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The human circadian system creates and maintains cellular and systemic rhythmicity essential for the temporal organization of physiological processes promoting homeostasis and environmental adaptation. Sleep disruption and loss of circadian rhythmicity fundamentally affects master homeostasic regulating systems at the crossroads of peripheral and central susceptibility pathways, similar to acute or chronic stress and, thus, may play a central role in the development of stress-related disorders. Direct and indirect human and animal PTSD research accordingly suggests circadian-system-linked sleep, neuroendocrine, immune, metabolic and autonomic dysregulation, linking circadian misalignment to PTSD pathophysiology. Additionally, there is evidence that sleep and circadian disruption may represent a vital pre-existing risk factor in the prediction of PTSD development, while sleep-related symptoms are among the most prominent in trauma-associated disorders. These facts may represent a need for a shift towards a more chronobiological understanding of traumatic sequel and could support better prevention, evaluation and treatment of sleep and circadian disruption as first steps in PTSD management. In this special issue, we highlight and review recent advances from human sleep and chronobiological research that enhances our understanding of the development and maintenance of trauma-related disorders. Sleep and circadian disruption may be crucially involved in the development and maintenance of traumatic-stress-related disorders. There is a need for a chronobiological shift towards better evaluation, understanding and treatment of traumatic stress sequel.

Chromium has been studied since the end of the 19th century, when carcinogenic effects of hexavalent Cr were discovered. Essentiality of trivalent Cr was demonstrated in 1959; Cr3+ has been studied in humans and laboratory animals since the 1970s and it is only since the 1990s that Cr has been studied as an essential element in livestock animals with the same intensity. Trivalent Cr is essential to normal carbohydrate, lipid and protein metabolism. It is biologically active as part of an oligopeptide - chromodulin - potentiating the effect of insulin by facilitating insulin binding to receptors at the cell surface. Cr absorption is low, ranging between 0.4 and 2.0% for inorganic compounds while the availability of organic Cr is more than 10 times higher. Absorbed Cr circulates in blood bound to the beta-globulin plasma fraction and is transported to tissues bound to transferrin. Absorbed Cr is excreted primarily in urine, by glomerular filtration; a small amount is excreted through perspiration, bile and in milk. This review describes Cr metabolism, the different biological functions of Cr and symptoms of Cr deficiency.

Background: Humans have an evolutionary need for a well-preserved internal 'clock', adjusted to the 24-hour rotation period of our planet. This intrinsic circadian timing system enables the temporal organization of numerous physiologic processes, from gene expression to behaviour. The human circadian system is tightly and bidirectionally interconnected to the human stress system, as both systems regulate each other's activity along the anticipated diurnal challenges. The understanding of the temporal relationship between stressors and stress responses is critical in the molecular pathophysiology of stress-and trauma-related diseases, such as posttraumatic stress disorder (PTSD). Objectives/Methods: In this narrative review, we present the functional components of the stress and circadian system and their multilevel interactions and discuss how traumatic stress can affect the harmonious interplay between the two systems. Results: Circadian dysregulation after trauma exposure (posttraumatic chronodisruption) may represent a core feature of trauma-related disorders mediating enduring neurobiological correlates of traumatic stress through a loss of the temporal order at different organizational levels. Posttraumatic chronodisruption may, thus, affect fundamental properties of neuroendocrine, immune and autonomic systems, leading to a breakdown of biobehavioral adaptive mechanisms with increased stress sensitivity and vulnerability. Given that many traumatic events occur in the late evening or night hours, we also describe how the time of day of trauma exposure can differentially affect the stress system and, finally, discuss potential chronotherapeutic interventions. Conclusion: Understanding the stress-related mechanisms susceptible to chronodisruption and their role in PTSD could deliver new insights into stress pathophysiology, provide better psychochronobiological treatment alternatives and enhance preventive strategies in stress-exposed populations. * The human circadian and stress system are both essential for biobehavioural regulation with numerous reciprocal interaction. * Posttraumatic chronodisruption (i.e., circadian dysregulation after trauma) represents a core feature of PTSD, mediating neurobiological correlates of trauma through multilevel temporal order loss.

