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Biomedical subjects

R Fraser

Publications and source records attributed to R Fraser.

At least 73 records · Page 4Linked to original sources
PubMed1999

Evaluation of gastric emptying and motility in diabetic gastroparesis with magnetic resonance imaging: effects of cisapride.

OBJECTIVE: The motor mechanisms that underlie both slow gastric emptying in diabetic gastroparesis and its acceleration by cisapride are poorly understood. We have recently shown that magnetic resonance imaging (MRI) allows concurrent evaluation of both gastric emptying and regional gastric motility. METHODS: Emptying and motility were measured in eight diabetic patients with previously demonstrated delayed gastric emptying using a rapid MRI technique during oral administration of cisapride and placebo. Studies were performed in a double blind fashion and each patient acted as his own control. Subjects were studied supine for 120 min in a 1.5 Tesla MRI scanner after ingestion of 500 ml of 10% Intralipid. Gastric emptying corrected for the volume of secretions was determined every 15 min using transaxial scans. Each transaxial scan was followed by 120 coronal scans at 1 s intervals. Coronal scans were angled to provide simultaneous imaging of the proximal and distal stomach. MRI studies were also performed in seven diabetic patients with normal emptying who served as disease controls. RESULTS: Emptying was slower in the gastroparetic patients (t(1/2): 124 +/- 10 min) compared to patients with normal emptying (81 +/- 9 min, p < 0.05). Cisapride accelerated gastric emptying (74 +/- 5 vs 124 +/- 10 min) in patients with gastroparesis. The contraction amplitudes in the proximal stomach of gastroparetic patients were increased during cisapride treatment (17.2% +/- 1.8% vs 13.2% +/- 0.6%; p < 0.02), whereas antral contraction frequency, amplitude, and velocity were unchanged. CONCLUSIONS: We conclude that cisapride-induced acceleration of liquid gastric emptying in diabetic gastroparesis does not appear to result from changes in antral contractility, but may be related to changes in proximal gastric tone or gastric outlet resistance.

Adult↗
PubMed1999

Evidence that nitric oxide mechanisms regulate small intestinal motility in humans.

BACKGROUND: Non-cholinergic non-adrenergic neural mechanisms involving nerves containing NO have been shown to modulate smooth muscle in the gastrointestinal tract, and it has been suggested that release from tonic NO inhibition may be important in the regulation of cyclical fasting small intestinal motility. AIMS: To evaluate the role of NO mechanisms in the regulation of fasting small intestinal motor activity in humans using a specific NO synthase inhibitor, NG-monomethyl-L-arginine ( L-NMMA). METHODS: In seven healthy male volunteers, duodenal and jejunal pressures were measured for four hours with a nine lumen manometric catheter. Volunteers attended on four separate days on which they received an intravenous infusion either saline or L-NMMA (0.5, 2, or 4 mg/kg/h) in random order. Intravenous infusions began 10 minutes after completion of phase III of the migrating motor complex (MMC). RESULTS: The first episode of phase III activity occurred earlier after infusion of 2 and 4 mg/kg/h L-NMMA than after infusion of 0.5 mg/kg/h L-NMMA or saline (mean (95% confidence interval) 52 (36-68) and 57 (18-97) v 116 (69-193) and 145 (64-226) minutes respectively) with a resultant MMC cycle length of 82 (59-105) and 86 (46-126) v 132 (49-198) and 169 (98-240) minutes respectively. The total number of phase III activities during the four hour recording was increased (p<0.05) by L-NMMA at a dose of 4 mg/kg/h (2 (1-3)) but not at 2 mg/kg/h (1.5 (1-2)) or 0.5 mg/kg/h (1.3 (1-2)) compared with saline (1.3 (0.6-2)). L-NMMA had no effect on the duration, velocity, number of contractions per minute, length of migration, or site of origin of phase III of the MMC. The duration of phase I activity was shorter (p<0.05) with 4 mg/kg/h L-NMMA than with saline (12 (1-23) v 31 (19-44) minutes). CONCLUSIONS: These observations suggest that NO mechanisms play a role in the regulation of fasting small intestinal motor activity in humans.

Adult↗
PubMed1999

Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2.

