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Salmonids are a species of high commercial value in Chilean aquaculture, where muscle is the final product of the industry. Fish can be affected by stress during intensive cultures, increasing susceptibility to infections. Recently, we reported that muscle is an important focus of immune reactions. However, studies have shown the immunosuppressive effect of stress only in lymphoid organs, and few studies have been conducted on muscle and immunity. Hence, we determine the effects of cortisol on the immune-like response of fish myotubes challenged with Piscirickettsia salmonis by three trials. First, rainbow trout primary culture of muscle was cultured and treated with cortisol (100 ng/mL) for 3 and 4 h. Second, myotubes were challenged with P. salmonis (MOI 50) for 4, 6 and 8 h. And third, muscle cell cultures were pretreated with cortisol and then challenged with P. salmonis. The mRNA levels of glucocorticoid pathway and innate immunity were evaluated by qPCR. Cortisol increased the klf15 levels and downregulated the innate immune-related tlr5m gene and antimicrobial peptides. P. salmonis challenge upregulated several immune-related genes. Finally, cortisol pretreatment followed by P. salmonis challenge differentially modulated stress- and immune-related genes. These data suggest that fish muscle cells possess an intrinsic immune response and are differentially regulated by cortisol, which could lead to bacterial outbreaks in muscle under stress conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The new coronavirus (SARS-CoV-2) appearance in Wuhan, China, did rise the new virus disease (COVID-19), which spread globally in a short time, leading the World Health Organization to declare a new global pandemic. To contain and mitigate the spread of SARS-CoV-2, specific public health procedures were implemented in virtually all countries, with a significant impact on society, making it difficult to keep the regular practice of physical activity. It is widely accepted that an active lifestyle contributes to the improvement of general health and preservation of cardiovascular, respiratory, osteo-muscular and immune system capacities. The positive effects of regular physical activity on the immune system have emerged as a pivotal trigger of general health, underlying the beneficial effects of physical activity on multiple physiological systems. Accordingly, recent studies have already pointed out the negative impact of physical inactivity caused by the social isolation imposed by the public sanitary authorities due to COVID-19. Nevertheless, there are still no current narrative reviews evaluating the real impact of COVID-19 on active lifestyle or even discussing the possible beneficial effects of exercise-promoted immune upgrade against the severity or progression of COVID-19. Based on the consensus in the scientific literature, in this review, we discuss how an exercise adherence could adequately improve immune responses in times of the 'COVID-19 Era and beyond'., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

In salmonids, stress responses increase cortisol levels and disease susceptibility, including to Flavobacterium psychrophilum (Fp), the causative agent of BCWD. A BCWD-resistant line (R-line) of rainbow trout was used here to investigate potential differences in immunoglobulin response after a combined treatment of cortisol and Fp, as compared to a susceptible (S-line) control line. Expression of membrane and secreted immunoglobulin heavy chains mu and tau were determined by RT-qPCR in spleen and anterior kidney. Cortisol treatment did not affect B cell development in the anterior kidney, but delayed IgM responses at the early stage of infection in the spleen of both lines. An earlier IgM response was a determining factor in differential disease progression between resistant- and susceptible fish after Fp-challenge. S-line fish had a delayed and exacerbated IgM response after cortisol implant indicative of a detrimental cycle of sustained IgM responses and high pathogen loads. In contrast, R-line fish had delayed but milder, and protective IgM responses and cleared pathogen successfully. Fp challenge after cortisol implant increased serum cortisol levels on days 3 and 5 compared to mock treatments in S-line fish, but only on day 3 in R-line. Hence, combined cortisol treatment and Fp challenge differentially modulated B cell activation and Fp loads in BCWD-resistant and susceptible lines of rainbow trout. We propose that under conditions of increased stress, BCWD-resistant fish may remain immunologically better equipped to respond to infections compared to BCWD susceptible fish., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Altered hypothalamic-pituitary-adrenal (HPA) function and related changes in circulating glucocorticoids have been implicated in the pathogenesis of numerous diseases that involve dysregulated immune function. Glucocorticoid hormones have both direct and indirect modulatory effects on both pro- and anti-inflammatory aspects of the immune system, including granulocytic and lymphocytic leukocyte subsets. However, past findings are complicated by inconsistencies across studies in how glucocorticoids and immune markers interact and relate to disease risk. Some incongruencies are likely due to an overreliance on single-unit (e.g., HPA or one immune marker) measures, and a failure to consider ecological exposures that may shape the base levels or correspondence between these systems. Here, we test single-unit and diurnal measures of HPA axis and immune system interactions in a less-industrial ecological setting with relatively high parasite loads., Methods: In a sample of 114 Honduran women (mean age = 36 years), morning and evening blood samples were analyzed to quantify granulocytes, lymphocytes, and immunoglobulin-E (IgE). Saliva was collected over 2 days (8 samples per woman) to measure peak cortisol, cumulative cortisol, and slope of decline. These repeated measures of saliva and venous blood were used to investigate associations between single-point and diurnal salivary cortisol and leukocytes, under variable levels of past parasite exposure (proxied by IgE)., Results: Individuals with less of a decline in cortisol (i.e., "flatter" decline) show less of an increase in lymphocytes (2.27% increase in cells/μL/hr; 95% CI: 0.91-7.29; p = .01) across the day compared to those with steeper cortisol decline (7.5% increase in lymphocytes; 95% CI: 5.79-9.34; p < .001). IgE levels did not modify this association. Interestingly, IgE did moderate relationships between measures of cortisol and granulocytes: diurnal cortisol was positively associated with granulocytes, only in individuals with high previous exposure to parasites. There were no consistent relationships between single-unit measures of cortisol, lymphocytes or granulocytes, regardless of past parasite exposure., Discussion: Results demonstrate that the relationship between HPA function and immune modulation cannot be fully understood without an understanding of local disease ecology. These results highlight the importance of research that seeks to identify etiologies of disease across environmental contexts., (© 2020 Wiley Periodicals LLC.)

