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Biomedical subjects

A Compston

Publications and source records attributed to A Compston.

At least 37 records · Page 2Linked to original sources
PubMed1995

Brain repair.

Significant improvements in the treatment of common neurological diseases can be expected over the next few years from the application of advances now occurring in the basic neurosciences. In many disorders of the central nervous system, disability accumulates as a result of the degenerative process and its failure to repair. In part, this is because with differentiation, cells in the adult nervous system lose the ability to proliferate and migrate. A family of growth factors orchestrates proliferation, migration, differentiation and survival of neurones and glia; because certain of these growth factors also protect from injury cells which they support during development, there should soon be opportunities for limiting damage following a variety of insults and for rescuing degenerating neurones and glia. The discovery that axon regeneration is actively inhibited, perhaps in order to maintain stability in the complex systems and circuits that are established during development, suggests new strategies for enhancing axonal regeneration in spinal and head injury. Recruiting cells that are capable of restoring glial-neuronal interactions into areas of damage will be an important part of the brain repair strategy but it may prove possible to restore complex cellular arrangements through cell implantation only. Grafted neurones survive, produce appropriate neurotransmitters, form connections and restore some behaviours, but their relative inability to grow limits the degree of structural and functional repair that can be achieved: nevertheless, nerve cell implantation is now being used in the management of certain neurodegenerative diseases of the human central nervous system. There are also prospects for increasing the remyelination which occurs following acute inflammatory disease of the central nervous system, through the combination of immunological treatments that limit the disease process, growth factors that recruit oligodendrocytes and implantation of glial progenitors into demyelinated areas.

Animals↗
PubMed1995

Mechanisms of damage and repair in multiple sclerosis--a review.

Pathological features of MS include perivascular inflammation and demyelination with oligodendrocyte loss; in addition, attempts at remyelination are often unsuccessful and may culminate in astrocytic scarring. One approach to investigating the biological principles underlying these processes is to use in vitro systems to analyse single-cell behaviour as well as cell-cell interactions. This paper reviews such data concerned with cell injury and repair which illuminate both demyelination and remyelination. In tissue culture oligodendrocytes are susceptible to injury via cell-mediated and humoral mechanisms. Substances including complement and tumour necrosis factor are capable of killing rat oligodendrocytes in vitro; surface complement activation also initiates a number of intracellular processes within oligodendrocytes as well as providing ligands for phagocytic interactions. The reasons for oligodendrocyte complement activation are discussed, but it appears that species differences exist when extrapolating these data to humans. Myelination and remyelination can also be studied both in vitro and in vivo using defined cell populations. Results from these studies may eventually help to explain some pathological features of MS, including astrocytosis and factors governing the limits of remyelination.

Animals↗
PubMed1995

Guidance of oligodendrocytes and their progenitors by substratum topography.

Oligodendrocyte progenitors arise in subventricular zones and migrate extensively during development before differentiating into mature oligodendrocytes, which myelinate nerve tracts in the central nervous system. We have used microfabricated substrata, containing periodic patterns of contours similar to those of central nervous system axons to assess the influence in vitro of substratum topography on oligodendrocytes isolated from 7 day rat optic nerve. Antiganglioside antibody A2B5 positive oligodendrocyte-type 2 astrocyte progenitors, and galactocerebroside positive and myelin basic protein positive oligodendrocytes, were highly aligned by surface contours as small as 100 nm depth and 260 nm repeat spacing. Rat optic nerve astrocytes also aligned on surface contours, but rat hippocampal and cerebellar neurons were unresponsive. Oligodendrocytes demonstrated enhanced parallel extension of their processes on narrow repeating topography in an arrangement similar to that found in the intact optic nerve. This is in marked contrast to the phenotype displayed by this cell type on planar substrata. Neither oligodendrocytes nor oligodendrocyte-type 2 astrocyte progenitors showed high-order F-actin cytoskeletal networks; thus their alignment on gratings is unlikely to result from deformation of actin cables and focal contacts. In contrast, aligned astrocytes showed striking arrangements of actin stress fibres. These results establish glial cells as potentially the most topographically sensitive cell types within the central nervous system. Furthermore, the topographical pattern inducing maximal alignment of oligodendrocyte lineage cells corresponds to the diameters of single axons within the 7 day optic nerve. Thus the migration of oligodendrocyte-type 2 astrocyte progenitors and axonal ensheathment by oligodendrocytes may be guided by axonal topography within the developing nerve.

Animals↗
PubMed1995

Human oligodendrocytes are not sensitive to complement. A study of CD59 expression in the human central nervous system.

BACKGROUND: One or more components of the oligodendrocyte-myelin unit are the target of immune attack in multiple sclerosis. The role of complement in this process has been suggested by the demonstration in vitro that rat oligodendrocytes are sensitive to lysis by Ab-independent complement attack, partly because of a lack of the complement regulatory protein molecule, CD59. EXPERIMENTAL DESIGN: This study assessed the sensitivity in vitro of human oligodendrocytes derived from neurosurgical specimens to complement attack and analyzed CD59 expression on their surface. The presence of CD59 was also examined in the human central nervous system during myelination and in both the normal and diseased adult brain. RESULTS: Human oligodendrocytes are insensitive in vitro to complement attack in the absence of Ab and using the Ab YTH 53.1 and were shown to possess CD59 on their surface. CD59 is absent from the human central nervous system before myelination, at which stage strong expression occurs in areas of myelin production. CD59 expression is then normally down-regulated but is particularly strong in reactive astrocytes in diseases such as multiple sclerosis. CONCLUSIONS: The findings suggest that the previous demonstration of rat oligodendrocyte complement sensitivity and lack of CD59 expression do not extend to the human central nervous system. There may be a role for CD59 in normal human myelination.

Adult↗
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↗