Search PubMed⌕ Search

Biomedical subjects

R Fraser

Publications and source records attributed to R Fraser.

At least 91 records · Page 5Linked to original sources
PubMed1998

Glucocorticoid receptor polymorphism in genetic hypertension.

The Milan hypertensive strain of rat (MHS) displays abnormalities in both renal function and adrenocortical activity. While the pressor role of the former has been studied in detail, the role of the latter has not yet been clearly evaluated. In the present study, glucocorticoid receptor (GR) binding characteristics in liver cytosol from adult MHS and Milan normotensive controls (MNS) have been investigated. Dexamethasone, aldosterone and corticosterone were bound with lower affinity to cytosol of MHS rats compared with that of MNS rats. This pattern of binding could explain the raised plasma corticosterone concentrations and adrenocortical hypertrophy previously noted in MHS. The coding sequence of MHS and MNS GR genes have been determined. The MHS gene differed in four respects from that of MNS: three silent point mutations and a polymorphic microsatellite region in exon 2. The latter polymorphism has been used in cosegregation studies of F2 hybrids of MHS x MNS. The MHS GR genotype was associated with hypercalciuria and lower blood pressure in female rats and lower body weight in male rats. Although the effect on blood pressure is small, it is consistent with the affinity data. MHS GR genotype cosegregated with lower blood pressure in F2 rats and displayed a lower affinity in binding studies. In conclusion, GR polymorphism may be responsible for differences of adrenocortical function between MHS and MNS. This may lead to a reduction in the blood pressure difference between the two strains.

Animals↗
PubMed1998

The role of bronchial biopsy and washing in the diagnosis of allergic bronchopulmonary aspergillosis.

The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is usually established on the basis of clinical, serologic, and radiologic criteria, of which eight are commonly cited. Although histologic abnormalities are not usually considered, a study of lobectomy/lung biopsy specimens provided evidence that the combination of mucoid impaction of bronchi with "allergic" mucin and fungal hyphae is diagnostic of ABPA. We attempted to explore the use of surgical specimens in the diagnosis of ABPA by examining endobronchial biopsy specimens and washings. Bronchial biopsy specimens obtained from 1990 to 1995 that contained fungal hyphae were reviewed and assessed for the presence of "allergic" mucin and bronchial wall abnormalities. We also reviewed cytologic specimens and clinical, serologic, and radiologic findings of the corresponding patients. Five biopsy specimens had fungal hyphae and associated "allergic" mucin. In some patients, the mucin was small in amount and contained degenerated eosinophils that resembled macrophages. None of the patients was thought to have ABPA clinically. All of the five had bronchial mucoid impaction at bronchoscopy. After additional investigation, only one patient fulfilled all of the eight traditional criteria for ABPA; one other patient fulfilled six criteria. Although some tests were not completed in the remaining three patients, follow-up and/or response to steroids was consistent with ABPA in all of the three. Four patients had bronchial washing performed at the time of biopsy. Cytologic examination showed one to be normal except for inflammatory cells that did not include eosinophils; three others showed mucus containing eosinophils intermixed with Charcot-Leyden crystals and scattered hyphae. We conclude that patients with ABPA might have atypical manifestations of disease and not meet standard diagnostic criteria. Bronchoscopy with bronchial biopsy and washing plays a role in detecting these patients. The presence of "allergic" mucin might be overlooked in the small biopsy fragments obtained by bronchoscopy.

Adult↗
PubMed1997

Abnormal epinephrine release in young adults with high personal and high parental blood pressures.

