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Biomedical subjects

G M Besser

Publications and source records attributed to G M Besser.

At least 235 records · Page 13Linked to original sources
PubMed1988

Hypertriglyceridaemia and diabetes mellitus: cause or effect?

Two patients with hypertriglyceridaemia which was diagnosed several years before the onset of diabetes are described. In the first case a 54-year-old man presented with hypertriglyceridaemia and normal glucose tolerance. After 4 years he developed severe hypertriglyceridaemia (22 mmol/l) which was first ascribed to poor compliance but soon afterwards diabetes was diagnosed and good blood glucose control minimized the hypertriglyceridaemia. The second patient, a female, aged 27 years, with the polycystic ovarian syndrome, presented with eruptive xanthoma after several years of mild hyperlipidaemia. There was severe hyperlipidaemia (triglyceride 140 mmol/l, cholesterol 42 mmol/l) which required urgent plasmapheresis. Diabetes was diagnosed and treated with insulin at this time but the patient was taking the oral contraceptive pill and also had a deficiency of apolipoprotein CII.

Adult↗
PubMed1988

Modulation of the actions of tyrosine by alpha 2-adrenoceptor blockade.

1. Eight normal subjects were given, in double-blind, random order L-tyrosine 50, 250 and 500 mg kg-1 and placebo orally. Plasma tyrosine concentrations rose in a dose-dependent manner, without affecting the concentrations of the other large neutral amino acids. Tyrosine stimulated the secretion of prolactin and thyrotrophin (TSH) but had no effect on the plasma concentrations of adrenocorticotrophic hormone (ACTH), cortisol, growth hormone or the gonadotrophins. 2. The lack of a stimulant effect of tyrosine on ACTH secretion was presumed to be due to activation of one of the negative feedback mechanisms that control the rate of synthesis and release of the catecholamines, and this hypothesis was tested by examining the effects of the alpha 2-adrenoceptor antagonist idazoxan on the actions of tyrosine. 3. Seven normal males were given on 6 separate occasions tyrosine 250 and 500 mg kg-1 and placebo orally following pretreatment with saline and idazoxan (0.1 mg kg-1 i.v.). Following pretreatment with idazoxan, tyrosine stimulated the secretion of ACTH and noradrenaline in a dose-dependent manner, although neither tyrosine nor idazoxan on their own had any effect on the secretion of either substance. 4. The lack of effect of tyrosine when given on its own appears to be due, to partly, to activation of alpha 2-adrenoceptors, which inhibit the release of noradrenaline. Idazoxan caused a small increase in systolic blood pressure, both when given on its own and in combination with tyrosine. Neither tyrosine nor idazoxan had any significant effect on the state of behavioural arousal, as measured by visual analogue scales, or on the secretion of growth hormone or the gonadotrophins.

Adrenergic alpha-Antagonists↗
PubMed1988

Acetylcholine and norepinephrine stimulate the release of corticotropin-releasing factor-41 from the rat hypothalamus in vitro.

The effects of the two putative neurotransmitters acetylcholine and norepinephrine on immunoreactive CRF-41 release from incubated rat hypothalami were studied. Acetylcholine at concentrations of 10(-11) to 10(-7) M stimulated CRF-41 release. This effect was blocked in a dose-dependent manner by the muscarinic antagonist atropine (10(-9) to (-7) M). The nicotinic antagonist hexamethonium was ineffective at a dose of 10(-7) M, but produced slight inhibition of this response at 10(-5) M. Norepinephrine at concentrations of 10(-10) to 10(-6) M also produced a dose-dependent stimulation of CRF-41 release. The beta-adrenoceptor antagonists propranolol (10(-5) M) and timolol (10(-6) M) blocked norepinephrine-induced CRF-41 release. The alpha 1-adrenoceptor antagonists thymoxamine (10(-5) M), prazosin (10(-5) M), and corynanthine (10(-4) M), and the alpha 2-antagonist idazoxan (10(-5) M), were ineffective. Potassium depolarization (56 mM) caused stimulation of CRF-41 release which was dependent on the presence of calcium in the incubation medium. Authenticity of immunoreactive CRF-41 released was demonstrated by chromatographic criteria using gel filtration and reversed phase HPLC. These results provide evidence for a stimulatory role of acetylcholine and norepinephrine on CRF-41 release, and consequently on hypothalamo-pituitary-adrenal axis in the rat, through actions at a hypothalamic level. The stimulatory effect of acetylcholine is mediated principally through muscarinic receptors and that of norepinephrine through beta-adrenoceptors.

Acetylcholine↗
PubMed1988

Opioid peptides do not modulate atrial natriuretic peptide or aldosterone release under basal conditions in man.

