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J David Spence

Publications and source records attributed to J David Spence.

At least 19 recordsLinked to original sources
PubMed2007

Intensive management of risk factors for accelerated atherosclerosis: the role of multiple interventions.

Patients at high risk of vascular events can reduce their risk by 75% to 80% through a combination of lifestyle changes and medical therapy. These include smoking cessation, a Mediterranean diet, daily exercise, maintaining a fit weight, moderate consumption of alcohol, effective control of blood pressure and diabetes, intensive treatment with lipid-lowering drugs and antiplatelet agents, and perhaps treatment with vitamins to lower homocysteine. Much of this is achieved primarily by the patient; physicians need to become better at assisting their patients in making lifestyle changes. Effective control of treatment-resistant hypertension can be improved by individualizing medical therapy to the underlying cause, based on measurement of plasma renin and aldosterone. Measurement of carotid plaque may be useful by providing feedback on the success of therapy.

Atherosclerosis↗
PubMed2007

The effect of mesna on plasma total homocysteine concentration in hemodialysis patients.

BACKGROUND: Plasma total homocysteine (tHcy) level is an independent risk factor for the development of atherosclerosis. The degree of risk in most of the population is decreased by using dietary vitamin supplementation; however, more than 90% of patients with end-stage renal disease have increased tHcy levels despite supplementation. Only a small fraction of tHcy is removed by hemodialysis because of extensive disulfide bonding to albumin. The objective of this study is to determine whether a single intravenous dose of mesna, a thiol-containing drug analogue of taurine, facilitates tHcy clearance during hemodialysis. METHODS: Initial in vitro thiol exchange tests were performed with mesna in plasma from dialysis patients. Mesna, 300 micromol/L (49.2 mg/L), was incubated with plasma at 37 degrees C, and free homocysteine was measured at various times. In vivo, mesna activity was tested in 10 hemodialysis patients by administering 2.5 or 5.0 mg/kg of mesna intravenously at the beginning of a treatment cycle. Blood samples were drawn throughout dialysis, and plasma tHcy levels were compared with those obtained from a previous dialysis session in which mesna was not administered. RESULTS: In vitro, mesna liberated 36.5% +/- 2.5% of protein-bound homocysteine in 30 minutes. In vivo, a single 2.5-mg/kg dose of mesna was ineffective; however, at 5.0 mg/kg, it caused a 55.2% +/- 3.9% decrease in plasma tHcy levels postdialysis compared with a 34.2% +/- 5.3% decrease with dialysis alone (P < 0.001). CONCLUSION: Intravenous mesna causes a rapid decrease in plasma tHcy levels during hemodialysis.

Adult↗
PubMed2006

Carotid ultrasound phenotypes in vulnerable populations.

BACKGROUND: Biomarkers of carotid atherosclerosis range from those that are widely available and relatively simple to measure such as serum cholesterol levels, and B-mode Ultrasound measurement of intima media thickness (IMT) to those that are more complex and technologically demanding but perhaps potentially more sensitive and specific to disease such as total plaque volume and total plaque area measured from 3-dimensional ultrasound images. In this study we measured and compared intima media thickness (IMT), total plaque volume (TPV) and total plaque area (TPA) in two separate populations, both vulnerable to carotid atherosclerosis. METHODS: In total, 88 subjects (mean age 72.8) with carotid stenosis of at least 60%, based on a peak Doppler flow, and 82 subjects (mean age 60.9) with diabetic nephropathy were assessed in a cross-sectional study. Conventional atherosclerotic risk factors were examined and the associations and correlations between these and carotid ultrasound phenotypes measured from B-mode and 3-dimensional ultrasound images were assessed. RESULTS: IMT and TPV were only modestly correlated in the two separate populations (r = .6, p < .01). ANOVA analyses indicated that both IMT and TPV were significantly associated with age (p < .001) and Framingham score (p < .05), but only TPV was associated with diabetes (p < .001) and presence of plaque ulcerations (p < .01) CONCLUSION: IMT and TPV were modestly correlated in a diabetic patient population and only TPV was associated with diabetes and the presence of plaque ulcerations in a diabetic population and carotid stenosis group. The 3-dimensional information provided by TPV can be critically important in unmasking association with risk factors not observed with less complex single-dimension assessments of carotid atherosclerosis such as those provided by IMT.

Aged↗
PubMed2006

Tutorial in biostatistics: Analyzing associations between total plasma homocysteine and B vitamins using optimal categorization and segmented regression.

