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

Referees’ Decision Making Behavior and the Sport Home Advantage Phenomenon

The aim of this investigation was to examine the decision making behavior of soccer officials (referees) in English Premiership matches to establish whether a bias, as perceived by the media and professional players, does or does not exist. Using notational analysis, this investigation used three trained professional soccer referees to assess the decisions made by match-day officials in favor of home and away teams during the entirety of ten-matched Premiership soccer fixtures. Results revealed a non-significant trend, x2 = .843, p > .05, where the number of decisions awarded by the referees favored the home team. However, significant differences were observed in the number of contentious and incorrect / missed decisions awarded in favor of the home teams compared to away teams, χ2 = 4.17, p < .05 and χ2 = 3.86, p < .05, respectively. Conclusions from this investigation indicate that soccer referees exhibit bias in favor of home teams and suggest that referee decision making behavior may be one mechanistic explanation of the home advantage phenomenon in soccer

Terahertz thermometry: combining hyperspectral imaging and temperature mapping at terahertz frequencies

The accurate and non-invasive determination of multiple physical parameters, with well-defined spatial resolution, is crucial for applications in manufacturing, chemistry, medicine and biology. Specifically, the ability to simultaneously measure both temperature and spectral signatures is still experimentally unavailable. To this end, we propose a mapping technique for biological systems, which exploits a linear correlation between terahertz wave reflectivity and temperature, and allows to spatially and spectrally resolve thermal distributions. This method is applied to a model biological system in two relevant cases where in one example, nanoplasmonic-induced photothermal effects are imaged gaining new insights into collective heating phenomena. In the second example, we demonstrate a joint thermal-hyperspectral imaging approach to chemically map the presence of a model drug formulation and simultaneously investigate its thermal stability in our biological system. This concept can be easily extended and widely applied to all materials that demonstrate a measurable change in their dielectric properties

Salivary cortisone to estimate cortisol exposure and sampling frequency required based on serum cortisol measurements

Context: Population studies frequently measure cortisol as a marker of stress and excess cortisol is associated with increased mortality. Cortisol has a circadian rhythm and frequent blood sampling is impractical to assess exposure. We investigated measuring salivary cortisone and examined sampling frequency required to determine cortisol exposure. Methods: Serum and saliva with cortisol and cortisone measured by LC-MS/MS in independent cohorts. The relationship between serum cortisol and salivary cortisone was analysed in cohort 1 using a linear mixed effects model and resulting fixed effects component was applied to cohort 2. Saliva cannot easily be collected when sleeping so we determined minimum sampling required to estimate cortisol exposure (eAUC) using 24-hour cortisol profiles (AUC24) and calculated the relative error (RE - a measure similar to the coefficient of variation) for the eAUC. Results: >90% of variability in salivary cortisone could be accounted for by change in serum cortisol. A single serum cortisol measurement was a poor estimate of AUC24 especially in the morning or last thing at night (RE > 68%), however 3 equally spaced samples gave a median RE of 0% (Interquartile range (IQR) between -15.6% and 15.1%). In patients with adrenal incidentalomas the eAUC based on 3 serum cortisol samples showed a difference between those with autonomous cortisol secretion and those without (p=0.03). Interpretation: Accepting that most people sleep 7-8 hours, using approximately 8-hourly salivary cortisone measurements provides a non-invasive method of estimating 24-hour cortisol exposure for population studies

The geometric evolution of aortic dissections: Predicting surgical success using fluctuations in integrated Gaussian curvature

Clinical imaging modalities are a mainstay of modern disease management, but the full utilization of imaging-based data remains elusive. Aortic disease is defined by anatomic scalars quantifying aortic size, even though aortic disease progression initiates complex shape changes. We present an imaging-based geometric descriptor, inspired by fundamental ideas from topology and soft-matter physics that captures dynamic shape evolution. The aorta is reduced to a two-dimensional mathematical surface in space whose geometry is fully characterized by the local principal curvatures. Disease causes deviation from the smooth bent cylindrical shape of normal aortas, leading to a family of highly heterogeneous surfaces of varying shapes and sizes. To deconvolute changes in shape from size, the shape is characterized using integrated Gaussian curvature or total curvature. The fluctuation in total curvature (δK) across aortic surfaces captures heterogeneous morphologic evolution by characterizing local shape changes. We discover that aortic morphology evolves with a power-law defined behavior with rapidly increasing δK forming the hallmark of aortic disease. Divergent δK is seen for highly diseased aortas indicative of impending topologic catastrophe or aortic rupture. We also show that aortic size (surface area or enclosed aortic volume) scales as a generalized cylinder for all shapes. Classification accuracy for predicting aortic disease state (normal, diseased with successful surgery, and diseased with failed surgical outcomes) is 92.8±1.7%. The analysis of δK can be applied on any three-dimensional geometric structure and thus may be extended to other clinical problems of characterizing disease through captured anatomic changes

Modified-release hydrocortisone to provide circadian cortisol profiles

Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. Setting: The study was performed at a Clinical Research Facility. Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009