BACKGROUND: Increased activity of the sympathetic nervous system has been proposed as a cause of high blood pressure (BP) and may be related to diet and body weight. To determine the role of these factors in predisposition to high BP, we studied 100 young adults with high or low BP from families in which both parents had either high or low BP. METHODS AND RESULTS: Plasma catecholamine, glucose, and insulin levels were measured before and after an oral glucose load. There was a significant correlation between fasting plasma norepinephrine and mean arterial pressure (P=.001). Subjects with high BP, irrespective of parental BP, were heavier (P=.003) and fatter (P=.002) and had a greater rise in plasma insulin (P=.003) following glucose than those with low BP. Offspring with high BP whose parents also had high BP showed an unexpected rise in plasma epinephrine (P=.004) following glucose. This adrenal medullary response was not the result of high parental or high personal BP alone as it was not seen in offspring with low BP whose parents had high BP or in offspring with high BP whose parents had low BP. CONCLUSIONS: Irrespective of family history, high BP is associated with increased body weight and hyperinsulinemia and reflects personal environment and behavior. However, abnormal epinephrine release is characteristic of the combination of genetic, environmental, and behavioral factors that is associated with high personal BP and a familial predisposition to high BP.

Adolescent↗
PubMed1997

Effects of nitrous oxide on electrocorticography during epilepsy surgery.

Interictal spikes on intraoperative electrocorticography during epilepsy are used to tailor resections. There have been a few systematic quantitative studies of anesthetic effects on these interictal discharges, and none on the effects of nitrous oxide (N2O). We calculated spike rates on ECoG on and off N2O in 18 epilepsy surgery patients with subdural strips and grids, analyzing the most active recording contract. In a blinded analyses ten patients had fewer spikes on N2O, while eight patients had more spikes on N2O. The mean spike rates did not differ (41/min on N2O and 40/min off N2O). Spike rate on and off N2O were compared using the non-parametric Wilcoxon matched pairs test. These rates were not significantly different. Our study indicates that N2O in doses employed dose not effect interictal spikes and this agent may be used during epilepsy surgery without concerns about suppression of epileptiform activity.

Electroencephalography↗
PubMed1997

In vivo and in vitro effects of carbenoxolone on glucocorticoid receptor binding and glucocorticoid activity.

Carbenoxolone potentiates the mineralocorticoid activity of endogenous glucocorticoid hormones by inhibiting the enzyme 11 beta-hydroxysteroid dehydrogenase, which converts cortisol and corticosterone to inactive 11-oxo-derivatives. We addressed the question of whether glucocorticoid activity is also affected by carbenoxolone. Using a rat model involving low dose corticosterone treatment, we found that carbenoxolone neither potentiated nor inhibited the modest increases in blood pressure or reductions in weight gain caused by steroid treatment. Other indices of glucocorticoid activity including white blood cell number, thymus weight, and down regulation of the glucocorticoid receptor were unaffected. In vitro studies with liver and kidney cytosol preparations indicated that carbenoxolone did compete for 3H-dexamethasone binding sites. Carbenoxolone was 5-10 times more effective than glycyrrhetinic acid, 20-30 thousand times less effective than dexamethasone, and is therefore, approximately 1000 times less effective than corticosterone. Analysis of dexamethasone-binding curves indicated a single class of receptor. We conclude that carbenoxolone at the dose tested does not have intrinsic glucocorticoid activity in vivo, nor does it modulate the activities of corticosterone. Carbenoxolone binds weakly to the glucocorticoid receptor. It is not clear whether this weak affinity accounts for some or any of the direct in vitro effects of high concentrations of carbenoxolone that others have described.

Animals↗
PubMed1997

Characterisation of relaxation of the lower oesophageal sphincter in healthy premature infants.

BACKGROUND: Gastro-oesophageal reflux disease causes significant morbidity in premature infants, but the role of dysfunction of the lower oesophageal sphincter (LOS) in this condition is unclear. METHODS: Oesophageal manometry was performed after gavage feeding in 13 healthy preterm neonates (postmenstrual age > or = 33 weeks) with a perfused sleeve with side hole assembly. Swallow related (both single and multiple) and transient LOS relaxations (TLOSRs) were identified and the characteristics of these events defined. Reflux was identified with manometric criteria (common cavity episodes). RESULTS: Five hundred and eleven relaxation of the LOS were observed, 55% related to single swallows, 23% related to multiple swallows, and 22% TLOSRs. The time to maximal LOS relaxation was longer for TLOSRs than for single or multiple swallows (mean (SEM) 5.0 (0.3) s v 3.0 (0.1) s and 3.3 (0.1) s, p < 0.0001 and p < 0.005). The durations of multiple swallows and TLOSRs were longer than single swallows (12.2 (0.5) s and 11.2 (0.4) s v 5.3 (0.2) s, p < 0.0001). Most of the oesophageal body common cavity episodes (94%) occurred during TLOSRs. CONCLUSIONS: In healthy preterm infants (postmenstrual age > or = 33 weeks) the motor events associated with LOS relaxation were similar to those seen in healthy adults. TLOSRs may be an important mechanism of reflux in premature infants.

