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Biomedical subjects

D A Compston

Publications and source records attributed to D A Compston.

At least 91 records · Page 5Linked to original sources
PubMed1990

Features of multiple sclerosis in older patients in South Wales.

Multiple sclerosis (MS) may occur outside the commonly accepted age range. Data relating to features of MS in a population in South Wales have been analysed to find features which characterise older patients. The older patients are more severely disabled due to the accumulation of visual defects and motor signs and symptoms. The course of the disease is marked by single localised attacks with long remissions. Those with onset over 50 years deteriorate more rapidly, but in those who were over 50 at the time of interview, this did not occur. It is suggested that there is no essential difference in MS in older patients, but there may be features which reflect normal ageing and diseases commoner in old age.

Adolescent↗
PubMed1990

Oligodendrocyte susceptibility to injury by T-cell perforin.

Myelin injury in multiple sclerosis (MS) appears to be immune mediated, but the mechanisms remain unidentified. It has been shown previously that oligodendrocytes, which synthesize and maintain myelin in the central nervous system (CNS), are susceptible to attack by homologous complement and that injury may be reversible when lysis is resisted by vesicular removal of membrane attack complexes. Here it is reported that oligodendrocytes are also highly susceptible to attack by T-cell perforin, and respond similarly to sublethal attack by shedding membrane vesicles. These findings imply that oligodendrocytes are vulnerable to lysis and/or reversible injury by a variety of closely related pore-forming immune effectors; following blood-brain barrier disruption, attack by one or several of these molecules may cause transient or irreversible myelin injury. Furthermore, these results provide the first indication that vesicular repair mechanisms may allow nucleated cells to recover from perforin-mediated cell injury.

Animals↗
PubMed1989

Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement.

Oligodendrocytes synthesize myelin in the central nervous system and maintain it in lamellar sheaths around axons. Techniques for studying oligodendrocyte development in vitro can be used, indirectly, to investigate the myelin injury that occurs in human and experimental demyelinating disease. Cell-mediated immune mechanisms are necessary but not sufficient to induce myelin damage in vivo; more recently complement has also been implicated in the pathogenesis both of multiple sclerosis and experimental allergic encephalomyelitis. Previously we have demonstrated that antibody-independent complement activation occurs in vitro at the oligodendrocyte surface. Here we show that the ensuing oligodendrocyte injury is reversible, and that recovery involves the release of membrane-attack complex-enriched vesicles from the surface of viable cells. The demonstration of morphologically and immunochemically identical vesicles in the cerebrospinal fluid of patients with multiple sclerosis suggests that reversible complement-mediated injury contributes to myelin damage in vivo.

Animals↗
PubMed1989

Immunohistochemical localisation of terminal complement component C9 in experimental allergic encephalomyelitis.

The deposition of terminal complement component C9 within the central nervous system (CNS) has been studied immunohistochemically in three models of experimental allergic encephalomyelitis (EAE) in the rat; inflammatory EAE induced by the passive transfer of myelin basic protein-specific T cells (tEAE), antibody-mediated, demyelinating tEAE and a subacute/chronic model induced by active immunisation with guinea pig spinal cord tissue in adjuvant. Two distinct patterns of C9 reactivity were observed, a diffuse staining of the tissue adjacent to inflammatory lesions, similar to that seen for other extra-vasculated serum proteins, and also granular, sometimes fibrillar C9 deposits around some inflammed vessels and in areas of active demyelination. The latter staining pattern was most pronounced in animals with acute antibody-mediated demyelinating tEAE, in which extensive, but transient, subpial and perivascular granular deposits of C9 were associated with regions of acute demyelination. A similar pattern of granular C9 reactivity was also associated with demyelinating lesions in animals with actively induced chronic progressive EAE. However, these C9 deposits were not observed in rats with purely inflammatory, clinically mild tEAE, although C9 deposition was occasionally observed around a small number of inflammed vessels in animals with hyperacute, lethal tEAE. These observations demonstrate that deposition of C9, the major component of the cytolytic membrane attack complex, in EAE is related to myelin injury rather than CNS inflammation.

Animals↗
PubMed1989

Normal rat serum cytotoxicity against syngeneic oligodendrocytes. Complement activation and attack in the absence of anti-myelin antibodies.

The role of complement in mediating oligodendrocyte and myelin injury has been investigated by studying the effects of normal adult rat serum on syngeneic cultured neonatal glial cells. Rat serum has cytotoxic activity directed against oligodendrocytes but not astrocytes, the potency of which increases with cell maturation. The effects of heat inactivation, decomplemented rat serum, EGTA treatment, removal of any possible anti-myelin antibody by absorption using syngeneic myelin and absence of surface staining for immunoglobulins on serum-treated oligodendrocytes, C9 depletion and reconstitution, and oligodendrocyte staining for surface C9 demonstrate that this cytotoxicity is mediated by complement via antibody independent activation of the classical pathway and is membrane attack complex dependent. These findings significantly extend the previous demonstration of complement activation by extracted myelin, and may have significance for the pathogenesis of demyelinating diseases.

