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  1. Article ; Online: Motor Neuron Generation from iPSCs from Identical Twins Discordant for Amyotrophic Lateral Sclerosis.

    Seminary, Emily R / Santarriaga, Stephanie / Wheeler, Lynn / Mejaki, Marie / Abrudan, Jenica / Demos, Wendy / Zimmermann, Michael T / Urrutia, Raul A / Fee, Dominic / Barkhaus, Paul E / Ebert, Allison D

    Cells

    2020  Volume 9, Issue 3

    Abstract: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no ... ...

    Abstract Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder characterized by the loss of the upper and lower motor neurons. Approximately 10% of cases are caused by specific mutations in known genes, with the remaining cases having no known genetic link. As such, sporadic cases have been more difficult to model experimentally. Here, we describe the generation and differentiation of ALS induced pluripotent stem cells reprogrammed from discordant identical twins. Whole genome sequencing revealed no relevant mutations in known ALS-causing genes that differ between the twins. As protein aggregation is found in all ALS patients and is thought to contribute to motor neuron death, we sought to characterize the aggregation phenotype of the sporadic ALS induced pluripotent stem cells (iPSCs). Motor neurons from both twins had high levels of insoluble proteins that commonly aggregate in ALS that did not robustly change in response to exogenous glutamate. In contrast, established genetic ALS iPSC lines demonstrated insolubility in a protein- and genotype-dependent manner. Moreover, whereas the genetic ALS lines failed to induce autophagy after glutamate stress, motor neurons from both twins and independent controls did activate this protective pathway. Together, these data indicate that our unique model of sporadic ALS may provide key insights into disease pathology and highlight potential differences between sporadic and familial ALS.
    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; Autophagy ; Cell Survival ; Glutamic Acid/metabolism ; Humans ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Motor Neurons/metabolism ; Motor Neurons/pathology ; Protein Aggregates ; Solubility ; Twins, Monozygotic ; Whole Genome Sequencing
    Chemical Substances Protein Aggregates ; Glutamic Acid (3KX376GY7L)
    Language English
    Publishing date 2020-02-28
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells9030571
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Thesis ; Audio / Video: The effectiveness of directing the learner's attention to her kinesthetic feedback in learning to perform two gymnastic stunts

    Wheeler, Lynn Ellen

    1974  

    Author's details by Lynn Ellen Wheeler
    Size IX, 59 Blatt: Illustrationen
    Edition [Mikrofiche-Ausg.]
    Document type Thesis ; Audio / Video
    Thesis / German Habilitation thesis Thesis (Master of Science), Washington State University, 1974
    HBZ-ID HT016424733
    Database Central Library of Sport Science of the German Sport University Cologne

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  3. Article ; Online: Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

    Frank, Samuel / Testa, Claudia M / Stamler, David / Kayson, Elise / Davis, Charles / Edmondson, Mary C / Kinel, Shari / Leavitt, Blair / Oakes, David / O'Neill, Christine / Vaughan, Christina / Goldstein, Jody / Herzog, Margaret / Snively, Victoria / Whaley, Jacquelyn / Wong, Cynthia / Suter, Greg / Jankovic, Joseph / Jimenez-Shahed, Joohi /
    Hunter, Christine / Claassen, Daniel O / Roman, Olivia C / Sung, Victor / Smith, Jenna / Janicki, Sarah / Clouse, Ronda / Saint-Hilaire, Marie / Hohler, Anna / Turpin, Denyse / James, Raymond C / Rodriguez, Ramon / Rizer, Kyle / Anderson, Karen E / Heller, Hope / Carlson, Alexis / Criswell, Susan / Racette, Brad A / Revilla, Fredy J / Nucifora, Frederick / Margolis, Russell L / Ong, MaryJane / Mendis, Tilak / Mendis, Neila / Singer, Carlos / Quesada, Monica / Paulsen, Jane S / Brashers-Krug, Thomas / Miller, Amanda / Kerr, Jane / Dubinsky, Richard M / Gray, Carolyn / Factor, Stewart A / Sperin, Elaine / Molho, Eric / Eglow, Mary / Evans, Sharon / Kumar, Rajeev / Reeves, Christina / Samii, Ali / Chouinard, Sylvain / Beland, Monica / Scott, Burton L / Hickey, Patrick T / Esmail, Sherali / Fung, Wai Lun Alan / Gibbons, Clare / Qi, Lina / Colcher, Amy / Hackmyer, Cory / McGarry, Andrew / Klos, Kevin / Gudesblatt, Mark / Fafard, Lori / Graffitti, Laura / Schneider, Daniel P / Dhall, Rohit / Wojcieszek, Joanne M / LaFaver, Kathrin / Duker, Andrew / Neefus, Erin / Wilson-Perez, Hilary / Shprecher, David / Wall, Paola / Blindauer, Karen A / Wheeler, Lynn / Boyd, James T / Houston, Emily / Farbman, Eric S / Agarwal, Pinky / Eberly, Shirley W / Watts, Arthur / Tariot, Pierre N / Feigin, Andrew / Evans, Scott / Beck, Chris / Orme, Constance / Edicola, Jon / Christopher, Emily

    JAMA

    2017  Volume 316, Issue 1, Page(s) 40–50

    Abstract: Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.: ... ...

    Abstract Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.
    Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.
    Design, setting, and participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.
    Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.
    Main outcomes and measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test.
    Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia.
    Conclusions and relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.
    Trial registration: clinicaltrials.gov Identifier: NCT01795859.
    MeSH term(s) Adrenergic Uptake Inhibitors/therapeutic use ; Chorea/drug therapy ; Cytochrome P-450 CYP2D6/metabolism ; Double-Blind Method ; Drug Administration Schedule ; Female ; Humans ; Huntington Disease/drug therapy ; Maintenance Chemotherapy/methods ; Male ; Middle Aged ; Tetrabenazine/analogs & derivatives ; Tetrabenazine/therapeutic use ; Treatment Outcome
    Chemical Substances Adrenergic Uptake Inhibitors ; Cytochrome P-450 CYP2D6 (EC 1.14.14.1) ; deutetrabenazine (P341G6W9NB) ; Tetrabenazine (Z9O08YRN8O)
    Language English
    Publishing date 2017-02-12
    Publishing country United States
    Document type Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2958-0
    ISSN 1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
    ISSN (online) 1538-3598
    ISSN 0254-9077 ; 0002-9955 ; 0098-7484
    DOI 10.1001/jama.2016.8655
    Database MEDical Literature Analysis and Retrieval System OnLINE

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