricles are filled with a complex, protein-rich fluid called cerebrospinal fluid (CSF). However, CSF has not been widely analysed from either an embryological or evolutionary perspective. Recently, it has been demonstrated in higher vertebrates that embryonic cerebrospinal fluid has key functions in delivering diffusible signals and nutrients to the developing brain, thus contributing to the proliferation, differentiation and survival of neural progenitor cells, and to the expansion and patterning of the brain. Moreover, it has been shown that the composition and homeostasis of CSF are tightly controlled in a time-dependent manner from the closure of the anterior neuropore, just before the initiation of primary neurogenesis, up to the formation of functional choroid plexuses. In

  19. Polyphenol-rich fraction of Parquetina nigrescens mitigates dichlorvos-induced neurotoxicity and apoptosis

    Directory of Open Access Journals (Sweden)

    Grace Onyeche Ochigbo

    2017-01-01

    Conclusion: This study showed that dichlorvos caused cellular and tissue neurotoxicity by inhibiting AchE activity, induced oxidative stress and apoptosis in rats with prominent effects on the cerebellum than cerebrum. The prf of P. nigrescens showed amelioration of neurotoxicity by its antioxidative and antiapoptotic properties in rats exposed to dichlorvos.

  20. Trends in International Trade in Higher Education: Implications and Options for Developing Countries. Education Working Paper Series, Number 6

    Science.gov (United States)

    Bashir, Sajitha

    2007-01-01

    This paper analyzes the trends, underlying factors and implications of the trade in higher education services. The term "trade in higher education" refers to the purchase of higher education services from a foreign country using domestic resources. The objectives of this paper are to provide policy makers in developing countries, World Bank staff,…

  1. Education for Sustainable Development in Ethnic Autonomous Areas of China: A Comparison of Two Curriculum Initiatives and Their Educational Implications

    Science.gov (United States)

    Khoo, Yishin

    2015-01-01

    This paper examines the educational implications of two curriculum initiatives in China that have produced curricular materials promoting education for sustainable development (ESD) in minority-populated ethnic autonomous areas in China. The two curriculum projects present distinctive discourses, conceptions, models, frameworks and scopes of ESD…

  2. An Assessment of FY2016 Locally Developed Questions from the DEOMI Organizational Climate Survey: Recommendations and Potential Implications

    Science.gov (United States)

    2017-07-11

    1 An Assessment of FY2016 Locally Developed Questions from the DEOMI Organizational Climate Survey: Recommendations and Potential Implications...Equal Opportunity Management Institute (DEOMI) Organizational Climate Survey (DEOCS). The top 15 questions were ranked across a total of 180,797...Department of Equal Opportunity Management Institute Organizational Climate Survey (DEOCS) for fiscal year 2016 by commanders across the Department

  3. Implications of a neural network model of early sensori-motor development for the field of developmental neurology

    NARCIS (Netherlands)

    van Heijst, JJ; Touwen, BCL; Vos, JE

    1999-01-01

    This paper reports on a neural network model for early sensori-motor development and on the possible implications of this research for our understanding and, eventually, treatment of motor disorders like cerebral palsy. We recapitulate the results we published in detail in a series of papers [1-4].

  4. Education for Sustainable Development in Ethnic Autonomous Areas of China: A Comparison of Two Curriculum Initiatives and Their Educational Implications

    Science.gov (United States)

    Khoo, Yishin

    2015-01-01

    This paper examines the educational implications of two curriculum initiatives in China that have produced curricular materials promoting education for sustainable development (ESD) in minority-populated ethnic autonomous areas in China. The two curriculum projects present distinctive discourses, conceptions, models, frameworks and scopes of ESD…

  5. Developmental neurotoxicity of the organophosphorus insecticide chlorpyrifos: from clinical findings to preclinical models and potential mechanisms.

    Science.gov (United States)

    Burke, Richard D; Todd, Spencer W; Lumsden, Eric; Mullins, Roger J; Mamczarz, Jacek; Fawcett, William P; Gullapalli, Rao P; Randall, William R; Pereira, Edna F R; Albuquerque, Edson X

    2017-08-01

    Organophosphorus (OP) insecticides are pest-control agents heavily used worldwide. Unfortunately, they are also well known for the toxic effects that they can trigger in humans. Clinical manifestations of an acute exposure of humans to OP insecticides include a well-defined cholinergic crisis that develops as a result of the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that hydrolyzes the neurotransmitter acetylcholine (ACh). Prolonged exposures to levels of OP insecticides that are insufficient to trigger signs of acute intoxication, which are hereafter referred to as subacute exposures, have also been associated with neurological deficits. In particular, epidemiological studies have reported statistically significant correlations between prenatal subacute exposures to OP insecticides, including chlorpyrifos, and neurological deficits that range from cognitive impairments to tremors in childhood. The primary objectives of this article are: (i) to address the short- and long-term neurological issues that have been associated with acute and subacute exposures of humans to OP insecticides, especially early in life (ii) to discuss the translational relevance of animal models of developmental exposure to OP insecticides, and (iii) to review mechanisms that are likely to contribute to the developmental neurotoxicity of OP insecticides. Most of the discussion will be focused on chlorpyrifos, the top-selling OP insecticide in the United States and throughout the world. These points are critical for the identification and development of safe and effective interventions to counter and/or prevent the neurotoxic effects of these chemicals in the developing brain. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

  6. Chemotherapy-induced peripheral neurotoxicity and ototoxicity: new paradigms for translational genomics.

    Science.gov (United States)

    Travis, Lois B; Fossa, Sophie D; Sesso, Howard D; Frisina, Robert D; Herrmann, David N; Beard, Clair J; Feldman, Darren R; Pagliaro, Lance C; Miller, Robert C; Vaughn, David J; Einhorn, Lawrence H; Cox, Nancy J; Dolan, M Eileen

    2014-03-12

    In view of advances in early detection and treatment, the 5-year relative survival rate for all cancer patients combined is now approximately 66%. As a result, there are more than 13.7 million cancer survivors in the United States, with this number increasing by 2% annually. For many patients, improvements in survival have been countered by therapy-associated adverse effects that may seriously impair long-term functional status, workplace productivity, and quality of life. Approximately 20% to 40% of cancer patients given neurotoxic chemotherapy develop chemotherapy-induced peripheral neurotoxicity (CIPN), which represents one of the most common and potentially permanent nonhematologic side effects of chemotherapy. Permanent bilateral hearing loss and/or tinnitus can result from several ototoxic therapies, including cisplatin- or carboplatin-based chemotherapy. CIPN and ototoxicity represent important challenges because of the lack of means for effective prevention, mitigation, or a priori identification of high-risk patients, and few studies have applied modern genomic approaches to understand underlying mechanisms/pathways. Translational genomics, including cell-based models, now offer opportunities to make inroads for the first time to develop preventive and interventional strategies for CIPN, ototoxicity, and other treatment-related complications. This commentary provides current perspective on a successful research strategy, with a focus on cisplatin, developed by an experienced, transdisciplinary group of researchers and clinicians, representing pharmacogenomics, statistical genetics, neurology, hearing science, medical oncology, epidemiology, and cancer survivorship. Principles outlined herein are applicable to the construction of research programs in translational genomics with strong clinical relevance and highlight unprecedented opportunities to understand, prevent, and treat long-term treatment-related morbidities.

  7. Nutritional status of foster children in the U.S.: Implications for cognitive and behavioral development.

    Science.gov (United States)

    Tooley, Ursula A; Makhoul, Zeina; Fisher, Philip A

    2016-11-01

    Children in foster care are at greater risk for poor health, physical, cognitive, behavioral, and developmental outcomes than are children in the general population. Considerable research links early nutrition to later cognitive and behavioral outcomes. The aim of this narrative review is to examine the prevalence of poor nutrition and its relation to subsequent health and development in foster children. Relevant studies for inclusion were identified from numerous sources (e.g., PubMed, Google Scholar, and reference sections). Inclusion criteria were studies published between 1990 and 2016 of (i) the nutritional status of children in foster care or (ii) the nutritional status of children exposed to early adversity (e.g., low-income and internationally adopted children) or (iii) the developmental effects of poor nutrition and micronutrient deficiencies. Two key findings that have adverse implications for cognitive development emerged: (i) the prevalence of anemia and iron-deficiency anemia is higher among foster children than among the general population of children in the U.S., and (ii) the developmental demands of catch-up growth post-placement may lead to micronutrient deficiencies even after children have begun sufficient dietary intake of these nutrients. Moreover, there is a paucity of recent studies on the nutritional status of children in foster care, despite the multiple factors that may place them at risk for malnutrition. Attention to nutritional status among care providers and medical professionals may remove one of the possible negative influences on foster children's development and in turn significantly alter their trajectories and place them on a more positive path early in life. Recommendations for further research, policy, and practice are discussed.

  8. Geyser decline and extinction in New Zealand: energy development impacts and implications for environmental management.