Animals↗
PubMed1989

Myelin-oligodendrocyte glycoprotein (MOG) is a surface marker of oligodendrocyte maturation.

The myelin-oligodendrocyte glycoprotein (MOG) is a minor component of central nervous system myelin. Using neonatal rat optic nerve oligodendrocyte cultures we have compared the development in vitro of MOG with galactocerebroside, myelin basic protein and 2' ,3'-cyclic-nucleotide 3'-phosphodiesterase. MOG appears on the surface of oligodendrocytes 1-2 days later than these other oligodendrocyte markers, suggesting that MOG may be a useful indicator of oligodendrocyte maturation. The relevance of these findings for investigating mechanisms of myelin injury in vitro and the role of oligodendrocyte damage in demyelinating disease is discussed.

Animals↗
PubMed1989

The role of complement in the pathogenesis of experimental allergic encephalomyelitis.

The role of complement in the pathogenesis of demyelination and inflammation has been investigated in a synergistic model of acute experimental allergic encephalomyelitis (EAE) in the Lewis rat. Depletion of serum complement with cobra venom factor (CVF) suppressed the clinical expression of acute inflammatory EAE induced either by immunization with 50 micrograms guinea pig basic protein (MBP) in Freund's complete adjuvant, or by the passive transfer of 10(7), but not 5 X 10(7) MBP activated spleen cells. Despite the suppression of clinical disease in actively induced EAE, treatment with CFF only had a significant effect on the severity of CNS inflammation in early disease (12 days postimmunization) when the number of inflammatory foci was reduced by 35%. Three days later this difference had resolved and no significant difference could be detected in the severity of CNS inflammation, although control animals exhibited severe disease, the CVF treated group being clinically normal. Demyelination in these models is initiated by systemic injection of the antimyelin oligodendrocyte glycoprotein (MOG) monoclonal antibody, 8-18C5, which in vitro lyses oligodendrocytes in a dose, Fc and complement-dependent manner and in vivo induces extensive CNS demyelination in rats with EAE. Treatment with CVF reduced the ability of this antibody to initiate demyelination in vivo and furthermore, its F(ab)2' fragment had no effect on the clinical course of EAE and was unable to initiate demyelination in normal animals. Complement-dependent mechanisms are therefore involved both in the clinical expression of acute inflammatory lesions and in the pathogenesis of antibody-mediated demyelination in EAE.

Animals↗
PubMed1989

A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity.

A population based study of von Recklinghausen neurofibromatosis in south east Wales (population 668,100) identified 69 families with 135 affected members (prevalence 1/4950 of the population). In these families penetrance of the NF-1 gene was 100% by the age of five years. The genetic fitness of NF-1 sufferers was found to be reduced to 0.47, the effect being more marked in males than females (f = 0.31 and 0.60, respectively). Forty-one of 135 cases were judged to represent new disease mutations and the mutation rate was estimated to lie between 3.1 x 10(-5) and 10.4 x 10(-5). A parental age effect for new mutations was not found, nor was a maternal effect on disease severity.

Adolescent↗
PubMed1989

A genetic study of von Recklinghausen neurofibromatosis in south east Wales. II. Guidelines for genetic counselling.

The age of appearance and diagnostic value of the major defining features of von Recklinghausen neurofibromatosis (NF-1) have been studied in 168 cases from 73 families. In assessing children of an affected patient, those who have inherited the gene can be distinguished from their normal sibs on the basis of whether or not café au lait (CAL) spots are present by the age of five years. Lisch nodules appear before cutaneous neurofibromas and are a useful clinical aid in the assessment of unusual cases, those in whom the diagnosis is equivocal, and children with multiple CAL spots but no family history of NF-1. Sixty-nine of the families were identified through a population based study in south east Wales and the frequency of complications in 135 affected subjects from these families has been used to develop figures for genetic counselling. For these purposes, the complications of NF-1 can be usefully divided into four categories: intellectual handicap (33%) (moderate/severe retardation 3.2%, minimal retardation/learning difficulties 29.8%); complications developing in childhood and causing lifelong morbidity (8.5%); 'treatable' complications which can develop at any age (15.7%); and malignant or CNS tumours (4.4 to 5.2%).

Adolescent↗
PubMed1989

Estimation of age dependent penetrance in facioscapulohumeral muscular dystrophy by minimising ascertainment bias.

