5 results on '"Angus B. Gane"'
Search Results
2. Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus
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Charis Wong, Jenna M Gregory, Jing Liao, Kieren Egan, Hanna M Vesterinen, Aimal Ahmad Khan, Maarij Anwar, Caitlin Beagan, Fraser S Brown, John Cafferkey, Alessandra Cardinali, Jane Yi Chiam, Claire Chiang, Victoria Collins, Joyce Dormido, Elizabeth Elliott, Peter Foley, Yu Cheng Foo, Lily Fulton-Humble, Angus B Gane, Stella A Glasmacher, Áine Heffernan, Kiran Jayaprakash, Nimesh Jayasuriya, Amina Kaddouri, Jamie Kiernan, Gavin Langlands, D Leighton, Jiaming Liu, James Lyon, Arpan R Mehta, Alyssa Meng, Vivienne Nguyen, Na Hyun Park, Suzanne Quigley, Yousuf Rashid, Andrea Salzinger, Bethany Shiell, Ankur Singh, Tim Soane, Alexandra Thompson, Olaf Tomala, Fergal M Waldron, Bhuvaneish T Selvaraj, Jeremy Chataway, Robert Swingler, Peter Connick, Suvankar Pal, Siddharthan Chandran, and Malcolm Macleod
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General Medicine - Abstract
ObjectivesMotor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART:NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.MethodsWe conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.ResultsFrom the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.DiscussionFor future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.
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- 2023
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3. Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study
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Jasmine Ng, Jerard Ross, Peter J. D. Andrews, Alan Jaap, Neil Turner, Helen Cook, Jon Stone, Michael G. K. Jones, Simon P. Hart, William Whiteley, Martin McKechnie, Billie Morrow, Graham McKillop, Laura Middleton, Sandra Dewar, Himanshu Shekhar, Susan Kealley, Laura Butler, Ashok Mathews, Donald Macleod, Neo Stavrinos, Andrew Elder, Ali Harmouche, Bethany Threlfall, Stuart McClellan, Frank Morrow, Ioannis P. Fouyas, Christopher P. Derry, Martin Dennis, Latana Munang, Peter Lange, Nicola L. Bell, David Summers, Judith Anderson, Robert Walker, Cathie Sudlow, Simon Leigh-Smith, Sarah Chambers, Robin Sellar, Patrick R. Taylor, Mark Hughes, Fiona Hughes, Jon Murchison, Richard Knight, Tim Russell, Moyra Masson, Donald Noble, Fiona Duncan, Claire Gordon, Ashok Jacob, M O Fitzpatrick, Randy Smith, Lynn McCallum, Belinda Weller, Katherine Jackson, Alasdair Gray, Angus B Gane, Siddharthan Chandran, Fiona Maxwell, Stanko Yordanov, Robert G. Will, Peter Foley, Patrick Statham, Henry Simms, Jon McCafferty, Colin Smith, Patricia Cantley, Alastair Crosswaite, Helen Spiers, Margarethe van Dijke, Yi Ng, Elizabeth Macdonald, Kate Enright, Gillian R. Kerr, Steven Makin, Katrina Dodds, Tom Fitzgerald, Simon Kerrigan, David Grant, Neil Hunter, Olayinka A Ogundipe, Claire Stirling, Astley Ainslie, Ian R. Whittle, Donald Farquhar, Jane Fothergill, Anne Knox, Andrew Jamieson, James M. Wilson, Alison Pollock, Andrew M. McIntosh, Andrew James Williams, Gillian Mead, Zoe Morris, Malcolm R. Macleod, Matthew J. Reed, Matthew Wilson, Colin B. Josephson, Brian Campbell, G. R. Nimmo, Brendan Sargent, Mark Rodrigues, Alastair Fitzgerald, Suvankar Pal, Colin J Mumford, Wendy Morley, Trish Elder-Gracie, Conor Maguire, Imran Liaquat, Sam Moultrie, James W. Dear, Peter Bodkin, Joanna M. Wardlaw, Johann R. Selvarajah, Antonia Torgersen, Iain Todd, Ralph Bouhaidar, Kristiina Rannikmäe, Syed Alhadad, Dilip Patel, Dave Caesar, Edinburgh Liberton Hospitals, Lynn M Myles, Fergus N. Doubal, Wendy Young, Kate Ahmad, Jonathan Rhodes, Anne Addison, Peter Sandercock, Rod Gibson, Seona Broadbent, Tim Morse, Gareth Clegg, Anant Kamat, Robin Henderson, Katherine Murray, Sudipto Ghosh, Sarah L. Keir, Joyce Stuart, Tom J Moullaali, Andrew J Coull, Rustam Al-Shahi Salman, Matthew King, Scott Ramsay, Linda Spence, Graham Mackay, Geraint Roberts, Mara Sittampalam, Laura Cunningham, Richard Davenport, Susan Duncan, Simon Dummer, Hamza Soleiman, Ross Murphy, James W. Ironside, Neshika Samarasekera, Paul Brennan, Peter Keston, Elaine Bisset, James J M Loan, Jonathan Carter, Brian Frier, David Hunt, Tracey Millar, Russell Hewett, Lewis Morrison, Mano Shanmuganathan, and Robin Grant