Significant correlation of body sodium and potassium with blood pressure (BP) may suggest a role for aldosterone in essential hypertension. In patients with this disease, the ratio of plasma renin to plasma aldosterone may be lower than in control subjects and plasma aldosterone levels may be more sensitive to angiotensin II (Ang II) infusion. Because essential hypertension is partly genetic, it is possible that altered control of aldosterone synthase gene expression or translation may be responsible. We compared the frequency of 2 linked polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (IC), in groups of hypertensive and normotensive subjects. In a larger population, the relationship of aldosterone excretion rate to these polymorphisms was also evaluated. In 138 hypertensive subjects, there was a highly significant excess of TT homozygosity (SF-1) over CC homozygosity compared with a group of individually matched normotensive control subjects. The T allele was significantly more frequent than the C allele in the hypertensive group compared with the control group. Similarly, there was a highly significant relative excess of the conversion allele over the "wild-type" allele and of conversion homozygosity over wild-type homozygosity in the hypertensive group compared with the control group. In 486 subjects sampled from the North Glasgow Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) population, SF-1 and IC genotypes were compared with tetrahydroaldosterone excretion rate. Subjects with the SF-1 genotypes TT or TC had significantly higher excretion rates than those with the CC genotype. The T allele was associated with higher excretion rates than the C allele. However, no significant differences were found in excretion rate between subjects of different IC genotype. Urinary aldosterone excretion rate may be a useful intermediate phenotype linking these genotypes to raised BP. However, no causal relationship has yet been established, and it is possible that the polymorphisms may be in linkage with other causative mutations.

Adult↗
PubMed1999

Cortisol effects on body mass, blood pressure, and cholesterol in the general population.

The effects of excess cortisol secretion on blood pressure and fat deposition are well documented, but the importance of this glucocorticoid in controlling these processes in normal individuals is less clear. We studied the relationship between cortisol excretion rate (tetrahydrocortisol [THF]+allo-THF+tetrahydrocortisone [THE]) and a range of important cardiovascular risk factors in 439 normal subjects (238 male) sampled from the North of Glasgow (Scotland) population. There were marked gender differences: female subjects were lighter and had lower blood pressures and cortisol levels, whereas HDL cholesterol was higher. The pattern of cortisol metabolism was also different; the index of 11beta-hydroxysteroid dehydrogenase activity (THF+allo-THF/THE) was lower and that of 5alpha-reductase (allo-THF/THF) was higher. There was a strong correlation of blood pressure (positive), cholesterol (positive), and HDL cholesterol (negative in women, positive in men) with age. Cortisol excretion rate did not correlate with blood pressure but correlated strongly with parameters of body habitus (body mass index and waist and hip measurements [positive]) and HDL cholesterol (negative). With multiple regression analysis, there remained a significant association of cortisol excretion rate with HDL cholesterol in men and women and with body mass index in men. These results suggest that glucocorticoids regulate key components of cardiovascular risk.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.

A 36-yr-old woman was referred to the endocrine clinic for investigation of oligomenorrhea, hirsutism, and acne. She was plethoric and overweight with central fat distribution. Plasma cortisol was normal, but her adrenal glands were enlarged (CT scan). Urinary tetrahydrocortisone excretion rate was consistently high, raising the possibility of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) deficiency. In addition, 5beta- reduction of cortisol and cortisone was markedly enhanced. The levels of all cortisol metabolites were suppressed normally with dexamethasone, but conversion of oral cortisone acetate to plasma cortisol was delayed and subnormal compared with that of healthy volunteers. This was accompanied by a larger than normal increase in plasma cortisone concentration. Thus, the defect appears to be in 11beta-HSD1 activity and not in 5beta-reductase activity. Three close relatives of the subject showed no comparable abnormalities, and analysis of the coding region and exon/intron boundaries of the 11beta-HSD1 gene of the case revealed no differences from the consensus sequence. The defect may lie outside the coding region. Alternatively, some other inherited or acquired defect may lead to inhibition of this enzyme system.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1999

Familial pattern of corticosteroids and their metabolism in adult human subjects--the Scottish Adult Twin Study.

