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https://www.readbyqxmd.com/read/29221425/riluzole-does-not-improve-lifespan-or-motor-function-in-three-als-mouse-models
#1
Marion C Hogg, Luise Halang, Ina Woods, Karen S Coughlan, Jochen H M Prehn
BACKGROUND: Riluzole is the most widespread therapeutic for treatment of the progressive degenerative disease amyotrophic lateral sclerosis (ALS). Riluzole gained FDA approval in 1995 before the development of ALS mouse models. We assessed riluzole in three transgenic ALS mouse models: the SOD1G93A model, the TDP-43A315T model, and the recently developed FUS (1-359) model. METHODS: Age, sex and litter-matched mice were treated with riluzole (22 mg/kg) in drinking water or vehicle (DMSO) from symptom onset...
December 8, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/29217859/efficacy-of-transdermal-buprenorphine-patch-on-post-operative-pain-relief-after-elective-spinal-instrumentation-surgery
#2
Saikat Niyogi, Pratibha Bhunia, Jisnu Nayak, Sankari Santra, Amita Acharjee, Indrani Chakraborty
Background and Aims: Transdermal buprenorphine patch (TDB) is increasingly used for chronic pain management because of non-invasive dosing, longer duration of action and minimal side effects. However its role in acute post-operative pain management for spinal instrumentation surgery is not well established. The aim of this study was to evaluate the analgesic efficacy of buprenorphine patch for postoperative pain relief in patients undergoing spinal instrumentation surgery. Methods: In this randomised, placebo-controlled, double-blinded, prospective study, 70 adult patients undergoing elective spinal instrumentation surgery were randomly allocated into two groups-TDB Group (buprenorphinepatch) and TDP Group (placebo patch)...
November 2017: Indian Journal of Anaesthesia
https://www.readbyqxmd.com/read/29216908/clinical-and-neuropathological-features-of-als-ftd-with-tia1-mutations
#3
Veronica Hirsch-Reinshagen, Cyril Pottier, Alexandra M Nicholson, Matt Baker, Ging-Yuek R Hsiung, Charles Krieger, Pheth Sengdy, Kevin B Boylan, Dennis W Dickson, Marsel Mesulam, Sandra Weintraub, Eileen Bigio, Lorne Zinman, Julia Keith, Ekaterina Rogaeva, Sasha A Zivkovic, David Lacomis, J Paul Taylor, Rosa Rademakers, Ian R A Mackenzie
Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years)...
December 7, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/29216365/tyrosyl-dna-phosphodiesterases-rescuing-the-genome-from-the-risks-of-relaxation
#4
Ajinkya S Kawale, Lawrence F Povirk
Tyrosyl-DNA Phosphodiesterases 1 (TDP1) and 2 (TDP2) are eukaryotic enzymes that clean-up after aberrant topoisomerase activity. While TDP1 hydrolyzes phosphotyrosyl peptides emanating from trapped topoisomerase I (Top I) from the 3' DNA ends, topoisomerase 2 (Top II)-induced 5'-phosphotyrosyl residues are processed by TDP2. Even though the canonical functions of TDP1 and TDP2 are complementary, they exhibit little structural or sequence similarity. Homozygous mutations in genes encoding these enzymes lead to the development of severe neurodegenerative conditions due to the accumulation of transcription-dependent topoisomerase cleavage complexes underscoring the biological significance of these enzymes in the repair of topoisomerase-DNA lesions in the nervous system...
December 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29215728/multiple-neuronal-pathologies-are-common-in-young-patients-with-pathologically-proven-frontotemporal-lobar-degeneration
#5
Rachel H Tan, Yue Yang, Glenda M Halliday
AIMS: The past decade has seen a surge in studies identifying mixed pathologies in elderly populations. Importantly however, few studies have focussed on mixed pathology in Frontotemporal Lobar Degeneration (FTLD), particularly in younger cases. METHODS: The present study study examined concomitant pathological neuronal inclusions of TDP-43, hyperphosphorylated tau and α-synuclein protein in the anterior cingulate, hippocampus and entorhinal cortex in young (≤65 years at death) versus elderly (≥80 years at death) cases with pathologically-confirmed FTLD (n=52) or Alzheimer's disease (AD) (n=47)...
