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Biomedical subjects

G F Watts

Publications and source records attributed to G F Watts.

At least 55 records · Page 3Linked to original sources
PubMed2001

Vascular function of the peripheral circulation in patients with nephrosis.

BACKGROUND: Nephrotic syndrome is associated with abnormal lipoprotein metabolism and increased risk of coronary heart disease. Endothelial dysfunction, an early phase of atherogenesis that manifests as impaired flow-mediated dilation (FMD) of the peripheral circulation, may link these associations. METHODS: We examined endothelial function of the brachial artery and forearm resistance arteries in 15 patients with nephrosis (NP), 15 patients with primary hyperlipidemia (HL) alone, and 15 normolipidemic, nonproteinuric subjects (NC) matched for age, sex, and weight. The NP and HL groups had similar serum cholesterol and triglyceride concentrations. Post-ischemic FMD (endothelium-dependent) and glyceryl trinitrate-mediated dilation (GTNMD; endothelium-independent) of the brachial artery were studied using ultrasonography and computerized edge detection software. Postischemic forearm blood flow was also measured using plethysmography. RESULTS: Postischemic FMD of the brachial artery was significantly lower in the NP and HL groups compared with NC group (mean +/- SE): NP 4.91 +/- 0.8%, HL 4.53 +/- 0.6%, NC 8.45 +/- 0.5% (P < 0.001). There were no significant differences among the groups in baseline diameter and GTNMD of the brachial artery, nor in maximal forearm blood flow and flow debt repayment of the forearm microcirculation. Significant differences in FMD among the groups were principally related to differences in serum low-density lipoprotein cholesterol. CONCLUSIONS: Patients with NP have abnormal endothelium-dependent but preserved endothelium-independent dilation of the brachial artery following an ischemic stimulus. Postischemic forearm microcirculatory function is unimpaired. Dyslipoproteinemia is probably the principal cause of endothelial dysfunction of conduit arteries in patients with NP and the basis for their increased risk of cardiovascular disease.

Adult↗
PubMed2001

Oxidant stress in nephrotic syndrome: comparison of F(2)-isoprostanes and plasma antioxidant potential.

BACKGROUND: The nephrotic syndrome (NS) is associated with an increased risk of coronary heart disease. Increased oxidant stress may contribute to this by means of hyperlipidaemia and/or hypoalbuminaemia. In this study we assessed the contributory role of oxidant stress, as measured by F(2)-isoprostanes and plasma oxygen radical absorbance capacity (ORAC), in subjects with NS. METHODS: We studied 14 subjects with NS and 17 age- and sex-matched healthy non-proteinuric controls. Measurement of plasma and urinary F(2)-isoprostanes was carried out using a combination of silica and reverse-phase cartridges, high-performance liquid chromatography, and gas chromatography mass spectrometry using electron-capture negative ionization. The plasma ORAC assay measured the decrease in fluorescence of phycoerythrin added to plasma in the presence of a free-radical generator. The ORAC value (microM) was calculated as the ratio of the area under the fluorescence decay curve for plasma to the area under the fluorescence decay curve for a Trolox standard. RESULTS: Plasma ORAC was significantly lower in NS patients compared with controls: mean (standard error) NS patients 3306 microM (286); controls 4882 microM (496), P=0.011. In univariate linear regression analysis, plasma albumin was significantly positively correlated with plasma ORAC (r=0.40, P=0.03). Plasma and urinary F(2)-isoprostanes did not differ significantly between NS and control groups. CONCLUSIONS: This study demonstrates that in the NS there is decreased free-radical trapping capacity of plasma that is inversely correlated with hypoalbuminaemia, but no increase in plasma and urinary F(2)-isoprostanes. Decreased total plasma antioxidant potential in combination with hyperlipidaemia may contribute to the increased risk of cardiovascular disease seen in NS.

Absorption↗
PubMed2001

Long-term predictors of coronary artery disease and mortality in type 1 diabetes.

