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Biomedical subjects

E R Trimble

Publications and source records attributed to E R Trimble.

At least 19 recordsLinked to original sources
PubMed2006

Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men.

Obesity is a low grade inflammatory state associated with premature cardiovascular morbidity and mortality. Along with traditional risk factors the measurement of endothelial function, insulin resistance, inflammation and arterial stiffness may contribute to the assessment of cardiovascular risk. We conducted a randomised placebo controlled trial to assess the effects of 12 weeks treatment with a PPAR alpha agonist (fenofibrate) and a PPAR gamma agonist (pioglitazone) on these parameters in obese glucose tolerant men. Arterial stiffness was measured using augmentation index and pulse wave velocity (PWV). E-selectin, VCAM-1 and ICAM-1 were used as markers of endothelial function. Insulin sensitivity improved with pioglitazone treatment (p=0.001) and, in keeping with this, adiponectin increased by 85.2% (p<0.001). Pro-inflammatory cytokine levels (TNFalpha, IL-6 and IL-1 beta) fell with both treatments (p<0.01 for TNFalpha and IL-1 beta, p<0.001 for IL-6). VCAM-1 and ICAM-1 were reduced with both treatments (p<0.001 for VCAM-1, p<0.05 for ICAM-1) and E-selectin improved with pioglitazone treatment (p=0.05). Both treatments resulted in a fall in augmentation index. PWV fell by 17.4% with fenofibrate treatment (p<0.001) and 16.3% with pioglitazone treatment (p<0.001). Pioglitazone and fenofibrate treatment of obese, glucose tolerant men reduces inflammation, improves markers of endothelial function and reduces arterial stiffness. These results suggest that treatment with PPAR agonists has potential to reduce the incidence of premature cardiovascular disease associated with obesity.

Adult↗
PubMed2003

Diabetes-induced activation of protein kinase C inhibits store-operated Ca2+ uptake in rat retinal microvascular smooth muscle.

AIMS/HYPOTHESIS: To assess the effects of diabetes-induced activation of protein kinase C (PKC) on voltage-dependent and voltage-independent Ca2+ influx pathways in retinal microvascular smooth muscle cells. METHODS: Cytosolic Ca2+ was estimated in freshly isolated rat retinal arterioles from streptozotocin-induced diabetic and non-diabetic rats using fura-2 microfluorimetry. Voltage-dependent Ca2+ influx was tested by measuring rises in [Ca2+]i with KCl (100 mmol/l) and store-operated Ca2+ influx was assessed by depleting [Ca2+]i stores with Ca2+ free medium containing 5 micromol/l cyclopiazonic acid over 10 min and subsequently measuring the rate of rise in Ca2+ on adding 2 mmol/l or 10 mmol/l Ca2+ solution. RESULTS: Ca2+ entry through voltage-dependent L-type Ca2+ channels was unaffected by diabetes. In contrast, store-operated Ca2+ influx was attenuated. In microvessels from non-diabetic rats 20 mmol/l D-mannitol had no effect on store-operated Ca2+ influx. Diabetic rats injected daily with insulin had store-operated Ca2+ influx rates similar to non-diabetic control rats. The reduced Ca2+ entry in diabetic microvessels was reversed by 2-h exposure to 100 nmol/l staurosporine, a non-specific PKC antagonist and was mimicked in microvessels from non-diabetic rats by 10-min exposure to the PKC activator phorbol myristate acetate (100 nmol/l). The specific PKCbeta antagonist LY379196 (100 nmol/l) also reversed the poor Ca2+ influx although its action was less efficacious than staurosporine. CONCLUSION/INTERPRETATION: These results show that store-operated Ca2+ influx is inhibited in retinal arterioles from rats having sustained increased blood glucose and that PKCbeta seems to play a role in mediating this effect.

Animals↗
PubMed2003

Interaction of glucose and long chain fatty acids (C18) on antioxidant defences and free radical damage in porcine vascular smooth muscle cells in vitro.

