Biomedical subjects

N F Taylor

Publications and source records attributed to N F Taylor.

At least 37 records · Page 2Linked to original sources

PubMed1999

Angular movements of the pelvis and lumbar spine during self-selected and slow walking speeds.

We studied the effect of walking at a self-selected and at a slower speed on the angular movements of the pelvis and lumbar spine. We also studied how interpretation of speed effects on lumbar spine movements was influenced by frame of reference, either relative to the pelvis or relative to a global reference frame. Twenty-seven subjects without pathology walked on a treadmill at either self-selected or 60% of self-selected speed. The movements of the pelvis and lumbar spine, as represented by surface markers, were recorded by videocameras and the three-dimensional angles computed by the PEAK motion measurement system. Results indicated that the amplitudes of pelvic list (P<0.05) and pelvic axial rotation (P<0. 05) were decreased at slow walking speed. Relative to the pelvis, the amplitude of lumbar lateral flexion was decreased with slower walking (P<0.01). In contrast, when lumbar spine movements were measured relative to a global reference frame, no differences were detected due to decreased walking speed. This suggests, firstly, that the effect of walking speed when evaluating the significance of decreased movements of the pelvis and of the lumbar spine (relative to the pelvis) of subjects walking at slower than self-selected speeds should be considered and secondly, that movement of the lumbar spine should be interpreted with respect to a frame of reference.

Adult↗

PubMed1999

Manipulative physiotherapists can reliably palpate nominated lumbar spinal levels.

Palpating a nominated spinal level is a prerequisite to more complex tasks such as palpating the level most likely to be the source of the patient's symptoms. The aim of this study was to investigate the reliability of physiotherapists with a post-graduate qualification in manipulation (manipulative physiotherapists) in palpating the lumbar spines of patients in a clinical setting. Three pairs of manipulative physiotherapists palpated the randomly-nominated lumbar spinal levels of 20 patients presenting to their practices for treatment of low-back pain. Each therapist marked the skin overlying the spinous process of the nominated spinal level with an ultraviolet pen and these marks were transcribed onto transparencies for analysis. The therapists obtained an overall weighted kappa of 0.92 indicating almost perfect agreement for locating the nominated spinal level. The results of this study indicate that manipulative physiotherapists can reliably palpate nominated lumbar spinal levels, suggesting further training in spinal therapy enhances the palpatory skills of physiotherapists in palpating nominated lumbar spinal levels.

Analysis of Variance↗

PubMed1999

Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.

The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSD), an oxo-reductase converting E to F (11betaHSD1) and a dehydrogenase (11betaHSD2) converting F to E. 11betaHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11betaHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20-40 mg/month for at least 12 months), GH rose from 7.1 +/- 1.5 to 17.5 +/- 4.3 mU/L (mean +/- SE), and insulin-like growth factor I (IGF-I) rose from 43.0 +/- 8.8 to 82.1 +/- 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 +/- 0.06 to 0.60 +/- 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11betaHSD2 activity) suggested that this was due to inhibition of 11betaHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 +/- 49.2 to 29.3 +/- 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 +/- 0.06 to 0.63 +/- 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11betaHSD1 or 11betaHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11betaHSD1 isozyme indicated a dose-dependent inhibition of 11betaHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11betaHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11betaHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11betaHSD1 expression.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1998

Sexual dimorphism in 11 beta hydroxysteroid dehydrogenase activity and its relation to fat distribution and insulin sensitivity; a study in hypopituitary subjects.

