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Biomedical subjects

L H Rees

Publications and source records attributed to L H Rees.

At least 127 records · Page 7Linked to original sources
PubMed1985

Characterisation by high performance liquid chromatography of circulating growth hormone releasing factors in a human plasma.

Three forms of circulating immunoreactive human growth hormone-releasing factor (ir-hGRF) have been identified from a patient whose acromegaly was associated with a disseminated carcinoid tumour. This is the first known report of the molecular forms of ir-hGRF in human plasma. High performance liquid chromatography (HPLC) on a C3, wide pore reversed-phase column and gel filtration chromatography were used in conjunction with a sensitive radioimmunoassay (RIA). The greatly elevated concentration of the ir-hGRF in plasma from this patient was 25,000 ng/l (normal range less than 60 ng/l). Gel filtration (G50) chromatography of the plasma revealed a single peak which coeluted with synthetic hGRF-40. However, reversed-phase HPLC of Vycor-extracted plasma resolved the ir-hGRF into three components, which coeluted with synthetic hGRF-40 (69%), hGRF-44 (22%) and hGRF-37 (9%). At present it is not clear if the three forms are natural variants or whether either or both hGRF-40 and hGRF-37 are cleavage products of hGRF-44.

Acromegaly↗
PubMed1985

Effects of dopamine and morphine on immunoreactive somatostatin and LH-releasing hormone secretion from hypothalamic fragments in vitro.

Dopamine and morphine modulate GH and LH release, probably at a hypothalamic locus. To investigate this in more detail, we studied the influence of these substances on somatostatin and LH-releasing hormone (LHRH) release from rat hypothalamic fragments in vitro. Hypothalamic fragments were incubated in Earle's medium. After 60 min of preincubation, medium from two 20-min incubations was collected and somatostatin and LHRH levels measured by radioimmunoassay. Dopamine (10 nmol/1-0.1 mmol/l) induced a progressive increase (r = 0.41; P less than 0.01) in basal somatostatin levels. K+ (30 mmol/l)-induced somatostatin release was also increased (r = 0.54; P less than 0.01) by increasing doses of dopamine. Metoclopramide (10 mumol/l) blocked the dopamine (1 mumol/l)-induced increase in somatostatin release. No significant relationship between dopamine and LHRH was found either basally or after K+ (30 mmol/l) stimulation. Basal somatostatin was negatively correlated (r = -0.63; P less than 0.01) with morphine concentrations. No significant correlation was found after K+ (30 mmol/l) depolarization. Basal LHRH release was not influenced by morphine, while K+ (30 mmol/l)-induced release was significantly lower than controls only at a concentration of 10 nmol/l. These results suggest that dopamine and morphine act at a hypothalamic level to modulate GH release through alterations in somatostatin secretion. Dopamine and morphine have no consistent effect on hypothalamic LHRH release.

Animals↗
PubMed1985

Ectopic hormones.

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APUD Cells↗
PubMed1985

Neuroendocrine and cardiovascular changes in septic shock and after cardiac surgery: effect of high-dose corticosteroid therapy.

Plasma levels of beta-endorphin-like immunoreactivity (BLI) were similarly elevated in patients with septic shock (group A) and in normotensive subjects recovering from cardiac surgery (group B) (1231 +/- 483 pg ml-1 and 1,240 +/- 355 pg ml-1, respectively). In neither group was cardiac output reduced, but total peripheral resistance index (TPRI) was low in group A and low or normal in group B. Intravenous methylprednisolone (MP) 30 mg kg-1 variably suppressed BLI by a mean of only 30% in group A, while in group B, BLI usually rose and then fell following MP. In group A percentage changes in BLI were positively correlated with percentage changes in cardiac index (CI) and mean arterial pressure (MAP) (r = .83, P less than .01, r = .59, P less than .05 respectively). No such correlations were found in group B. These findings suggest that increases in circulating beta-endorphin are unlikely to be responsible for myocardial depression or hypotension in septic shock. ACTH levels were in general normal in group A but were consistently elevated in group B, although plasma cortisol was similarly elevated in both groups. Furthermore there was a good correlation between percentage changes in ACTH and BLI following MP in group B (r = .87, P less than .01) but not in group A. Possible explanations for these findings are discussed.

Adrenocorticotropic Hormone↗
PubMed1984

Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly.