We assessed clinical and biochemical predictors of death and/or cardiovascular disease in 147 type 1 diabetes mellitus (DM) patients followed-up for 14 years. At follow-up, 28 of patients (19%) had died, and 25 patients (18%) had developed or died of coronary artery disease (CAD). At baseline, those who died had significantly higher serum creatinine (p=0.001) and urine albumin/creatinine ratio (p=0.016), greater prevalence of retinopathy (p=0.006), lower serum apolipoprotein A1 (p=0.046), and lower daily insulin dose (p=0.024) than those who survived. CAD patients had a longer duration of diabetes (p<0.001), were older at the onset of diabetes and at presentation (p=0.001), and had higher prevalences of retinopathy (p=0.005) and neuropathy (p=0.016). The CAD group also had higher baseline serum creatinine (p=0.02), lower HDL cholesterol (p=0.004) and apolipoprotein A1 (p=0.007) and higher LDL cholesterol (p=0.028) and apolipoprotein B concentrations (p=0.027). Under logistic regression analysis (adjusted for age and sex), baseline urine albumin/creatinine ratio (p=0.003), presence of retinopathy (p=0.004), serum creatinine (p=0.028), and serum urea (p=0.034) were the most powerful predictors of mortality, while duration of diabetes (p<0.0001), baseline HDL cholesterol (p=0.012), serum creatinine (p=0.02), apolipoprotein B (p=0.038), LDL cholesterol (p=0.039), and systolic blood pressure (p=0.055) were the strongest predictors of CAD. These findings emphasize the role of abnormal lipoprotein metabolism in the development of CAD in type 1 DM. Indicators of renal impairment and the presence of retinopathy seem to be of greater importance in predicting overall mortality.

Adult↗
PubMed2001

Postprandial dyslipidemia in men with visceral obesity: an effect of reduced LDL receptor expression?

Postprandial lipemia after an oral fat challenge was studied in middle-aged men with visceral obesity. The two groups had similar plasma cholesterol levels, but obese subjects had higher levels of plasma triglyceride and reduced amounts of high-density cholesterol. Fasting plasma insulin was fourfold greater in obese subjects because of concomitant insulin resistance, with a calculated HOMA score of 3.1 +/- 0.6 vs. 0.8 +/- 0.2, respectively. Plasma apolipoprotein B(48) (apoB(48)) and retinyl palmitate (RP) after an oral fat challenge were used to monitor chylomicron metabolism. Compared with lean subjects, the fasting concentration of apoB(48) was more than twofold greater in obese individuals, suggestive of an accumulation of posthydrolyzed particles. After the oral lipid load, the incremental areas under the apoB(48) and RP curves (IAUC) were both significantly greater in obese subjects (apoB(48): 97 +/- 17 vs. 44 +/- 12 microg.ml(-1). h; RP: 3,120 +/- 511 vs. 1,308 +/- 177 U. ml(-1). h, respectively). A delay in the conversion of chylomicrons to remnants probably contributed to postprandial dyslipidemia in viscerally obese subjects. The triglyceride IAUC was 68% greater in obese subjects (4.7 +/- 0.6 vs. 2.8 +/- 0.8 mM. h, P < 0.06). Moreover, peak postprandial triglyceride was delayed by approximately 2 h in obese subjects. The reduction in triglyceride lipolysis in vivo did not appear to reflect changes in hydrolytic enzyme activities. Postheparin plasma lipase rates were found to be similar for lean and obese subjects. In this study, low-density lipoprotein (LDL) receptor expression on monunuclear cells was used as a surrogate marker of hepatic activity. We found that, in obese subjects, the binding of LDL was reduced by one-half compared with lean controls (70.9 +/- 15.07 vs. 38.9 +/- 4.6 ng LDL bound/microg cell protein, P = 0.02). Because the LDL receptor is involved in the removal of proatherogenic chylomicron remnants, we suggest that the hepatic clearance of these particles might be compromised in insulin-resistant obese subjects. Premature and accelerated atherogenesis in viscerally obese, insulin-resistant subjects may in part reflect delayed clearance of postprandial lipoprotein remnants.

