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ZusammenfassungSARS-CoV‑2 und die damit assoziierte COVID-19-Erkrankung stellen Gesundheitssysteme weltweit vor große Herausforderungen. Fast täglich werden neue Erkenntnisse zu Diagnostik, Klinik und Therapie der Erkrankung publiziert. Dieser Fallbericht beschreibt den letalen Krankheitsverlauf eines 81-jährigen Patienten ohne pulmonale Vorerkrankungen, der als Komplikation der COVID-19-Pneumonie unter nichtinvasiver High-Flow-Sauerstofftherapie eine Riesenbulla entwickelte. Pathophysiologisch kommen/kommt eine virusbedingte diffuse Zerstörung des Alveolargewebes und/oder die „patient self-inflicted lung injury“ in Betracht.

The outbreak of SARS-CoV‑2 and the associated COVID-19 pandemic pose major challenges to healthcare systems worldwide. New data on diagnosis, clinical presentation and treatment of the disease are published on a daily basis. This case report describes the fatal course of severe COVID-19 pneumonia in an 81-year-old patient with no previous pulmonary disease who developed a giant bulla during non-invasive high-flow oxygen therapy. Virus-induced diffuse destruction of alveolar tissue or patient self-inflicted lung injury (P-SILI) are discussed as possible pathomechanisms. Future studies must determine whether lung-protective mechanical ventilation with high levels of sedation and paralysis to suppress spontaneous respiratory drive and to reduce transpulmonary pressure can prevent structural lung damage induced both by the virus and P‑SILI in COVID-19 patients with ARDS.SARS-CoV‑2 und die damit assoziierte COVID-19-Erkrankung stellen Gesundheitssysteme weltweit vor große Herausforderungen. Fast täglich werden neue Erkenntnisse zu Diagnostik, Klinik und Therapie der Erkrankung publiziert. Dieser Fallbericht beschreibt den letalen Krankheitsverlauf eines 81-jährigen Patienten ohne pulmonale Vorerkrankungen, der als Komplikation der COVID-19-Pneumonie unter nichtinvasiver High-Flow-Sauerstofftherapie eine Riesenbulla entwickelte. Pathophysiologisch kommen/kommt eine virusbedingte diffuse Zerstörung des Alveolargewebes und/oder die „patient self-inflicted lung injury“ in Betracht.

BACKGROUND Patients undergoing cardiac surgery commonly develop systemic inflammation associated with tissue edema, which impairs outcome. One main pathomechanism leading to the edema is the deterioration of the endothelial glycocalyx, a key component of the vascular barrier. In animal models hydrocortisone has proved to be protective for the glycocalyx. OBJECTIVE This trial evaluates the effect of hydrocortisone on glycocalyx integrity in patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS In a prospective, randomized interventional pilot trial, 30 patients received either hydrocortisone (100 mg over 10 min) or placebo (saline control) before surgery. Plasma concentrations of glycocalyx constituents (syndecan-1, heparan sulfate) and various clinical parameters (respiratory and renal function, inflammatory markers, use of vasopressors, length of stay at the intensive care unit) were measured. Primary endpoint was a significant difference of glycocalyx constituents in plasma. Comparisons were made with Friedman's and Wilcoxon tests (paired data), or the Kruskal-Wallis and Mann-Whitney U tests (unpaired data). Holm-Bonferroni method was used for post-hoc corrections. RESULTS Heparan sulfate and syndecan-1 increased significantly during and after cardiac surgery with cardiopulmonary bypass in both groups. Whereas the maximum increase of heparan sulfate was 12.3-fold in the control vs. 3.8-fold in the pretreated group (p

Item does not contain fulltext Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

Aims: Animal experiments have shown that the endocannabinoid system (ECS) plays an important role in the regulation of ethanol intake. We investigated these effects in healthy volunteers who consumed a moderate amount of ethanol (red wine) and measured plasma levels of the endocannabinoids (ECs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) to test whether alcohol consumption influences the ECS in humans. Grape juice or plain non-sparkling water served as non-alcoholic control liquids. Methods: In total, 55 adults were enrolled in this study and assigned to one of three groups drinking either 250 ml of red wine (28.0 g of ethanol