Glucocorticoid hormones, acting via nuclear receptors, regulate many metabolic processes, including hepatic gluconeogenesis. It recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but also by intracellular 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs), which interconvert active corticosterone (cortisol in humans) and inert 11-dehydrocorticosterone (cortisone in humans). 11 beta-HSD type 2, a dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data suggest the type 1 isozyme (11 beta-HSD-1) may function as an 11 beta-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11 beta-HSD-1 gene. These mice were unable to convert inert 11-dehydrocorticosterone to corticosterone in vivo. Despite compensatory adrenal hyperplasia and increased adrenal secretion of corticosterone, on starvation homozygous mutants had attenuated activation of the key hepatic gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, presumably, because of relative intrahepatic glucocorticoid deficiency. The 11 beta-HSD-1 -/- mice were found to resist hyperglycemia provoked by obesity or stress. Attenuation of hepatic 11 beta-HSD-1 may provide a novel approach to the regulation of gluconeogenesis

Background: Exposure to adversity in utero is thought to increase susceptibility to develop posttraumatic stress disorder (PTSD) following later life trauma, due to neurobiological programming effects during critical developmental periods. It remains unknown whether effects of prenatal adversity on PTSD susceptibility are modulated by genetic variations in neurobiological pathways implicated in PTSD susceptibility. Objective: We investigated whether genetic variation in the glucocorticoid receptor (GR) modulated effects of prenatal famine exposure on late adulthood PTSD symptom severity after trauma exposure in childhood and mid-to-late adulthood. Method: We included N = 439 term-born singleton adults (mean age: 72 years, 54.2% women) from the Dutch Famine Birth Cohort, born around the time of the Dutch Famine of 1944/1945, divided into exposure and control groups based on timing of the famine during gestation. Participants filled out self-report questionnaires on childhood (Childhood Trauma Questionnaire) and mid-to-late adulthood (Life Events Checklist for DSM-5) trauma, and current PTSD symptom severity (PTSD Checklist for DSM-5). GR haplotypes were determined from four functional GR single nucleotide polymorphisms (ER22/23EK, N363S, BclI and exon 9β) in previously collected DNA. Linear regression analyses were performed to investigate associations of GR haplotype and prenatal famine exposure in conjunction with later life trauma on PTSD symptom severity. Results: We observed a significant three-way interaction between the GR Bcll haplotype, famine exposure during early gestation, and adulthood trauma exposure on PTSD symptom severity in late adulthood. Only participants exposed to famine during early gestation without the GR Bcll haplotype showed a significantly stronger positive association between adulthood trauma and PTSD symptom severity than non-exposed participants, indicating increased PTSD susceptibility. Conclusions: Our results illustrate the importance of integrated approaches considering genetics and environmental contexts throughout various life periods, including the rarely investigated prenatal environment, to elucidate how PTSD susceptibility evolves throughout life. HIGHLIGHTS Adversity during pregnancy is thought to increase offspring's PTSD risk following later life trauma, but exact neurobiological mechanisms underlying this process remain unknown. We found that effects of prenatal famine exposure on PTSD symptom severity were influenced by genetic variation in the glucocorticoid receptor, which signals effects of the stress hormone cortisol. Integrated approaches considering genetics and environmental contexts throughout both early and later life are important to understand how PTSD risk evolves throughout life.

Efficient prevention of posttraumatic stress disorder (PTSD) needs to target individuals with an increased risk for adverse outcome after trauma. Prognostic or prescriptive biological markers assessed early posttrauma may inform personalized treatment recommendations. To test prognostic and prescriptive effects of early (posttraumatic) autonomic and endocrine markers on PTSD symptom development. Autonomic and endocrine markers were assessed within 12 days posttrauma and before treatment initiation within a randomized placebo-controlled trial investigating repeated oxytocin administration as preventive intervention for PTSD. Linear mixed effects models were used to test the effects of heart rate (variability), resting cortisol, morning cortisol and cortisol awakening response (CAR), cortisol suppression by dexamethasone and resting oxytocin on PTSD symptoms 1.5, 3 and 6 months posttrauma in men (n = 54), women using hormonal contraception (n = 27) and cycling women (n = 19). We found significant prognostic effects of resting oxytocin and cortisol suppression. In women using hormonal contraception, higher oxytocin was associated with higher PTSD symptoms across follow-up. Stronger cortisol suppression by dexamethasone, reflecting increased glucocorticoid receptor feedback sensitivity, was associated with lower PTSD symptoms across follow-up in men, but with higher symptoms at 1.5 months in women using hormonal contraception. These effects were independent of treatment condition. No further significant prognostic or prescriptive effects were detected. Our exploratory study indicates that resting oxytocin and glucocorticoid receptor feedback sensitivity early posttrauma are associated with subsequent PTSD symptom severity. Notably, prognostic effects depended on sex and hormonal contraception use, emphasizing the necessity to consider these factors in biomedical PTSD research.

