Stress responses in surgical trainees during simulation-based training courses in laparoscopy.

BACKGROUND: Simulation-based training courses in laparoscopy have become a fundamental part of surgical training programs. Surgical skills in laparoscopy are challenging to master, and training in these skills induces stress responses in trainees. There is limited data on trainees' stress levels, the stress responses related to training on different laparoscopic simulators, and how previous experiences influence trainees' stress response during a course. This study investigates physiologic, endocrine and self-reported stress responses during simulation-based surgical skills training in a course setting. METHODS: We conducted a prospective observational study of trainees attending basic laparoscopic skills training courses at a national training centre. During the three-day course, participants trained on different laparoscopic simulators: Two box-trainers (the D-box and P.O.P. trainer) and a virtual reality simulator (LAPMentor™). Participants' stress responses were examined through heart rate variability (HRV), saliva cortisol, and the State Trait Anxiety Inventory-6 (STAI-6). The correlation between previous laparoscopic experiences and stress response measurements was explored. RESULTS: Twenty-four surgical trainees were included in the study. Compared to resting conditions, stress measures were significantly higher during simulation-training activity (the D-box (SDNN = 58.5 ± 23.4; LF/HF-ratio = 4.58 ± 2.71; STAI-6 = 12.3 ± 3.9, P < 0.05), the P.O.P trainer (SDNN = 55.7 ± 7.4; RMSSD = 32.4 ± 17.1; STAI-6 = 12.1 ± 3.9, P < 0.05), and the LAPMentor™ (SDNN = 59.1 ± 18.5; RMSSD = 34.3 ± 19.7; LF/HF-ratio = 4.71 ± 2.64; STAI-6 = 9.9 ± 3.0, P < 0.05)). A significant difference in endocrine stress response was seen for the simulation-training activity on the D-box (saliva cortisol: 3.48 ± 1.92, P < 0.05), however, no significant differences were observed between the three simulators. A moderate correlation between surgical experience, and physiologic and endocrine stress response was observed (RMSSD: r=-0.31; SDNN: r=-0.42; SD2/SD1 ratio: r = 0.29; Saliva cortisol: r = 0.46; P < 0.05), and a negative moderate correlation to self-reported stress (r=-0.42, P < 0.05). CONCLUSION: Trainees have a significant higher stress response during simulation-training compared to resting conditions, with no difference in stress response between the simulators. Significantly higher cortisol levels were observed on the D-box, indicating that simulation tasks with time pressure stress participants the most. Trainees with more surgical experience are associated with higher physiologic stress measures, but lower self-reported stress scores, demonstrating that surgical experience influences trainees' stress response during simulation-based skills training courses.

Effect of feeding frequency on reproductive performances and stress responses in gestating sows.

The objective of this study was to investigate the influence of feeding frequency on a sow's reproductive performance and stress response during gestation. A total of twenty multiparous sows (Yorkshire × Landrace) were used in a completely randomized design based on their parity, body weight (BW), and backfat thickness (BFT), and the sows were allotted to two different feeding systems: 1) once daily feeding (OF) and 2) twice daily feeding (TF) in corn-soybean meal based diets. The gestation diet was formulated to contain 3,265 kcal of metabolizable energy (ME) / kg, 12.90% of crude protein (CP), and 0.75 % of total lysine. The lactation diet was formulated to contain 3,265 kcal of ME / kg, 16.80% of CP, and 1.08% of total lysine and provided ad libitum during lactation. In gestation, sow BFT and BF changes were not affected by feeding frequency, but higher BW and BW gain from day 35 to 90 and day 35 to 110 were observed in OF sow (p < 0.10). In lactation, feeding frequency did not influence on BW, BW gain, BFT, BF changes, average daily feed intake, and wean-to-estrus interval. Also, there were no differences in litter size, litter weight and piglet weight in lactating sows. OF sows had higher (p < 0.05; p < 0.10) protein, solid-not-fat, and total solid concentrations in colostrum compared to TF sows, while OF sows had a lower (p < 0.05) lactose concentration in colostrum compared to TF sows. Sows in OF showed significantly lower average daily water consumption (ADWC) from day 35 to 110 of gestation (p < 0.05). While there were no significant differences in stereotypic behaviors and salivary cortisol levels during gestation between treatments, the OF sows showed less time spending on the activity at day 105 (p < 0.05). In conclusion, reduced feeding frequency increased BW gain during gestation, decreased activation time, and changed the colostrum composition. This information may contribute to the understanding of the physiological and behavioral change of gestating sows by manipulating feeding frequency.

