Effects of parabolic flight and spaceflight on the endocannabinoid system in humans

The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions, from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast, highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well-tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations, which returned to baseline values after the cosmonauts' return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions

Glucocorticoid-endocannabinoid interaction in cardiac surgical patients: relationship to early cognitive dysfunction and late depression

Background: Endocannabinoids (ECs) are rapidly acting immune-modulatory lipid-signaling molecules that are important for adaptation to stressful and aversive situations. They are known to interact with glucocorticoids and other stress-responsive systems. Maladaptation to acute or chronic stress represents a major risk factor for the development of psychiatric disorders. In the present study, we administered stress doses of hydrocortisone in a prospective, randomized, placebo-controlled double-blind study in patients undergoing cardiac surgery (CS) to examine the relationship between the use of glucocorticoids, plasma EC levels, and the occurrence of early postoperative cognitive dysfunction (delirium) and of later development of depression. Methods: We determined plasma levels of the ECs anandamide and 2-arachidonoylglycerol (2-AG) in CS patients of the hydrocortisone (n=56) and the placebo group (n=55) preoperatively, at postoperative day (POD) 1, at intensive care unit discharge, and at 6 months after CS (n=68). Postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association IVth Edition (DSM-IV) criteria, and depression was determined by validated questionnaires and a standardized psychological interview (Structured Clinical Interview for DSM-IV). Results: Stress doses of hydrocortisone did not affect plasma EC levels and the occurrence of delirium or depression. However, patients who developed delirium on POD 1 had significantly lower preoperative 2-AG levels of the neuroprotective EC 2-AG (median values, 3.8 vs. 11.3 ng/ml; p=0.03). Preoperative 2-AG concentrations were predictive of postoperative delirium (sensitivity=0.70; specificity=0.69; cutoff value=4.9 ng/ml; receiver operating characteristic curve area=0.70; 95% confidence interval=0.54-0.85). Patients with depression at 6 months after CS (n=16) had significantly lower anandamide and 2-AG levels during the perioperative period. Conclusions: A low perioperative EC response may indicate an increased risk for early cognitive dysfunction and long-term depression in patients after CS. Glucocorticoids do not seem to influence this relationship

Stress Induced Immune Dysregulation: A Continuum Spanning Antarctica Winterover, Spaceflight, and Terrestrial Patients

Spaceflight is a unique environment characterized by stress, microgravity, isolation, circadian misalignment, and radiation exposure and impacts immune health. Planned long duration missions to Mars are a top priority for NASA and mitigating the negative health consequences of spaceflight is particularly important. Terrestrial analogs are a vital aspect of spaceflight research since data from astronauts is limited and it is costly to receive samples from ISS. The most relevant ground analog would include station lifestyle, stress, disrupted circadian rhythms and isolation. This analysis compares various aspects of immune dysregulation in astronauts during long-duration orbital spaceflight to groundanalogs. Astronaut data were also compared to a clinical immunodeficiency population, shingles patients, to help interpret clinical risks during deep space missions. A comprehensive evaluation was performed across hypoxic interior Antarctica, normoxic coastal Antarctica, HERA, and astronauts which included plasma and mitogen stimulated cytokine profiles, T-cell function, and peripheral leukocyte distribution. A cross platform analysis was then performed to define in-flight immune alterations, determine analog appropriateness, and interpret clinical risk

PlanHab Study: Consequences of combined normobaric hypoxia and bed rest on adenosine kinetics

Adenosine plays a role in the energy supply of cells and provokes differential, hormone-like functions in circulating cells and various tissues. Its release is importantly regulated by oxygen tension. This renders adenosine and its kinetics interesting to investigate in humans subjected to low oxygen conditions. Especially for space exploration scenarios, hypoxic conditions - together with reduced gravity - represent two foreseen living conditions when planning manned long-duration space missions or planetary habitats. The PlanHab study investigated microgravity through inactivity in bed rest and normobaric hypoxia to examine their independent or combined effect on adenosine and its kinetics. Healthy male subjects (n = 14) completed three 21-day interventions: hypoxic bed rest (HBR); hypoxic ambulatory confinement (HAMB); normoxic bed rest (NBR). The interventions were separated by 4 months. Our hypothesis of a hypoxia-triggered increase in adenosine was confirmed in HAMB but unexpectedly also in NBR. However, the highest adenosine levels were noted following HBR. Furthermore, the percentage of hemolysis was elevated in HBR whereas endothelial integrity markers stayed low in all three interventions. In summary, these data suggest that neocytolysis accounts for these effects while we could reduce evidence for microcirculatory changes

