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Biomedical subjects

Andrew Brown

Publications and source records attributed to Andrew Brown.

17 recordsLinked to original sources
PubMed2006

Identifying inflamed carotid plaques using in vivo USPIO-enhanced MR imaging to label plaque macrophages.

BACKGROUND: Inflammation within atherosclerotic lesions contributes to plaque instability and vulnerability to rupture. We set out to evaluate the use of a macrophage labeling agent to identify carotid plaque inflammation by in vivo magnetic resonance imaging (MRI). METHODS AND RESULTS: Thirty patients with symptomatic severe carotid stenosis scheduled for carotid endarterectomy underwent multi-sequence MRI of the carotid bifurcation before and after injection of ultrasmall superparamagnetic particles of iron oxide (USPIOs). USPIO particles accumulated in macrophages in 24 of 30 plaques (80%). Areas of signal intensity reduction, corresponding to USPIO/macrophage-positive histological sections, were visualized in 24 of 27 (89%) patients, with an average reduction in signal intensity induced by the USPIO particles of 24% (range, 3.1% to 60.8%). CONCLUSIONS: USPIO-enhanced MRI can identify plaque inflammation in vivo by accumulation of USPIO within macrophages in carotid plaques.

Carotid Stenosis↗
PubMed2006

Differential modulatory effects of annexin 1 on nitric oxide synthase induction by lipopolysaccharide in macrophages.

Annexin-1 (ANXA1) is a glucocorticoid-regulated protein that modulates the effects of bacterial lipopolysaccharide (LPS) on macrophages. Exogenous administration of peptides derived from the N-terminus of ANXA1 reduces LPS-stimulated inducible nitric oxide synthase (iNOS) expression, but the effects of altering the endogenous expression of this protein are unclear. We transfected RAW264.7 murine macrophage-like cell lines to over-express constitutively ANXA1 and investigated whether this protein modulates the induction of iNOS, cyclooxygenase-2 (COX-2) and tumour necrosis factor-alpha (TNF-alpha) in response to LPS. In contrast to exogenous administration of N-terminal peptides, endogenous over-expression of ANXA1 results in up-regulation of LPS-induced iNOS protein expression and activity. However, levels of iNOS mRNA are unchanged. ANXA1 has no effect on COX-2 or TNF-alpha production in response to LPS. In experiments to investigate the mechanisms underlying these phenomena we observed that activation of signalling proteins classically associated with iNOS transcription was unaffected. Over-expression of ANXA1 constitutively activates extracellular signal regulated kinase (ERK)-1 and ERK-2, components of a signalling pathway not previously recognized as regulating LPS-induced iNOS expression. Inhibition of ERK activity, by the inhibitor U0126, reduced LPS-induced iNOS expression in our cell lines. Over-expression of ANXA1 also modified LPS-induced phosphorylation of the ERK-regulated translational regulation factor eukaryotic initiation factor 4E. Our data suggest that ANXA1 may modify iNOS levels by post-transcriptional mechanisms. Thus differential effects on iNOS expression in macrophages are seen when comparing acute administration of ANXA1 peptides versus the chronic endogenous over-expression of ANXA1.

Animals↗
PubMed2006

Osteogenic protein-1 : a review of its utility in spinal applications.

The potentially revolutionary effect that bone morphogenic proteins (BMPs) could have on orthopaedic surgery has fueled an exhaustive research effort that continues today. Upwards of 1.5 million bone-grafting operations take place in the US annually, with the anterior and posterior iliac crest being the most common donor site for autologous bone graft. Harvesting autologous bone graft, however, is not benign. It is postulated that a synthetic bone graft containing BMPs would possess the characteristics of autologous bone that allow new bone formation: osteogenesis, osteoinduction, and osteoconduction, without the negative repercussions related to bone harvesting. As a result of the ensuing research following their discovery some 40 years ago by Marshall Urist, the basic science behind BMPs has been largely uncovered. New information on BMPs now comes from clinical trials regarding their utility and efficacy in surgical applications. To date, BMPs have been studied in skeletal bone surgery throughout the body, and have been found to be particularly useful in surgical applications such as spinal arthrodesis. Osteogenic protein-1 (OP-1), or recombinant human BMP-7, is one subtype of BMPs that has shown particular potential in clinical trials. Pre-clinical and clinical studies have, thus far, garnered OP-1 a Humanitarian Device Exemption approval for spinal applications in the US. As clinical trials with larger patient numbers and longer clinical follow-up are completed, the usefulness of OP-1 as a bone graft substitute will be better elucidated.

