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Bjarke Jensen, Bastiaan Jd Boukens, Dane A Crossley, Justin Conner, Rajiv Ahmet Mohan, Karel van Duijvenboden, Alex V Postma, Christopher R Gloschat, Ruth M Elsey, David Sedmera, Igor R Efimov, Vincent M Christoffels
Mammals and birds have a specialized cardiac atrioventricular conduction system enabling rapid activation of both ventricles. This system may have evolved together with high heart rates to support their endothermic state (warm-bloodedness), and is seemingly lacking in ectothermic vertebrates from which first mammals then birds independently evolved. Here, we studied the conduction system in crocodiles ( Alligator mississippiensis ), the only ectothermic vertebrates with a full ventricular septum. We identified homologues of mammalian conduction system markers ( Tbx3-Tbx5, Scn5a, Gja5, Nppa-Nppb ) and show the presence of a functional atrioventricular bundle...
March 22, 2018: ELife
Daniel R Scoles, Stefan M Pulst
Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2...
March 21, 2018: RNA Biology
David D Bushart, Ravi Chopra, Vikrant Singh, Geoffrey G Murphy, Heike Wulff, Vikram G Shakkottai
Objective: Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice. Methods: Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice...
March 2018: Annals of Clinical and Translational Neurology
Asmah Hamid, Farah Wahida Ibrahim, Teoh Hooi Ming, Mohd Nazir Nasrom, Norelina Eusoff, Khairana Husain, Mazlyzam Abdul Latif
BACKGROUND: Zingiber zerumbet (L.) Smith belongs to the Zingiberaceae family that is widely distributed throughout the tropics, particularly in Southeast Asia. It is locally known as 'Lempoyang' and traditionally used to treat fever, constipation and to relieve pain. It is also known to possess antioxidant and anti-inflammatory activities. Based on these antioxidant and anti-inflammatory activities, this study was conducted to investigate the effects of ethyl-acetate extract of Z. zerumbet rhizomes against ethanol-induced brain damage in male Wistar rats...
March 20, 2018: BMC Complementary and Alternative Medicine
Magdalena Mazurak, Jacek Kusa
December 2017 was the 230th anniversary of Jan Evangelista Purkinje's birth, which prompted us to review the life of this remarkable man who established the world's first department of physiology in Wroclaw and whose name is immortalized in the cardiologic eponym, Purkinje fibers. This paper offers an overview of Purkinje's life, legacy, and numerous scientific discoveries.
February 2018: Texas Heart Institute Journal
Jonathan P Cranford, Thomas J O'Hara, Christopher T Villongco, Omar M Hafez, Robert C Blake, Joseph Loscalzo, Jean-Luc Fattebert, David F Richards, Xiaohua Zhang, James N Glosli, Andrew D McCulloch, David E Krummen, Felice C Lightstone, Sergio E Wong
Patient-specific models of the ventricular myocardium, combined with the computational power to run rapid simulations, are approaching the level where they could be used for personalized cardiovascular medicine. A major remaining challenge is determining model parameters from available patient data, especially for models of the Purkinje-myocardial junctions (PMJs): the sites of initial ventricular electrical activation. There are no non-invasive methods for localizing PMJs in patients, and the relationship between the standard clinical ECG and PMJ model parameters is underexplored...
March 16, 2018: Cardiovascular Engineering and Technology
Martha L Streng, Laurentiu S Popa, Timothy J Ebner
It is hypothesized that the cerebellum implements a forward internal model that transforms motor commands into predictions about upcoming movements. The predictions are compared with sensory feedback to generate sensory prediction errors critical to controlling movements. The simple spike firing of cerebellar Purkinje cells both lead and lag movement consistent with representations of motor predictions and sensory feedback. This study tests whether this leading and lagging modulation provides the prediction and sensory feedback necessary to compute sensory prediction errors...
March 15, 2018: Nature Communications
Kevin C Kemp, Rimi Dey, Johan Verhagen, Neil J Scolding, Maria M Usowicz, Alastair Wilkins
Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative...
March 14, 2018: Acta Neuropathologica
Kevin C Kemp, Kelly Hares, Juliana Redondo, Amelia J Cook, Harry R Haynes, Bronwen R Burton, Mark A Pook, Claire M Rice, Neil J Scolding, Alastair Wilkins
OBJECTIVES: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here we report the neuro-reparative effects of myeloablative allogeneic bone marrow transplantation in a humanised murine model of the disease. METHODS: Mice received a transplant of fluorescently-tagged sex mis-matched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioural motor performance tests...
March 13, 2018: Annals of Neurology
Chandrakanth Reddy Edamakanti, Jeehaeh Do, Alessandro Didonna, Marco Martina, Puneet Opal
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the protein ATXN1, which is involved in transcriptional regulation. Although symptoms appear relatively late in life, primarily from cerebellar dysfunction, pathogenesis begins early, with brain-wide transcriptional changes detectable as early as a week after birth in SCA1 knock-in mice. Given the importance of this postnatal period for cerebellar development, we asked whether this region might be developmentally altered by mutant ATXN1...
March 13, 2018: Journal of Clinical Investigation
Doreen Huppert, Thomas Brandt
Seasickness, fear of heights, and adverse effects of alcohol were the major areas where descriptions of vertigo and dizziness were found in Roman, Greek, and Chinese texts from about 730 BC-600 AD. A few detailed accounts were suggestive of specific vestibular disorders such as Menière's attacks (Huangdi Neijing, the Yellow Thearch's Classic of Internal Medicine) or vestibular migraine (Aretaeus of Cappadocia). Further, the etymological and metaphorical meanings of the terms and their symptoms provide fascinating historical insights, e...
