Dissociation of the diurnal variation of aldosterone and cortisol in anephric subjects

Dissociation of the diurnal variation of aldosterone and cortisol in anephric subjects. Diurnal variation of plasma aldosterone and cortisol concentration in man was studied in 13 anephric subjects and 7 normal subjects. All subjects were ambulatory and active throughout the study except during an 8-hour sleep period. Six anephric subjects received Kayexalate® (sodium polystyrene sulfonate) during the studies to prevent potassium accumulation and increase in plasma potassium concentration. Diurnal variation of plasma aldosterone concentration with peak and nadir concentrations at 12:00 noon and 12:00 midnight respectively was demonstrated in the studies on normal subjects. Changes in plasma aldosterone concentration were not significantly correlated with changes in plasma cortisol concentration but were highly correlated with changes in PRA (P < 0.001). There was a highly significant correlation between plasma aldosterone and potassium concentration in the anephric subjects studied without Kayexalate® administration (P < 0.001). In the anephric subjects who received Kayexalate®, plasma aldosterone and potassium concentration remained stable, and no correlation could be demonstrated. No diurnal variation of plasma aldosterone concentration could be demonstrated in either group of anephric subjects, whereas plasma cortisol concentration varied as in the studies on normal subjects. Conclusion. Diurnal variation of plasma aldosterone concentration is dependent on continued stimulation by the renin-angiotensin system. Loss of this stimulation has no demonstrable effect on the diurnal variation of plasma cortisol concentration.Dissociation des variations nycthémérales de l'aldostérone et du cortisol chez les sujets anéphriques. Les variations nycthémérales de l'aldostérone et du cortisol plasmatiques chez l'homme ont été étudiées chez 13 sujets anéphriques et 7 sujets normaux. Tous les sujets étaient ambulatoires excepté pendant une période de sommeil de 8 heures. Six sujets anéphriques receivaient du Kayexalate® (sodium polystyrene sulfonate) afin d'empêcher une accumulation de potassium et une augmentation de la kaliémie. Des variations nycthémérales de l'aldostéronémie avec un pic et un nadir à midi et minuit, respectivement, ont été observées chez les sujets normaux. Les modifications de l'aldostéronémie ne sont pas significativement corrélées avec les modifications du cortisol plasmatique mais très corrélées avec celles de PRA (P < 0,001). Il existe une corrélation très significative entre l'aldostéronémie et la kaliémie chez les sujets anéphriques étudiés en dehors de l'administration de Kayexalate (P < 0,001). Chez les sujets anéphriques recevant du Kayexalate l'aldostéronémie et la kaliémie sont stables et aucune corrélation n'est obtenue. Aucune variation nycthémérale de l'aldostéronémie n'a été observé dans les groupes de sujets anéphriques alors que la concentration de cortisol plasmatique varie comme chez les sujets normaux. Il peut être conclu de ces études que les variations nycthémérales de l'aldostéronémie dépendent de la stimulation par le système rénine-angiotensine. La perte de cette stimulation n'a pas d'effet sur la cortisolémie

Comprehensive overview of the structure and regulation of the glucocorticoid receptor

Glucocorticoids are among the most prescribed drugs worldwide for the treatment of numerous immune and inflammatory disorders. They exert their actions by binding to the glucocorticoid receptor (GR), a member of the nuclear receptor superfamily. There are several GR isoforms resulting from alternative RNA splicing and translation initiation of the GR transcript. Additionally, these isoforms are all subject to several transcriptional, post-transcriptional, and post-translational modifications, all of which affect the protein's stability and/or function. In this review, we summarize recent knowledge on the distinct GR isoforms and the processes that generate them. We also review the importance of all known transcriptional, post-transcriptional, and post-translational modifications, including the regulation of GR by microRNAs. Moreover, we discuss the crucial role of the putative GR-bound DNA sequence as an allosteric ligand influencing GR structure and activity. Finally, we describe how the differential composition and distinct regulation at multiple levels of different GR species could account for the wide and diverse effects of glucocorticoids

Sampling diverse characters improves phylogenies:craniodental and postcranial characters of vertebrates often imply different trees

This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/evo.12884Morphological cladograms of vertebrates are often inferred from greater numbers of characters describing the skull and teeth than from postcranial characters. This is either because the skull is believed to yield characters with a stronger phylogenetic signal (i.e., contain less homoplasy), because morphological variation therein is more readily atomized, or because craniodental material is more widely available (particularly in the palaeontological case). An analysis of 85 vertebrate datasets published between 2000 and 2013 confirms that craniodental characters are significantly more numerous than postcranial characters, but finds no evidence that levels of homoplasy differ in the two partitions. However, a new partition test, based on tree-to-tree distances (as measured by the Robinson Foulds metric) rather than tree length, reveals that relationships inferred from the partitions are significantly different about one time in three, much more often than expected. Such differences may reflect divergent selective pressures in different body regions, resulting in different localized patterns of homoplasy. Most systematists attempt to sample characters broadly across body regions, but this is not always possible. We conclude that trees inferred largely from either craniodental or postcranial characters in isolation may differ significantly from those that would result from a more holistic approach. We urge the latter.This work was supported by a University of Bath URS award to RCPM, Leverhulme Trust Grant F/00351/Z and BBSRC grant BB/K015702/1 to MAW, JTF Grant 43915 to Mark Wilkinson and MAW, and NERC fellowship NE/I020253/1 to RSS

