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Biomedical subjects

J Collier

Publications and source records attributed to J Collier.

At least 91 records · Page 5Linked to original sources
PubMed1992

Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.

Nitric oxide (NO), synthesised from L-arginine, contributes to the regulation of blood pressure and to host defence. We describe in-vitro and in-vivo evidence that NO synthesis can be inhibited by an endogenous compound, NG,NG-dimethylarginine (asymmetrical dimethylarginine, ADMA). In man, this inhibitor is found in plasma and more than 10 mg is excreted in urine over 24 h. However, in patients with end-stage chronic renal failure, who have little or no urine output, elimination is blocked and circulating concentrations of the inhibitor rise sufficiently to inhibit NO synthesis. Accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction associated with chronic renal failure.

Adult↗
PubMed1992

Analysis of the p53 tumor-suppressor gene in hepatocellular carcinomas from Britain.

Human hepatocellular carcinomas from patients in Britain, an area of low prevalence of hepatocellular carcinoma and low dietary exposure to aflatoxin B1, were analyzed for mutations in the p53 tumor-suppressor gene. Abnormalities in the p53 gene were detected in 2 of 19 hepatocellular carcinomas by polymerase chain reaction--single-stranded conformation polymorphism. Direct sequencing of the evolutionarily conserved regions of p53 (exons 5, 6, 7 and 8), where mutations have been commonly found in a variety of tumors, confirmed that only two hepatocellular carcinomas had mutations in p53, one a 6-bp deletion of codons 158 and 159 (exon 5) and the other a G to A transition at codon 286 (exon 8). No mutations were found in any hepatocellular carcinoma in exons 6 and 7; in particular all tumors had wild-type sequence at codon 249, which has been reported to be a mutational hot spot in the p53 gene in hepatocellular carcinomas from high incidence areas such as China and southern Africa. Abnormalities in p53 expression were examined by immunohistochemistry and found in 1 of the 19 hepatocellular carcinomas. These findings show that p53 mutations are infrequently involved in the malignant transformation of hepatocytes in an area of low hepatocellular carcinoma prevalence. They support the suggestion of a possible link between dietary exposure to aflatoxin and selective G to T mutations at codon 249 of the p53 gene. Our observations also indicate that hepatitis B virus infection alone, present in six of the hepatocellular carcinomas examined, does not account for the specificity for codon 249 mutations reported from endemic areas.

Base Sequence↗
PubMed1992

The effect of endothelium-derived nitric oxide on ex vivo whole blood platelet aggregation in man.

The effects of changes in endogenous endothelium-derived nitric oxide (NO) on forearm blood flow and ex vivo platelet aggregation have been studied in 7 healthy volunteers. Measurements were made of forearm blood flow and ex vivo collagen-stimulated platelet aggregation during unilateral brachial artery infusions of saline, acetylcholine (ACh), NG monomethyl-L-arginine (L-NMMA), and prostacyclin (PGI2). The uninfused arm acted as a control. Forearm blood flow was increased by ACh, an agent which stimulates NO release, and decreased by L-NMMA, an agent which stereospecifically inhibits NO synthesis. Collagen-stimulated platelet aggregation measured ex vivo in whole blood draining the infused arm was unaltered by either ACh or L-NMMA. Conversely, PGI2, an agent which acts independently of NO, caused an increase in forearm blood flow which was accompanied by significant inhibition of platelet aggregation. The results suggest that release of endothelium-derived NO in quantities sufficient to cause substantial changes in blood vessel tone does not lead to changes in platelet aggregation in the blood flowing through the vessels. It is, however, still possible that endothelium-derived NO modulates platelet activity at the level of the endothelium.

Acetylcholine↗
PubMed1992

Effect of acute plasma volume expansion on peripheral arteriolar tone in healthy subjects.

1. Using venous occlusion plethysmography, we have investigated the forearm blood flow response in healthy subjects to the acute plasma volume expansion caused by a rapid intravenous infusion of saline. The contribution made to this response by nitric oxide has been investigated using local intra-arterial infusions of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine. 2. The infusion of 1000 ml of saline over 25 min caused plasma volume to increase by about 7%, and resulted in a rise in forearm blood flow, with no change in arterial blood pressure. The onset of the blood flow response occurred within 10 min and blood flow remained elevated above baseline 20 min after the end of the saline infusion. 3. Local intra-arterial infusion of NG-monomethyl-L-arginine alone caused a reduction in forearm blood flow which was maximal at the end of the infusion and gradually recovered to baseline levels over 40 min. 4. When local intra-arterial infusion of NG-monomethyl-L-arginine was followed by plasma volume expansion, the calculated effect of NG-monomethyl-L-arginine was such as to abolish the vasodilator response to saline. 5. The effect of local intra-arterial infusion of NG-monomethyl-L-arginine on forearm blood flow was greater when the drug was given after volume expansion had occurred, than when it was given before the administration of saline. However, in control experiments the vasoconstrictor response to noradrenaline was also enhanced after the administration of the volume load in comparison with the response to noradrenaline given alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗
PubMed1992

The vascular endothelium in diabetes and hypertension.