Animals↗
PubMed2005

Stress analysis of carotid plaque rupture based on in vivo high resolution MRI.

Atheromatous carotid plaque rupture is responsible for the majority of ischaemic strokes in the developed world. Plaque rupture has been associated with plaque morphology, plaque components' properties, inflammation and local stress concentration. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in vivo. This study combined the recent advances in finite element analysis (FEA) and MRI, and performed stress analysis of five vulnerable carotid plaques based on the geometry derived from in vivo MRI. Image segmentation was based on multi-spectral MRI and co-registered with histology for plaque characterization. Plaque fibrous cap, lipid pool and vessel wall were modelled as isotropic, incompressible hyperelastic materials undergoing large deformation under pulse pressure loading. High stress concentrations were predicted at the shoulders and the thinnest fibrous cap regions of the plaque, and the mean maximal stresses were found to be higher in the ruptured plaques (683.3 kPa) than those in the unruptured plaques (226.9 kPa). The effect of the relative stiffness of fibrous cap to lipid pool on the stress within the cap itself was studied. It was shown that larger relative stiffness of fibrous cap to lipid pool resulted in higher stress within the cap. Thus, it is likely that high stress concentrations in vulnerable plaque may cause plaque rupture and lead to acute ischaemic sequelae. A combination of in vivo high resolution MRI and FEA could potentially act as a useful tool to assess plaque vulnerability and risk stratify patients with carotid atheroma.

Aged↗
PubMed2005

Neuropathology of dementia in Parkinson's disease: a prospective, community-based study.

Twenty-two patients with Parkinson's disease drawn from a community-based study were followed prospectively until their deaths. Even though 18 patients had dementia, none fulfilled Braak and Braak or The National Institute on Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association, whereas all patients had limbic or neocortical Lewy body disease. The Lewy body score and Braak and Braak stage were significantly associated with the rate of cognitive decline, but only the Lewy body score was associated with the rate of cognitive decline in the univariate analyses. This study strongly suggests that Lewy body disease is the main substrate driving the progression of cognitive impairment in Parkinson's disease.

Aged↗
PubMed2005

Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Anti-tumor necrosis factor alpha agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12-month double-blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor-prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months. METHODS: All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months. RESULTS: Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C-reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX-treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between-group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05). CONCLUSION: Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.

Antibodies, Monoclonal↗
PubMed2004

Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies.

We have analyzed genetic data for 326 microsatellite markers that were typed uniformly in a large multiethnic population-based sample of individuals as part of a study of the genetics of hypertension (Family Blood Pressure Program). Subjects identified themselves as belonging to one of four major racial/ethnic groups (white, African American, East Asian, and Hispanic) and were recruited from 15 different geographic locales within the United States and Taiwan. Genetic cluster analysis of the microsatellite markers produced four major clusters, which showed near-perfect correspondence with the four self-reported race/ethnicity categories. Of 3,636 subjects of varying race/ethnicity, only 5 (0.14%) showed genetic cluster membership different from their self-identified race/ethnicity. On the other hand, we detected only modest genetic differentiation between different current geographic locales within each race/ethnicity group. Thus, ancient geographic ancestry, which is highly correlated with self-identified race/ethnicity--as opposed to current residence--is the major determinant of genetic structure in the U.S. population. Implications of this genetic structure for case-control association studies are discussed.

Case-Control Studies↗
PubMed2004

The centenary of the discovery of the Bragg peak.