AIMS/HYPOTHESIS: Abnormalities of glucose and fatty acid metabolism in diabetes are believed to contribute to the development of oxidative stress and the long term vascular complications of the disease; therefore the interactions of glucose and long chain fatty acids on free radical damage and endogenous antioxidant defences were investigated in vascular smooth muscle cells. METHODS: Porcine vascular smooth muscle cells were cultured in 5 mmol/l or 25 mmol/l glucose for 10 days. Fatty acids, stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2) and alpha-linolenic acid (18:3) were added with defatted bovine serum albumin as a carrier for the final three days. RESULTS: Glucose (25 mmol/l) alone caused oxidative stress in the cells as evidenced by free radical-mediated damage to DNA, lipids, and proteins. The addition of fatty acids (0.2 mmol/l) altered the profile of free radical damage; the response was J-shaped with respect to the degree of unsaturation of each acid, and oleic acid was associated with least damage. At a lower concentration alpha-linolenic acid (0.01 mmol/l) was markedly different in that, when added to 25 mmol/l glucose it resulted in a decrease in free radical damage to DNA, lipids and proteins. This was accompanied by a marked increase in antioxidant and glutathione concentrations as well as by increased gene expression is of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in glutathione synthesis. CONCLUSIONS/INTERPRETATION: The results clearly show that glucose and fatty acids interact in the production of oxidative stress in vascular smooth muscle cells.

Animals↗
PubMed2003

Acute respiratory distress syndrome in long-chain 3-hydroxyacyl-CoA dehydrogenase and mitochondrial trifunctional protein deficiencies.

Inborn errors of metabolism have not previously been recognized as a risk factor for acute respiratory distress syndrome (ARDS). We report this complication in four patients with defects of the mitochondrial trifunctional protein (MTP). This enzyme catalyses three steps in the beta-oxidation of long-chain fatty acids. Three of the patients were homozygous for the 'common' 1528G>C mutation in the alpha-subunit of the MTP, giving rise to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The fourth patient did not carry this mutation but had severely decreased activities of long-chain 3-hydroxyacyl-CoA dehydrogenase and long-chain 3-ketoacyl-CoA thiolase. One patient died and histology in this patient showed severe interstitial pulmonary fibrosis. The other three patients recovered after being ventilated for up to 6 months. The high frequency of ARDS in patients with MTP defects suggests that this inborn error may be a risk factor for ARDS.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2002

Follow up of fetal outcome in cases of maternal phenylketonuria in Northern Ireland.

BACKGROUND: Maternal phenylketonuria (PKU) can result in multiple congenital anomalies. In Northern Ireland, the prevalence of PKU is relatively high at 1 in 4000. OBJECTIVE: To assess the outcome of 39 pregnancies in 20 mothers. RESULTS: Dietary control was established before conception in 17 pregnancies (44%). Five mothers with hyperphenylalaninaemia had 11 pregnancies. There were no congenital anomalies in this group, and all appear to be developing normally. Fifteen women with classical PKU had 28 pregnancies. One pregnancy ended in a first trimester miscarriage. Twelve out of 27 (44%) completed pregnancies produced babies with a congenital anomaly and/or developmental delay. CONCLUSIONS: Most problems occurred when dietary control was not established until after the 2nd trimester. As the cohort of young women with treated PKU is growing steadily, maternal PKU is going to become an even greater cause for concern.

Adult↗
PubMed2001

Restoration of glutathione levels in vascular smooth muscle cells exposed to high glucose conditions.