The aim of this study was to investigate the alterations in the neuroendocrine-immune functions by using human peripheral blood mononuclear cells (hPBMCs) from three age groups (young, middle-aged, and old) of men and women for the analyses of lymphocyte proliferation and cytokine production, expression of cell signaling molecules, nitric oxide (NO) production, and expression of p-tyrosine hydroxylase (TH). Serum was examined for levels of testosterone in men, 17-β-estradiol in women, and cortisol in both sexes. Lymphoproliferation, expression of p-ERK, p-CREB, p-Akt, and p-TH, and levels of serum sex steroid hormones declined with age in men and women. However, TNF-α production and serum cortisol level increased with age in men and women. mTOR expression was higher in older men while it was lower in older women. IFN-γ and IL-6 production and expression of p-TH and p-mTOR were differentially regulated in men and women. These results suggest that intracellular signaling mediators may be involved in the age-related alterations in the neuroendocrine-immune interactions in men and women., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Previous research on the association between testosterone (T) and immunity has produced conflicting results., Objectives: We address two potential reasons for these empirical inconsistencies in the present research. First, the association between T and immunity may depend on which branch of the immune system is considered. Here, we examine secretory IgA (sIgA), a measure of mucosal immunity functionally related to respiratory infection risk. Second, the association between T and immunity may depend on a third regulatory variable. Therefore, we examine the interaction between T and cortisol (CORT) as well as their independent and combined effects on mucosal immunity. To do this, we explore intra-individual associations between sIgA, CORT, and T within a single day (i.e., morning vs. evening) and across 2 sequential mornings. We target two samples of men: (1) cisgender (i.e., born and identifying as men), and (2) transgender (i.e., born female but identifying as men) undergoing T therapy for gender realignment., Materials and Methods: One hundred and forty-eight adult men (transgender n = 29) provided saliva samples at three time points: (1) upon waking, (2) before sleep on the same day, and (3) upon waking the following day. Samples were assayed in duplicate for sIgA, T and CORT., Results: For cisgender men, sIgA, T, and CORT exhibited clear circadian rhythms and were significantly related within and between samples. For transgender men, evidence for circadian change was found for sIgA and CORT, but not T. Further, sIgA was associated with CORT, but not T., Discussion and Conclusions: This study provides the first evidence that salivary T and sIgA concentrations are associated within a single day and across sequential days for cisgender men. Differences between cis- and transgender men suggest that this may only be true for T levels driven by endogenous production; however, future studies should employ a larger sample size., (Copyright © 2020. Published by Elsevier Inc.)

Immune function, height and resource accumulation comprise important life history traits in humans. Resource availability models arising from life history theory suggest that socioeconomic conditions influence immune function, growth and health status. In this study, we tested whether there are associations between family income during ontogeny, adult height, cortisol level and immune response in women. A hepatitis B vaccine was administered to 66 young Latvian women from different socioeconomic backgrounds, and blood samples were then collected to measure the level of antibodies that the women produced in response to the vaccination. Cortisol levels were measured from plasma samples pre- and post-vaccination. Women from wealthier families had lower cortisol levels, and women from the highest family income group had the highest levels of antibody titers against hepatitis B vaccine. No significant relationships were observed between cortisol level and immune function, nor between family income and height. The results show that income level during ontogeny is associated with the strength of immune response and with psychoneuroendocrine pathways underlying stress perception in early adulthood. The findings indicate that the quality of the developmental niche is associated with the condition-dependent expression of immune function and stress response.

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC 50 -dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC 50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F ( NR3C1-1F ), IC 50-DEX , and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

Psychological distress persisting for weeks or more promotes pro-inflammatory immune dysregulation, a risk factor for a range of chronic diseases. We have recently shown that mindfulness training reduces distress among university students. Here we present an exploratory trial to study immune dysregulation in a cohort of students who were exposed to progressively greater stress as the exam period approached, and to explore whether mindfulness training mitigated this dysregulation. Healthy University of Cambridge students were randomised to join an 8-week mindfulness course (N = 27), or to mental health support as usual (N = 27). Psychological distress, immune cell proportions, cytokines, CRP and serum cortisol were measured at baseline and during the exam period. Increased distress was associated with statistically significant increases in the proportion of B cells, regardless of trial arm (*p = 0.027). There were no other associations between any of the measured parameters, distress or mindfulness. Our finding that the proportion of B cells increases with psychological distress supports the findings of other studies. However, we found no evidence that mindfulness training is able to buffer the effects of psychological distress on healthy participants' immune system. In order to detect these effects, should they exist, larger randomised trials will be required.

Introduction: The essential amino acid tryptophan (TRP) is primarily degraded through the kynurenine (KYN) pathway, which is dysregulated in several chronic diseases. KYN pathway metabolites have immune- and neuro-modulatory properties and are involved in th de novo synthesis of nicotinamide adenine dinucleotide (NAD+). Currently, little evidence exists demonstrating that physical exercise may influence this pathway. However, differences between acute and chronic stimuli as well as the influence of exercise modalities remain to be investigated. Here, we provide an overview of existing studies and present results of a randomized cross-over trial on acute effects of a single-bout of resistance and endurance exercise., Methods: 24 healthy male adults conducted both an acute endurance exercise (EE) and resistance exercise (RE) session. Blood samples were collected before, immediately after and one hour after cessation of each exercise session. Outcomes comprised serum levels of TRP, KYN, kynurenic acid (KA), quinolinic acid (QA) and calculated ratios. Gene expression of the enzymes indoleamine 2,3 dioxygenase (IDO) 1 and kynurenine aminotransferase (KAT) 4 was measured in peripheral blood mononuclear cells (PBMCs). Moreover, serum concentrations of the potential KYN pathway mediators interleukin (IL)-6 and cortisol were determined. Finally, we investigated baseline correlations between immune cell subsets, potential mediators and initial KYN pathway activation outcomes., Results: The KYN/TRP ratio correlated positively with IL-6 and CD56bright NK-cells and negatively with CD56dim NKcells. Expression of IDO1 in PBMCs correlated positively with IL-6, regulatory T-cells and CD56bright NK-cells, whereas negative correlations to cytotoxic T-cells and CD56dim NKcells were revealed. A significant time effect on KYN/TRP ratio was detected for RE. Regarding KA and KA/KYN ratio, an increase after exercise followed by a decrease at the follow- up measurement was revealed in EE. KAT4 expression also increased after exercise in EE. Moreover, elevated QA levels were observed after the EE session., Conclusions: In contrast to chronic exercise interventions, single-bouts of endurance exercise provoke acute alterations on KYN pathway outcomes in humans. Our results indicate that EE induces stronger alterations than RE. Enhanced conversion of KYN to both, KA and QA suggest a peripheral KYN clearance, thereby preventing pathological accumulation within the CNS. Future acute and chronic exercise studies are needed to examine the role of NAD+ synthesis starting with TRP and the interplay between KYN pathway activation and mid- to long-term immunological modulations., (Copyright © 2020 International Society of Exercise and Immunology. All rights reserved.)

The pineal gland is the main organ involved in the transduction process converting environmental light information into a melatonin response. Since light environment was described as an important factor that could affect physiology of teleosts, and because melatonin is a crucial hormone regulating numerous physiological processes, we hypothesized that environmental light may act on both stress and circadian axes which in turn could influence the immune status of pike perch. Therefore, we investigated the effects of two light spectra (red and white) and two light intensities (10 and 100 lx) with a constant photoperiod 12L (8:00-20:00) /12D on pike perch physiological and immune responses. Samples were collected at 04:00 and 16:00 at days 1 and 30 of the experiment. Stress markers, plasma melatonin levels, humoral innate immune markers, and expression of key immune genes in the head kidney were assessed. Light intensity clearly affected pike perch physiology. This included negative growth performances, increase in stress status, decrease in plasma melatonin levels, and immune depression. Light spectrum had only little influences. These results demonstrate that high stress status may have impacted melatonin production and secretion by the pineal organ. The drop in circulating melatonin and the increase in stress status may both be involved in the immune suppression., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The purpose of this study was to investigate the impact of a training season (approximately 7 months) on physiological and salivary immune-endocrine markers in master athletes. Nine male master athletes were evaluated at the beginning of the season (M1) and a week after the main official competition at the end of the sports season (M2). The controlled variables included Maximal oxygen consumption, anthropometric, physiological, and salivary immune-endocrine markers. Master athletes presented a reduced percentage of fat mass and increased lean body mass at the end of the season. VO 2max values were similar at M1 and M2, while the maximal heart rate and lactate were lower at M2. No differences were observed in Immunoglobulin A and cortisol levels between moments, whereas testosterone levels and the testosterone/cortisol ratio were significantly lower at the end of the season. The results suggest that maintaining regular training throughout life has positive effects on body composition and improves physiological fitness. However, care should be taken to avoid fatigue as indicated by lower testosterone levels at the end of the season., (© 2018 Wiley Periodicals, Inc.)

