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Rog D.J.,Greater Manchester Neurosciences Center

For some years a mixture of anecdotal report and data from animal models have implied a potential role for cannabis-based medicines in ameliorating a variety of symptoms of multiple sclerosis. Only recently however have large randomised controlled trials (RCTs) examined these potential effects rigorously. At present the results of RCTs have lacked a coherent message to the prescribing clinician and reasons for such heterogeneity in cannabinoid trials are discussed. © 2010 Elsevier GmbH. Source

Goldman A.M.,Baylor College of Medicine | Behr E.R.,St Georges, University of London | Semsarian C.,University of Sydney | Bagnall R.D.,University of Sydney | And 3 more authors.

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death. © 2016 International League Against Epilepsy. Source

Cooper P.N.,Greater Manchester Neurosciences Center | Westby M.,Guideline | Pitcher D.W.,Worcestershire Royal Hospital | Bullock I.,Guideline
Annals of Internal Medicine

Description: Transient loss of consciousness (TLoC) is common and often leads to incorrect diagnosis, unnecessary investigation, or inappropriate choice of specialist referral. In August 2010, the National Institute for Health and Clinical Excellence published a guideline that addressed the initial assessment of and most appropriate specialist referral for persons who have experienced TLoC. The guideline focused on correct diagnosis and relevant specialist referral and did not make treatment recommendations. This synopsis describes the principal recommendations concerning assessment and referral of a patient with TLoC. Methods: The National Clinical Guideline Centre developed the guidelines by using the standard methodology of the National Institute for Health and Clinical Excellence. A multidisciplinary guideline panel generated review questions, discussed evidence, and formulated recommendations. The panel included a technical team from the National Clinical Guideline Centre, who reviewed and graded all relevant evidence identified from literature searches published in English up to November 2009 and performed healtheconomic modeling. Both guideline development and final modifications were informed by comments from stakeholders and the public. Recommendations: The panel made clear recommendations regarding the assessment of a person after TLoC, which emphasized the importance of clinical reasoning in diagnosis. Persons with uncomplicated faint, situational syncope, or orthostatic hypotension should receive electrocardiography but do not otherwise require immediate further investigation or specialist referral. Persons with features that suggest epilepsy should be referred for specialist neurologic assessment; brief seizure-like activity was recognized as a common occurrence during syncope that should not be regarded as indicating epilepsy. Persons with a suspected cardiac cause for TLoC or in whom TLoC is unexplained after initial assessment should receive specialist cardiovascular assessment. Guidance was provided on the appropriate choices of cardiovascular investigation, according to the presenting clinical circumstances. © 2011 American College of Physicians. Source

Kobylecki C.,University of Manchester | Kobylecki C.,Greater Manchester Neurosciences Center | Cenci M.A.,Lund University | Crossman A.R.,University of Manchester | Ravenscroft P.,University of Manchester
Journal of Neurochemistry

Overactivity of striatal α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) glutamate receptors is implicated in the pathophysiology of l-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). In this study, we evaluated the behavioural and molecular effects of acute and chronic blockade of Ca2+-permeable AMPA receptors in animal models of PD and LID. The acute effects of the Ca2+-permeable AMPA receptor antagonist 1-trimethylammonio-5-(1-adamantane-methylammoniopentane) dibromide hydrobromide (IEM 1460) on abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat and LID in the MPTP-lesioned non-human primate were assessed. Subsequently, the effects of chronic treatment of 6-OHDA-lesioned rats with vehicle, l-DOPA/benserazide (6/15 mg/kg, i.p.) + vehicle or l-DOPA + IEM 1460 (3 mg/kg, i.p.) on behavioural and molecular correlates of priming for LID were evaluated. In the 6-OHDA-lesioned rat and MPTP-lesioned non-human primate, acute treatment with IEM 1460 (1-3 mg/kg) dose-dependently reduced LID without adverse effects on motor performance. Chronic co-treatment for 21 days with IEM 1460 reduced the induction of AIMs by l-DOPA in the 6-OHDA-lesioned rat without affecting peak rotarod performance, and attenuated AIMs score by 75% following l-DOPA challenge (p < 0.05). Chronic IEM 1460 treatment reversed l-DOPA-induced up-regulation of pre-proenkephalin-A, and normalised pre-proenkephalin-B mRNA expression in the lateral striatum, indicating an inhibition of both behavioural and molecular correlates of priming. These data suggest that Ca2+-permeable AMPA receptors are critically involved in both the induction and subsequent expression of LID, and represent a potential target for anti-dyskinetic therapies. © 2010 The Authors. Source

Smith M.J.,University of Manchester | O'Sullivan J.,University of Manchester | Bhaskar S.S.,University of Manchester | Hadfield K.D.,University of Manchester | And 10 more authors.
Nature Genetics

One-third of all primary central nervous system tumors in adults are meningiomas. Rarely, meningiomas occur at multiple sites, usually occurring in individuals with type 2 neurofibromatosis (NF2). We sequenced the exomes of three unrelated individuals with familial multiple spinal meningiomas without NF2 mutations. We identified two individuals with heterozygous loss-of-function mutations in the SWI/SNF chromatin-remodeling complex subunit gene SMARCE1. Sequencing of SMARCE1 in six further individuals with spinal meningiomas identified two additional heterozygous loss-of-function mutations. Tumors from individuals with SMARCE1 mutations were of clear-cell histological subtype, and all had loss of SMARCE1 protein, consistent with a tumor suppressor mechanism. Our findings identify multiple-spinal-meningioma disease as a new discrete entity and establish a key role for the SWI/SNF complex in the pathogenesis of both meningiomas and tumors with clear-cell histology. © 2013 Nature America, Inc. All rights reserved. Source

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