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A Compston

Publications and source records attributed to A Compston.

At least 55 records · Page 3Linked to original sources
PubMed1994

Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis.

The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a "meta-analysis", the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.

Antigens, CD↗
PubMed1994

Future prospects for the management of multiple sclerosis.

A comprehensive strategy for the future management of multiple sclerosis will involve limiting the inflammatory process and repairing the damage. Monoclonal antibody therapy offers one means for achieving very rapid and substantial antiinflammatory effects, but the presently available reagents will almost certainly not prove to be definitive. Other candidates in the cascade of events that leads to myelin destruction will need to be considered, including TNF-alpha and other cytokines. But for the large number of individuals who are currently disabled, the more ambitious but realizable approach of glial repair holds the best hope for reversing persistent disabilities, transferring the technology and discoveries of contemporary experimental cellular neurobiology to the clinic.

Adult↗
PubMed1994

Brain repair: an overview.

The need to limit disease processes in the central nervous system and repair the damage is a major challenge for contemporary medicine but one which can now be addressed by applying the techniques of molecular, cellular, systems and behavioral neuroscience; we can be confident that, in due course, the brain repair strategy will work and have dividends for individuals with a range of neurological diseases.

Animals↗
PubMed1994

Myelination in vitro of rodent dorsal root ganglia by glial progenitor cells.

Oligodendrocytes synthesize myelin in the mammalian central nervous system; they develop from glial progenitors which, at least in vitro, are bipotential and also differentiate into astrocytes. Maturation of these O-2A progenitors is known to be influenced by growth factors and by extracellular matrix molecules. We investigated the effect of neurons on glial development by co-culturing highly purified rodent embryonic dorsal root ganglia with neonatal O-2A progenitors. Neurons produce signals, including platelet-derived growth factor BB and basic fibroblast growth factor, which stimulate progenitor cells to synthesize DNA; axonal contact is associated with down-regulation in the expression of complex ganglioside surface molecules on O-2A progenitors; with maturation, many of these cells develop into oligodendrocytes allowing the normal process of myelination to take place, but neurons also promote the differentiation of type 2 astrocytes. This orchestration of proliferation and differentiation in O-2A progenitor cells favours the development of glial-neuronal interactions needed for saltatory conduction of the nerve impulse.

Animals↗
PubMed1994

Multiple sclerosis.

Differences in the risk of multiple sclerosis depending on racial background, and the high clinical concordance rates in monozygotic compared with dizygotic twins, have stimulated attempts to identify and locate genes that confer susceptibility to the disease. The risk of multiple sclerosis is increased from 1 in 800 in northern European Caucasians to 1 in 3 in the monozygotic co-twins of affected individuals, with intermediate rates for siblings, offspring and more distant relatives. Concordance rates in monozygotic and dizygotic co-twins of affected individuals rise to 35% and 15%, respectively when magnetic resonance imaging is used to supplement clinical evidence for disease status. The increased recurrence risk in relatives of patients with multiple sclerosis is consistent with a model in which more than one gene contributes to susceptibility. Population studies have demonstrated an association with the class 2 major histocompatibility complex (MHC) phenotypes DR15 and DQw6 and their corresponding genotypes DRB1.1501, DRB5.0101 and DQA1.0102, DQB2.0602. An extensive search, using population studies, for other polymorphic alleles involved in restriction of the immune response may have yielded an additional candidate gene in the VH2-5 immunoglobulin heavy-chain variable region. Identity by descent analysis of candidate genes encoded within the alpha-chain of the T-cell receptor and the gene for myelin basic protein has failed to demonstrate linkage; paradoxically, this is also true for the MHC class 2 region, despite the population association. However, studies involving a large number of sibling pairs have reported a bias in the distribution of T-cell receptor beta-chain variable region haplotype sharing, favouring linkage. This becomes more marked when stratification is made for the presence of DR2 in both affected siblings, suggesting an interaction between genetic polymorphisms encoded within the MHC and T-cell receptor genes, as expected from their known functional co-operation in antigen presentation. The same is true for the immunoglobulin heavy chain, providing provisional evidence for linkage to a gene encoded within the immunoglobulin heavy-chain variable region in families reported from the UK. Taken together, these findings demonstrate the importance of family studies in elucidating the genetic basis of multiple sclerosis, and confirm that several genes are involved, one or more of which regulates genetic restriction of the immune response. The contribution made by the susceptibility genes that have provisionally been identified, occurring in isolation or together, can account for only a proportion of the increased risk of multiple sclerosis implicated by family studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Genes↗
PubMed1993

Limiting and repairing the damage in multiple sclerosis.

Inflammation of the brain depends upon migration of activated lymphocytes across the blood brain barrier bringing to the abluminal surface of cerebral blood vessels a variety of cellular and soluble immune mediators. Treatments which reduce the availability of circulating lymphocytes or limit their entry into the nervous system influence human and experimental inflammatory brain disease. The knowledge that inflammatory processes in the brain culminate in contact between microglia and the oligodendrocyte-myelin unit, which is damaged by local release of tumour necrosis factor, provides additional opportunities for treatment. In these diseases, disability results both from the inflammatory process and the failure of precursor cells to enter the lesions, differentiate and remyelinate the naked axons. The probability for the future is that a combination of manoeuvres involving limitation of the inflammatory process, increased availability of glial progenitors and re-establishment of their developmental growth factor environment will be needed to repair demyelinated lesions.

