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Behavioral Abnormalities (behavioral + abnormality)
Selected AbstractsLong-term neurological and functional outcome in Nipah virus infectionANNALS OF NEUROLOGY, Issue 3 2007James J. Sejvar MD Objective Nipah virus (NiV) is an emerging zoonosis. Central nervous system disease frequently results in high case-fatality. Long-term neurological assessments of survivors are limited. We assessed long-term neurologic and functional outcomes of 22 patients surviving NiV illness in Bangladesh. Methods During August 2005 and May 2006, we administered a questionnaire on persistent symptoms and functional difficulties to 22 previously identified NiV infection survivors. We performed neurologic evaluations and brain magnetic resonance imaging (MRI). Results Twelve (55%) subjects were male; median age was 14.5 years (range 6,50). Seventeen (77%) survived encephalitis, and 5 survived febrile illness. All but 1 subject had disabling fatigue, with a median duration of 5 months (range, 8 days,8 months). Seven encephalitis patients (32% overall), but none with febrile illness had persistent neurologic dysfunction, including static encephalopathy (n = 4), ocular motor palsies (2), cervical dystonia (2), focal weakness (2), and facial paralysis (1). Four cases had delayed-onset neurologic abnormalities months after acute illness. Behavioral abnormalities were reported by caregivers of over 50% of subjects under age 16. MRI abnormalities were present in 15, and included multifocal hyperintensities, cerebral atrophy, and confluent cortical and subcortical signal changes. Interpretation Although delayed progression to neurologic illness following Nipah fever was not observed, persistent fatigue and functional impairment was frequent. Neurologic sequelae were frequent following Nipah encephalitis. Neurologic dysfunction may persist for years after acute infection, and new neurologic dysfunction may develop after acute illness. Survivors of NiV infection may experience substantial long-term neurologic and functional morbidity. Ann Neurol 2007 [source] Effects of early seizures on later behavior and epileptogenicityDEVELOPMENTAL DISABILITIES RESEARCH REVIEW, Issue 2 2004Gregory L. Holmes Abstract Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. Understanding the critical periods of vulnerability of the developing nervous system to seizure-induced changes may provide insights into parallel or divergent processes in the development of autism. In experimental rodent models, the consequences of seizures are dependent on age, etiology, seizure duration, and frequency. Recurring seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, changes in excitatory neurotransmitter receptor distribution, and decreased neurogenesis. These changes occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well-documented following early-onset seizures, the mechanisms of seizure-induced dysfunction remain unclear. MRDD Research Reviews 2004;10:101,105. © 2004 Wiley-Liss, Inc. [source] Hippocampal structure and the action of cholinomimetic drugsDRUG DEVELOPMENT RESEARCH, Issue 3 2002John G. Csernansky Abstract Cholinomimetic drugs have become the clinical standard for the treatment of patients with dementia of the Alzheimer type (DAT). However, uncertainty remains as to the proportion of patients that respond to such drugs, and how one might predict the capacity for response before treatment is begun. The thesis of the present review is that the neuroanatomical integrity of the hippocampus determines, at least in part, the capacity of DAT patients to respond to cholinomimetic drugs. Neuroimaging studies suggest that volume losses and other neuroanatomical deformities of the hippocampus are common in patients with even mild DAT. Moreover, more severe neuroanatomical deformities of the hippocampus are associated with more severe dementia symptoms and more rapid clinical decline. Animal research, including studies of cholinergic antagonists, glutamatergic antagonists, hippocampal lesions, and animals with mutant amyloid precursor protein genes, demonstrate that behavioral abnormalities similar to those found in DAT patients, especially those related to memory, are associated with hippocampal pathology. Cholinomimetic drugs, in particular, the cholinesterase inhibitors, have been shown to reverse some but not all of these behavioral abnormalities. More research is needed in DAT patients to determine whether an analysis of hippocampal structure or function can reliably predict the outcome of treatment with cholinomimetic drugs. Further work in animals is also needed to