Background: Pre-and post-traumatic hypothalamic-pituitary-adrenal (HPA) axis markers have been studied to predict posttraumatic stress disorder (PTSD) risk, but its acute reactivity cannot be measured in real-life settings. Experimental paradigms can depict the cortisol response to stimuli that simulate traumatic events. Objective: To review experimental studies on the cortisol response to traumatic stimuli and the correlation between cortisol and PTSD symptoms. Method: Experimental, (un-)published studies in German or English from any year were eligible if they confronted non-traumatized humans with traumatic stimuli, assessed cortisol before, during or after stimulus presentation and subsequent PTSD symptoms. The literature was searched via PubMed, PubPsych, PsychINFO, PsycArticle, Web of Science, EMBASE, ProQuest and ClinicalTrials.gov up to 16th February 2021. Risk of bias was assessed with the Cortisol Assessment List. Multilevel-meta-analyses were conducted under the random effects model. The standardized mean change (d SMC ) indicated the cortisol response. Coefficient r indicated the correlations between cortisol and PTSD symptoms. Results: 14 studies, investigating 1004 individuals, were included. A cortisol response was successfully induced between 21 and 40 min post-presentation onset (k observations  = 25, d SMC  = 0.15 [.03; .26]). Cortisol was not associated with overall or cluster-level PTSD symptoms. On a symptom-level, higher pre-presentation onset cortisol was correlated with lower state tension (k = 8, r = −.18 [−.35; −.01]), higher state happiness (k = 8, r = −.34 [−.59; −.03], variable inverted) and lower state anger (k = 9, r = −.14 [−.26; −.01]). Higher post-presentation onset cortisol was correlated with higher state happiness (k = 16, r = −.20 [−.33; −.06]) and lower state sadness (k = 17, r = −.16 [−.25; −.05]), whereas cortisol response was positively correlated with state anxiety (k = 9, r = .16 [0.04; 0.27]). Conclusions: Experimental paradigms effectively induce a cortisol response. Higher basal cortisol, higher cortisol, as measured after traumatic stimulus presentation, and a lower cortisol response were associated with more adaptive emotional reactions. These markers did not predict longer-term PTSD symptoms. Experimental trauma paradigms successfully induced a cortisol response. Cortisol was predictive for single state, emotion-related symptoms, but not overall PTSD symptoms. Trauma paradigms shed light into the immediate post-trauma period that is hard to capture in real life, but the gap between experimental and naturalistic settings is difficult to overcome.