Hyperglycemia-induced oxidative stress may play a key role in the pathogenesis of diabetic vascular disease. The purpose of this study was to determine the effects of glucose on levels of glutathione (a major intracellular antioxidant), the expression of gamma-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione de novo synthesis), and DNA damage in human vascular smooth muscle cells in vitro. High glucose conditions and buthionine sulphoximine, an inhibitor of gamma-glutamylcysteine synthetase, reduced intracellular glutathione levels in vascular smooth muscle cells. This reduction was accompanied by a decrease in the mRNA expression of both subunits of gamma-glutamylcysteine synthetase as well as an increase in DNA damage. In high glucose conditions, incubation of the vascular smooth muscle cells with alpha-lipoic acid and L-cystine restored glutathione levels. We suggest that the decrease in GSH levels seen in high glucose conditions is mediated by the availability of cysteine (rate-limiting substrate in de novo glutathione synthesis) and the gene expression of the gamma-glutamylcysteine synthetase enzyme. Glutathione depletion is associated with an increase in DNA damage, which can be reduced when glutathione levels are restored.

Aorta↗
PubMed2000

Very low density lipoprotein subfractions in Type II diabetes mellitus: alterations in composition and susceptibility to oxidation.

AIMS/HYPOTHESIS: Type II (non-insulin-dependent) diabetes mellitus is associated with raised triglycerides and increased very low density lipoprotein cholesterol. The aim of this study was to assess if very low density lipoprotein subfraction composition and potential to oxidise were altered in this condition. METHODS: Very low density lipoprotein was separated into four subfractions (A-->D) by a novel, rapid ultracentrifugation procedure. Analysis of each subfraction included lipid and fatty acid composition. Preformed peroxides were measured spectrophotometrically and conjugated dienes were used as an indicator of in vitro lipid oxidation. RESULTS: In all results we compared patient and control subfractions. Mean fasting plasma glucose was 8.9 +/- 2.0 mmol/l in patients vs 5.1 +/- 0.4 mmol/l in control subjects (p < 0.001); patient HbA1c was 7.6 +/- 1.4%. Patient total lipid standardised for apo B was higher than controls in subfractions A, B and C; A, 201 vs 60; B, 191 vs 40; C, 63 vs 21; D, 29 vs 34 micromol lipid per mg apo B (p < 0.05). Preformed peroxides were higher in all patient subfractions compared with controls: A, 340 vs 48; B, 346 vs 42; C, 262 vs 28; D, 54 vs 16 nmol per mg apo B (p < 0.001). Patient subfractions A and D were more susceptible to in vitro oxidation. Monounsaturated fatty acids were lower in patients subfractions, 35.2 vs 36.7; B, 35.1 vs 38.7; C, 34.4 vs 36.5; D, 33.0 vs 35.5 as per cent total (p < 0.05). CONCLUSIONS/INTERPRETATION: These results indicate abnormalities in very low density lipoprotein subfraction composition and oxidation profile in Type II diabetic subjects, which are characteristic of more atherogenic particles and that may contribute to the development of cardiovascular disease in these patients.

Apolipoproteins B↗
PubMed2000

Effect of genotype on changes in intelligence quotient after dietary relaxation in phenylketonuria and hyperphenylalaninaemia.

BACKGROUND: Associations between genotype and intellectual outcome in patients with phenylketonuria are complicated because intelligence is influenced by many variables, including environmental factors and other genetic determinants. Intellectual changes with age, both on and after relaxation of diet, vary within the patient population. This study aims to determine whether a significant association exists between genotype and change in intelligence after relaxation of diet. METHODS: 125 patients with hyperphenylalaninaemia and phenylketonuria whose diet was relaxed after 8 years of age. Verbal, performance, and full scale intelligence quotients at 8, 14, and 18 years were expressed as standard deviation scores (IQ-SDS), and genotype as predicted residual enzyme activity (PRA) of phenylalanine hydroxylase. RESULTS: IQ-SDS at 8, 14, and 18 years were significantly below normal; no association was found between PRA and IQ-SDS. Significant reductions in verbal and full scale IQ-SDS occurred between 8 and 14 years and 8 and 18 years. There was a significant association between PRA and the reduction in verbal, performance, and full scale IQ between these years. Multiple regression analysis of 18 year results, using 8 year results as covariates, supported the association between PRA and IQ-SDS; after adjustment for phenylalanine control, both up to and after the age of 8 years, the full scale IQ-SDS at 14 and 18 years was 0.15 higher for each 10% increase in PRA. CONCLUSIONS: Genotype might be useful in predicting the likelihood of intellectual change in patients with hyperphenylalaninaemia and phenylketonuria whose diet is relaxed after the age of 8 years.