A highly specific and sensitive radioimmunoassay was developed for measuring circulating growth hormone releasing factor (GRF) in human plasma. Before measuring immunoreactive GRF plasma samples were extracted on to Vycor glass. Immunoreactive GRF concentrations in plasma samples from 37 fasting normal subjects ranged from less than 10 to 60 ng/l (mean 21 ng/l). Fasting concentrations in 76 out of 80 acromegalic subjects were within the normal range, but the remaining four patients had values of 92 to 25 000 ng/l. Of these, only the patient with the highest concentration had evidence of ectopic GRF secretion from a disseminated carcinoid tumour. Two of the others had longstanding pituitary tumours, and the fourth patient had a pituitary growth hormone (GH) secreting tumour proved by its removal and subsequent remission of acromegaly. There was no correlation between serum GH and plasma immunoreactive GRF concentrations, irrespective of whether the patients were untreated or had been given radiotherapy or dopamine agonists. The assay should help elucidate the physiological role(s) of GRF and may also prove useful in differentiating between pituitary and hypothalamic defects in patients with acromegaly.

Acromegaly↗
PubMed1984

Glucose-induced changes in somatostatin-14 and somatostatin-28 released from rat hypothalamic fragments 'in vitro'.

Previous data suggest that somatostatin is present and released from the hypothalamus in several molecular forms, basally and after K+ or electrical stimulation. In order to evaluate the proportions of somatostatin-14 (S14) and somatostatin-28 (S28) released during a stimulus which may be more closely related to the control of growth hormone secretion 'in vivo', we studied the molecular forms of somatostatin released from hypothalamic fragments ' in vitro', during incubations with different glucose concentrations (1.35 and 22mM), which we have previously shown to be inversely related to somatostatin release. Sephadex G-50 chromatography demonstrated that both forms are released in the same proportions (S14: 70%; S28: 30%) during incubation with different glucose concentrations; there is a parallel increase in both forms when low glucose is used. Although on a molar basis less S28 is released than S14, the higher potency, longer duration of action and higher affinity for pituitary receptors of S28 suggests that it may be of major physiological importance.

Animals↗
PubMed1984

Release of beta endorphin and met-enkephalin during exercise in normal women: response to training.

Plasma beta endorphin and met-enkephalin concentrations were measured in response to treadmill exercises in 15 normal women before, during, and after an intensive programme of exercise training. Significant release of beta endorphin occurred in all three test runs, and the pattern and amount of release were not altered by training. Before training dramatic release of met-enkephalin was observed in seven subjects and smaller rises observed in a further four, and this response was almost abolished by training. This represents the first observed "physiological" stimulus to met-enkephalin release. Endogenous opioid peptides play a part in adaptive changes to exercise training and probably contribute to the menstrual disturbances of women athletes.

Adaptation, Physiological↗
PubMed1984

Growth hormone releasing factor: comparison of two analogues and demonstration of hypothalamic defect in growth hormone release after radiotherapy.

Human pancreatic growth hormone releasing factor (hpGHRF(1-40] stimulates the release of growth hormone in normal subjects and some patients with growth hormone deficiency. A study comparing the shorter chain amidated analogue hpGHRF(1-29) with an equivalent dose of hpGHRF(1-40) in seven normal subjects showed no significant difference in growth hormone response between the two preparations. Six patients with prolactinomas were also tested; these patients had received megavoltage radiotherapy previously but had developed growth hormone deficiency as shown by insulin induced hypoglycaemia. In all six patients 200 micrograms hpGHRF(1-40) or hpGHRF(1-29)NH2 produced an increase in the serum growth hormone concentration. These data suggest that hpGHRF(1-29)NH2 may be useful for testing the readily releasable pool of growth hormone in the pituitary and that cases of hypothalamo-pituitary irradiation resulting in growth hormone deficiency may be due to failure of synthesis or delivery of endogenous GHRF from the hypothalamus to pituitary cells.

Adult↗
PubMed1984

Treatment of prolactinomas with megavoltage radiotherapy.

The outcome of treatment of 36 women with prolactinomas using megavoltage radiotherapy combined with interim dopamine agonists (bromocriptine, lysuride, pergolide) was reviewed; 16 of the women showed radiological evidence of a macroadenoma. The most common presenting symptom was secondary amenorrhoea; 26 of the patients had galactorrhoea. In 29 patients who wished to conceive the ovulation rate (as indicated by circulating progesterone concentrations) was 97% and the successful fertility rate 86%. No patient had enlargement of the tumour during pregnancy and there were no complications of radiotherapy. No further tumour enlargement was detected in serial skull radiographs, and an improvement in size of the fossa was noted in 45% of those assessed. When medical treatment was withdrawn a mean of 4.2 years (range 1-11) after radiotherapy in the 27 patients who had completed their families the serum prolactin concentration had fallen appreciably in 26 of them and later became normal in eight. The incidence of growth hormone deficiency rose from 24% of the whole group before radiotherapy to 79% afterwards. Only one patient required thyroxine, and one was receiving gonadotrophin. No patient became deficient in adrenocorticotrophic hormone. A regimen of megavoltage radiotherapy and interim bromocriptine allows women with prolactinomas safely to undergo pregnancy and results in the long term prospect of tumour shrinkage and control of hyperprolactinaemia.

