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Biomedical subjects

A Jamieson

Publications and source records attributed to A Jamieson.

At least 37 records · Page 2Linked to original sources
PubMed1996

Corticosteroids in essential hypertension: multiple candidate loci and phenotypic variation.

1. The role of genetically determined changes in adrenal steroid production, metabolism and action in the pathogenesis of cardiovascular disease in man is considered by studying three loci that are important in corticosteroid function. 2. Variation at the glucocorticoid receptor locus can be identified as a biallelic restriction fragment length polymorphism (Bcl1); subjects with contrasting genotypes show altered skin vasoconstrictor responses to topically applied budesonide without any significant change in leucocyte receptor binding characteristics. 3. In a case control study of patients with essential hypertension, we have shown evidence of reduced 11 beta-hydroxysteroid dehydrogenase activity, with an elevated ratio of cortisol to cortisone metabolites in urine. 4. The genes encoding 11 beta-hydroxylase and aldosterone synthase are highly homologous. Studies in the Milan hypertensive rat show variation at this locus, which may account for the increased steroid synthesis noted in the hypertensive strain; in man, a chimaeric gene comprising 5' regulatory regions from 11 beta-hydroxylase and 3' coding sequence from aldosterone synthase accounts for the autosomal dominant condition Dexamethasone Suppressible Hyperaldosteronism. Variation in the precise location of the crossover site between the two genes does not account for the observed phenotypic heterogeneity in this condition. 5. Measurement of basal plasma steroid levels in subjects with essential hypertension show an increased ratio of 11-deoxycortisol/cortisol, consistent with reduced activity of 11 beta-hydroxylase in the zona fasciculata. 6. In summary, three loci involved in corticosteroid synthesis, metabolism and action can independently affect cardiovascular phenotypes; their roles in determining pathophysiological changes, including hypertension, remain to be studied.

Adrenal Cortex Hormones↗
PubMed1996

Altered 11 beta-hydroxylase activity in glucocorticoid-suppressible hyperaldosteronism.

Corticosteroid 11 beta-hydroxylation is catalyzed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and patients with Conn's syndrome. Based on both 11-deoxycortisol/cortisol (S:F) and 11-deoxycorticosterone/corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with the basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all of these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone, and DOC concentrations appeared to be more sensitive to ACTH in GSH than in the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in this condition and may contribute to the phenotype variability.

Adrenal Cortex Neoplasms↗
PubMed1995

Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes.

Fibrin deposition is characteristic of inflammatory diseases. The monocytes is central to the inflammatory response and can affect fibrinolysis by expression of urokinase (u-PA) and plasminogen activator inhibitor types 1 and 2 (PAI-1 and PAI-2, respectively). This study examines whether thrombin, which promotes fibrin deposition, can contribute to fibrin persistence by modulating expression of proteins of the fibrinolytic system. Monocytes were isolated from human peripheral blood and analyzed for PAI-2, PAI-1, and u-PA antigens by enzyme-linked immunosorbent assay (ELISA). Monocytes responded to thrombin by increased expression of PAI-2 in a dose- and time-dependent manner, with maximal synthesis at a concentration of 1 U/mL to 10 U/mL. This trend was also evident for PAI-1, which was present at much lower levels. Thrombin and lipopolysaccharide (LPS) stimulated comparable levels of PAI-2, studied at the antigen and mRNA level. The dose effet of LPS on PAI-2 and PAI-1 was found to differ from that of thrombin. The level of u-PA was undetectable by ELISA and zymography in all samples. Thrombin stimulates PAI-2 synthesis by human monocytes, therefore creating an imbalance in the fibrinolytic system. This may contribute to persistence of fibrin, deposited during inflammation.

Fibrin↗
PubMed1995

Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric gene on phenotypic expression.

1. Genetic analysis of five kindreds with glucocorticoid-suppressible hyperaldosteronism, four of whom had not been subjected to any previous genetic analysis, revealed three different crossover breakpoints within the five kindreds clustered in the exon 3-intron 4 region of the chimaeric gene. The site of the crossover point had no effect on blood pressure within the kindreds studied. 2. The gene causing glucocorticoid-suppressible hyperaldosteronism was in strong linkage disequilibrium with an allele of a newly described restriction enzyme polymorphism of the aldosterone synthase gene promoter region, suggesting a possible role for this allele in the development of the chimaeric gene. 3. A novel observation on subjects inheriting glucocorticoid-suppressible hyperaldosteronism from their mothers showed that they had significantly higher plasma aldosterone concentrations and mean arterial blood pressures than those inheriting glucocorticoid-suppressible hyperaldosteronism from their fathers. 4. These results raise the possibility that chronic exposure in utero to elevated plasma aldosterone concentrations may result in the permanent programming of mineralocorticoid-dependent blood pressure regulatory mechanisms, which is amplified in later life by the elevated plasma aldosterone concentrations found in glucocorticoid-suppressible hyperaldosteronism.