Modulations of Neuroendocrine Stress Responses During Confinement in Antarctica and the Role of Hypobaric Hypoxia

The Antarctic continent is an environment of extreme conditions. Only few research stations exist that are occupied throughout the year. The German station Neumayer III and the French-Italian Concordia station are such research platforms and human outposts. The seasonal shifts of complete daylight (summer) to complete darkness (winter) as well as massive changes in outside temperatures (down to -80 degrees C at Concordia) during winter result in complete confinement of the crews from the outside world. In addition, the crew at Concordia is subjected to hypobaric hypoxia of similar to 650 hPa as the station is situated at high altitude (3,233 m). We studied three expedition crews at Neumayer Ill (sea level) (n = 16) and two at Concordia (high altitude) (n = 15) to determine the effects of hypobaric hypoxia on hormonal/metabolic stress parameters [endocannabinoids (ECs), catecholamines, and glucocorticoids] and evaluated the psychological stress over a period of 11 months including winter confinement. In the Neumayer III (sea level) crew, EC and n-acylethanolamide (NAE) concentrations increased significantly already at the beginning of the deployment (p < 0.001) whereas catecholamines and cortisol remained unaffected. Over the year, ECs and NAEs stayed elevated and fluctuated before slowly decreasing till the end of the deployment. The classical stress hormones showed small increases in the last third of deployment. By contrast, at Concordia (high altitude), norepinephrine concentrations increased significantly at the beginning (p < 0.001) which was paralleled by low EC levels. Prior to the second half of deployment, norepinephrine declined constantly to end on a low plateau level, whereas then the EC concentrations increased significantly in this second period during the overwintering (p < 0.001). Psychometric data showed no significant changes in the crews at either station. These findings demonstrate that exposition of healthy humans to the physically challenging extreme environment of Antarctica (i) has a distinct modulating effect on stress responses. Additionally, (ii) acute high altitude/hypobaric hypoxia at the beginning seem to trigger catecholamine release that downregulates the EC response. These results (iii) are not associated with psychological stress

Planning of shoulder prothesis based on 3D-CT-files: development of measurement parameters for the glenoid on cadavers