Corticosteroids are important in the regulation of normal physiology and are key factors in regulating cardiovascular physiology and disease, the development of which is known to have a genetic component. However, there is little information on the extent to which plasma and urine steroid levels are determined by familial and genetic factors. We have examined basal and ACTH-stimulated plasma steroid levels and 24-h corticosteroid metabolite excretion rates in 146 pairs of adult twins [75 monozygotic (MZ); 71 dizygotic (DZ)]. Intraclass correlation coefficients were measured for all variables; several plasma steroid measurements were strongly related in both (MZ) and (DZ) twins, consistent with a familial pattern. These included basal levels of 11-deoxycortisol and aldosterone. ACTH-stimulated plasma aldosterone levels were also significantly correlated, to a significant degree, in both MZ and DZ twins. The index of 11beta-hydroxysteroid dehydrogenase activity (tetrahydrocortisol + allotetrahydrocortisol/tetrahydrocortisone) and of the more specific index of activity of the type 2 isoform of this enzyme (urine free cortisol/cortisone) also correlated, to a similar degree, in DZ and MZ twins. In contrast, for the basal and ACTH-stimulated plasma concentrations and 24-h urine excretion rates of several corticosteroids, there was evidence of significant heritability (H2), in that correlation in MZ twins was greater than in DZ. For example, basal plasma corticosterone concentrations (B) (H2 = 0.44), basal and stimulated 11-deoxycorticosterone concentrations (DOC) (H2 = 0.44 and 0.41, respectively), stimulated 11-deoxycortisol concentrations (H2 = 0.53), and the index of 11beta-hydroxylase activity DOC/B (H2 = 0.49) were all significantly heritable. For the urinary variables, 24-h tetrahydrodeoxycortisol (H2 = 0.59) and free aldosterone (H2 = 0.56) were significantly heritable. Our data provide the first evidence that plasma and urine levels of important glucocorticoids and mineralocorticoids show a strong familial pattern, and in some instances, there is evidence of a genetic component to this. This suggests that corticosteroids have a plausible role in essential hypertension that has a similar heritable component.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1998

Effects of dexamethasone on functional and pathological changes in rat bronchi caused by high acute exposure to chlorine.

We assessed the effects of dexamethasone on functional and histological changes after acute exposure to a high level of chlorine gas in an animal model of reactive airways dysfunction syndrome (RADS). Sprague-Dawley male rats were exposed to 1500 ppm of chlorine for 5 min and treated with either dexamethasone (dex; 300 micrograms/kg/day) or saline intraperitoneally for 7 days. Lung resistance (RL), airway responsiveness to inhaled methacholine (MCh), airway wall morphometric measurements, and bronchoalveolar lavage (BAL) cells were assessed over a 2-week period after exposure. Dex administration significantly attenuated both chlorine-induced increased RL and chlorine-induced increased responsiveness to methacholine compared with saline: -2.7 +/- 6.8% vs 102.3 +/- 36.6% change from baseline RL (P < 0.01) and 2.5 +/- 0.6 mg/ml vs 1.2 +/- 0.7 mg/ml in the MCh concentration required to double the RL from baseline (P < 0.01). There was a tendency, albeit nonsignificant, for improvement in some indices of epithelial injury. Dex significantly attenuated the postexposure neutrophilic cellular response in BAL 1 day after exposure (15.8 +/- 4.9% neutrophils in the dex group vs 49.8 +/- 2.7% neutrophils in the saline group) (P < or = 0.001). Our results show that dex administration helps maintain pulmonary function, reduces BAL inflammatory cell number, and tends to improve some morphometric airway wall structure parameters in rats exposed to chlorine.

Animals↗
PubMed1998

Mechanisms of gastroesophageal reflux in healthy premature infants.