determine the limitations of cholinomimetic drugs for reversing various types of cognitive deficits, and to develop and test other pharmacological strategies for the treatment of DAT. Drug Dev. Res. 56:531,540, 2002. © 2002 Wiley-Liss, Inc. [source] Lethal and sublethal effects of polychlorinated biphenyls on Rana sylvatica tadpolesENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 1 2002Wesley K. Savage Abstract In static experiments, we exposed tadpoles of the wood frog (Rana sylvatica) to sediment collected from a riverine wetland in the St. Lawrence River basin that is highly contaminated with polychlorinated biphenyls (PCBs). Significant mortality occurred early in the experiment and was not explained by a simple dose-dependent relationship. Direct sediment contact resulted in higher tadpole mortality compared with tadpoles suspended in mesh containers above the sediment. Sublethal effects of exposure were also apparent, characterized by behavioral abnormalities, including reduced activity levels and swimming speed, that differed depending on whether tadpoles were in contact with or suspended above the sediment. We demonstrate in this experiment that PCB-contaminated sediment induced significant mortality and behavioral dysfunction in early development, but the effects on natural populations existing in the contaminated region is not known. [source] Levetiracetam in the Treatment of Idiopathic Generalized EpilepsiesEPILEPSIA, Issue 2005Richard Grünewald Summary:, Since its introduction into clinical practice in 1999, levetiracetam, the S enantiomer of piracetam, has rapidly found a secure place, initially in the therapy of partial onset seizures and subsequently in the treatment of idiopathic generalized epilepsies (IGE). It has many of the properties of an "ideal" antiepileptic drug, including rapid absorption, linear pharmokinetics, and sparse drug interactions. Tolerabiliy is generally excellent in both adults and children, although tiredness is a common dose-limiting adverse effect. Occasionally the drug can precipitate behavioral abnormalities, especially in patients with learning disability. There is a wide safety margin in overdose. In common with most antiepileptic drugs its mode of action remains uncertain. Levetiracetam binds to a specific site in the brain, influences intracellular calcium currents and reverses negative allosteric modulators of GABA- and glycine-gated currents in vitro. Its effectiveness has been demonstrated in animal models of epilepsy and in clinical trials of partial onset and IGE. Treatment of IGEs may be straightforward, with many patients demonstrating an excellent and robust response to valproate monotherapy. However, there remains a significant minority of patients for whom valproate is unsuitable, including those who experience unacceptable adverse effects (e.g., weight gain or hair loss) and women of childbearing age in whom the teratogenic potential of valproate is unacceptable. Therapeutic response to lamotrigine in this group is often disappointing, and many clinicians now are turning to the choice of levetiracetam. Efficacy in generalized tonic,clonic seizures and myoclonus is usually apparent and some patients experience improvement in typical absences. Experience of combinations of levetiracetam with other antiepileptic drugs is limited in IGE and the responses are largely anecdotal. In our hands, patients with refractory IGEs may respond to combinations of levetiracetam with valproate, lamotrigine, and phenobarbital, and adverse effects when they occur are usually limited to tiredness. Levetiracetam does not interact with the oral contraceptive pill, simplifying treatment in women of childbearing age. Although animal data look encouraging, questions over levetiracetam's teratogenic potential and overall safety in pregnancy will remain for many years to come. [source] Mutation and evolutionary analyses identify NR2E1- candidate-regulatory mutations in humans with severe cortical malformationsGENES, BRAIN AND BEHAVIOR, Issue 6 2007R. A. Kumar Nuclear receptor 2E1 (NR2E1) is expressed in human fetal and adult brains; however, its role in human brain,behavior development is unknown. Previously, we have corrected the cortical hypoplasia and behavioral abnormalities in Nr2e1,/, mice using a genomic clone spanning human NR2E1, which bolsters the hypothesis that NR2E1 may similarly play a role in human cortical and behavioral development. To test the hypothesis that humans with abnormal brain,behavior development may have null or hypomorphic NR2E1 mutations, we undertook the first candidate mutation screen of NR2E1 by