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Jonathan Golledge

Publications and source records attributed to Jonathan Golledge.

13 recordsLinked to original sources
PubMed2007

Association between IL-8 cytokine and cognitive performance in an elderly general population--the MEMO-Study.

OBJECTIVES: To investigate the associations between circulating cytokines and specific neuropsychological domains of cognitive functioning (memory, processing speed and motor function) and general cognitive function (MMSE) in healthy elderly individuals. METHODS: In a cross-sectional study of 369 community dwelling elderly subjects, we examined the relationship between serum IL-1beta, sIL-4R, IL-6, IL-8, IL-10, IL-12 and TNF-alpha concentrations and cognitive performance using an extensive standardized and validated cognitive test battery assessing memory, word fluency, perceptual/cognitive speed, attention and executive functioning, and motor speed. RESULTS: Multivariate analysis adjusted for various confounders and Bonferroni correction for multiple comparisons demonstrated that increased serum concentrations of IL-8 were associated with poor performance in the memory and speed domains and in motor function. No significant associations were found between the remaining cytokines and domains of cognitive functioning. Global cognitive functioning, as measured with MMSE, was not associated with any cytokine. CONCLUSIONS: This study suggests an association between circulating IL-8 concentrations and cognitive dysfunction in the elderly. An interaction between this cytokine and glial cells may help explain the pathophysiological mechanisms leading to cognitive impairment in our study group.

Aged↗
PubMed2006

Association between osteopontin and human abdominal aortic aneurysm.

OBJECTIVES: In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm (AAA) was investigated. METHODS AND RESULTS: OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P=0.004) for the population cohort and 4.08 (1.67 to 10.00, P=0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P=0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion. CONCLUSIONS: Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth.

Adult↗
PubMed2006

Association of obesity and metabolic syndrome with the severity and outcome of intermittent claudication.

BACKGROUND: Obesity is recognized as an independent predictor of coronary artery disease; however, its importance in peripheral arterial disease is less clear. The aim of this study was to assess the association between obesity and the severity and outcome of intermittent claudication. METHODS: This study was a prospective cohort study based at a tertiary referral center. Sixty patients with intermittent claudication selected for conservative treatment were assessed for obesity and metabolic syndrome by using the International Diabetes Federation definition. Other risk factors, including diabetes, hypertension, smoking history, serum lipids, adipocytokines, and C-reactive protein, were measured by clinical and blood assessment. Obesity and metabolic syndrome were related to the severity of peripheral arterial disease, defined by ankle-brachial pressure index and graded treadmill measured maximum walking distance (MWD) and initial claudication distance, by using multiple linear regression analysis allowing for traditional atherosclerotic risk factors. Patients were followed up for 24 months, and combined outcome was reported in terms of death, cardiovascular events, or requirement for revascularization. The effect of obesity and metabolic syndrome on outcome was investigated by using Kaplan-Meier and Cox proportional hazard analysis. RESULTS: Obesity and serum adiponectin were independently associated with the severity of peripheral arterial disease measured by ankle-brachial pressure index (P = .03 and .001), initial claudication distance (P = .009 and .03), and MWD (P = .001 and .04). Metabolic syndrome was independently associated only with MWD (P = .02). By 24 months, outcome events occurred in 37% +/- 7% and 43% +/- 9% of patients with metabolic syndrome or obesity, respectively, compared with 0% and 11% +/- 6% of those without these diagnoses. Waist circumference independently predicted the likelihood of outcome events (relative risk, 1.16; 95% confidence interval, 1.08-1.26; P < .001). CONCLUSIONS: These findings, if confirmed in other cohorts, suggest the importance of treating obesity in patients with intermittent claudication. Serum adiponectin concentrations may be an important guide to the efficacy of treatment in patients with intermittent claudication and obesity.

Aged↗
PubMed2006

Abdominal aortic aneurysm: pathogenesis and implications for management.