OBJECTIVES: The aim of this study was to characterize the motor events responsible for gastroesophageal reflux (GER) and esophageal acid clearance in a cohort of healthy preterm infants. STUDY DESIGN: Esophageal motility was recorded for 2 to 3 hours after a feeding in 24 preterm infants, 31 to 38 weeks' postmenstrual age, by using a sleeveside hole micromanometric assembly incorporating a pH probe. RESULTS: Sixty acid GER episodes were recorded by pH probe, and 133 non-acid GER episodes were recorded manometrically by the presence of esophageal common cavities. Of the 193 GER episodes, 159 (82%) were associated with transient lower esophageal sphincter relaxation (TLESR). TLESRs were significantly longer in duration than single swallows (15.1 seconds vs 5.6 seconds, P < .001) and had lower nadir pressures (0.8 mm Hg vs 2.3 mm Hg, P < .001). A total of 3216 esophageal body pressure waves were analyzed; 70% of swallow-induced pressure waves were peristaltic in sequence compared with 5% of swallow-unrelated pressure waves. During periods of esophageal acidification (pH below 4), peristaltic esophageal body pressure wave sequences cleared acid refluxate more effectively than nonperistaltic pressure wave sequences. CONCLUSIONS: In healthy preterm infants, TLESRs are the predominant mechanism underlying GER, and esophageal clearance mechanisms are well developed by at least 31 weeks' postmenstrual age.

Cohort Studies↗
PubMed1998

A novel portable perfused manometric system for recording of small intestinal motility.

The development of solid-state catheters with miniature pressure transducers and portable dataloggers with a large memory capacity has allowed recording of gastrointestinal motility in ambulant subjects. Developments in silicone rubber extrusion technology made it possible to build a perfused manometric system, using a perfused manometric assembly requiring a low volume of perfusate. In the present study the feasibility of recording and automated analysis of small intestinal motility using a perfused multiple lumen manometric system was evaluated in seven healthy volunteers. Pressures were recorded from 12 sideholes arranged in four clusters spaced at 10-cm intervals from the catheter tip. Each channel was perfused at 0.15 mL min-1 with degassed water by a portable, low-compliance, perfusion pump. The 12 sidehole recording channels were connected to external transducers mounted on a belt. Pressure data were stored in two dataloggers. Motility was recorded in the sitting (30 min), and supine (30 min) position, during walking (30 min) and postprandially (90 min). Using purpose-built software baseline variations were corrected for and manometric variables (number of pressure waves, mean amplitude and motility index) calculated. Bench testing of the manometric assembly showed a median baseline pressure offset of 4.2 kPa (range 3.7-10.1) and upon occlusion a rise rate of 27.8 kPa sec-1 (range 19.7-30.8). Changes in body position affected baseline pressures so that compared to the supine position changes in baseline pressure varied between 1.5 +/- 0.7 kPa and 1.9 +/- 0.6 kPa during sitting (P < 0.02), and between 1.7 +/- 0.7 kPa and 1.5 +/- 0.9 kPa during walking (P < 0.03). Manometric recordings obtained during the fasting period showed an increase in small intestinal motor activity during walking. In the postprandial period no differences in motility variables were observed within one cluster and in time. Recording of small intestinal motility with a multiple-channel silicone rubber manometric assembly with a portable perfusion system is a feasible technique which is relatively inexpensive. Computer-assisted data processing allows for adequate elimination of artefacts and automated numerical analysis.

Adult↗
PubMed1998

Small intestinal dysmotility following abdominal irradiation in the rat small intestine.

Abdominal symptoms such as diarrhoea, abdominal cramps and vomiting are common during and after abdominal radiotherapy for gynaecological and pelvic malignancy. It has recently been recognized that small intestinal dysmotility may contribute to these symptoms but the underlying mechanisms are unclear in part because of the technical difficulties inherent in performing studies in irradiated small intestine. The aim of the current study was to evaluate small intestinal motor activity using perfused micromanometric techniques in 6-8-cm segments of ileum during arterial perfusion with isotonic oxygenated fluorocarbon solution. Intestinal segments from six rats were studied 4 days after treatment with 10 Gy abdominal irradiation. Ileal segments from nine nonirradiated animals acted as controls. For each experiment the total number of pressure waves, high-amplitude (> 20 mmHg, long-duration > 6 sec) pressure waves, and long (> 20 associated) bursts of pressure waves were determined. Irradiation had no effect on the overall number of pressure waves, but increased high-amplitude long-duration (HALD) pressure waves (248 vs 7, P < 0.01). In control animals HALD waves were localized to a single recording site but after radiotherapy 74% of HALD waves were temporally associated with similar pressure waves in other manometric channels. Forty-seven per cent of associated HALD waves migrated aborally. Retrograde migration of HALD waves was seen in five segments following irradiation. Irradiation abolished bursts of > 20 pressure waves.