The effect of two analogues of [Met]-enkephalin, [D-Ala2,N-Phe4,Met(0)-ol5]-enkephalin and its guanyl derivative, on plasma concentrations of atrial natriuretic peptide (ANP) and serum aldosterone in six normal subjects was investigated. All subjects were given a 1 litre water load to inhibit vasopressin release. Both analogues, when injected i.v. at a dose of 100 micrograms, stimulated release of prolactin and GH and inhibited serum cortisol; there was no significant change in blood pressure, pulse rate or urine output. Neither plasma concentrations of ANP nor serum aldosterone levels changed significantly after injection of either analogue at a low or high dose. Naloxone, given i.v. as an 8 mg bolus, also failed to alter concentrations of either ANP or aldosterone, while it significantly stimulated the release of serum LH and cortisol. It was concluded that under basal conditions opiate receptors are unable to modulate plasma ANP or serum aldosterone concentrations.

Adult↗
PubMed1988

Plasma levels of neuropeptide tyrosine Y (NPY) are increased in human sepsis but are unchanged during canine endotoxin shock despite raised catecholamine concentrations.

Alterations in levels of adrenal vein and circulating immunoreactive neuropeptide tyrosine Y (NPY), as well as systemic catecholamine concentrations, have been investigated in the dog after endotoxin administration. Eighteen dogs were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. Severe shock was produced by the administration of a large bolus of Escherichia coli endotoxin followed by a continuous infusion. In two further animals the left lumbar adrenal vein was cannulated and an intermittent choke allowed retrograde sampling of the adrenal effluent. The production of hypodynamic shock was associated with marked increases in systemic catecholamine concentrations but there were no consistent changes in adrenal vein or systemic immunoreactive NPY levels. In contrast, circulating concentrations of immunoreactive NPY were markedly raised above the normal range in five patients with septic shock.

Animals↗
PubMed1988

Characterization of immunoreactive dynorphin in human phaeochromocytomas.

The prodynorphin-derived opioids, dynorphin (DYN) and alpha-neoendorphin (alpha NE) were studied in 24 human phaeochromocytomas and related tumours. Nineteen tumours, extracted in HCl (0.1 mol/l), contained concentrations of immunoreactive DYN (ir-DYN) ranging from less than 0.5 to 794 pmol/g wet weight. None of the extracts in HCl contained ir-alpha NE (all less than 2.4 pmol/g). Sephadex G-50 gel filtration chromatography of ir-DYN in HCl (0.1 mol/l) extracts of six tumours revealed three small peaks of ir-DYN of higher molecular size (approximately 12,000, 6000 and 3000 daltons), a minor peak of ir-DYN eluting just after DYN(1-17), and a broad major peak, consisting of at least three components, which was significantly retarded and eluted after the salt volume of the column. High-pressure liquid chromatography (HPLC) of these extracts revealed multiple peaks of ir-DYN, most of which did not coelute with any synthetic DYN peptides. On both gel filtration chromatography and HPLC, one of the minor peaks coeluted with DYN(1-32). None of the peaks of ir-DYN coeluted with DYN(1-17) which had been acetylated using acetic anhydride. Extracts of the same tumours in acetic acid (0.1 mol/l) yielded similar values for ir-DYN content, but parallelism in the assay was improved. Sephadex G-50 chromatography revealed a different pattern of ir-DYN with a major peak coeluting with DYN(1-17) and, in two tumours, a minor peak coeluting with DYN(1-8). Studies with HPLC revealed, however, that substantial degradation of synthetic DYN occurred during extraction in acetic acid (0.1 mol/l) in spite of the precautions taken. Phaeochromocytomas frequently contain ir-DYN in concentrations which may approach that of the mammalian pituitary. These tumours did not, however, contain ir-alpha NE and, with the possible exception of a small amount of DYN(1-32), the ir-DYN present did not correspond with any known sequences. Thus, whilst prodynorphin is expressed in phaeochromocytomas, it does not seem to be processed to the usual end-products, and post-translational modifications therefore seem likely. Enzymatic degradation of DYN may occur during extraction in acetic acid (0.1 mol/l), and this medium should, therefore, be avoided in studies of such labile peptides.

Adrenal Gland Neoplasms↗
PubMed1987

Treatment of growth-hormone deficiency with growth-hormone-releasing hormone.

18 prepubertal growth-hormone (GH)-deficient children were treated with twice-daily subcutaneous injections of a growth-hormone-releasing hormone analogue, GHRH (1-29) NH2. In 12 of the children the height velocity rose on GHRH treatment, and 8 were judged to have shown a worthwhile response to therapy in that their height velocities during the first 6 months of treatment increased by greater than 2 cm/yr (range 2.7-11.2 cm/yr). These 8 children have now been treated for 6 to 18 months and their increase in height velocity has been maintained. In the 14 patients who had previously received human GH (hGH) height velocity on hGH correlated with that on GHRH. 4 of these patients showed growth deceleration with GHRH, for unknown reasons. A pretreatment peak serum GH response of above 30 mU/l during an intravenous GHRH test was predictive of a good growth response to GHRH but a lower peak did not preclude a growth response. There was no consistent evidence of a priming or desensitisation effect of therapy on the GH responses to GHRH. Although anti-GHRH antibodies developed in 14 patients, these did not seem to have adverse effects on either growth or the GH responses to GHRH. GHRH (1-29) NH2 therapy is an alternative to conventional hGH in the treatment of some GH-deficient children. Ideal dose regimens need to be established.

