ORCID Profile
0000-0002-7817-8832
Current Organisations
Leeds Teaching Hospitals NHS Trust
,
University of Leeds
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2004
DOI: 10.1161/01.STR.0000117238.75736.53
Abstract: Background and Purpose— Genetic influences are important in multifactorial cerebral small-vessel disease (SVD) and may act via endothelial dysfunction. Nitric oxide (NO) synthesized by endothelial nitric oxide synthase (eNOS) is a key mediator of endothelial function. We determined the role of 3 potentially functional eNOS polymorphisms (T-786C, intron 4ab, G894T) located toward the 5′ flanking end of the gene as risk factors for SVD and different SVD subtypes: isolated lacunar infarction (n=137) and ischemic leukoaraiosis (n=160). Methods— Three hundred patients with SVD and 600 community controls were studied. Genotypes were determined through polymerase chain reaction with or without restriction fragment digestion. Nitrate (NO x ) levels were determined in a subgroup by use of a Griess method. Polymorphisms were tested in idually and in combination with haplotype analysis. Results— The intron 4a variant was protective against SVD. This effect was confined to isolated lacunar infarction (odds ratio, 0.55 95% confidence interval, 0.35 to 0.86 P =0.01). Haplotypes encountered were significantly different in this subtype compared with controls ( P =0.001), with the -786C promoter/intron 4a combination particularly underrepresented. NO x levels were associated with the T-786C locus ( P =0.03) but only in the presence of the intron 4a allele ( P =0.07 for interaction). Conclusions— The intron 4ab insertion/deletion genotype was associated with isolated lacunar infarction. Haplotype and functional studies suggested that the protective effect of the 4a variant could be mediated through changes in eNOS promoter activity and increased NO levels. The specific association with isolated symptomatic lacunar infarction and not ischemic leukoaraiosis may reflect different etiopathogeneses of the 2 subtypes. Lack of NO could predispose to localized microatheroma in proximal arterioles rather than diffuse arteriosclerosis affecting distal perforating vessels.
Publisher: Oxford University Press (OUP)
Date: 2004
DOI: 10.1093/BRAIN/AWH023
Publisher: Elsevier BV
Date: 04-2007
DOI: 10.1016/J.CLINEURO.2006.11.002
Abstract: Behçet's disease is a chronic relapsing multisystem vasculitis with 49% of cases involving the CNS. Recently there have been two reports of neuro-Behçet's disease (NB) successfully treated with the tumour necrosis factor alpha (TNFalpha) monoclonal antibody infliximab. We describe a patient with longstanding NB who was poorly responsive to azathioprine, cyclosporin, thalidomide and methotrexate. She showed a remarkable response when treated with the recombinant human TNFalpha receptor protein, etanercept. To the best of our knowledge this is the first report of NB successfully treated with etanercept.
Publisher: BMJ
Date: 04-1996
Abstract: To test the design and feasibility of a very large randomised controlled trial assessing the efficacy and safety of antithrombotic therapy started within 48 hours of symptom onset in patients with suspected acute ischaemic stroke. Randomised controlled multicentre open study, with a 3 x 2 factorial design, allocating patients to: medium dose subcutaneous heparin (12,500 units twice per day), versus low dose subcutaneous heparin (5000 units twice per day) versus no heparin and aspirin (300 mg daily) versus no aspirin. Treatment was given for two weeks or until discharge from hospital if sooner. 984 patients were randomised. CT was performed in 924 (94%) (before randomisation in 622/984 (63%). Within 14 days: 97 patients had died (10%), 30 (3.0%) had a fatal or non-fatal recurrent ischaemic stroke, nine (0.9%) had fatal or non-fatal recurrent stroke due to intracranial haemorrhage, and eight (0.8%) had a fatal or non-fatal pulmonary embolus. At six months, vital status was known for 975 patients (99%), of whom 210 (22%) were dead, 373 (38%) were alive but dependent, and 225 (23%) were independent but not fully recovered. The trial procedures proved practicable and a wide variety of patients were recruited. S le size calculation based on the event rates confirmed that reliable evidence on the balance of risk and benefit of early antithrombotic therapy might require a study with more than 20,000 patients. Recruitment rates in the pilot study indicated that if about 200 hospitals participated, recruitment could be completed by 1997.
Publisher: Oxford University Press (OUP)
Date: 02-2003
DOI: 10.1093/BRAIN/AWG040
Abstract: Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood s les. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P <or= 0.006). The ischaemic leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of leukoaraiosis (P <or= 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for John Bamford.