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Alhassane Diallo, Heike Jacobi, Arron Cook, Robyn Labrum, Alexandra Durr, Alexis Brice, Perrine Charles, Cecilia Marelli, Caterina Mariotti, Lorenzo Nanetti, Marta Panzeri, Maria Rakowicz, Anna Sobanska, Anna Sulek, Tanja Schmitz-Hübsch, Ludger Schöls, Holger Hengel, Bela Melegh, Alessandro Filla, Antonella Antenora, Jon Infante, José Berciano, Bart P van de Warrenburg, Dagmar Timmann, Sylvia Boesch, Massimo Pandolfo, Jörg B Schulz, Peter Bauer, Paola Giunti, Jun-Suk Kang, Thomas Klockgether, Sophie Tezenas du Montcel
BACKGROUND: Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias...
April 2018: Lancet Neurology
Tetsuo Ashizawa
No abstract text is available yet for this article.
April 2018: Lancet Neurology
Li-Yun Fann, Ying Chen, Da-Chen Chu, Shao-Ju Weng, Heng-Cheng Chu, Alexander T H Wu, Jiann-Fong Lee, Ahmed Atef Ahmed Ali, Tsung-Chih Chen, Hsu-Shan Huang, Kuo-Hsing Ma
The small-molecule naphtha [2,3-f]quinoxaline-7,12-dione (NSC745887) can effectively inhibit the proliferation of various cancers by trapping DNA-topoisomerase cleavage. The aim of this study was to elucidate cellular responses of NSC745887 in human glioblastoma multiforme (GBM, U118MG and U87MG cells) and investigate the underlying molecular mechanisms. NSC745887 reduced the cell survival rate and increased the sub-G1 population in dose- and time-dependent manners in GBM cells. Moreover, NSC745887 increased expression of γH2AX and caused DNA fragmentation leading to DNA damage...
February 23, 2018: Oncotarget
Elan D Louis, James H Meyers, Ashley D Cristal, Ruby Hickman, Pam Factor-Litvak
BACKGROUND: Endophenotypes are measurable clinical characteristics that may be present in individuals with increased risk for disease (e.g., unaffected family members). Endophenotypes are useful; they may clarify diagnosis in genetic studies and foster the development of animal models. In recent years, problems with balance and mild gait ataxia have been associated with essential tremor (ET). We compared gait and balance of first-degree relatives of ET cases (FD-ET) to that of age-matched controls (Co)...
March 13, 2018: Parkinsonism & related Disorders
Luis Velázquez-Pérez, Roberto Rodríguez-Labrada, Reidenis Torres-Vega, Ricardo Ortega-Sánchez, Jacqueline Medrano-Montero, Rigoberto González-Piña, Yaimeé Vázquez-Mojena, Georg Auburger, Ulf Ziemann
OBJECTIVE: Corticospinal tract (CST) dysfunction is common in the pre-ataxic stage of spinocerebellar ataxia type 2 (SCA2) but quantitative assessment of its progression over time has not been explored. The aim of this study was to quantify the progression of CST dysfunction in pre-ataxic SCA2 using transcranial magnetic stimulation (TMS). METHODS: Thirty-three pre-ataxic SCA2 mutation carriers and a 33 age- and gender-matched healthy controls were tested at baseline and 2-years follow-up by standardized clinical exams, validated clinical scales, and TMS...
March 15, 2018: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
Antonella Sferra, Fabiana Fattori, Teresa Rizza, Elsabetta Flex, Emanuele Bellacchio, Alessandro Bruselles, Stefania Petrini, Serena Cecchetti, Massimo Teson, Fabrizia Restaldi, Andrea Ciolfi, Filippo M Santorelli, Ginevra Zanni, Sabina Barresi, Claudia Castiglioni, Marco Tartaglia, Enrico Bertini
Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration, and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as "tubulinopathies", characterized by a wide range of neuronal defects resulting from defective proliferation, migration, and function...