    Science.gov (United States)

    Barrick, Kenneth A

    2007-06-01

    Geysers are rare natural phenomena that represent increasingly important recreation, economic, and scientific resources. The features of geyser basins, including hot springs, mud pots, and fumaroles, are easily damaged by human development. In New Zealand, the extinction of more than 100 geysers provides important lessons for the environmental management of the world's remaining geyser basins. The impacts on New Zealand's geysers are described in sequential "phases," including the following: the first use of geothermal resources by the indigenous people-the Maori; early European-style tourism and spa development; streamside geyser decline caused by river level modification at the Spa geyser basin; multiple geyser basin extinctions caused by industrial-scale geothermal well withdrawal at Wairakei; the drowning of geysers at Orakeikorako after the filling of a hydroelectric reservoir; and geyser decline caused by geothermal well heating systems in Rotorua City. The crisis in Rotorua prompted preservation of the few remaining geysers at Whakarewarewa -- the last major geyser basin in New Zealand. The New Zealand government ordered the geothermal wells within 1.5 km of Pohutu Geyser, Whakarewarewa, to be closed, which was a locally controversial measure. The well closure program resulted in a partial recovery of the Rotorua geothermal reservoir, but no extinct geysers recovered. The implications of recent geothermal computer modeling and future planning are discussed. The New Zealand case suggests that the protection of geysers requires strong regulations that prevent incompatible development at the outset, a prescription that is especially relevant for the future management of the geothermal fields adjacent to the geyser basins of Yellowstone National Park, U.S.A.

  9. Geyser Decline and Extinction in New Zealand—Energy Development Impacts and Implications for Environmental Management

    Science.gov (United States)

    Barrick, Kenneth A.

    2007-06-01

    Geysers are rare natural phenomena that represent increasingly important recreation, economic, and scientific resources. The features of geyser basins, including hot springs, mud pots, and fumaroles, are easily damaged by human development. In New Zealand, the extinction of more than 100 geysers provides important lessons for the environmental management of the world’s remaining geyser basins. The impacts on New Zealand’s geysers are described in sequential “phases,” including the following: the first use of geothermal resources by the indigenous people—the Maori; early European-style tourism and spa development; streamside geyser decline caused by river level modification at the Spa geyser basin; multiple geyser basin extinctions caused by industrial-scale geothermal well withdrawal at Wairakei; the drowning of geysers at Orakeikorako after the filling of a hydroelectric reservoir; and geyser decline caused by geothermal well heating systems in Rotorua City. The crisis in Rotorua prompted preservation of the few remaining geysers at Whakarewarewa—the last major geyser basin in New Zealand. The New Zealand government ordered the geothermal wells within 1.5 km of Pohutu Geyser, Whakarewarewa, to be closed, which was a locally controversial measure. The well closure program resulted in a partial recovery of the Rotorua geothermal reservoir, but no extinct geysers recovered. The implications of recent geothermal computer modeling and future planning are discussed. The New Zealand case suggests that the protection of geysers requires strong regulations that prevent incompatible development at the outset, a prescription that is especially relevant for the future management of the geothermal fields adjacent to the geyser basins of Yellowstone National Park, U.S.A.

  10. Functional groups show distinct differences in nitrogen cycling during early stand development: implications for forest management.

    Energy Technology Data Exchange (ETDEWEB)

    Aubrey, Doug, P.; Coyle, David, R. Coleman, Mark, D.

    2011-08-26

    Nutrient acquisition of forest stands is controlled by soil resource availability and belowground production, but tree species are rarely compared in this regard. Here, we examine ecological and management implications of nitrogen (N) dynamics during early forest stand development in productive commercial tree species with narrow (Populus deltoides Bartr. and Platanus occidentalis L.) and broad (Liquidambar styraciflua L. and Pinus taeda L.) site requirements while grown with a range of nutrient and water resources. We constructed N budgets by measuring N concentration ([N]) and N content (N{sub C}) of above- and belowground perennial and ephemeral tissues, determined N uptake (N{sub UP}), and calculated N use efficiency (NUE). Forest stands regulated [N] within species-specific operating ranges without clear temporal or treatment patterns, thus demonstrating equilibrium between tissue [N] and biomass accumulation. Forest stand N{sub C} and N{sub UP} increased with stand development and paralleled treatment patterns of biomass accumulation, suggesting productivity is tightly linked to N{sub UP}. Inclusion of above- and belowground ephemeral tissue turnover in N{sub UP} calculations demonstrated that maximum N demand for narrow-sites adapted species exceeded 200 kg N ha{sup -1} year{sup -1} while demand for broad-site adapted species was below this level. NUE was species dependent but not consistently influenced by N availability, suggesting relationships between NUE and resource availability were species dependent. Based on early stand development, species with broad site adaptability are favored for woody cropping systems because they maintain high above- and belowground productivity with minimal fertilization requirements due to higher NUE than narrow site adapted species.

  11. The implication of nutritional psychopedagogy in the matrix of personal development

    Directory of Open Access Journals (Sweden)

    Maria Dorina PASCA

    2010-08-01

    Full Text Available The birth of conceptual nutritional psycho-pedagogy represents the compulsory matrix for the development and maintenance of human and personal value. Thus, it must respond both from the point of view of attitude and behavior through education and from a structural point of view to the social command, enclosing the individual in a quality segment of his existence, starting from the nutritional act. Being a new and interdisciplinary domain, nutritional psycho pedagogy, determines, by the implication in the personalized act of nutrition, the acknowledgment of the fact that “eating is an art” and, at the same time, it makes responsible the ones who sustain that “they live to eat” and/or “they eat to live”. This fact cognitively implies both the acknowledgment and the application of the component elements necessary for the approach of a healthy life style which determines the improvement of the life quality, as a response of personal identity. We wonder: Is the nutritional psycho pedagogy able toanswer the question “Tell me what you eat and I will tell you who you are”.

  12. Health effect of agricultural pesticide use in China: implications for the development of GM crops

    Science.gov (United States)

    Zhang, Chao; Hu, Ruifa; Huang, Jikun; Huang, Xusheng; Shi, Guanming; Li, Yifan; Yin, Yanhong; Chen, Zhaohui

    2016-01-01

    It is notable that the adoption of GM glyphosate-tolerant crops increases glyphosate use but reduces non-glyphosate herbicide use; and adoption of GM insect-resistant crops significantly reduces insecticide use. While the health hazard of pesticide use has been well documented, little literature evaluates the health effects of different pesticides related to GM crops in an integrated framework. This study aims to associate the uses of different pesticides related to GM crops with the blood chemistry panel and peripheral nerve conduction of Chinese farmers. Pesticides used by farmers were recorded and classified as glyphosate, non-glyphosate herbicides, chemical lepidopteran insecticides, biological lepidopteran insecticides, non-lepidopteran insecticides and fungicides. The multivariate regression results show that none of the examined 35 health indicators was associated with glyphosate use, while the use of non-glyphosate herbicides was likely to induce renal dysfunction and decrease of serum folic acid. The use of chemical lepidopteran insecticides might be associated with hepatic dysfunction, serum glucose elevation, inflammation and even severe nerve damage. In this context, if GM crops are adopted, the alterations in pesticide use may benefit farmer health in China and globe, which has positive implications for the development of GM crops. PMID:27721390

  13. Agonistic behaviour in juvenile southern rock lobster, Jasusedwardsii (Decapoda, Palinuridae): implications for developing aquaculture.

    Science.gov (United States)

    Carter, Chris G; Westbury, Heath; Crear, Bradley; Simon, Cedric; Thomas, Craig

    2014-01-01

    The Southern rock lobster, Jasusedwardsii, is a temperate species of spiny lobster with established well managed fisheries in Australia and New Zealand. It has also been under consideration as a species with aquaculture potential. Agonistic behaviour has important consequences under aquaculture conditions that encompass direct effects, such as damage or death of protagonists, and indirect effects on growth that relate to resource access, principally food and refuge. This study aimed to identify and characterize behaviours and to make a preliminary investigation of their occurrence under tank culture. Juvenile Jasusedwardsii were examined in a flow-through seawater system using a remote video camera system. Twenty-nine behaviours were divided into three sub-groups: aggressive (11), avoidance (6) and others (12). Aggressive behaviours included attacks, pushing, lifting, clasping and carrying an opponent. Avoidance behaviours included moving away in a backwards-, forwards- or side-stepping motion as well as with more vigorous tail flips. These behaviours were components of twelve behavioural groups that described contact, attack and displacement between individuals. Activity was crepuscular with two clear peaks, one in the morning and the other in the evening. The occurrence of behavioural groups was not different between the morning and evening. The frequency of aggressive behaviours was not affected by changes made to stocking density or access to food. The implications of agonistic behaviours are discussed further in relation to developing aquaculture.

  14. The two-component model of memory development, and its potential implications for educational settings.

    Science.gov (United States)

    Sander, Myriam C; Werkle-Bergner, Markus; Gerjets, Peter; Shing, Yee Lee; Lindenberger, Ulman

    2012-02-15

    We recently introduced a two-component model of the mechanisms underlying age differences in memory functioning across the lifespan. According to this model, memory performance is based on associative and strategic components. The associative component is relatively mature by middle childhood, whereas the strategic component shows a maturational lag and continues to develop until young adulthood. Focusing on work from our own lab, we review studies from the domains of episodic and working memory informed by this model, and discuss their potential implications for educational settings. The episodic memory studies uncover the latent potential of the associative component in childhood by documenting children's ability to greatly improve their memory performance following mnemonic instruction and training. The studies on working memory also point to an immature strategic component in children whose operation is enhanced under supportive conditions. Educational settings may aim at fostering the interplay between associative and strategic components. We explore possible routes towards this goal by linking our findings to recent trends in research on instructional design. Copyright © 2011 Elsevier Ltd. All rights reserved.