Axons↗
PubMed1993

Problems with rating scales for multiple sclerosis: a novel approach--the CAMBS score.

Current rating scales for multiple sclerosis are unsatisfactory because they score each patient's condition without indicating the clinical context in which that score has been obtained. The Cambridge Multiple Sclerosis Basic Score (CAMBS) offers a solution to this problem by recording current status in the context of the clinical course. CAMBS distinguishes disability from handicap and indicates the independent contribution of relapse and progression to current clinical activity. Single scores of between 1 and 5 are assigned to each of these indices, giving a simple four component analysis for each clinical encounter, e.g. disability 3; relapse 1; progression 2; handicap 1.

Humans↗
PubMed1992

Cellular organisation of the optic nerve and the implications for optic neuritis.

Opportunities for studying growth, degeneration and repair in the central nervous system have altered over the last decade with the development of techniques for culturing neurones and glia and the availability of immunological or molecular markers that identify separate lineages and their progeny. Much pioneering work has been carried out in the rodent optic nerve but the principles that emerge are representative for other parts of the nervous system; development of neurones and glia may differ substantially in rats and man, so that assumptions must be made in extrapolating from properties of the rat optic nerve to diseases of the human central nervous system.

Adult↗
PubMed1992

Epidemiology and genetics of multiple sclerosis.

Epidemiological data suggest an aetiological role for both genetic and environmental factors in multiple sclerosis (MS), but these have yet to be fully characterized. It is probable that MS susceptibility is determined by polygenes but specific loci need to be identified.

Cross-Cultural Comparison↗
PubMed1991

The pathogenesis of demyelinating disease: insights from cell biology.

Cellular and humoral immune mechanisms have been implicated in the pathogenesis of human and experimental demyelinating diseases of the CNS. How these interact in the complex sequence of events that culminates in phagocytosis of myelin by macrophages has yet to be resolved. The relationship between leakage of the blood-brain barrier and demyelination, the reason why recurrent inflammatory demyelination occurs--seemingly in the absence of an antigen-specific immune response--and the lack of effective remyelination all require explanation if a coherent account of immunologically mediated demyelination is to be achieved. One approach to these problems is to study in vitro the developmental and cellular biology of oligodendrocytes--the glial cells responsible for the synthesis and maintenance of CNS myelin. This provides experimental opportunities not offered by more direct investigation of the intact nervous system, but carries the clear disadvantage that observations made in vitro cannot necessarily be extrapolated to humans.

Animals↗
PubMed1990

The effect of methylprednisolone on lymphocyte phenotype and function in patients with multiple sclerosis.

The extent to which symptomatic improvement in patients with multiple sclerosis treated with intravenous methylprednisolone depends on immunological actions of corticosteroids is unknown. In this study the effect of methylprednisolone on circulating T and B cell function has been assessed in vitro and in vivo. Low molar concentrations of methylprednisolone increased pokeweed mitogen-stimulated IgG synthesis by unfractionated lymphocytes in 20 patients with multiple sclerosis and 15 controls. Treatment with methylprednisolone was associated with increased IgG synthesis in a further cohort of 26 affected individuals although dose responsiveness to methylprednisolone was uninfluenced in these patients. Sequential concanavalin A-pokeweed mitogen-induced IgG synthesis by mononuclear cells was also stimulated by methylprednisolone. Phenotypic analysis of paired samples from 12 patients with multiple sclerosis, taken before and after treatment showed no alteration in CD4 or CD8 cells, their suppressor inducer or suppressor subpopulations or activated lymphocytes.

CD4-Positive T-Lymphocytes↗
PubMed1989

Immune mechanisms in the pathogenesis of demyelinating diseases.

The loss of myelin which characterises many human and experimental demyelinating diseases, among them multiple sclerosis, is thought to be immune mediated, but the precise mechanisms responsible remain unknown despite intense research. Normally, myelin in the central nervous system (CNS) is protected from systemic immune responses by the blood brain barrier, which separates nervous tissue from the peripheral circulation. Here we review evidence suggesting that an understanding of the demyelinating disorders may be helped by considering their immune pathogenesis in two stages. The first is damage to the blood brain barrier; this appears to be cell mediated, and allows infiltration into the CNS of other immune effectors. These include complement and also macrophages, which together may mediate the second stage, injury to the myelin/oligodendrocyte complex.

Animals↗
PubMed1988

The 150th anniversary of the first depiction of the lesions of multiple sclerosis.

The clinical and pathological features of multiple sclerosis were fully described, in France and subsequently in England, during the latter half of the XIXth century but clinical descriptions, personal accounts and depictions of the disease had appeared at various times over the previous 50 years. Jean Cruveilhier is usually credited with having first illustrated the lesions of multiple sclerosis in the second tome of his pathological atlas which bears the title date 1835. But the 40 livraisons which make up this work were published separately in parts and documentary evidence contained within the second volume indicates that the putative case of multiple sclerosis cannot have appeared earlier than 1841. Robert Carswell also may have published his pathological atlas in parts but the work was completed by 1838 and so his depiction of the lesions of multiple sclerosis, appearing on plate 4 fig 1, predates Cruveilhier's by at least three years. Curiously, Carswell and Cruveilhier each observed their pathological material in Paris but they cannot have depicted the same individual. 1988 is therefore the 150th anniversary of the depiction of the lesions of multiple sclerosis; the unnamed patient was French, the illustrator a Scotsman.

Brain↗