Burnout has several different definitions, and attempts have been made to discriminate between burnout as a psychological construct and burnout as a clinical entity. A large body of research has focused on elucidating the biological link between stress exposure and burnout and/or finding a clinically usable biomarker for burnout. The objective of this narrative review is to summarize the main endocrine and immune findings in relation to burnout. The literature has primarily focused on dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. However, albeit the large body of studies, it cannot be concluded that clear effects are seen on HPA axis function in people with burnout. The HPA axis and anabolic acute reactivity to stress might be affected in clinical burnout. Plausible, effects of chronic stress might rather be seen when measuring responses to acute stress rather than resting state hormonal levels. Studies on other hormones, including thyroid hormones, prolactin and growth hormone in burnout subjects are inconclusive. It is important to note that this field is faced with many methodological challenges, one being the diurnal and pulsatile nature of many of the hormones of interest, including cortisol, which is not always considered. Another challenge is the heterogeneity regarding definitions and measurements of stress and burnout. Existing studies on burnout and immune function are heterogeneous regarding the results and no firm conclusion can be made if clinically relevant immune changes are present in burnout subjects. An overall conclusion is that existing research cannot confirm any homogenous reliable endocrinological or immunological changes related to burnout.

Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette-Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p < .01) in boys only, was negatively associated with naïve helper T-cell concentrations in both sexes at both 6 (p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.

Small-molecule detection is important for many applications including clinical diagnostics, drug discovery, and measurements of environmental samples and agricultural products. Current techniques for small-molecule detection suffer from various limitations including low analytical sensitivity and complex sample processing. Furthermore, as a result of their small size, small molecules are difficult to detect using an antibody pair in a traditional sandwich assay format. To overcome these limitations, we developed an ultrasensitive competitive immunoassay for small-molecule detection using Single Molecule Arrays (Simoa). We show that the competitive Simoa assay is approximately 50-fold more sensitive than the conventional ELISA. We performed theoretical calculations to determine the factors that influence the sensitivity of competitive Simoa assays and used them to achieve maximal sensitivity. We also demonstrate detection of small molecules in complex biological samples. We show that the competitive Simoa assay is a simple, fast, and highly sensitive approach for ultrasensitive detection of small molecules.

Malaria reduces host fitness and survival by pathogen-mediated damage and inflammation. Disease tolerance mechanisms counter these negative effects without decreasing pathogen load. Here, we demonstrate that in four different mouse models of malaria, adrenal hormones confer disease tolerance and protect against early death, independently of parasitemia. Surprisingly, adrenalectomy differentially affects malaria-induced inflammation by increasing circulating cytokines and inflammation in the brain but not in the liver or lung. Furthermore, without affecting the transcription of hepatic gluconeogenic enzymes, adrenalectomy causes exhaustion of hepatic glycogen and insulin-independent lethal hypoglycemia upon infection. This hypoglycemia is not prevented by glucose administration or TNF-α neutralization. In contrast, treatment with a synthetic glucocorticoid (dexamethasone) prevents the hypoglycemia, lowers cerebral cytokine expression and increases survival rates. Overall, we conclude that in malaria, adrenal hormones do not protect against lung and liver inflammation. Instead, they prevent excessive systemic and brain inflammation and severe hypoglycemia, thereby contributing to tolerance.

Cortisol is a steroidal hormone and an important stress marker. Free serum cortisol concentration has been identified to correlate well with free salivary cortisol. In this present work an electrochemical immunosensor was developed to determine cortisol concentration within the physiological concentration range found in human saliva. The immunosensor is based on a direct competitive enzyme linked immunoassay using a home-made cortisol-alkaline phosphatase (AP) conjugate synthesized in our laboratory with disposable graphite screen-printed electrodes (SPEs). 1-nalphtyl phosphate (1-NP) was used as an enzymatic substrate and a square wave voltammetry (SWV) for electrochemical detection. To study method suitability for use with saliva samples, calibration curves were performed both in buffer and saliva. In buffer standard samples showed a limit of detection (LOD) of 0.6 ng/ml and working range (WR) of 0.2-44.6 ng/ml with good reproducibility (RSD 10%). Saliva matrix effect was removed effectively with Salivette Cortisol collection device (polyethylene) and a calibration curve showed similar characteristics as in buffer with LOD 1.7 ng/ml and WR 0.5-55.1 ng/ml (RSD 8%) demonstrating the possibility to determine human salivary cortisol within the desired human physiological range. Spiked saliva samples were analyzed with the developed immunosensor presenting excellent 92-114% recovery. Comparison to liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method showed strong 0.90 correlation between methods indicating good accuracy of the developed immunosensor., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objects: To compare surgical inflammatory response (SIR) after radical cystectomy (RC) in a porcine model using minimal invasive techniques. Additionally we aimed to investigate the potential immunosuppressive ability of preoperative CO 2 -pneumoperitoneum (CO 2 P)., Materials and Methods: Forty female landrace pigs were randomized to five groups: Three intervention groups all having a cystectomy and an ileal conduit either done by robot-assisted laparoscopic technique with intracorporeal urinary diversion (RALC) or an open mini-laparotomy with or without prior CO 2 P (OMC ± CO 2 P). Two control sham groups with or without prior CO 2 P (S ± CO 2 P). Serum samples were obtained preoperatively, immediately postoperative, 24, 48 and 72 hours postoperatively, and the inflammatory mediators CRP, Haptoglobin, Ceruloplasmin, Albumin, Cortisol, IL-4, IL-6, IL-12 and IFN-α were measured., Results: Operative time was significantly longer in RALC compared to open groups (OMC ± CO 2 P) (p's < .0001). CRP and Haptoglobin levels were significantly higher for surgical intervention groups (SIG) compared to controls 24, 48 and 72 hours postoperatively (p's < .001). At 48 hours, CRP was higher for RALC vs OMC + CO 2 P (p = .029). At 72 hours, Haptoglobin was higher for RALC vs open groups (p's < .024). Ceruloplasmin, cortisol, albumin, IL-4, IL-6, IL-12 and IFN-α, revealed no significant differences between SIG., Conclusions: No major differences were found between RALC and OMC regarding the degree of tissue trauma quantified by inflammatory markers. Thirty minutes of CO 2- insufflation preoperative appears to have a transient immunosuppressive effect of the innate postoperative SIR, whereas prolonged CO 2 P apparently diminishes this effect.