Abdomen↗
PubMed1998

Structure-function relationships of aldosterone synthase and 11 beta-hydroxylase enzymes: implications for human hypertension.

1. The genes encoding aldosterone synthase (CYP11B2) and 11 beta-hydroxylase (CYP11B1) are very similar at the nucleotide level (> 95% homology). Despite this and the corresponding similarity of amino acid sequence, there are considerable differences in functional and substrate specificity of the two enzymes. In the present study we have examined the role of two amino acids that differ between the two enzymes (147 and 248) to determine the difference between aldosterone synthase and 11 beta-hydroxylase capacity to 11-hydroxylate 11-deoxycorticosterone (DOC). 2. Plasmids containing cDNA encoding wild-type aldosterone synthase, wild-type 11 beta-hydroxylase and mutated forms of aldosterone synthase (D147E and I248T), in which the codons for residues 147 (aspartate exon 3) or 248 (isoleucine exon 4) had been altered to encode the corresponding amino acids (glutamate and threonine respectively) from 11 beta-hydroxylase were transiently expressed in non-steroidogenic COS-7 cells. All transfections were cotransfected with bovine adrenodoxin. Cells were then incubated with [3H]-DOC for 48 h and the production of corticosterone (B), 18-hydroxycorticosterone (18-OHB) and aldosterone measured by measuring tritriated products using thin layer chromatography. 3. Compared with wild-type aldosterone synthase, the mutated form (D147E) encoding amino acid 147 from 11 beta-hydroxylase was more efficient in 11 beta-hydroxylation of deoxycorticosterone (B:DOC ratio 0.53 +/- 0.05 (wild type) to 3.05 +/- 0.37 (mutant); P < 0.001). However, 18-hydroxylation of B and conversion of this steroid into aldosterone were unaffected. There was a 20% increase in the production of aldosterone from DOC (P < 0.05). However, in comparison with wild-type 11 beta-hydroxylase, the mutated aldosterone synthase (D147E) was still less efficient (B:DOC ratio 6.2 +/- 0.41). The mutated aldosterone synthase (I248T) encoding amino acid 248 from 11 beta-hydroxylase showed no changes in conversion of DOC to B or in the production of aldosterone. 4. These data demonstrate that position 147 has an important effect on the efficiency of 11 beta-hydroxylation of DOC and indicate that this is a key difference between the two enzymes in determining functional specificity. However, other residues must also contribute to efficiency of 11-hydroxylation of 11 beta-hydroxylase. In contrast, amino acid 248, which is one of the few differences between the two enzymes in exon 4, does not affect enzyme efficiency. As altered activity of aldosterone synthase and 11 beta-hydroxylase has been proposed as an important intermediate phenotype in essential hypertension, such studies will help our understanding of the structure-function relationships that will be necessary in order to understand how genetic changes may contribute to observed differences in phenotype.

18-Hydroxycorticosterone↗
PubMed1998

Physiological changes in insulin resistance in human pregnancy: longitudinal study with the hyperinsulinaemic euglycaemic clamp technique.

OBJECTIVE: To perform measurements of insulin resistance serially in pregnancy and after childbirth in normal women. DESIGN: Longitudinal study. SETTING: Teaching hospital. METHODS: Ten normal women were studied using the hyperinsulinaemic euglycaemic clamp technique before pregnancy, at 16, 26 and 36 weeks gestation, and 8 weeks after delivery. All women breastfed their infants. Insulin resistance was measured by the glucose infusion rate required to maintain the plasma glucose at 4.5 mmol/l. RESULTS: There was a progressive increase in insulin resistance in all women as pregnancy progressed. The increase in resistance was most marked between 16 and 26 weeks of gestation, with only minimal progression thereafter. Lactation does not alter insulin resistance. CONCLUSION: The timing and extent of changes in insulin resistance are of physiological importance because they affect all classes of maternal and fetal substrates.

Adult↗
PubMed1998

Vagus nerve stimulation for symptomatic generalized epilepsy: a pilot study.

