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Biomedical subjects

C P Hawkins

Publications and source records attributed to C P Hawkins.

At least 19 recordsLinked to original sources
PubMed2006

APOE epsilon variation in multiple sclerosis susceptibility and disease severity: some answers.

BACKGROUND: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. METHODS: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Alleles↗
PubMed2005

Novel polymorphism in the promoter region of the human nerve growth-factor gene.

We describe a novel T to C transition at position -198 from the transcription start of the human nerve growth-factor (NGF) gene. In British Caucasoid healthy control group that we have genotyped, T and C allele frequencies are 0.633 and 0.367, respectively. This polymorphism affects vitamin D receptor (VDR) binding to its motif in the NGF promoter.

Alleles↗
PubMed2004

Susceptibility and outcome in MS: associations with polymorphisms in pigmentation-related genes.

Multiple sclerosis (MS) risk is determined by environment and genes. The authors investigated in 419 cases and 422 controls if polymorphism in the vitamin D receptor (VDR), melanocortin-1 receptor (MC1R), and tyrosinase (TYR) genes is linked with MS risk and outcome. VDR ff was associated with reduced (odds ratio [OR] = 0.59) and MC1R His294-encoding alleles with increased (OR = 2.21) risk. MC1R Glu84/Glu84 was linked with disability (OR = 5.65). These preliminary data suggest a role for these genes in MS pathogenesis.

Adult↗
PubMed2004

Association of protein kinase C alpha (PRKCA) gene with multiple sclerosis in a UK population.

Twin, family and adoption studies suggest that susceptibility to multiple sclerosis is substantially mediated by genetic factors. Linkage to human chromosome 17q, homologous to a locus linked to experimental animal models of multiple sclerosis, has been widely replicated and the region likely to harbour a multiple sclerosis susceptibility gene has recently been refined to a 2.5 Mb region of 17q22-24. The candidate multiple sclerosis susceptibility gene, protein kinase C alpha (PRKCA), maps within this interval and association with 35 single-nucleotide polymorphism (SNP) markers, spanning the gene with a median spacing of 7.8 kb, was tested using a case-control approach. Single-marker genotype and estimated haplotype frequencies were compared in UK unrelated cases with multiple sclerosis (n = 184) and healthy controls (n = 340) in order to investigate association with susceptibility to disease. A haplotype of two SNPs mapping to the proximal region of the gene showed evidence for association with susceptibility (Bonferroni-corrected P value = 1.1 x 10(-5)). These findings suggest that further investigation of the PRKCA gene is warranted, particularly in cohorts with evidence of linkage to 17q22. Most of the SNPs investigated in this study were intronic and screening to identify disease-associated functional mutations is now required. Our results suggest that the promoter and proximal gene region should be not only included but prioritized in any screening strategy.

Adult↗
PubMed2003

Does trauma trigger multiple sclerosis? 1: A controversy.

The potential role of trauma in the development of multiple sclerosis is important but controversial. Patients commonly ask about this and it has important medicolegal ramifications. In addressing such issues this article will consider both physical and psychological trauma, examine pathogenic mechanisms, and discuss the evidence for and against a relationship.

Blood-Brain Barrier↗
PubMed2003

Does trauma trigger multiple sclerosis? 2: A medicolegal view.

Set against the scientific debate in multiple sclerosis are a number of medicolegal cases in which the scientific evidence has been examined in the context of specific events. It is instructive to understand something of the legal approach to cause and association, and to consider this in relation to individual cases.

Adult↗
PubMed2002

Interleukin 1 genotypes in multiple sclerosis and relationship to disease severity.

We studied the association between clinical outcome in MS and allelic variants single nucleotide polymorphisms (SNPs) of interleukin-1alpha (IL-1alpha), IL-1beta and a variable number tandem repeat (VNTR) in IL-1 receptor antagonist (IL-1RN). A total of 377 patients with MS were studied. Significant associations between IL-1 genotypes and clinical outcome were found using logistic regression after correction for gender, onset age and disease duration. The same trends were subsequently demonstrated in a second independent group of 67 primary progressive patients. Our results suggest that genetically determined immunomodulation mediated by IL-1 influences long-term prognosis in multiple sclerosis (MS).

Adjuvants, Immunologic↗
PubMed2001

HLA-DRB1 and disease outcome in multiple sclerosis.

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.

Adult↗
PubMed2000

Glutathione S-transferase polymorphisms in MS: their relationship to disability.

BACKGROUND: Oxidative stress has been implicated in inflammatory demyelination. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1/GSTT1), encode low activity variants (GSTP1), or are associated with variable inducibility (GSTM3). OBJECTIVES: To investigate the association between clinical outcome in MS and allelic variants of GSTM1, GSTM3, GSTT1, and GSTP1. METHODS: Four hundred patients with clinically definite MS were studied. Disability was measured using the Kurtzke Expanded Disability Status Scale (EDSS). Disability was graded as mild (EDSS 0-4), moderate (4.5-5.5), or severe (EDSS 6-10). PCR-based genotyping was performed using DNA extracted from lymphocytes. Significant associations between GST genotypes and clinical outcome were corrected for gender, onset age, and disease duration using logistic regression. RESULTS: We found that the GSTM3 AA genotype was associated with severe disability in patients with a disease duration of more than 10 years (p = 0.027, n = 177, OR = 2.4, 95% CI = 1.1-5.0). Homozygosity for both GSTM1*0 and GSTP1*Ile105 containing allele was associated with severe disability in patients with a disease duration greater than 10 years (p = 0.022, n = 179, OR = 5.0, 95% CI = 1.3-19.8). CONCLUSIONS: Our results suggest that long-term prognosis in MS is influenced by a genetically determined ability to remove the toxic products of oxidative stress.

