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Alan D Marmorstein, Adiv A Johnson, Lori A Bachman, Cynthia Andrews-Pfannkoch, Travis Knudsen, Benjamin J Gilles, Matthew Hill, Jarel K Gandhi, Lihua Y Marmorstein, Jose S Pulido
Autosomal recessive bestrophinopathy (ARB) is caused by mutations in the gene BEST1 which encodes bestrophin 1 (Best1), an anion channel expressed in retinal pigment epithelial (RPE) cells. It has been hypothesized that ARB represents the human null phenotype for BEST1 and that this occurs due to nonsense mediated decay (NMD). To test this hypothesis, we generated induced pluripotent stem cells (iPSCs) from a patient with ARB and her parents. After differentiation to retinal pigment epithelial (iPSC-RPE) cells, both BEST1 mRNA and Best1 protein expression were compared to controls...
March 14, 2018: Scientific Reports
Thomas D Baird, Ken Chih-Chien Cheng, Yu-Chi Chen, Eugen Buehler, Scott E Martin, James Inglese, J Robert Hogg
The nonsense-mediated mRNA decay (NMD) pathway detects aberrant transcripts containing premature termination codons (PTCs) and regulates expression of 5-10% of non-aberrant human mRNAs. To date, most proteins involved in NMD have been identified by genetic screens in model organisms; however, the increased complexity of gene expression regulation in human cells suggests that additional proteins may participate in the human NMD pathway. To identify proteins required for NMD, we performed a genome-wide RNAi screen against >21,000 genes...
March 12, 2018: ELife
Takashi Komatsu, Fusanori Kunugita, Mahito Ozawa, Yoshihiro Satoh, Reisuke Yoshizawa, Shingen Owada, Youhei Sawa, Yoshihiro Morino, Motoyuki Nakamura
Background and methods There is little information concerning the influence of the heart rhythm on the vascular endothelial function in patients with non-valvular atrial fibrillation (AF) compared with studies concerning sinus rhythm (SR). The present study included paroxysmal (n=184) or chronic (n=53) AF patients without heart failure and control subjects with SR (n=79) matched for age, gender and the CHA2 DS2 -VASc score. Paroxysmal AF was defined as episodes that terminated spontaneously within 7 days, while chronic AF was defined as longstanding AF that was refractory to cardioversion for 12 months or longer...
March 9, 2018: Internal Medicine
Aleksander Siniarski, Maciej Haberka, Magdalena Mostowik, Renata Gołębiowska-Wiatrak, Małgorzata Poręba, Krzysztof Piotr Malinowski, Zbigniew Gąsior, Ewa Konduracka, Jadwiga Nessler, Grzegorz Gajos
BACKGROUND AND AIMS: Numerous recent studies conducted in different clinical settings have focused on the benefits of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in the prevention of cardiovascular diseases. There is limited evidence that patients with type 2 diabetes (T2D) and very high cardiovascular risk can also benefit from a high dose of n-3PUFAs, especially those on optimal medical therapy as recommended by the guidelines. The aim of the present study was to assess the impact of high-dose n-3 PUFA treatment on endothelial function in patients with T2D and established atherosclerotic cardiovascular disease (ASCVD)...
March 2, 2018: Atherosclerosis
Andrew D Nguyen, Thi A Nguyen, Jiasheng Zhang, Swathi Devireddy, Ping Zhou, Anna M Karydas, Xialian Xu, Bruce L Miller, Frank Rigo, Shawn M Ferguson, Eric J Huang, Tobias C Walther, Robert V Farese
Frontotemporal dementia (FTD) is the most common neurodegenerative disorder in individuals under age 60 and has no treatment or cure. Because many cases of FTD result from GRN nonsense mutations, an animal model for this type of mutation is highly desirable for understanding pathogenesis and testing therapies. Here, we generated and characterized Grn R493X knockin mice, which model the most common human GRN mutation, a premature stop codon at arginine 493 (R493X). Homozygous Grn R493X mice have markedly reduced Grn mRNA levels, lack detectable progranulin protein, and phenocopy Grn knockout mice, with CNS microgliosis, cytoplasmic TDP-43 accumulation, reduced synaptic density, lipofuscinosis, hyperinflammatory macrophages, excessive grooming behavior, and reduced survival...