PURPOSE: Patients with symptomatic generalized epilepsy (SGE) may have antiepileptic drug (AED)-resistant mixed generalized seizures. Vagus nerve stimulation (VNS) reduces partial seizures and may help SGE. METHODS: We added VNS to stable AED therapy in five SGE patients. Nine-month postoperative VNS treatment seizure rates were compared to a 1-month preoperative baseline. RESULTS: All patients had mixed generalized seizures, EEG generalized slow spike-and-wave and behavioral abnormalities. Median number of previous AEDs taken was 6 (range 5-12). Median baseline seizure rate was 75/month (range 29-110). VNS produced a median seizure rate production of -41% (range -40% - -85%). Adverse events reported in one patient each were: incisional infection, choking sensation and voice change; and coughing (noted by two patients). One patient discontinued VNS due to coughing. CONCLUSIONS: We conclude that VNS may be useful add-on therapy for SGE. A larger, controlled, and blinded trial may be warranted.

Adult↗
PubMed1998

Acute effects of therapeutic irradiation for prostatic carcinoma on anorectal function.

AIM: The incidence of anorectal symptoms after radiotherapy (RTH) for localised pelvic malignant disease is unclear. In addition, the effects of pelvic irradiation on both anorectal motility and sensory function are poorly defined. A prospective study was therefore performed on 35 patients (55-82 years of age) with localised prostatic carcinoma before and four to six weeks after RTH to assess its effects on anorectal function. METHODS: Anorectal symptoms were assessed by questionnaire. Anorectal pressures at rest and in response to voluntary squeeze, rectal distension, and increases in intra-abdominal pressure were evaluated with perfused sleeve side hole manometry. Rectal sensation was tested during graded balloon distension. Rectal compliance was calculated by the pressure-volume relation obtained during the testing of rectal sensation. Ultrasound was used to determine anal sphincter structure and integrity. RESULTS: RTH had no effect on anal sphincter morphology. The frequency of defecation increased after RTH (7 (3-21) v 10 (3-56) bowel actions a week; p < 0.01). After RTH, 16 patients had faecal urgency and eight faecal incontinence, compared with five and one respectively before RTH (p < 0.01 for each). Basal and squeeze sleeve recorded pressures were reduced after RTH (54 (3) v 49 (3) mm Hg (p < 0.05) and 111 (8) v 102 (8) mm Hg (p < 0.01), before and after RTH respectively; means (SEM)). Rectal compliance was reduced after RTH (1.2 v 1.4 mm Hg/ml, p < 0.05). After RTH, threshold volumes for perception of rectal distension were lower in the 16 patients who either experienced faecal urgency for the first time (13 patients) or reported worsening of this symptom (three patients) compared with the remaining patients (34 (4) v 48 (5) ml respectively, p < 0.05). CONCLUSION: Faecal incontinence (23%) is a common problem four to six weeks after RTH for prostatic carcinoma and is associated with minor reductions in anal sphincter pressures. The high prevalence of faecal urgency in patients after RTH may be related to alterations in rectal perception of stool.

Aged↗
PubMed1998

Human alpha-adducin gene, blood pressure, and sodium metabolism.

The adducin genes contribute significantly to population variation in rat blood pressure and cell membrane sodium transport. The 460Trp mutation of the human alpha-adducin gene has been associated with hypertension, in particular hypertension sensitive to sodium restriction. We studied the relationship between the 460Trp mutation and population variation in blood pressure and sodium metabolism. From 603 Scottish families, we selected 151 offspring and 224 parents with blood pressures in either the upper (high) or bottom (low) 30% of the population distribution and measured the 460Trp mutation using allele-specific hybridization. In offspring, we also measured exchangeable sodium, plasma volume, and total body water. Plasma levels of components of the renin-angiotensin system, atrial natriuretic peptide, and cellular sodium and transmembrane sodium efflux were also estimated. The overall frequency of the 460Trp mutation was 27.1%. In offspring and parent groups, we found no difference in the genotype or allele frequencies of the 460Trp mutation between subjects with high or low blood pressure. There was no overall association between the alpha-adducin genotypes and blood pressure variation. In offspring, the 460Trp mutation was not associated with any significant differences in body fluid volumes or exchangeable sodium; levels of plasma renin, angiotensin II, aldosterone, or atrial natriuretic peptide; intracellular sodium; or ouabain-sensitive transmembrane sodium efflux. These findings suggest that in our Scottish population, the alpha-adducin 460Trp polymorphism is not related to blood pressure and does not affect whole body or cellular sodium metabolism.