Bragg published curves for ionization of air by radium alpha particles in December 1904 demonstrating that ionization density increased sharply near the end of range. The accepted view was that ionization would decrease exponentially with depth. This depth dose pattern is the basis for the dose distributional advantage of charged particles relative to photons.

Alpha Particles↗
PubMed2004

Association of kidney function and hemoglobin with left ventricular morphology among African Americans: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Left ventricular (LV) hypertrophy (LVH) is present in more than 70% of patients with kidney failure. Hypertension and anemia, 2 strong risk factors for LVH, are common in patients with moderate kidney dysfunction. It is unknown whether kidney function and lower hemoglobin levels are associated with LV morphological characteristics among African Americans with moderate kidney dysfunction, independent of blood pressure. METHODS: As part of the Atherosclerosis Risk in Communities Study, 1,968 African Americans aged 50 to 75 years underwent an echocardiogram after 6 to 9 years of follow-up. LV mass was indexed (LVMI) to body surface area. Glomerular filtration rate (GFR) was estimated from calibrated serum creatinine levels measured at baseline and after 3 years (<30 mL/min/1.73 m2 excluded). Hemoglobin was measured at baseline and after 3 years. Blood pressure was measured every 3 years. RESULTS: A mean GFR of 30 to 59 mL/min/1.73 m2 was associated with a 15.3 g/m2 greater LVMI, 0.9 mm greater posterior wall thickness, and 1.0 mm greater interventricular septal thickness compared with a GFR of 90 mL/min/1.73 m2 or greater. These associations remained after adjustment for age, sex, hemoglobin level, blood pressure, and other covariates. Wall thickness and LVMI increased with lower GFR less than 75 mL/min/1.73 m2 (5.5 g/m2 greater LVMI [95% confidence interval (CI), 0.9 to 10.1] per 10 mL/min/1.73 m2 lower GFR). A lower hemoglobin level was associated with greater LV diameter (0.5 mm [95% CI, 0.2 to 0.7] per 1 g/dL [10 g/L]), but not wall thickness, after adjustment. CONCLUSION: These results in a general population sample of middle-aged African Americans suggest that moderately decreased kidney function independently predicts greater LV wall thickness, and lower hemoglobin level independently predicts greater LV diameter. These findings may explain, in part, the high risk for cardiovascular disease observed among individuals with kidney disease.

Black or African American↗
PubMed2003

Detection of rare disseminated tumor cells identifies head and neck cancer patients at risk of treatment failure.

PURPOSE: This study was designed to help establish the most appropriate samples and tests to detect disseminated tumor cells (DTCs) for head and neck cancer patients. EXPERIMENTAL DESIGN: Samples of bone marrow (BM) and central venous blood (CVB), collected preoperatively, and BM and peripheral venous blood, collected 3 months transcription postoperatively, were screened for the presence of DTCs using immunocytochemistry (ICC) with a pan-cytokeratin antibody and E48 reverse transcriptase-PCR. The molecular approach was also applied to intraoperative CVB. RESULTS: The concordance between the molecular and ICC tests applied to preoperative samples, measured by Cohen's kappa, was not uniformly good, which likely reflected sampling errors, heterogeneity of E48 antigen expression, or stochastic effects. However, testing samples of BM and CVB preoperatively with the molecular or ICC approaches gave results that predicted disease-free survival and distant-metastases-free survival. Application of a single preoperative test predicted development of distant metastases, and the prediction could be improved by combining information derived from testing both CVB and BM. Applying two tests to the same sample of blood or BM served to validate the findings from a single assay but did not improve the prediction. Testing the intraoperative sample of CVB was also a sensitive predictor of distant metastases, but testing BM or blood 3 months postsurgery was not useful. CONCLUSIONS: These findings suggest that detection of DTCs pre- or intraoperatively indicates a high risk of local and distant recurrence and reduced survival in head and neck cancer.

Bone Marrow↗
PubMed2003

Evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension.