Fragestellung : Beim Ersatz des Glenoids im Rahmen der Schulterendoprothetik ist eine detaillierte Kenntnis über die nicht einsehbaren Bereiche der Scapula notwendig. Bisher sind nur wenige Parameter zur präoperativen Ausmessung des Glenoids bekannt. Zur Planung und Analyse des Glenoidersatzes wurde in dieser Arbeit ein Messprotokoll für 8 Parameter erstellt. Diese wurden in ihrer Aussagekraft durch Messung in verschiedenen Ebenen, durch Bestimmung von Korrelationen und im Seitenvergleich beurteilt. Material und Methoden : Zur Messung wurden 43 Schultern anatomischer Präparate (Alter 64-95 Jahre, 8 gepaarte männliche Schultern, 13 gepaarte weibliche Schultern+ 1 einzelne weibliche Schulter) mit dem Siemens Sensation-S16 Computertomographen untersucht und mit einem hier erarbeiteten standardisierten Messprotokoll und der Siemens Syngo-Software vermessen. An einem Präparat wurde die Messgenauigkeit durch mehrfach wiederholte Messungen bestimmt. Ergebnisse: Der anterior-posteriore Durchmesser des Glenoids betrug axial 2,57cm (±0,27) und sagittal 2,77cm (± 0,27), der kranio-kaudale Durchmesser koronar 3,29cm (± 0,3) und sagittal 3,31cm (± 0,3), die Glenoidfläche 7,88cm² (±1,3), der Inklinationswinkel 51,8° (±4,13), die Scapulahalsbreite 1,36cm (± 0,2), die Scapulahalstiefe 3,45cm (± 0,5), die Glenoidtiefe axial 0,24cm (± 0,09), die Glenoidtiefe koronar 0,43cm (±0,10) und die Retroversion des Glenoids betrug 2° (±3,35). Hohe positive Korrelationen fanden sich beim anterior-posterioren Durchmesser in sagittaler und axialer Ebene (0,83), beim anterior-posterioren Durchmesser axial und sagittal mit der Glenoidfläche (0,81/0,87), beim kranio-kaudalen Durchmesser koronar und sagittal mit der Glenoidfläche (0,86/0,90), sowie zwischen der gemessenen und der mit einer Ellipse bzw. einem Rechteck (0,97) berechneten Glenoidfläche. Der Seitenvergleich zwischen rechter und linker Schulter zeigt kleine signifikante Unterschiede bei einzelnen Parametern. Da die Abweichungen im Millimeterbereich liegen, kann bei der Prothesenplanung von der gesunden auf die kranke Schulter geschlossen werden. Schlussfolgerung: Das in dieser Arbeit erstellte Messprotokoll kann ganz oder teilweise bei der präoperativen Planung des Glenoidersatzes eingesetzt werden. Die bisher in der Literatur beschriebenen Parameter für die Vermessung des Glenoids wurden durch die Glenoidtiefe und die Scapulahalsbreite/-tiefe ergänzt. Die Messung gleicher Parameter in verschiedenen Ebenen des CT-Datensatzes ergab kleine charakteristische Unterschiede.Abstract Questioning : For the replacement of the glenoid in shoulder prothetics a detailed knowledge of the hidden parts of the scapula is necessary. Until now only little parameters are known fort the preoperative measurement of the glenoid. In this study a protocol for the measurement of 8 parameters for the planning and analysis of the glenoid replacement was established. Those parameters were evaluated in their meaning when measured in different CT planes, when correlated between each other and when compared between the left and the right shoulder. Material and methods : The measurement was executed on 43 shoulders of cadavers (aged between 64-95 years, 8 pairs of male shoulders, 13 pairs of female shoulders + 1 single female shoulder) with the Siemens Sensation – S16 computed tomography, its Siemens Syngo-Software and our established standardized protocol of measurement. The precision of the measurement was shown through repeated measurements on one cadaveric shoulder. durch mehrfach wiederholte Messungen bestimmt. Results: The anterior-posterior diameter of the glenoid in the axial plane was 2,57cm (±0,27) and in the sagittal plane 2,77cm (±0,27), the cranio-caudal diameter in the coronal plane 3,29cm (±0,3) and in the sagittal plane 3,31cm (±0,3), the glenoid surface 7,88cm² (±1,3), the inclination angle 51,8° (±4,13), the width of the scapula collar 1,36cm (±0,2), the depth of the scapula collar 3,45cm (±0,5), the depth of the glenoid cavity in the axial plane 0,24cm (±0,09), the depth of the glenoid cavity in the coronal plane 0,43cm (±0,10) and the retroversion of the glenoid was 2° (±3,35). High positive correlations were found for the anterior-posterior diameter in the sagittal and axial plane (0,83), for the anterior-posterior diameter in the axial and sagittal plane with the glenoid surface (0,81/0,87), for the cranio-caudal diameter in the coronal and sagittal plane with the glenoid surface (0,86/0,90), as for the measured glenoid surface with the calculated surface of an ellipse respectively a rectangle (0,97). The comparison between right and left shoulder showed small significant differences for single parameters. As the differences lie in the millimeter range, one can conclude from the measures of the healthy shoulder to the measures of the ill shoulder for the prothetic planning. geschlossen werden. Conclusion: The protocol of measurement established in this study can fully or partly be integrated in the preoperative planning of the glenoid replacement. Parameters for the measurement of the glenoid described in former literature were completed by the depth of the glenoid cavity and the width/depth of the scapula collar. The measurement of equal parameters in different CT planes showed small characteristic differences

PlanHab: Hypoxia counteracts the erythropoietin suppression, but seems to exaggerate the plasma volume reduction induced by 3 weeks of bed rest