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Adult ,Male ,peri-hematomal edema ,medicine.medical_specialty ,Brain Edema ,030204 cardiovascular system & hematology ,survival ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Hematoma ,Edema ,Long term survival ,medicine ,Humans ,Spontaneous intracerebral hemorrhage ,Prospective Studies ,Aged ,Cerebral Hemorrhage ,Intracerebral hemorrhage ,Community based ,business.industry ,Research ,medicine.disease ,INCEPTION COHORT ,intracerebral hemorrhage ,radiology ,Surgery ,Stroke ,Neurology ,outcome ,Female ,medicine.symptom ,business ,Cohort study ,030217 neurology & neurosurgery - Abstract
Background Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. Aims In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. Methods We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3–6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. Results Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68–83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9–21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear ( R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08–2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63–1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11–1.42); p = 0.0004). Conclusion Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. Data access statement Anonymized summary data may be requested from the corresponding author.
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- 2021
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4. Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis
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Arpan R Mehta, Niels Menezes, Ralf Watzlawick, Stephen M. Anderton, Hans Lassmann, David Baker, Angus B. Gane, Marco Canizares, Don J. Mahad, Jon D. Laman, Kenneth Smith, Bert A. 't Hart, Graham R. Campbell, Siddharthan Chandran, Gareth Pryce, Jasmine Dean, Simon Licht-Mayer, Alexander Fullerton, Susan M. Fleetwood-Walker, Yolanda S. Kap, Roderick N. Carter, Daniel M. Altmann, David A. Lyons, Markus Kipp, Sarah Al-Azki, Aniket Ghosh, Robin J.M. Franklin, Jan M. Schwab, Moses Rodriguez, Jordon Dunham, Stephanie E J Zandee, Nicholas M. Morton, Michele Zagnoni, Chao Zhao, Katie McGill, Bruce D. Trapp, Rory Mitchell, Apollo - University of Cambridge Repository, Translational Immunology Groningen (TRIGR), Molecular Neuroscience and Ageing Research (MOLAR), and Franklin, Robin [0000-0001-6522-2104]
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TK ,PGC-1-ALPHA ,Axonal loss ,Biology ,Mitochondrion ,RAPID ISOLATION ,MOUSE ,Neuroprotection ,Pathology and Forensic Medicine ,GENE DELETION ,Multiple sclerosis ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,DNA DELETIONS ,medicine ,Animals ,Humans ,Axon ,Demyelinating Disorder ,Mitochondrial transport ,030304 developmental biology ,0303 health sciences ,Original Paper ,Organelle Biogenesis ,RECEPTOR ,Demyelination and neuroprotection ,medicine.disease ,Axons ,TRANSPORT ,humanities ,PHOSPHOLIPASE-D ,3. Good health ,Mitochondria ,medicine.anatomical_structure ,Mitochondrial biogenesis ,nervous system ,EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS ,Nerve Degeneration ,Neurology (clinical) ,MYELINATION ,Neuroscience ,030217 neurology & neurosurgery ,Demyelinating Diseases - Abstract
Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders. Electronic supplementary material The online version of this article (10.1007/s00401-020-02179-x) contains supplementary material, which is available to authorized users.
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- 2020
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5. Air travel with limbs immobilised in casts
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Neil Jain, Edward Martin Holt, Angus B. Gane, and Moez Zeiton
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Orthodontics ,business.industry ,Medicine ,Surgery ,General Medicine ,business ,Air travel - Published
- 2014
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