Adolescent↗
PubMed2000

Lactulose-mannitol intestinal permeability test: a useful screening test for adult coeliac disease.

The aim of this study was to determine the value of the lactulose mannitol intestinal permeability test in screening the general adult population for unrecognized enteropathy and latent coeliac disease. Subjects with positive serology (identified by screening carried out by the Belfast MONICA Project) along with controls were followed-up after 3 years and classified as having transient serology, persistent serology or coeliac disease. A 5-h urine collection was performed following the ingestion of 5 g lactulose, 2 g mannitol and glucose as an osmotic filler. Urinary concentrations of lactulose and mannitol were measured by enzymatic analysis. Percentage lactulose excretion (%LE) (0.94 versus 0.31, P<0.001) and lactulose mannitol excretion ratio (LMER) (0.12 versus 0.02, P<0.001) were significantly higher in screening-detected coeliac disease subjects compared with MONICA controls. The sensitivity of the permeability test was 87% in the screening situation compared with 81% in the clinical situation. In subjects with persistent and transient serology the LMER did not differ significantly from that of controls. The lactulose-mannitol test is a useful test for screening the general adult population for coeliac disease. Subjects with persistent and transient serology did not differ from MONICA controls and are unlikely to have latent coeliac disease.

Adult↗
PubMed1999

Effect of glucose on endothelin-1-induced calcium transients in cultured bovine retinal pericytes.

Published work has shown that endothelin-1-induced contractility of bovine retinal pericytes is reduced after culture in high concentrations of glucose. The purpose of the present study was to establish the profile of endothelin-1-induced calcium transients in pericytes and to identify changes occurring after culture in high concentrations of glucose. Glucose had no effect on basal levels of cytosolic calcium or on endothelin-1-induced calcium release from intracellular stores. However, influx of calcium from the extracellular medium after endothelin-1 stimulation was reduced in pericytes that had been cultured in 25 mM D-glucose. L-type Ca(2+) currents were identified by patch clamping. The L-type Ca(2+) channel agonist, (-)-Bay K8644, caused less influx of calcium from the extracellular medium in pericytes that had been cultured in 25 mM D-glucose than in those cultured with 5 mM D-glucose. However, 3-O-methylglucose, a nonmetabolizable analogue of glucose which can cause glycation, had similar effects to those of high concentrations of glucose. The results suggest that reduced function of the L-type Ca(2+) channel that occurs in bovine retinal pericytes after culture in high concentrations of D-glucose is probably due to glycation of a channel protein.

Animals↗
PubMed1998

The effects of glucose-induced oxidative stress on growth and extracellular matrix gene expression of vascular smooth muscle cells.