Adolescent↗
PubMed1995

Left ventricular mass in hereditary human hypertension: glucocorticoid-suppressible hyperaldosteronism.

BACKGROUND: The mineralocorticoid hormone aldosterone may be an important mediator of pathological ventricular hypertrophy and heart failure. Much of the evidence for this arises from experimental work in rat models of mineralocorticoid-dependent hypertension, and a pathological role in humans is still uncertain. SUBJECTS: Eleven subjects with glucocorticoid-suppressible hyperaldosteronism, a hereditary form of hyperaldosteronism and hypertension, and 10 age- and sex-matched control subjects were studied. RESULTS: The subjects with glucocorticoid-suppressible hyperaldosteronism had a higher mean blood pressure and plasma aldosterone concentration, and lower plasma renin concentration, than the control subjects. Left ventricular mass index was not significantly different in the subjects with glucocorticoid-suppressible hyperaldosteronism than in the control subjects. When the subjects with glucocorticoid-suppressible hyperaldosteronism were subdivided into those with and those without hypertension, no difference in left ventricular mass index could be detected between the subgroups or between either subgroup and the control subjects. However, there was a significant correlation between basal plasma aldosterone and left ventricular mass index in the subjects with glucocorticoid-suppressible hyperaldosteronism (r = 0.66, P < 0.03). CONCLUSIONS: Despite marked elevations in plasma aldosterone concentrations from birth in subjects with glucocorticoid-suppressible hyperaldosteronism, left ventricular hypertrophy did not occur. The degree of hyperaldosteronism in the subjects was mild compared with other conditions and, although an effect on left ventricular mass index could be detected, the present results indicate that other factors may be necessary for the development of left ventricular hypertrophy.

Adolescent↗
PubMed1995

Dexamethasone-suppressible hyperaldosteronism: clinical, biochemical and genetic relations.

Clinical, biochemical and molecular data on five kindreds with dexamethasone-suppressible hyperaldosteronism are reviewed. The clinical phenotype varies from severe, early onset hypertension to much milder blood pressure elevation; hypokalaemia is usually mild. The genetic basis of the syndrome reflects the presence of a chimaeric gene derived from an unequal crossover between CYP11B1 and CYP11B2, resulting in ACTH-sensitive aldosterone synthase activity. In five kindreds, at least three different mutations have been identified, suggesting that allelic predisposition might lead to increased geographical prevalence of the condition in Celtic populations.

Adrenal Cortex Hormones↗
PubMed1995

Peripheral blood monocyte synthesis of plasminogen activator inhibitor 2 in response to native and modified LDL.

Fibrin deposition is a characteristic feature of the atherosclerotic plaque. The balance of fibrinolytic activity is modulated by plasminogen activators (PAs) and plasminogen activator inhibitors (PAIs). We examined expression of components of the fibrinolytic system by peripheral blood monocytes following stimulation by native LDL and LDL modified by acetylation, copper oxidation or minimal modification. Monocytes responded to LDL stimulation by increased production of PAI-2, with no corresponding increase in u-PA. PAI-1 was detected but did not change relative to untreated control; u-PA was undetectable in all samples. Native LDL consistently upregulated PAI-2; this stimulation was not inhibited by inclusion of antioxidants. Acetylated, copper oxidized and minimally modified LDLs increased production of PAI-2, but the ability to stimulate PAI-2 synthesis varied between preparations of modified LDL. Increased levels of PAI-2 in a local environment such as the artery wall may promote fibrin persistence.

Acetylation↗
PubMed1994

The effectiveness of using co-dominant polymorphic allelic series for (1) checking pedigrees and (2) distinguishing full-sib pair members.

