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Biomedical subjects

G H Beastall

Publications and source records attributed to G H Beastall.

At least 19 recordsLinked to original sources
PubMed1994

Insulin-like growth factor binding protein 1 response to acute insulin induced hypoglycaemia in type 1 diabetes.

OBJECTIVES: Insulin is believed to be the prime regulator of insulin-like growth factor binding protein 1 (IGFBP-1) secretion, and in normal subjects acute insulin induced hypoglycaemia exerts a rapid effect on concentrations of IGFBP-1, and may also influence insulin-like growth factor I (IGF-I) concentrations. The rise in IGFBP-1 concentrations in normal subjects following hypoglycaemia has been suggested to be due to suppression of endogenous insulin secretion. We have examined this further by studying diabetics with no endogenous insulin secretion. DESIGN: We have compared the IGFBP-1 response to acute insulin induced hypoglycaemia in normal subjects and patients with Type 1 (insulin dependent) diabetes mellitus. METHODS: Insulin tolerance tests were performed using a bolus of insulin (0.15 U/kg), in six control subjects and six patients with Type 1 diabetes. MEASUREMENTS: Serum levels of IGFBP-1, insulin, glucose, and IGF-I were measured at regular intervals during the insulin tolerance test. RESULTS: Blood glucose fell to a nadir which coincided with the onset of the acute autonomic reaction 'R' in both groups. The basal concentration of IGF-I was significantly lower in the diabetic group at 0.4 +/- 0.1 kU/l, compared to 0.9 +/- 0.1 kU/l in the control group, but there was no significant change in IGF-I concentrations in response to hypoglycaemia in either group. Hypoglycaemia provoked a fall in IGFBP-1 in patients with Type 1 diabetes, from 38 +/- 9 micrograms/l basally to 17 +/- 3 micrograms/l at R + 120 minutes, with a return to basal values of 45 +/- 11 micrograms/l at R + 180 minutes. In the control subjects there was no fall in IGFBP-1, but a significant increase to 71 +/- 14 micrograms/l at R + 180 minutes. CONCLUSION: This difference in the IGFBP-1 response in the presence of a similar glucose response suggests that in Type 1 diabetes there may be different sensitivities to the actions of exogenous insulin on IGFBP-1 regulation.

Adult↗
PubMed1992

Pancreatic and pituitary hormonal responses to insulin-induced hypoglycaemia during muscarinic cholinergic blockade in man.

To investigate the role of muscarinic cholinergic mechanisms in mediating the pancreatic and pituitary hormonal responses to hypoglycaemia, six normal subjects were studied during acute insulin-induced hypoglycaemia under control conditions, and during blockade with intravenous atropine. During atropine blockade the response of pancreatic polypeptide was suppressed while the maximum response of plasma glucagon was significantly higher. The increment in plasma vasopressin was also increased significantly during cholinergic blockade. During blockade with atropine the responses of plasma prolactin was reduced, with a slight but significant reduction in the growth hormone response, and although a similar maximum response of plasma ACTH was achieved, this rise was delayed. These results implicate involvement of a cholinergic muscarinic inhibitory and stimulatory mechanisms in regulating the responses of pancreatic and pituitary hormones to hypoglycaemia.

Adrenocorticotropic Hormone↗
PubMed1992

Beta endorphin release in patients after spontaneous and provoked acute myocardial ischaemia.

BACKGROUND: In animal models of circulatory shock and heart failure concentrations of the endogenous opioid peptide beta endorphin are raised and opioid receptor blockade improves haemodynamic variables and survival. This study was performed to identify whether acute myocardial ischaemia provokes the release of beta endorphin in humans. METHODS: Observational study in a university cardiology centre. Serial measurements of beta endorphin made by specific radioimmunoassay were correlated with other clinical and neuroendocrine variables that were measured prospectively. Fifty five patients with acute myocardial ischaemia and 26 patients undergoing elective coronary angioplasty of the left anterior descending coronary artery were studied. RESULTS: beta endorphin concentrations were raised above the upper limit of normal in 31/42 (74%) patients with confirmed myocardial infarction, 3/13 (23%) patients with unstable angina, and 10/24 (42%) patients after coronary angioplasty. There was no evidence of myocardial release of beta endorphin. There were significant positive correlations between beta endorphin and the concentrations of adrenocorticotrophic hormone, cortisol, and arginine vasopressin. In patients with acute myocardial ischaemia there was a significant positive correlation between the peak concentrations of creatine kinase and beta endorphin but no correlation with visual analogue scores of the intensity of chest pain. The highest beta endorphin concentrations were seen in patients whose clinical course was complicated by the development of heart failure. CONCLUSIONS: beta endorphin release is a component of the neuroendocrine activation associated with myocardial ischaemia/infarction.