Deglutition↗
PubMed1997

Acute hyperglycaemia affects anorectal motor and sensory function in normal subjects.

BACKGROUND: The pathogenesis of anorectal dysfunction, which occurs frequently in patients with diabetes mellitus, is poorly defined. Recent studies indicate that changes in the blood glucose concentration have a major reversible effect on gastrointestinal motor function. AIMS: To determine the effects of physiological changes in blood glucose and hyperglycaemia on anorectal motor and sensory function in normal subjects. SUBJECTS: In eight normal subjects measurements of anorectal motility and sensation were performed on separate days while blood glucose concentrations were stabilised at 4, 8, and 12 mmol/l. METHODS: Anorectal motor and sensory function was measured using a sleeve/sidehole catheter incorporating a balloon, and electromyography. RESULTS: The number of spontaneous anal relaxations was greater at 12 mmol/l than at 8 and 4 mmol/l glucose (p < 0.05 for both). Anal squeeze pressures were less at a blood glucose of 12 mmol/l when compared with 8 and 4 mmol/l (p < 0.05 for both). During rectal distension, residual anal pressures were not significantly different between the three blood glucose concentrations. Rectal compliance was greater (p < 0.05) at a blood glucose of 12 mmol/l when compared with 4 mmol/l. The threshold volume for initial perception of rectal distension was less at 12 mmol/l when compared with 4 mmol/l (40 (20-100) ml versus 10 (10-150) ml, p < 0.05). CONCLUSIONS: An acute elevation of blood glucose to 12 mmol/l inhibits internal and external anal sphincter function and increases rectal sensitivity in normal subjects. In contrast, physiological changes in blood glucose do not have a significant effect on anorectal motor and sensory function.

Acute Disease↗
PubMed1997

Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in humans: studies with the CCK antagonist loxiglumide.

BACKGROUND: Exogenous cholecystokinin (CCK) inhibits antral motility and slows gastric emptying (GE) but the effect of endogenous CCK on the gastric motor mechanisms responsible for GE remains unclear. METHODS: The effect of the CCK-A antagonist loxiglumide (LOX) on GE and motility was studied using magnetic resonance imaging in six healthy volunteers after ingestion of 500 ml Intralipid 10% (550 kcal). Subjects were studied in the supine position on two occasions during intravenous infusion of LOX (66 mumol/kg/h for 10 min followed by 22 mumol/kg/h) or placebo. GE was determined every 15 minutes using transaxial abdominal scans and motility was studied by means of 120 coronal scans, 1.2 seconds apart. For each coronal image the proximal and distal (antral) diameters were measured at a fixed point in the stomach to determine contraction frequency (ACF) and amplitude (AMP). RESULTS: GE was faster during LOX infusion than placebo (t1/2 31 (22) versus 115 (67) minutes, p < 0.03). There was little variation in the diameter of the proximal stomach with either LOX or placebo. In the distal stomach marked contractile activity was observed during LOX (ACF 2.9 (0.2) versus 1.5 (2.9) during placebo, p < 0.01). AMP also increased during LOX compared with placebo (56 (22)% versus 27 (16)%, p < 0.001). CONCLUSION: The increases in antral motility are likely to contribute to the acceleration of GE and suggest that CCK may regulate GE by acting on the distal stomach although an effect on the proximal stomach cannot be excluded.

Adult↗
PubMed1997

Effects of insulin-like growth factor-I administration on radiation enteritis in rats.