PURPOSE: To review recent research into the function of endothelial cells in relation to diabetes and hypertension, and the implications for cardiovascular control. ENDOTHELIAL FUNCTIONS: Endothelial cells extract and inactive circulating hormones, convert inactive precursors into vasoactive products, and synthesize and secrete vasodilator and vasoconstrictor mediators, which also modify platelet function and cell growth. DIABETES: Abnormalities in endothelial cell morphology and function are recognized features of diabetes. Diminished endothelium-dependent relaxation and enhanced endothelium-dependent contraction have been described. HYPERTENSION: Similar defects in endothelial cell function have been demonstrated in animal and human hypertension. These might lead to increased vascular tone, vasospasm, platelet activation and atheroma. THERAPY: Certain drugs modify or mimic endothelium-derived mediators. Endothelial dysfunction may contribute to cardiovascular pathology, but the precise clinical and therapeutic significance of modifying endothelial function remains to be determined.

Blood Platelets↗
PubMed1992

Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.

Nitric oxide (NO) is a widespread biological mediator with myriad functions. We have demonstrated that methylated arginines capable of inhibiting NO synthesis circulate in the plasma of healthy volunteers and are excreted unchanged in the urine. Up to 10 mg of asymmetric dimethylarginine is excreted in the urine every day, and this compound inhibits NO synthesis in vitro and in vivo, in animals and in humans. This finding raises the possibility that these compounds may act as endogenous regulators of the L-arginine:NO pathway in health and disease.

Amino Acid Oxidoreductases↗
PubMed1992

Synovial and serum levels of triamcinolone following intra-articular administration of triamcinolone acetonide in the horse.

Seven mature thoroughbred horses, weighing between 400 and 541 kg, were each injected intra-articularly into three joints with 6 mg/joint of triamcinolone acetonide (Vetalog). The fourth joint, the control, was injected with saline. Synovial fluid was taken from all four legs of the horses on days 1, 2, 3, 4, 5, 6, 7, 8, 11, and 15 following the injections. Triamcinolone acetonide was assayed by a radioimmunoassay. Blood was collected at 1, 2, 4, 6, 12 h and on days 1, 2, 3, 4, 5, 6, 7, 8, 11, and 15 following injection of either triamcinolone or saline. Both cortisol and triamcinolone were assayed. The results show that the synovial fluid level of triamcinolone was 7.5 micrograms/ml 1 day following treatment and decreased to 10 ng/ml by the 4th day. These low levels were maintained for approximately 14 days. By the 15th day, the triamcinolone was below a detectable level. Serum levels of triamcinolone increased to 3 ng/ml within 1 h and further increased to a peak of 4.3 ng/ml at 4th h. The level then decreased to 2 ng/ml at 24 h and to nearly an undetectable level in 48 h. The mean level of serum cortisol, on the other hand, gradually decreased as the serum level of triamcinolone increased. As the serum level of triamcinolone reached an undetectable level on the 2nd day, the serum cortisol level gradually increased and returned to the pre-administration level by the 5th day. These results showed that the intra-articular administration of triamcinolone maintained triamcinolone in the synovial fluid for 4-14 days and that the triamcinolone reached the blood within 1 h. The serum level of triamcinolone was maintained for 2 days and resulted in the inhibition of adrenal function for 4 days.

Animals↗
PubMed1992

Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes.

Patients with insulin-dependent diabetes mellitus have an increased mortality and morbidity due to vascular complications. Nitric oxide from the vascular endothelium contributes to the control of normal vascular tone, and endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease. In this study we have examined basal and stimulated nitric oxide-mediated vasodilatation in insulin-dependent diabetics and age- and sex-matched healthy controls. Drugs were infused locally into the brachial artery and forearm blood flow measured using venous occlusion plethysmography. Noradrenaline and NG-monomethyl-L-arginine produced similar reductions in resting forearm blood flow in healthy controls. However, in the diabetics, NG-monomethyl-L-arginine was significantly less effective than noradrenaline. Comparing between groups, the response to NG-monomethyl-L-arginine was also significantly less in the diabetics compared with the healthy controls. The response to sodium nitroprusside was significantly less in the diabetics compared with the healthy controls, whereas the responses to both acetylcholine and verapamil were the same in the two groups. The results provide evidence for an abnormality of basal nitric oxide-mediated dilatation in the forearm arterial bed of patients with insulin-dependent diabetes mellitus, and suggest that the vascular smooth muscle is less sensitive to nitric oxide.

Acetylcholine↗
PubMed1992

Isolated reduction in single-breath diffusing capacity in the evaluation of exertional dyspnea.