December 7, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29213521/distinct-phospho-tdp-43-brain-distribution-in-two-cases-of-ftd-one-associated-with-als
#6
Álvaro C B Guedes, Ricardo Santin, André S R Costa, Keli C Reiter, Arlete Hilbig, Liana L Fernandez
INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD)...
July 2017: Dementia & Neuropsychologia
https://www.readbyqxmd.com/read/29213490/neuropathological-findings-in-entorhinal-cortex-of-subjects-aged-50-years-or-older-and-their-correlation-with-dementia-in-a-sample-from-southern-brazil
#7
Edson Rodrigues Neto, Mariana K Fonseca, Álvaro C B Guedes, Francine H Oliveira, Arlete Hilbig, Liana Lisboa Fernandez
Introduction: The aims of this study were to survey neurodegenerative changes detected by abnormal protein deposits in the Entorhinal Cortex (EC) of subjects aged 50 years or older and to correlate these findings with suspected dementia, as detected by the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly). Methods: Fourteen brains were submitted to the immunohistochemistry technique for different proteins (beta-amyloid, tau, α-synuclein and phospho-TDP-43) and data obtained compared with IQCODE scores...
January 2017: Dementia & Neuropsychologia
https://www.readbyqxmd.com/read/29209226/uncertainty-quantification-reveals-the-importance-of-data-variability-and-experimental-design-considerations-for-in-silico-proarrhythmia-risk-assessment
#8
Kelly C Chang, Sara Dutta, Gary R Mirams, Kylie A Beattie, Jiansong Sheng, Phu N Tran, Min Wu, Wendy W Wu, Thomas Colatsky, David G Strauss, Zhihua Li
The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a global initiative intended to improve drug proarrhythmia risk assessment using a new paradigm of mechanistic assays. Under the CiPA paradigm, the relative risk of drug-induced Torsade de Pointes (TdP) is assessed using an in silico model of the human ventricular action potential (AP) that integrates in vitro pharmacology data from multiple ion channels. Thus, modeling predictions of cardiac risk liability will depend critically on the variability in pharmacology data, and uncertainty quantification (UQ) must comprise an essential component of the in silico assay...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29203801/de-novo-design-of-rna-binding-proteins-with-a-prion-like-domain-related-to-als-ftd-proteinopathies
#9
Kana Mitsuhashi, Daisuke Ito, Kyoko Mashima, Munenori Oyama, Shinichi Takahashi, Norihiro Suzuki
Aberrant RNA-binding proteins form the core of the neurodegeneration cascade in spectrums of disease, such as amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Six ALS-related molecules, TDP-43, FUS, TAF15, EWSR1, heterogeneous nuclear (hn)RNPA1 and hnRNPA2 are RNA-binding proteins containing candidate mutations identified in ALS patients and those share several common features, including harboring an aggregation-prone prion-like domain (PrLD) containing a glycine/serine-tyrosine-glycine/serine (G/S-Y-G/S)-motif-enriched low-complexity sequence and rich in glutamine and/or asparagine...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29201009/in-vitro-and-in-silico-risk-assessment-in-acquired-long-qt-syndrome-the-devil-is-in-the-details
#10
REVIEW
William Lee, Monique J Windley, Jamie I Vandenberg, Adam P Hill
Acquired long QT syndrome, mostly as a result of drug block of the Kv11. 1 potassium channel in the heart, is characterized by delayed cardiac myocyte repolarization, prolongation of the T interval on the ECG, syncope and sudden cardiac death due to the polymorphic ventricular arrhythmia Torsade de Pointes (TdP). In recent years, efforts are underway through the Comprehensive in vitro proarrhythmic assay (CiPA) initiative, to develop better tests for this drug induced arrhythmia based in part on in silico simulations of pharmacological disruption of repolarization...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/29197146/is-myocardial-repolarization-duration-associated-with-repolarization-heterogeneity
#11
Keith A Marill, Pat Dorsey, Anthony Holmes, Ketaki Muthal, Emily S Miller, Joel Xue
BACKGROUND: Dispersion of repolarization is theorized as one mechanism by which myocardial repolarization prolongation causes lethal torsades de pointes, (TdP). Our primary purpose was to determine whether prolongation of myocardial repolarization as measured by the heart rate-corrected J-to-T peak interval (JTpkc), is associated with repolarization heterogeneity as measured by transmural dispersion, defined as the median duration from the peak to the end of the T wave (TpTe). METHODS: A retrospective cohort study was performed at a single urban tertiary ED from July 2011-September 2012...