The effects of physical exercise stress on the endocannabinoid system in humans are almost unexplored. In this prospective study, we investigated in a crossover design and under field conditions at different altitudes the effects of physical exercise on the endocannabinoid system (ECS) in 12 trained healthy volunteers. For determination of alterations on the ECS three different protocols were analyzed: Protocol A (physical exercise at lower altitude) involved strenuous hiking below 2,100 m, whereas Protocol B (physical exercise by active ascent to high altitude) involved hiking up to 3,196 m, an accommodation at the cottage and a descent the next day. Protocol C (passive ascent) included a helicopter ascent to 3,196 m, an overnight stay at this altitude and a flight back to the base camp the following day. The cumulative hiked altitude in Protocol A and B was comparable (~1,650 m). The blood EC concentrations of anandamide increased significantly in Protocol A/B from baseline (T0) 0.12 ± 0.01/0.16 ± 0.02 (mean ± SEM) to 0.27 ± 0.02/0.42 ± 0.02 after exercise (T1) (p < 0.05). Anandamide levels in Protocol C remained stable at 0.20 ± 0.02. We conclude that the ECS is activated upon strenuous exercise whereas the combination with hypoxic stress further increases its activity. The reduced partial pressure of oxygen at high altitude alone did not affect this system. In summary, physical exercise activates the endocannabinoid system, whereas the combination with high altitude enhances this activation. This discloses new perspectives to adaptation mechanisms to physical exercise.

Peri-operative acute renal failure requiring renal replacement therapy is common (5-30%) after cardiac surgery and associated with a mortality of approximately 50%. Pre-operative renal impairment seems to be the most important risk factor for frank postoperative renal failure. To help evaluate the risk factors, we conducted a prospective observational trial of 1574 consecutive patients with normal pre-operative renal function (creatinine110 micromol.l(-1)). Renal failure was defined as the need for renal replacement therapy. After univariate analysis of previously described risk factors, those who differed significantly between patients with or without renal failure were enrolled into a multivariate classification and regression tree (CART) statistical model that identifies the most 'predictive' risk factors and creates a ranked list of these. In patients with pre-operatively normal renal function, a serum level of lactate1.1 mmol.l(-1) in the first 24 h after the operation was the strongest predictor for the development of renal failure.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. The pathogenesis of this syndrome is not clear; however, it includes complex interactions between the nervous and the immune system resulting in chronic inflammation, pain and trophic changes. This interaction may be mediated by chronic stress which is thought to activate the endogenous cannabinoid (endocannabinoid) system (ECS). We conducted an open, prospective, comparative clinical study to determine plasma level of the endocannabinoid anandamide by high-performance liquid chromatography and a tandem mass spectrometry system in 10 patients with CRPS type I versus 10 age- and sex-matched healthy controls. As compared to healthy controls, CRPS patients showed significantly higher plasma concentrations of anandamide. These results indicate that the peripheral ECS is activated in CRPS. Further studies are warranted to evaluate the role of the ECS in the limitation of inflammation and pain.

Die extrakorporale Membranoxigenation (ECMO) bildet neben einer Vielzahl anderer, konservativer Therapieansatze eine Behandlungsalternative beim schweren, akuten Lungenversagen (veno-venose Systeme) und in Ausnahmefallen auch beim akuten Herz-Kreislaufversagen (veno-arterielle Systeme). Beide Methoden kommen bei hochselektierten Patienten in spezialisierten Zentren zur Anwendung, in Ausnahmefallen ist aber auch ein mobiler Einsatz und auch Transport von Patienten unter ECMO moglich. Kontrollierte Studien konnten bisher keinen Uberlebensvorteil bei Anwendung dieser Technik nachweisen, sie kann jedoch in Einzelfallen lebensrettend sein. Langzeituberlebende Patienten nach Einsatz dieser Technik zeigen signifikante Einschrankungen ihrer gesundheitsbezogenen Lebensqualitat (HRQL), wobei es aber uber Jahre nach Verlassen der Intensivstation zu einer langsamen Normalisierung kommt und schwere Einschrankungen selten sind. Chronische Post-Traumatische Belastungsstorungen (PTSD) und andere stress-assoziierte Erkrankungen finden sich bei Patienten nach ECMO Therapie in bis zu 30% der Falle. Chronische Stresserkrankungen haben einen signifikant negativen Effekt auf die erreichte HRQL und sind im Gesamtverlauf der Rehabilitationsphase zu berucksichtigen.