  15. Recent developments in studies of l-stepholidine and its analogs: chemistry, pharmacology and clinical implications.

    Science.gov (United States)

    Mo, Jiao; Guo, Yang; Yang, Yu-She; Shen, Jing-Shan; Jin, Guo-Zhang; Zhen, Xuechu

    2007-01-01

    Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.

  16. Vietnamese Migrant Workers in Thailand - Implications for Leveraging Migration for Development

    Directory of Open Access Journals (Sweden)

    Nancy HUYEN NGUYEN

    2014-05-01

    Full Text Available A greater flow of people to and from each of the Mekong countries is catching the attention of the general public and academic researchers. As one of the fastest growing countries in the GMS, Thailand is attracting the majority of migrant workers from its neighbours. At a smaller scale, when compared with those from Lao PDR, Cambodia and Myanmar, Vietnamese workers are also joining this increasing trend in immigration to Thailand. By analyzing information from secondary data sources, this research paper attempts to provide further insights into the social and economic impacts generated by the Vietnamese migrant workers in Thailand both at home and the host country. The study discovers that moving to Thailand for work has eased the pressures of rural unemployment and underemployment that have plagued Vietnam recently. Meanwhile, Vietnamese workers are helping soothe the stress caused by the increasing demand for unskilled and low skilled labourers in Thailand. The study further learns that the long-established community of Vietnamese migrants in Thailand is encouraging the increasing movement of Vietnamese workers to Thailand. The study findings suggest meaningful implications for future policies in leveraging labour migration for development.

  17. Identification of Mushroom body miniature, a zinc-finger protein implicated in brain development of Drosophila

    Science.gov (United States)

    Raabe, Thomas; Clemens-Richter, Susanne; Twardzik, Thomas; Ebert, Anselm; Gramlich, Gertrud; Heisenberg, Martin

    2004-01-01

    The mushroom bodies are bilaterally arranged structures in the protocerebrum of Drosophila and most other insect species. Mutants with altered mushroom body structure have been instrumental not only in establishing their role in distinct behavioral functions but also in identifying the molecular pathways that control mushroom body development. The mushroom body miniature1 (mbm1) mutation results in grossly reduced mushroom bodies and odor learning deficits in females. With a survey of genomic rescue constructs, we have pinpointed mbm1 to a single transcription unit and identified a single nucleotide exchange in the 5′ untranslated region of the corresponding transcript resulting in a reduced expression of the protein. The most obvious feature of the Mbm protein is a pair of C2HC zinc fingers, implicating a function of the protein in binding nucleic acids. Immunohistochemical analysis shows that expression of the Mbm protein is not restricted to the mushroom bodies. BrdUrd labeling experiments indicate a function of Mbm in neuronal precursor cell proliferation. PMID:15375215

  18. Agonistic behaviour in juvenile southern rock lobster, Jasus edwardsii (Decapoda, Palinuridae: implications for developing aquaculture

    Directory of Open Access Journals (Sweden)

    Chris Carter

    2014-11-01

    Full Text Available The Southern rock lobster, Jasus edwardsii, is a temperate species of spiny lobster with established well managed fisheries in Australia and New Zealand. It has also been under consideration as a species with aquaculture potential. Agonistic behaviour has important consequences under aquaculture conditions that encompass direct effects, such as damage or death of protagonists, and indirect effects on growth that relate to resource access, principally food and refuge. This study aimed to identify and characterize behaviours and to make a preliminary investigation of their occurrence under tank culture. Juvenile Jasus edwardsii were examined in a flow-through seawater system using a remote video camera system. Twenty-nine behaviours were divided into three sub-groups: aggressive (11, avoidance (6 and others (12. Aggressive behaviours included attacks, pushing, lifting, clasping and carrying an opponent. Avoidance behaviours included moving away in a backwards-, forwards- or side-stepping motion as well as with more vigorous tail flips. These behaviours were components of twelve behavioural groups that described contact, attack and displacement between individuals. Activity was crepuscular with two clear peaks, one in the morning and the other in the evening. The occurrence of behavioural groups was not different between the morning and evening. The frequency of aggressive behaviours was not affected by changes made to stocking density or access to food. The implications of agonistic behaviours are discussed further in relation to developing aquaculture.

  19. Generation X: implications for faculty recruitment and development in academic health centers.

    Science.gov (United States)

    Bickel, Janet; Brown, Ann J

    2005-03-01

    Differences and tensions between the Baby Boom generation (born 1945-1962) and Generation X (born 1963-1981) have profound implications for the future of academic medicine. By and large, department heads and senior faculty are Boomers; today's residents and junior faculty are Generation X'ers. Looking at these issues in terms of the generations involved offers insights into a number of faculty development challenges, including inadequate and inexpert mentoring, work-life conflicts, and low faculty morale. These insights suggest strategies for strengthening academic medicine's recruitment and retention of Generation X into faculty and leadership roles. These strategies include (1) improving career and academic advising by specific attention to mentoring "across differences"--for instance, broaching the subject of formative differences in background during the initial interaction; adopting a style that incorporates information-sharing with engagement in problem solving; offering frequent, frank feedback; and refraining from comparing today to the glories of yesterday; to support such improvements, medical schools should recognize and evaluate mentoring as a core academic responsibility; (2) retaining both valued women and men in academic careers by having departments add temporal flexibility and create and legitimize less-than-full-time appointments; and (3) providing trainees and junior faculty with ready access to educational sessions designed to turn their "intellectual capital" into "academic career capital."Given the trends discussed in this article, such supports and adaptations are indicated to assure that academic health centers maintain traditions of excellence.

  20. Trends in Global Nutrition Policy and Implications for Japanese Development Policy.

    Science.gov (United States)

    Nomura, Marika; Takahashi, Kenzo; Reich, Michael R

    2015-12-01

    Although the issue of nutrition was long underrepresented in the global health agenda, it regained international attention with the introduction of the Scaling Up Nutrition (SUN) framework. A historical review of global nutrition policies over 4 decades illustrates the evolution of nutrition policy themes and the challenges confronted by SUN. This study reviews major events in global nutrition policy from the 1970s to the SUN movement around 2010 to illustrate the dynamics of global agenda setting for nutrition policy along with implications for the government of Japan. The events are categorized according to each decade's nutrition paradigm: nutrition and its socioeconomic features in the 1970s, nutrition and community programs in the 1980s, nutrition as a political issue in the 1990s, and nutrition and evidence in the 2000s. This study identified 2 findings: First, the arguments that led to a global consensus on nutrition policy generated paradigm shifts in core ideas, and second, in response to these paradigm shifts, global nutrition policies have changed significantly over time. With regard to Japan, this analysis concludes that the government of Japan can take a greater initiative in the global health community as supporter of SUN by strategically developing a combination of financial, political, and practical approaches to improve global nutrition policy through the concepts of Universal Health Coverage and Human Security. © The Author(s) 2015.

  1. Getting to NO Alzheimer’s Disease: Neuroprotection versus Neurotoxicity Mediated by Nitric Oxide

    Directory of Open Access Journals (Sweden)

    Rachelle Balez

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is a neurodegenerative disorder involving the loss of neurons in the brain which leads to progressive memory loss and behavioral changes. To date, there are only limited medications for AD and no known cure. Nitric oxide (NO has long been considered part of the neurotoxic insult caused by neuroinflammation in the Alzheimer’s brain. However, focusing on early developments, prior to the appearance of cognitive symptoms, is changing that perception. This has highlighted a compensatory, neuroprotective role for NO that protects synapses by increasing neuronal excitability. A potential mechanism for augmentation of excitability by NO is via modulation of voltage-gated potassium channel activity (Kv7 and Kv2. Identification of the ionic mechanisms and signaling pathways that mediate this protection is an important next step for the field. Harnessing the protective role of NO and related signaling pathways could provide a therapeutic avenue that prevents synapse loss early in disease.

  2. A curious case of oxaliplatin-induced neurotoxicity: recurrent, self-limiting dysarthria.

    Science.gov (United States)

    Joseph, Ranjit; Dasanu, Constantin A

    2014-10-01

    This report presents a unique case of oxaliplatin-induced neurotoxicity featuring acute, recurrent, self-limiting dysarthria following multiple subsequent infusions of oxaliplatin. A 65-year-old man started chemotherapy for metastatic pancreatic adenocarcinoma with oxaliplatin-irinotecan-leucovorin-5-fluorouracil (FOLFIRINOX). During the first and subsequent infusions of oxaliplatin, the patient developed episodes of dysarthria that lasted between 2 and 4 h after oxaliplatin infusions, followed by their complete and uneventful resolution. A thorough neurological examination showed no new neurologic deficits except for very fine tongue fasciculations. Recognizing this self-limiting toxic effect of oxaliplatin is important in order to avoid dose reductions that may affect clinical outcomes.