Formulae express the effectiveness of parentage exclusion tests and differences separating full-sib pairs by compounding genotypic information on discrete examples of co-dominant alleles segregating at gene loci on different autosomes. Such polymorphisms occur among structural genes and polymorphic DNA sequences. Two general formulae state the theoretical effectiveness of using co-dominant alleles for (1) testing parentage and (2) distinguishing sibs. The formula for parentage exclusion tates the probability (PE) that a given series of co-dominant alleles of known frequency should detect a falsely recorded father (or mother). The other formula describes how genetic polymorphism can distinguished closely related individuals. It states the probability (PS) that alleles distinguish the members of full-sib pairs, dizygotic twins and tissue chimeras. To derive the two general formulae, particular formulae were calculated for n = 2, 3 and 4 co-dominant alleles. By increasing the numbers of alleles, the formulae were seen to contain recurrent patterns which were then expressed in the two general formulae for n alleles. Some examples demonstrate applications of the two formulae in problems concerning parentage and sibship.

Alleles↗
PubMed1994

Rapid diagnosis of glucocorticoid suppressible hyperaldosteronism in infants and adolescents.

Glucocorticoid suppressible hyperaldosteronism (GSH) is an uncommon form of dominantly inherited hypertension. Presentation with hypertension and complications such as stroke in early life are well recognised. The use of a simple genetic test carried out on blood or placenta facilitates the detection of infants and children with GSH before the development of hypertension, allowing prompt treatment of hypertension if it occurs, and an opportunity to study the effects of growth and environmental influences on the progression of the condition.

Adolescent↗
PubMed1993

The effect of interleukin-4 on tumour necrosis factor-alpha induced expression of tissue factor and plasminogen activator inhibitor-1 in human umbilical vein endothelial cells.

The pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is able to alter the haemostatic balance of human umbilical vein endothelial cells (HUVECs) towards that of a procoagulant and anti-fibrinolytic state. Treatment of HUVECs in culture with human recombinant TNF-alpha (0.5-50 U/ml; 6 h) significantly increased total cell expression of tissue factor (TF) 10-fold from 40 mU/well to 400-500 mU/well. Levels of plasminogen activator inhibitor-1 (PAI-1) antigen secreted from HUVECs also increased up to 2-fold in concentration-dependent fashion following addition of TNF-alpha (10-100 U/ml; 24 h). TNF-alpha induced total and cell surface expression of TF on HUVECs was significantly inhibited when the cells were pre-incubated with interleukin-4 (IL-4; p < 0.001). This effect was time and concentration dependent. Pretreatment of HUVECs with IL-4 for 4 h had no significant effect, but increasing inhibition of total TF expression occurred after 8 and 16 h pre-incubations. Treatment with IL-4 at 20 and 200 U/ml significantly inhibited cell surface TF responses induced by TNF-alpha, whereas a low concentration (0.2 U/ml) was without effect. In contrast, the production of PAI-1 from HUVECs stimulated by TNF-alpha (50 U/ml) was unaffected by the presence and/or prior incubation with 200 U/ml IL-4. Thus, IL-4 may regulate the pro-coagulant but not the antifibrinolytic effects of TNF-alpha at sites of vascular inflammation.

Cells, Cultured↗
PubMed1993

The Effect of Practical Dietary Counseling on Food Variety and Regurgitation Frequency after Gastroplasty for Obesity.

After obesity surgery, the primary measurement of success is the amount of weight lost. There has, however, been little assessment of how patients cope with the dietary constraints imposed by gastroplasty. Similarly, dietary patterns adopted to cope with these constraints have not been studied fully. These factors are of great importance in terms of nutritional adequacy, patient acceptability and long-term success. A study involving 32 patients was conducted to ascertain whether practical nutritional intervention and extensive follow-up would improve the overall outcome of the gastroplasty operation with respect to the type of foods tolerated and the incidence of regurgitation or vomiting experienced. To quantify success in terms of frequency of regurgitation and variety of food intake a vomiting/eating (V/E) score was devised. The results showed that the group of patients with more intensive practical education and counseling had a more varied intake of food and coped better with a wider variety of solid foods in the long term. Despite a more solid diet they did not regurgitate food as frequently as patients with less education, and over half the study group of patients reported no regurgitation at all. From this study, it is proposed that patients can be assessed and categorized postoperatively using a V/E scale. This scale numerically scores success with diet after gastroplasty, which, when recorded in conjunction with subsequent weight loss, can give a better quantification of success after obesity surgery.

Journal Article↗