Vascular smooth muscle cell (VSMC) dysfunction plays a role in diabetic macrovasculopathy and this may include abnormalities in growth characteristics and the extracellular matrix. As the actual mechanisms by which glucose induces VSMC dysfunction remain unclear, the aim of this study was to assess the potential role of glucose-induced oxidative stress. Porcine aortic VSMCs were cultured for 10 days in either 5 mmol/l normal glucose or 25 mmol/l D-glucose (high glucose). There was evidence of oxidative stress as indicated by a 50% increase in intracellular malondialdehyde (p < 0.05), increased mRNA expression of CuZn superoxide dismutase and Mn superoxide dismutase (by 51% and 37% respectively, p < 0.01) and a 50% decrease in glutathione in 25 mmol/l D-glucose (p < 0.001). Growth was increased by 25.0% (p < 0.01). mRNA expression of extracellular matrix proteins (collagens I, III, IV and fibronectin) was not altered by high glucose in these experimental conditions. Repletion of glutathione with N-acetyl L-cysteine (1 mmol/l) in VSMC grown in high glucose was associated with reduction in malondialdehyde and restored growth to that of normal glucose. The water soluble analogue of vitamin E, Trolox (200 mumol/l), reduced malondialdehyde concentrations, but had no effect on glutathione depletion or the increased growth rate seen with high glucose. The addition of buthionine sulphoximine (10 mumol/l) to VSMC cultured in normal glucose reduced glutathione, increased malondialdehyde and increased growth to a similar extent as that found in high glucose alone. These results suggest that thiol status, rather than lipid peroxides, is a key factor in modulating VSMC growth and that mRNA expression of extracellular matrix proteins is not increased in VSMC under conditions of glucose-induced oxidative stress.

Animals↗
PubMed1998

A simple method for assessing copper-mediated oxidation of very-low-density lipoprotein isolated by rapid ultracentrifugation.

The association of very-low-density lipoprotein (VLDL) with atherosclerosis remains controversial. However, studies have shown that oxidative modification of VLDL can promote foam cell formation, leading to the development of atherosclerosis. A rapid method is described which will allow the significance of VLDL oxidation to be assessed in clinical studies. VLDL was isolated from heparinized plasma by a 1-h, single spin ultracentrifugation. Total protein was standardized to 25 mg/L. Oxidation was promoted by the addition of copper ions (17.5 mumol/L, final concentration) incubated at 37 degrees C. Conjugated diene production was followed at 234 nm. Total assay preparation time was 2 h. Urate greatly inhibited the oxidation of VLDL and was successfully removed by size exclusion chromatography. VLDL isolated from frozen plasma (-70 degrees C) was stable for 15 weeks. This simple, rapid method for the isolation of VLDL may be applied to assess the significance of VLDL oxidation in disease.

Copper↗
PubMed1998

Glucose-induced oxidative stress in vascular contractile cells: comparison of aortic smooth muscle cells and retinal pericytes.

Free radical-mediated damage to vascular cells may be involved in the pathogenesis of diabetic vasculopathy. The aim of this study was to compare the extent of glucose-induced oxidative stress in both vascular smooth muscle cells (VSMCs) and pericytes and the effect on antioxidant enzyme gene expression and activities. Porcine aortic VSMC and retinal pericytes were cultured in either 5 or 25 mmol/l glucose for 10 days. Intracellular malondialdehyde (MDA) was measured as a marker of peroxidative damage, and mRNA expression of CuZn-SOD, MnSOD, catalase, and glutathione peroxidase (GPX) were measured by Northern analysis. Glutathione (GSH) was also measured. There was a significant increase in MDA in VSMCs in 25 mmol/l glucose (1.34 +/- 0.11 vs. 1.88 +/- 0.24 nmol/mg protein, 5 vs. 25 mmol/l D-glucose, mean +/- SE, n = 15, P < 0.01), but not in pericytes (0.38 +/- 0.05 vs. 0.37 +/- 0.05 nmol/mg protein, n = 11). There was a significant decrease in GSH in both cell types (VSMC, 1.40 +/- 0.13 vs. 0.69 +/- 0.12 nmol/mg protein, n = 15, P < 0.001; pericytes, 1.97 +/- 0.17 vs. 0.94 +/- 0.16 nmol/mg protein, n = 11, P < 0.001). mRNA expression of CuZnSOD and MnSOD was increased only in VSMCs (by 58.5 +/- 8.1 and 41.0 +/- 6.9%, respectively, n = 8, P < 0.01). CuZnSOD protein was increased by approximately 120% (P < 0.00001). None of the antioxidant enzyme activities was altered between 5 and 25 mmol/l glucose in either cell type. Both MnSOD activities and GSH concentrations were higher in pericytes compared with VSMC under basal (5 mmol/l) conditions (P < 0.05 and P < 0.02, respectively). These results demonstrate glucose-induced reduction of GSH in both cells, but only in VSMC is there evidence of oxidant damage in the form of lipid peroxidation, implying significant differences in intracellular responses to glucose between contractile cells in the macro- and microvasculature.

