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[PMID]: 29524880
[Au] Autor:Huang D; Jin L; Li Z; Wu J; Zhang N; Zhou D; Ni X; Hou T
[Ad] Address:Department of Neurology, Guangzhou Hospital of Traditional Chinese Medicine, Guangzhou, Guangdong, 510130, China. Electronic address: huang_dehong1@163.com.
[Ti] Title:Isoorientin triggers apoptosis of hepatoblastoma by inducing DNA double-strand breaks and suppressing homologous recombination repair.
[So] Source:Biomed Pharmacother;101:719-728, 2018 Mar 07.
[Is] ISSN:1950-6007
[Cp] Country of publication:France
[La] Language:eng
[Ab] Abstract:Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo. Mechanistic studies showed that Iso triggered cell apoptosis by inducing DNA double-stranded breaks and blocking the initiation process of homologous recombination repair, which was related to the attenuation of ataxia telangiectasia mutated (ATM) activation and inhibiting the binding of phosphorylated ataxia telangiectasia mutated (pATM) and the MRE11-RAD50-NBS1 (MRN) complex. Furthermore, Iso markedly sensitized HB cells to the anti-proliferative effects of the poly ADP-ribose polymerase (PARP) inhibitor olaparib both in vivo and in vitro. Taken together, our study first showed that Iso was a DNA-damage agent, and the combination of Iso with a PARP inhibitor might be a promising strategy for treating HB patients.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29524657
[Au] Autor:Coarelli G; Romano S; Travaglini L; Ferraldeschi M; Nicita F; Spadaro M; Fornasiero A; Frontali M; Salvetti M; Bertini E; Ristori G
[Ad] Address:Assistance Publique-Hôpitaux de Paris (AP-HP) & Paris 13 University, Avicenne Hospital, Neurology Department, 93009, Bobigny, France.
[Ti] Title:Novel homozygous GBA2 mutation in a patient with complicated spastic paraplegia.
[So] Source:Clin Neurol Neurosurg;168:60-63, 2018 Mar 03.
[Is] ISSN:1872-6968
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurological disorders characterized primarily by a pyramidal syndrome with lower limb spasticity, which can manifest as pure HSP or associated with a number of neurological or non-neurological signs (i.e., complicated HSPs). The clinical variability of HSPs is associated with a wide genetic heterogeneity, with more than eighty causative genes known. Recently, next generation sequencing (NGS) has allowed increasing genetic definition in such a heterogeneous group of disorders. We report on a 56- year-old man affected by sporadic complicated HSP consisting of a pyramidal syndrome, cerebellar ataxia, congenital cataract, pes cavus, axonal sensory-motor peripheral neuropathy and cognitive decline. Brain MRI showed cerebellar atrophy and thin corpus callosum. By NGS we found a novel homozygous biallelic c.452-1G > C mutation in the b-glucosidase 2 gene (GBA2), known to be causative for autosomal recessive hereditary spastic paraplegia type 46 (SPG46). The rarity of this inherited form besides reporting on a novel mutation, expands the genetic and clinical spectrum of SPG46 related HSP.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

  3 / 45405 MEDLINE  
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[PMID]: 29471072
[Au] Autor:Cunha AF; Felippe ISA; Ferreira-Junior NC; Resstel LBM; Guimarães DAM; Beijamini V; Paton JFR; Sampaio KN
[Ad] Address:Department of Pharmaceutical Sciences, Federal University of Espírito Santo, Vitória, ES, Brazil.
[Ti] Title:Neuroreflex control of cardiovascular function is impaired after acute poisoning with chlorpyrifos, an organophosphorus insecticide: Possible short and long term clinical implications.
[So] Source:Toxicology;398-399:13-22, 2018 Feb 19.
[Is] ISSN:1879-3185
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract:Although it is well-established that severe poisoning by organophosphorus (OP) compounds strongly affects the cardiorespiratory system, the effects of sub-lethal exposure to these compounds on the neural control of cardiovascular function are poorly explored. The aim of this study was to evaluate the effects of acute sub-lethal exposure to chlorpyrifos (CPF), a commonly used OP insecticide, on three basic reflex mechanisms involved in blood pressure regulation, the peripheral chemoreflex, the baroreflex and the Bezold-Jarisch reflex. Adult male Wistar rats were injected intraperitoneally with a single dose of CPF (30 mg/kg) or saline (0.9%). 24 h after injections, cardiovascular reflexes were tested in awake rats. Potassium cyanide (KCN) and phenylbiguanide (PBG) were injected intravenously to activate the chemoreflex and the Bezold-Jarisch reflex, respectively. The baroreflex was activated by phenylephrine and sodium nitroprusside infusions. Blood samples were taken for measurements of butyrylcholinesterase (BChE) activity while acetylcholinesterase (AChE) activity was measured in brainstem samples. Animals treated with CPF presented signs of intoxication such as ataxia, tremor, lacrimation, salivation, tetany, urination and defecation. The hypertensive and the bradycardic responses of the chemoreflex as well as the hypotensive and bradycardic responses of the Bezold-Jarisch reflex were attenuated in CPF treated animals (P < 0.05). Concerning the baroreflex responses, CPF treatment reduced the bradycardia plateau, the range and the gain of the reflex (P < 0.05). Plasma BChE and brainstem AChE were both reduced significantly after CPF treatment (P < 0.05). Our results showed that acute sub-lethal exposure to CPF impairs the cardiovascular responses of homeostatic and defensive cardiovascular reflexes. These effects are associated with a marked inhibition of plasma BChE and brainstem AChE.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher

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[PMID]: 29360998
[Au] Autor:Tagge CA; Fisher AM; Minaeva OV; Gaudreau-Balderrama A; Moncaster JA; Zhang XL; Wojnarowicz MW; Casey N; Lu H; Kokiko-Cochran ON; Saman S; Ericsson M; Onos KD; Veksler R; Senatorov VV; Kondo A; Zhou XZ; Miry O; Vose LR; Gopaul KR; Upreti C; Nowinski CJ; Cantu RC; Alvarez VE; Hildebrandt AM; Franz ES; Konrad J; Hamilton JA; Hua N; Tripodis Y; Anderson AT; Howell GR; Kaufer D; Hall GF; Lu KP; Ransohoff RM; Cleveland RO; Kowall NW; Stein TD; Lamb BT; Huber BR; Moss WC; Friedman A; Stanton PK; McKee AC; Goldstein LE
[Ad] Address:Molecular Aging and Development Laboratory, Boston University School of Medicine, Boston, MA 02118, USA.
[Ti] Title:Concussion, microvascular injury, and early tauopathy in young athletes after impact head injury and an impact concussion mouse model.
[So] Source:Brain;141(2):422-458, 2018 Feb 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The mechanisms underpinning concussion, traumatic brain injury, and chronic traumatic encephalopathy, and the relationships between these disorders, are poorly understood. We examined post-mortem brains from teenage athletes in the acute-subacute period after mild closed-head impact injury and found astrocytosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. To investigate causal mechanisms, we developed a mouse model of lateral closed-head impact injury that uses momentum transfer to induce traumatic head acceleration. Unanaesthetized mice subjected to unilateral impact exhibited abrupt onset, transient course, and rapid resolution of a concussion-like syndrome characterized by altered arousal, contralateral hemiparesis, truncal ataxia, locomotor and balance impairments, and neurobehavioural deficits. Experimental impact injury was associated with axonopathy, blood-brain barrier disruption, astrocytosis, microgliosis (with activation of triggering receptor expressed on myeloid cells, TREM2), monocyte infiltration, and phosphorylated tauopathy in cerebral cortex ipsilateral and subjacent to impact. Phosphorylated tauopathy was detected in ipsilateral axons by 24 h, bilateral axons and soma by 2 weeks, and distant cortex bilaterally at 5.5 months post-injury. Impact pathologies co-localized with serum albumin extravasation in the brain that was diagnostically detectable in living mice by dynamic contrast-enhanced MRI. These pathologies were also accompanied by early, persistent, and bilateral impairment in axonal conduction velocity in the hippocampus and defective long-term potentiation of synaptic neurotransmission in the medial prefrontal cortex, brain regions distant from acute brain injury. Surprisingly, acute neurobehavioural deficits at the time of injury did not correlate with blood-brain barrier disruption, microgliosis, neuroinflammation, phosphorylated tauopathy, or electrophysiological dysfunction. Furthermore, concussion-like deficits were observed after impact injury, but not after blast exposure under experimental conditions matched for head kinematics. Computational modelling showed that impact injury generated focal point loading on the head and seven-fold greater peak shear stress in the brain compared to blast exposure. Moreover, intracerebral shear stress peaked before onset of gross head motion. By comparison, blast induced distributed force loading on the head and diffuse, lower magnitude shear stress in the brain. We conclude that force loading mechanics at the time of injury shape acute neurobehavioural responses, structural brain damage, and neuropathological sequelae triggered by neurotrauma. These results indicate that closed-head impact injuries, independent of concussive signs, can induce traumatic brain injury as well as early pathologies and functional sequelae associated with chronic traumatic encephalopathy. These results also shed light on the origins of concussion and relationship to traumatic brain injury and its aftermath.awx350media15713427811001.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1801
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx350