  3. Mothball withdrawal encephalopathy: case report and review of paradichlorobenzene neurotoxicity.

    Science.gov (United States)

    Cheong, Raymond; Wilson, Robin K; Cortese, Irene C M; Newman-Toker, David E

    2006-12-01

    Paradichlorobenzene (PDB) is a common household deodorant and pesticide found in room deodorizers, toilet bowl fresheners, and some mothballs. Although human exposure to the compound is generally limited and harmless, PDB in larger doses can produce neurotoxic effects, including a chemical "high" similar to that seen with inhalants such as toluene. Although rare, frank addiction to PDB has been reported, and, in such cases, has been associated with gait ataxia, tremor, dysarthria, limb weakness, and bradyphrenia, in various combinations. In such cases, the adverse neurologic consequences have been presumed to result from a direct toxic effect of this small, organic molecule. We report a case of chronic mothball ingestion where profound encephalopathy with cognitive, pyramidal, extrapyramidal, and cerebellar features appears to have been largely the result of PDB withdrawal, rather than direct toxicity. This case raises important questions about the mechanism of PDB neurotoxicity and possible treatment options for PDB-addicted patients. We propose that in cases with clear clinical deterioration after abstinence, readministration and gradual taper of PDB might be considered a therapeutic option.

  4. PACAP27 is protective against Tat-induced neurotoxicity

    Science.gov (United States)

    Rozzi, Summer J.; Borelli, Giulia; Ryan, Kerry; Steiner, Joseph P.; Reglodi, Dora; Mocchetti, Italo; Avdoshina, Valeriya

    2014-01-01

    Human immunodeficiency virus type-1 (HIV) infection of the central nervous system promotes neuronal injury and apoptosis that culminate in HIV-associated neurocognitive disorders. Viral proteins, such as transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanism remains unclear. To determine the effects of Tat, rat cortical neurons were exposed to nanomolar concentrations of Tat for various time points. Within a few hours, Tat induced the production of reactive oxygen species (ROS), and other indices of mitochondrial destabilization. In addition, we observed a significant induction of DNA double strand breaks (DSBs) by Tat. We next investigated the neuroprotective activity of the pituitary adenylate cyclase-activating polypeptide 27 (PACAP27) against these cardinal features of Tat-induced neurodegeneration. PACAP27 (100 nM) inhibited all Tat-mediated toxic effects including DNA DSBs. Importantly, PACAP27 prevented the induction of neuronal loss induced by Tat. The neuroprotective effect of PACAP27 is correlated with its ability to release the anti-apoptotic chemokine CCL5. Our data support a mechanism of Tat neurotoxicity in which Tat induces mitochondrial destabilization, thus increasing the release of ROS, which causes DNA DSBs leading to cell death. PACAP27, through CCL5, mitigates the effects of Tat-induced neuronal dysfunction, suggesting that PACAP27 could be a new strategy for an adjunct therapy against HIV-associated neurocognitive disorders. PMID:24696163

  5. Subchronic organophosphorus ester-induced delayed neurotoxicity in mallards

    Science.gov (United States)

    Hoffman, D.J.; Sileo, L.; Murray, H.C.

    1984-01-01

    Eighteen-week-old mallard hens received 0, 10, 30, 90, or 270 ppm technical grade EPN (phenylphosphonothioic acid O-ethyl-O-4-nitrophenyl ester) in the diet for 90 days. Ataxia was first observed in the 270-ppm group after 16 days, in the 90-ppm group after 20 days, in the 30-ppm group after 38 days; 10 ppm failed to produce ataxia. By the end of 90 days all 6 birds in the 270-ppm group exhibited ataxia or paralysis whereas 5 of 6 birds in the 90-ppm group and 2 of 6 birds in the 30-ppm group were visibly affected. Treatment with 30 ppm or more resulted in a significant reduction in body weight. Brain neurotoxic esterase activity was inhibited by averages of 16, 69, 73, and 74% in the 10-, 30-, 90-, and 270-ppm groups, respectively. Brain acetylcholinesterase, plasma cholinesterase, and plasma alkaline phosphatase were significantly inhibited as well. Distinct histopathological effects were seen in the 30-, 90-, and 270-ppm groups which included demyelination and degeneration of axons of the spinal cord. Additional ducks were exposed in a similar manner to 60-, 270-, or 540-ppm leptophos (phosphonothioic acid O-4-bromo-2,5-dichlorophenyl-O-methylphenyl ester) which resulted in similar behavioral, biochemical, and histopathological alterations. These findings indicate that adult mallards are probably somewhat less sensitive than chickens to subchronic dietary exposure to organophosphorus insecticides that induce delayed neurotoxicity.

  6. The chemical substances and the neurotoxic effect on workers

    Directory of Open Access Journals (Sweden)

    Rosa Morales

    2013-12-01

    Full Text Available (Received: 2013/10/02 - Accepted: 2013/12/13Tens of thousands of workers are exposed to pollution by the neurotoxicity found in their different workplaces, small businesses, handcrafting industries and even at home. The problem gets worst due to the lack of information on the risks posed by these substances and the safety controls to be taken during its use, on the other hand, the overconfidence that exists about the abstraction of this danger when it comes to the exposure to small doses of toxicity by ignoring the cumulative effects of these substances every time they enter the body. In Ecuador, nowadays there are few studies that distinguish this exposure to these substances, and none on the incidence of the neurotoxic syndrome, considering it an important field to research. Workers who are exposed to chemical toxic substances are now associated to adverse human health effects, due to its aggression and because of the worker´s safety before breaking health directly. They enter the body by the respiratory, dermal or digestive system, and show a great affinity with the body grease so that it accumulates and affects the different organs, tissues, the central nervous system, the bone marrow and liver. Immediate acute and chronic long-term effects were detected due to the intensity and duration of the exposure. Some symptoms include drowsiness, loss of appetite, headache, dizziness, depression, anxiety, nervousness, fatigue, irritability, memory problems, mental sluggishness, apathy, seizures, motor skills incoordination, genetic alterations, among others.

  7. Unusual neurotoxic envenomations by Vipera aspis aspis snakes in France.

    Science.gov (United States)

    de Haro, L; Robbe-Vincent, A; Saliou, B; Valli, M; Bon, C; Choumet, V

    2002-03-01

    Vipera aspis aspis (V.a.a.) is the most dangerous poisonous snake in South-Eastern France. The clinical symptoms observed after V.a.a. envenomations involve mostly local signs (pain, edema) associated in the more severe cases with systemic symptoms (gastro-intestinal and cardiovascular manifestations). Since 1992, several unusual cases of moderate and severe 'neurotoxic' envenomations by V.a.a. snakes have been reported in a very localized area in South-Eastern France. Most of the human patients mainly suffered neurological signs owing to cephalic muscle paralysis. Drowsiness and dyspnea were observed for the most severe cases. Envenomed animals suffered respiratory distress and paralysis. The local signs were never as severe as observed after envenomations by vipers in other French regions. Human patients with moderate or severe clinical features received two intravenous injections of Viperfav antivenom, the first dose inducing the decrease of the neurological signs and the second reducing significantly the edema. Neurotoxic components immunologically cross-reacting with toxins from V. ammodytes ammodytes venom from Eastern Europe were detected in the blood of all patients suffering neurological symptoms after a V.a.a. bite. The protective efficacy of various antivenoms was evaluated in mice. The existence of geographical variations in the composition of V.a.a. venom emphasizes on the use of polyvalent antivenom in the treatment of viper envenomations in France.

  8. Self-concept of people with intellectual disabilities: Implications for support program development

    Directory of Open Access Journals (Sweden)

    Petrović Boban

    2012-01-01

    Full Text Available Self-concept is defined as a sum of perception, thoughts, feelings, evaluation and prediction about oneself as an experienced object, as a participant in the interaction with physical and social environment. As such, this topic is often encountered in working with children, young people and adults with intellectual disabilities (PWID. However, self-concept of PWID has been investigated mainly through psychometric paradigm, using different types of questionnaires for assessment. This did not provide either enough possibilities for active participation of people with ID in the research process, or the possibilities to reach adequate initial information about self-concept of PWID, which may serve as a baseline for development of support programs for self-determination of PWID. Therefore, this study aimed to examine self-concept of PWID in various domains of interest for PWID: global self-image, personality traits, competencies, difficulties in everyday life, awareness of one's own (intellectual disabilities. The research was conducted through a series of five focus groups, with active participation of PWID, through combined workshop activities and discussions in small groups. Focus groups were conducted once a week and 16 participants were divided into two groups, of different ages (22 to 53 years, sex, type and degree of difficulties. All participants spent most of their lives in institutions. Since 2004, they have been living at supported housing for people with disabilities. Based on the analysis of the participants' testimony, there were three global issues with regard to general self-concept: competences and interests, physical appearance, and social roles. With regard to personality traits, attributes such as 'good', 'obedient', 'valuable' occur most frequently. With regard to their competencies and difficulties, those which are most important for full daily life in supported housing have been cited most often. While they recognize their

  9. An Interview with Robert M. Gagne: Developments in Learning Psychology; Implications for Instructional Design; and Effects of Computer Technology on Instructional Design and Development.

