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M T Jones

Publications and source records attributed to M T Jones.

At least 73 records · Page 4Linked to original sources
PubMed1984

Characteristics of corticosteroid inhibition of adrenocorticotrophin release from the anterior pituitary gland of the rat.

The occurrence and nature of corticosteroid inhibition of ACTH secretion at the rat anterior pituitary gland was investigated using three experimental models: animals bearing lesions of the basal hypothalamus, and two preparations of the gland incubated in vitro; these were tissue segments and collagenase-dispersed cells. Release of ACTH in the experiments was provoked using one of three distinct stimuli: acid extracts of whole hypothalami, corticotrophin releasing activity released by serotonin from hypothalami incubated in vitro and synthetic ovine corticotrophin releasing factor. Irrespective of whether ACTH was measured directly by radioimmunoassay (in the experiments in vitro) or indirectly in terms of corticosterone production (in the lesioned animals), its stimulated release from the anterior pituitary gland was inhibited by corticosterone. Two phases of inhibition were observed; these had some of the characteristics inferred previously from experiments with intact animals and designated fast feedback and delayed feedback. However, the fast feedback demonstrable in lesioned animals did not show the rate-sensitivity shown previously in intact animals. 11-Deoxycortisol (or 11-deoxycorticosterone) and prednisolone proved to be agonists of corticosterone in provoking fast feedback in lesioned animals, whereas they had been shown respectively to act as an antagonist or to have no effect in intact rats. Several steroids were able to cause delayed feedback in lesioned rats, but beclomethasone dipropionate (shown to be an agonist of corticosterone in intact rats) proved to have no inhibitory effect at the anterior pituitary gland of lesioned animals. It is concluded that the dynamics of corticosteroid feedback mechanisms at the anterior pituitary gland, as indicated by experiments in lesioned animals, differ from those operative in the intact animals. Other work suggests that a more important site for such inhibitory mechanisms in vivo is the hypothalamus.

Adrenocorticotropic Hormone↗
PubMed1983

Differential penetration of three anterior pituitary peptide hormones into the cerebrospinal fluid of rhesus monkeys.

This paper demonstrates marked differences between blood levels and those in the CSF for three anterior pituitary peptide hormones, prolactin, luteinizing hormone (LH) and adrenocorticotrophin (ACTH) in the rhesus monkey. CSF levels of endogenous prolactin (measured by radioimmunoassay) are about 20% of those in the blood, and this proportion remains constant under conditions of persistent ('steady-state') hyperprolactinaemia (induced by injecting sulpiride). Acutely elevating prulactin, by either an intravenous injection of exogenous ovine prolactin, or sulpiride, resulted in similar rates of entry by prolactin into the CSF, suggesting that retrograde portal flow is not an important mechanism. LH, measured by bioassay, is also present in the CSF, but the CSF/blood ratio is 5-10 times less than for prolactin. Castration, causing blood LH levels to rise, resulted in equivalent changes in CSF, so that the ratio remains constant, though still much lower than for prolactin. There are significant correlations between individual animals in the blood and CSF content of prolactin and LH. In marked contrast, whilst ACTH is found (by cytochemical assay) in the CSF of both intact and adrenalectomized monkeys, no significant change in CSF levels occurs despite 10-fold changes in the plasma of adrenalectomized animals following withdrawal of cortisol. Nor is there any correlation between blood and CSF ACTH levels over a wide range of concentrations. These results show that each of the three peptides studied has a distinct pattern of entry into the CSF from the vascular compartment.

Adrenalectomy↗
PubMed1983

24-hour variation in content and release of hypothalamic neuropeptides in the rat.