Comprehensive assessment of memory function, inhibitory control, neural activity, and cortisol levels in late pregnancy.

A considerable proportion of women subjectively perceive a detriment to their cognitive capacity during pregnancy, with decreased memory functions being the most frequently self-reported concerns. However, objective investigation of these perceived cognitive deficits has yielded inconsistent results. This study focused on memory functions during late pregnancy using multiple tasks designed to assess various memory indices, for example, working memory, learning rate, immediate recall, proactive and retroactive interference, delayed recall, retrieval efficiency, visuospatial constructional ability, recognition, and executive function. Additionally, sustained attention and inhibitory control were examined using a combined recognition stop-signal task. Electrophysiological brain activity during this task was recorded using a 128-channel electroencephalographic-event-related potential system. Salivary cortisol levels were assessed both prior to and following the experimental session. In contrast to the widely held belief, results demonstrated that women in late pregnancy did not exhibit a decline in their performance across the various memory tests. In terms of accuracy, there was not a single task in which poorer performance was found for pregnant women. The quality of memory performance was comparable, and in some cases even superior, among women in the pregnancy group. On the stop-signal task, pregnant women exhibited significantly better performance, and their electrophysiological data revealed greater centrally distributed P300 amplitude to "stop" signs, which may signify an enhanced neural efficiency in the domains of inhibitory executive control. Endocrine results revealed that pregnant women exhibited significantly lower levels of salivary cortisol, suggesting an attenuation of hypothalamic-pituitary-adrenocortical axis activity, which may contribute to the optimization of fetal development and growth.

Chronic stress, social support, and symptoms at midlife. Is there a buffering effect?

OBJECTIVES: This study was designed to examine associations among measures of stress, social support, and symptoms at midlife. Specifically, the study examined whether support buffered against the negative effects of stress on severity of symptoms grouped via factor analyses into emotional instability, vaso-somatic symptoms, mood disturbances, and aches and pains. METHODS: We used cross-sectional data from n = 119 women aged 40-55 in Nagaland, India. Midlife symptoms were measured with the help of questionnaires, and factor analysis was used to identify latent factors. Stress and social support were measured by Perceived Stress Scale and Multidimensional Scale of Perceived Social Support, respectively. Chronic stress was measured by fingernail cortisol. RESULTS: After adjusting for menopausal status, tobacco use, body mass index, and socioeconomic status, cortisol level was positively associated with emotional instability (p < 0.01), vaso-somatic symptom score (p < 0.05), and total symptoms at midlife (p < 0.05). Familial support was negatively associated with emotional instability (p < 0.05) and total symptoms at midlife (p < 0.05). However, no significant associations were observed with spousal or friend support. Although no significant interactions between stress, social support, and symptoms at midlife were observed, spousal support when stratified as high and low support using the means, perceived stress and vaso-somatic symptoms indicated an interaction. CONCLUSION: Cortisol level and support from family were independently associated with symptoms at midlife. The study highlights the importance of family ties and support for navigating the stressors of everyday life among women in Nagaland.

On the complex relationship between resilience and hair cortisol levels in adolescence despite parental physical abuse: a fourth wave of resilience research.

