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Biomedical subjects

R Fraser

Publications and source records attributed to R Fraser.

At least 109 records · Page 6Linked 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

Sodium status, corticosteroid metabolism and blood pressure in normal human subjects and in a patient with abnormal salt appetite.

1. A patient with severe hypertension was found to have mildly impaired 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) activity on the basis of urinary steroid metabolite ratios, low plasma aldosterone, angiotensin II and renin levels and marginally low levels of plasma potassium. 2. The patient also had a compulsively high salt intake. 3. We tested the hypothesis that high salt intake may affect 11 beta-HSD activity. 4. High salt intake in normal subjects did not significantly alter either blood pressure or 11 beta-HSD activity. 5. We suggest that the potentially small hypertensive effect of the partial enzyme deficiency in our patient, also reported in patients with essential hypertension, has been markedly amplified by the very high salt intake.

Adrenal Cortex Hormones↗
PubMed1996

The Cathlocator: a novel non-radiological method for the localization of enteral tubes.

Safe placement of nasogastric tubes requires reliable positioning of the tip of the tube within the stomach. Radiology and aspiration are currently used to confirm tube position, but suffer from significant problems of cost and efficacy, respectively. We have developed a novel method to locate the position of a catheter tip within the body, using the detection of low energy electromagnetic field generated in a coil located in the catheter with an external hand-held unit (Cathlocator). In vitro, the unit detected the distance of the coil from the detector with an accuracy of 0.1 cm over a range of 4-12 cm. In vivo studies were performed in 11 healthy volunteers using a purpose-built manometric assembly that incorporated the signal generating coil in its tip. In all subjects the Cathlocator showed the position of the signal generating coil to be cranial to the xiphisternum when manometric and transmucosal potential difference criteria showed it to be located above the lower oesophageal sphincter. When the coil was within the stomach, the Cathlocator identified its position within the epigastric, umbilical and left hypochondrial regions of the abdomen. The distance of the coil from the surface was significantly greater when in the duodenum mean (+/- s.e.m. 7.6 +/- 0.3 cm; P < 0.001) and oesophagus (8.6 +/- 0.2 cm; P < 0.002) than the stomach (5.0 +/- 0.4 cm). In one subject studied twice there was a close correlation between the location and depth measured by the device on each occasion. The Cathlocator is a novel non-radiological device that has the potential to be useful in the placement of gastrointestinal catheters.

Adult↗
PubMed1996

Measurement of proximal and distal gastric motility with magnetic resonance imaging.

The precise motor mechanisms associated with gastric emptying of nutrient liquids are unclear, in part because of difficulties in measuring the motility from the proximal and distal stomach simultaneously. We have now examined proximal and distal gastric motility, using a novel magnetic resonance imaging (MRI) technique. In seven healthy volunteers (4 males, 3 females; 27-37 yr), gastric emptying and motility were determined on two occasions after ingestion of 500 ml 10% and 25% dextrose labeled with 1 mM gadolinium tetraazacyclododecane tetraacetic acid, using a 1.5-tesla Philips Gyroscan ACS II scanner. Gastric emptying was determined every 15 min with a series of transaxial scans. After each series of transaxial scans, 120 coronal scans, 1.2 s apart, were performed through the antrum and proximal stomach. For each coronal slice the diameters of the proximal stomach and the antrum were measured to determine the number of contractions per minute and depth (%basal diameter). Gastric emptying (half-emptying time) was faster after ingestion of 10% compared with 25% dextrose (49 +/- 15 vs. 118 +/- 37 min; P < 0.01). After both meals, the diameter of the proximal stomach remained relatively constant, whereas there were marked fluctuations in the diameter of the antrum. Mean (+/- SD) frequency (2.8 +/- 0.6 vs. 2.0 +/- 0.8/min; P < 0.001) and depth (40 +/- 17% vs. 34 +/- 16%; P < 0.04) of antral contractions were higher after 10% dextrose compared with 25% dextrose. Rapid MRI techniques allow simultaneous measurement of both gastric emptying and motor function of different gastric regions. The increase in the frequency and depth of distal gastric contractions during ingestion of 10% compared with 25% dextrose supports the concept that the antrum contributes to the regulation of gastric emptying of nutrient liquids.

Adult↗
PubMed1996

Prevalence of Helicobacter pylori infection and chronic dyspeptic symptoms among immigrants from developing countries and people born in industrialized countries.

The relationship between Helicobacter pylori infection and chronic dyspepsia is controversial. To determine the effect of H. pylori infection on dyspeptic symptoms, we compared the prevalence of H. pylori infection in immigrants from developing countries and people born in industrialized countries. Upper abdominal symptoms were assessed by a questionnaire and H. pylori infection was determined with a 13C-urea breath test and serology. H. pylori infection was found in 63% of subjects from developing countries and 11% of subjects from industrialized countries. There was no difference in the prevalence of dyspeptic symptoms between the 2 groups. The lack of difference in chronic dyspeptic symptoms between the groups, despite a major difference in the H. pylori prevalence, suggests that H. pylori infection is not a major contributor to chronic dyspepsia.

