224 results found
Ford H, Nicholas R, 2005, Multiple sclerosis., Clin Evid, Pages: 1637-1651, ISSN: 1462-3846
Vora AJ, Malik O, Nicholas R, et al., 2005, The UK Multiple Sclerosis Tissue Bank - a resource for research, 18th World Congress of Neurology, Publisher: ELSEVIER SCIENCE BV, Pages: S254-S254, ISSN: 0022-510X
Nicholas RS, Roncaroli F, Vora AJ, et al., 2005, The pathological basis of disability in multiple sclerosis subjects with frequent early relapses, 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS, Publisher: HODDER ARNOLD, HODDER HEADLINE PLC, Pages: S41-S42, ISSN: 1352-4585
Vora AJ, Taylor K, Ghebrenegus I, et al., 2005, Brain weight in multiple sclerosis-independent of clinical parameters, 21st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/10th Annual Meeting of Rehabilitation in MS, Publisher: HODDER ARNOLD, HODDER HEADLINE PLC, Pages: S42-S42, ISSN: 1352-4585
Vora A, Patel N, Ghebrenegus I, et al., 2005, The UK Multiple Sclerosis Tissue Bank - a resource for research, 106th Annual Meeting of the British-Neuropathological-Society, Publisher: WILEY, Pages: 240-241, ISSN: 0305-1846
Vora A, Patel N, Ghebrenegus I, et al., 2004, The UK multiple sclerosis tissue bank - a resource for research, 20th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple- Sclerosis/9th Annual Meeting of Rehabilitation in MS, Publisher: ARNOLD, HODDER HEADLINE PLC, Pages: S155-S155, ISSN: 1352-4585
Nicholas RS, Partridge J, Donn RP, et al., 2003, The role of the PTPRC (CD45) mutation in the development of multiple sclerosis in the North West region of the United Kingdom., J Neurol Neurosurg Psychiatry, Vol: 74, Pages: 944-945, ISSN: 0022-3050
BACKGROUND: A point mutation in protein tyrosine phosphatase receptor, type c polypeptide (PTPRC) has been associated with familial multiple sclerosis. This CG mutation at position 77 of exon 4 results in altered expression of CD45 isoforms on immune cells. OBJECTIVE: To study the incidence of PTPRC mutations in subjects with multiple sclerosis in the North West region of the United Kingdom. METHODS: Affected and unaffected subjects from five pedigrees with familial multiple sclerosis, 330 non-familial cases of multiple sclerosis, and 197 controls were studied. Genomic DNA was amplified using CD45IE34 and CD45IE44 primers, digested with Mspl, and run on an agarose gel. Polymerase chain reaction products were sequenced to exclude any other mutations. RESULTS: No PTPRC exon 4 genomic mutations were seen in any of the five families. In the non-familial cases the incidence of mutation was 4.1% in 197 controls and 5.1% in 330 multiple sclerosis patients. No significant association was found in this study with this mutation and disease susceptibility, sex, or an extended disability scale score of < 5.5. CONCLUSIONS: This candidate does not appear to influence the development of familial multiple sclerosis in this population. The negative result could arise from a type II error owing to the number of families and non-familial cases screened. Alternatively it might suggest that the contribution of the PTPRC mutation depends upon the genetic background.
Nicholas R, Stevens S, Wing M, et al., 2003, Oligodendroglial-derived stress signals recruit microglia in vitro., Neuroreport, Vol: 14, Pages: 1001-1005, ISSN: 0959-4965
Rat oligodendrocytes cultured without the essential survival factors serum and insulin die over a 48 h period. Analysis of supernatants from these dying cultures reveals a microglial chemokine released in advance of significant cell death. The observed microglial chemotactic effect is dose-dependent and not due to release of cellular debris. Interferon (IFN)-gamma activated microglia are more sensitive to the microglial chemokine. We show in co-culture that recruited non-activated microglia can enhance oligodendroglial survival whereas IFN-gamma activation of microglia induces contact-dependent oligodendroglial death. Thus, whilst the initial recruitment of microglia by stressed oligodendroglia may represent part of a survival process engaged by injured cells, this does not necessarily ensure survival.