Introduction: To understand the family's role in adolescents' mental health development and the connection to neurodevelopmental disorders related to experienced parental physical abuse, we first explored resilience pathways longitudinally and secondly, connected the identified patterns to adolescents' hair cortisol levels that are rooted in the hypothalamic-pituitary-adrenal axis as the main stress response system and connected brain structure alterations. Methods: We analyzed longitudinal online questionnaire data for three consecutive high school years (from seventh to ninth grade) and four survey waves from a representative sample of n = 1609 high school students in Switzerland on violence-resilience pathways. Furthermore, we collected students' hair samples from a subsample of n = 229 at survey wave 4. About 30% of the participating adolescents had been physically abused by their parents. Out of the overall sample, we drew a subsample of adolescents with parental abuse experiences (survey wave 1 n = 509; survey wave 2 n = 506; survey wave 3 n = 561; survey wave 4 n = 560). Results: Despite the odds, about 20-30% of adolescents who have experienced parental physical abuse escaped the family violence cycle and can be called resilient. By applying a person-oriented analytical approach via latent class and transition analysis, we longitudinally identified and compared four distinct violence-resilience patterns. We identified violence resilience as a multidimensional latent construct, which includes hedonic and eudaimonic protective and risk indicators. Because resilience should not solely be operationalized based on the lack of psychopathology, our latent construct included both feeling good (hedonic indicators such as high levels of self-esteem and low levels of depression/anxiety and dissociation) and doing well (eudaimonic indicators such as high levels of self-determination and self-efficacy as well as low levels of aggression toward peers). Discussion: The present study confirmed that higher cortisol levels significantly relate to the comorbid pattern (internalizing and externalizing symptoms), and further confirmed the presence of lasting alterations in brain structures. In this way, we corroborated the insight that when studying the resilience pathways and trajectories of abused adolescents, biological markers such as hair cortisol significantly enhance and deepen the understanding of the longitudinal mechanisms of psychological markers (e.g., self-determination, self-esteem, self-efficacy) that are commonly applied in questionnaires.

The Importance of PET Imaging to Understanding Whole-Body Cortisol Metabolism in Alzheimer's Disease.

Excess cortisol is associated with more severe cognitive decline, Alzheimer's disease, and related dementia phenotypes. The intracellular enzyme 11ß-HSD1 regenerates active cortisol from inactive cortisone. In this current issue, high regional brain occupancy of Xanamemtrademark, determined by [11C]TARACT PET imaging of 11ß-HSD1, in cognitively normal individuals and mild cognitive impartment/Alzheimer's disease (AD) patients is presented. In the future, comprehensive kinetic modeling using arterial sampling for occupancy studies, and whole-body PET imaging of 11ß-HSD1 enzyme levels, in combination with stable isotope studies of cortisol metabolism, can provide broad insight into enzyme levels and activity in AD and other relevant diseases.

Social niche shapes social behavior and cortisol concentrations during adolescence in female guinea pigs.

Individualized social niches arise in social groups, resulting in divergent social behavior profiles among group members. During sensitive life phases, the individualized social niche can profoundly impact the development of social behavior and associated phenotypes such as hormone (e.g. cortisol) concentrations. Focusing on adolescence, we investigated the relationship between the individualized social niche, social behavior, and cortisol concentrations (baseline and responsiveness) in female guinea pigs. Females were pair-housed in early adolescence (initial social pair formation), and a social niche transition was induced after six weeks by replacing the partner with either a larger or smaller female. Regarding social behavior, dominance status was associated with aggression in both the initial social pairs and after the social niche transition, and the results suggest that aggression was rapidly and completely reshaped after the social niche transition. Meanwhile, submissive behavior was rapidly reshaped after the social niche transition, but this was incomplete. The dominance status attained in the initial social pair affected the extent of submissive behavior after the social niche transition, and this effect was still detected three weeks after the social niche transition. Regarding cortisol concentrations, higher baseline cortisol concentrations were measured in dominant females in the initial social pairs. After the social niche transition, cortisol responsiveness significantly increased for the females paired with a larger, older female relative to those paired with a smaller, younger female. These findings demonstrate that the social niche during adolescence plays a significant role in shaping behavior and hormone concentrations in females.

