Spironolactone-induced inhibition of aldosterone biosynthesis in primary aldosteronism: Morphological and functional studies

Twenty-five patients harboring aldosterone-producing adenomas were treated with spironolactone for 2-170 days immediately preoperatively. In the early period of administration of the drug (up to 27 days), plasma and urinary aldosterone decreased sharply while plasma renin activity (PRA) and serum potassium were rising. During this period of time, spironolactone bodies (SB), which form exclusively in cells actively producing aldosterone, were forming rapidly in the tumor cells but not in the inactive glomerulosa cells proper. The SB appear to be a morphological expression of a block in aldosterone biosynthesis. Since SB do not occur in normal fasciculata cells, which, like glomerulosa cells, also synthesize corticosterone, it is concluded that spironolactone inhibition of aldosterone biosynthesis occurs between corticosterone and aldosterone. Recent studies in vitro by others have suggested that the inhibition occurs at the corticosterone-methyl oxidase step, I (Ulick's nomenclature). The great diuresis of sodium and retention of potassium resulting from continued administration of the drug sharply activates aldosterone stimulatory factors. Aldosterone production may return to baseline levels in several weeks but it is inappropriately low in relation to the levels of PRA and serum potassium. With the further passage of time (average 4-6 wk), aldosterone production may increase 50%-100% above baseline levels, suggesting that the block has disappeared or is receding. At this time SB are diminishing in number and by 170 days of the drug they have virtually disappeared. We have hypothesized, among other possibilities, that recovery of the ability to convert corticosterone to aldosterone occurs by virtue of a mechanism activated by sodium deficiency, independent of angiotensin, which stimulates step 1 of the corticosterone-methyl oxidase system. As the block in the final step(s) of the biosynthetic pathway recedes, the existing elevated levels of angiotensin become much more effective in stimulating the production of aldosterone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22806/1/0000363.pd

Primary hyperaldosteronism caused by adrenocortical carcinoma

Since the syndrome of primary hyperaldosteronism was described by Jerome Conn in 1955, over 300 patients with this disorder have been identified in the medical centers of Vanderbilt University and the University of Michigan. The most frequent cause of this endocrinopathy has been a solitary adenoma of the adrenal cortex (72%); bilateral adrenocortical hyperplasia has been the cause of primary hyperaldosteronism in 27% of cases; less frequently, the cause has been multiple and/or bilateral adenomas (1%). During the last 4 years in these 2 medical centers, we have encountered 3 patients who have had biochemically proven primary hyperaldosteronism due to adrenocortical carcinoma. Each of these unusual cases is summarized with review of the recent literature . Depuis que le syndrome d'hyperaldostéronisme primitif a été décrit par Jerôme Conn en 1955 plus de 300 sujets qui en étaient victimes ont été identifiés à la Vanderbilt University de Nashville et à l'University of Michigan de Ann Arbor. La cause la plus fréquente de cette endocrinopathie répond à un adénome solitaire de la cortico-surrénale (72%) alors que l'hyperplasie corticale des 2 surrénales est plus rarement à son origine (27%), les adénomes multiples et/ou bilatéraux étant rarissimes (1%). Au cours des 4 dernières années 3 cas d'hyperaldosteronisme dû à un cancer de la cortico-surrénale ont été observés dans les 2 centres. Chacun de ces cas exceptionnels est exposé cependant que la littérature récente concernant l'hyperalderosteronisme est analysée. Desde la descripción del síndrome de hiperaldosteronismo primario por Jeremo Conn en 1955, más de 300 pacientes con esta entidad han sido identificados en nuestros 2 centros médicos, la Universidad de Vanderbilt (Nashville) y la Universidad de Michigan (Ann Arbor). La causa más frecuente de esta endocrinopatía ha sido el adenoma solitario de la corteza suprarrenal (72%); la hiperplasia adrenocortical bilateral ha sido la causa del hiperaldosteronismo primario en 27% de los casos; con menor frecuencia se han presentado los adenomas multiples y/o bilaterales (1%). En los 4 últimos años hemos encontrado 3 pacientes con hiperaldosteronismo primario comprobado bioquímicamente producido por carcinoma adrenocortical. Se presenta cada uno de estos casos poco usuales junto con una revisión de la literatura reciente.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41275/1/268_2005_Article_BF01655546.pd

Toward an internally consistent astronomical distance scale

Accurate astronomical distance determination is crucial for all fields in astrophysics, from Galactic to cosmological scales. Despite, or perhaps because of, significant efforts to determine accurate distances, using a wide range of methods, tracers, and techniques, an internally consistent astronomical distance framework has not yet been established. We review current efforts to homogenize the Local Group's distance framework, with particular emphasis on the potential of RR Lyrae stars as distance indicators, and attempt to extend this in an internally consistent manner to cosmological distances. Calibration based on Type Ia supernovae and distance determinations based on gravitational lensing represent particularly promising approaches. We provide a positive outlook to improvements to the status quo expected from future surveys, missions, and facilities. Astronomical distance determination has clearly reached maturity and near-consistency.Comment: Review article, 59 pages (4 figures); Space Science Reviews, in press (chapter 8 of a special collection resulting from the May 2016 ISSI-BJ workshop on Astronomical Distance Determination in the Space Age

Advancing biological understanding and therapeutics discovery with small-molecule probes

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery