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D A Compston

Publications and source records attributed to D A Compston.

At least 55 records · Page 3Linked to original sources
PubMed1995

Susceptibility to multiple sclerosis and the immunoglobulin heavy chain variable region.

A haplotype marker consisting of three biallelic restriction fragment length polymorphism (RFLP) loci from the VH-2 variable gene family was examined in 124 families with sibling pairs concordant for multiple sclerosis, 178 unrelated patients and 159 unaffected controls to investigate the role of the immunoglobulin heavy chain gene cluster in susceptibility to multiple sclerosis. Evidence for linkage was assessed using the affected sibling pair method of identity by descent, modified to allow for haplotype sharing on a probabilistic basis in families where haplotypes could not be assigned with certainty. The estimated probabilities of affected siblings sharing 0, 1 or 2 haplotypes were Z0 = 0.20, Z1 = 0.45, Z2 = 0.35. This deviation from the expected sharing probabilities of Z0 = 0.25, Z1 = 0.5, Z2 = 0.25 provides evidence for weak linkage (P < 0.05; equivalent to a lod score of 0.84); however, no significant allelic or haplotypic association was observed. Linkage without a population association suggests that a gene encoded on 14q confers susceptibility to multiple sclerosis, although this is not any of the existing VH-2 polymorphisms.

Alleles↗
PubMed1995

Sequence of the human homologue of a mitochondrially encoded murine transplantation antigen in patients with multiple sclerosis.

There is some evidence that mitochondrial genes may contribute to susceptibility to multiple sclerosis (MS), and a mitochondrial DNA-encoded peptide, the N-terminal portion of NADH-dehydrogenase subunit 1, acts as a transplantation antigen in mice. We have analysed the DNA sequence of the corresponding region of human mitochondrial DNA in 87 patients with MS, 10 with Leber's hereditary optic neuropathy in association with an MS-like illness, and 31 control subjects. This sequence appears to be highly conserved. Only three base pair changes were identified, each being found once only in one control and two patients, and these are likely to be harmless polymorphisms. There is thus no evidence that polymorphism in this region contributes to genetic susceptibility in MS.

Animals↗
PubMed1995

Multiple sclerosis and the HLA-D region: linkage and association studies.

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.

Adult↗
PubMed1995

Multiple sclerosis in the north Cambridgeshire districts of East Anglia.

The Cambridgeshire multiple sclerosis register was established in 1989 and initially reported a prevalence of 130/10(5) population for south and east Cambridgeshire (south Cambs). This survey has now been extended to the northern county districts where there were 449 patients with multiple sclerosis in population of 378,959 on 1 July 1993 (118/10(5); 95% confidence interval (95% CI) 108-130). Four hundred and four had either definite or probable disease (107/10(5); 95% CI: 98-118). This matches the highest figures in the series of seven epidemiological surveys carried out in southern England over the past decade. Comparison with these and other studies indicates that no latitudinal gradient of disease is found in southern England despite spanning four degrees of latitude.

Adolescent↗
PubMed1995

The T-cell receptor beta locus and susceptibility to multiple sclerosis.

Assessments of genetically determined variations in the T-cell antigen receptor in multiple sclerosis (MS) have yielded conflicting results. We used three restriction fragment length polymorphisms (RFLPs) and a polymorphic microsatellite repeat as markers for the T-cell receptor (TCR) beta locus (7q32-35) in multiplex MS families. Affected sibling-pair analysis of the RFLP data failed to show evidence for linkage (127 families) whereas analysis of the microsatellite data (86 families) provided weak evidence for linkage with a maximum lod score of 0.98 (p < 0.05). We repeated the analysis in those families (n = 53) in which the affected sibling pairs were concordant for the HLA haplotype DR15/DQ6. This altered the proportion of affected siblings sharing 0, 1, 2 RFLP haplotypes from 0.24, 0.50, and 0.26 (p = NS) before stratification to 0.16, 0.41, and 0.43 (p < 0.05) in the DR15/DQ6 positive pairs alone; for the microsatellite data, sharing altered from 0.16, 0.50, and 0.34 (p < 0.05) in all pairs to 0.07, 0.49, and 0.44 (p < 0.01) in the DR15/DQ6 concordant siblings.

Adult↗
PubMed1995

Correlations between changes in disability and T2-weighted brain MRI activity in multiple sclerosis: a follow-up study.