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients.

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

Higher paracetamol levels are associated with elevated glucocorticoid concentrations in hair: findings from a large cohort of young adults.

Paracetamol is one of the most commonly used over-the-counter medications. Experimental studies suggest a possible stress-suppressing effect of paracetamol in humans facing experimental stress-inducing paradigms. However, no study has investigated whether paracetamol and steroid hormones covary over longer time frames and under real-life conditions. This study addresses this gap by investigating associations between steroid hormones (cortisol, cortisone, and testosterone) and paracetamol concentrations measured in human hair, indexing a timeframe of approximately three months. The data came from a large community sample of young adults (N = 1002). Hair data were assayed using liquid chromatography-tandem mass spectrometry. Multiple regression models tested associations between paracetamol and  steroid hormones, while adjusting for a wide range of potential confounders, such as sex, stressful live events, psychoactive substance use, hair colour, and body mass index. Almost one in four young adults from the community had detectable paracetamol in their hair (23%). Higher paracetamol hair concentrations were robustly associated with more cortisol (ß = 0.13, ηp = 0.016, p < 0.001) and cortisone (ß = 0.16, ηp = 0.025, p < 0.001) in hair. Paracetamol and testosterone hair concentrations were not associated. Paracetamol use intensity positively correlated with corticosteroid functioning across several months. However, a potential corticosteroid-inducing effect of chronic paracetamol use has yet to be tested in future experimental designs.

Oxidative Stress Induced by Cortisol in Human Platelets.

Hypercortisolism is known to affect platelet function. However, few studies have approached the effect of exogenous cortisol on human platelets, and the results obtained are conflicting and unconvincing. In this study, the effect of exogenous cortisol on several parameters indicative of oxidative status in human platelets has been analysed. We have found that cortisol stimulates ROS production, superoxide anion formation, and lipid peroxidation, with these parameters being in strict correlation. In addition, cortisol decreases GSH and membrane SH-group content, evidencing that the hormone potentiates oxidative stress, depleting platelet antioxidant defence. The involvement of src, syk, PI3K, and AKT enzymes in oxidative mechanisms induced by cortisol is shown. The main sources of ROS in cells can include uncontrolled increase of NADPH oxidase activity and uncoupled aerobic respiration during oxidative phosphorylation. Both mechanisms seem to be involved in ROS formation induced by cortisol, as the NADPH oxidase 1 inhibitor 2(trifluoromethyl)phenothiazine, and rotenone and antimycin A, complex I and III inhibitor, respectively, significantly reduce oxidative stress. On the contrary, the NADPH oxidase inhibitor gp91ds-tat, malate and NaCN, complex II and IV inhibitor, respectively, have a minor effect. It is likely that, in human platelets, oxidative stress induced by cortisol can be associated with venous and arterial thrombosis, greatly contributing to cardiovascular diseases.

Variations in thyroid hormone levels in endangered St. Lawrence Estuary belugas: Potential linkage with stress and organohalogen contaminant exposure.

The St. Lawrence Estuary (SLE) beluga (Delphinapterus leucas) population is highly exposed to an array of contaminants that were identified as one of the causes to the non-recovery of this endangered and declining population. In the last decade, an increasing number of parturition-associated complications and calf mortality has been reported in this population. It was suggested that elevated exposure to organohalogens (e.g., the halogenated flame retardants polybrominated diphenyl ethers [PBDEs]) and stress could play a role in this phenomenon by perturbing thyroid hormones. The objective of this study was to investigate the impact of concentrations of organohalogen contaminants and stress (cortisol levels) on thyroid hormone variations in adult male and female SLE belugas. Because plasma could not be collected in SLE belugas for ethical reasons, skin biopsy (n = 40) was used as a less-invasive alternative matrix to determine organohalogens (PBDEs and other halogenated flame retardants, polychlorinated biphenyls, and organochlorine pesticides), cortisol, and thyroid hormones (triiodothyronine [T3] and thyroxine [T4]), and their metabolites reverse T3 and 3,5-diiodothyronine [3,5-T2]). Cortisol and thyroid hormones were analyzed by ultra-performance liquid chromatography-multiple reactions monitoring mass spectrometry (UPLC-MRM/MS). This method was compared using skin and plasma samples obtained from Arctic belugas. Comparisons of linear models showed that cortisol was a weak predictor for T4, rT3 and 3,5-T2. Specifically, there was a weak significant negative association between T4 and cortisol levels. Moreover, in male SLE belugas, a weak significant positive association was found between T3 and Σ34PBDE concentrations in skin. Our findings suggest that stress (i.e., elevated skin cortisol levels) along with organohalogen exposure (mainly PBDEs) may be associated with thyroid hormone level perturbations in skin of cetaceans.