March 6, 2018: Proceedings of the National Academy of Sciences of the United States of America
Michelle Chatwin, Michel Toussaint, Miguel R Gonçalves, Nicole Sheers, Uwe Mellies, Jesus Gonzales-Bermejo, Jesus Sancho, Brigitte Fauroux, Tiina Andersen, Brit Hov, Malin Nygren-Bonnier, Matthieu Lacombe, Kurt Pernet, Mike Kampelmacher, Christian Devaux, Kathy Kinnett, Daniel Sheehan, Fabrizio Rao, Marcello Villanova, David Berlowitz, Brenda M Morrow
This is a unique state of the art review written by a group of 21 international recognized experts in the field that gathered during a meeting organized by the European Neuromuscular Centre (ENMC) in Naarden, March 2017. It systematically reports the entire evidence base for airway clearance techniques (ACTs) in both adults and children with neuromuscular disorders (NMD). We not only report randomised controlled trials, which in other systematic reviews conclude that there is a lack of evidence base to give an opinion, but also include case series and retrospective reviews of practice...
March 2018: Respiratory Medicine
Nur Hidayah Jamar, Paraskevi Kritsiligkou, Chris M Grant
Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways...
March 1, 2018: Scientific Reports
Luka Jeraj, Ana Spirkoska, Mateja Kaja Ježovnik, Pavel Poredoš
BACKGROUND: Deep vein thrombosis (DVT) affects more than one out of 1,000 people every year, of which 50 % develop post-thrombotic syndrome (PTS). Studies indicated that patients with DVT have deteriorated arterial wall function, while less is known about the association with PTS. We therefore investigated this relationship further. PATIENTS AND METHODS: A total of 120 patients treated for DVT of the lower extremity and a control group of 40 subjects without DVT were included...
February 27, 2018: VASA. Zeitschrift Für Gefässkrankheiten
Maaike van Putten, Annemieke Aartsma-Rus, Miranda D Grounds, Joe N Kornegay, Anna Mayhew, Thomas H Gillingwater, Shin'ichi Takeda, Markus A Rüegg, Annamaria De Luca, Kanneboyina Nagaraju, Raffaella Willmann
A workshop took place in 2015 to follow up TREAT-NMD activities dedicated to improving quality in the preclinical phase of drug development for neuromuscular diseases. In particular, this workshop adressed necessary future steps regarding common standard experimental protocols and the issue of improving the translatability of preclinical efficacy studies.
2018: Journal of Neuromuscular Diseases
George J Francis, Amy E Cook, Donald W Morrish, K Ming Chan, Hernish J Acharya
Many neuromuscular diseases (NMD) result in muscle weakness, immobility and greater fracture risk. The objective of this study is to determine the fracture risk of adult patients at a multidisciplinary NMD clinic. Fracture risk was calculated using the Fracture Risk Assessment Tool, the presence of osteoporosis was quantified using bone densitometry and contributing co-morbidities were screened through serum markers. Of the 36 patients studied, 47% were found to be of moderate and high fracture risk. Two thirds of these patients had not been previously screened or treated for osteoporosis...
2018: Journal of Neuromuscular Diseases
Marwa Ajmi, Asma Omezzine, Slim Achour, Dorra Amor, Haithem Hamdouni, Fatma Ben Fredj Ismaïl, Nabila Ben Rejeb, Chedia Laouani Kechrid, Essia Boughzela, Ali Bouslama
PURPOSE: We aimed to study potential variables involved in interindividual variability to acenocoumarol (AC) response in order to establish a pharmacogenetic algorithm (PA) that includes clinical and genetic factors to predict adequate AC dose to stabilize anticoagulation in a cohort of Tunisian patients. METHODS: Genotyping of the CYP2C9, VKORC1, CYP4F2, and CALU polymorphisms was conducted on 246 patients using PCR-RFLP technique. AC normalized maintenance dose (NMD): ((mean maintenance dose/international normalized ratio (INR)) equilibrium) was calculated...
February 26, 2018: European Journal of Clinical Pharmacology
Luuk N van Oosten, Martijn W H Pinkse, Mervin Pieterse, Pierre Escoubas, Peter D E M Verhaert
Venom and toxin samples derived from animal origins are a rich source of bioactive peptides. A high proportion of bioactive peptides that have been identified in venom contain one or more disulfide bridges, which are thought to stabilize tertiary structure, and therefore influence the peptides' specificity and activity. In this chapter, we describe a label-free mass spectrometry-based screening workflow specifically to detect peptides that contain inter- and intramolecular disulfide bonds, followed by elucidation of their primary structure...
2018: Methods in Molecular Biology
Jung-Chun Lin
Alternative splicing has been widely demonstrated to function as pivotal regulation in specifying cellular fates and biological functions. The relative expression or cellular localization of a splicing factor constitutes an important mechanism in spatiotemporal programming of cell- and stage-specific splicing profiles. In this study, results of deep RNA-sequencing (RNA-Seq) analyses first revealed the reprogrammed splicing profile and reduced expression of serine/arginine-rich splicing factor protein kinase 1 (SRPK1) throughout the development of brown adipose tissue (BAT)...