OBJECTIVE: Sexual dimorphism of 11 beta hydroxysteroid dehydrogenase activity (11 beta HSD) as measured by the urinary 11-OH/11-oxo cortisol metabolite ratio has been documented in healthy subjects. Since body composition, fat distribution and insulin sensitivity vary between the sexes we have investigated whether these factors may account for the observed difference. Studies were performed in ACTH deficient hypopituitary subjects to eliminate the effect of feedback modulation of cortisol secretion. DESIGN AND PATIENTS: 44 hypopituitary patients, (m:f, 32:12), median age 51 years, median weight 86 kg, on hydrocortisone and other replacement therapy as appropriate were studied. MEASUREMENT: Urine 11-OH/11-oxo cortisol metabolites and serum and urine cortisone (E) and cortisol (F) were measured in relation to total cortisol metabolites and cortisol binding globulin; fat distribution was assessed by Dual Energy X-ray absorptiometry (DXA), and insulin sensitivity by homeostatic model of assessment. RESULTS: Cortisol bioavailability (total urine cortisol metabolites, urine free cortisol and cortisol binding globulin) was similar in both sexes. The 11-OH/11-oxo ratio was lower in females than males (median; 0.99 vs 1.3, P < 0.03) while thyroid status was similar. Females had higher percentage fat (median 47.7 vs 34.9, P < 0.01); total fat (median 39.5 vs 34.9 kg, P < 0.01), android fat (median 9.1 vs 6.6 kg, P < 0.01); gynoid fat (median; 9.9 vs 6.8 kg, P < 0.05) and lower insulin sensitivity (median 15.3 vs 30.6, P < 0.01). In all subjects, the 11-OH/11-oxo ratio was inversely related to body weight (P < 0.01), % fat (P < 0.05), total fat (P < 0.01), android fat (P < 0.01), gynoid fat, (P < 0.01) and directly correlated to insulin sensitivity, P < 0.01. Stepwise regression analysis showed gynoid fat to be the most important factor determining the 11-OH/11-oxo ratio. In 24 subjects (f:m, 8:16) on exogenous sex steroid therapy insulin sensitivity was similar but the sexual dimorphism of the 11-OH/11-oxo ratio remained unchanged (median; 1.0 vs 1.7, P < 0.05). The urine and serum F and E and their ratio (F/E) were similar in these groups. CONCLUSION: These data confirm the presence of sexual dimorphism in 11 beta-hydroxysteroid dehydrogenase activity in hypopituitary patients as described in normal individuals. This is the first in vivo evidence that this dimorphism is related to body composition. Our findings suggest that sexual dimorphism may be determined by the activity of type 1 and not type 2 11 beta-hydroxysteroid dehydrogenase.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1998

The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 beta-hydroxysteroid dehydrogenase activity.

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11-hydroxy/11-oxo-cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1 and 2), the enzymes responsible for cortisol-cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement. DESIGN: Patients received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacement (0.25 U/kg/week). PATIENTS: Seven hypopituitary adults (three men and four women, age range 47-64 years) with combined GH and ACTH deficiency. Three additional patients with GH deficiency, but intact ACTH reserve, were also studied. MEASUREMENTS: Urine steroid metabolite profiles were measured in 24-hour urine collections by gas chromatography after each week of treatment. Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 activity. RESULTS: Total urinary CoM increased with rising doses of HC, but at each particular HC dose, were unchanged after GH (before versus after GH, median (range): 9.67 (7.86-12.59) versus 9.93 (8.31-14.08); 15.87 (12.37-31.39) versus 17.07 (12.64-23.81); 26.68 (19.07-42.14) versus 26.77 (8.01-37.62) mg/24 hours). The urine ratio 11-hydroxy/11-oxo-CoM decreased significantly with GH treatment, at each HC dose schedule (1.22 (1.02-1.96) versus 0.92 (0.83-1.63) P = 0.018; 1.53 (1.30-2.23) versus 1.23 (0.93-1.46) P = 0.018; 1.87 (1.45-2.70) versus 1.56 (1.22-1.79) P = 0.018). The urinary ratio tetrahydrocortisols/tetrahydrocortisone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P = 0.049; P = 0.018; P = 0.043). In contrast, the urinary 20-hydroxy/20-oxo-CoM ratio exhibited a small increase with GH, suggesting that the changes observed above were not simply due to changes in redox status. The patients with GH deficiency, but intact ACTH reserve, demonstrated changes in urine steroid profiles similar to the group receiving hydrocortisone replacement. Urinary free cortisone and urinary free cortisol/free cortisone ratios did not change with GH therapy, but the serum cortisol/ cortisone ratio fell significantly with GH therapy at each hydrocortisone dose. CONCLUSIONS: GH therapy decreases the urinary ratios 11-hydroxy/11-oxo-cortisol metabolites and tetrahydrocortisols/tetrahydrocortisone, but not urinary free cortisone or the urinary free cortisol/free cortisone ratio. This effect is not secondary to reduced cortisol availability. These findings provide further evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alternative site of 11 beta-hydroxysteroid dehydrogenase-1 activity.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1997

Withdrawal reactions with selective serotonin re-uptake inhibitors as reported to the WHO system.