Adolescent↗
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↗
PubMed1996

Undergraduate teaching in the community: can general practice deliver?

BACKGROUND: All UK medical schools are revising their curricula following the General Medical Council recommendations to increase general practice involvement in undergraduate education. However, workload in general practice has increased in recent years, raising questions about its ability to maintain, let alone extend, its educational activities. AIM: The aim of this study was examine whether recent changes in general practice have affected delivery of practice-based undergraduate education and to assess the extent to which practices will be able to increase their involvement in teaching. METHOD: A postal questionnaire survey was conducted of the lead clinical teachers and their partners in the practices to which students from Leicester Medical School had been attached in the last 2 years. RESULTS: The questionnaire was completed by 32 out of the 39 lead teachers and 134 of the 150 partners, an overall response rate of 88%. There was widespread support for departmental teaching requirements, but only 17 lead teachers (44%) felt that the suggested reduction by 25% of patients seen per session while teaching was feasible. A total of 14 lead teachers (47%) felt that the ability of their practice to deliver high-quality teaching had declined since 1990. Altogether, 113 (87%) of all doctors in teaching practices felt that time pressures had increased during this period, and 139 (88%) felt that present levels of remuneration were inadequate. The majority of these doctors felt that general practice was the preferred location for learning generic clinical skills and were interested in participating. Nevertheless, most were not prepared to increase their involvement in teaching under present arrangements. CONCLUSION: Practice-based teachers appreciate the need for quality teaching, remain enthusiastic about teaching and are, in principle, willing to take an increased teaching load. However, recent changes have made delivery of teaching more difficult, and if an expansion in practice-based teaching is to occur, more realistic levels of funding and support are a prerequisite.

Attitude of Health Personnel↗
PubMed1995

Regulation of murine acid secretion by CO2.

To determine whether endogenous metabolic sources alone provide sufficient CO2 for acid secretion in mammals, basal and stimulated acid secretion and metabolic CO2 production were measured concurrently in mouse stomachs, in vitro, without exogenous CO2, and after addition of 5% CO2 serosally. Basal acid secretion was varied by changing luminal pH from 3.2 to 4.0. In the absence of an exogenous supply of CO2 acid secretion was stable under basal conditions and increased during cholinergic stimulation with carbachol. Serosal CO2 supply increased basal and stimulated acid secretion. The increase in basal acid secretion depended on the initial level of acid secretion. At pH 4.0, exogenous CO2 increased acid output (mean +/- SD) by 13% from 112 +/- 11 nmol/min to 126 +/- 8 nmol/min (P < 0.03), whereas at pH 3.6 the increase was 40% (63 +/- 14 to 88 +/- 20 nmol/min, P < 0.04) and 157% at pH 3.2 (21 +/- 13 to 54 +/- 14 nmol/min, P < 0.002). Following cholinergic stimulation a maximal acid output of 321 +/- 38 nmol/min was attained without serosal CO2, whilst addition of 5% CO2 to the serosal solution increased maximal acid secretion by 49% to 479 +/- 96 nmol/min (P < 0.005). Metabolic activity, measured as total gastric CO2 production, was greater as acid secretion rates increased [239 +/- 20 nmol/min at 21 +/- 13 nmol/min (luminal pH 3.2) versus 406 +/- 28 nmol/min at 321 +/- 17 nmol/min (after cholinergic stimulation)]. The data support the concept that basal and sub-maximal acid secretion can be maintained by CO2 available from metabolic sources, but full expression of the acid secretory apparatus requires exogenous CO2.

Animals↗
PubMed1995

Effects of the glucocorticoid antagonist RU486 in spontaneously hypertensive and Sprague Dawley rats.

The effect of a low dose of the gluco-corticoid receptor antagonist, RU486, was tested in spontaneously hypertensive (SHR) and in Sprague Dawley (SD) rats. In SD rats, RU486 (50 micrograms/day, 18 days) significantly increased growth rate and thymus weight, probably by antagonising the actions of endogenous glucocorticoid hormones. Blood pressure and plasma corticosterone levels were not affected by RU486 at this dose. In leucocytes, RU486 treatment in vivo reduced the number of glucocorticoid binding sites but did not affect binding affinity. In contrast, growth rate and thymus weight were not altered in SHR when treated with the same dose of RU486 for a longer period (60 days). Blood pressure was unaffected as were leucocyte glucocorticoid receptor characteristic. Glucocorticoid receptor binding characteristics for RU486 were similar for liver cytosol of SD and SHR. We conclude that the apparent difference in sensitivity to RU486 between strains is probably not due to differences in interaction of the antagonist with the glucocorticoid receptor but may be caused by differences in pharmacokinetics of RU486 between strains.