Apolipoprotein B-48↗
PubMed2001

Improved analysis of brachial artery ultrasound using a novel edge-detection software system.

Brachial artery ultrasound is commonly employed for noninvasive assessment of endothelial function. However, analysis is observer dependent and susceptible to errors. We describe studies on a computerized edge-detection and wall-tracking software program to allow more accurate and reproducible measurement. In study 1, three purpose-built Perspex phantom arteries, 3.00, 4.00, and 6.00 mm in diameter, were measured with the software. There was a mean bias of 11 microm (P < 0.001 at each level) between known and measured values; the mean resolving power of the software was estimated as 8.3 microm. In study 2, the mean intraobserver coefficient of variation of repeated measures of flow-mediated dilation (FMD) using the software (6.7%) was significantly lower than that for traditional manual measurements using the intima-lumen interfaces (24.8%, P < 0.05) and intima-media interfaces (32.5%, P < 0.05). In study 3, 24 healthy volunteers underwent repeat testing twice within 1 wk; the coefficients of variation for between-visit reproducibility of FMD and response to glyceryl trinitrate using the software were 14.7 and 17.6%, respectively. Assuming 80% power and an alpha of 0.05, eight subjects with matched controls would be required, in a parallel designed study, to detect an absolute 2.5% change in FMD. In summary, we have developed a semiautomated computerized vascular ultrasound analysis system that will improve the power of clinical intervention studies to detect small changes in arterial diameter.

Analysis of Variance↗
PubMed2001

Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test.

We have developed a stable isotope breath test for the assessment of chylomicron remnant metabolism and report the results from the breath test in human subjects selected for disorders of chylomicron or remnant metabolism. In type I hyperlipemia, the phenotype is extreme hypertriglyceridemia due to a lack of lipoprotein lipase activity, which causes the failure of remnant formation. The type III dyslipidemia phenotype is caused by the inefficient removal of chylomicron remnants from plasma, generally because of homozygosity for apolipoprotein E2 alleles. The breath test was predicted to be abnormal in type III hyperlipemia, whereas a priori in type I hyperlipemia defective remnant clearance was not anticipated. Subjects were injected with lipid emulsions prepared with a composition similar to normal chylomicron remnants. The emulsions contained cholesteryl ester incorporating the stable nonradioactive isotope (13)C in the fatty acid moiety. End exhalation breath was collected at intervals after intravenous injection of the remnant-like emulsions and analyzed for (13)C enrichment by isotope-ratio mass spectrometry. Compared with the group of normolipemic men, the fractional catabolic rate of remnants measured by the breath test was significantly decreased (P = 0.006) in subjects with type III dyslipidemia. In the group with type I hyperlipemia, the fractional catabolic rate was not different (P = 0.233) from the control group. Therefore, the underlying capacity for remnant catabolism was normal in this group of markedly hypertriglyceridemic subjects. By short-circuiting the step of lipolysis, the remnant-like emulsion breath test provides direct information about remnant clearance and metabolism, which should assist in investigations of postprandial lipid metabolism.

Adolescent↗
PubMed2000

Molecular recognition of human CD1b antigen complexes: evidence for a common pattern of interaction with alpha beta TCRs.

Ag-specific T cell recognition is mediated through direct interaction of clonotypic TCRs with complexes formed between Ag-presenting molecules and their bound ligands. Although characterized in substantial detail for class I and class II MHC encoded molecules, the molecular interactions responsible for TCR recognition of the CD1 lipid and glycolipid Ag-presenting molecules are not yet well understood. Using a panel of epitope-specific Abs and site-specific mutants of the CD1b molecule, we showed that TCR interactions occur on the membrane distal aspects of the CD1b molecule over the alpha1 and alpha2 domain helices. The location of residues on CD1b important for this interaction suggested that TCRs bind in a diagonal orientation relative to the longitudinal axes of the alpha helices. The data point to a model in which TCR interaction extends over the opening of the putative Ag-binding groove, making multiple direct contacts with both alpha helices and bound Ag. Although reminiscent of TCR interaction with MHC class I, our data also pointed to significant differences between the TCR interactions with CD1 and MHC encoded Ag-presenting molecules, indicating that Ag receptor binding must be modified to accommodate the unique molecular structure of the CD1b molecule and the unusual Ags it presents.