Adolescent↗
PubMed1987

Failure to preserve fertility in patients with Hodgkin's disease.

The hypothesis that the "down-regulated" gonad is less vulnerable to the effects of cytotoxic chemotherapy for advanced Hodgkin's disease has been investigated. Thirty men and eighteen women were randomly allocated to receive an agonist analogue of gonadotrophin-releasing hormone prior to, and for the duration of, cytotoxic chemotherapy. Buserelin (d-Ser-[TBU]6 LHRH ethylamide) was prescribed in two different dosage schedules to twenty men, and in a single dosage schedule to eight women. A standard gonadotrophin-releasing hormone test (GnRH 100 micrograms) was performed 1 week prior to and on day 1 of each cycle of chemotherapy. In all patients peak luteinizing hormone responses to GnRH were suppressed throughout treatment. The higher of the two dosage schedules used in the men caused more effective suppression of luteinizing hormone, and both regimens led to an initial suppression of peak follicle-stimulating hormone responses to GnRH, which was not maintained. At follow-up assessment up to 3 years from the completion of treatment, all men treated with buserelin were profoundly oligospermic and four of the eight women were amenorrhoeic. All ten male controls were profoundly oligospermic, and six of nine female controls were amenorrhoeic. In the dosages and schedules investigated, buserelin was ineffective in conserving fertility.

Amenorrhea↗
PubMed1987

Observations on the function of normal adrenomedullary tissue in patients with phaeochromocytomas and other paragangliomas.

123I-MIBG is a norepinephrine analogue used for imaging phaeochromocytomas and other paragangliomas. In this study 7 normal volunteers and 31 subjects with high or borderline high plasma catecholamine and urinary metanephrine and VMA levels were investigated. In the normals the uptake by the adrenal medulla was in the range of 0.01%-0.21% of the injected dose at 22 h. In 22 subjects there was no evidence for any paraganglioma, with the uptake by the adrenal medulla in the range of 0.01%-0.22% of the injected dose at 22 h. In nine patients there was evidence of a paraganglioma on imaging which was confirmed on surgery. The uptake by the tumours was in the order of 0.001%-0.14% of the injected dose per gram of tumour tissue. In all nine cases the non-tumorous adrenal medulla could be visualized; the uptake in the adrenals was in the range of 0.01%-0.21% of the injected dose. This study shows that in the presence of elevated plasma catecholamines of tumour origin the unaffected adrenal medullary tissue retains the capacity for 123I-MIBG uptake. In the two cases also studied by adrenal venous sampling, catecholamine release was also within the normal range.

3-Iodobenzylguanidine↗
PubMed1987

The effects of a gonadotropin-releasing hormone agonist on testicular histology.

We have described the histologic changes in the testes of men treated with buserelin for prostatic cancer. If these changes are reversible, then the agonist analogues, together with testosterone replacement therapy, could be used safely for male contraception. If the changes are irreversible, then boys with central precocious puberty treated with such compounds would be of normal height, but sterile.

Aged↗
PubMed1987

Dissociation between circulating concentrations of immunoreactive growth hormone releasing factor and growth hormone in normal human subjects.

Using a highly specific radioimmunoassay we have measured immunoreactive human growth hormone releasing factor (ir-hGRF) concentrations in the peripheral circulation of a total of 12 normal subjects. Neither insulin-induced hypoglycaemia, intravenous arginine nor oral carbohydrate caused any change in venous plasma ir-hGRF concentrations, despite the expected stimulation and suppression respectively of growth hormone secretion. Growth hormone secretion was not increased by oral fat or protein but each of these two foods stimulated ir-hGRF concentrations two- to four-fold. Spontaneous pulses of growth hormone secretion on control days were unaccompanied by any increase in plasma ir-hGRF. The dissociation between peripheral circulating ir-hGRF and growth hormone responses demonstrated under different circumstances suggests that an important source of human growth hormone releasing factor lies outside the hypothalamus and that secretion from this source is unconnected with the normal control of pituitary growth hormone secretion.

Adult↗
PubMed1987

The effect of enkephalin analogue on pituitary hormone release in human obesity.