Adult↗
PubMed2000

Correlation of MRI lesions with visual psychophysical deficit in secondary progressive multiple sclerosis.

The aim of this work was, first, to clarify the nature of the relationship between the sensory deficit in the demyelinated visual pathway and morphological changes revealed by MRI and, secondly, to test whether there was a preferential effect of demyelination for either the magnocellular or parvocellular pathway in established multiple sclerosis. Twenty-four patients with secondary progressive multiple sclerosis were studied psychophysically and by MRI of the optic nerve and brain. MRI was performed with a Phillips (0.5T) scanner. Visual pathway MRI lesion load was evaluated independently using the total optic nerve lesion length and lesion area seen on STIR (short inversion time inversion recovery) images of the optic nerve and the total post-chiasmal lesion area on T(1)-, T(2)- and proton-density-weighted images of the brain. Psychophysical tests determined 75%-seeing thresholds for horizontal gratings consisting of isoluminant red and green sinusoids of the same spatial frequency combined out-of-phase for preferential stimulation of the parvocellular system and in-phase for preferential stimulation of the magnocellular system. It was found that, in this group of patients, visual psychophysical loss was significantly correlated with lesion area seen on proton density MRI sequences of the post-chiasmal visual pathway, and that the parvocellular pathway was more affected than the magnocellular pathway, especially at lower spatial frequencies.

Adolescent↗
PubMed2000

Polymorphisms of apolipoprotein E; outcome and susceptibility in multiple sclerosis.

Allelic variants of the apolipoprotein E (APOE) gene influence the course of several neurological diseases. In multiple sclerosis the concentration of APOE in cerebrospinal fluid and its intrathecal synthesis is reduced. Specific isoforms of APOE may also be important and it has been suggested that possession of the epsilon4 allele may be associated with a more aggressive disease process. These data prompted us to re-examine, in a large group of patients with multiple sclerosis, the proposal that allelism in the apolipoprotein gene influences disease course. Genotypes were determined in a well-defined group of 370 unrelated Caucasians with clinically definite multiple sclerosis and in 159 healthy controls. Age at onset, sex, disease duration, disease subtype were recorded. Disability was measured using the Kurtzke expanded disability status score in patients with a disease duration of 10 years or greater. There was no significant difference in APOE allele or genotype frequencies between patients and controls, between disease subtypes or between genders. APOE genotype did not significantly influence age of onset, and no significant relationship between genotype, allele frequency and disease severity was found. This study suggests that individual APOE alleles or genotypes do not determine disease susceptibility or the clinical course of multiple sclerosis.

Adult↗
PubMed1999

The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group.

OBJECTIVE: To determine the effect of humanized monoclonal antibody against alpha4 integrin (reactive with alpha4beta1 integrin or very-late antigen-4) on MRI lesion activity in MS. METHODS: A randomized, double-blind, placebo-controlled trial in 72 patients with active relapsing-remitting and secondary progressive MS was performed. Each patient received two IV infusions of anti-alpha4 integrin antibody (natalizumab; Antegren) or placebo 4 weeks apart and was followed up for 24 weeks with serial MRI and clinical assessment. RESULTS: The treated group exhibited significantly fewer new active lesions (mean 1.8 versus 3.6 per patient) and new enhancing lesions (mean 1.6 versus 3.3 per patient) than the placebo group over the first 12 weeks. There was no significant difference in the number of new active or new enhancing lesions in the second 12 weeks of the study. The number of baseline-enhancing lesions (i.e., lesions that enhanced on the baseline scan) that continued to enhance 4 weeks following the first treatment was not significantly different between the two groups. The number of patients with acute MS exacerbations was not significantly different in the two groups during the first 12 weeks (9 in the treated group versus 10 in placebo) but was higher in the treatment group in the second 12 weeks (14 versus 3; p = 0.005). The study was not, however, designed to look definitively at the effect of treatment on relapse rate. Treatment was well tolerated. CONCLUSIONS: Short-term treatment with monoclonal antibody against alpha4 integrin results in a significant reduction in the number of new active lesions on MRI. Further studies will be required to determine the longer term effect of this treatment on MRI and clinical outcomes.

Adult↗
PubMed1998

MRI of optic nerve and postchiasmal visual pathways and visual evoked potentials in secondary progressive multiple sclerosis.

We studied the relationship between abnormalities shown by MRI and functional disturbances in the visual pathway as assessed by the visual evoked potential (VEP) in 25 patients with established multiple sclerosis (MS); only 4 of whom had a history of acute optic neuritis. Optic nerve MRI was abnormal in 19 (76%) and is thus useful in detecting subclinical disease. Optic nerve total lesion length and area on the STIR sequence was found to correlate significantly with prolongation of the VEP latency. This may reflect a predominantly demyelinating rather than inflammatory origin for the signal change in the optic nerve.

Adult↗
PubMed1998

Biodiversity of stream insects: variation at local, basin, and regional scales.

We review the major conceptual developments that have occurred over the last 50 years concerning the factors that influence insect biodiversity in streams and examine how well empirical descriptions and theory match. Stream insects appear to respond to both spatial and temporal variation in physical heterogeneity. At all spatial scales, the data largely support the idea that physical complexity promotes biological richness, although exceptions to this relationship were found. These exceptions may be related to how we measure habitat complexity at finer spatial scales and to factors that influence regional richness, such as biogeographic history, at broader spatial scales. However, the degree to which local stream insect assemblages are influenced by regional processes is largely unknown.

Journal Article↗