We obtained two conventional unenhanced T2-weighted brain MRI scans, separated by an interval of 24 to 36 months, in 281 patients with multiple sclerosis (MS). At the time of each scan, clinical disability was rated using the Kurtzke Expanded Disability Status Scale (EDSS). Changes in disability between the two examinations correlated weakly but significantly with the number of new (Spearman's rank correlation coefficient = 0.13; p = 0.02) and enlarging (Spearman's rank correlation coefficient = 0.18; p = 0.002) MRI lesions. This result suggests that brain T2-weighted MRI is a useful supplementary marker of disease activity in definitive (phase III) clinical treatment trials in MS.

Adult↗
PubMed1995

Ex-vivo whole blood cultures for predicting cytokine-release syndrome: dependence on target antigen and antibody isotype.

Ex-vivo whole blood assays have been evaluated for their ability to accurately predict the risk of a first-dose cytokine reaction developing in vivo following therapeutic antibody infusion. Tumour necrosis factor alpha (TNF alpha) release was rapidly detected in cultures incubated with either anti-CD52 antibodies of the human IgG1 or rat IgG2b isotype, and to a lesser extent with a human IgG4 isotype. Endotoxin contamination of the antibodies was not responsive for cytokine release, since polymixin B failed to inhibit cytokine release using concentrations of this antibiotic which neutralized the enhanced cytokine release seen from LPS-spiked antibody. A rat IgG2b antibody to CD45 and a human IgG1 anti-CD3 also induced significant TNF release, however, an aglycosyl anti-CD3 mutant devoid of adverse side-effects in vivo, did not result in cytokine release in vitro. Since the pattern of cytokine release seen following the clinical use of these antibodies was in good agreement with the findings of the ex-vivo whole cultures, this demonstrates the usefulness of this assay to predict cytokine release in vivo.

Adult↗
PubMed1994

Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis.

The observation of a multiple sclerosis (MS)-like illness in patients, particularly women, who carry the most common Leber's hereditary optic neuropathy mitochondrial DNA (mtDNA) mutation may indicate a contributory role for mitochondrial genes in genetic susceptibility to MS. We screened 307 unrelated MS patients, ascertained from population surveys, for the pathogenic Leber's hereditary optic neuropathy mutations at positions 11778 and 3460 of mtDNA, and also studied 20 patients with prominent and early optic nerve involvement. In addition, these 307 patients and 129 control subjects were investigated for the base change at position 13708, which has been suggested to play a role in the pathogenesis of Leber's hereditary optic neuropathy. Neither of the pathogenic mtDNA mutations occurred in the unselected MS patients. The 13708 base change was present in MS patients at a frequency similar to that in healthy control subjects. Three of the patients selected on the basis of severe optic nerve involvement had either the 11778 (one) or 3460 (two) mutations associated with Leber's hereditary optic neuropathy. All were women and none had affected relatives. We conclude that these mutations do not contribute to genetically determined susceptibility in typical MS patients, although a mitochondrial genetic component in the etiology of MS remains possible. A subgroup of MS patients, particularly females with severe bilateral visual failure due to optic neuropathy, may harbor a Leber's hereditary optic neuropathy mutation and we suggest that mtDNA analysis is appropriate in these patients.

Adult↗
PubMed1994

Cerebrospinal fluid concentrations of the complement MAC inhibitor CD59 in multiple sclerosis and patients with other neurological disorders.

Rodent oligodendrocytes have a unique susceptibility among glia to the lytic effects of complement, due in part to a deficiency in CD59 (protectin), a key surface inhibitor of the complement membrane attack complex (MAC). The possibility that shedding of CD59 by human oligodendrocytes contributes to complement-mediated oligodendrocyte injury in inflammatory demyelinating disease has been investigated by estimating levels of CD59 in cerebrospinal fluid samples from 12 patients with demyelinating disease of the central nervous system and 13 with other neurological diseases. No significant differences were found between patients and controls, or between patients with active and those with clinically inactive demyelinating disease, providing no direct support for oligodendrocyte shedding of CD59 in multiple sclerosis.

Antigens, CD↗
PubMed1994

The effect of methylprednisolone on monocyte eicosanoid production in patients with multiple sclerosis.