Abdominal aortic aneurysm (AAA) affects approximately 5% of elderly men and is responsible for a significant number of deaths in Western Countries. At present surgery by open or endovascular means is the only widely used therapy for this condition. In this review we examine the risk factors, serum, and genetic associations of AAA. Epidemiology studies suggest that smoking cessation and control of cholesterol and blood pressure should reduce the number of patients developing AAA. Natural history studies suggest that smoking cessation should reduce the rate of progression of AAA. Clear level 1 evidence for drug treatments of AAA are presently lacking; however, animal and human in vitro studies suggest that medication targeted at reducing inflammation and proteolysis are most likely to be beneficial, with limited data to support the use of statins, Angiotensin II inhibitors, and macrolides. Work has commenced in understanding which patients, identified by clinical, serum, and genotype, are more at risk of AAA progression and thus should be selected out for aggressive treatment. Well designed large multicenter randomized controlled trials are required to examine the medical treatment of AAA.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Association of osteoprotegerin with human abdominal aortic aneurysm progression.

BACKGROUND: Abdominal aortic aneurysm (AAA) is characterized by destruction of the arterial media associated with loss of vascular smooth muscle cells, infiltration of mononuclear cells, and high concentration of metalloproteinases (MMPs) and cytokines. Osteoprotegerin (OPG) has recently been identified in atherosclerosis. The presence and functional importance of OPG in human AAA was investigated. METHODS AND RESULTS: In 146 men with small AAA followed up by ultrasound for 3 years, serum OPG was weakly correlated with aneurysm growth rate. Western analysis showed 3-, 8-, and 12-fold-greater OPG concentrations in human AAA biopsies compared with biopsies of atherosclerotic narrowed aorta (1.4+/-0.1 versus 0.5+/-0.1 ng/mg tissue; P=0.002), postmortem nondiseased abdominal aorta (1.4+/-0.1 versus 0.2+/-0.1 ng/mg tissue; P<0.001), and nondiseased thoracic aorta (1.4+/-0.1 versus 0.1+/-0.06 ng/mg tissue; P<0.001). Healthy human aortic vascular smooth muscle cells incubated with recombinant human (rh)OPG (0 to 20 ng rhOPG/10(5) cells per 1 mL per 24 hours) developed an aneurysmal phenotype defined by impaired cell proliferation (P<0.001), increased apoptosis (P<0.01), and increased MMP-9 (92 kDa) expression (P<0.001). Incubation of monocytic THP-1 cells with 1 ng rhOPG/10(5) cells per 1 mL per 24 hours induced a 2-fold increase in MMP-9 expression (P<0.001), a 1.5-fold increase in MMP-2 activity (P=0.005), and a 2-fold stimulation of IL-6 production in these cells (P=0.02). Finally, secretion of OPG from human AAA explant was abrogated by treatment with the angiotensin II blocker irbesartan, with the reduction in secreted levels averaging 63.0+/-0.9 ng/mg tissue per 48-hour period. CONCLUSIONS: These findings support a role for OPG in the growth of human AAA and suggest a potential benefit for angiotensin II blockade in slowing aneurysm expansion.

Adult↗
PubMed2004

Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis.

BACKGROUND AND PURPOSE: The aim of this study was to compare the concentration of osteoprotegerin (OPG), receptor activator of nuclear factor kappaB ligand (RANKL), and osteopontin (OPN) in stable (asymptomatic) and unstable (symptomatic) carotid atherosclerosis. In addition, we were interested in the effect of angiotensin II blockade on the secretion of these proteins by unstable atherosclerosis. METHODS: Endarterectomy samples removed from patients with recent (within 6 weeks) or no previous focal neurological symptoms were assessed by immunohistochemistry, Western analysis, and explant culture. Concentrations of OPG, RANKL, and OPN were measured by mean optical density (MOD), densitometry of protein bands, and enzyme-linked immunosorbent assay of supernatants from explant culture, and compared between symptomatic and asymptomatic patients. RESULTS: The concentration of OPG and OPN within the proximal internal carotid (PIC) part of the endarterectomy specimen removed from symptomatic patients was elevated 2- and 4-fold, respectively. Although the concentration of RANKL did not differ according to patients' symptoms, the quantity of OPG secreted by explants of the PIC was greater in explants from symptomatic patients and could be significantly reduced within 48 hours of incubation with the angiotensin II blocker irbesartan. CONCLUSIONS: OPG and OPN are upregulated in symptomatic human carotid atherosclerosis with possible implications for plaque stability. Angiotensin II blockade is able to downregulate OPG secretion in vitro.