Adenoma↗
PubMed1984

Plasma levels and biochemical characterisation of circulating met-enkephalin in canine endotoxin shock.

Endogenous opioid peptides have been implicated in the pathophysiology of shock (1-5). In anaesthetised mongrel dogs, administration of E coli endotoxin caused a rise in plasma met-enkephalin-like immunoreactivity (MLI). Biochemical characterisation of MLI by gel filtration chromatography revealed various molecular forms: 31K, 8K, 3-5K and the native pentapeptide in approximately equal amounts. After enzymatic treatment of column fractions the 31K form predominated (90.7%). This is the first demonstration of elevated MLI in endotoxin shock.

Animals↗
PubMed1984

Bombesin-like immunoreactivity in human gastrointestinal tract.

In the present study the distribution and molecular characteristics of bombesin-like immunoreactivity (BLI) were studied in acid extracts of human gastrointestinal tract. The highest levels were found in the fundus, antrum, pylorus and pancreas with lower levels in the duodenum, jejunum, terminal ileum and colon. BLI was also detected in both the muscle and mucosal layers of the antrum and colon. Sephadex G-50 gel chromatography under acid dissociating conditions revealed two peaks of immunoreactivity, one in the position of synthetic porcine gastrin releasing peptide (GRP) and the second eluting with synthetic amphibian bombesin. Variations in the proportions of the two molecular forms were seen in different regions of the gut. In the stomach and pancreas greater than 70% of the BLI eluted with the GRP marker while in pylorus, jejunum and terminal ileum only 20% was present in this form. Reverse-phase ODS silica HPLC of the major antral BLI peak, utilising a methanol/trifluoroacetic acid gradient indicated that this peptide was similar to porcine GRP. We have therefore (1) demonstrated the presence and heterogeneity of bombesin-like immunoreactivity throughout the human gastrointestinal tract and (2) shown for the first time that a proportion of this BLI closely resembles porcine GRP.

Animals↗
PubMed1984

'Dynorphin' in plasma: enzymatic artifact and authentic immunoreactivity.

The potent opioid peptide dynorphin (DYN) is found in posterior pituitary vasopressinergic neurones and in adrenal medullary cells suggesting that secretion into plasma is likely. We have developed a sensitive radioimmunoassay in order to study plasma DYN in man. It transpired that extraction prior to assay was essential since unextracted plasma caused gross and non-parallel inhibition of binding of tracer. Plasma extracted using leached silica glass ( Vycor ) caused inhibition of tracer binding which diluted in parallel to synthetic DYN suggesting the presence of substantial amounts of DYN-like immunoreactivity ( irDYN ) in plasma. Further investigation however demonstrated that this irDYN was artifactual and caused by enzymatic degradation of tracer. Although use of Seppak C18 cartridges resulted in reliable extraction of synthetic porcine DYN from acidified plasma, we have not detected irDYN in any plasma so far studied using this technique. However, extraction of non-acidified plasma using our antibody coupled to Sepharose CNBr-activated 4B followed by gel filtration chromatography demonstrated a single peak of irDYN of molecular size similar to DYN. These data suggested that a small amount of a DYN-like peptide does circulate in human plasma although this is not identical to porcine DYN(1-17). The implication of our results for the measurement of other similar peptides in plasma is discussed.

Animals↗
PubMed1984

Cloning and characterization of cDNAs encoding human gastrin-releasing peptide.