OBJECTIVE: The present study was performed both to investigate whether there might be a difference between the selective serotonin re-uptake inhibitors, (SSRIs) with regard to the incidence of withdrawal reactions, and to describe the associated symptoms. From the WHO database, therefore, all case reports from the year of introduction for each of the SSRIs, fluoxetine, paroxetine and sertraline, were retrieved. Sales figures were obtained from Intercontinental Medical Statistics International. The reporting rates were calculated as the number of reports per million defined daily doses (DDDs) sold per year. RESULTS: The reporting rate of withdrawal reactions for paroxetine was found to be higher than that for sertraline and fluoxetine in each of the countries selected for detailed analyses (US, UK and Australia), as well as for all 16 countries combined. Moreover, using the WHO system of organ classification, the ratio of central nervous system to psychiatric withdrawal symptoms was 1.9 and 2.1 for paroxetine and sertraline, respectively, whereas that for fluoxetine was 0.48, indicating a possible qualitative difference between the SSRIs with respect to the nature of the withdrawal syndrome.

1-Naphthylamine↗

PubMed1997

How does cystitis affect a comparative risk profile of tiaprofenic acid with other non-steroidal antiinflammatory drugs? An international study based on spontaneous reports and drug usage data. ADR Signals Analysis Project (ASAP) Team.

Series of well-documented case reports strongly suggest a causal association between tiaprofenic acid and a form of aseptic cystitis, which can cause serious and long-term morbidity if the drug is not withdrawn promptly. These findings are supported in the Australian and UK spontaneous reporting data-bases. Using sales data as the denominator, a comparison of NSAIDs in the WHO drug monitoring data-base indicates that the reaction is specific to tiaprofenic acid and cannot be accounted for by changes in reporting patterns in certain countries or years. Delayed recognition is an important feature of this reaction and possible reasons for this are discussed. Comparison of the risk profiles of seven NSAIDs indicated that tiaprofenic acid had the poorest risk profile, compared with NSAIDs of similar efficacy, when cystitis reports were included. The results suggest that combining spontaneous reports, classified according to severity, with sales data may enhance the ability of drug monitoring data-bases to contribute to risk benefit appraisals.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1996

The relationship between the effects of metyrapone treatment on depressed mood and urinary steroid profiles.

In order to investigate mechanisms by which the adrenal 11 beta-hydroxylase inhibitor metyrapone might exert its antidepressant effect, we used gas chromatography to analyse the 24 h urinary steroid profiles from six females with major depression taking part in a trial of metyrapone (2-4 g/day) as an antidepressant. Due to concurrent administration of hydrocortisone (30 mg/day), plasma cortisol levels were not significantly reduced. Treatment with metyrapone resulted in greatly increased urinary excretion of 11-deoxy corticosteroids, including the GABA-modulatory steroid tetrahydro-11-deoxycorticosterone (from 68 +/- 34 to 219 +/- 75 micrograms/24 h, p < .05). Metyrapone also had multiple extra-adrenal effects on corticosteroid metabolism, including inhibition of the peripheral conversion of cortisone to cortisol as demonstrated by a significant decrease in the ratio of 11 beta-hydroxy/11-oxo metabolites of cortisol (from 0.81 +/- 0.08 to 0.46 +/- 0.04, p < .01). The decreased Montgomery-Asberg Depression Rating Scale scores seen during treatment with metyrapone did not correlate with changes in plasma cortisol, but did correlate significantly with total 11-deoxycortisol metabolites (r = 0.778, n = 12, p < .01). We conclude that, in addition to decreased cortisol synthesis, increased secretion of cortisol precursors and reduced local bioavailability of cortisol may play a role in the antidepressant effect of metyrapone.

Adult↗

PubMed1996

Angular movements of the lumbar spine and pelvis can be reliably measured after 4 minutes of treadmill walking.

OBJECTIVE: To determine the familiarization period required to obtain consistent measurements of the angular movements of the lumbar spine and pelvis during treadmill walking. DESIGN: An in vivo study with repeated measures every 2 min over 10 min. BACKGROUND: Walking on a treadmill can initially be an unfamiliar experience. No data were available to indicate the length of time required for treadmill familiarization prior to taking measurements of the angular movements of the lumbar spine and pelvis. The familiarization period has implications for the use of this technique in clinical testing. METHODS: The angular movements of the lumbar spine and pelvis were examined by thePEAK 3D motion measurement system in 16 untrained, normal subjects walking for 10 min on a treadmill at either self-selected or 60% of self-selected speed. RESULTS: The reliability of the angular measurements of the spine and pelvis were all greater than 0.83 (ICC) after 4 min of treadmill walking and did not appear to increase after 4 min. No changes in the amplitudes of the angular movements of the lumbar spine and pelvis could be detected after 4 min of treadmill walking, or of the absolute difference scores beyond 2 min of treadmill walking, in either normal or slow-speed walking groups. CONCLUSIONS: Angular movements of the lumbar spine and pelvis were consistent after 4 min of treadmill walking by normal subjects, both at self-selected and slow walking speeds, indicating that reliable measurements of these parameters could be taken at that time.

