Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study

Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible. Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study). Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk

Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion

Context Adrenal incidentalomas (AIs) are found commonly on axial imaging. Around 30% exhibit autonomous cortisol secretion (ACS) associated with increased cardiovascular events and death. Objective We hypothesized that AI/ACS patients have an abnormal cortisol rhythm that could be reversed by use of carefully timed short-acting cortisol synthesis blockade, with improvement in cardiovascular disease markers. Design, Setting, and Participants In a phase 1/2a, prospective study (Eudract no. 2012-002586-35), we recruited six patients with AI/ACS and two control groups of six sex-, age-, and body mass index–matched individuals: (1) patients with AI and no ACS (AI/NoACS) and (2) healthy volunteers with no AI [healthy controls (HC)]. Twenty-four-hour circadian cortisol analysis was performed to determine any differences between groups and timing of intervention for cortisol lowering using the 11β-hydroxylase inhibitor metyrapone. Circadian profiles of serum interleukin-6 (IL-6) were assessed. Results Serum cortisol levels in group AI/ACS were significantly higher than both group AI/NoACS and group HC from 6 PM to 10 PM [area under the curve (AUC) difference: 0.81 nmol/L/h; P = 0.01] and from 10 PM to 2 AM (AUC difference: 0.86 nmol/L/h; P < 0.001). In light of these findings, patients with ACS received metyrapone 500 mg at 6 PM and 250 mg at 10 PM, and cortisol rhythms were reassessed. Postintervention evening serum cortisol was lowered, similar to controls [6 PM to 10 PM (AUC difference: –0.06 nmol/L/h; P = 0.85); 10 PM to 2 AM (AUC difference: 0.10 nmol/L/h; P = 0.76)]. Salivary cortisone showed analogous changes. IL-6 levels were elevated before treatment [10 PM to 2 PM (AUC difference: 0.42 pg/mL/h; P = 0.01)] and normalized post treatment. Conclusions In AI/ACS, the evening and nocturnal cortisol exposure is increased. Use of timed evening doses of metyrapone resets the cortisol rhythm to normal. This unique treatment paradigm is associated with a reduction in the cardiovascular risk marker IL-6

The turn of the valve: representing with material models

Many scientific models are representations. Building on Goodman and Elgin’s notion of representation-as we analyse what this claim involves by providing a general definition of what makes something a scientific model, and formulating a novel account of how they represent. We call the result the DEKI account of representation, which offers a complex kind of representation involving an interplay of, denotation, exemplification, keying up of properties, and imputation. Throughout we focus on material models, and we illustrate our claims with the Phillips-Newlyn machine. In the conclusion we suggest that, mutatis mutandis, the DEKI account can be carried over to other kinds of models, notably fictional and mathematical models

Captivating behaviour: mouse models, experimental genetics and reductionist returns in the neurosciences

This a post-print, author-produced version of an article accepted for publication in The Sociological Review. Copyright © 2010 Wiley Blackwell. The definitive version is available at www3.interscience.wiley.comNo Abstract availabl

Making science at home: visual displays of space science and nuclear physics at the Science Museum and on television in postwar Britain

The public presentation of science and technology in postwar Britain remains a field open to exploration. Current scholarship on the topic is growing but still tends to concentrate on the written word, thus making theorizing, at this stage, difficult. This paper is an attempt to expand the literature through two case studies that compare and synthesize displays of scientific and technological knowledge in two visual media, the Science Museum and television, in the 1950s and 1960s. The topics of these case studies are space exploration and nuclear energy. The thesis this paper explores is that both media fleshed out strategies of displays based on the use of categories from everyday life. As a result, outcomes of large-scale public scientific and technological undertakings were interwoven within audiences’ daily life experiences, thus appearing ordinary rather than extraordinary. This use of symbols and values drawn from private life worked to alleviate fears of risk associated with these new fields of technological exploration and at the same time give them widespread currency in the public sphere

Organisms in experimental research

Rachel A. Ankeny and Sabina Leonell