Adrenal Glands↗
PubMed1995

Esophageal body and lower esophageal sphincter function in healthy premature infants.

BACKGROUND & AIMS: Gastroesophageal reflux is a common problem in premature infants. The aim of this study was to use a novel manometric technique to measure esophageal body and lower esophageal sphincter pressures in premature infants. METHODS: Micromanometric feeding assemblies (OD, < or = 2 mm) incorporating 4-9 manometric channels were used in 49 studies of 27 premature neonates. Esophageal body motility was recorded at three sites for 20 minutes after feeding. Twenty attempts (one per minute) were made to stimulate swallowing via facial stimulation (Santmyer reflex). In 32 studies lower esophageal sphincter pressures were recorded (sleeve) for 15 minutes before and after feeding. RESULTS: Peristaltic motor patterns were less common than non-peristaltic motor patterns (26.6% vs. 73.4%; P < 0.0001) that comprised 31.1% synchronous, 34.6% incomplete, and 6.3% retrograde pressure waves. Reflex swallowing was elicited more frequently in neonates older than 34 weeks postconceptional age than in younger infants (33.4% vs. 20.4%; P < 0.05). Mean lower esophageal sphincter pressure was 20.5 +/- 1.7 mm Hg before and 13.7 +/- 1.3 mm Hg after feeding (P < 0.0005). CONCLUSIONS: Premature infants show nonperistaltic esophageal motility that may contribute to poor clearance of refluxed material. In contrast, the lower esophageal sphincter mechanisms seem well developed.

Deglutition↗
PubMed1995

Differences in temperature-sensitive receptor binding of glucocorticoids in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

Glucocorticoid receptor binding was compared in liver cytosol preparations from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats using homologous displacement of [3H]dexamethasone. At 5 degrees C, there was no difference in receptor binding affinity or concentration between strains for dexamethasone, corticosterone or aldosterone. At 37 degrees C, affinity for dexamethasone was lower than at 5 degrees C for both rat strains and decreased with time. However, at this higher temperature, binding affinity in the SHR preparation was consistently higher than in the WKY preparation. The WKY preparation had a higher receptor concentration. The rate of dissociation of the [3H]dexamethasone-receptor complex prepared at 5 degrees C and then incubated at 37 degrees C was rapid but not different between strains. A possible explanation of these results is that the relationship of the heat shock proteins to the receptor heterocomplex is different between strains. Evidence exists of a genetic difference in Hsp 70 between SHR and WKY rats, although its cosegregation with blood pressure has not been established.

Aldosterone↗
PubMed1995

Regulation of adrenocortical steroidogenesis by benzodiazepines.

Benzodiazepines affect steroidogenesis in at least four ways depending on concentration and adrenocortical cell type. Firstly, at micromolar concentrations, they inhibit steroidogenic enzymes. Competition for microsomal 17- and 21-hydroxylase activity explains the inhibition of ACTH-stimulated aldosterone and cortisol synthesis by diazepam and midazolam. At slightly higher concentrations, we have evidence that 11 beta-hydroxylase activity is also inhibited. Secondly, at sub-micromolar concentrations, calcium influx is inhibited. T-type and L-type calcium channels appear to be blocked, this impairs signal response coupling and, in particular, decreases angiotensin- and K(+)-stimulated aldosterone synthesis in zona glomerulosa cells. Thirdly, the mitochondrion of steroidogenic tissues is a sensitive site for the stimulatory effects of benzodiazepines. Aldosterone synthesis from added HDL-cholesterol by cultured bovine zona glomerulosa cells is stimulated by diazepam, RO5-4864 and PK11195. The fourth site of benzodiazepine's effect on steroidogenesis is particular to zona glomerulosa cells. In addition to cholesterol side chain cleavage, the final part of the aldosterone biosynthetic pathway, the conversion from deoxycorticosterone is controlled. Although high micromolar concentrations of diazepam appear to be inhibitory, lower nanomolar concentrations stimulate the synthesis of aldosterone from added deoxycorticosterone. In vivo, a fifth site of benzodiazepine activity may influence plasma steroid concentrations. Competition between steroids and benzodiazepines for hepatic clearance enzymes may affect half lives of both drugs and hormones.

Adrenal Glands↗
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

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

Adult↗
PubMed1995

Acute adrenal insufficiency: a new presentation of Castleman's disease.

We report the case of a 35-year-old patient who presented with acute adrenal insufficiency, then developed fever, hypoalbuminuria, anasarca, thrombocytopaenia and anaemia. Lymphadenopathy appeared later with microscopic features typical of Castleman's disease. Clinical remission followed treatment with intravenous immunoglobulin. Circulating interleukin-6 levels were elevated initially but were normal after immunoglobulin therapy. We surmise that high circulating levels of interleukin-6 (and ACTH) may have induced haemorrhagic necrosis of the adrenal glands and accounted for the constitutional symptoms.

Acute Disease↗