sequencing its entire coding region, untranslated, splice site, proximal promoter and evolutionarily conserved non-coding regions in 56 unrelated patients with cortical disorders, namely microcephaly. We then genotyped the candidate mutations in 325 unrelated control subjects and 15 relatives. We did not detect any coding region changes in NR2E1; however, we identified seven novel candidate regulatory mutations that were absent from control subjects. We used in silico tools to predict the effects of these candidate mutations on neural transcription factor binding sites (TFBS). Four candidate mutations were predicted to alter TFBS. To facilitate the present and future studies of NR2E1, we also elucidated its molecular evolution, genetic diversity, haplotype structure and linkage disequilibrium by sequencing an additional 94 unaffected humans representing Africa, the Americas, Asia, Europe, the Middle East and Oceania, as well as great apes and monkeys. We detected strong purifying selection, low genetic diversity, 21 novel polymorphisms and five common haplotypes at NR2E1. We conclude that protein-coding changes in NR2E1 do not contribute to cortical and behavioral abnormalities in the patients examined here, but that regulatory mutations may play a role. [source] Floxed allele for conditional inactivation of the GABAB(1) geneGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 3 2004Corinne Haller Abstract GABAB receptors are the G-protein-coupled receptors for the neurotransmitter GABA. GABAB receptors are broadly expressed in the nervous system. Their complete absence in mice causes premature lethality or,when mice are viable,epilepsy, impaired memory, hyperalgesia, hypothermia, and hyperactivity. A spatially and temporally restricted loss of GABAB function would allow addressing how the absence of GABAB receptors leads to these diverse phenotypes. To permit a conditional gene inactivation, we flanked critical exons of the GABAB(1) gene with lox511 sites. GABAB(1)lox511/lox511 mice exhibit normal levels of GABAB(1) protein, are fertile, and do not display any behavioral phenotype. We crossed GABAB(1)lox511/lox511 with Cre-deleter mice to produce mice with an unrestricted GABAB receptor elimination. These GABAB(1),/, mice no longer synthesize GABAB(1) protein and exhibit the expected behavioral abnormalities. The conditional GABAB(1) allele described here is therefore suitable for generating mice with a site- and time-specific loss of GABAB function. genesis 40:125,130, 2004. © 2004 Wiley-Liss, Inc. [source] Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide levelGLIA, Issue 3 2005Inge Zöller Abstract Galactosylceramide (GalC) is the major sphingolipid of the myelin membrane. Mice lacking GalC due to ceramide galactosyltransferase (CGT) deficiency form unstable and functionally affected myelin and exhibit a progressive demyelination, accompanied by severe motor coordination deficits. In addition to oligodendrocytes, CGT is also expressed in other cells, e.g., neurons and astrocytes. We examined the possibility that lack of CGT in these cells contributes to the phenotype of CGT-deficient mice. Toward this aim, we generated transgenic mice expressing CGT under the control of oligodendrocyte-specific proteolipid protein (PLP) promoter and examined the possibility of a transgenic rescue of CGT-deficient mice. CGT-deficient mice expressing the PLP-CGT transgene did not show any behavioral abnormalities, normal myelin structure, and MBP levels. CGT activity as well as GalC and sulfatide levels of rescued mice were not significantly different from wild-type controls. Thus, transgenic rescue with the PLP-CGT transgene was apparently complete. In contrast to wild-type and rescued mice, PLP-CGT transgenic mice on a wild-type background exhibited significantly elevated CGT activity which directly correlated with an increase in non-hydroxy fatty acid (NFA)-GalC, but not ,-hydroxy fatty acid (HFA)-GalC. HFA-GalC decreased in adult transgenic mice, indicating that NFA-GalC, but not HFA-GalC levels are limited by CGT activity. As a consequence, the total amount of GalC is unchanged over a rather wide range of CGT expression levels in the mouse brain. Our results indicate that loss of CGT in oligodendrocytes is exclusively responsible for the myelin structural deficits, demyelination, and behavioral abnormalities in CGT-deficient mice. © 2005 Wiley-Liss, Inc. [source] Progranulin: normal function and role in neurodegenerationJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Jason L. Eriksen Abstract Progranulin (PGRN) is a multifunctional protein that has attracted significant