Biodiversity conservation strategies are increasingly focused on regions outside national protected areas, where animals face numerous anthropogenic threats and must coexist with human settlements, livestock, and agriculture. The effects of these potential threats are not always clear, but they could have profound implications for population viability. We used savannah elephants (Loxodonta africana) as a case study to assess the physiological stress associated with living in a human-livestock-dominated landscape. We collected samples over two 3-month periods in 2007 and 2008. We used fecal DNA to identify 96 individual elephants in a community conservation area (CCA) and measured fecal glucocorticoid metabolite (FGM) concentrations as a proxy for stress. The CCA is community Maasai land managed for livestock and wildlife. We compared the FGM concentrations from the CCA to FGM concentrations of 40 elephants in Amboseli National Park and 32 elephants in the Maasai Mara National Reserve, where human settlements and intense livestock grazing were absent. In the CCA, we found no significant individual differences in FGM concentrations among the elephants in 2007 (p = 0.312) or 2008 (p = 0.412) and no difference between years (p = 0.616). The elephants in the CCA had similar FGM concentrations to the Maasai Mara population, but Amboseli elephants had significantly lower FGM concentrations than those in either Maasai Mara or the CCA (Tukey pairwise test, p < 0.001), due primarily to females excreting significantly lower FGM relative to males (p = 0.025). In the CCA, there was no relation among female group size, average pairwise group relatedness, and average group FGM concentration. We found no clear evidence of chronic stress in elephants living on CCA communal land, which is encouraging for conservation strategies promoting the protection of animals living outside protected areas. Las estrategias de conservación se enfocan cada vez más hacia regiones fuera de áreas nacionales protegidas, donde los animales enfrentan numerosas amenazas antropogénicas y deben coexistir con asentamientos humanos, ganado y agricultura. Los efectos de esas amenazas potenciales no siempre son claros, pero podrían tener implicaciones profundas para la viabilidad poblacional. Utilizamos elefantes africanos (Loxodonta africana) como un estudio de caso para evaluar el estrés fisiológico asociado con vivir en un paisaje dominado por humanos y ganado. Recolectamos muestras en 2 períodos de 3 meses en 2007 y 2008. Utilizamos ADN fecal para identificar a 96 elefantes individuales en un área de conservación comunitaria (ACC) y medimos las concentraciones del metabolito glucocorticoide fecal (MGF) como un indicador de estrés. El ACC es tierra Maasai comunitaria manejada para ganado y vida silvestres. Comparamos las concentraciones de MGF en el ACC con las concentraciones de MGF de 40 elefantes del Parque Nacional Amboseli y 32 elefantes de la Reserva Nacional Maasai Mara, donde no hay asentamientos humanos ni pastoreo intensivo. En el ACC, no encontramos diferencias individuales significativas en las concentraciones de MGF entre los elefantes en 2007 (p = 0.312) ni 2008 (p = 0.412) ni entre años (p = 0.616). Los elefantes en el ACC tuvieron concentraciones similares de MGF a la población de Maasai Mara, pero los elefantes de Amboseli tuvieron concentraciones de MGF significativamente menores que las de Maasai Mara o el ACC. (prueba pareada de Tukey, p < 0.001), debido principalmente a que las hembras excretan significativamente menos MGF que los machos (p = 0.025). En el ACC, no hubo relación entre el tamaño del grupo de hembras, la similitud promedio de grupos pareados, ni la concentración de MGF promedio del grupo. No encontramos evidencias claras de estrés crónico en elefantes viviendo en el ACC, lo cual es alentador para las estrategias de conservación que promueven la protección de animales que viven fuera de áreas protegidas.

Introducción: el síndrome de Cushing secundario al uso crónico de corticoides exógenos es una alteración endocrina producida por la exposición prolongada a estos fármacos, los cuales se emplean habitualmente en el tratamiento de diversas enfermedades inflamatorias y autoinmunes. Una de sus complicaciones más graves es la insuficiencia adrenal secundaria, que puede presentarse posterior al síndrome de retirada de corticoides (SRC). Este síndrome ocurre cuando los glucocorticoides se suspenden de forma abrupta, lo que provoca la supresión del eje hipotálamo-hipofisiario-adrenal (HHA) y, en consecuencia, una disminución aguda de la producción endógena de cortisol, provocando crisis adrenal. Objetivo: informar sobre los riesgos asociados al uso indiscriminado de corticoides, sus efectos adversos para la salud debido al uso prolongado y las consecuencias del cese abrupto de estos medicamentos. Presentación del caso: paciente que utilizo? glucocorticoides por tiempo prolongado para manejo de dolor crónico, posteriormente desarrollo? síndrome de Cushing exógeno. Tras el síndrome de retirada de corticoides, se evidencio? supresión del eje HHA y, como consecuencia, insuficiencia adrenal (IA). Discusión y conclusión: se estima que entre el 70 % y el 90 % de los casos de síndrome de Cushing son por uso de corticoides exógenos. Tras la suspensión abrupta del tratamiento puede ocurrir una crisis adrenal secundaria al síndrome de retirada de corticoides. En Colombia, el fácil acceso a glucocorticoides favorece su uso inadecuado; por ello, el diagnóstico debe basarse en una adecuada historia clínica y estudios de laboratorio ante la sospecha.