Violent aggression in humans may involve a modified response to stress, but the underlying mechanisms are not well understood. Here we show that naturally present autoantibodies reactive to adrenocorticotropic hormone (ACTH) exhibit distinct epitope-binding profiles to ACTH peptide in subjects with a history of violent aggression compared with controls. Namely, while nonaggressive male controls displayed a preferential IgG binding to the ACTH central part (amino acids 11-24), subjects who had committed violent acts of aggression had IgG with increased affinity to ACTH, preferentially binding to its N terminus (amino acids 1-13). Purified IgGs from approximately half of the examined sera were able to block ACTH-induced cortisol secretion of human adrenal cells in vitro, irrespective of the source of sample (from a control subject or a violent aggressor). Nevertheless, in the resident-intruder test in mice, i.p. injection of residents with ACTH and IgG from aggressive subjects, but not from control subjects, shortened latency for the first attack against intruders. Immunohistochemical screening of violent aggressors' sera on rat brain and pituitary sections did not show IgG binding to ACTH-producing cells, but 4 of 16 sera revealed selective binding to a nonidentified antigen in vasopressinergic neurons of the hypothalamic paraventricular and supraoptic nuclei. Thus, the data show that ACTH-reactive plasmatic IgGs exhibit differential epitope preference in control and violently aggressive subjects. These IgGs can modulate ACTH-induced cortisol secretion and, hence, are involved in the regulation of the stress response. However, the possible role of ACTH-reactive autoantibodies in aggressive behavior needs further investigation., Competing Interests: Conflict of interest statement: P.D. has received research grants from Nestlé and Fresenius Kabi and honoraria for speeches and consulting from Nestlé, Fresenius-Kabi, and Aguettant, is a cofounder of TargEDys SA, and is a member of its advisory board. S.O.F. is a cofounder of and serves as a consultant to TargEDys SA. N.L. and R.L. are currently employees of TargEDys SA. T.H. owns shares in AstraZeneca., (Copyright © 2018 the Author(s). Published by PNAS.)

Knowledge of endocrine stress responses can be advantageous for understanding how animals respond to their environment. One tool in wildlife endocrinology is to measure the adrenocortical activity as a parameter of disturbance of animals. Fecal glucocorticoid metabolites (GCMs) provide a noninvasive assessment of adrenocortical activity. Using an adrenocorticotropic hormone (ACTH) challenge administered to 28 captive coyotes (Canis latrans), we measured the levels of plasma cortisol, and fecal cortisol and corticosterone metabolites (i.e., GCMs). Our goal was to determine the dose-response in the plasma and fecal samples following the injection and determine if there were effects of sex, age, and time of day. Specifically, animals were anesthetized for ~ 90 min with treatment animals intravenously injected with exogenous ACTH and control animals receiving saline. We collected blood samples prior to injection and at 4 different time points post-injection. We also collected fecal samples 2 days pre- and 2 days post-injection to measure fecal GCMs and determine if an endocrine stress response could be detected in fecal samples. We found a definite response in cortisol levels in the plasma for coyotes to the ACTH challenge. There was a response in fecal corticosterone 1 day post-injection, but the control males showed a similar response indicating a handling effect. Fecal cortisol levels did not indicate a response to the ACTH challenge, and were significantly lower than corticosterone concentrations. We also found significant sex, but not age or diurnal, differences in fecal GCMs. Radioimmunoassays for fecal corticosterone levels appeared to be a reliable indicator of physiological stress in coyotes.

Sleep is essential for health. Slow wave sleep (SWS), the deepest sleep stage hallmarked by electroencephalographic slow oscillations (SOs), appears of particular relevance here. SWS is associated with a unique endocrine milieu comprising minimum cortisol and high aldosterone, growth hormone (GH), and prolactin levels, thereby presumably fostering efficient adaptive immune responses. Yet, whether SWS causes these changes is unclear. Here we enhance SOs in men by auditory closed-loop stimulation, i.e., by delivering tones in synchrony with endogenous SOs. Stimulation intensifies the hormonal milieu characterizing SWS (mainly by further reducing cortisol and increasing aldosterone levels) and reduces T and B cell counts, likely reflecting a redistribution of these cells to lymphoid tissues. GH remains unchanged. In conclusion, closed-loop stimulation of SOs is an easy-to-use tool for probing SWS functions, and might also bear the potential to ameliorate conditions like depression and aging, where disturbed sleep coalesces with specific hormonal and immunological dysregulations.

Problem: Heightened maternal stress affects trophoblast function and increases risk for adverse pregnancy outcomes., Methods of Study: Studies were performed using the first-trimester trophoblast cell line, Sw.71. Cytokines were quantified using qPCR and ELISA. Epigenetic regulation of cytokines was characterized by inhibiting histone deacetylation (1 μmol/L suberoylanilide hydroxamic acid [SAHA]) or methylation (5 μmol/L 5-azacytidine), or with chromatin immunoprecipitation (ChIP) with a pan-acetyl histone-3 antibody. Invasion assays used Matrigel chambers., Results: Cortisol inhibited expression of CSF2 (GM-CSF) and CSF3 (G-CSF) in trophoblast cells. Cortisol-associated inhibition was dependent on DNA methylation and was not affected by acetylation. There was also a modest decrease in trophoblast invasion, not dependent on loss of CSFs., Conclusion: In first-trimester trophoblast cells, the physiological glucocorticoid, cortisol, inhibited two cytokines with roles in placental development and decreased trophoblast invasion. Cortisol-associated changes in trophoblast function could increase the risk for immune-mediated abortion or other adverse pregnancy outcomes., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recent studies have shown that production of cortisol not only takes place in several non-adrenal peripheral tissues such as epithelial cells but, also, the local inter-conversion between cortisone and cortisol is regulated by the 11β-hydroxysteroid dehydrogenases (11β-HSDs). However, little is known about the activity of this non-adrenal glucocorticoid system in cancers., Methods: The presence of a functioning glucocorticoid system was assessed in human skin squamous cell carcinoma (SCC) and melanoma and further, in 16 epithelial cell lines from 8 different tissue types using ELISA, western blotting and immunofluorescence. 11β-HSD2 was inhibited both pharmacologically and by siRNA technology. Naïve CD8 + T cells were used to test the paracrine effects of cancer-derived cortisol on the immune system in vitro. Functional assays included cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical data of 11β-HSD expression were generated using tissue microarrays of 40 cases of human SCCs as well as a database featuring 315 cancer cases from 15 different tissues., Results: We show that cortisol production is a common feature of malignant cells and has paracrine functions. Cortisol production correlated with the magnitude of glucocorticoid receptor (GR)-dependent inhibition of tumour-specific CD8 + T cells in vitro. 11β-HSDs were detectable in human skin SCCs and melanoma. Analyses of publicly available protein expression data of 11β-HSDs demonstrated that 11β-HSD1 and -HSD2 were dysregulated in the majority (73%) of malignancies. Pharmacological manipulation of 11β-HSD2 activity by 18β-glycyrrhetinic acid (GA) and silencing by specific siRNAs modulated the bioavailability of cortisol. Cortisol also acted in an autocrine manner and promoted cell invasion in vitro and cell-cell adhesion and cohesion in two- and three-dimensional models. Immunohistochemical analyses using tissue microarrays showed that expression of 11β-HSD2 was significantly reduced in human SCCs of the skin., Conclusions: The results demonstrate evidence of a cancer-associated glucocorticoid system and show for the first time, the functional significance of cancer-derived cortisol in tumour progression.