Heutzutage gilt die Herztransplantation (HTX) als Goldstandard der Therapie der chronischen und terminalen Herzinsuffizienz. Das akute Transplantatversagen (ATV) nach HTX ist eine dramatische Komplikation, die mit einer hohen Morbiditat und Mortalitat einhergeht. Als Risikofaktoren konnten bisher eine verlangerte Ischamiezeit, eine schlechte Organqualitat und eine akuten Abstosungsreaktion identifiziert werden. Folge des ATV ist nicht selten ein Multiorganversagen (MOV). Als therapeutische Optionen stehen primar konservative Masnahmen, wie die Behandlung mit Katecholaminen und Phosphodiesterasehemmern zur Verfugung, die jedoch selbst mit Nebenwirkungen und potentiellen Komplikationen vergesellschaftet sind. Bei Versagen konservativer Masnahmen muss haufig auf mechanische Kreislaufunterstutzungssysteme zuruckgegriffen werden, die sich von der intraaortalen Ballonpumpe bis zur Implantation eines biventrikularen Assist-devices erstrecken. Kalziumsensitizer steigern die kardiale Kontraktilitat, ohne die intrazellulare Kalziumkonzentration zu beeinflussen und umgehen somit die Nebenwirkungen eines Kalziumuberangebots. Wir berichten von zwei Fallen ATV nach HTX, das sich jeweils nach der Gabe von Levosimendan, einem Kalziumsensitizer, rasch erholte.

© 2014, National Academy of Sciences. All rights reserved. Previous studies have provided extensive evidence that administration of cannabinoid drugs after training modulates the consolidation of memory for an aversive experience. The present experiments investigated whether the memory consolidation is regulated by endogenously released cannabinoids. The experiments first examined whether the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are released by aversive training. Inhibitory avoidance training with higher footshock intensity produced increased levels of AEA in the amygdala, hippocampus, and medial prefrontal cortex (mPFC) shortly after training in comparison with levels assessed in rats trained with lower footshock intensity or unshocked controls exposed only to the training apparatus. In contrast, 2-AG levels were not significantly elevated. The additional finding that posttraining infusions of the fatty acid amide hydrolase (FAAH) inhibitor URB597, which selectively increases AEA levels at active synapses, administered into the basolateral complex of the amygdala (BLA), hippocampus, or mPFC enhanced memory strongly suggests that the endogenously released AEA modulates memory consolidation. Moreover, in support of the view that this emotional training-associated increase in endocannabinoid neurotransmission, and its effects on memory enhancement, depends on the integrity of functional interactions between these different brain regions, we found that disruption of BLA activity blocked the training-induced increases in AEA levels as well as the memory enhancement produced by URB597 administered into the hippocampus or mPFC. Thus, the findings provide evidence that emotionally arousing training increases AEA levels within prefrontal-limbic circuits and strongly suggest that this cannabinoid activation regulates emotional arousal effects on memory consolidation.

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.