February 20, 2018: Biochimica et Biophysica Acta
Valentin Schellhas, Christian Glatz, Ingo Beecken, Angelika Okegwo, Anna Heidbreder, Peter Young, Matthias Boentert
BACKGROUND: On initiation of long-term non-invasive ventilation (NIV), intermittent upper airway obstruction has rarely been described as possibly treatment-induced. Inspiratory pressure effects and the use of an oronasal interface may promote obstructive events in some patients with neuromuscular disease (NMD) and amyotrophic lateral sclerosis (ALS) in particular. METHODS: We evaluated clinical data from 212 patients in whom NIV was initiated using an oronasal mask...
February 17, 2018: Sleep & Breathing, Schlaf & Atmung
Maria-Jesus Pueyo, Ramon Escuriet, M Pérez-Botella, I de Molina, D Ruíz-Berdun, S Albert, S Díaz, P Torres-Capcha, V Ortún
AIM: To explore the effect of hospital's characteristics in the proportion of obstetric interventions (OI) performed in singleton fullterm births (SFTB) in Catalonia (2010-2014), while incentives were employed to reduce C-sections. METHODS: Data about SFTB assisted at 42 public hospitals were extracted from the dataset of hospital discharges. Hospitals were classified according to the level of complexity, the volume of births attended, and the adoption of a non-medicalized delivery (NMD) strategy...
February 10, 2018: Health Policy
Svetlana Krasnokutsky, Aaron Garza Romero, Daisy Bang, Virginia C Pike, Binita Shah, Talia F Igel, Irina Dektiarev, Yu Guo, Judy Zhong, Stuart D Katz, Michael H Pillinger
To determine whether arterial responsiveness is impaired among patients with gout, and whether arterial responsiveness inversely correlates with serum urate and inflammatory measures. This is a cross-sectional study of untreated gout subjects (n = 34) and non-gout healthy controls (n = 64). High-resolution dynamic ultrasound-measured flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent arterial responsiveness respectively. Serum urate (sUA) and high-sensitivity C-reactive protein (hsCRP) were measured in the gout group, and correlated with FMD and NMD responses...
February 15, 2018: Clinical Rheumatology
Cathy Zhang, Michelle Ramsay, Panagis Drakatos, Joerg Steier
Background: Patients with neuromuscular disease (NMD) are at risk of developing sleep-disordered breathing (SDB) with hypercapnic respiratory failure. We hypothesised that a self-administered questionnaire (SiNQ-5 scores) may be useful to assess patients who are established on treatment for NMD with SDB. Methods: Patients attending a tertiary referral centre filled in the SiNQ-5 (range 0-10 points, lower scores indicating fewer symptoms). The questionnaire contains five questions related to breathlessness, sleep and posture...
January 2018: Journal of Thoracic Disease
Chan Hee Koh, Savva Pronin, Mark Hughes
OBJECTIVES: Damage to critical brain regions causes deficits in important neurological functions. Chondroitinase ABC (ChABC) has been shown to promote neuroplasticity and may ameliorate neurological deficits caused by disease or trauma. This systematic review identifies and evaluates preclinical studies of ChABC as a treatment for acute brain injury. METHODS: Four databases were searched for studies relating to ChABC and brain or brain injuries. Controlled studies in mammals with acute brain injuries treated with ChABC were included in meta-analyses of neurobehavioural outcomes...
February 13, 2018: Brain Injury: [BI]
Gloria T Haskell, Michael C Adams, Zheng Fan, Krunal Amin, Roberto J Guzman Badillo, Linran Zhou, Christopher Bizon, Nizar Chahin, Robert S Greenwood, Laura V Milko, Yael Shiloh-Malawsky, Kristy R Crooks, Natasha Strande, Michael Tennison, Christian R Tilley, Alicia Brandt, Kirk C Wilhelmsen, Karen Weck, James P Evans, Jonathan S Berg
Objective: To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs). Methods: We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup...
February 2018: Neurology. Genetics
Davide Barbagallo, Angela Caponnetto, Matilde Cirnigliaro, Duilia Brex, Cristina Barbagallo, Floriana D'Angeli, Antonio Morrone, Rosario Caltabiano, Giuseppe Maria Barbagallo, Marco Ragusa, Cinzia Di Pietro, Thomas Birkballe Hansen, Michele Purrello
Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5): it was significantly downregulated in GBM biopsies as compared to normal brain tissues ( p -value < 0...
February 6, 2018: International Journal of Molecular Sciences
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