The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery., Competing Interests: In kind contribution of INergy (NCT02987296) and Tinzaparin (NCT01455831) from Enhanced Medical Nutrition and Leo Pharma, respectively.

Background: There have been few studies regarding the results of the Korean standard patch test., Objectives: The purpose of this study was to analyze the type and frequency of common contact allergens in Korea and to compare the results with those of previous reports., Methods: From June 2009 to June 2014, 330 patients with suspected allergic contact dermatitis who visited our clinic were tested using the Korean standard patch test., Results: The highest sensitization rate was found for nickel sulfate (47.58%). There was a significant gender difference in the prevalence of sensitization to nickel sulfate (OR = 2.41, p = .0004) and wool alcohol (OR = 2.85, p = .0358). Higher sensitization to nickel sulfate (OR = 1.18, p = .0159), 4-phenylenediamine (OR = 1.23, p= .003), tixocortol-21-pivalte (OR 1.48, p = .0212) and lower sensitization to thimerosal (OR = 0.77, p = .0023) were associated with increasing age. Patients with allergic contact dermatitis on the scalp had a significantly higher risk of sensitization to 4-phenylenediamine (OR = 3.07, p = .0013). Patients with allergic contact dermatitis on the hands had significantly higher risks of sensitization to wool alcohol (OR = 3.44, p = .0083), formaldehyde (OR = 2.52, p = .0178), and colophony (OR = 2.05, p = .0499)., Conclusions: These results demonstrate trends in patch test results in Korea and the basis for the presumption of the route of allergen exposure.

Background: Untreated disorders of the adrenocortical system, such as Cushing's or Addison's disease, can be fatal, and accurate quantification of a patient's cortisol levels is vital for diagnosis. The objective of this study was to assess the analytical performance of a new fully-automated Elecsys® Cortisol II assay (second generation) to measure cortisol levels in serum and saliva., Methods: Four European investigational sites assessed the intermediate precision and reproducibility of the Cortisol II assay (Roche Diagnostics) under routine conditions. Method comparisons of the Cortisol II assay vs. liquid chromatography-tandem mass spectrometry (LC-MS/MS), the gold standard for cortisol measurement, were performed. Cortisol reference ranges from three US sites were determined using samples from self-reported healthy individuals., Results: The coefficients of variation (CVs) for repeatability, intermediate precision, and reproducibility for serum samples were ≤2.6%, ≤5.8%, and ≤9.5%, respectively, and for saliva were ≤4.4% and ≤10.9%, and ≤11.4%, respectively. Agreement between the Cortisol II assay and LC-MS/MS in serum samples was close, with a slope of 1.02 and an intercept of 4.473 nmol/L. Reference range samples were collected from healthy individuals (n=300) and serum morning cortisol concentrations (5-95th percentile) were 166.1-507 nmol/L and afternoon concentrations were 73.8-291 nmol/L. Morning, afternoon, and midnight saliva concentrations (95th percentile) were 20.3, 6.94, and 7.56 nmol/L, respectively., Conclusions: The Cortisol II assay had good precision over the entire measuring range and had excellent agreement with LC-MS/MS. This test was found suitable for routine diagnostic application and will be valuable for the diagnosis of adrenocortical diseases.

This study investigates whether a single session of routine morning basketball or volleyball training affects saliva levels of cortisol, alpha-amylase (sAA) and secretory immunoglobulin A (sIgA) in boys aged 14–18 years. Twenty-nine boys who participate in basketball or volleyball training, recruited from the Marcin Gortat’s Athletic Championship School in Lodz, were enrolled in the study. The 90-minute routine exercise program included 15 minutes of warm-up followed by basketball or volleyball practice. Unstimulated saliva samples were collected prior to and immediately after the exercise, and were analysed using ELISA. One training session resulted in a significant increase of sAA concentration in all participants, as well as in the volleyball and basketball subgroups (p=0.00022; p=0.0029; p=0.0011; respectively). Post-exercise cortisol levels were significantly lower than pre-exercise levels (p=0.00002) throughout the group, as well as in the volleyball and basketball subgroups (p=0.0048; p=0.0019; p=0.0048; respectively). The exercise protocol did not significantly affect sIgA level, either in the whole examined group or the volleyball subgroup, however a weak significant increase of sIgA was observed in the basketball subgroup (p=0.046). The routine morning training session comprising a warm-up followed by basketball or volleyball practice seems to activate the sympatho-adrenal-medullary system, with a subsequent increase of alpha-amylase, but does not affect oral immunity in 14-18-year-old boys.

Cortisol levels in bodily fluids represent a useful index for pituitary-adrenal function, and thus practical anti-cortisol antibodies are required. We have studied "antibody-breeding" approaches, which involve in vitro evolution of antibodies to improve their antigen-binding performances. Here, we produced an antibody fragment to measure serum cortisol levels with over 30-fold enhanced affinity after single mutagenesis and selection steps. A mouse anti-cortisol antibody, Ab-CS#3, with insufficient affinity for practical use, was chosen as the prototype antibody. A "wild-type" single-chain Fv fragment (wt-scFv; K a , 3.4×10 8  M -1 ) was prepared by bacterial expression of a fusion gene combining the V H and V L genes for this antibody. Then, random point mutations were generated separately in V H or V L by error-prone PCR, and the resulting products were used to assemble scFv genes, which were displayed on filamentous phages. Repeated panning of the phage library identified a mutant scFv (scFv#m1-L10) with an over 30-fold enhanced affinity (K a 1.2×10 10  M -1 ). Three amino acid substitutions (Cys49Ser, Leu54Pro, and Ser63Gly) were observed in its V L sequence. In a competitive enzyme-linked immunosorbent assay (ELISA), the mutant scFv generated dose-response curves with measuring range ca. 0.03-0.6 ng/assay cortisol, midpoint of which (0.15 ng/assay) was 7.3-fold lower than that of wt-scFv. Although cortisone, 11-deoxycortisol, and prednisolone showed considerable cross-reactivity, the mutant scFv should enable sensitive routine cortisol assays, except for measurement after metyrapone or high-dose of prednisolone administrations. Actually, cortisol levels of control sera obtained with the scFv-based ELISA were in the reference range.