The tissue content of up to eight neuropeptides, viz bombesin (BOM), cholecystokinin (CCK-8), neurotensin (NT), neuropeptide Y (NPY), peptide histidine isoleucine amide (PHI), somatostatin (SRIF), substance P (SP) and vasoactive intestinal polypeptide (VIP), in rat hypothalami removed at various times of the day, was measured using specific radioimmunoassays. There was significant variation in the content of BOM, CCK-8, NT, PHI, SP and VIP across a 24-h period. The levels of BOM, CCK-8 and NT were lowest around the onset of darkness (1900 h) and rose throughout the night to reach a peak around the time of lights on. Hypothalamic content of all eight peptides fell between 0700 h and 1300 h by an average of 45 +/- 4%. Basal release of these peptides, as well as that in the presence of 48 mM potassium (K+), was measured from hypothalami removed between 0700 and 1900 h and incubated in vitro in a CSF-like medium. Basal secretion of NT significantly increased, whilst that of CCK-8 significantly decreased over the same period. There was no significant change in the basal release of the other neuropeptides. The release in the presence of 48 mM K+ of SP decreased significantly during the day, whilst that of VIP significantly increased. There was also a significant change in the stimulated release of BOM, levels falling during the morning and rising again at 1900 h. 48 mM K+ caused a significant increase in the release of SRIF and SP at all times tested. Whilst 48 mM K+ induced a significantly higher release of CCK-8 and NT in the morning, this stimulus was ineffective in the evening. The contrary was true in the case of BOM, NPY and VIP, where a significant stimulation was induced only at 1900 h. The possible implications of these findings are discussed.

Animals↗
PubMed1983

The evaluation of sodium valproate in the treatment of Nelson's syndrome.

It has previously been reported that sodium valproate (Epilim) lowers plasma ACTH levels in Nelson's syndrome. This report describes further experience with its use. Ten patients with Nelson's syndrome were treated with sodium valproate (600-1200 mg/day) for 5-32 weeks. Plasma ACTH was measured by cytochemical methods and RIA. Initial treatment for 5-12 weeks significantly (P less than 0.005) lowered plasma ACTH from a pretreatment mean of 2460 +/- 1870 ng/liter to 480 +/- 330 ng/liter, and the ACTH circadian rhythm was restored in two patients. On discontinuing treatment, plasma ACTH levels remained suppressed for 3 weeks and rose to pretreatment values in 5-12 weeks. Two patients' plasma ACTH levels failed to show a second response to treatment, while a third patient had a favorable second response to treatment over 32 weeks. In six patients, skin pigmentation lightened with treatment, and in one patient, a reduction in size of a pituitary microadenoma, demonstrated radiographically, occurred with treatment. gamma-Aminobutyric acid and sodium valproate were shown to be ineffective in inhibiting ACTH secretion from cultured pituitary tumor cells from a patient with Nelson's syndrome. The results show that sodium valproate is effective in some cases of Nelson's syndrome. We suggest that it reduces the hypersecretion of ACTH by enhancing gamma-aminobutyric acid function in the hypothalamus, thereby inhibiting the release of corticotropin-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1983

Biphasic inhibition of bioactive hypothalamic corticotrophin releasing factor secretion in vitro by corticosterone and prevention of the second phase by various steroids.

The effect of various steroids on the functional activity of the rat hypothalamus in vitro was investigated. The addition of corticosterone (10(-7) mol/l) for 30 min to the incubation medium inhibited immediately the release of bioactive corticotrophin releasing factor (CRF) by tissue induced by serotonin (2.6 X 10(-8) mol/l). This was followed by a period lasting from 30 min (coincident with removal of the steroid from the medium) to 60 min when no inhibition was seen. Finally a second period of suppression of hypothalamic CRF activity in vitro was shown to be fully established 120 min after addition of the steroid. In more detailed investigations the latter inhibition was shown to occur when the tissue was exposed to the steroid (3 X 10(-7) mol/l) for 5 or 30 min, but not for 1 min, and it was dose-related. Of other steroids investigated, progesterone in high concentrations (3 X 10(-6 mol/l) suppressed to a small extent the functional activity of the hypothalamus in vitro but 17 alpha-hydroxyprogesterone, 11 alpha-hydroxyprogesterone, 11 alpha, 17 alpha-dihydroxyprogesterone and 11-epicortisol had no effect on the delayed inhibition. Progesterone (10(-7) mol/l) potentiated the ability of corticosterone (10(-8) mol/l) to induce the delayed suppression of hypothalamic CRF activity in vitro. In contrast, 17 alpha-hydroxyprogesterone, 11 alpha-hydroxyprogesterone, 11 alpha, 17 alpha-dihydroxyprogesterone and 11-epicortisol competitively antagonized this inhibitory action of corticosterone (3 X 10(-7) mol/l) in a dose-related manner (1.5 X 10(-8)-3 X 10(-8) mol/l). The action of the antagonist 11-epicortisol was similar whether it was added to the tissue in vitro before corticosterone or antagonist and agonist were added together. The functional characterization of steroid action on the hypothalamus may lead to a clearer understanding of the mechanism by which the compounds influence hormone release.

Animals↗
PubMed1981

Effect of treatment with sodium valproate and diazepam on plasma corticotropin in Nelson's syndrome.

Six patients with Nelson's syndrome were given sodium valproate with or without diazepam for 3 or 5 weeks. Initial high plasma adrenocorticotropic hormone (ACTH) concentrations were greatly reduced by treatment and returned to high levels when treatment was stopped. Diazepam did not add significantly to the effects of sodium valproate alone. Three patients reported a decrease in the severity and frequency of headaches while on sodium valproate. In five patients abnormal skin pigmentation was reduced. Sodium valproate is a gamma-aminobutyric acid (GABA) transaminase inhibitor and it is suggested that the drug raises GABA levels in the hypothalamus and that this is responsible for the reduction in ACTH secretion. The data are consistent with the hypothesis that Nelson's syndrome is a neuroendocrine disease caused by a deficiency in the hypothalamic GABA-ergic system.

Adrenocorticotropic Hormone↗
PubMed1980

Feasibility of testing DNA repair inhibitors for mutagenicity by a simple method.

A simple screening methodology for the determination of mutagenicity of DNA repair inhibitors has been tested in this laboratory. Radiation-resistant E. coli B/r and WP2 hcr+ and hcr- are suitable strains for mutagenicity testing. In these strains irradiated with 40-60 ergs/mm2, chemicals which interfere with repair of ultraviolet-induced pre-mutational lesions can be shown to enhance significantly the frequency of mutations to streptomycin resistance. This phenomenon is termed "mutational synergism" [18,20]. We have attempted to apply the procedure for securing data for "mutational synergism" between ultraviolet (UV) radiation and a number of antimalarial drugs including quinine hydrochloride (50 microgram/ml), quinine hydrobromide (50 microgram/ml), primaquine diphosphate (50 microgram/ml), chloroquine (50 microgram/ml), quinine (50 microgram/ml) and quinacrine dihydrochloride (25 microgram/ml). All drugs tested give synergistic effects with UV light. The synergistic activity ranges from 3- to 35-fold. Quinine and quinacrine dihydrochloride have been found to be much more efficient enhancers of the mutagenic effect of UV than caffeine. In general, we have found that the expression of synergistic action occurs at a concentration well below the minimum inhibitory concentration (MIC) with the drugs tested. The implication of these observations in the establishment of a screening method for the evaluation of the mutagenicity of DNA repair inhibitors is discussed.

DNA↗
PubMed1980

Using discriminant function analysis with clinical, demographic and historical variables to diagnose schizophrenia.

An effort was made to formalize the critical clinical, demographic and historical features of schizophrenia through the development of a reliable assessment questionnaire. The criterion diagnosis was established via traditional hospital procedures and was substantiated by psychometric measures. Raters with comparable diagnostic experience were familiarized with each of the clinical, demographic and historical features before evaluating the presence or absence in a sample of both psychiatric in-patients and out-patients. A structured, standardized interview was used to reduce inconsistency and oversight due to variability in interviewing techniques and coverage of psychopathology. Using the coefficients of the discriminative functions of five major symptoms (loose associations, autism, loss of ego boundaries, emotional blunting, delusions) and two demographic and historical features (family history of mental illness, poor social relations) correctly classified 98 per cent of the total sample of 253 patients. A subsequent investigation demonstrated the utility and generalizability of the proposed system. The assets and liabilities of using such an approach are discussed.

Adolescent↗
PubMed1979

The effect of cyproheptadine on the release of corticotrophin releasing factor.