March 14, 2018: Human Molecular Genetics
Shinji Kakei, Takahiro Ishikawa, Jongho Lee, Takeru Honda, Donna S Hoffman
BACKGROUND: In order to optimize outcomes of novel therapies for cerebellar ataxias (CAs), it is desirable to start these therapies while declined functions are restorable: i.e. while the so-called cerebellar reserve remains. OBJECTIVE: In this mini-review, we tried to define and discuss the cerebellar reserve from physiological and morphological points of view. METHOD: The cerebellar neuron circuitry is designed to generate spatiotemporally organized outputs, regardless of the region...
March 15, 2018: CNS & Neurological Disorders Drug Targets
Jorge C Kattah
Background: Previous series of bilateral vestibular loss (BVL) identified numerous etiologies, but surprisingly, a cause in a significant number of cases remains unknown. In an effort to understand possible etiology and management strategies, a global effort is currently in progress. Here, I contribute my 10-year experience with both acute and chronic BVL during the 2007-2017 decade. Methods: This is a retrospective review of the charts and EMR of patients diagnosed with BVL in the last 10 years...
2018: Frontiers in Neurology
Stefania Squadrone, Paola Brizio, Cecilia Mancini, Maria Cesarina Abete, Alfredo Brusco
Spinocerebellar ataxia type 2 (SCA2) is a neurological disorder characterized by cerebellar dysfunction. The possible association between metals and neurodegenerative diseases is under constant investigation, with particular focus on their involvement in oxidative stress and their potential role as biomarkers of these pathologies. Whole blood samples of SCA2 patients and of healthy individuals were subjected to multi-elemental analysis by inductively coupled plasma-mass spectrometry (ICP-MS). Reduced levels of manganese and copper were found in SCA2 patients, while zinc and vanadium concentrations were significantly higher in patients compared to controls...
May 2018: Journal of Trace Elements in Medicine and Biology
Rajani Singh, Rajnish Arora, Raj Kumar
Chiari malformations (CMs) are variant structural setup of cerebellum and brain stem at the craniovertebral junction. Normally the cerebellum and parts of the brain stem lie above the foramen magnum. When the part of the cerebellum and/or brainstem protrudes into the upper spinal canal through foramen magnum, it is defined as CM. Chiari malformations may develop when part of the skull is smaller than normal or misshapen, due to which the cerebellum herniates into spinal canal through foramen magnum. This compresses the cerebellum and brainstem affecting functions controlled by these parts and blocks the flow of cerebrospinal fluid that surrounds and cushions the brain and spinal cord...
March 14, 2018: Journal of Craniofacial Surgery
Justin Stebbing, Kalpit Shah, Lei Cheng Lit, Teresa Gagliano, Angeliki Ditsiou, Tingting Wang, Franz Wendler, Thomas Simon, Krisztina Sára Szabó, Timothy O'Hanlon, Michael Dean, April Camilla Roslani, Swee Hung Cheah, Soo-Chin Lee, Georgios Giamas
Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment...
March 15, 2018: Oncogene
Orrin Devinsky, Anup D Patel, Elizabeth A Thiele, Matthew H Wong, Richard Appleton, Cynthia L Harden, Sam Greenwood, Gilmour Morrison, Kenneth Sommerville
OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N -desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol)...
March 14, 2018: Neurology
Michael H Parkinson, Ana P Bartmann, Lisa M S Clayton, Suran Nethisinghe, Rolph Pfundt, J Paul Chapple, Mary M Reilly, Hadi Manji, Nicholas J Wood, Fion Bremner, Paola Giunti
Autosomal recessive spastic ataxia of Charlevoix-Saguenay is a rare neurodegenerative disorder caused by mutations in the SACS gene. Thickened retinal nerve fibres visible on fundoscopy have previously been described in these patients; however, thickening of the retinal nerve fibre layer as demonstrated by optical coherence tomography appears to be a more sensitive and specific feature. To test this observation, we assessed 292 individuals (191 patients with ataxia and 101 control subjects) by peripapillary time-domain optical coherence tomography...