BACKGROUND: Acute radiation-induced damage to the small bowel occurs frequently during abdominal radiotherapy. Since the small intestine is selectively responsive to the growth-promoting effects of insulin-like growth factor-I (IGF-I), we investigated the effects of IGF-I administration on mucosal recovery from radiation enteritis in the rat. METHODS: Rats received a single 10-Gy dose of total abdominal irradiation followed by implantation of mini-pumps infusing either IGF-I or vehicle for 4 days. After the rats had been killed, gut organs were weighed before light microscopic and biochemical examination. RESULTS: Irradiated rats receiving IGF-I lost less body weight than vehicle-treated rats, whereas the wet weights of the stomach, small intestine, and colon were increased by 10%, 19%, and 21%, respectively, and crypt depth was increased in the duodenum, jejunum, and ileum. CONCLUSIONS: IGF-I administration after abdominal irradiation increased small-intestinal mass and improved indicators of mucosal integrity, suggesting acceleration of small-intestinal mucosal recovery from radiation injury.

Animals↗
PubMed1997

Effects of fractionated abdominal irradiation on small intestinal motility--studies in a novel in vitro animal model.

Disordered small intestinal motility occurs frequently during acute radiation enteritis. However, the characteristics and time course of the motor dysfunction are poorly defined. These parameters were assessed in a novel animal model of radiation enteritis. Ileal pressures were recorded in vitro with perfused micromanometric catheter using an arterially perfused ileal loop in 22 ferrets following fractionated abdominal irradiation (9 doses 2.50 Gy thrice weekly for 3 weeks). Tissue damage was graded histologically. Studies were performed 3 to 29 days after irradiation. Tissue from 7 control animals was also studied. All treated animals developed diarrhoea. Histology showed changes consistent with mild to moderate radiation enteritis. Following irradiation, there was an initial increase in frequency followed by a non-significant reduction in the frequency, but not the amplitude of ileal pressure waves. The frequency of pressure waves showed an inverse relationship with time after radiation (r = -0.634, p < 0.002). There was no relationship between motility and histology. We conclude that abdominal irradiation is associated with a time-dependent reduction in ileal motility which does not correlate with light microscopic changes.

Animals↗
PubMed1996

Plasma angiotensin II, predisposition to hypertension, and left ventricular size in healthy young adults.

BACKGROUND: We studied the correlates of left ventricular mass (LVM) in 84 healthy young adults aged 16 to 24 years from the general population. Subjects were selected according to predisposition to hypertension into four groups with either high or low personal blood pressures and either high or low parental blood pressures. METHODS AND RESULTS: LVM was measured by echocardiography, and measurements of blood pressure, heart rate, body dimensions, and plasma concentrations of components of the renin-angiotensin system were made under resting conditions. LVM was similar in individuals predisposed to hypertension (high personal and parental blood pressures) and those with contrasting predisposition (low personal and parental pressures). Regression analysis of the combined groups showed that LVM correlated closely with body size, particularly lean body mass (r=.69, P<.0001) and systolic (r=.35, P<.0001) but not diastolic blood pressure. Plasma angiotensin II (r=.39, P<.0001), renin (r=.302, P<.01), and angiotensin-converting enzyme (r=.22, P<.05) showed significant correlation with LVM. Multiple regression analysis revealed that plasma angiotensin II was the most important component of the renin-angiotensin system and that its effect was independent of systolic blood pressure and body size. CONCLUSIONS: These findings provide evidence in humans that angiotensin II exerts a direct on myocardial size. This association may have important implications for the complications and treatment of left ventricular hypertrophy.

Adolescent↗
PubMed1996

The effect of acute hyperglycaemia on small intestinal motility in normal subjects.