High-risk pregnancy and its relationship with the neurodevelopment and behavior of 2-year-old children.

High-risk pregnancies elevate maternal stress, impacting offspring neurodevelopment and behavior. This study, involving 112 participants, aimed to compare perceived stress, neurodevelopment, and behavior in high-risk and low-risk pregnancies. Two groups, high-risk and low-risk, were assessed during pregnancy for stress using hair cortisol and psychological analysis. At 24 months post-birth, their children's neurodevelopment and behavior were evaluated. Results revealed higher perceived stress and pregnancy-related concerns in high-risk pregnancies, contrasting with low-risk pregnancies. Offspring from high-risk pregnancies displayed elevated internalizing behavior scores, while low-risk pregnancies showed higher externalizing behavior scores. Additionally, women in low-risk pregnancies exhibited increased cortisol concentrations 24 months post-delivery. These findings underscore the necessity for early stress detection and prevention programs during pregnancy, particularly in high-risk cases, to enhance maternal and infant health.

Ultrasensitive cortisol electrochemical immunosensor amplifying by Au single-atom nanozymes and HRP enzymes.

Cortisol, a corticosteroid hormone as a primary stress hormone response to internal and external stress, has been regarded as a gold standard reliable biomarker to evaluate human mental stress. The double enzymes strategy, using nanozyme and enzyme amplifying the electrochemical signal, has been widely used to improve the performance of electrochemical biosensors. An ultra-sensitive electrochemical cortisol sensor based on Au single-atom nanozymes had been fabricated through HRP labeled anti-cortisol antibody binding with Au by Au-S bond. Based on the high catalytic activity of Au single-atom nanozymes and the high selectivity of HRP-labeled anti-cortisol antibodies, the cortisol electrochemical sensor-based Au single-atom nanozymes had an excellent response to cortisol, such as high electrochemical activity, high sensitivity, high selectivity, and wide linear range (0.15-300 ng mL-1) and low detection (0.48 pg mL-1) through the four-parameter logistic model with 95% confidence. The electrochemical cortisol sensor was used to determine the cortisol concentration of human saliva at different times.

Placental Cortisol Dysregulation in Mothers with Experiences of Childhood Adversity: Potential Mechanisms and Clinical Implications.

Adverse childhood experiences (ACEs) are extremely prevalent in the United States population. Although ACEs occurs in childhood, exposure to them has been associated with adverse future pregnancy outcomes and an increased risk of poorer social determinants of health, which further drive the risk of negative pregnancy outcomes. In addition, maternal ACE exposure has been linked to poor infant and child outcomes, highlighting the intergenerational transmission of risk from mother to child. While alterations along the Maternal-Placental-Fetal Hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to be involved, the exact biological pathway underlying this intergenerational passage of risk is mostly unknown. This present work will highlight what is known about pregnancy-related stress hormone physiology, discuss the potential mechanisms of action of ACEs on cortisol regulation, and suggest opportunities for further clinical and translational studies.