In any family study using information gathered retrospectively, the influence of the method of ascertainment on the observed segregation ratio in sibships needs careful consideration. The study of kindred members from outside the area of primary ascertainment is invaluable in providing segregation data with minimal ascertainment bias. For facioscapulohumeral muscular dystrophy (FSHD), using this approach, and based on the presence or absence of characteristic clinical signs rather than on an historical account of age at onset, estimates were derived for penetrance of the FSHD gene of less than 5% for ages 0 to 4 years, 21% for ages 5 to 9, 58% for ages 10 to 14, 86% for ages 15 to 19, and 95% penetrance for age 20 years and over. No difference between families was identified. These figures should facilitate genetic counselling and the interpretation of genetic linkage study results in FSHD.

Adolescent↗
PubMed1989

Dual labelling of circulating CD8 cells in patients with multiple sclerosis.

Peripheral blood T cell phenotypes have been analysed in serial samples from patients with multiple sclerosis, their unaffected relatives and controls using a panel of antibodies chosen to distinguish T suppressor and activated suppressor cells from other CD8 lymphocytes. Overall, the percentage of Leu 2a cells correlated with alterations in the Leu 2a/15 suppressor sub-population (r = 0.79, p less than 0.001). Fewer circulating Leu 2a and Leu 2a/15 positive cells were identified in multiple sclerosis patients than unaffected individuals but there was no alteration in percentage of activated (Leu 2a/DR) CD8 cells. These findings suggest that the fluctuations in CD8 cells, characteristic of patients with multiple sclerosis, are due to alterations in T suppressor phenotype; this may then lower the threshold for activation of other T cell subpopulations.

CD4-Positive T-Lymphocytes↗
PubMed1989

Quantitative magnetic resonance imaging in multiple sclerosis: the effect of high dose intravenous methylprednisolone.

Magnetic resonance imaging was performed on 50 patients with clinically definite or probable multiple sclerosis before and 15 days after starting treatment with intravenous methylprednisolone (0.5 g daily for 5 days). Scans were abnormal in 49 patients. New lesions had appeared on the second scan in nine individuals and in seven a single pre-existing lesion appeared to have become smaller but in no case were lesions seen to disappear. Two patients showed both reduction in the size of an abnormal area and development of a single new lesion indicating that corticosteroids do not appear rapidly to alter the process underlying plaque formation. Measurements of relaxation times were performed in 12 randomly selected patients. All showed elevated values in normal appearing white matter but not cortex before treatment compared with 18 healthy controls. After treatment a significant decrease of T1 and T2 was observed in cortex, and of T1 alone in normal appearing white matter. No significant change could be detected within lesions, a finding attributed to the wide range of relaxation values observed at these sites before treatment. Since brain water content is increased in normal appearing white matter of multiple sclerosis patients, and is significantly reduced by high-dose methylprednisolone, resolution of oedema may contribute to the rapid spontaneous or corticosteroid induced symptomatic recovery that characterises the disease in its early stages.

Adult↗
PubMed1989

The incidence and mortality of multiple sclerosis in south east Wales.

The incidence of multiple sclerosis was shown to be 8.2/10(5)/year (definite or probable 5.4 and suspected 2.8/10(5)/year) during a 3 year prospective study carried out in an area of south east Wales which has a high prevalence of the disease (120/10(5). Mortality in affected individuals who were prevalent at the start of the survey was 3.1/10(5)/year; many deaths resulted from direct complications of multiple sclerosis but 38% were due to unrelated causes. The rate at which new cases were identified approximately matched deletions from the register arising from death, outward migration and other causes so that prevalence did not change significantly during the survey (1985-1988).

Adolescent↗
PubMed1989

Reversible injury of cultured rat oligodendrocytes by complement.

Rat oligodendrocytes are lysed on exposure to normal homologous serum as a result of classical pathway complement activation and attack in the absence of anti-myelin antibodies. The effect of non-lethal complement attack on oligodendrocytes in vitro was studied by exposing dissociated neonatal rat optic nerve cell cultures to low concentrations of complement alone and also in the presence of oligodendrocyte-specific monoclonal antibodies. Regardless of the mode of complement activation, non-lethal complement attack led to reversible cell injury, recovery following a transient rise in intracellular calcium and fall in ATP in the absence of membrane permeabilization to propidium iodide. A single episode of non-lethal injury had no effect on the ability of oligodendrocytes subsequently to express cell-specific antigens, but repeated episodes had a cumulative effect and ultimately resulted in cell death. Reversible and/or lytic complement-mediated oligodendrocyte injury has implications for the pathogenesis of human and experimental demyelinating diseases.

Adenosine Triphosphate↗