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[PMID]: 29236946
[Au] Autor:Minnerop M; Kurzwelly D; Rattay TW; Timmann D; Hengel H; Synofzik M; Stendel C; Horvath R; Schüle R; Ramirez A
[Ad] Address:Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, 52425 Jülich, Germany.
[Ti] Title:Reply: POLR3A variants in hereditary spastic paraplegia and ataxia.
[So] Source:Brain;141(1):e2, 2018 Jan 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx291

  6 / 45405 MEDLINE  
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[PMID]: 29228109
[Au] Autor:Gauquelin L; Tétreault M; Thiffault I; Farrow E; Miller N; Yoo B; Bareke E; Yoon G; Suchowersky O; Dupré N; Tarnopolsky M; Brais B; Wolf NI; Majewski J; Rouleau GA; Gan-Or Z; Bernard G
[Ad] Address:Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Canada.
[Ti] Title:POLR3A variants in hereditary spastic paraplegia and ataxia.
[So] Source:Brain;141(1):e1, 2018 Jan 01.
[Is] ISSN:1460-2156
[Cp] Country of publication:England
[La] Language:eng
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1712
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[St] Status:In-Data-Review
[do] DOI:10.1093/brain/awx290

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[PMID]: 28467418
[Au] Autor:Khare S; Nick JA; Zhang Y; Galeano K; Butler B; Khoshbouei H; Rayaprolu S; Hathorn T; Ranum LPW; Smithson L; Golde TE; Paucar M; Morse R; Raff M; Simon J; Nordenskjöld M; Wirdefeldt K; Rincon-Limas DE; Lewis J; Kaczmarek LK; Fernandez-Funez P; Nick HS; Waters MF
[Ad] Address:Department of Neurology, University of Florida, Gainesville, FL, United States of America.
[Ti] Title:A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking.
[So] Source:PLoS One;12(5):e0173565, 2017.
[Is] ISSN:1932-6203
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The autosomal dominant spinocerebellar ataxias (SCAs) are a diverse group of neurological disorders anchored by the phenotypes of motor incoordination and cerebellar atrophy. Disease heterogeneity is appreciated through varying comorbidities: dysarthria, dysphagia, oculomotor and/or retinal abnormalities, motor neuron pathology, epilepsy, cognitive impairment, autonomic dysfunction, and psychiatric manifestations. Our study focuses on SCA13, which is caused by several allelic variants in the voltage-gated potassium channel KCNC3 (Kv3.3). We detail the clinical phenotype of four SCA13 kindreds that confirm causation of the KCNC3R423H allele. The heralding features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia and lifetime improvement in motor and cognitive function that implicate compensatory neural mechanisms. Targeted expression of human KCNC3R423H in Drosophila triggers aberrant wing veins, maldeveloped eyes, and fused ommatidia consistent with the neurodevelopmental presentation of patients. Furthermore, human KCNC3R423H expression in mammalian cells results in altered glycosylation and aberrant retention of the channel in anterograde and/or endosomal vesicles. Confirmation of the absence of plasma membrane targeting was based on the loss of current conductance in cells expressing the mutant channel. Mechanistically, genetic studies in Drosophila, along with cellular and biophysical studies in mammalian systems, demonstrate the dominant negative effect exerted by the mutant on the wild-type (WT) protein, which explains dominant inheritance. We demonstrate that ocular co-expression of KCNC3R423H with Drosophila epidermal growth factor receptor (dEgfr) results in striking rescue of the eye phenotype, whereas KCNC3R423H expression in mammalian cells results in aberrant intracellular retention of human epidermal growth factor receptor (EGFR). Together, these results indicate that the neurodevelopmental consequences of KCNC3R423H may be mediated through indirect effects on EGFR signaling in the developing cerebellum. Our results therefore confirm the KCNC3R423H allele as causative for SCA13, through a dominant negative effect on KCNC3WT and links with EGFR that account for dominant inheritance, congenital onset, and disease pathology.
[Mh] MeSH terms primary: Receptor, Epidermal Growth Factor/metabolism
Shaw Potassium Channels/genetics
Spinocerebellar Degenerations/genetics
[Mh] MeSH terms secundary: Animals
CHO Cells
Cricetinae
Cricetulus
Drosophila melanogaster
Female
Humans
Male
Pedigree
Protein Transport
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (KCNC3 protein, human); 0 (Shaw Potassium Channels); EC 2.7.10.1 (Receptor, Epidermal Growth Factor)
[Em] Entry month:1709
[Cu] Class update date: 180311
[Lr] Last revision date:180311
[Js] Journal subset:IM
[Da] Date of entry for processing:170504
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0173565