    Science.gov (United States)

    Lipsitz, Lawrence

    1982-01-01

    The emergence of cognitive psychology as an important source for theories of learning, the relationship between information processing theories of learning and behaviorist theories, the implications of recent developments in cognitive psychology for instructional design, and the role of computers in instruction are among the topics addressed in…

  10. Association between depression and development of coronary artery disease: pathophysiologic and diagnostic implications

    Directory of Open Access Journals (Sweden)

    Sakamoto

    2011-03-01

    Full Text Available Carlos V Serrano Jr1, Karina Tiemi Setani2, Erica Sakamoto2, Anna Maria Andrei3, Renério Fraguas41Heart Institute (InCor, 2Medical School, University of São Paulo, Brazil; 3Albert Einstein Hospital, São Paulo, Brazil; 4Department and Institute of Psychiatry, Medical School, University of São Paulo, BrazilAbstract: Depression and coronary artery disease (CAD are both extremely prevalent diseases. In addition, compromised quality of life and life expectancy are characteristics of both situations. There are several conditions that aggravate depression and facilitate the development of CAD, as well as provoke a worse prognosis in patients with already established CAD: inferior adherence to medical orientations (medications and life style modifications, greater platelet activation and aggregation, endothelial dysfunction, and impaired autonomic dysfunction (lowered heart rate variability. Recent literature has shown that depression alone is becoming an independent risk factor for cardiac events both in primary and secondary prevention. As the diagnosis of depression in patients with heart disease is difficult, due to similarities of symptoms, the health professional should perform a careful evaluation to differentiate the clinical signs of depression from those related with general heart diseases. After a myocardial infarction, depression is an independent risk factor for mortality. Successful therapy of depression has been shown to improve patients’ quality of life and cardiovascular outcome. However, multicentric clinical trials are needed to support this inference. A practical liaison between qualified professionals is necessary for the better management of depressed patients with excess risk in developing CAD. Accordingly, pathophysiological and clinical implications between depression and CAD are discussed in this article.Keywords: depression, coronary artery disease, behavioral disorders, prognosis

  11. Let-7a is a direct EWS-FLI-1 target implicated in Ewing's sarcoma development.

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    Claudio De Vito

    Full Text Available Ewing's sarcoma family tumors (ESFT are the second most common bone malignancy in children and young adults, characterized by unique chromosomal translocations that in 85% of cases lead to expression of the EWS-FLI-1 fusion protein. EWS-FLI-1 functions as an aberrant transcription factor that can both induce and suppress members of its target gene repertoire. We have recently demonstrated that EWS-FLI-1 can alter microRNA (miRNA expression and that miRNA145 is a direct EWS-FLI-1 target whose suppression is implicated in ESFT development. Here, we use miRNA arrays to compare the global miRNA expression profile of human mesenchymal stem cells (MSC and ESFT cell lines, and show that ESFT display a distinct miRNA signature that includes induction of the oncogenic miRNA 17-92 cluster and repression of the tumor suppressor let-7 family. We demonstrate that direct repression of let-7a by EWS-FLI-1 participates in the tumorigenic potential of ESFT cells in vivo. The mechanism whereby let-7a expression regulates ESFT growth is shown to be mediated by its target gene HMGA2, as let-7a overexpression and HMGA2 repression both block ESFT cell tumorigenicity. Consistent with these observations, systemic delivery of synthetic let-7a into ESFT-bearing mice restored its expression in tumor cells, decreased HMGA2 expression levels and resulted in ESFT growth inhibition in vivo. Our observations provide evidence that deregulation of let-7a target gene expression participates in ESFT development and identify let-7a as promising new therapeutic target for one of the most aggressive pediatric malignancies.

  12. Quality of Early Childhood Development Programs in Global Contexts: Rationale for Investment, Conceptual Framework and Implications for Equity.

    OpenAIRE

    2011-01-01

    Early childhood development programs—which often involve the health, education, child welfare, and other sectors—are of great interest to policymakers, service providers, and families around the globe. This paper proposes that equity in access and quality are critical to effect sustainable and meaningful change in these programs in developing countries. The paper conceptualizes quality across settings and systems and identifies implications for policymakers, practitioners, and researchers...

  13. Evaluation of the potency of two novel bispyridinium oximes (K456, K458) in comparison with oxime K203 and trimedoxime to counteract tabun-induced neurotoxicity in rats.

    Science.gov (United States)

    Kassa, Jiri; Misik, Jan; Karasova, Jana Z

    2013-09-01

    The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 85% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.

  14. Chemotherapy-Induced Peripheral Neurotoxicity and Complementary and Alternative Medicines: Progress and Perspective

    Directory of Open Access Journals (Sweden)

    Xiao-Lan eCheng

    2015-10-01

    Full Text Available Chemotherapy-induced peripheral neurotoxicity (CIPN is a severe and dose-limiting side effect of antineoplastic drugs. It can cause sensory, motor and autonomic system dysfunction, and ultimately force patients to discontinue chemotherapy. Until now, little is understood about CIPN and no consistent standard of care is available. Since CIPN is a multifactorial disease, the clinical efficacy of single pharmacological drugs is disappointing, prompting patients to seek out alternative treatment options. Complementary and alternative medicines (CAMs, especially herbal medicines, are well known for their multifaceted implications and widely used in human health care. So far, several phytochemicals, plant extracts, and herbal formulas have been evaluated for their possible therapeutic potential in preventing onset and progression of CIPN in experimental models. Clinical acupuncture has also been shown to improve CIPN symptoms. In this review, we will give an outline of our current knowledge on the research advances of CIPN, the role of CAMs in alleviating CIPN and possible lacunae in research that needs to be addressed.

  15. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications.

    Science.gov (United States)

    Cusi, Kenneth

    2012-04-01

    As obesity reaches epidemic proportions, nonalcoholic fatty liver disease (NAFLD) is becoming a frequent cause of patient referral to gastroenterologists. There is a close link between dysfunctional adipose tissue in NAFLD and common conditions such as metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease. This review focuses on the pathophysiology of interactions between adipose tissue and target organs in obesity and the resulting clinical implications for the management of nonalcoholic steatohepatitis. The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells, that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of nonalcoholic steatohepatitis. At the clinical level, adipose tissue insulin resistance contributes to type 2 diabetes mellitus and cardiovascular disease. Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (eg, significant weight loss, exercise, thiazolidinediones) or preventing activation of inflammatory pathways and oxidative stress (ie, vitamin E, thiazolidinediones) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established. Better understanding of pathways that link dysregulated adipose tissue, metabolic dysfunction, and liver lipotoxicity will result in improvements in the clinical management of these challenging patients. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Posting behaviour patterns in an online smoking cessation social network: implications for intervention design and development.

    Directory of Open Access Journals (Sweden)

    Benjamin Healey

    Full Text Available Online Cessation Support Networks (OCSNs are associated with increased quit success rates, but few studies have examined their use over time. We identified usage patterns in New Zealand's largest OCSN over two years and explored implications for OCSN intervention design and evaluation.We analysed metadata relating to 133,096 OCSN interactions during 2011 and 2012. Metrics covered aggregate network activity, user posting activity and longevity, and between-user commenting. Binary logistic regression models were estimated to investigate the feasibility of predicting low user engagement using early interaction data.Repeating periodic peaks and troughs in aggregate activity related not only to seasonality (e.g., New Year, but also to day of the week. Out of 2,062 unique users, 69 Highly Engaged Users (180+ interactions each contributed 69% of all OCSN interactions in 2012 compared to 1.3% contributed by 864 Minimally Engaged Users (< = 2 items each. The proportion of Highly Engaged Users increased with network growth between 2011 and 2012 (with marginal significance, but the proportion of Minimally Engaged Users did not decline substantively. First week interaction data enabled identification of Minimally Engaged Users with high specificity and sensitivity (AUROC= 0.94.Results suggest future research should develop and test interventions that promote activity, and hence cessation support, amongst specific user groups or at key time points. For example, early usage information could help identify Minimally Engaged Users for tests of targeted messaging designed to improve their integration into, or re-engagement with, the OCSN. Furthermore, although we observed strong growth over time on varied metrics including posts and comments, this change did not coincide with large gains in first-time user persistence. Researchers assessing intervention effects should therefore examine multiple measures when evaluating changes in network dynamics over time.