Alterations of Whole-Body Glucose Metabolism in a Feline SARS-CoV-2 Infection Model.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been especially devastating to patients with comorbidities, including metabolic and cardiovascular diseases. Elevated blood glucose during SARS-CoV-2 infection increased mortality of COVID-19 patients, although the mechanisms are not well understood. It has been previously demonstrated that glucose transport and utilization is a crucial pathway for other highly infectious RNA viruses. Thus, we hypothesized that SARS-CoV-2 infection could lead to alterations in cellular and whole-body glucose metabolism. Specific pathogen free domestic cats were intratracheally inoculated with USA-WA1/2020 (Wild-type) SARS-CoV-2 or vehicle-inoculated, then sacrificed at 4- and 8-days post-inoculation (dpi). Blood glucose and cortisol concentrations were elevated at 4 and 8 dpi. Blood ketones, insulin, and angiotensin 2 concentrations remained unchanged throughout the experimental timeline. SARS-CoV-2 RNA was detected in the lung and heart, without changes in angiotensin converting enzyme 2 (ACE2) RNA expression. In the lung, SARS-CoV-2 infection increased glucose transporter 1 (GLUT1) protein level at 4 and 8 dpi., while GLUT4 level was only upregulated at 8 dpi. In the heart, GLUT-1 and -4 protein levels remained unchanged. Furthermore, GLUT1 level was upregulated in the skeletal muscle at 8 dpi, and AMPK was activated in the heart of infected cats. SARS-CoV-2 infection increased blood glucose concentration and pulmonary GLUT protein levels. These findings suggest that SARS-CoV-2 infection induces metabolic reprogramming primarily in the lung to support viral replication. Furthermore, this translational feline model mimicked human COVID-19 and could be used to explore novel therapeutic targets to treat metabolic disease during SARS-CoV-2 infection.

Wearable Sensing Device Integrated with Prestored Reagents for Cortisol Detection in Sweat.

Wearable sweat sensors have achieved rapid development since they hold great potential in personalized health monitoring. However, a typical difficulty in practical processes is the control of working conditions for biorecognition elements, e.g., pH level and ionic strength in sweat may decrease the affinity between analytes and recognition elements. Here, we developed a wearable sensing device for cortisol detection in sweat using an aptamer as the recognition element. The device integrated functions of sweat collection, reagent prestorage, and signal conversion. Especially, the components of prestored reagents were optimized according to the inherent characteristics of sweat samples and electrodes, which allowed us to keep optimal conditions for aptamers. The sweat samples were transferred from the inlet of the device to the reagent prestored chamber, and the dry preserved reagents were rehydrated with sweat and then arrived at the aptamer-modified electrodes. Sweat samples of volunteers were analyzed by the wearable sensing device, and the results showed a good correlation with those of the ELISA kit. We believe that this convenient and reliable wearable sensing device has significant potential in self-health monitoring.

Refugee health and physiological profiles in transitional settlements in Serbia and Kenya: Comparative evidence for effects of gender and social support.

When armed conflict compels people to flee from their homelands, they embark on protracted journeys during which they experience wide ranging physical, social, and psychological challenges. Few studies have focused on refugee psychosocial and physiological profiles during the transitional phase of forced migration that often involves temporary sheltering. Transient refugees' experiences can vary substantially based on local socio-ecological conditions in temporary settlements, including the length of stay, living conditions, as well as the availability and accessibility of physical and social resources. In this study, we compared physiological and psychosocial data from refugees (N=365; 406 observations) in Serbia and Kenya, respectively, with divergent temporal (length of stay) and socio-ecological conditions. In Serbia, refugees resided in asylum centers (mean stay: 0.9 y); in Kenya they were living in Kakuma Refugee Camp (mean stay: 8.8 y), one of the world's largest camps at the time. We had limited ability to directly compare psychosocial measures and used meta-analytic techniques to evaluate predictors of refugee mental and physical health at the two sites, including based on perceived social support. Refugees in Serbia had higher fingernail cortisol (p < 0.001) and were less likely to have elevated C-reactive protein (CRP) levels (p < 0.01) than refugees in Kakuma. We found common gender differences in both settings; women had lower cortisol but higher EBV antibody titers and higher likelihood of having elevated CRP compared to men (all p < 0.01). Woman also reported poorer mental and physical health (p < 0.001). These physiological and health differences may reflect variation between men and women in their psychosocial and physical experiences of factors such as stress, violence, and trauma during their journeys and as transitional refugees. Finally, we also found that refugees with lower levels of perceived social support reported poorer physical and mental health (p < 0.001). Although our results are cross-sectional, they suggest that this intermittent phase of the refugee experience is a key window for helping enhance refugee well-being through an emphasis on interpersonal and community support systems.