UNLABELLED: STUDY SETTINGS AND INTERVENTIONS: Sixty individuals complaining of dyspnea on exertion, but with normal spirometry and lung volumes and normal chest roentgenograms were reviewed for this study. These individuals were selected from a large group of outpatients (552 individuals over a seven-year period) who were referred to our laboratory for exercise testing to determine the cause of their exertional dyspnea. They were grouped according to the single-breath diffusing capacity, with those less than 70 percent of predicted in the low DCO group (group 1) and those greater than 70 percent of predicted in the normal DCO group (group 2). Both study groups underwent an incremental exercise test. RESULTS: Twenty-three individuals had a DCO less than 70 percent of predicted. During exercise, seven of these (30 percent) had an abnormal PaO2 and five had an abnormal P(A-a)O2. Thirty-seven people had a normal DCO. Thirty-six of these (97 percent) had a normal PaO2 and P(A-a)O2 during exercise. Overall, eight individuals had an abnormal PaO2 or P(A-a)O2 during exercise; seven of these had an abnormally low DCO at rest. CONCLUSIONS: Based on this selected group of a subpopulation, we conclude that the DCO is an important determinant of the diagnostic approach to a patient with dyspnea who is otherwise normal. If all pulmonary functions, including DCO are normal, an exercise study will fail to reveal abnormal PaO2 or P(A-a)O2 in 97 percent of the cases. However, a low DCO has a poor predictive value with respect to abnormal gas exchange during exercise. Therefore, when investigating exertional dyspnea, based on this selected subpopulation, if the spirometry, lung volumes, and DCO are normal, one may forego additional invasive gas exchange evaluation. However, an abnormal DCO warrants further physiologic testing.

Blood Gas Analysis↗
PubMed1992

Effect of local intra-arterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal.

OBJECTIVE: There is indirect evidence that the nitric oxide system may be impaired in hypertensive patients. The objective of this study was to examine basal nitric oxide-mediated dilation in hypertensive patients. DESIGN: The forearm blood flow (FBF) response to noradrenaline and NG-monomethyl-L-arginine (L-NMMA), a stereospecific inhibitor of nitric oxide synthesis, was compared in seven untreated hypertensive patients and 17 normotensive controls. METHODS: Drugs were infused locally into the brachial artery and FBF measured using venous occlusion plethysmography. RESULTS: In normotensives noradrenaline (60, 120 and 240 pmol/min) and L-NMMA (1,2 and 4 mumol/min) produced similar reductions in resting FBF. In the hypertensives L-NMMA was significantly less effective than noradrenaline, such that the threshold dose for L-NMMA vasoconstriction was increased and the overall response to L-NMMA reduced. Furthermore, when noradrenaline was used as an internal control there was a significant negative relationship between the response to L-NMMA and blood pressure. When the responses to L-NMMA and noradrenaline were compared between groups, the response to L-NMMA was significantly less in hypertensives compared with normotensives, whereas there was no statistical difference in the response to noradrenaline between the two groups. CONCLUSIONS: The results suggest an abnormality of basal nitric oxide-mediated dilation in the forearm arteriolar bed of patients with untreated essential hypertension.

Adult↗
PubMed1991

Dilator actions of arginine in human peripheral vasculature.

1. L-Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: D-arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess L-arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of L- and D-arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, L- and D-arginine free base and L- and D-arginine hydrochloride (all four preparations at a dose of 5 mumol/min) all caused a significant increase in venous diameter. The responses of the L- and D-enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, L- and D-arginine free base and L- and D-arginine hydrochloride were without effect at doses of 10 and 40 mumol/min. However, at doses of 160 mumol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Construction and expression of plasmids containing mutated diphtheria toxin A-chain-coding sequences.

We previously demonstrated that cells can be killed through transfection of an expression plasmid that encodes the diphtheria toxin A-chain fragment (DT-A). This report describes the construction of expression plasmids containing three mutant DT-A-coding sequences substituting glutamic acid 148 with aspartic acid, serine, or glutamine which are known to have 100- to 300-fold-reduced ADP-ribosylation activity measured in vitro. The toxicity of these constructs was determined in cotransfection experiments using HeLa and 293 cells with a luciferase expression plasmid as the reporter. Dose responses were compared for the three new DT-A mutant plasmids and for the corresponding plasmids containing wild-type DT-A and the previously characterized tox 176 mutant. The dose required to produce 50% inhibition of control luciferase expression in 293 embryonic kidney cells for the five plasmids ranged from 0.01 micrograms for wild-type DT-A to 1.2 micrograms for the least toxic plasmid, which replaces glutamic acid 148 with glutamine. In conclusion, a wide range of DT-A toxicity can be achieved by using plasmid expression vectors that encode different DT-A mutations.

Diphtheria Toxin↗