The study examined the distinct and synergistic effects of hypoxia and bed rest on the erythropoietin (EPO) concentration and relative changes in plasma volume (PV). Eleven healthy male lowlanders underwent three 21-day confinement periods, in a counterbalanced order: (1) normoxic bed rest (NBR;PIO2: 133.1 +/- 0.3 mmHg);(2) hypoxic bed rest (HBR;PIO2: 90.0 +/- 0.4 mmHg, ambient simulated altitude of similar to 4000 m);and (3) hypoxic ambulation (HAMB;PIO2: 90.0 +/- 0.4 mmHg). Blood samples were collected before, during (days 2, 5, 14, and 21) and 2 days after each confinement to determine EPO concentration. Qualitative differences in PV changes were also estimated by changes in hematocrit and hemoglobin concentration along with concomitant changes in plasma renin concentration. NBR caused an initial reduction in EPO by similar to 39% (P = 0.04). By contrast, HBR enhanced EPO (P = 0.001), but the increase was less than that induced by HAMB (P < 0.01). All three confinements caused a significant reduction in PV (P < 0.05), with a substantially greater drop in HBR than in the other conditions (P < 0.001). Thus, present results suggest that hypoxia prevents the EPO suppression, whereas it seems to exaggerate the PV reduction induced by bed rest

The role of glucocorticoids, catecholamines and endocannabinoids in the development of traumatic memories and posttraumatic stress symptoms in survivors of critical illness

Critically ill patients are at an increased risk for traumatic memories and post-traumatic stress disorder (PTSD). Memories of one or more traumatic events play an important part in the symptom pattern of PTSD. Studies in long-term survivors of intensive care unit (ICU) treatment demonstrated a clear and vivid recall of traumatic experiences and the incidence and intensity of PTSD symptoms increased with the number of traumatic memories present. Preclinical evidence has clearly shown that the consolidation and retrieval of traumatic memories is regulated by an interaction between the noradrenergic, the glucocorticoid and the endocannabinoid system. Critically ill patients in the ICU frequently require treatment with adrenenergic or glucocorticoid drugs and often receive sedative medications; among them propofol is known to influence endocannabinoid signaling. Critical illness could therefore represent a useful model for investigating adrenergic, glucocorticoid as well as endocannabinoid effects on traumatic memory and PTSD development in stressed humans. The endocannabinoid system is an important regulator of HPA-axis activity during stress, an effect which has also been demonstrated in humans. Likewise, a single nucleotide polymorphism (SNP) of the glucocorticoid receptor (GR) gene (the BclI-SNP), which enhances the sensitivity of the glucocorticoid receptors to cortisol and possibly HPA-axis feedback function, was associated with enhanced emotional memory performance in healthy volunteers. The presence of the BclI-SNP increased the risk for traumatic memories and PTSD symptoms in patients after ICU therapy and was linked to lower basal cortisol levels. A number of small studies have demonstrated that the administration of cortisol to critically ill or injured patients results in a significant reduction of PTSD symptoms after recovery without influencing the number of traumatic memories. These glucocorticoid effects can possibly be explained by a cortisol-induced temporary impairment in traumatic memory retrieval which has previously been demonstrated in both rats and humans. The hypothesis that stress doses of glucocorticoids or the pharmacologic manipulation of glucocorticoid-endocannabinoid interaction during traumatic memory consolidation and retrieval could be useful for prophylaxis and treatment of PTSD after critical illness should be tested in larger controlled studies. © 2013 Elsevier Inc. All rights reserved

One year in the extreme isolation of Antarctica : is this enough to modulate an 'allergic' sensitization?

(1) Background: After spending a year wintering in Antarctica, individual expedition members have reported increased or even new allergic reactions to environmental allergens after their return. (2) Methods: Blood samples from five overwintering crews were analyzed using the chip based multiplex ALEX Allergy Explorer (MacroArray Diagnostics GmbH, Austria). (3) Results: About one third of the 39 participants displayed specific IgEs against pollen. In most individuals, kinetics showed a reduction in the specific IgE at the time about nine months after deployment to Antarctica. Five participants had the highest specific IgE levels after returning to the “normal” world. The examination of the specific IgE relative to house dust mites and storage mites showed different kinetics. Six out of 10 had the highest specific IgE concentrations at the inner Antarctic measurement time point. These data corresponded well to the general situation in the stations. At the stations themselves, there were almost no pollen particle load, especially at Concordia. (4) Conclusions: Antarctic long-term confinement can induce an altered immune function, which is in some individuals pronounced after return to the familiar allergen environment. Future prospective studies in larger cohorts are needed to further specify these first results