December 2, 2017: Annals of Noninvasive Electrocardiology
https://www.readbyqxmd.com/read/29196813/sense-encoded-poly-gr-dipeptide-repeat-proteins-correlate-to-neurodegeneration-and-uniquely-co-localize-with-tdp-43-in-dendrites-of-repeat-expanded-c9orf72-amyotrophic-lateral-sclerosis
#12
Shahram Saberi, Jennifer E Stauffer, Jie Jiang, Sandra Diaz Garcia, Amy E Taylor, Derek Schulte, Takuya Ohkubo, Cheyenne L Schloffman, Marcus Maldonado, Michael Baughn, Maria J Rodriguez, Don Pizzo, Don Cleveland, John Ravits
Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models...
December 1, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/29192591/torsades-de-pointes-associated-with-qt-prolongation-after-catheter-ablation-of-paroxysmal-atrial-fibrillation
#13
Yae Min Park, Mi Suk Cha, Woong Chol Kang, Mi-Seung Shin, Young-Hoon Kim, In Suck Choi, Eak Kyun Shin
A 79-year-old woman who underwent catheter ablation for paroxysmal atrial fibrillation presented with Torsades de Pointes (TdP). Aggravation of prolonged QT interval which is most likely due to neural modulation by catheter ablation, played major role in the initiation of TdP. The patient was successfully treated with isoproterenol during acute stage and discharged after stabilization without implantation of permanent pacemaker or implantable cardioverter defibrillator.
September 2017: Indian Pacing and Electrophysiology Journal
https://www.readbyqxmd.com/read/29191947/a-proteomic-network-approach-across-the-als-ftd-disease-spectrum-resolves-clinical-phenotypes-and-genetic-vulnerability-in-human-brain
#14
Mfon E Umoh, Eric B Dammer, Jingting Dai, Duc M Duong, James J Lah, Allan I Levey, Marla Gearing, Jonathan D Glass, Nicholas T Seyfried
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlap in clinical presentation, neuropathology, and genetic underpinnings. The molecular basis for the overlap of these disorders is not well established. We performed a comparative unbiased mass spectrometry-based proteomic analysis of frontal cortical tissues from postmortem cases clinically defined as ALS, FTD, ALS and FTD (ALS/FTD), and controls. We also included a subset of patients with the C9orf72 expansion mutation, the most common genetic cause of both ALS and FTD Our systems-level analysis of the brain proteome integrated both differential expression and co-expression approaches to assess the relationship of these differences to clinical and pathological phenotypes...
November 30, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/29191244/frequency-characteristics-and-risk-factors-of-qt-interval-prolonging-drugs-and-drug-drug-interactions-in-cancer-patients-a-multicenter-study
#15
Qasim Khan, Mohammad Ismail, Sehrash Khan
BACKGROUND: Cancer patients may receive a high number of medications with the potential to prolong QT interval and subsequent TdP (torsades de pointes). This study aimed to identify the prevalence of QT prolonging drugs, their TdP risk, QT prolonging drug-drug interactions (QT-DDIs), levels, predictors, and TdP risk of drugs involved in QT-DDIs. METHODS: This multicenter study included cancer patients from three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan...