attention in the neuroscience community following the recent discovery of PGRN mutations in some cases of frontotemporal dementia. Most of the pathogenic mutations result in null alleles, and it is thought that frontotemporal dementia in these families results from PGRN haploinsufficiency. The neuropathology associated with PGRN mutations is characterized by the presence of tau-negative, ubiquitin-immunoreactive neuronal inclusions (frontotemporal lobar degeneration with ubiquitinated inclusions) that are also positive for the transactivation response DNA binding protein with Mr 43 kD. The clinical phenotype includes behavioral abnormalities, language disorders and parkinsonism but not motor neuron disease. There is significant clinical variation between families with different PGRN mutations and among members of individual families. The normal function of PGRN is complex, with the full-length form of the protein having trophic and anti-inflammatory activity, whereas proteolytic cleavage generates granulin peptides that promote inflammatory activity. In the periphery, PGRN functions in wound healing responses and modulates inflammatory events. In the CNS, PGRN is expressed by neurons and microglia; consequently, reduced levels of PGRN could affect both neuronal survival and CNS inflammatory processes. In this review, we discuss current knowledge of the molecular genetics, neuropathology, clinical phenotype and functional aspects of PGRN in the context of neurodegenerative disease. [source] Remission and Resurgence of Anxiety-Like Behavior Across Protracted Withdrawal Stages in Ethanol-Dependent RatsALCOHOLISM, Issue 9 2007Yu Zhao Background:, Alcohol dependence is a chronic disorder in which withdrawal symptoms often persist after detoxification. The purpose of the present experiment was to characterize susceptibility to stress and anxiogenic stimuli in rats over an extended time period following ethanol withdrawal. Methods:, Male Wistar rats were made dependent via ethanol vapor exposure. The rats were then tested in the elevated plus-maze during acute ethanol withdrawal (ACW, ,8 hour), early "protracted" withdrawal (EPW, 2 weeks), or late "protracted" withdrawal (LPW, 6, 12 weeks) following brief restraint or no stress. Principal components analysis was used to identify constructs underlying plus-maze behavior. Results:, Three factors characterized plus-maze performance: anxiety, locomotor activity, and risk assessment/decision making. Spontaneous anxiety-like behavior was increased during ACW, decreased to levels of ethanol-naïve controls during EPW, but markedly resurged during LPW. Withdrawal did not alter sensitivity to the anxiety-like effects of restraint stress. All ethanol-dependent rats showed locomotor hypoactivity that, in contrast to anxiety, remained stable throughout all withdrawal stages. Neither ethanol withdrawal nor restraint stress altered mean "risk assessment/decision making" scores, though ethanol withdrawal altered the emission of "risk assessment/decision making" behavior in relation to anxiety-like behavior and behavioral activation state. Conclusions:, The findings illustrate and model the spontaneous, severe, and long-lasting nature of behavioral abnormalities that accompany withdrawal from chronic, intermittent ethanol intoxication. The dynamic remission and resurgence in symptoms of negative affect (i.e., behavioral signs of anxiety) during "protracted" withdrawal may complicate recovery from alcoholism. [source] In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiencyNMR IN BIOMEDICINE, Issue 5 2010M. Henneke Abstract Adenylosuccinate lyase (ADSL) deficiency is an inherited metabolic disorder affecting predominantly the central nervous system. The disease is characterized by the accumulation of succinylaminoimidazolecarboxamide riboside and succinyladenosine (S-Ado) in tissue and body fluids. Three children presented with muscular hypotonia, psychomotor delay, behavioral abnormalities, and white matter changes on brain MRI. Two of them were affected by seizures. Screening for inborn errors of metabolism including in vitro high resolution proton MRS revealed an ADSL deficiency that was confirmed genetically in all cases. All patients were studied by in vivo proton MRS. In vitro high resolution proton MRS of patient cerebrospinal fluid showed singlet resonances at 8.27 and 8.29,ppm that correspond to accumulated S-Ado. In vivo proton MRS measurements also revealed a prominent signal at 8.3,ppm in gray and white matter brain regions of all patients. The resonance was undetectable in healthy human brain. In vivo proton MRS provides a conclusive