Aged↗
PubMed2004

Arterial flow induces changes in venous endothelium which are modified by calcium channel blockers.

INTRODUCTION: Adaptation of saphenous vein to arterial flow may be critical to the results of bypass. The present paper summarizes work recently presented as a Hunterian Lecture. Work includes in vitro investigation of the response of saphenous vein endothelium to arterial flow and assessment of its clinical importance using a cohort of patients undergoing vein bypass surgery. METHODS: Freshly excised human saphenous vein segments were placed in an in vitro flow circuit to simulate arterial and venous flow conditions. Changes in the endothelial expression of proteins were assessed using a combination of immunohistochemistry and Western blotting. The role of ion channels in the changes seen induced by arterial flow in the saphenous vein endothelium was assessed by addition of ion channel blocking medication to the medium perfusing vein segments. A cohort of patients undergoing vein bypass surgery were followed to assess graft patency and the influence of prescribed medication on its outcome. RESULTS: After arterial flow conditions, the staining area for the endothelial adhesin ICAM-1 and nitric oxide synthase were increased, while that of the anticoagulant protein thrombomodulin was decreased. The concentration of the important stimulant of the clotting cascade tissue factor was unaffected by arterial flow. These changes were modulated by the addition of ion channel blocking drugs to the vein perfusate. In particular, nifedipine abolished the reduction in thrombomodulin, but increased the amount of tissue factor. In a series of 236 patients undergoing primary infra-inguinal vein grafts, prescription of calcium channel blocker was associated with improved primary patency. CONCLUSIONS: Important changes in the venous endothelium are induced by arterial flow. Ion channel blocking drugs have the potential to modulate these responses.

Arteries↗
PubMed2002

The intermittent claudication questionnaire: a patient-assessed condition-specific health outcome measure.

INTRODUCTION: As yet, there is no patient-assessed, condition-specific instrument for the assessment of health-related quality of life in intermittent claudication. We evaluated the intermittent claudication questionnaire (ICQ) for properties required of a measure of health outcome. METHODS AND RESULTS: Interviews with patients with intermittent claudication and vascular specialist opinion produced a pool of statements used to itemize a self-completed ICQ. This was piloted in 20 patients for practicality and then administered to 124 stable claudicants. Reliability was assessed through a retest in 63 (51%) patients at 14 days and analysis of Cronbach's alpha for internal consistency. Spearman's correlation coefficient was used to assess construct validity in comparisons between the ICQ and ankle brachial pressure index, treadmill-walking distances, the walking impairment questionnaire, the EuroQol, and the Short Form-36. Responsiveness of the ICQ to changes in health was assessed in 60 patients treated conservatively and 40 patients undergoing angioplasty. The standardized response mean was used to identify the most responsive instrument in the study. A 16-item ICQ with a test-retest intraclass correlation of 0.95 and Cronbach's alpha of.94 was produced. One hundred twenty-one (98%) patients completed the ICQ (mean time, 3.7 minutes). The ICQ correlated better with the EuroQol (r = 0.58) and 7 out of 8 subscales of the Short Form-36 (r = 0.33-0.68) compared with the walking impairment questionnaire. The ICQ demonstrated the largest standardized response mean in relation to health transition compared with the other instruments. CONCLUSIONS: The patient-assessed ICQ is a practical, reliable, valid, and responsive measure of patient health-related quality of life in intermittent claudication.

Adult↗