December 1, 2017: BMC Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29186589/detergent-insoluble-proteins-and-inclusion-body-like-structures-immunoreactive-for-prkdc-dna-pk-dna-pkcs-ftl-nnt-and-aifm1-in-the-amygdala-of-cognitively-impaired-elderly-persons
#16
Jozsef Gal, Jing Chen, Yuriko Katsumata, David W Fardo, Wang-Xia Wang, Sergey Artiushin, Douglas Price, Sonya Anderson, Ela Patel, Haining Zhu, Peter T Nelson
Misfolded protein in the amygdala is a neuropathologic feature of Alzheimer disease and many other neurodegenerative disorders. We examined extracts from human amygdala (snap-frozen at autopsy) to investigate whether novel and as yet uncharacterized misfolded proteins would be detectable. Polypeptides from the detergent-insoluble, urea-soluble protein fractions of amygdala were interrogated using liquid chromatography-electrospray ionization-tandem mass spectrometry. Among the detergent-insoluble proteins identified in amygdala of demented subjects but not controls were Tau, TDP-43, Aβ, α-synuclein, and ApoE...
November 24, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29186501/the-amygdala-as-a-locus-of-pathologic-misfolding-in-neurodegenerative-diseases
#17
Peter T Nelson, Erin L Abner, Ela Patel, Sonya Anderson, Donna M Wilcock, Richard J Kryscio, Linda J Van Eldik, Gregory A Jicha, Zsombor Gal, Ruth S Nelson, Bela G Nelson, Jozsef Gal, Md Tofial Azam, David W Fardo, Matthew D Cykowski
Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases...
November 22, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29186496/anterior-cingulate-cortex-tdp-43-pathology-in-sporadic-amyotrophic-lateral-sclerosis
#18
Heiko Braak, Kelly Del Tredici
Neuronal constituents of the human anterior cingulate cortex displayed morphological changes related to the 43-kDa transactive response DNA-binding protein (TDP-43) in advanced pathological stages of sporadic amyotrophic lateral sclerosis (sALS). By using nonphosphorylation-dependent TDP-43 immunocytochemistry, it was seen that the changes in susceptible pyramidal cells of the superficial cellular layers II-IIIab differed from those in the deep layers IIIc-Vb: A complete loss of nuclear TDP-43 expression (i...
November 27, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/29184569/the-seed-repair-response-during-germination-disclosing-correlations-between-dna-repair-antioxidant-response-and-chromatin-remodeling-in-medicago-truncatula
#19
Andrea Pagano, Susana de Sousa Araújo, Anca Macovei, Paola Leonetti, Alma Balestrazzi
This work provides novel insights into the effects caused by the histone deacetylase inhibitor trichostatin A (TSA) during Medicago truncatula seed germination, with emphasis on the seed repair response. Seeds treated with H2O and TSA (10 and 20 μM) were collected during imbibition (8 h) and at the radicle protrusion phase. Biometric data showed delayed germination and impaired seedling growth in TSA-treated samples. Comet assay, performed on radicles at the protrusion phase and 4-days old M. truncatula seedlings, revealed accumulation of DNA strand breaks upon exposure to TSA...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/29184497/novel-two-step-classifier-for-torsades-de-pointes-risk-stratification-from-direct-features
#20
Jaimit Parikh, Viatcheslav Gurev, John J Rice
While pre-clinical Torsades de Pointes (TdP) risk classifiers had initially been based on drug-induced block of hERG potassium channels, it is now well established that improved risk prediction can be achieved by considering block of non-hERG ion channels. The current multi-channel TdP classifiers can be categorized into two classes. First, the classifiers that take as input the values of drug-induced block of ion channels (direct features). Second, the classifiers that are built on features extracted from output of the drug-induced multi-channel blockage simulations in the in-silico models (derived features)...
2017: Frontiers in Pharmacology
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