  17. Mechanisms of rotenone-induced neurotoxicity in PC 12 cells

    Institute of Scientific and Technical Information of China (English)

    Wei Han; Lizhong Sun; Jiafeng Chen; Ming Chang; Hongyan Huo; Linsen Hu

    2008-01-01

    BACKGROUND: Rotenone-induced neurotoxicity in PC 12 cells has been widely used to study the pathogenesis of Parkinson's disease. However, the precise mechanisms underlying rotenone-induced dopaminergic neuronal degeneration in Parkinson's disease remains unclear.OBJECTIVE: To establish rotenone-induced neurotoxicity in PC 12 cells, and to investigate the possible action pathways to rotenone-induced neural cell injury at the protein level.DESIGN, TIME AND SETTING: A controlled proteomics study was performed at the Department of Nearology, First Hospital, Jilin University between March 2006 and March 2007.MATERIALS: PC 12 cells were obtained from Shanghai Cell Bank of Chinese Academy of Sciences, China.Rotenone was provided by Sigma, USA.METHODS: PC 12 cells in logarithmic growth phase were treated under experimental and control conditions, respectively. A total of 0.5 μ mol/L rotenone, or the same amount of Dulbecco's modified eagle's medium (DMEM), was added in the experimental and control conditions, respectively.MAIN OUTCOME MEASURES: Following 72 hours of rotenone treatment, cellular survival rate was determined by methyl thiazolyl tetrazolium assay, and apoptotic changes were detected by Hoechst 33342 staining. Total cellular protein was extracted to acquire differential protein expression data utilizing two-dimensional differential in-gel electrophoresis. To identify differential protein spots, matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) was used.RESULTS: In the MTT assay, the experimental condition induced significantly less cell survival compared to the control condition (P < 0.01 ). Hoechst 33342 staining revealed a larger number of apoptotic cells under the experimental condition compared to the control condition (P < 0.01 ), as determined by the presence of nuclear condensation, pyknosis, and nuclear fragmentation. Two-dimensional electrophoresis results showed that the differential expression of protein

  18. Δ9-tetrahydrocannabinol prevents methamphetamine-induced neurotoxicity.

    Directory of Open Access Journals (Sweden)

    M Paola Castelli

    Full Text Available Methamphetamine (METH is a potent psychostimulant with neurotoxic properties. Heavy use increases the activation of neuronal nitric oxide synthase (nNOS, production of peroxynitrites, microglia stimulation, and induces hyperthermia and anorectic effects. Most METH recreational users also consume cannabis. Preclinical studies have shown that natural (Δ9-tetrahydrocannabinol, Δ9-THC and synthetic cannabinoid CB1 and CB2 receptor agonists exert neuroprotective effects on different models of cerebral damage. Here, we investigated the neuroprotective effect of Δ9-THC on METH-induced neurotoxicity by examining its ability to reduce astrocyte activation and nNOS overexpression in selected brain areas. Rats exposed to a METH neurotoxic regimen (4 × 10 mg/kg, 2 hours apart were pre- or post-treated with Δ9-THC (1 or 3 mg/kg and sacrificed 3 days after the last METH administration. Semi-quantitative immunohistochemistry was performed using antibodies against nNOS and Glial Fibrillary Acidic Protein (GFAP. Results showed that, as compared to corresponding controls (i METH-induced nNOS overexpression in the caudate-putamen (CPu was significantly attenuated by pre- and post-treatment with both doses of Δ9-THC (-19% and -28% for 1 mg/kg pre- and post-treated animals; -25% and -21% for 3 mg/kg pre- and post-treated animals; (ii METH-induced GFAP-immunoreactivity (IR was significantly reduced in the CPu by post-treatment with 1 mg/kg Δ9-THC1 (-50% and by pre-treatment with 3 mg/kg Δ9-THC (-53%; (iii METH-induced GFAP-IR was significantly decreased in the prefrontal cortex (PFC by pre- and post-treatment with both doses of Δ9-THC (-34% and -47% for 1 mg/kg pre- and post-treated animals; -37% and -29% for 3 mg/kg pre- and post-treated animals. The cannabinoid CB1 receptor antagonist SR141716A attenuated METH-induced nNOS overexpression in the CPu, but failed to counteract the Δ9-THC-mediated reduction of METH-induced GFAP-IR both in the PFC and CPu. Our

  19. P-gp substrate-induced neurotoxicity in an Abcb1a knock-in/Abcb1b knock-out mouse model with a mutated canine ABCB1 targeted insertion.

    Science.gov (United States)

    Swain, M D; Orzechowski, K L; Swaim, H L; Jones, Y L; Robl, M G; Tinaza, C A; Myers, M J; Jhingory, M V; Buckely, L E; Lancaster, V A; Yancy, H F

    2013-06-01

    Certain dog breeds, especially Collies, are observed to exhibit neurotoxicity to avermectin drugs, which are P-glycoprotein (P-gp) substrates. This neurotoxicity is due to an ABCB1 gene mutation (ABCB1-1Δ) that results in non-functional P-gp expression. A developed Abcb1a knock-in/Abcb1b knock-out mouse model expressing the ABCB1-1Δ canine gene was previously reported and mice exhibited sensitivity upon ivermectin administration. Here, model and wild-type mice were administered P-gp substrates doramectin, moxidectin, and digoxin. While knock-in/knock-out mice exhibited ataxia, lethargy and tremor, wild-type mice remained unaffected. In addition, no neurotoxic clinical signs were observed in either mouse type administered domperidone, a P-gp substrate with no reported neurotoxicity in ABCB1-1Δ Collies. Overall, neurotoxic signs displayed by model mice closely paralleled those observed in ivermectin-sensitive Collies. This model can be used to identify toxic P-gp substrates with altered safety in dog populations and may reduce dog use in safety studies that are part of the drug approval process.

  20. A peptide disrupting the D2R-DAT interaction protects against dopamine neurotoxicity.

    Science.gov (United States)

    Su, Ping; Liu, Fang

    2017-09-01

    Dopamine reuptake from extracellular space to cytosol leads to accumulation of dopamine, which triggers neurotoxicity in dopaminergic neurons. Previous studies have shown that both dopamine D2 receptor (D2R) and dopamine transporter (DAT) are involved in dopamine neurotoxicity. However, blockade of either D2R or DAT causes side effects due to antagonism of other physiological functions of these two proteins. We previously found that DAT can form a protein complex with D2R and its cell surface expression is facilitated via D2R-DAT interaction, which regulates dopamine reuptake and intracellular dopamine levels. Here we found that an interfering peptide (DAT-S1) disrupting the D2R-DAT interaction protects neurons against dopamine neurotoxicity, and this effect is mediated by inhibiting DAT cell surface expression and inhibiting both caspase-3 and PARP-1 cleavage. This study demonstrates the role of the D2R-DAT complex in dopamine neurotoxicity and investigated the potential mechanisms, which might help better understand the mechanisms of dopamine neurotoxicity. The peptide may provide some insights to improve treatments for dopamine neurotoxicity and related diseases, such as Parkinson's disease, as well as methamphetamine- and 3,4-methsylenedioxy methamphetamine-induced neurotoxicity. Copyright © 2017. Published by Elsevier Inc.

  1. Cyanobacterial Xenobiotics as Evaluated by a Caenorhabditis elegans Neurotoxicity Screening Test

    Directory of Open Access Journals (Sweden)

    Jingjuan Ju

    2014-04-01

    Full Text Available In fresh waters cyanobacterial blooms can produce a variety of toxins, such as microcystin variants (MCs and anatoxin-a (ANA. ANA is a well-known neurotoxin, whereas MCs are hepatotoxic and, to a lesser degree, also neurotoxic. Neurotoxicity applies especially to invertebrates lacking livers. Current standardized neurotoxicity screening methods use rats or mice. However, in order to minimize vertebrate animal experiments as well as experimental time and effort, many investigators have proposed the nematode Caenorhabditis elegans as an appropriate invertebrate model. Therefore, four known neurotoxic compounds (positive compounds: chlorpyrifos, abamectin, atropine, and acrylamide were chosen to verify the expected impacts on autonomic (locomotion, feeding, defecation and sensory (thermal, chemical, and mechanical sensory perception functions in C. elegans. This study is another step towards successfully establishing C. elegans as an alternative neurotoxicity model. By using this protocol, anatoxin-a adversely affected locomotive behavior and pharyngeal pumping frequency and, most strongly, chemotactic and thermotactic behavior, whereas MC-LR impacted locomotion, pumping, and mechanical behavior, but not chemical sensory behavior. Environmental samples can also be screened in this simple and fast way for neurotoxic characteristics. The filtrate of a Microcystis aeruginosa culture, known for its hepatotoxicity, also displayed mild neurotoxicity (modulated short-term thermotaxis. These results show the suitability of this assay for environmental cyanotoxin-containing samples.

  2. Documenting PyroCb Development on High-Intensity Boreal Fires: Implications for the Arctic Atmosphere

    Science.gov (United States)

    Stocks, B. J.; Fromm, M. D.; Servranckx, R.; Lindsey, D.

    2007-12-01

    The recent confirmation that smoke from high-intensity boreal forest fires can reach the Upper Troposphere/Lower Stratosphere (UTLS) through pyroconvection and be transported long distances has raised concern over the wider-scale environmental impact of boreal fire smoke. This concern is further elevated as climate change projections indicate a significant increase in the frequency and severity of boreal forest fires over the next century. Smoke in the UTLS is frequently transported to the Arctic and may have important implications for the radiative energy budget in the polar region. Soot deposition from fires may lead to enhanced melting of sea ice and glaciers, and the chemical impact of fire emissions at high altitudes is largely unknown. This knowledge gap will be addressed during the International Polar Year (IPY), as boreal fire emissions will be tracked and documented in detail through aerial, satellite and ground-based measurements, as a key component of the POLARCAT (Polar Study using Aircraft, Remote Sensing, Surface Measurements and Models, of Climate, Chemistry, Aerosols, and Transport) and ARCTAS (Arctic Research of the Composition of the Troposphere from Aircraft and Satellites) projects to be conducted in 2008. A large fire in the Canadian Northwest Territories burned throughout the month of June 2007, in a remote region where forest fires are not actively suppressed, eventually reaching 90,000 hectares in size. This fire was monitored for blowup one week in advance; it erupted into pyroconvection on June 25, 2007. We present an analysis of this event combining satellite data with ground-based measurements to document the development and impact of this classic pyroCb event. Under extreme fire danger conditions, the fire burned close to 20,000 hectares on that day. Fire behavior was consistent with predictions using the Canadian Fire Behavior Prediction System, with the fire spreading at 2.7 km/hr, consuming 33,000 kg of fuel hourly, generating an

  3. Neurotoxicity and Biomarkers of Lead Exposure:a Review

    Institute of Scientific and Technical Information of China (English)

    Kang-sheng Liu; Jia-hu Hao; Yu Zeng; Fan-chun Dai; Ping-qing Gu

    2013-01-01

    Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups:biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone;the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer’s disease, Parkinson’s disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.