Studies of the Mechanism through Which Sodium Depletion Increases Aldosterone Biosynthesis

Although considerable effort has been directed toward an understanding of the extra-adrenal factors that regulate aldosterone secretion, comparatively little attention has been given to the intraadrenal mechanisms through which these factors effect an increase in aldosterone biosynthesis. It has been established that aldosterone is synthesized by the adrenal cortex by a series of reactions that involve progesterone, deoxycorticosterone, and corticosterone as successive precursors (1-4). It is possible that cholesterol (4, 5) is a precursor of progesterone in this pathway and that 18-hydroxycorticosterone is an intermediate between corticosterone and aldosterone (6, 7). Since it is known that depletion of body sodium (natropenia) is ah effective stimulus to aldosterone secretion (8, 9) and excretion (10), this study was undertaken to provide information as to where in this biosynthetic pathway sodium depletion exerts its stimulatory effect. The idea that the natropenic stimulus to aldosterone secretion is mediated by increases in plasma angiotensin has much to recommend it (11-14), but this concept has not been established to the satisfaction of all investigators (15-17). Therefore, in the present investigation it was considered desirable to make no assumptions as to what the mediator of the natropenic stimulus to aldosterone secretion might be but, rather, to study the intact human organism under conditions of controlled sodium intake. Experiments were designed to determine whether the stimulus of sodium depletion * Submitted for publication August 13, 1965; accepte

Hormonal responses to acute volume changes in anephric subjects

Hormonal responses to acute volume changes in anephric subjects. The response of plasma aldosterone and cortisol concentrations to acute volume depletion was studied in 18 chronically anephric subjects and four recently nephrectomized subjects. Volume-depleting hemodialysis and hemodialysis without volume depletion produced insignificant changes in plasma aldosterone concentrations in chronically anephric subjects. Failure of volume depletion to increase plasma aldosterone concentrations in these subjects could not be attributed to reductions in plasma potassium concentrations and was in marked contrast to the effect on plasma cortisol concentrations, which increased significantly during volume depletion. Changes in plasma cortisol concentrations exhibited a negative correlation with changes in diastolic blood pressure (r = -0.712, P < 0.001) and were shown to correspond to similar changes in plasma ACTH concentrations. Comparable increases in plasma cortisol and ACTH concentrations were also demonstrated in the studies on recently nephrectomized subjects, who, in contrast to chronically anephric subjects, exhibited increases in plasma aldosterone concentrations which were concordant with the changes in plasma cortisol and ACTH concentrations. These findings suggest that plasma aldosterone concentrations are regulated by a volume-sensitive mechanism in recently nephrectomized subjects but not in chronically anephric subjects. We interpret these data as evidence of aldosterone responsiveness to ACTH that persists for a limited time only after removal of the stimulus provided by the renin-angiotensin system. Volume-related changes in plasma cortisol and ACTH concentrations occur in the absence of stimulation by a functioning renin-angiotensin system.Réponses hormonales à des modifications aiguës volémiques chez des sujets anéphriques. La réponse des concentrations plasmatiques d'aldostérone et de cortisol à une déplétion volémique aiguë a été étudiée chez 18 sujets anéphriques chroniques et chez quatre sujets récemment néphrectomisés. Une hémodialyse avec déplétion volémique et une hémodialyse sans déplétion volémique ont entraîné des modifications non significatives des concentrations d'aldostérone plasmatique chez les sujets anéphriques chroniques. L'absence d'augmentation des concentrations d'aldostérone plasmatique lors de la déplétion volémique chez ces malades ne pouvait pas être attribuée à des diminutions des concentrations potassiques plasmatiques et était en opposition marquée avec l'effet sur la cortisolémie, qui s'est élevée significativement pendant la déplétion volémique. Les modifications de la cortisolémie étaient corrélées négativement avec les modifications de la pression artérielle diastolique (r = -0,712, P < 0,001), et il a été montré qu'elles correspondaient à des modifications similaires des concentrations plasmatiques d'ACTH. Des augmentations comparables des concentrations plasmatiques de cortisol et d'ACTH ont également été démontrées dans l'étude de sujets récemment néphrectomisés, lesquels, par opposition avec les sujets anéphriques chroniques, avaient des augmentations des concentrations d'aldostérone plasmatique qui étaient concordantes avec les modifications des concentrations plamatiques de cortisol et d'ACTH. Ces résultats suggèrent que les concentrations d'aldostérone sont régulées par un mécanisme sensible au volume chez les sujets récemment néphrectomisés, mais non chez les sujets anéphriques chroniques. Nous interprétons ces données comme une preuve de la réponse de l'aldostérone à l'ACTH qui persiste seulement pendant un temps limité après suppression du stimulus que réalise le système rénine-angiotensine. Des modifications liées au volume des concentrations plasmatiques de Cortisol et d'ACTH surviennent en l'absence de stimulation par un système rénine-angiotensine fonctionnel