March 12, 2018: Brain: a Journal of Neurology
Mariko Nishibe, Yu Katsuyama, Toshihide Yamashita
The motor deficit of the reeler mutants has largely been considered cerebellum related, and the developmental consequences of the cortex on reeler motor behavior have not been examined. We herein showed that there is a behavioral consequence to reeler mutation in models examined at cortex-dependent bimanual tasks that require forepaw dexterity. Using intracortical microstimulation, we found the forelimb representation in the motor cortex was significantly reduced in the reeler. The reeler cortex required a significantly higher current to evoke skeletal muscle movements, suggesting the cortical trans-synaptic propagation is disrupted...
March 13, 2018: Brain Structure & Function
Laura Alice Santos de Oliveira, Camilla Polonini Martins, Carlos Henrique Ramos Horsczaruk, Débora Cristina Lima da Silva, Luiz Felipe Vasconcellos, Agnaldo José Lopes, Míriam Raquel Meira Mainenti, Erika de Carvalho Rodrigues
Background and Purpose: The motor impairments related to gait and balance have a huge impact on the life of individuals with spinocerebellar ataxia (SCA). Here, the aim was to assess the possibility of retraining gait, improving cardiopulmonary capacity, and challenging balance during gait in SCA using a partial body weight support (BWS) and a treadmill. Also, the effects of this training over functionality and quality of life were investigated. Methods: Eight SCA patients were engaged in the first stage of the study that focused on gait training and cardiovascular conditioning...
2018: Rehabilitation Research and Practice
Josef Davidsson, Andreas Puschmann, Ulf Tedgård, David Bryder, Lars Nilsson, Jörg Cammenga
Germline mutations in the SAMD9 and SAMD9L genes, located in tandem on chromosome 7, are associated with a clinical spectrum of disorders including the MIRAGE syndrome, ataxia-pancytopenia syndrome and myelodysplasia and leukemia syndrome with monosomy 7 syndrome. Germline gain-of-function mutations increase SAMD9 or SAMD9L's normal antiproliferative effect. This causes pancytopenia and generally restricted growth and/or specific organ hypoplasia in non-hematopoietic tissues. In blood cells, additional somatic aberrations that reverse the germline mutation's effect, and give rise to the clonal expansion of cells with reduced or no antiproliferative effect of SAMD9 or SAMD9L include complete or partial chromosome 7 loss or loss-of-function mutations in SAMD9 or SAMD9L...
February 25, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ali Harati, Rolf Schultheiß, Stefan Rohde, Thomas Deitmer
BACKGROUND: Jugulotympanic paraganglioma (JTP) are benign, high-vascularized lesions that frequently invade the jugular foramen, temporal bone, the upper neck, and the posterior fossa cavity, resulting in a wide variety of clinical symptoms. METHODS: In this retrospective study, we assess the clinical symptoms and discuss the individual multidisciplinary treatment and outcome of 22 patients with JTP. RESULTS: In 12 patients, a hearing deficit was the presenting symptom, whereas pulsatile tinnitus and otalgia were present in six and four patients respectively...
March 10, 2018: Journal of Clinical Medicine
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
Sahra Gibbon, Waleska Aureliano
Within the context of a globalising agenda for genetic research where 'global health' is increasingly seen as necessarily informed by and having to account for genomics, the focus on rare genetic diseases is becoming prominent. Drawing from ethnographic research carried out separately by both authors in Brazil, this paper examines how an emerging focus on two different arenas of rare genetic disease, cancer genetics and a class of degenerative neurological diseases known as Ataxias, is subject to and a product of the dynamics of inclusion and exclusion as this concerns participation in research and access to health care...
April 2018: Anthropology & Medicine
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