Adolescent↗
PubMed1998

Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats.

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min. Lung resistance (RL), responsiveness to inhaled methacholine (MCh), the airway epithelium and bronchoalveolar lavage (BAL) were assessed over a 3 month period after exposure. RL increased significantly up to 3 days after exposure, reaching a maximal change of 110+/-16% from baseline. There was a significant decrease in the concentration of MCh required to increase RL by 0.20 cmH2O x mL(-1) x s from days 1-7 after exposure. In some rats, MCh hyperresponsiveness and RL changes persisted after exposure for as long as 1 and 3 months, respectively. Histological evaluation with morphometric evaluation revealed epithelial flattening, necrosis, increase in smooth muscle mass and evidence of epithelial regeneration. BAL showed an increased number of neutrophils. The timing of maximal abnormality in the appearance of the epithelium (days 1-3) corresponded to that of the maximal functional changes. Acute high chlorine exposure results in functional and pathological abnormalities that resolve in the majority of animals after a variable period; however, these changes can persist in some animals. Functional abnormalities in the initial stages may be related to airway epithelial damage.

Administration, Inhalation↗
PubMed1998

Glucocorticoid receptor polymorphism, skin vasoconstriction, and other metabolic intermediate phenotypes in normal human subjects.

Genetic variation of the glucocorticoid receptor (GR) locus is associated with differences in blood pressure. To define the intermediate phenotypes associated with this variation, we investigated the biochemical and clinical significance of a BclI restriction fragment length polymorphism of the GR locus in 64 normal male volunteers. Blood samples were genotyped as either AA (homozygous large allele; n = 6), Aa (heterozygous; n = 51), or aa (homozygous small allele, n = 7). Four primary glucocorticoid variables were measured including GR binding characteristics and glucocorticoid-sensitive lysozyme release of leukocytes in vitro and the blanching response of forearm skin to budesonide. A large number of secondary variables (urinary and plasma steroid measurements, blood pressure and indices of body fat metabolism, and routine biochemical and hematological measurements) were also considered. In vivo sensitivity to budesonide was greater in AA than aa individuals (mean +/- SE EC50 values: 13 +/- 5 and 42 +/- 10 ng; P < 0.01). In contrast, leukocytes of AA subjects tended to have lower affinity and reduced sensitivity for dexamethasone, although these effects were not statistically significant. Based on urinary steroid measurements, 11 beta-hydroxysteroid dehydrogenase activity [ratio of tetrahydrocortisol (THF) to tetrahydrocortisone (THE) metabolites] was not affected by genotype. The relative activities of 5 alpha- and 5 beta-reductase activity (allo-THF/THF + THE) appeared lower in AA than aa subjects (0.22 +/- 0.04 cf. 0.33 +/- 0.06; P < 0.005) but were not judged to be significantly different when corrected for multiple comparisons. Single and multivariate analyses were carried out to determine which variables influence GR binding characteristics and glucocorticoid responsiveness and to see whether cardiovascular risk factors (blood pressure and body fat) were influenced by glucocorticoid-dependent functions. Only 15-20% of the variations in the dissociation constant (Kd) and maximum binding capacity (Bmax) were influenced by other variables; plasma cholesterol was the most important for affinity and plasma sodium concentration for binding capacity. Multivariate analysis showed that several factors including GR genotype and urinary cortisol account for 10% of the variation of in vivo responses to glucocorticoid hormones; plasma calcium concentration was the only variable that contributed to in vitro sensitivity of leukocytes to dexamethasone. Glucocorticoid-dependent responses were of negligible importance in determining blood pressure or percentage body fat within the narrow physiological ranges of the present study. We conclude that GR genotype affects steroid sensitivity in a tissue-specific manner because of altered GR function or possibly because of linkage to a locus that controls hormone access to the receptor by influencing steroid metabolism.

Adipose Tissue↗