Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation

Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/ inhibition causes hypertension, whereas deficiency/ inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/ inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis

Interstitial cortisol levels obtained by adipose tissue microdialysis in mechanically ventilated septic patients: correlations with total and free serum cortisol

Introduction: The aim of this study was to measure cortisol in the interstitial fluid of mechanically ventilated septic patients using MD and to examine the correlation between interstitial cortisol levels and total along with free serum cortisol. Methods: A prospective study including 31(20 men) septic patients. All patients met the ACCP/SCCM criteria for sepsis. Upon sepsis an MD catheter was inserted in the subcutaneous tissue of the upper thigh. MD sampling was done on days 1 and 2, six times/day. The collected samples were analyzed for free cortisol, glucose, pyruvate, lactate, glycerol and lactate/pyruvate ratio. Blood samples were collected for routine hematology and biochemistry on the same days. Age, gender, sepsis stage, administration of vasopressors, death in the ICU and 28-day mortality were recorded. APACHE II scores for day 1 and SOFA scores for days 1 and 2 were calculated. Results: Seventeen patients were given norepinephrine. Albumin on day 1 was uniformly low. One-third of patients died. Cortisol values in the interstitial fluid remained constant (P = 0.480). Serum total cortisol (P = 0.116) and serum total cortisol/albumin ratio (P = 0.127) were also constant. On day 2 serum-free cortisol was higher than MD-free cortisol. Log MD cortisol correlated strongly with the log serum total cortisol and serum-free cortisol on day 2 correlated well with serum total cortisol. Day 1 log MD cortisol correlated positively with log MD pyruvate and log APACHE II. Day 2 log MD cortisol correlated positively with norepinephrine dose and log SOFA score. There were no other significant correlations of MD cortisol. Conclusions: Adipose tissue cortisol is strongly correlated with serum total and free cortisol, suggesting that serum cortisol reflects tissue cortisol availability. The utility of MD in studying cortisol dynamics needs to be further investigated

Evidence for an emotional adaptive function of dreams: A cross-cultural study

The function of dreams is a longstanding scientific research question. Simulation theories of dream function, which are based on the premise that dreams represent evolutionary past selective pressures and fitness improvement through modified states of consciousness, have yet to be tested in cross-cultural populations that include small-scale forager societies. Here, we analyze dream content with cross-cultural comparisons between the BaYaka (Rep. of Congo) and Hadza (Tanzania) foraging groups and Global North populations, to test the hypothesis that dreams in forager groups serve a more effective emotion regulation function due to their strong social norms and high interpersonal support. Using a linear mixed effects model we analyzed 896 dreams from 234 individuals across these populations, recorded using dream diaries. Dream texts were processed into four psychosocial constructs using the Linguistic Inquiry and Word Count (LIWC-22) dictionary. The BaYaka displayed greater community-oriented dream content. Both the BaYaka and Hadza exhibited heightened threat dream content, while, at the same time, the Hadza demonstrated low negative emotions in their dreams. The Global North Nightmare Disorder group had increased negative emotion content, and the Canadian student sample during the COVID-19 pandemic displayed the highest anxiety dream content. In conclusion, this study supports the notion that dreams in non-clinical populations can effectively regulate emotions by linking potential threats with non-fearful contexts, reducing anxiety and negative emotions through emotional release or catharsis. Overall, this work contributes to our understanding of the evolutionary significance of this altered state of consciousness. © 2023. Springer Nature Limited

The interrelated effect of sleep and learning in dogs (Canis familiaris); an EEG and behavioural study

The active role of sleep in memory consolidation is still debated, and due to a large between-species variation, the investigation of a wide range of different animal species (besides humans and laboratory rodents) is necessary. The present study applied a fully non-invasive methodology to study sleep and memory in domestic dogs, a species proven to be a good model of human awake behaviours. Polysomnography recordings performed following a command learning task provide evidence that learning has an effect on dogs’ sleep EEG spectrum. Furthermore, spectral features of the EEG were related to post-sleep performance improvement. Testing an additional group of dogs in the command learning task revealed that sleep or awake activity during the retention interval has both short- and long-term effects. This is the first evidence to show that dogs’ human-analogue social learning skills might be related to sleep-dependent memory consolidation

Simultaneous measurement of endogenous cortisol, cortisone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate in nails by use of UPLC-MS-MS

Steroid hormone concentrations are mostly determined by using different body fluids as matrices and applying immunoassay techniques. However, usability of these approaches may be restricted for several reasons, including ethical barriers to invasive sampling. Therefore, we developed an ultra-performance LC-MS-MS method for high-throughput determination of concentrations of cortisol, cortisone, dehydroepiandrosterone (DHEA), and DHEA sulfate (DHEAS) in small quantities of human nails. The method was validated for linearity, limits of detection and quantification, recovery, intra and interassay precision, accuracy, and matrix effect. Samples from 10 adult women were analyzed to provide proof-of-principle for the method's applicability. Calibration curves were linear (r (2)?14% for all analytes) and accuracy (relative error (%) -8.3% to 12.2% for all analytes). The median (pg mg(-1), range) hormone concentrations were 69.5 (36-158), 65 (32-133), 212 (50-1077), and 246 (115-547) for cortisol, cortisone, DHEA, and DHEAS, respectively. This method enables measurement of cortisol, cortisone, DHEA, and DHEAS in small quantities of human nails, leading to the development of applications in endocrinology and beyond

Serum regulates cortisol bioactivity by corticosteroid-binding globulin-dependent and independent mechanisms, as revealed by combined bioassay and physicochemical assay approaches

Context Corticosteroid-binding globulin (CBG) is the principal carrier of natural glucocorticoids in the circulation, and we hypothesized that it modulates glucocorticoid bioactivity (GBA). Alterations in CBG, the presence of noncortisol, naturally occurring glucocorticoids and the use of potent, synthetic glucocorticoids, all make it difficult to assess adrenal activity in-vivo; these problems can be addressed by a glucocorticoid bioassay. Design and subjects A bioassay was developed for serum GBA and a physicochemical ultrafiltration-liquid chromatography-tandem mass spectrometry assay for free serum cortisol (FreeF). We studied individuals homozygous and heterozygous for a nonfunctioning CBG variant (CBG G237V) and healthy controls. Results FreeF concentrations were similar in healthy controls, and those with absent functional CBG, but surprisingly we found low GBA in CBG null individuals. This may suggest that CBG delivers cortisol to target cells. However, further experiments revealed that dilution of serum in the bioassay caused release of cortisol from CBG, resulting in elevated GBA measurements in all but the CBG G237V homozygotes. Furthermore, we identified a specific and potent inhibitory effect of high concentration serum on glucocorticoid sensitivity of the recipient cells used in the bioassay. Analysis of inflammatory synovial fluid, a filtrate of serum with lower CBG concentration, revealed elevated free cortisol compared to noninflammatory synovial fluid, a change not attributable to interconversion between cortisol and cortisone. Conclusions Our findings reveal that dilution of CBG enhances cortisol release, and so bioactivity, and also that serum potently induces glucocorticoid resistance in target cells. © 2011 Blackwell Publishing Ltd