  8 / 45405 MEDLINE  
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[PMID]: 29524103
[Au] Autor:Olszewska DA; McVeigh T; Fallon EM; Pastores GM; Lynch T
[Ad] Address:Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin, Ireland. Diana.angelika.olszewska@gmail.com.
[Ti] Title:The benefits of a Neurogenetics clinic in an adult Academic Teaching Hospital.
[So] Source:Ir J Med Sci;, 2018 Mar 09.
[Is] ISSN:1863-4362
[Cp] Country of publication:Ireland
[La] Language:eng
[Ab] Abstract:Genetics is the backbone of Neurology, where a number of disorders have a genetic aetiology and are complex, requiring a dedicated Neurogenetics clinic. Genetics in the Republic of Ireland is under-resourced, with the lowest number of consultants per million of population in Europe. In November 2014, we established the monthly adult Neurogenetics clinic in Ireland, staffed by 2 consultants and 2 registrars from each speciality. We see patients with complex rare neurological conditions that may potentially have an underlying genetic basis, in the presence or absence of a family history. We performed a retrospective cohort analysis, reviewing symptoms and work-up data. Twenty-seven patients attended a pilot clinic over 12 months. Conditions encountered included Parkin-related PD, leucodystrophy, ataxia, fronto-temporal lobar degeneration, spinocerebellar ataxia type 6 (SCA6) and ataxia-telangiectasia. Identification of pathogenic mutations directed screening, treatment and facilitated onward genetic counselling (n = 10, 33%). A number of novel mutations were identified in MAPT gene ("missing tau mutation" McCarthy et al., Brain, 2015), SLCA1 gene and GRN (progranulin). Phenotypic features not previously reported were seen; e.g. writer's cramp in SCA6; paroxysmal myoclonus in the glucose transporter protein type 1 (GLUT1) deficiency. Breast cancer screening for ATM mutations carriers and referral to international experts in two undiagnosed patients were arranged. The establishment of a Neurogenetics clinic has addressed a gap in service and allowed identification of rare and atypical diagnoses.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:Publisher
[do] DOI:10.1007/s11845-018-1784-3

  9 / 45405 MEDLINE  
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[PMID]: 29523818
[Au] Autor:Fam HK; Choi K; Fougner L; Lim CJ; Boerkoel CF
[Ad] Address:BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
[Ti] Title:Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria.
[So] Source:Sci Rep;8(1):4304, 2018 Mar 09.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a nuclear and mitochondrial protein that in nuclei and in vitro repairs blocked 3' DNA termini such as 3' phosphotyrosine conjugates resulting from stalling of topoisomerase I-DNA intermediates. Its mutation also causes spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1). Because Tdp1 colocalizes with mitochondria following oxidative stress, we hypothesized that Tdp1 repairs mitochondrial DNA (mtDNA) and that mtDNA damage mediates entry of Tdp1 into the mitochondria. To test this, we used S. cerevisiae mutants, cultured mouse and human cells, and a Tdp1 knockout mouse. H O - and rotenone-induced cellular and intramitochondrial reactive oxygen species (ROS) activated oxidant-responsive kinases P38 and ERK1, and the translocation of Tdp1 from the nucleus to the mitochondria via the TIM/TOM complex. This translocation occurred independently of mtDNA. Within the mitochondria, Tdp1 interacted with Ligase III and reduced mtDNA mutations. Tdp1-deficient tissues had impaired mitochondrial respiration and decreased viability. These observations suggest that Tdp1 maintains mtDNA integrity and support the hypothesis that mitochondrial dysfunction contributes to the pathology of SCAN1.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-22547-8

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[PMID]: 29523816
[Au] Autor:Cheron G; Márquez-Ruiz J; Cheron J; Prigogine C; Ammann C; Lukowski R; Ruth P; Dan B
[Ad] Address:Laboratory of Electrophysiology, Université de Mons, Mons, Belgium. gcheron@ulb.ac.be.
[Ti] Title:Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD.
[So] Source:Sci Rep;8(1):4220, 2018 Mar 09.
[Is] ISSN:2045-2322
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review
[do] DOI:10.1038/s41598-018-22654-6


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