Antibodies, Blocking↗
PubMed2000

Differential effects of eicosapentaenoic acid and docosahexaenoic acid on vascular reactivity of the forearm microcirculation in hyperlipidemic, overweight men.

BACKGROUND: Recent evidence supports differential effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the 2 major omega3 fatty acids of marine origin, on blood pressure in humans and vascular reactivity in adult spontaneously hypertensive rats. We investigated possible differences in the effects of purified EPA or DHA on forearm vascular reactivity in overweight hyperlipidemic men that might contribute to the blood pressure-lowering effects of fish oils. METHODS AND RESULTS: With a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to receive 4 g/d purified EPA, DHA, or olive oil (placebo) capsules while continuing their usual diets for 6 weeks. Forearm blood flow (FBF) was measured with venous occlusion, strain-gauge plethysmography during the sequential intra-arterial administration of acetylcholine (7.5, 15, and 30 microg/min), sodium nitroprusside (1.5, 3, and 10 microg/min), norepinephrine (10, 20, and 40 ng/min), a single-dose infusion of N:(G)-monomethyl-L-arginine (L-NMMA) (1 mg/min), and coinfusion of acetylcholine (7.5, 15, and 30 microg/min) and L-NMMA. Forty of the 56 subjects who completed the study underwent FBF measurements. Plasma phospholipid EPA levels increased significantly (P:<0.0001) after supplementation with EPA, and DHA composition increased with DHA supplementation (P:<0.0001). Relative to placebo, DHA, but not EPA, supplementation significantly improved FBF in response to acetylcholine infusion (P:=0.040) and coinfusion of acetylcholine with L-NMMA (P:=0.040). Infusion of L-NMMA alone showed no group differences. DHA significantly enhanced dilatory responses to sodium nitroprusside (P:<0.0001) and attenuated constrictor responses to norepinephrine (P:=0.017). CONCLUSIONS: Relative to placebo, DHA, but not EPA, enhances vasodilator mechanisms and attenuates constrictor responses in the forearm microcirculation. Improvements in endothelium-independent mechanisms appear to be predominant and may contribute to the selective blood pressure-lowering effect observed with DHA compared with EPA in humans.

Acetylcholine↗
PubMed2000

Sterol 27-hydroxylase acts on 7-ketocholesterol in human atherosclerotic lesions and macrophages in culture.

27-Hydroxycholesterol (27OH) is the major oxysterol in human atherosclerotic lesions, followed by 7-ketocholesterol (7K). Whereas 7K probably originates nonenzymically, 27OH arises by the action of sterol 27-hydroxylase, a cytochrome P450 enzyme expressed at particularly high levels in the macrophage and proposed to represent an important pathway by which macrophages eliminate excess cholesterol. We hypothesized and here show that 27-hydroxylated 7-ketocholesterol (270H-7K) is present in human lesions, probably generated by the action of sterol 27-hydroxylase on 7K. Moreover, [(3)H]27OH-7K was produced by human monocyte-derived macrophages (HMDMs) supplied with [(3)H]7K but not in HMDMs from a patient with cerebrotendinous xanthomatosis (CTX) shown to have a splice-junction mutation of sterol 27-hydroxylase. Whereas [(3)H]27OH-7K was predominantly secreted into the medium, [(3)H]-27OH formed from [(3)H]-cholesterol was mostly cell-associated. The majority of supplied [(3)H]7K was metabolized beyond 27OH-7K to aqueous-soluble products (apparently bile acids derived from the sterol 27-hydroxylase pathway). Metabolism to aqueous-soluble products was ablated by a sterol 27-hydroxylase inhibitor and absent in CTX cells. Sterol 27-hydroxylase therefore appears to represent an important pathway by which macrophages eliminate not only cholesterol but also oxysterols such as 7K. The fact that 7K (and cholesterol) still accumulates in lesions and foam cells indicates that this pathway may be perturbed in atherosclerosis and affords a new opportunity for the development of therapeutic strategies to regress atherosclerotic lesions.