The effect of cyproheptadine was tested on the neurotransmitter-induced release of corticotrophin releasing factor (CRF) from the rat hypothalamus in vitro. It was found that cyproheptadine inhibited both acetylcholine and 5-hydroxytryptamine-induced release of CRF. Cyproheptadine did not interfere with the ACTH releasing ability of CRF. These results suggest that cyproheptadine reduces the high circulating levels of ACTH in some patients suffering from Cushing's disease and Nelson's syndrome by inhibiting CRF secretion.

Acetylcholine↗
PubMed1977

Cotton dust sampling, II--vertical elutriation.

Cotton dust sampling by vertical elutriation has existed since 1970. Early medical correlations using this method of sampling used median values instead of mean values because of unexpected high and low values. The methodology necessary to obtain consistent results is difficult to achieve and worthy of review.

Air Pollutants↗
PubMed1977

Structure-activity relationship of various corticosteroids on the feedback control of corticotrophin secretion.

Several steroids occurring in the pathway of corticosteroid biosynthesis were investigated for their ability to exert a fast or delayed feedback inhibition of stress-induced release of corticotrophin. Rats were injected subcutaneously with vehicle or a steroid either 10 min (fast feedback) or 4 h (delayed feedback) before they were subjected to stress which consisted of a 2 min exposure to ether vapour. 2 Changes in plasma corticosterone concentration and in vitro corticosterone production by excised adrenal glands were used as indices of corticotrophin release. 3 Among the steroids tested only 11beta, 21-dihydroxypregn-4-ene-3, 20-dione (corticosterone) and 11beta, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (cortisol) inhibited the stress response 10 min after their administration. Therefore, it appears that the fast feedback mechanism is limited to steroids with a 21-hydroxyl and a 11beta-hydroxyl group. 4 In contrast, many steroids caused inhibition of the stress response 4 h after their administration. These steroids were corticosterone, cortisol, 21-hydroxypregn-4-ene-3, 20-dione (11-deoxycorticosterone), 17alpha, 21-dihydroxypregn-4-ene-3, 20-dione (11-deoxycortisol), 11beta-hydroxypregn-4-ene-3, 20-dione (11beta-hydroxyprogesterone) and 11beta, 17alpha-dihydroxypregn-4-ene-3, 20-dione (11beta, 17alpha-dihydroxyprogesterone). Thus, either the 21-hydroxyl group (e.g. 11-deoxycorticosterone) or the 11beta-hydroxyl group (e.g. 11beta-hydroxyprogesterone) is sufficient for delayed feedback activity. The 11alpha-hydroxyl group, e.g. 11alpha, 17alpha, 21-trihydroxypregn-4-ene-3, 20-dione (11-epicortisol) renders the steroid inactive on both feedback mechanisms. 5 18,21-Dihydroxypregn-4-ene-3, 20-dione (18-hydroxydeoxycorticosterone) was found to be the only steroid that is secreted by the adrenal gland of the rat in quantities sufficient to cause exaggeration of the stress-induced release of corticotrophin. This steroid has been implicated as a possible hypertensive agent, and its role in the control of corticotrophin secretion is discussed here.

Adrenal Cortex Hormones↗
PubMed1977

Dynamics and mechanics of corticosteroid feedback at the hypothalamus and anterior pituitary gland.

Corticosteroid feedback mechanisms were investigated at the hypothalamic level using the rat hypothalamus in vitro and the pituitary level using basal hypthalamic-lesioned rats. Both fast and delayed corticosteroid feedback effects were demonstrated at the level of the hypothalamus and pituitary gland with doses of corticosteroids within or near the physiological range. These two phases of feedback were separated temporally by a 'silent period' during which no feedback was apparent. Studies on the mechanism of action of corticosteroids at the hypothalamic level showed that the fast feedback mechanism acts by inhibition of release whilst the delayed feedback mechanism acts by inhibition of both synthesis and release. The fast feedback action of corticosterone does not appear to act by excitation of neuroinhibitory pathways since neither picrotoxin nor phentolamine prevented the feedback action of corticosteroids in vitro. Corticosterone inhibition of corticotrophin releasing factor release was overcome by depolarization of the membrane with K+ suggesting that the mechanism of action of the fast feedback of corticosteroids is by membrane stabilization.

Acetylcholine↗