BACKGROUND AND PURPOSE: Hypertension is an important risk factor for stroke, and the 2 diseases may share susceptibility genes in common. We sought to identify genomic regions influencing susceptibility to both hypertension and stroke. SUBJECTS AND METHODS: Genome-wide linkage scans were performed in samples of 338 white and 265 black hypertensive sibships recruited by the Genetic Epidemiology Network of Arteriopathy Study of the NHLBI Family Blood Pressure Program (FBPP). The hypertensive sibships were stratified by positive (+FH) or negative (-FH) family history of stroke. Genome-wide scans were repeated in each stratum, and the results were compared within each ethnic group by a regression-based analysis of heterogeneity. RESULTS: In whites, the best evidence for linkage was found on chromosome 16 in the unstratified sample of hypertensive sibpairs (logarithm of odds [LOD]=1.85 at 71 cM). In blacks, the best evidence for linkage was found on chromosome 2 in the unstratified sample of hypertensive sibpairs (LOD=1.95 at 230 cM). Additional evidence for linkage (LOD >or=1.5) was observed among white hypertensive sibpairs with a -FH on chromosome 13 and among black hypertensive sibpairs with a +FH of stroke on chromosome 19. CONCLUSIONS: Significant evidence for linkage heterogeneity among hypertensive sibpairs stratified by family history of stroke suggests the presence of genes influencing susceptibility to both hypertension and stroke on chromosomes 13 (whites) and 19 (blacks). Although no significant evidence of heterogeneity was observed on chromosome 16 in whites and chromosome 2 in blacks, these chromosomes do provide evidence of linkage to hypertension.

Adult↗
PubMed2003

Genome-wide linkage analyses for hypertension genes in two ethnically and geographically diverse populations.

We report the results of a genome-wide linkage scan for hypertension genes in 450 African American hypertensive sibpairs from Jackson, MS, and 539 non-Hispanic white hypertensive sibpairs from Rochester, MN. In the Jackson samples we identified one LOD score peak >1.0 on chromosome 1. In the Rochester sample, no genomic region had a LOD score >1.0. These analyses provide no appreciable evidence of hypertension genes with strong effects independent of other genetic and environmental contexts and suggest that stratified linkage analyses may be required to identify hypertension susceptibility genes in these populations.

Adult↗
PubMed2002

Caveats in the neuropsychological assessment of African Americans.

This preliminary investigation examined the predictive accuracy of six neuropsychological tests in a population of non-brain-injured African Americans. False positives were unacceptably high on five of the neuropsychological tests administered. These pilot data raise important questions about the utility of neuropsychological test norms with groups dissimilar in sociocultural background to the normative population. These findings are examined in terms of the relative merits of the race-homogenous and race-comparative paradigms and underscore the importance of conducting normative studies that involve ethnic minority populations.

Black or African American↗
PubMed1999

Obesity Hypertension in the Atherosclerosis Risk in Communities Cohort: Implications of Obesity Guidelines.

An estimated 55% of the U.S. adults are overweight or obese (body mass index [BMI] equals 25 kg/m2). Overweight individuals have a threefold increased risk for the development of hypertension compared to lean individuals. The National Institutes of Health, National Heart, Lung, and Blood Institute (NHLBI) guidelines for treatment of overweight and obese adults recommend weight reduction strategies including pharmacologic treatment with antiobesity agents approved by the FDA. Treatment is recommended for obese individuals and for overweight persons with other risk factors for cardiovascular disease (CVD) including hypertension. This analysis of the Atherosclerosis Risk In Communities (ARIC) cohort for overweight/ obese hypertensive participants indicate that 64% of the hypertensive participants in ARIC deserve consideration for treatment with antiobesity agents according to the current NHLBI guidelines. Thus far there are no long term morbidity and mortality clinical trials to determine the safety of antiobesity agents currently approved by the FDA. The authors caution health care providers in the use of these agents in the obese patient with hypertension. (c)1999 by Le Jacq Communications, Inc.

Journal Article↗