Journal Article↗

PubMed1996

Sex differences in the human metabolism of cortisol.

Sex differences in steroid metabolism have been clearly demonstrated in animal studies, but few studies have addressed this question in the human. Our preliminary studies suggested human sex differences in both cortisol production and metabolism. We therefore looked in more detail at indices of cortisol metabolism derived from 24 hour urinary steroid profiles in a group of 20 men and 20 women who were age-matched, drug-free and had no endocrine disorder. Steroid analysis was by high resolution gas chromatography. Men excreted more total cortisol metabolites (7620 +/- 620 v 4750 +/- 380 micrograms/24 h, p < 0.001), 11-oxo metabolites of cortisol (11-oxo FM, 4320 +/- 400 v 2890 +/- 250 micrograms/24 h, p < 0.001) and 11 beta-hydroxy metabolites of cortisol (11-OH FM, 3290 +/- 240 v 1860 +/- 140 micrograms/24 h, p < 0.001). These differences remained significant when corrected for body surface area. The ratio of 11-oxo FM/11-OH FM, an index of 11 beta-hydroxysteroid dehydrogenase (11-HSD) activity, was higher in women (1.57 +/- 0.07 v 1.31 +/- 0.06, p < 0.01). The ratios of 5 alpha/5 beta and 20-oxo/20-OH metabolites of cortisol were both higher in men (1.07 +/- 0.15 v 0.58 +/- 0.04, p < 0.01, and 2.78 +/- 0.06 v 2.27 +/- 0.11, p < 0.01), while the ratio of 20 alpha/20 beta metabolites of cortisol was higher in women (1.79 +/- 0.13 v 1.32 +/- 0.06, p < 0.01). We conclude that there are considerable sex differences in both the production and metabolism of cortisol in healthy men and women. In particular, the data are consistent with a sex difference in 11-HSD activity, with relatively greater conversion of cortisol to cortisone in women.

Chromatography, Gas↗

PubMed1996

Evidence for independent modulation of human 11-HSD and 5 alpha/5 beta reductase activities.

The increased ratio of 5 alpha to 5 beta reduced steroids associated with apparent mineralocorticoid excess (AME) may be a necessary consequence of altered 11 beta-hydroxysteroid dehydrogenase (11-HSD) activity. In order to test this hypothesis we have compared changes in 11-HSD activity and 5 alpha/5 beta reduction in a variety of clinical and experimental conditions. The ratio of 11-oxo/11 beta-hydroxy metabolites of cortisol (11-oxo/11-OH FM) was used as an index of 11-HSD activity and the ratio of allotetrahydrocortisol/ tetrahydrocortisol (allo THF/THF) was used as an index of 5 alpha/5 beta reduction. Ratios were derived from 24 hour urinary steroid profiles measured by high resolution gas chromatography. The clinical conditions studied were Cushing's Syndrome, Major Depression and hirsutism. In each study, the patient group were compared with age-matched healthy controls. For the experimental conditions, subjects treated with either hydrocortisone, dexamethasone, metyrapone or finasteride acted as their own controls. No consistent relationship was found between changes in the ratios of 11-oxo/11-OH FM and allo THF/THF. We conclude that there is no evidence of consistent metabolic interaction between 11-HSD and 5 alpha/5 beta reductase activities under a wide range of conditions. Furthermore, the patterns of metabolic changes seen in these conditions are no less characteristic, although more subtle, than the well-documented metabolic changes seen in inborn errors of steroid metabolism.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1995

Extra-adrenal effects of metyrapone include inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase: a model for 11-HSD I deficiency.