March 12, 2018: Journal of Neurology
Maxime W C Rousseaux, Tyler Tschumperlin, Hsiang-Chih Lu, Elizabeth P Lackey, Vitaliy V Bondar, Ying-Wooi Wan, Qiumin Tan, Carolyn J Adamski, Jillian Friedrich, Kirk Twaroski, Weili Chen, Jakub Tolar, Christine Henzler, Ajay Sharma, Aleksandar Bajić, Tao Lin, Lisa Duvick, Zhandong Liu, Roy V Sillitoe, Huda Y Zoghbi, Harry T Orr
Polyglutamine (polyQ) diseases are caused by expansion of translated CAG repeats in distinct genes leading to altered protein function. In spinocerebellar ataxia type 1 (SCA1), a gain of function of polyQ-expanded ataxin-1 (ATXN1) contributes to cerebellar pathology. The extent to which cerebellar toxicity depends on its cognate partner capicua (CIC), versus other interactors, remains unclear. It is also not established whether loss of the ATXN1-CIC complex in the cerebellum contributes to disease pathogenesis...
March 7, 2018: Neuron
Hirokazu Hirai, Masanobu Kano
Neurodegenerative diseases such as spinocerebellar ataxias and autoantibody-associated disorders of the central nervous system often affect the cerebellum, resulting in motor deficits. Recent studies have revealed that most of these disorders impair type 1 metabotropic glutamate receptor (mGluR1) and/or the closely associated signaling molecules in cerebellar Purkinje cell. Since the signaling pathway triggered by mGluR1 activation in Purkinje cell plays a pivotal role in coordinated movements and motor learning, pharmacological repair of aberrant mGluR1 signaling in Purkinje cell is critical for mitigation of cerebellar symptoms...
March 8, 2018: Current Opinion in Pharmacology
Guy Cheron, Javier Márquez-Ruiz, Julian Cheron, Cynthia Prigogine, Claudia Ammann, Robert Lukowski, Peter Ruth, Bernard Dan
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...
March 9, 2018: Scientific Reports
Walaa M El-Hady, Azza A A Galal
The neurological effects of manganese (Mn) exposure on adults consuming contaminated water remain unclear. Accordingly, the current experiment was planned to explore the neurotoxic consequences of subchronic Mn exposure via contaminated water and to examine whether ebselen (Ebs) improved these outcomes. Rats exposed to oral MnCl2 (50 mg/kg body weight) for 30 successive days exhibited reduced rearing and ambulation. Furthermore, Mn administration increased brain Mn concentrations and induced superoxide dismutase, catalase, and glutathione depletion...
March 7, 2018: Biological Trace Element Research
Prabhpreet Singh, Amit Noheria
Invasive electrophysiology (EP) mapping and catheter ablation has increasingly become the standard of care for many cardiac arrhythmias like supraventricular tachycardias, atrial fibrillation, premature ventricular complexes (PVC), and monomorphic ventricular tachycardia. In this review, we discuss the recent progress made in the mapping and ablation of ventricular fibrillation (VF). Ventricular activation during VF is apparently disorganized, making mapping and interpretation difficult. Prolonged mapping during VF would require mechanical circulatory support as VF causes complete hemodynamic collapse...
March 6, 2018: Current Treatment Options in Cardiovascular Medicine
Perry M Elliott
No abstract text is available yet for this article.
April 15, 2018: International Journal of Cardiology
Kirstine Calloe, Anders K Broendberg, Alex H Christensen, Lisbeth N Pedersen, Morten S Olesen, Maria de Los Angeles Tejada, Soren Friis, Morten B Thomsen, Henning Bundgaard, Henrik K Jensen
BACKGROUND: SCN5A mutations can lead to different cardiac diseases. Recently, SCN5A mutations have been linked to the clinical entity multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by ventricular ectopy and dilated cardiomyopathy. METHODS & RESULTS: A family with a uniform MEPPC-like phenotype, associated with complex atrial and ventricular arrhythmias and dilated cardiomyopathy caused by a high frequency of ventricular ectopy was clinically assessed...
April 15, 2018: International Journal of Cardiology
Md Suhail Alam, Bruce Cooper, Joseph D Farris, Kasturi Haldar
Histone deacetylase (HDAC) inhibitors are of significant interest as drugs. However, their use to treat neurological disorders has raised concern because HDACs are required for brain function. We have previously shown that a triple combination formulation (TCF) of the pan HDACi vorinostat (Vo), 2-hydroxypropyl-beta-cyclodextrin (HPBCD) and polyethylene glycol (PEG) 400 improves pharmacokinetic exposure and entry of Vo into the brain. TCF treatment significantly delayed both neurodegeneration and death in the Npc1nmf164 murine model of Niemann-Pick Type C (NPC) disease...
March 1, 2018: Scientific Reports
Stephanie Zur Nedden, Rafaela Eith, Christoph Schwarzer, Lucia Zanetti, Hartwig Seitter, Friedrich Fresser, Alexandra Koschak, Angus Jm Cameron, Peter J Parker, Gottfried Baier, Gabriele Baier-Bitterlich
Increasing evidence suggests that synapse dysfunctions are a major determinant of several neurodevelopmental and neurodegenerative diseases. Here we identify protein kinase N1 (PKN1) as a novel key player in fine-tuning the balance between axonal outgrowth and presynaptic differentiation in the parallel fiber (PF)-forming cerebellar granule cells (Cgc). Postnatal Pkn1-/- animals showed a defective PF-Purkinje cell (PC) synapse formation. In vitro, Pkn1-/- Cgc exhibited deregulated axonal outgrowth, elevated AKT phosphorylation and higher levels of neuronal differentiation-2 (NeuroD2), a transcription factor preventing presynaptic maturation...
March 1, 2018: Journal of Clinical Investigation
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