Glucocorticoids are steroid hormones that once bound to their receptor interact with the DNA binding domain. Almost 1000-2000 genes are sensitive to their effects, including immune/inflammatory response genes. However, their role in pathophysiology and therapy is still debated. We performed a literature survey using the key words glucocorticoids, inflammation, autoimmune disease, rheumatology and adrenal glands in order to define important targets for this review on glucocorticoids. Considering endogenous/exogenous glucocorticoids in chronic inflammatory diseases brought up five major points for discussion: inadequately low production of endogenous cortisol relative to systemic inflammation (the disproportion principle); changes of the systemic and local cortisol-to-cortisone shuttle (reactivation and degradation of cortisol); inflammation-induced glucocorticoid resistance; highlights of present glucocorticoid therapy; and the role of circadian rhythms in action of cortisol. Much of this information becomes understandable in the context of neurohormonal energy regulation as recently summarized. The optimization of long-term low-dose glucocorticoid therapy in chronic inflammatory diseases arises from the understanding of the above mentioned aspects. Since glucocorticoid resistance is a consequence of inflammation, adequate anti-inflammatory therapy is mandatory., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of the study was to gauge both the immune and neuroendocrine function in Ultra High Risk for psychosis (UHR) subjects and compare them with a cohort presenting with First Episode Psychosis (FEP). We recruited two groups, the first group consisted of 12 UHR males and the second of 25 males with FEP. We measured serum cortisol levels at 08:00, 12:00, 18:00 with their Area Under Curve with respect to the ground (AUCg) and the increase (AUCi) and we measured serum cytokines levels, Interleukin-1a, IL-1a, IL-2, IL-4,IL-5,IL-6,IL-8, IL-10,IL-12, IL-17a, Tumor Necrosis Factor-a (TNF-a), Interferon-γ (IFN-γ). Dexamethasone Suppression Test (DST) was also performed . The results suggest higher levels of both pro-inflammatory (TNF-a, IL-2, IL-12, IFN-γ) and anti-inflammatory (IL-10) cytokines in the FEP group compared with the UHR counterparts. Regarding the HPA axis function, the prodromal subjects showed a trend for higher AUCg and AUCi change/decrease cortisol levels. On the contrary, the DST results did not differ between the groups. No significant associations were demonstrated within each group among cytokines, cortisol and psychopathology. The findings favor a hypothesis of a relatively increased mobilization of both the pro- and anti-inflammatory cytokine networks, in FEP compared with that of UHR subjects., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Seasonal changes in environmental conditions are accompanied by significant adjustment of multiple biological processes. In temperate regions, the day fraction, or photoperiod, is a robust environmental cue that synchronizes seasonal variations in neuroendocrine and metabolic function. In this work, we propose a semimechanistic mathematical model that considers the influence of seasonal photoperiod changes as well as cellular and molecular adaptations to investigate the seasonality of immune function. Our model predicts that the circadian rhythms of cortisol, our proinflammatory mediator, and its receptor exhibit seasonal differences in amplitude and phase, oscillating at higher amplitudes in the winter season with peak times occurring later in the day. Furthermore, the reduced photoperiod of winter coupled with seasonal alterations in physiological activity induces a more exacerbated immune response to acute stress, simulated in our studies as the administration of an acute dose of endotoxin. Our findings are therefore in accordance with experimental data that reflect the predominance of a proinflammatory state during the winter months. These changes in circadian rhythm dynamics may play a significant role in the seasonality of disease incidence and regulate the diurnal and seasonal variation of disease symptom severity., (Copyright © 2016 the American Physiological Society.)

Corticosteroid-binding globulin (CBG) delivers anti-inflammatory cortisol to inflamed tissues upon elastase-based proteolysis of the exposed reactive center loop (RCL). However, the molecular mechanisms that regulate the RCL proteolysis by co-existing host and bacterial elastases in inflamed/infected tissues remain unknown. We document that RCL-localized Asn(347) glycosylation fine-tunes the RCL cleavage rate by human neutrophil elastase (NE) and Pseudomonas aeruginosa elastase (PAE) by different mechanisms. NE- and PAE-generated fragments of native and exoglycosidase-treated blood-derived CBG of healthy individuals were monitored by gel electrophoresis and LC-MS/MS to determine the cleavage site(s) and Asn(347) glycosylation as a function of digestion time. The site-specific (Val(344)-Thr(345)) and rapid (seconds to minutes) NE-based RCL proteolysis was significantly antagonized by several volume-enhancing Asn(347) glycan features (i.e. occupancy, triantennary GlcNAc branching, and α1,6-fucosylation) and augmented by Asn(347) NeuAc-type sialylation (all p < 0.05). In contrast, the inefficient (minutes to hours) PAE-based RCL cleavage, which occurred equally well at Thr(345)-Leu(346) and Asn(347)-Leu(348), was abolished by the presence of Asn(347) glycosylation but was enhanced by sialoglycans on neighboring CBG N-sites. Molecular dynamics simulations of various Asn(347) glycoforms of uncleaved CBG indicated that multiple Asn(347) glycan features are modulating the RCL digestion efficiencies by NE/PAE. Finally, high concentrations of cortisol showed weak bacteriostatic effects toward virulent P. aeruginosa, which may explain the low RCL potency of the abundantly secreted PAE during host infection. In conclusion, site-specific CBG N-glycosylation regulates the bioavailability of cortisol in inflamed environments by fine-tuning the RCL proteolysis by endogenous and exogenous elastases. This study offers new molecular insight into host- and pathogen-based manipulation of the human immune system., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: To investigate the effect of military stress on immune response and Helicobacter pylori stomach infections., Methods: In this prospective, observational study, the Symptom Checklist-90 questionnaire was completed by military recruits before and following a 3-month basic training programme. H. pylori immunoglobulin (Ig)G levels, C(14)-urea breath-test values and levels of cortisol, catecholamine, and certain humoral and cellular immune responses were measured before and after the basic training., Results: For 60 military recruits, somatization, depression and paranoid ideation scores were significantly increased after, compared with before, basic training. Post-training H. pylori IgG detection revealed three additional cases of H. pylori infection. Post-training C(14)-urea breath-test values were significantly higher compared with before training - thus suggesting higher levels of H. pylori colonization in the stomach. Post-training cortisol and catecholamine levels were increased, while serum IgG levels were decreased; complement component (C)3 and C4 levels remained unchanged. Post-training CD4(+) and CD8(+) T-cell percentages and the CD4(+)/CD8(+) ratio were significantly reduced compared with before training. Serum interleukin (IL)-2 levels were lower and IL-10 levels were higher following training and there was a significant decrease in the IL-2/IL-10 ratio., Conclusion: Military stress may reduce humoral and cellular immune responses and may aggravate the severity of H. pylori infection., (© The Author(s) 2016.)

Plasma magnesium concentration alterations, hypercortisolaemia, and systemic inflammation are observed in major depressive disorder (MDD). This exploratory study examined whether, and to what extent, plasma magnesium is related to C-reactive protein (CRP) levels and cortisolaemia in MDD. The concentrations of plasma magnesium, salivary CRP, and baseline plasma cortisol were studied in 20, treatment-naïve MDD patients with short-illness-duration, first affective episodes and 20 matched controls. Depressed patients showed a basal score higher than 20 on the Hamilton Rating Scale for Depression (HAMD-17). Significantly higher magnesium (p = 0.016) and baseline cortisol (p = 0.01) concentrations were observed in MDD as compared to controls. No significant difference in CRP concentrations between the MDD and control groups was observed. A significant negative correlation was seen between magnesium and CRP in MDD (p<0.01), whereas no correlation was found in controls. A significant positive correlation was found between cortisol and CRP, both in MDD subjects (p = 0.008) and controls (p = 0.004). No significant correlations were observed between magnesium and cortisol levels. The study supports data for hypercortisolaemia in MDD, but provides no evidence of primary hypomagnesaemia or elevated CRP levels in drug-naïve MDD patients with short-illness-duration. The study supports the hypothesis linking hypercortisolaemia to systemic inflammation, with hypermagnesaemia exerting an immunomodulatory action at early stages of the disease.