BACKGROUND AND OBJECTIVE: Previous studies suggesting effects of metyrapone on extra-adrenal corticosteroid metabolism have involved significant alterations in plasma cortisol. We have therefore studied effects of metyrapone on urinary excretion of steroids in a group of patients treated concurrently with hydrocortisone so that changes in plasma cortisol were minimized. DESIGN: Replacement doses of hydrocortisone (30 mg/day) were given concurrently with metyrapone (2-4 g/day) for 2 weeks. Blood samples were taken and 24-hour urinary steroid collections were made at baseline and after 1 and 2 weeks of treatment. PATIENTS: Subjects were 6 female patients with major depression from a trial of metyrapone as an antidepressant. MEASUREMENTS: Urinary steroid profiles were measured by gas chromatography; plasma cortisol and urinary free cortisol were measured by fluorescence immunoassay. RESULTS: Plasma cortisol levels were not significantly decreased by treatment, while excretion of 11-deoxycortisol metabolites increased eightfold after 2 weeks indicating that concurrent hydrocortisone administration had not suppressed the adrenal. Ratios reflecting 11 beta-hydroxy/11-oxo metabolites of cortisol were significantly decreased, consistent with inhibition of the 11-oxoreductase activity of 11 beta-hydroxysteroid dehydrogenase (11-HSD). Other changes included significant decreases in the rates of 5 alpha vs 5 beta and of 20 alpha vs 20 beta reduction of corticosteroids. CONCLUSIONS: Metyrapone has multiple effects on extra-adrenal corticosteroid metabolism and is the only agent we know of which selectively inhibits 11-oxoreductase. Metyrapone thus provides a model for 11-HSD I deficiency and a tool for in-vitro studies of cortisol-cortisone interconversion. The results also suggest mechanisms whereby corticosteroid effects can be regulated separately from corticosteroid synthesis.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1994

The effect of growth hormone replacement on cortisol metabolism and glucocorticoid sensitivity in hypopituitary adults.

OBJECTIVE: Growth hormone (GH) replacement therapy in hypopituitary adults is associated with sodium and water retention. The underlying mechanisms are incompletely understood and a possible contribution of altered cortisol metabolism or action has not been evaluated. We have investigated the effect of GH replacement therapy on cortisol metabolism, cortisol binding globulin and in-vitro glucocorticoid sensitivity in a group of adult hypopituitary patients. DESIGN AND PATIENTS: We studied 19 adult hypopituitary patients (18 adult onset, M:F, 6:13), who were receiving conventional hydrocortisone (16 patients), thyroxine (14 patients), triiodothyronine (1 patient), sex steroid (9 patients), human chorionic gonadotrophin (1 patient) or desmopressin (6 patients) replacement during a 6-month, double blind controlled trial of GH therapy (active:placebo, 8:11) followed by a 6-month open phase of GH (mean dose: 0.2 IU/kg/week, range 0.051-0.27) and after a 6-week washout phase following discontinuation of GH therapy. MEASUREMENTS: Twenty-four-hour urine free cortisol, cortisol metabolites (CoM), ratio 11-hydroxy/11-oxo CoM (F/E) and ratio 5 alpha/beta tetrahydrocortisol were measured at 6 months, 12 months and after the 6 week washout phase. Serum cortisol binding globulin was measured basally, at 6 months, 12 months and after washout. Glucocorticoid sensitivity was determined in lymphocyte preparations from 8 patients, during GH therapy and after washout, using an in-vitro technique dependent on dexamethasone suppression of phytohaemagglutinin-stimulated thymidine incorporation into DNA. Plasma renin activity and aldosterone were measured after 6-12 months GH therapy and after washout. RESULTS: After 6 months of GH, in patients on hydrocortisone (n = 9), there were significant decreases in CoM (mean decrement 21%, P < 0.01), F/E (mean decreased from 1.27 to 1.0, P = 0.04; reference range 0.33-1.29) and 5 alpha/5 beta tetrahydrocortisol (mean decreased from 0.67 to 0.48, P = 0.01) and a subsequent increase after washout. Patients not on hydrocortisone (n = 2) demonstrated a normal basal F/E falling by 25% on GH therapy but no change in CoM. During 12 months of GH therapy, patients on hydrocortisone (n = 7) demonstrated a further trend to decrement in CoM (P = 0.09) which reversed after washout (P = 0.04). Urine free cortisol tended to fall during GH therapy and increased significantly following washout after 12 months treatment (P < 0.02). Serum cortisol binding globulin decreased by 20% (P < 0.05) during 12 months GH treatment but remained within the reference range. In-vitro studies demonstrated a trend to reduced glucocorticoid sensitivity on GH therapy; the maximum inhibition of phytohaemagglutinin by dexamethasone tended to be less on GH therapy (P = 0.052) and was also lower than in 29 normal volunteers (P < 0.05). There were no significant changes in plasma renin but there was a small increment in aldosterone in recumbent patients (P = 0.04) during the open phase of GH therapy in the placebo arm. CONCLUSIONS: GH therapy in hypopituitary adults is associated with an apparent reduction in availability of administered hydrocortisone as measured by urine cortisol metabolites and urine free cortisol. This effect is unlikely to be clinically significant except possibly in ACTH deficient subjects on suboptimal hydrocortisone replacement. The changes in F/E suggest that GH may directly or indirectly modulate the activity of 11 beta-hydroxysteroid dehydrogenase. The apparent decrease in glucocorticoid sensitivity during GH therapy, demonstrated in vitro, merits further investigation.