Acute Disease↗
PubMed1992

Sleep shift dissociates the nocturnal peaks of parathyroid hormone (1-84), nephrogenous cyclic adenosine monophosphate, and prolactin in normal men.

The secretion of PTH(1-84) and PRL over a 24-h period in normal subjects has been shown to be highly correlated, with changes in PRL occurring approximately 2 h after those in PTH(1-84). It has been postulated that there may be neuroendocrine control common to PTH(1-84) and PRL. As the secretion of PRL is known to be strongly influenced by sleep we investigated the effect of a 7-h acute sleep shift on the nocturnal secretion of PTH(1-84), PRL, and nephrogenous cAMP, a marker of PTH(1-84) bioactivity. Six normal male subjects were studied on two occasions (study A sleep, 0100-0800 h; study B, 0800-1400 h) with samples withdrawn at 30-min intervals. Sleep shift produced the expected shift in PRL secretion to new time of sleep. The overall timing of the PTH(1-84) nocturnal peak (0200-0600 h) was not altered by sleep shift. However, the start of the rise in PTH(1-84) (0200-0300 h) was blunted (P less than 0.05), and the peak of nephrogenous cAMP, coincident with the nocturnal rise in PTH(1-84) in study A, was markedly attenuated (P less than 0.01). Thus whereas the results of this study argue against a direct neuroendocrine link between PTH(1-84) and PRL, it is postulated that sleep shift disrupts a high degree of temporal organization which, under normal conditions, may allow concerted metabolic effects between PTH(1-84) and other hormones over a 24-h period.

Adult↗
PubMed1991

Production and characterisation of monoclonal antibodies to parathyroid hormone (1-34).

Monoclonal antibodies to the biologically active N terminal region of parathyroid hormone (PTH) suitable for use in the measurement of circulating PTH concentrations have proved difficult to produce. In this study, no serum PTH antibody titres could be detected in mice using synthetic human PTH (1-34) (free or coupled to albumin) or PTH (1-10) (coupled to keyhole limpet haemocyanin) as immunogen. A consistent response to PTH (1-34) peptide was obtained in DA rats. We have produced five monoclonal antibodies to PTH (1-34) derived from the fusion of DA rat spleen cells and the mouse myeloma line X63 Ag.8.653. Bulk production of the antibodies was achieved using congenitally athymic mice for ascites production. Antibody assessment studies revealed the antibodies to be sensitive to the oxidation state of the methionine residues in PTH (1-34). Two of the antibodies, 3B3 and 6E3, were shown to be of potential use in measuring circulating PTH (1-84) when used in combination with available antibodies to C terminal PTH. A third antibody, 4G3, which failed to recognise PTH (1-84) when used in combination with 3B3, formed the basis of a specific assay for PTH (1-34).

Animals↗
PubMed1991

Direct and indirect assessment of the parathyroid hormone response to pamidronate therapy in Paget's disease of bone and hypercalcaemia of malignancy.