The in vitro effect of methylprednisolone on prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and thromboxane B2 (TXB2) synthesis by adherent monocytes was examined using samples of peripheral blood from 15 patients with multiple sclerosis and 18 normal controls. Eicosanoid production by monocytes was reduced in patients compared with controls and there was a dose-dependent inhibitory effect of methylprednisolone on eicosanoid production in both groups. In vitro production of PGE2 and TXB2 but not LTB4 was reduced in patients with multiple sclerosis following intravenous treatment with methylprednisolone compared with pretreatment samples. In a separate cohort of 20 patients with multiple sclerosis and 15 controls, the in vitro inhibition of PGE2 release by methylprednisolone was not associated with reduced pokeweed-mitogen-stimulated immunoglobulin G synthesis by peripheral blood mononuclear cells. These results suggest that methylprednisolone inhibits monocyte-macrophage function, but this effect is not specific to patients with multiple sclerosis.

Adult↗
PubMed1994

No linkage between multiple sclerosis and the T cell receptor alpha chain locus.

Susceptibility to multiple sclerosis (MS) is genetically determined but it is thought that more than one gene contributes to development of the disease. We report a study of linkage to one candidate, the T cell receptor alpha chain locus, on chromosome 14, in affected sibling pairs. Markers with high polymorphism information contents were used to assign haplotypes identical by descent and state. Forty nine pairs were studied using restriction fragment length polymorphisms (RFLP) and 82 pairs were investigated using a microsatellite repeat polymorphism. In neither case did genotype or haplotype sharing differ significantly from expected rates. Stratification of patients according to DR15 status did not alter the distribution of haplotypes in affected siblings. We conclude that the T cell receptor alpha locus is not linked to susceptibility in patients with MS from the United Kingdom.

Base Sequence↗
PubMed1994

No linkage or association between multiple sclerosis and the myelin basic protein gene in affected sibling pairs.

Myelin basic protein was examined as a candidate gene for susceptibility to multiple sclerosis using two adjacent amplification fragment length polymorphisms (AmpFLPs), containing seven and six highly informative alleles respectively. No allelic association was found with multiple sclerosis, comparing 77 cases and 88 controls, and there was no evidence for linkage in 73 affected sibling pairs, using the methods of identity by descent and identity by state.

Adult↗
PubMed1994

A placebo-controlled trial of isoprinosine in patients with multiple sclerosis.

Isoprinosine was used under double-blind, randomised, and placebo-controlled conditions in 52 patients with relapsing/remitting or progressive multiple sclerosis. All patients received pulsed treatment with methylprednisolone. There was no significant effect of treatment on clinical disability or the accumulation of MRI abnormalities, after correction of results for multiple comparisons. It is concluded that isoprinosine is not effective therapy for multiple sclerosis.

Administration, Oral↗
PubMed1994

British Isles survey of multiple sclerosis in twins: MRI.

64/105 subjects who have a twin with multiple sclerosis included in a study of clinical concordance also underwent MRI of the brain. 8/23 monozygotic and 1/41 dizygotic co-twins from this subgroup were clinically concordant of whom 8/9 had MRI appearances typical of multiple sclerosis. Of the 48 clinically discordant twins aged less than 60, abnormalities on MRI were detected in 6/15 (40%) monozygotic and 13/33 (39%) dizygotic twins compared with 7/37 (19%) healthy age-matched controls. Abnormalities on MRI typical of multiple sclerosis (defined by the Fazekas criteria) were, however, present in only 2/15 (13%) monozygotic and 3/33 (9%) dizygotic twins and 0/37 controls. These results suggest that about 10% of monozygotic and dizygotic twins have "subclinical multiple sclerosis". It is likely that most of the MRI abnormalities seen in clinically discordant twins, however, represent incidental pathology.

Adolescent↗
PubMed1994

The British Isles survey of multiple sclerosis in twins.

During a 27-month recruitment period, we identified 146 individuals with multiple sclerosis (MS) who have a twin. A single clinician interviewed and examined 105 pairs of twins, and we confirmed zygosity using minisatellite probes. Including two suspected cases, 11 of 44 (25%) monozygotic twin pairs were concordant compared with two of 61 (3%) dizygotic twin pairs--two of 33 (6%) like-sexed and zero of 28 (0%) opposite-sexed. MRI was performed in 64 of 105 co-twins, and showed abnormalities consistent with demyelination in 13% of monozygotic and 9% of dizygotic co-twins who were clinically unaffected. These findings are similar to the results of most previous studies of MS in twins in which zygosity was not unequivocally established and where the majority of clinically unaffected co-twins were not studied by MRI; the difference in concordance rates in monozygotic and dizygotic twins indicates a significant genetic component in the etiology of MS.

Adolescent↗