We have prepared and cloned cDNAs derived from poly(A)+ RNA from a human pulmonary carcinoid tumor rich in immunoreactivity to gastrin-releasing peptide, a peptide closely related in structure to amphibian bombesin. Mixtures of synthetic oligodeoxyribonucleotides corresponding to amphibian bombesin were used as hybridization probes to screen a cDNA library prepared from the tumor RNA. Sequencing of the recombinant plasmids shows that human gastrin-releasing peptide (hGRP) mRNA encodes a precursor of 148 amino acids containing a typical signal sequence, hGRP consisting of 27 or 28 amino acids, and a carboxyl-terminal extension peptide. hGRP is flanked at its carboxyl terminus by two basic amino acids, following a glycine used for amidation of the carboxyl-terminal methionine. RNA blot analyses of tumor RNA show a major mRNA of 900 bases and a minor mRNA of 850 bases. Blot hybridization analyses using human genomic DNA are consistent with a single hGRP-encoding gene. The presence of two mRNAs encoding the hGRP precursor protein in the face of a single hGRP gene raises the possibility of alternative processing of the single RNA transcript.

Amino Acid Sequence↗
PubMed1984

Endocrine dysfunction in children with Crohn's disease.

A series of 14 children with Crohn's disease and growth retardation was screened for endocrine dysfunction. Four children presented with growth failure. All had normal cortisol responses to insulin-induced hypoglycaemia. Ten children had normal growth hormone responses in the same test, while four had abnormal responses. Gonadotrophin responsiveness to luteinizing hormone releasing hormone (LHRH) paralleled the clinical evidence of puberty, or its lack. Serum total thyroxine was normal in every patient, while serum total triiodothyronine was low in six; in these six patients serum triiodothyronine normalised with treatment. Serum folate was subnormal in 13 patients and the erythrocyte sedimentation rate was elevated in all at the time of diagnosis. Our results demonstrate a spectrum of endocrine changes seen in children with Crohn's disease, particularly prepubertal gonadotrophin responses to LHRH and a relative preservation of growth hormone and cortisol responsiveness to hypoglycaemia, with a defect in thyroxine to triiodothyronine conversion in severely ill children. Serum folate and sedimentation rate may be useful screening tests for Crohn's disease in a child presenting with failure of growth.

Adolescent↗
PubMed1984

Corticotrophin releasing factor: responses in normal subjects and patients with disorders of the hypothalamus and pituitary.

Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (+/- SE) was 276 +/- 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r = -0.56; P less than 0.02). The mean peak serum cortisol was 662 +/- 34 nmol/l and the mean peak corticosterone was 28.6 +/- 3.8 nmol/l. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r = 0.84; P less than 0.0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 micrograms of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome and normal serum cortisol levels, those with pituitary-dependent disease showed an enhanced ACTH response to CRF-41 as compared with the ectopic ACTH group, but there was some overlap between the two groups. Acromegalic patients did not show a GH response to CRF-41. We conclude that administration of CRF-41 is a safe new method for investigating disorders of the hypothalamo-pituitary axis.

Acromegaly↗
PubMed1984

A study of the relationship between circulating beta-endorphin-like immunoreactivity and post partum 'blues'.

Plasma beta-endorphin-like immunoreactivity was studied in 43 pregnant women at 36 weeks gestation and in 23 of these at delivery and 24 h post-partum; an attempt made to correlate changes with various social, psychological and obstetric factors, including the 'post-natal blues'. Beta-endorphin levels were elevated at 36 weeks gestation and term, increased to very high levels during labour and fell rapidly within 1 h of delivery. A negative correlation was observed between the woman's estimate of her pain in labour and the beta-endorphin levels post-partum, suggesting an analgesic role for beta-endorphin in labour. A positive correlation was also observed between the levels of beta-endorphin at delivery and the woman's attitude to her pregnancy at 36 weeks and a negative correlation between the 'post-natal blues score' and the beta-endorphin level at 36 weeks. However, the 'blues' did not correlate either with the beta-endorphin level at delivery or 24 h post-partum nor with its rate of fall in the first 24 h. Our general finding that there was no consistent social, psychological or obstetric factor which predisposes women to develop 'post-natal blues' still supports the hypothesis that humoral factors, of which beta-endorphin may be one, rather than psychological factors are important in the genesis of this syndrome.

Endorphins↗
PubMed1984

Corticotrophin releasing factor: effects on circulating gut and pancreatic peptides in man.

As a CRF-like peptide has been isolated from human gut, we investigated the effect of synthetic CRF-41 100 micrograms on gut and pancreatic peptides in six normal subjects. There was a significant rise in pancreatic polypeptide compared to a control infusion, but no change in plasma insulin, pancreatic glucagon, gastrin, somatostatin, motilin, neurotensin, gastric inhibitory peptide, or cholecystokinin was seen. In addition, there was no change in circulating met-enkephalin. We conclude that the rise in pancreatic polypeptide seen after CRF administration may suggest a role for a CRF-like peptide in the control of pancreatic function.

Adult↗