Nicholas RS, Stevens S, Wing MG, et al., 2002, Microglia-derived IGF-2 prevents TNFalpha induced death of mature oligodendrocytes in vitro., J Neuroimmunol, Vol: 124, Pages: 36-44, ISSN: 0165-5728
Insulin-like growth factor-2 (IGF-2) present in media conditioned by non-activated and interferon gamma (IFN gamma)-treated microglia reduces galactocerebroside(+) (GalC) oligodendrocyte apoptosis in cultures derived both from the CG4 cell line and primary rat cortices. Microglia-derived IGF-2 also acts in each culture system to block GalC(+) oligodendrocyte toxicity resulting from soluble microglial-derived tumour necrosis factor alpha (TNF alpha). IGF-2 inhibits TNF alpha-induced c-Jun kinase (JNK) activation of the CG4 cell line. Microglial activation results in the release of soluble factors that are potentially toxic to oligodendrocytes but this may be offset by the production of soluble factors that protect these vulnerable cells. Allowing for extrapolation of these in vitro findings to intact tissue, our observations suggest one mechanism for limiting bystander damage in the context of inflammatory brain disease.
Nicholas RS, Wing MG, Compston A, 2001, Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF-kappa B., Eur J Neurosci, Vol: 13, Pages: 959-967, ISSN: 0953-816X
We demonstrate a role for nonactivated rat microglia in the survival and maturation of oligodendrocyte precursor cells (OPCs). Media conditioned by nonactivated microglia increase the number of surviving galactocerebroside(+) (GalC(+)) oligodendrocytes in vitro at 48 h by inhibiting the apoptosis of OPCs and stimulating their maturation to GalC+ oligodendrocytes. These effects are not observed with medium conditioned by microglia activated with interferon-gamma (IFN-gamma). Conditioned medium from nonactivated microglia is associated with upregulation in OPCs of nuclear factor of kappa binding (NF-kappa B) p65 subunit. The use of antisense to the inhibitor of kappa binding (I kappa B) induces p65 subunit activation in OPCs and, in common with medium conditioned by nonactivated microglia, also inhibits OPC apoptosis and promotes cell maturation. Anti-platelet-derived growth factor (PDGF) antibody abolishes this effect even though PDGF-A chain is expressed at similar levels within both nonactivated and IFN-gamma-activated microglia and both conditioned media have similar levels of PDGF-A chain bioactivity. However, only conditioned medium from nonactivated microglia recruit phosphatidyl-3-inositol (PI-3) kinase to the PDGF-alpha receptor and synergise with endogenous PDGF-A chain to increase NF-kappa B activation. These results suggest that, dependent on their state of activation, microglia produce soluble factors that promote oligodendrocyte development through an effect on the PDGF-alpha receptor-signalling pathway.
Nicholas RS, Compston A, Brown DR, 2001, Inhibition of tumour necrosis factor-alpha (TNFalpha)-induced NF-kappaB p52 converts the metabolic effects of microglial-derived TNFalpha on mouse cerebellar neurones to neurotoxicity., J Neurochem, Vol: 76, Pages: 1431-1438, ISSN: 0022-3042
Activated microglia are implicated in the injury of neurones and macroglia both in vitro and in vivo. Here, we demonstrate that media conditioned by interferon-gamma treated microglia initially impair the metabolism of mouse cerebellar neurones grown in serum-free conditions without inducing cell death. Metabolic effects include inhibition of the ability of mitochondria to reduce 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and cytochrome oxidase activity. These effects are blocked by antibodies to tumour necrosis factor-alpha (TNFalpha), a cytokine produced by microglial activation, and they are not reproduced by media conditioned by resting microglia. The metabolic effects are evident for up to 24 h in vitro. More prolonged exposure, up to 48 h, results in TNFalpha dependent neuronal death as previously observed. Between 2 and 48 h TNFalpha present in media conditioned by interferon-gamma treated but not resting microglia is associated with nuclear factor kappa B (NF-kappaB) consensus sequence binding in paired mouse cerebellar neuronal cultures without affecting activation of the signal transducer and activator of transcription (STAT) transcription factor. Neuronal death can be accelerated by peptide blockade of the nuclear transport of NF-kappaB p52 subunit during exposure of cerebellar neurones to medium from interferon-gamma treated microglia. This toxicity is blocked by anti-TNFalpha antibody. Soluble factors released by activated microglia therefore contribute to neuronal dysfunction that is initially reversible but may culminate in neurotoxicity. Characterizing and manipulating these events in vivo theoretically provides an opportunity for neuroprotection in selected diseases affecting the central nervous system.