Steroids-producing nodules: a two-layered adrenocortical nodular structure as a precursor lesion of cortisol-producing adenoma.

BACKGROUND: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. METHODS: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. FINDINGS: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. INTERPRETATION: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. FUNDING: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.

Age-related increase in the expression of 11ß-hydroxysteroid dehydrogenase type 1 in the hippocampus of male rhesus macaques.

Introduction: The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11ß-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly. Methods: Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of (HSD11B1/HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory. Results: Older animals showed significantly (p < 0.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly (p < 0.05) higher hippocampal expression of HSD11B1 but not NR3C1 and NR3C2 (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant (p < 0.05) increase in the expression of the HSD11B1 was revealed at the protein level by western blot analysis. Discussion: The data suggest that an age-related increase in the expression of hippocampal HSD11B1 is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection.

Stress during pregnancy and fetal serum BDNF in cord blood at birth.

INTRODUCTION: Adverse environments during pregnancy impact neurodevelopment including cognitive abilities of the developing children. The mediating biological alterations are not fully understood. Maternal stress may impact the neurotrophic regulation of the offspring as early as in utero and at birth. Brain-derived neurotrophic factor (BDNF) is essential for neurodevelopment. Short-term higher levels of BDNF in mice upon stressors associate with lower BDNF later in life, which itself associates with depression in animals and humans. Stress including glucocorticoids may impact BDNF, but there is a lack of data at birth. This study investigated if stress near term associates with fetal BDNF at birth in humans. METHODS: Pregnant women near term who underwent primary cesarean sections (at 38.80±0.64 weeks), were included in this study (n=41). Stress at the end of pregnancy was assessed before the cesarean section by determining maternal depressive symptoms (EDPS), maternal state and trait anxiety (STAI-S and STAI-T), maternal prenatal distress (PDQ), stress over the past month (PSS), prenatal attachment to the offspring (PAI), maternal social support (F-Sozu), maternal early life stress (CTQ), socioeconomic status, and the glucocorticoids cortisol and cortisone (n=40) in amniotic fluid at birth. The association with fetal BDNF was analyzed. Cord blood serum of n=34 newborns at birth was analyzed for BDNF and newborn anthropometrics (weight, length and head circumference per gestational age at birth) were assessed. The association of fetal BDNF with anthropometrics at birth was analyzed. RESULTS: After a BDNF-outlier (>3 SD) was removed, higher fetal BDNF associated significantly with maternal depressive symptoms (r=0.398, p=0.022), with lower socioeconomic status as assessed by the average number of people per room in the household (r=0.526, p=0.002) and with borderline significance with net income per person in the household (r=-0.313, p=0.087) in the bivariate analyses. In multivariable analysis, BDNF stayed positively associated with maternal depressive symptoms (ß=0.404, 95% CI [7.057, 306.041], p=0.041) and lower net income per person in the household (ß=-0.562, 95% CI [-914.511, -60.523], p=0.027) when controlling for maternal age, maternal pre-pregnancy BMI, fetal sex and gestational age. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed in bivariate analyses or in multivariable analyses when controlling for maternal BMI and fetal sex. CONCLUSION: Maternal depressive symptoms and lower socioeconomic status associated with higher fetal BDNF when controlling for confounders. Fetal BDNF did not associate with newborn anthropometrics with the outlier removed. Further studies should investigate how early altered BDNF associate with the development and possibly psychopathology of the offspring.