  4. A Brief Review of Neurotoxicity Induced by Melamine.

    Science.gov (United States)

    An, Lei; Sun, Wei

    2017-08-01

    In September 2008, in China, tens of thousands of children were hospitalized, several even died, as a result of infant-formula milk adulterated with a synthetic chemical compound, melamine, and in the next few months, this crisis became the focus of attention worldwide. Although there are a number of articles about nephrotoxicity of melamine, the evidence of melamine toxicity on other organs is still scanty. Specially, several recent studies indicated that melamine can perturb the central nervous system (CNS) function and induce cognitive deficits, breaking the previous view that melamine toxicity is limited to the urinary system. This review focuses on some developmental consequences of melamine exposures through various routes in vitro and in vivo, from ethology to molecular and cellular assessments. The evidences demonstrate that the neurotoxic effects of melamine were varied from different route exposure. Finally, the relevant literature on the mechanisms of these aspects has been discussed, and some suggestions towards further researches have been presented.

  5. (-) deprenyl attenuates aluminium induced neurotoxicity in primary cortical cultures.

    Science.gov (United States)

    Munirathinam, S; Lakshmana, M K; Raju, T R

    1996-06-01

    The role of (-) deprenyl in offering neuroprotection to cortical neurons exposed to Aluminium chloride (AlCl3) was examined. Primary cortical cultures derived from newborn rats were exposed to AlCl3 on 6th day in vitro, at 100,200,400,600,800 and 1000 microM concentrations of AlCl3. After 48 h of AlCl3 exposure, many nerve cell bodies were swollen; a beading of neurites and a disruption of the neuritic network were also observed suggesting neurodegeneration. Lactate dehydrogenase (LDH) efflux increased in a dose-dependent manner (59-120%). (-) Deprenyl co-exposure at concentrations of 10(-7), 10(-8) and 10(-9) M significantly attenuated both the morphological alterations and the LDH efflux induced by AlCl3. This in vitro study has demonstrated that (-) deprenyl can protect neurons from aluminium induced neurotoxicity.

  6. PROTECTIVE EFFECT OF GREEN TEA FROM PAF-INDUCED NEUROTOXITY

    Institute of Scientific and Technical Information of China (English)

    Han Enji; Hah Xuefei; Joseph Rajiv

    2000-01-01

    Objective The protective effect of chinese green tea from PAF-induced neurotoxity was investigated Method LaN1 ( neuroblastoma cell line) was used as neuron. Lactate dehydrogenase (LDH) -release was an indicator of cell death. Cytoplasmic calcium was measured with Aequouin-loaded method. Results When applied to LaN1 cells, green tea in concentration 2mg/ml or stronger obviously damaged cells. If lower concentration (0. 5mg/ml and l.Omg/ml) of green tea were applied, green tea inhibited the elevation of intracellular calcium and reduced the cytotoxity induced by PAF in neurons. Conclusion PAF plays an important role in brain injury and stroke, the protective effect of green tea could be a basis to explore weather green tea or its derivative may have preventive and therapeutic potential for neuronal injury.

  7. The neurotoxicity of environmental aluminum is still an issue.

    Science.gov (United States)

    Bondy, Stephen C

    2010-09-01

    Evidence for the neurotoxicity of extended exposure to low levels of aluminum salts is described using an animal model treated with aluminum at low levels reflecting those found in some water supplies. Emphasis is given to the potential role of aluminum in acceleration and promotion of some indices characteristic of brain aging. These hallmarks include the appearance of excess levels of inflammation in specific brain areas. Aluminum salts can increase levels of glial activation, inflammatory cytokines and amyloid precursor protein within the brain. Both normal brain aging and to a greater extent, Alzheimer's disease are associated with elevated basal levels of markers for inflammation. These are not attributable to obvious exogenous stimuli and may reflect the lifespan history of the organism's immune responses. It is possible that aluminum salts can act as a subtle promoter of such apparently unprovoked responses.

  8. Neurotoxic behavioral effects of Lake Ontario salmon diets in rats

    Energy Technology Data Exchange (ETDEWEB)

    Hertzler, D.R. (State Univ. of New York, Oswego (USA))

    1990-03-01

    Six experiments were conducted to examine possible neurotoxic effects of the exposure to contaminants in Lake Ontario salmon administered through the diets of rats. Rats were fed different concentrations of fish (8%, 15% or 30%) in one of three diet conditions: Lake Ontario salmon, Pacific Ocean salmon, or laboratory rat chow only. Following 20 days on the diets, rats were tested for five minutes per day in a modified open field for one or three days. Lake Ontario salmon diets consistently produced significantly lower activity, rearing, and nosepoke behaviors in comparison with ocean salmon or rat chow diet conditions. A dose-response effect for concentration of lake salmon was obtained, and the attenuation effect occurred in males, females, adult or young animals, and postweaning females, with fish sampled over a five-year period. While only two of several potential contaminants were tested, both fish and brain analyses of mirex and PCBs relate to the behavioral effects.

  9. Promethazine protects against 3-nitropropionic acid-induced neurotoxicity.

    Science.gov (United States)

    Cleren, Carine; Calingasan, Noel Y; Starkov, Anatoly; Jacquard, Carine; Chen, Junya; Brouillet, Emmanuel; Beal, M Flint

    2010-01-01

    Promethazine (PMZ), an FDA-approved antihistaminergic drug, was identified as a potentially neuroprotective compound in a NINDS screening program. It was shown to protect against ischemia in mice, to delay disease onset in a mouse model of amyotrophic lateral sclerosis and to inhibit Ca(2+)-induced mitochondrial permeability transition in rat liver mitochondria. We investigated whether PMZ could protect against the neurotoxic effects induced by 3-nitropropionic acid (3-NP), an inhibitor of the succinate dehydrogenase, used to model Huntington's disease (HD) in rats. Lewis rats receiving chronic subcutaneous infusion of 3-NP were treated with PMZ. The findings indicate that chronic PMZ treatment significantly reduced 3-NP-induced striatal lesion volume, loss of GABAergic neurons and number of apoptotic cells in the striatum. PMZ showed a strong neuroprotective effect against 3-NP toxicity in vivo. Copyright 2009 Elsevier Ltd. All rights reserved.

  10. Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

    Science.gov (United States)

    Morigaki, Ryoma; Goto, Satoshi

    2017-01-01

    Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection. PMID:28590448

  11. Striatal Vulnerability in Huntington's Disease: Neuroprotection Versus Neurotoxicity.

    Science.gov (United States)

    Morigaki, Ryoma; Goto, Satoshi

    2017-06-07

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection.

  12. A plastic stabilizer dibutyltin dilaurate induces subchronic neurotoxicity in rats

    Institute of Scientific and Technical Information of China (English)

    Minghua Jin; Peilin Song; Na Li; Xuejun Li; Jiajun Chen

    2012-01-01

    Dibutyltin dilaurate functions as a stabilizer for polyvinyl chloride.In this study,experimental rats were intragastrically administered 5,10,or 20 mg/kg dibutyltin dilaurate to model sub-chronic poisoning.After exposure,our results showed the activities of superoxide dismutase and glutathione peroxidase decreased in rat brain tissue,while the malondialdehyde and nitric oxide content,as well as nitric oxide synthase activity in rat brain tissue increased.The cell cycle in the right parietal cortex was disordered and the rate of apoptosis increased.DNA damage was aggravated in the cerebral cortex,and the ultrastructure of the right parietal cortex tissues was altered.The above changes became more apparent with exposure to increasing doses of dibutyltin dilaurate.Our experimental findings confirmed the neurotoxicity of dibutyltin dilaurate in rat brain tissues,and demonstrated that the poisoning was dose-dependent.

  13. HIV-infected microglia mediate cathepsin B-induced neurotoxicity.

    Science.gov (United States)

    Zenón, Frances; Cantres-Rosario, Yisel; Adiga, Radhika; Gonzalez, Mariangeline; Rodriguez-Franco, Eillen; Langford, Dianne; Melendez, Loyda M

    2015-10-01

    HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we asked if microglia respond to HIV infection similarly by modifying the expression, secretion, and neurotoxic potential of cathepsin B and determined the in vivo relevance of these findings. HIV-1ADA-infected human primary microglia and CHME-5 microglia cell line were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and the neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIV encephalitis (HIVE) patients. HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at day 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.