In patients with either Paget's disease or hypercalcaemia associated with malignancy (HCM) we have assessed the parathyroid response to pamidronate therapy, both by immunoassay of serum intact parathyroid hormone PTH (1-84) and by measurement of indirect parameters of PTH bioactivity, tubular maximum reabsorption of phosphate (TmPO4/GFR) and nephrogenous cyclic AMP (NcAMP). In 12 patients with Paget's disease, therapy with pamidronate produced a small but significant decrease in adjusted serum calcium within the reference interval which was accompanied by a progressive increase in PTH (1-84) secretion and a corresponding fall in TmPO4/GFR and increase in NcAMP. In 12 patients with HCM pretreatment, PTH (1-84) concentrations were suppressed, whilst mean TmPO4/GFR was reduced and NcAMP was increased, compatible in most patients, with parathyroid hormone-related peptide (PTHrP) driven hypercalcaemia. Therapy with pamidronate produced the expected fall in serum calcium but caused an increase in PTH (1-84) secretion in the presence of absolute hypercalcaemia. The initial subnormal TmPO4/GFR decreased further to a nadir on day 5, and there was a corresponding further increase in NcAMP. By day 7, however, when PTH (1-84) concentrations were maximal, there was a significant paradoxical rise in TmPO4/GFR and a corresponding decrease in NcAMP. These data are consistent with a variable trigger point for PTH (1-84) secretion, one consequence of which is a reduction in the risk of hypocalcaemia following pamidronate. The results have major clinical implications for the interpretation of PTH (1-84) measurements in patients who are being treated or about to be treated for bone disease or for hypercalcaemia of malignancy (HCM).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.

1. Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2. Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4. Elimination half-lives (mean +/- s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 +/- 1.1 h; after 13.9 +/- 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 +/- 2.2 mumol l-1) were higher than predicted (16.5 +/- 4 mumol l-1). 5. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6. OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.

Adult↗
PubMed1991

A review of the role of established tumour markers.

Increasing numbers of commercial assays for the established tumour markers are available which are capable of excellent analytical performance. Whilst all these assays are useful as research tools, their clinical value is more limited and should be appreciated before any decision is taken to offer a tumour marker assay service. 1. Calcitonin (medullary carcinoma of thyroid), alphafetoprotein (hepatoma) and human chorionic gonadotrophin (choriocarcinoma) are the only tumour markers that can be used for screening for malignancy in high risk populations. 2. Hormones, paraproteins, alphafetoprotein, human chorionic gonadotrophin and prostate specific antigen are valuable in establishing the diagnosis of certain tumour types. 3. Alphafetoprotein and human chorionic gonadotrophin concentrations at the time of diagnosis are of value in predicting prognosis in specific tumour types. 4. Although their sensitivity for a particular tumour type may be poor, most tumour markers can be used for monitoring the therapy and follow-up of selected marker positive patients. Optimal clinical results of the management of patients with malignancy are usually obtained by specialist centres, and laboratory tumour marker services should be established so that they are appropriate to local oncology specialities.

Biomarkers, Tumor↗
PubMed1991

Specificity of two-site immunometric assays.

The assessment of specificity in two-site immunometric assays is complex. Conventional approaches based on standard substitution with cross-reactant may yield misleading results. An 'in-house' immunoradiometric assay (IRMA) for human growth hormone (hGH) appeared free from cross-reactivity with human placental lactogen (hPL) in a single point standard substitution experiment performed by the United Kingdom External Quality Assessment Scheme (UK EQAS). However, detailed studies based on the substitution of hGH standards with hPL cross-reactant, the addition of hPL cross-reactant to hGH standards and the recovery of added hGH from endogenous cross-reactant (sera from pregnant subjects) revealed gross cross-reactivity of hPL in the hGH assay. We recommend that the validation of assay specificity should require the demonstration of quantitative recovery of a range of analyte concentrations from human sera that contain varying endogenous concentrations of cross-reactant.

Calibration↗
PubMed1991

A two-site immunoradiometric assay for PTH(1-84) using N and C terminal specific monoclonal antibodies.

We report the development of a two-site immunoradiometric assay for PTH(1-84) based on two site-specific monoclonal antibodies--3B3 (radiolabelled antibody) specific for PTH(1-34) and ESQ1 (on solid phase) specific for PTH(74-84). Antibody 3B3 is sensitive to the oxidation of the methionine residues in PTH(1-34) therefore hydrogen peroxide (0.1 M) is added to the incubation mixture. Validation studies confirm quantitative recovery of both oxidized and reduced PTH(1-84). The assay has a minimum detection limit of 0.5 pmol/L and a range of 1.5-250 pmol/L with an intra-assay CV of less than 10% (2.8-250 pmol/L less than 5% CV). Studies on clinical samples indicate good discrimination between normal subjects (mean 2.21; range 1.0-5.0 pmol/L) and patients with primary hyperparathyroidism (mean 21.0; range 5.8-100 pmol/L) who in turn are well separated from patients with hypercalcaemia of malignancy (14/18 less than 0.5 pmol/L).