Recurrent myelitis is one of the predominant characteristics in patients with neuromyelitis optica (NMO). While paresis, visual loss, sensory deficits, and bladder dysfunction are well known symptoms in NMO patients, pain has been recognized only recently as another key symptom of the disease. Although spinal cord inflammation is a defining aspect of neuromyelitis, there is an almost complete lack of data on altered somatosensory function, including pain. Therefore, eleven consecutive patients with NMO were investigated regarding the presence and clinical characteristics of pain. All patients were examined clinically as well as by Quantitative Sensory Testing (QST) following the protocol of the German Research Network on Neuropathic Pain (DFNS). Additionally, plasma endocannabinoid levels and signs of chronic stress and depression were determined. Almost all patients (10/11) suffered from NMO-associated neuropathic pain for the last three months, and 8 out of 11 patients indicated relevant pain at the time of examination. Symptoms of neuropathic pain were reported in the vast majority of patients with NMO. Psychological testing revealed signs of marked depression. Compared to age and gender-matched healthy controls, QST revealed pronounced mechanical and thermal sensory loss, strongly correlated to ongoing pain suggesting the presence of deafferentation-induced neuropathic pain. Thermal hyperalgesia correlated to MRI-verified signs of spinal cord lesion. Heat hyperalgesia was highly correlated to the time since last relapse of NMO. Patients with NMO exhibited significant mechanical and thermal dysesthesia, namely dynamic mechanical allodynia and paradoxical heat sensation. Moreover, they presented frequently with either abnormal mechanical hypoalgesia or hyperalgesia, which depended significantly on plasma levels of the endogenous cannabinoid 2- arachidonoylglycerole (2-AG). These data emphasize the high prevalence of neuropathic pain and hyperalgesia in patients with NMO. The degree of mechanical hyperalgesia reflecting central sensitization of nociceptive pathways seems to be controlled by the major brain endocannabinoid 2-AG. peerReviewed

Contains fulltext : 125746.pdf (Publisher’s version ) (Open Access) BACKGROUND: Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. METHODS: We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. RESULTS: Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48 +/- 0.11 vs. 0.36 +/- 0.14 ng/ml, p = 0.01), 2-AG (8.93 +/- 3.20 vs. 6.26+/-2.10 ng/ml, p

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.

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.

Item does not contain fulltext There is extensive evidence that glucocorticoid hormones impair the retrieval of memory of emotionally arousing experiences. Although it is known that glucocorticoid effects on memory retrieval impairment depend on rapid interactions with arousal-induced noradrenergic activity, the exact mechanism underlying this presumably nongenomically mediated glucocorticoid action remains to be elucidated. Here, we show that the hippocampal endocannabinoid system, a rapidly activated retrograde messenger system, is involved in mediating glucocorticoid effects on retrieval of contextual fear memory. Systemic administration of corticosterone (0.3-3 mg/kg) to male Sprague-Dawley rats 1 h before retention testing impaired the retrieval of contextual fear memory without impairing the retrieval of auditory fear memory or directly affecting the expression of freezing behavior. Importantly, a blockade of hippocampal CB1 receptors with AM251 prevented the impairing effect of corticosterone on retrieval of contextual fear memory, whereas the same impairing dose of corticosterone increased hippocampal levels of the endocannabinoid 2-arachidonoylglycerol. We also found that antagonism of hippocampal beta-adrenoceptor activity with local infusions of propranolol blocked the memory retrieval impairment induced by the CB receptor agonist WIN55,212-2. Thus, these findings strongly suggest that the endocannabinoid system plays an intermediary role in regulating rapid glucocorticoid effects on noradrenergic activity in impairing memory retrieval of emotionally arousing experiences.

The endocannabinoid system (ECS) is an old and evolutionarily well preserved neurobiologic system controlling some key elements of organ homeostasis. In contrast to its long biologic history, the scientific record of the ECS is very short. Whereas the occurrence of genes for the endocannabinoid receptors has been described in ancient animals reaching at least as far back as the predecessor of tetrapods (amphibians reptiles, birds, and mammals), modern science has only more recently demonstrated that the ECS is involved in the regulation of a wide range of essential central and peripheral processes which include metabolism and feeding behavior, inflammatory- and anti-inflammatory immunologic reactions, neurobehavioral changes during stress and anxiety and the regulation of central functions such as cognition and memory. One of the most important roles of the ECS lies in the regulation and orchestration of the central and immunologic stress response to aversive and threatening life conditions. There are already data that the ECS is affected in humans during highly aversive conditions of parabolic flights and space flights as well as in other extreme living conditions (e.g. Antarctica). The ECS may therefore have an important function for adaption processes in such aversive conditions.