  14. Neurotoxic effects of levobupivacaine and fentanyl on rat spinal cord

    Directory of Open Access Journals (Sweden)

    Yesim Cokay Abut

    2015-02-01

    Full Text Available BACKGROUND: The purpose of the study was to compare the neurotoxic effects of intrathecally administered levobupivacaine, fentanyl and their mixture on rat spinal cord. METHODS: In experiment, there were four groups with medication and a control group. Rats were injected 15 µL saline or fentanyl 0.0005 µg/15 µL, levobupivacaine 0.25%/15 µL and fentanyl 0.0005 µg + levobupivacaine 0.25%/15 µL intrathecally for four days. Hot plate test was performed to assess neurologic function after each injection at 5th, 30th and 60th min. Five days after last lumbal injection, spinal cord sections between the T5 and T6 vertebral levels were obtained for histologic analysis. A score based on subjective assessment of number of eosinophilic neurons - Red neuron - which means irreversible neuronal degeneration. They reflect the approximate number of degenerating neurons present in the affected neuroanatomic areas as follows: 1, none; 2, 1-20%; 3, 21-40%; 4, 41-60%; and 5, 61-100% dead neurons. An overall neuropathologic score was calculated for each rat by summating the pathologic scores for all spinal cord areas examined. RESULTS: In the results of HPT, comparing the control group, analgesic latency statistically prolonged for all four groups.In neuropathologic investment, the fentanyl and fentanyl + levobupivacaine groups have statistically significant high degenerative neuron counts than control and saline groups. CONCLUSIONS: These results suggest that, when administered intrathecally in rats, fentanyl and levobupivacaine behave similar for analgesic action, but fentanyl may be neurotoxic for spinal cord. There was no significant degeneration with levobupivacaine, but fentanyl group has had significant degeneration.

  15. Oxidative stress in MeHg-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Farina, Marcelo, E-mail: farina@ccb.ufsc.br [Departamento de Bioquimica, Centro de Ciencias Biologicas, Universidade Federal de Santa Catarina, Florianopolis, SC (Brazil); Aschner, Michael [Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN (United States); Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN (United States); Rocha, Joao B.T., E-mail: jbtrocha@yahoo.com.br [Departamento de Quimica, Centro de Ciencias Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS (Brazil)

    2011-11-15

    Methylmercury (MeHg) is an environmental toxicant that leads to long-lasting neurological and developmental deficits in animals and humans. Although the molecular mechanisms mediating MeHg-induced neurotoxicity are not completely understood, several lines of evidence indicate that oxidative stress represents a critical event related to the neurotoxic effects elicited by this toxicant. The objective of this review is to summarize and discuss data from experimental and epidemiological studies that have been important in clarifying the molecular events which mediate MeHg-induced oxidative damage and, consequently, toxicity. Although unanswered questions remain, the electrophilic properties of MeHg and its ability to oxidize thiols have been reported to play decisive roles to the oxidative consequences observed after MeHg exposure. However, a close examination of the relationship between low levels of MeHg necessary to induce oxidative stress and the high amounts of sulfhydryl-containing antioxidants in mammalian cells (e.g., glutathione) have led to the hypothesis that nucleophilic groups with extremely high affinities for MeHg (e.g., selenols) might represent primary targets in MeHg-induced oxidative stress. Indeed, the inhibition of antioxidant selenoproteins during MeHg poisoning in experimental animals has corroborated this hypothesis. The levels of different reactive species (superoxide anion, hydrogen peroxide and nitric oxide) have been reported to be increased in MeHg-exposed systems, and the mechanisms concerning these increments seem to involve a complex sequence of cascading molecular events, such as mitochondrial dysfunction, excitotoxicity, intracellular calcium dyshomeostasis and decreased antioxidant capacity. This review also discusses potential therapeutic strategies to counteract MeHg-induced toxicity and oxidative stress, emphasizing the use of organic selenocompounds, which generally present higher affinity for MeHg when compared to the classically

  16. Rodent neurotoxicity bioassays for screening contaminated Great Lakes fish

    Energy Technology Data Exchange (ETDEWEB)

    Beattie, M.K.; Hoffman, R. [Univ. of Minnesota, Duluth, MN (United States); Gerstenberger, S. [Univ. of Illinois, Urbana, IL (United States). Dept. of Veterinary Biosciences; Dellinger, J.A. [Medical Coll. of Wisconsin, Milwaukee, MI (United States). Dept. of Preventive Medicine

    1996-03-01

    Standard laboratory rat neurotoxicity protocols were used to study the consequences resulting from the consumption of walleye (Stizostedion vitreum), whitefish (Coregonus clupeaformis), and lake trout (Salvelinus namaycush) from Lake Superior (LS) and the consumption of carp (Cyprinus carpio) from Little Lake Butte des Morte (LLBM) near Oshkosh, Wisconsin, USA. Two 90-d subchronic studies are described, including a 45-d exposure to fish diets using male Sprague-Dawley hooded rats, and a 90-d exposure to fish diets using female rats of the same species. Behavioral alterations were tested using a battery of behavioral tests. In addition, pharmacologic challenges using apomorphine and D-amphetamine were administered to the rats to reveal latent neurotoxic effects. Cumulative fish consumption data were recorded daily, weight gain recorded weekly, and behavior data collected prior to exposure, and on days 7, 14, 55 {+-} 2, 85 {+-} 2. Motor activity data were collected on days 30 {+-} 2, 60 {+-} 2, and 90 {+-} 2 of the feeding protocols. Brain tissue from rodents fed these fish were subsequently analyzed for either mercury (Hg) or polychlorinated biphenyls (PCB). Mercury concentrations were increased in the brains of the walleye-fed rats, and PCB concentrations ranged from 0.5 nl/L to 10 nl/L in the brains of rats fed carp from LLBM, a Lake Michigan tributary. Adult male rats fed LLBM carp for 45 d exhibited the greatest behavior responses to the dopaminergic agonist apomorphine on the accelerating rotarod, although these differences were not significant. The 90-d exposure of LS walleye or Hg-spiked LS walleye resulted in behavior alterations on tactile startle response and second footsplay. D-Amphetamine challenge caused changes in tactile startle response, second footsplay, and accelerating rotarod performance after consuming walleye diets. Rats fed LLBM carp had altered behavioral responses to apomorphine on the accelerating rotarod.

  17. The oral core vocabulary of typically developing English-speaking school-aged children: implications for AAC practice.

    Science.gov (United States)

    Boenisch, Jens; Soto, Gloria

    2015-03-01

    This study analyzes the core vocabulary used by typically developing school-aged English-speaking children in the United States while participating in a variety of school activities. The language of typically developing children, some of whom spoke English as a second language was recorded, transcribed and analyzed to identify the most frequently used words across samples. An inventory of oral core vocabulary of typically developing school-aged children resulted from this analysis. This inventory can be used as a source list for vocabulary selection for school-aged children with AAC needs. Implications for vocabulary selection are discussed.

  18. Subarachnoid hemorrhage associated with cyclosporine A neurotoxicity in a bone-marrow transplant recipient

    Energy Technology Data Exchange (ETDEWEB)

    Teksam, M.; Casey, S.O.; Michel, E.; Truwit, C.L. [Minnesota Univ., Minneapolis, MN (United States). Dept. of Radiology

    2001-03-01

    We report subarachnoid hemorrhage associated with cyclosporine A (CSA) neurotoxicity after bone-marrow transplantation for chronic myelogenous leukemia. CT showed occipital subarachnoid hemorrhage. MRI confirmed this, and demonstrated cortical and subcortical edema in the posterior temporal, occipital, and posterior frontal lobes bilaterally, which was typical of CSA neurotoxicity. Recognition of CSA neurotoxicity as the cause of the subarachnoid hemorrhage obviated angiographic investigation. After cessation of cyclosporine therapy, the cortical and subcortical edema resolved on follow-up MRI with some residual blood products in the subarachnoid space. (orig.)

  19. Profiling Jet Fuel on Neurotoxic Components With Comprehensive Two-Dimensional GC

    Science.gov (United States)

    2007-11-01

    vapor at -10 °C,( Ib ). 56 Table 9; Concentration time course of 8 neurotoxic components in JP-8 vapor at -10 °C,(Ia). 57 Table 10; Concentration...time course of 8 neurotoxic components in JP-8 vapor at -10 °C,( Ib ). 58 Table 11; Concentration time course of 9 neurotoxic components in JP-8 vapor...aerosol-vapor JP-8 jet fuel exposure affects neurobehavior and neurotransmitter levels in a rat model. J. Toxicol. Environ. Health A., (2007), 70, 1203

  20. Different Patterns of Sexual Identity Development over Time: Implications for the Psychological Adjustment of Lesbian, Gay, and Bisexual Youths

    OpenAIRE

    Rosario, Margaret; Schrimshaw, Eric W.; Hunter, Joyce

    2011-01-01

    Despite research documenting variability in the sexual identity development of lesbian, gay, and bisexual (LGB) youths, it remains unclear whether different developmental patterns have implications for the psychological adjustment of LGB youths. The current report longitudinally examines whether different patterns of LGB identity formation and integration are associated with indicators of psychological adjustment among an ethnically diverse sample of 156 LGB youths (ages 14 – 21) in New York ...