Adult↗
PubMed2000

Human CD1b and CD1c isoforms survey different intracellular compartments for the presentation of microbial lipid antigens.

CD1b and CD1c are antigen-presenting molecules that mediate recognition of bacterial lipids by T cells, but it is currently not known whether these two molecules are redundant or are specialized to perform different immunological functions. Here, we show that the distribution of CD1c in human dendritic cells was characterized by a high ratio of cell surface to intracellular molecules, whereas CD1b showed a reciprocal pattern of distribution. In contrast to the accumulation of CD1b in lysosomal major histocompatibility complex class II compartments, intracellular CD1c molecules accumulated in other endocytic compartments, most likely early and late endosomes. Deletion of the cytoplasmic tail of CD1c, containing a tyrosine-based internalization motif, abolished most of its intracellular localization. Functional studies using T cells specific for defined lipid antigens revealed that in contrast to CD1b-mediated antigen presentation, antigen presentation by CD1c was resistant to drugs inhibiting endosomal acidification and was independent of endosomal localization of CD1c. Taken together, these results support the hypothesis that CD1b and CD1c are specialized to survey the lipid content of different intracellular compartments.

Antigen Presentation↗
PubMed2000

Low expression level but potent antigen presenting function of CD1d on monocyte lineage cells.

CD1d is a key antigen-presenting molecule involved in the selection and activation of a highly conserved T cell subset known as NK T cells. In this study, we analyzed the expression, regulation and function of human CD1d by various antigen-presenting cells (APC) of myeloid origin, including circulating monocytes, monocyte-derived dendritic cells and macrophages. CD1d was expressed as a mature glycoprotein by these cells, and unlike the other members of the human CD1 family its expression was constitutive and was not strongly up-regulated by GM-CSF and IL-4 or a range of other cytokines. Despite their remarkably low surface expression of CD1d, all myeloid lineage cells tested were extremely potent APC for responses of NK T cell clones to the synthetic glycolipid antigen, alpha-galactosyl ceramide. Prominent localization of CD1d to the endocytic system of monocyte lineage cells was observed, and functional studies suggested that this was important for achieving efficient antigen loading onto CD1d. Overall, these results support the view that monocyte lineage cells are important stimulators of CD1d-restricted immune responses, while also underscoring the unique regulation of CD1d expression by these cells.

Antibodies, Monoclonal↗
PubMed2000

Kinetics of very-low-density lipoprotein apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies.

To further explore the physiology of very-low-density lipoprotein (VLDL) apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P < .001) of the hepatic secretion of apoB, which was higher in the fed state compared with the fasted state (1,819 +/- 188 v 1,046 +/- 61 mg/d, P < .001). In the fed state, apoB secretion increased with age (P = .003) and tended to be higher in men compared with women (P = .0065). The fractional catabolism of VLDL apoB decreased with weight (P = .0038) and was lower in men versus women (8.38 +/- 0.55 v 12.59 +/- 1.65 pools/d, P = .007), as well as patients that were carriers of the E4 allele compared with those who were not carriers of this allele (5.52 +/- 0.49 v 9.58 +/- 0.87 pools/d, P < .001). The VLDL apoB concentration in both the fed and fasted states was dependent on both the rate of hepatic production and fractional clearance of apoB. Plasma cholesterol, triglyceride, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol concentrations in the fasted state were principally determined by the fractional catabolism of VLDL apoB (P< .005). These findings suggest that under physiologic conditions in healthy individuals, the transport of VLDL apoB in plasma is predominantly determined by age, sex, body weight, apoE genotype, and prandial status.

Apolipoprotein B-100↗
PubMed2000

Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum lipids and lipoproteins, LDL particle size, glucose, and insulin in mildly hyperlipidemic men.