finding in ADSL deficiency and represents a reliable noninvasive diagnostic tool for this neurometabolic disorder. Copyright © 2010 John Wiley & Sons, Ltd. [source] Minocycline and doxycycline are not beneficial in a model of Huntington's diseaseANNALS OF NEUROLOGY, Issue 2 2003Donna L. Smith BSc Huntington's Disease (HD) is an inherited neurological disorder causing movement impairment, personality changes, dementia, and premature death, for which there is currently no effective therapy. The modified tetracycline antibiotic, minocycline, has been reported to ameliorate the disease phenotype in the R6/2 mouse model of HD. Because the tetracyclines have also been reported to inhibit aggregation in other amyloid disorders, we have investigated their ability to inhibit huntingtin aggregation and further explored their efficacy in preclinical mouse trials. We show that tetracyclines are potent inhibitors of huntingtin aggregation in a hippocampal slice culture model of HD at an effective concentration of 30,M. However, despite achieving tissue levels approaching this concentration by oral treatment of R6/2 mice with minocycline, we observed no clear difference in their behavioral abnormalities, or in aggregate load postmortem. In the light of these new data, we would advise that caution be exercised in proceeding into human clinical trials of minocycline. Ann Neurol 2003 [source] Brain Protection During Pediatric Cardiopulmonary BypassARTIFICIAL ORGANS, Issue 4 2010Xiaowei W. Su Abstract Improvements in peri- and postoperative surgical techniques have greatly improved outcomes for pediatric patients undergoing cardiopulmonary bypass (CPB) in the treatment of congenital heart defects (CHDs). With decreased mortality rates, the incidence of adverse neurological outcomes, comprising cognitive and speech impairments, motor deficits, and behavioral abnormalities, has increased in those patients surviving bypass. A number of mechanisms, including ischemia, reperfusion injury, hypothermia, inflammation, and hemodilution, contribute to brain insult, which is further confounded by unique challenges presented in the pediatric population. However, a number of brain monitoring and preventative techniques have been developed or are being currently evaluated in the practice of pediatric CPB. Monitoring techniques include electroencephalography, near-infrared as well as visible light spectroscopy, transcranial Doppler ultrasound, and emboli detection and classification quantitation. Preventative measures include hypothermic perfusion techniques such as deep hypothermic circulatory arrest, low-flow CPB, blood gas management, and pharmacologic prophylaxes, among others. The present review summarizes the principles of brain insult, neurodevelopmental abnormalities, monitoring techniques, methods of prevention, as well as preexisting morbidities and risk factors in pediatric CPB, with a focus on brain protection. Clinical and translational research is presented with the aim of determining methods that may optimize neurological outcomes post CPB and guiding further study. [source] Proteomics of Caenorhabditis elegans over-expressing human , -synuclein analyzed by fluorogenic derivatization,liquid chromatography/tandem mass spectrometry: identification of actin and several ribosomal proteins as negative markers at early Parkinson's disease stagesBIOMEDICAL CHROMATOGRAPHY, Issue 3 2008Tomoko Ichibangase Abstract It has been known that the over-expression of , -synuclein, the main protein of Lewy bodies in Parkinson's disease (PD), leads to neurodegeneration in PD models. In this study, the changes in protein expression between the transgenic over-expressing human , -synuclein wild type (, -synWT) and the control Caenorhabditis elegans were elucidated by fluorogenic derivatization,liquid chromatography/tandem mass spectrometry (FD-LC-MS/MS) proteome analysis, which is a highly selective, sensitive, repeatable and quantitative method for protein identification. Because the , -synuclein wild-type worms showed moderate levels of dopamine loss without overt behavioral abnormalities, it was suggested that the changes in proteins in the , -synWT are related in the sequence of the formation of Lewy bodies. Among more than 400 protein peaks detected, actin and several ribosomal proteins were identified for the first time as negative markers at early PD stages. Actin was suggested to be one of the important targets in the elucidation of the etiology of neuronal diseases such as PD or other synucleinopathies. Copyright © 2007 John Wiley & Sons, Ltd. 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