Adult↗

PubMed1993

Defects in the HSD11 gene encoding 11 beta-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency.

The syndrome of apparent mineralocorticoid excess (AME) is a form of low renin hypertension that is thought to be caused by congenital deficiency of 11 beta-hydroxysteroid dehydrogenase (11HSD) activity. This enzyme converts cortisol to cortisone and apparently prevents cortisol from acting as a ligand for the mineralocorticoid (type I) receptor. It also catalyzes the reverse oxoreductase (cortisone to cortisol) reaction. Four patients with AME and the parents of the first patient described (now decreased) were analyzed for mutations in the cloned HSD11 gene encoding an 11HSD enzyme. A patient with suspected cortisone reductase deficiency was also studied. No gross deletions or rearrangements in the HSD11 gene were apparent on hybridizations of blots of genomic DNA. Direct sequencing of polymerase chain reaction-amplified fragments corresponding to the coding sequences, intronexon junctions, and proximal untranslated regions of this gene revealed no mutations. AME may involve mutations in a gene for another enzyme with 11HSD activity or perhaps another cortisol-metabolizing enzyme.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed1991

Purification of glucose-inducible outer membrane protein OprB of Pseudomonas putida and reconstitution of glucose-specific pores.

A 43,000 molecular-weight, glucose-inducible, organic acid-repressible protein (OprB) was identified in the outer membrane of Pseudomonas putida. OprB was surface expressed in whole cells, had a high beta-sheet content, and was heat modifiable, as demonstrated by 125I-labeling, circular dichroism spectroscopy, and mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. OprB was extracted from outer membrane preparations by using 2% Lubrol PX with 10 mM EDTA and purified by DEAE-Sephacel ion exchange chromatography following ammonium sulfate precipitation. Reconstitution experiments with black lipid membranes showed that OprB formed small, cation-selective pores which bound glucose (KS = 110 mM) and other carbohydrates. However, the binding site of OprB appeared to be distinct from that of the maltodextrin-specific porin LamB from Escherichia coli.

Bacterial Outer Membrane Proteins↗

PubMed1991

Clubbing associated with oesophageal adenocarcinoma.

A patient with an oesophageal adenocarcinoma, recent onset of digital clubbing, and evidence of increased oestrogen synthesis is presented. In the discussion, some of the theories of the pathogenesis of clubbing are reviewed, together with previous reports of clubbing in gastro-oesophageal disorders. A possible unifying theory is proposed for our case which we believe is the first report of this triple association.

Adenocarcinoma↗

PubMed1991

Development of a circadian variation of plasma oxytocin concentration in the late gestation rhesus monkey.

The 24-h pattern of oxytocin (OT) concentrations in maternal plasma was investigated serially from 112-168 days gestation in four chair-restrained pregnant rhesus monkeys. No change in the mean daily plasma OT concentration was observed with advancing gestational age; there was a change in the pattern of plasma OT secretion throughout the period, however. About 21 days from delivery (150.8 +/- 1.8 days gestational age), plasma OT levels showed occasional fluctuations, distributed throughout the day. About 8 days from delivery (163.2 +/- 2.4 days gestational age), a clear circadian pattern of OT was detected, with an acrophase at 2200 h. These results suggest that there is a relationship between the pattern of OT secretion and advancing pregnancy. This may account partially for the increase in uterine activity known to occur in term rhesus monkeys.

Animals↗

PubMed1991

Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation?

We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol, plasma ACTH, and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight, 2, 8, and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF, plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma, although suspected, was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites, including 3 alpha,11 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha,11 beta,17 alpha,20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings, a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed, but no tumor was found. However, ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone, and 2) postoperatively when the patient was receiving steroid replacement only, and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar, offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case, providing an example of a previously unreported cause of hypercortisolemia.

Adrenal Glands↗