Data analysts consider standard regression models (e.g., generalized linear model) or nonparametric smoothing techniques (e.g., loess or splines) when examining the association between two variables. Before this step, a quantile-based summarization is typically used for exploring the exposure-response relationship. Unfortunately, these exploratory approaches may not be optimal or efficient for guiding the formal analysis in many biological and nutritional data settings. We suggest a recently developed method for selection of cutpoints as a tool of data summary and segmented regression as a modeling approach in the analysis of plasma total homocysteine and related vitamins. These methods are often complementary in discovering the underlying complex pattern of association.

Algorithms↗
PubMed2006

Nutrition and stroke prevention.

Nutrition is much more important in prevention of stroke than is appreciated by most physicians. The powerful effects of statin drugs in lowering the levels of fasting cholesterol, combined with an unbalanced focus on fasting lipids (as opposed to postprandial fat and oxidative stress), have led many physicians and patients to believe that diet is relatively unimportant. Because the statins can lower fasting lipids by &50% to 60%, and a low-fat diet only lowers fasting cholesterol by &5% to 10%, this error is perhaps understandable. However, a Cretan Mediterranean diet, which is high in beneficial oils, whole grains, fruits, and vegetables and low in cholesterol and animal fat, has been shown to reduce stroke and myocardial infarction by 60% in 4 years compared with the American Heart Association diet. This effect is twice that of simvastatin in the Scandinavian Simvastatin Survival Study: a reduction of myocardial infarction by 40% in 6 years. Vitamins for lowering of homocysteine may yet be shown to be beneficial for reduction of stroke; a key issue is the high prevalence of unrecognized deficiency of vitamin B(12), requiring higher doses of vitamin B(12) than have been used in clinical trials to date. Efforts to duplicate with supplementation the evidence of benefit for vitamins E, C, and beta carotene have been largely fruitless. This may be related to the broad combination of antioxidants included in a healthy diet. A Cretan Mediterranean diet is probably more effective because it provides a wide range of antioxidants from fruits and vegetables of all colors.

Diet↗
PubMed2006

Relationship of the metabolic syndrome to carotid ultrasound traits.

BACKGROUND: The metabolic syndrome is associated with increased vascular disease risk. We evaluated two carotid ultrasound measurements, namely intima media thickness and total plaque volume, in a Canadian Oji-Cree population with a high metabolic syndrome prevalence rate. METHODS: As part of the Sandy Lake Complications Prevalence and Risk Factor Study, 166 Oji-Cree subjects (baseline metabolic syndrome prevalence, 44.0%, according to the National Cholesterol Education Program Adult Treatment Panel III guidelines) were examined using a high-resolution duplex ultrasound scanner. RESULTS: Image analysis showed that mean intima media thickness was elevated in subjects with the metabolic syndrome (818 +/- 18 vs 746 +/- 20 microm), as was total plaque volume (125 +/- 26 vs 77.3 +/- 17.0 mm3). However, after adjustment for age and sex, the differences were significant only for intima media thickness (P = 0.039). Furthermore, a significant trend towards increased intima media thickness was observed with increasing numbers of metabolic syndrome components: mean intima media thickness was highest among individuals with all five metabolic syndrome components compared to those with none (866 +/- 55 vs 619 +/- 23 microm, P = 0.0014). A similar, but non-significant trend was observed for total plaque volume. CONCLUSION: This is the first study of the relationship between the metabolic syndrome and two distinct carotid ultrasound traits measured in the same individuals. The results suggest that standard intima media thickness measurement shows a more consistent and stronger association with the metabolic syndrome than does total plaque volume.

Adult↗
PubMed2006

Thiol exchange: an in vitro assay that predicts the efficacy of novel homocysteine lowering therapies.

Elevated plasma total homocysteine (tHcy) is a risk factor for atherosclerosis. Hcy is 70-80% bound to albumin as a disulfide. Recent trials have evaluated ability of thiol-containing drugs to exchange with protein bound Hcy and consequently increase its renal clearance. The objective of this study was to develop an in vitro assay to predict the efficacy of thiol-containing drugs to lower tHcy in the clinical setting. The assay was used to test the effects of N-acetylcysteine (NAC), mesna, captopril, dimercaptosuccinic acid (DMSA), and penicillamine. Hcy was added in vitro to plasma of healthy subjects (n = 6) and equilibrated. Concentrations of thiol exchange agent were added and incubated at 37 degrees C. Aliquots were removed at selected intervals and free Hcy determined. Mesna, captopril, and NAC caused a concentration-dependent increase in free Hcy. Three-hundred micromolar mesna and captopril had a greater effect than equimolar NAC, increasing free Hcy by 33.9 +/- 5.0% and 32.0 +/- 2.6%, respectively compared to 22.3 +/- 2.4% for NAC, p < 0.001. Our in vitro results indicate that mesna, captopril, and NAC effectively exchange with covalently bound Hcy. This assay can act as screening tool for novel tHcy lowering therapies and should spare the expense of negative trials.