Wing MG, Seilly DJ, Nicholas RS, et al., 1999, Comparison of C1q-receptors on rat microglia and peritoneal macrophages., J Neuroimmunol, Vol: 94, Pages: 74-81, ISSN: 0165-5728
A comparison of the expression and ligand specificity of the C1q (first complement component) receptor on rat microglia and peritoneal macrophages was made. This revealed that radiolabelled C1q was competed from the peritoneal macrophages with intact C1q, and additively displaced by calf-skin collagen and purified C1q globular heads, suggesting the presence of at least two receptors. This was in contrast to microglia, where radiolabelled C1q was displaced with intact C1q and to a modest degree with collagen, but not with globular heads. Taken together, this implies that under these conditions, peritoneal macrophages and microglia both express a C1q receptor which binds to the collagen-like region, and that peritoneal macrophages additionally express a molecule which binds to the globular head of C1q. Analysis of the ligand bound by these cells reflected the differences observed in the competitive binding experiments, with the novel identification of naturally-occurring peptides from the globular head of C1q bound to the peritoneal macrophages, but not the microglia.
Nicholas RS, Winter J, Wren P, et al., 1999, Peripheral inflammation increases the capsaicin sensitivity of dorsal root ganglion neurons in a nerve growth factor-dependent manner., Neuroscience, Vol: 91, Pages: 1425-1433, ISSN: 0306-4522
Inflammation results in a local increase in nerve growth factor production which potentially can modify the properties of nerve growth factor-responsive sensory neurons innervating the inflamed tissue. The sensitivity of primary sensory neurons to the neurotoxin capsaicin is regulated in vitro by nerve growth factor and we have now investigated the effect of complete Freund's adjuvant-induced inflammation on the capsaicin sensitivity of adult rat sensory neurons. Dorsal root ganglion neurons innervating inflamed tissue were identified in vivo by retrograde labelling with the dye Fast Blue. Neuronal capsaicin sensitivity was measured in vitro with a quantitative cobalt-uptake densitometric technique, and was shown to increase significantly five days after inflammation. This increase in sensitivity was dependent on nerve growth factor as it could be inhibited by systemic treatment with nerve growth factor neutralizing antibodies. The enhanced capsaicin sensitivity that results from Freund's adjuvant injection may contribute to inflammatory hyperalgesia.
Freeman JA, Playford ED, Nicholas RS, et al., 1996, A neurological rehabilitation unit: audit of activity and outcome., J R Coll Physicians Lond, Vol: 30, Pages: 21-26, ISSN: 0035-8819
A clinical audit was carried out to determine the impact of multidisciplinary rehabilitation in a specialist neurorehabilitation unit, and to demonstrate how outcome measurement can be incorporated into routine clinical audit. The study describes and interprets the results of one year's activity and outcome in a neurorehabilitation unit. A total of 138 patients were admitted to the 18 bedded unit between April 1994 and March 1995. The main outcome measures were: length of inpatient stay, admission and discharge destination, disability as measured by the Barthel Index and Functional Independence Measure, handicap as measured by the Environmental Status Scale and the Handicap Assessment Scale, and the time spent undertaking the audit. Improvement in disability was demonstrated in 112 (83%) patients and in handicap in 89 (66%) patients. The time taken to analyse the data on a quarterly basis was reduced from 20 hours for the first quarter to 4.5 hours for the last quarter. The results show that multidisciplinary inpatient neurorehabilitation leads to functional improvement in the majority of neurologically impaired patients. Outcome measurement and data collection can be incorporated into routine clinical practice once a sound methodology has been established.
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