Host stress is well known to result in flare-ups of many bacterial, viral and parasitic infections. The mechanism by which host stress is exploited to increase pathogen loads, is poorly understood. Here we show that Salmonella enterica subspecies enterica serovar Typhimurium employs a dedicated mechanism, driven by the scsA gene, to respond to the host stress hormone cortisol. Through this mechanism, cortisol increases Salmonella proliferation inside macrophages, resulting in increased intestinal infection loads in DBA/2J mice. ScsA directs overall Salmonella virulence gene expression under conditions that mimic the intramacrophagic environment of Salmonella, and stimulates the host cytoskeletal alterations that are required for increased Salmonella proliferation inside cortisol exposed macrophages. We thus provide evidence that in a stressed host, the complex interplay between a pathogen and its host endocrine and innate immune system increases intestinal pathogen loads to facilitate pathogen dispersal.

Fishes display a wide variation in their physiological responses to stress, which is clearly evident in the plasma corticosteroid changes, chiefly cortisol levels in fish. In the present study, we describe a novel label-free immunosensor for detecting plasma cortisol levels. The method is based on immunologic reactions and amperometric measurement using cyclic voltammetry. For the immobilization of the antibody on the surface of sensing electrode, we used a self-assembled monolayer of thiol-containing compounds. Using this electrode, we detect the CV signal change caused by the generation of antigen-antibody complex. The immunosensor showed a response to cortisol levels, and the anodic peak value linearly decreased with a correlation coefficient of 0.990 in diluted plasma. The specificity of the label-free immunosensor system was investigated using other steroid hormones, such as 17α, 20β-dihydroxy-4-pregnen-3-one, progesterone, estriol, estradiol, and testosterone. The specific detection of cortisol was suggested by a minimal change from -0.32 to 0.51 μA in the anodic peak value of the other steroid hormones. The sensor system was used to determine the plasma cortisol levels in Nile tilapia (Oreochromis niloticus), and the results were compared with those of the same samples determined using the conventional method (ELISA). A good correlation was obtained between values determined using both methods (correlation coefficient 0.993). These findings suggest that the proposed label-free immunosensor could be useful for rapid and convenient analysis of cortisol levels in fish plasma samples.

Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated in the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Chronic adrenal insufficiency (CAI) is characterized by a lack of glucocorticoid and mineralocorticoid production due to destroyed adrenal cortex cells. However, elevated cortisol secretion is thought to be a central part in a well-orchestrated immune response to stress. This raises the question to what extent lack of cortisol in CAI affects stress-related changes in immune processes. To address this question, 28 CAI patients (20 females) and 18 healthy individuals (11 females) (age: 44.3 ± 8.4 years) were exposed to a psychosocial stress test (Trier Social Stress Test: TSST). Half the patients received a 0.03 mg/kg body weight injection of hydrocortisone (HC) post-TSST to mimic a healthy cortisol stress response. Catecholamines and immune cell composition were assessed in peripheral blood and free cortisol measured in saliva collected before and repeatedly after TSST. CAI patients showed norepinephrine (NE) stress responses similar to healthy participants, however, epinephrine (E) as well as cortisol levels were significantly lower. HC treatment post-TSST resulted in cortisol increases comparable to those observed in healthy participants (interaction effects--NE: F=1.05, p=.41; E: F=2.56, p=.045; cortisol: F=13.28, p<.001). Healthy individuals showed the expected pattern of stress-related early lymphocyte increase with subsequent decrease below baseline. The opposite pattern was observed in granulocytes. While exhibiting a similar initial increase, lymphocytes kept increasing over the following 2h in untreated patients. HC treatment buffered this effect (interaction effects--lymphocyte%: F=7.31, p<.001; granulocyte%: F=7.71, p<.001). Using CAI in humans as a model confirms cortisol's central involvement in post-stress lymphocyte migration from blood into immune-relevant body compartments. As such, future studies should investigate whether psychosocial stress exposure may put CAI patients at an increased health risk due to attenuated immune responses to pathogens., (Copyright © 2015. Published by Elsevier Inc.)

Chronic stress is a major factor in the poor growth and immune performance of salmonids in aquaculture. However, the molecular mechanisms linking stress effects to growth and immune dysfunction is poorly understood. The suppressors of cytokine signaling (SOCS), a family of genes involved in the inhibition of JAK/STAT pathway, negatively regulates growth hormone and cytokine signaling, but their role in fish is unclear. Here we tested the hypothesis that cortisol modulation of SOCS gene expression is a key molecular mechanism leading to growth and immune suppression in response to stress in fish. Exposure of rainbow trout (Oncorhynchus mykiss) liver slices to cortisol, mimicking stress level, upregulated SOCS-1 and SOCS-2 mRNA abundance and this response was abolished by the glucocorticoid receptor antagonist mifepristone. Bioinformatics analysis confirmed the presence of putative glucocorticoid response elements in rainbow trout SOCS-1 and SOCS-2 promoters. Prior cortisol treatment suppressed acute growth hormone (GH)-stimulated IGF-1 mRNA abundance in trout liver and this involved a reduction in STAT5 phosphorylation and lower total JAK2 protein expression. Prior cortisol treatment also suppressed lipopolysaccharide (LPS)-induced IL-6 but not IL-8 transcript levels; the former but not the latter cytokine expression is via JAK/STAT phosphorylation. LPS treatment reduced GH signaling, but this was associated with the downregulation of GH receptors and not due to the upregulation of SOCS transcript levels by this endotoxin. Collectively, our results suggest that upregulation of SOCS-1 and SOCS-2 transcript levels by cortisol, and the associated reduction in JAK/STAT signaling pathway, may be a novel mechanism leading to growth reduction and immune suppression during stress in trout.

Hydrocortisone cream intended for atopic eczema often produces unwanted side effects after long-term use. These side effects are essentially due to repeated percutaneous administration of the medication for skin dermatitis, as atopic eczema is a relapsing disorder. Hence, there is a need to develop a new hydrocortisone formulation that will deliver the drug more effectively and require a reduced dosing frequency; therefore, the side effects could be minimized. In this study, a hydroxypropyl methylcellulose (HPMC) lyogel system based on 80% organic and 20% aqueous solvents containing 1% hydrocortisone was formulated. The hydrocortisone lyogel physicochemical characteristics, rheological properties, stability profile, and in vitro Franz cell drug release properties, as well as the in vivo therapeutic efficacies and dermal irritancy in Balb/c mice were investigated. The HPMC lyogel appeared clear and soft and was easy to rub on the skin. The lyogel also showed a higher drug release profile compared with commercial hydrocortisone cream. Similar to the cream, HPMC lyogels exhibited pseudoplastic behavior. From the mouse model, the hydrocortisone lyogel showed higher inflammatory suppressive effects than the cream. However, it did not reduce the transepidermal water loss as effectively as the control did. The dermal irritancy testing revealed that the hydrocortisone lyogel caused minimal irritation. In conclusion, HPMC lyogel is a promising vehicle to deliver hydrocortisone topically, as it showed a higher drug release in vitro as well as enhanced therapeutic efficacy in resolving eczematous inflammatory reaction compared with commercial cream.