BACKGROUND: Regular consumption of n-3 fatty acids of marine origin can improve serum lipids and reduce cardiovascular risk. OBJECTIVE: This study aimed to determine whether eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have differential effects on serum lipids and lipoproteins, glucose, and insulin in humans. DESIGN: In a double-blind, placebo-controlled trial of parallel design, 59 overweight, nonsmoking, mildly hyperlipidemic men were randomly assigned to receive 4 g purified EPA, DHA, or olive oil (placebo) daily while continuing their usual diets for 6 wk. RESULTS: Fifty-six men aged 48.8 +/- 1.1 y completed the study. Relative to those in the olive oil group, triacylglycerols fell by 0.45 +/- 0.15 mmol/L ( approximately 20%; P = 0.003) in the DHA group and by 0.37 +/- 0.14 mmol/L ( approximately 18%; P = 0.012) in the EPA group. Neither EPA nor DHA had any effect on total cholesterol. LDL, HDL, and HDL(2) cholesterol were not affected significantly by EPA, but HDL(3) cholesterol decreased significantly (6.7%; P = 0.032). Although HDL cholesterol was not significantly increased by DHA (3. 1%), HDL(2) cholesterol increased by approximately 29% (P = 0.004). DHA increased LDL cholesterol by 8% (P = 0.019). Adjusted LDL particle size increased by 0.25 +/- 0.08 nm (P = 0.002) with DHA but not with EPA. EPA supplementation increased plasma and platelet phospholipid EPA but reduced DHA. DHA supplementation increased DHA and EPA in plasma and platelet phospholipids. Both EPA and DHA increased fasting insulin significantly. EPA, but not DHA, tended to increase fasting glucose, but not significantly so. CONCLUSIONS: EPA and DHA had differential effects on lipids, fatty acids, and glucose metabolism in overweight men with mild hyperlipidemia.

Adult↗
PubMed2000

Effects of diet and serotonergic agonist on hepatic apolipoprotein B-100 secretion and endothelial function in obese men.

We studied the effects of a hypocaloric diet with or without a serotonergic agonist (dexfenfluramine, Df) on the hepatic secretion of very-low-density-lipoprotein (VLDL) apoB and endothelial function of the forearm microcirculation in 20 viscerally obese men. The kinetics of VLDL apoB were studied using an infusion of 1-((13)C)-leucine. Isotopic enrichment of apo B was measured using gas-chromatography mass spectrometry, and a multicompartmental model was used to estimate kinetic functions. Forearm vasodilatation was measured following an ischaemic stimulus using strain-gauge plethysmography, and visceral adipose tissue mass using magnetic resonance imaging. Compared with leaner subjects, the obese men had significantly higher hepatic apoB secretion (p<0.05) and lower forearm flow debt repayment (p<0.001). Both treatments produced similar decreases (p<0.05) in body weight, waist circumference, visceral adipose tissue and fasting plasma insulin. With diet alone, there was a significant decrease (p<0.05) in the plasma concentration and pool size hepatic secretion rate of VLDL apoB, as well as a significant increase (p<0.05) in post-ischaemic flow debt repayment. With diet plus Df, there were parallel responses in these variables, but only decreased forearm vascular resistance (p<0.05) was statistically significant. Combining both data sets, there was a highly significant reduction in hepatic apoB secretion rate (20. 9+/-2.0 vs. 14.7+/-1.6 mg/kg fat-free mass/day, p=0.005), as well as an increase in both maximal forearm blood flow (16.8+/-7.5 vs. 22. 2+/-8.5 ml/100 ml/min, p=0.006) and flow debt repayment (3.5+/-2.1 vs. 5.4+/-2.8 ml/100 ml, p=0.01), and a decrease in vascular resistance (6.7+/-3.7 vs. 5.1+/-4.4 mmHg/ml/100 ml/min, p=0.007). Obese men have increased hepatic secretion of apoB and endothelial dysfunction of the forearm microcirculation, and decreasing their visceral adipose tissue mass by diet (with or without a serotonergic agonist) improves these abnormalities. This may provide a mechanistic basis for the reduction in cardiovascular risk in obese patients who lose weight.

Apolipoproteins B↗