To elucidate further the role of opioid systems in the neuroendocrine alterations associated with obesity, we investigated the effect of the synthetic enkephalin analogue DAMME in 11 obese subjects and 10 lean controls. Prolactin responses to DAMME were similar in lean and obese, even in those obese subjects who had absent prolactin responses to insulin-induced hypoglycaemia. The obese showed impaired growth hormone release after both DAMME and insulin-induced hypoglycaemia compared to the lean subjects. The discordance of prolactin responses to DAMME and insulin-induced hypoglycaemia in the obese suggests that altered opioid systems are unlikely to account for the hypothalamic dysfunction present in obesity.

Adult↗
PubMed1987

Thymoxamine: lack of antihistaminic effects in clinical doses in man.

The purpose of this study was to investigate whether the alpha 1-adrenoceptor antagonist thymoxamine possesses antihistaminic activity in clinical doses in man, as has been reported on the guinea pig ileum in vitro. Five normal subjects were given on three separate occasions intravenous infusions of thymoxamine (0.15 mg kg-1 loading dose followed by 0.15 mg kg-1 h-1), chlorpheniramine (1.5 mg loading dose followed by 1.5 mg h-1) and normal saline (placebo). Intravenous bolus doses of histamine (1 and 2 micrograms kg-1) were given after pretreatment with propranolol 10 mg to block the beta-adrenoceptor agonist effects of the catecholamines released by the histamine injections. Histamine caused a dose-dependent reduction of FEV1 and FVC that was antagonised by chlorpheniramine but not by thymoxamine, suggesting that thymoxamine has no antihistaminic activity in the doses used in man. Thymoxamine caused a small enhancement of the bronchoconstrictor effect of the lower dose of histamine. The relatively selective action of thymoxamine makes it a suitable agent for the investigation of alpha 1-adrenoceptors.

Chlorpheniramine↗
PubMed1987

Food-induced cortisol secretion is mediated by central alpha-1 adrenoceptor modulation of pituitary ACTH secretion.

Food ingestion stimulates cortisol secretion in man, but the mechanism of this effect is unknown. We have investigated the possible role of adrenoceptors in the mediation of this effect. Six normal males were given continuous 3 h i.v. infusions of normal saline, methoxamine (alpha-1 adrenoceptor agonist) and thymoxamine (alpha-1 adrenoceptor antagonist). Methoxamine enhanced and thymoxamine attenuated the ACTH and cortisol responses to a standard meal given 60 min after commencement of the infusion. The drugs had no effect on nutrient absorption. Four patients with recent onset of pituitary ACTH deficiency and normally responsive adrenal glands showed no ACTH or cortisol rises after the standard meal, demonstrating that postprandial cortisol secretion is mediated by pituitary rather than gut ACTH. Our previous investigations have demonstrated that alpha-1 adrenoceptors stimulate pituitary ACTH secretion in man by an action within the blood brain barrier. We therefore conclude that postprandial cortisol secretion is mediated by central stimulant alpha-1 adrenoceptors modulating pituitary ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1987

Stilboestrol pretreatment of children with short stature does not affect the growth hormone response to growth hormone-releasing hormone.

Oestrogens are known to enhance both basal and stimulated GH secretion. To examine whether this effect is mediated through the hypothalamus or the pituitary we performed insulin tolerance and GH-releasing hormone (GHRH) tests with and without oestrogen priming in a group of 14 short children. Pretreatment with stilboestrol increased basal levels of GH and both peak and incremental levels during insulin hypoglycaemia. In contrast, there was no effect of stilboestrol priming on the GH response to either an i.v. bolus of 100 micrograms or 0.1 microgram/kg (range 2-6 microgram) of GHRH. The children had significantly higher GH responses to an unprimed GHRH than unprimed insulin tolerance test. We conclude stilboestrol priming acts through the hypothalamus presumably by increasing endogenous GHRH release, and that short children with a subnormal GH response to insulin hypoglycaemia show a greater response to GHRH; this suggests the presence of a hypothalamic cause for their decreased GH secretion.

Body Height↗
PubMed1987

Hyperprolactinaemia and microadenomas in primary hypothyroidism.

The presence at presentation of hyperprolactinaemia and abnormalities on high resolution computed tomographic (CT) scanning of the pituitary gland have been documented in 19 patients with primary hypothyroidism. The changes on thyroid hormone replacement were followed for up to 28 months after presentation. At presentation serum PRL was elevated in 12 subjects (454 to 2612 mU/l); after stabilization of thyroid replacement PRL remained raised in 9 patients (525 to 1888 mU/l) despite 10-18 months of treatment. Pretreatment CT scans showed enlarged pituitaries in 11 patients with suprasellar extension in five. In 11 patients there was initially an area of low attenuation suggesting a microadenoma and on rescanning this appearance remained in five patients. Hyperprolactinaemia in hypothyroid patients does not always return to normal with thyroid hormone replacement.

Adenoma↗