Animals↗
PubMed1997

Susceptibility of VLDL to oxidation in patients on regular haemodialysis.

Oxidation of VLDL in vitro increases macrophage uptake and promotes foam cell formation, and the dyslipidaemia of chronic renal failure is characterised by an increase in VLDL. However, little information is available with regard to the susceptibility of VLDL to oxidation in patients at increased risk of atherosclerosis. We have therefore assessed the composition and susceptibility to oxidation of VLDL from haemodialysis patients and control subjects. VLDL from haemodialysis patients contained increased lipid hydroperoxides (81.6 +/- 12.6 versus 16.1 +/- 3.4 nmol/mg protein, P < 0.001) and malondialdehyde (35.9 +/- 7.3 versus 16.0 +/- 4.1 nmol/mg protein, P < 0.05). Susceptibility to oxidation was increased as shown by an increased rate of propagation of the copper induced lipid peroxidation chain-reaction (11.6 +/- 1.5 x 10(-5) versus 7.6 +/- 1.1 x 10(-5)abs. U/min, P < 0.05) and a greater increase in conjugated diene formation during peroxidation (0.47 +/- 0.04 versus 0.25 +/- 0.03 abs. U, P < 0.001). Increased VLDL peroxidation in dialysis patients may contribute to the increased risk of cardiovascular disease observed in this group of patients.

Adult↗
PubMed1997

Abnormalities of serum apo A1 containing lipoprotein particles in patients with primary biliary cirrhosis.

Patients with primary biliary cirrhosis (PBC) do not appear to have an increased risk of cardiovascular disease despite elevations in serum cholesterol. Recent evidence has pointed to LpA1 (an apo A1 containing particle which contains apo A1 but not apo A2) in protecting against atherosclerosis. The aim of this study was to investigate apo Al containing particles in the serum of patients with PBC. Lipids and apolipoproteins were measured in 31 patients with PBC (30 females) and 27 control subjects (26 females). Patients were divided into 3 groups: group 1 with bilirubin < 18 micromol/l (n = 17); group 2 with bilirubin > 18 micromol/l (n = 11); and group 3 with end stage liver disease (ESLD, n = 3). As expected group 1 and 2 patients had higher total cholesterol, HDL cholesterol and phospholipids than control subjects. Apo B and apo A1 concentrations were similar to control subjects. However, LpA1 was greatly increased: 0.96 g/l (0.60-1.50), median (range) in group 1 and 1.09 g/l (0.75-1.33) in group 2 versus 0.62 g/l (0.45-0.93) for controls both P < 0.005 and the percentage of total apo A1 in the LpA1 fraction was increased: 54.8% (37.9-63.4) in group 1 and 55.7% (47.8-73.7) in group 2 versus 36.8% (25.1-49.1) for controls, both P < 0.005. Apo A2 concentration was reduced in group 1 0.38 g/l (0.30-0.51) and group 2 0.31 g/l (0.14-0.58) versus controls 0.43 g/l (0.36-0.57), P < 0.05 and P < 0.005 respectively. Patients with ESLD had reduced HDL cholesterol, apo A1, LpA1 and apo A2 compared to controls. These results suggest that PBC is associated with an altered distribution of apo A1 favouring an increased concentration of the protective LpA-I particles. Increased LpA1 concentration may be one of the factors contributing to the paradoxically low incidence of atherosclerosis in PBC patients.

Adult↗