Chemistry, Pharmaceutical↗
PubMed2006

Technology Insight: ultrasound measurement of carotid plaque--patient management, genetic research, and therapy evaluation.

Various methods have been used to quantify atherosclerosis, beginning in the mid-1980s with ultrasound measurement of carotid intima-media thickness (IMT), and going on to coronary calcification assessed by electron-beam CT, measurement of carotid plaque by ultrasound, and measurement of carotid wall thickness by MRI. In recent years, it has become clear that carotid IMT, coronary calcification and carotid plaque reflect biologically and genetically different aspects of the atherosclerotic process, and will respond differentially to therapy. IMT represents mainly hypertensive medial hypertrophy; this measure is more predictive of stroke than of myocardial infarction, and is only weakly associated with traditional coronary risk factors. Carotid plaque area, on the other hand, is more strongly associated with traditional risk factors, and is more predictive of myocardial infarction than of stroke. A quantitative trait, called 'unexplained atherosclerosis', expresses the extent to which an individual has excess carotid plaque not explained by traditional risk factors, or the extent to which an individual is protected from traditional risk factors. Unexplained progression of plaque is an even more powerful tool for genetic research, because age, which accounts for the greatest proportion of baseline plaque, has much less influence on the rate of progression. Compared with IMT, measurement of carotid plaque volume by three-dimensional ultrasound reduces by two orders of magnitude the sample size and duration of treatment needed to evaluate new therapies. Measurement of carotid plaque is, therefore, an important tool for patient management, genetic research and evaluation of new therapies for stroke prevention.

Atherosclerosis↗
PubMed2005

Disparate associations of a functional promoter polymorphism in PCK1 with carotid wall ultrasound traits.

BACKGROUND AND PURPOSE: Cytosolic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32), encoded by PCK1, catalyzes the first committed step in gluconeogenesis. We previously showed that a -232C>G promoter polymorphism within a cis-acting element required for basal and cAMP-mediated PCK1 gene transcription results in loss of negative regulation by insulin, contributing to worsened metabolic control in the context of insulin resistance. We hypothesized that this polymorphism would be associated with carotid atherosclerosis in a sample of 150 aboriginal Canadians. METHODS: Dependent variables were 2 distinct carotid traits, namely intima-media thickness (IMT) assessed using B-mode ultrasound and total carotid plaque volume (TPV) assessed using 3D ultrasound. RESULTS: Multivariate analysis showed significant but opposite associations of PCK1 genotype with these traits. Specifically, subjects with the PCK1-232G/G genotype had more carotid IMT (0.80+/-0.02 versus 0.73+/-0.03 mm; P=0.007) but less TPV (0.10+/-0.09 versus 0.38+/-0.13; P=0.03) than subjects with other genotypes. CONCLUSIONS: The findings connect the key enzyme in gluconeogenesis with atherosclerosis. The meaning of the opposing associations of PCK1 genotype with IMT and TPV is unclear; more work is required to confirm whether these might be distinct quantitative traits with different biological determinants.

Adolescent↗
PubMed2005

Vitamin Intervention For Stroke Prevention trial: an efficacy analysis.

BACKGROUND AND PURPOSE: The Vitamin Intervention for Stroke Prevention trial (VISP) intention-to-treat analysis did not show efficacy of combined vitamin therapy for recurrent vascular events in patients with nondisabling stroke. Reasons for lack of efficacy may have included folate fortification of grain products, inclusion of the recommended daily intake for B12 in the low-dose arm, treatment with parenteral B12 in patients with low B12 levels in both study arms, a dose of B12 too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy. We conducted an efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated. The criteria for this subgroup were defined before any data analysis. METHODS: For this analysis, we excluded patients with low and very high B12 levels at baseline (<250 and >637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12 malabsorption or to be taking B12 supplements outside the study and patients with significant renal impairment (glomerular filtration rate <46.18; the 10th percentile). RESULTS: This subgroup represents 2155 patients (37% female), with a mean age of 66+/-10.7 years. For the combined end point of ischemic stroke, coronary disease, or death, there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group (unadjusted P=0.049; adjusted for age, sex, blood pressure, smoking, and B12 level P=0.056). In Kaplan-Meier survival analysis comparing 4 groups, patients with a baseline B12 level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12 less than the median assigned to low-dose vitamin had the worst (P=0.02 for combined stroke, death, and coronary events; P=0.03 for stroke and coronary events). CONCLUSIONS: In the era of folate fortification, B12 plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients.

Aged↗