Introduction: Hypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment., Materials and Methods: Participants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables., Results: Each cortisol measure was associated with decreased survival time, adjusting for covariates (all p<.041). A one standard deviation increase in night cortisol was associated with a 46% greater likelihood of death. Patients in the high night cortisol group survived an estimated average of 3.3 years compared to 7.3 years for those in the low night cortisol group. Elevated ascites IL-6 was associated with each cortisol measure (all r>36, all p<.017)., Discussion: Abnormal cortisol rhythms assessed prior to treatment are associated with decreased survival in ovarian cancer and increased inflammation in the vicinity of the tumor. HPA abnormalities may reflect poor endogenous control of inflammation, dysregulation caused by tumor-associated inflammation, broad circadian disruption, or some combination of these factors. Nocturnal cortisol may have utility as a non-invasive measure of HPA function and/or disease severity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Bidirectional communication between the immune and neuroendocrine systems is not well understood in the context of traumatic brain injury (TBI). The purpose of this study was to characterize relationships between cerebrospinal fluid (CSF) cortisol and inflammation after TBI, and to determine how these relationships differ by outcome. CSF samples were collected from 91 subjects with severe TBI during days 0-6 post-injury, analyzed for cortisol and inflammatory markers, and compared to healthy controls (n=13 cortisol, n=11 inflammatory markers). Group-based trajectory analysis (TRAJ) delineated subpopulations with similar longitudinal CSF cortisol profiles (high vs. low cortisol). Glasgow Outcome Scale (GOS) scores at 6months served as the primary outcome measure reflecting global outcome. Inflammatory markers that displayed significant bivariate associations with both GOS and cortisol TRAJ (interleukin [IL]-6, IL-10, soluble Fas [sFas], soluble intracellular adhesion molecule [sICAM]-1, and tumor necrosis factor alpha [TNF]-α) were used to generate a cumulative inflammatory load score (ILS). Subsequent analysis revealed that cortisol TRAJ group membership mediated ILS effects on outcome (indirect effect estimate=-0.253, 95% CI (-0.481, -0.025), p=0.03). Correlational analysis between mean cortisol levels and ILS were examined separately within each cortisol TRAJ group and by outcome. Within the low cortisol TRAJ group, subjects with unfavorable 6-month outcome displayed a negative correlation between ILS and mean cortisol (r=-0.562, p=0.045). Conversely, subjects with unfavorable outcome in the high cortisol TRAJ group displayed a positive correlation between ILS and mean cortisol (r=0.391, p=0.006). Our results suggest that unfavorable outcome after TBI may result from dysfunctional neuroendocrine-immune communication wherein an adequate immune response is not mounted or, alternatively, neuroinflammation is prolonged. Importantly, the nature of neuroendocrine-immune dysfunction differs between cortisol TRAJ groups. These results present a novel biomarker-based index from which to discriminate outcome and emphasize the need for evaluating tailored treatments targeting inflammation early after injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In vitro and ex vivo studies assessing the impact of stress hormones on immune competence commonly replace the natural milieu of leukocytes with an artificial medium, excluding plasma factors, hormones, and cytokines. Given prevalent inconsistencies between in vitro, ex vivo, and in vivo findings, we studied whether such procedures could yield misleading outcomes regarding the impact of stress hormones on NK cell cytotoxicity (NKCC), using fresh human whole blood samples. We found that in the presence of plasma 10-30-fold higher concentrations of cortisol, epinephrine, and prostaglandin-E2 (PGE2) were required to reach suppression levels evident in the context of artificial medium. Importantly, whereas the NK suppressive effects of PGE2 occurred immediately and remained stable upon prolonged exposure, the suppressive effects of cortisol slowly increased over time. Last, to simulate the exclusion of stress factors in the ex vivo approach, we subjected whole blood to stress hormones (as occurs in vivo), and abruptly removed them. We found that the effects of epinephrine and PGE2 quickly disappeared, while the effects of cortisol persisted. Overall, these findings demonstrate the potential misleading nature of in vitro and ex vivo procedures, and specifically suggest that (i) the common in vitro findings of profound suppression of NKCC by stress hormones are overestimation of their direct effects expected in vivo; and (ii) the common ex vivo approach cannot reflect the direct in vivo suppressive effects of epinephrine and PGE2 on NKCC, while inflating the effects of glucocorticoids. Some of these fallacies may be circumvented by using non-delayed whole blood NKCC assays in humans., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This paper presents a novel approach of using a miniaturized potentiostat (M-P) chip (LMP91000) to perform full range cyclic voltammetry (CV) measurements for the detection of biomarkers. The LMP91000 evaluation board was reconfigured to perform three-electrode CV measurements in order to achieve electrochemical cortisol immunosensing. The microelectrodes for cortisol estimation were fabricated by immobilizing monoclonal anti-cortisol antibody (Anti-M-Cab) onto self-assembled monolayer (SAM) modified Au microelectrodes. The results obtained using the M-P were compared to those obtained using a conventional potentiostat. The M-P was successful in measuring cortisol levels in the range of pM. The outcomes of the studies suggest that M-P can effectively perform biochemical measurements on three electrode systems, enabling the development of miniature systems for point-of-care (POC) diagnosis., (Copyright © 2014. Published by Elsevier B.V.)

Endurance exercise can cause immunosuppression and increase the risk of upper respiratory illness. The present study examined changes in the secretion of T helper (Th) cell cytokines after endurance exercise. Ten highly trained road cyclists [mean±SEM: age 24.2±1.7 years; height 1.82±0.02 m; body mass 73.8±2.0 kg; peak oxygen uptake 65.9±2.3 mL/(kg•min)] performed 2 h of cycling exercise at 90% of the second ventilatory threshold. Peripheral blood mononuclear cells were isolated and stimulated with phytohemagglutinin. Plasma cortisol concentrations and the concentration of Th1/Th2/Th17 cell cytokines were examined. Data were analyzed using both traditional statistics and magnitude-based inferences. Results revealed a significant decrease in plasma cortisol at 4-24 h postexercise compared with pre-exercise values. Qualitative analysis revealed postexercise changes in concentrations of plasma cortisol, IL-2, TNF, IL-4, IL-6, IL-10, and IL-17A compared with pre-exercise values. A Th1/Th2 shift was evident immediately postexercise. Furthermore, for multiple cytokines, including IL-2 and TNF (Th1), IL-6 and IL-10 (Th2), and IL-17 (Th17), no meaningful change in concentration occurred until more than 4 h postexercise, highlighting the duration of exercise-induced changes in immune function. These results demonstrate the importance of considering "clinically" significant versus statistically significant changes in immune cell function after exercise.