Adult↗
PubMed1991

Post-traumatic hypothalamic-pituitary dysfunction presenting with biochemical features of primary hypothyroidism.

Two cases of post-traumatic hypothalamic-pituitary dysfunction are described where the primary pathology was shown to be understimulation of the pituitary by hypothalamic hormones. In each case, the biochemical presentation was a low serum thyroxine and elevated TSH concentration mimicking primary hypothyroidism. Treatment with thyroxine before cortisol replacement was not beneficial. In both cases, hydrocortisone therapy alone resulted in a rise in serum thyroxine and fall in serum TSH. Chronic cortisol deficiency may directly impair the thyroid response to TSH, whilst thyroxine appears to exert its feedback primarily at pituitary rather than hypothalamic level.

Adult↗
PubMed1991

Intact parathyroid hormone concentration and cyclic AMP metabolism in thyroid disease.

In 35 thyrotoxic patients and 35 patients receiving thyroxine replacement therapy mean serum intact parathyroid hormone concentrations were lower than in euthyroid normal volunteer controls. In 20 hypothyroid patients intact PTH was increased relative to euthyroid controls. Mean serum adjusted calcium was increased in thyrotoxic patients relative to euthyroid controls and in 8 toxic patients with elevated serum adjusted calcium (greater than 2.60 mmol/l) intact PTH was below the assay detection limit (less than 0.5 pmol/l). Indices of PTH activity were consistent with intact PTH measurements in thyrotoxic patients with nephrogenous cyclic adenosine monophosphate lower, tubular maximum reabsorption of phosphate higher, and urinary calcium creatinine ratio higher than controls. In hypothyroid patients these indices of PTH activity suggest relative end organ resistance to PTH with nephrogenous cyclic adenosine monophosphate similar, tubular maximum reabsorption of phosphate similar, and calcium creatinine ratio lower than in controls. In treated hypothyroid patients nephrogenous cyclic adenosine monophosphate was higher, tubular maximum reabsorption of phosphate similar, and calcium creatinine ratio higher than in controls. These results are compatible with the hypothesis that thyroid status modifies the renal responses to PTH (1-84).

Adolescent↗
PubMed1991

Effect of alpha-adrenergic blockade on pituitary hormonal responses to insulin-induced hypoglycemia in humans.

Arginine vasopressin, oxytocin and ACTH are released from the pituitary gland in response to acute hypoglycemia. To investigate the role of alpha-adrenergic mechanisms in mediating this response, 6 non-diabetic subjects were studied during hypoglycemia induced by 0.15 IU/kg i.v. insulin under control conditions, and during non-selective alpha-adrenergic blockade with phentolamine. In the control study plasma arginine vasopressin rose from 1.6 +/- 0.8 pmol/l (mean +/- SEM) basally to a maximum of 2.5 +/- 0.8 pmol/l following hypoglycemia (p less than 0.05). An exaggerated response was found during phentolamine blockade, with a maximum plasma vasopressin of 11.5 +/- 0.4 pmol/l (by analysis of variance, p less than 0.05). The plasma oxytocin response to hypoglycemia was similarly increased during phentolamine compared to control. Plasma growth hormone rose to 94 +/- 19 mU/l, and during blockade with phentolamine the response was significantly reduced reaching a peak of 34 +/- 7 mU/l (by analysis of variance, p less than 0.05). ACTH and prolactin both increased in response to hypoglycemia, but the increases were not affected by phentolamine. An alpha-adrenergic mechanism appears to inhibit the release of arginine vasopressin and oxytocin in response to hypoglycemia, but does not appear to affect the secretion of ACTH.

Adrenergic alpha-Antagonists↗