The effects of hyperglycaemia on postprandial small intestinal motor activity are unclear. Duodenal and jejunal pressures and duodeno-caecal transit were measured in eight healthy male volunteers during euglycaemia (blood glucose 4-6 mmol/l) and hyperglycaemia (blood glucose 12-15 mmol/l). Duodenal and jejunal pressures were recorded with a manometric assembly during intraduodenal infusion of 100 ml nutrient liquid comprising 14% protein, 31.5% fat and 54.5% carbohydrate together with 15 glactulose. Duodeno-caecal transit was determined by a breath hydrogen technique. The number of duodenal (p < 0.05) and jejunal (p < 0.01) pressure waves, excluding phase III episodes was reduced during hyperglycaemia compared to euglycaemia Hyperglycaemia was associated with earlier onset of phase III activity (30 +/- 12 vs 132 +/- 20 min; p < 0.05) Duodeno-caecal transit was slower during hyperglycaemia when compared to euglycaemia (114 +/- 17 vs 49 +/- 6 min, p < 0.01). We conclude that induced hyperglycaemia has major effects on postprandial small intestinal motility. The reduction in duodenal and jejunal motor activity is likely to explain the retardation of small intestinal transit during hyperglycaemia.

Acute Disease↗
PubMed1996

Metabolic base production and mucosal vulnerability during acid inhibition in a mammalian stomach in vitro.

Acid inhibition increases gastric mucosal susceptibility to damage by luminal acid. This might be due to reduced metabolic CO2 and bicarbonate whereas, during normal acid, secretion cytoprotective CO2/HCO3- production parallels acid production. Metabolic activity and mucosal damage caused by luminal acid perfusion was determined in an in vitro mouse stomach, with and without acid inhibition, and at 0%, 1%, or 5% serosal CO2 supply. Without acid inhibition there was no mucosal damage at any level of serosal CO2/HCO3- supply. Acid inhibition reduced metabolic CO2 production by 29% (P < 0.004) and resulted in microscopic damage to 55% of the mucosal area and perforation in four of five stomachs (P < 0.05). Although, 1% CO2 supply completely replaced the reduction in metabolic CO2, it did not protect against mucosal damage. Overreplacement by 5% serosal CO2/HCO3- was required to prevent damage. There was no correlation between luminal CO2/HCO3- output and mucosal damage. The protection by endogenous or exogenous CO2/HCO3- appears to act intracellularly rather than by intragastric or intercellular neutralization.

Acid-Base Equilibrium↗
PubMed1996

11 beta-Hydroxylase activity in glucocorticoid suppressible hyperaldosteronism: lessons for essential hypertension?

Corticosteroid 11 beta-hydroxylation is catalysed 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 in 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 basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all 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 chimaeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone and DOC concentrations, appeared to be more sensitive to ACTH in GSH than the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in the condition, and may contribute to the phenotypic variability.

Adrenocorticotropic Hormone↗
PubMed1996

Intraluminal micromanometry: an evaluation of the dynamic performance of micro-extrusions and sleeve sensors.

Conventional manometric techniques are unsuitable for studies in premature infants and small laboratory animals. We have therefore developed silicone rubber 5-lumen and 10-lumen micromanometric extrusions with an o.d. 2.0 mm and lumina of 0.35 mm i.d. This study evaluates the suitability of microextrusions for intraluminal perfusion manometry. Pressure offset, post-occlusion pressure rise rate and sphincter model studies were used to assess the manometric performance of the extrusions and a miniature sleeve sensor (25 mm long) at infusion rates of 0.01-0.1 mL min-1. Micro-extrusions (5-lumen/10-lumen, respectively) had offsets (per 100 cm of length) of 3.8/5.0 mmHg at 0.01 mL min-1 and 25.6/26.2 mmHg at 0.1 mL min-1 and rise rates (in 160 cm lengths) of 64/43 mmHg sec-1 at 0.01 mL min-1 and 330/224 mmHg sec-1 at 0.1 mL min-1. Infusion rates 0.025 mL min-1 produced rise rates 100 mmHg sec-1. The miniature sleeve sensor had minimal resistance to perfusion, rise rates of 3 mmHg sec-1 at 0.01 mL min-1 and 23 mmHg sec-1 at 0.1 mL min-1 and recorded pressure as accurately as a side hole. We conclude that the performance of micromanometric extrusions and sleeves is sufficient for intraluminal perfusion manometry.

Animals↗