Background Propofol is associated with postoperative mood alterations and induces a higher incidence of dreaming compared with other general anesthetics. These effects might be mediated by propofol's inhibitory action on fatty acid amide hydrolase, the enzyme that degrades the endocannabinoid anandamide. Because propofol is also associated with a higher incidence of traumatic memories from perioperative awareness and intensive care unit treatment and the endocannabinoid system is involved in regulating memory consolidation of emotional experiences, the authors investigated whether propofol, at anesthetic doses, modulates memory consolidation via an activation of the endocannabinoid system. Methods Male Sprague-Dawley rats were trained on an inhibitory avoidance task in which they received an inescapable foot shock upon entering the dark compartment of the apparatus. Drugs were administered intraperitoneally immediately or 30, 90, or 180 min after training. On the retention test 48 h later, the latency to reenter the dark compartment was recorded and taken as a measure of memory retention. Results The anesthetic doses of propofol administered after training significantly increased latencies of 48-h inhibitory avoidance performance (483.4 ± 181.3, 432.89 ± 214.06, 300 and 350 mg/kg, respectively; mean ± SD) compared with the corresponding vehicle group (325.33 ± 221.22, mean ± SD), which is indicative of stronger memory consolidation in propofol treated rats. Administration of a nonimpairing dose of the cannabinoid receptor antagonist rimonabant blocked the memory enhancement induced by propofol (123.39 ± 133.10, mean ± SD). Delayed administration of propofol 90 and 180 min after training or immediate posttraining administration of the benzodiazepine midazolam or the barbiturate pentobarbital did not significantly alter retention. Conclusions These findings indicate that propofol, in contrast to other commonly used sedatives, enhances emotional memory consolidation when administered immediately after a stressful event by enhancing endocannabinoid signaling.

Objective: Glucocorticoids play a major role in the consolidation and retrieval of traumatic information. They act through the glucocorticoid receptor, for which, in humans, several polymorphisms have been described. In particular, the BclI single-nucleotide polymorphism is associated with hypersensitivity to glucocorticoids and with susceptibility to development of major depression. Furthermore, in patients with posttraumatic stress disorder carrying the BclI GG genotype, cortisol levels were lower and showed an inverse relationship to posttraumatic stress disorder symptom intensity. Here, we studied the association of the BclI polymorphism with plasma cortisol levels, traumatic memories, posttraumatic stress disorder symptoms, and health-related quality of life outcomes in 126 patients undergoing cardiac surgery and intensive care unit therapy.Design: Prospective observational study.Setting: Cardiovascular intensive care unit in a university hospital.Patients: A total of 126 patients undergoing cardiac surgery and intensive care unit treatmentInterventions: No interventions were performed.Measurements and Main Results: Validated questionnaires were used to quantify end points. Measurements were taken 1 day before and 1 wk and 6 months after cardiac surgery. Homozygous carriers of the BclI G allele (n = 21) had significantly lower preoperative plasma cortisol levels and more long-term traumatic memories from intensive care unit therapy at 6 months after cardiac surgery than heterozygous carriers or noncarriers (1.9 +/- 1.4 vs. 1.0 +/- 1.2, p = .01). Anxiety was significantly more common as a long-term traumatic memory in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers (57% vs. 35%, p = .03). Posttraumatic stress disorder symptom scores were significantly higher at discharge from the intensive care unit in homozygous BclI G allele carriers than in heterozygous carriers or noncarriers. Only heterozygous carriers or BclI G allele noncarriers had a significant gain in health-related quality of life physical function at 6 months after cardiac surgery (p Conclusion: Homozygous BclI G allele carriers are at risk for traumatic memories, posttraumatic stress disorder symptoms, and lower health-related quality of life after cardiac surgery and intensive care unit therapy. The BclI single-nucleotide polymorphism may help to identify individuals at need for tailored medical care. (Crit Care Med 2011; 39: 643-650)

The endocannabinoid system (ECS) is an endogenous signalling system which includes the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and specific G-protein-coupled endocannabinoid receptors (CB1 and CB2). Recent studies have described important roles of the peripheral ECS in human atherosclerosis, cardiometabolic disorders, heart failure, and systemic inflammation. We sought to study changes in plasma endocannabinoid concentrations during cardiac surgery (CS) under general anaesthesia with isoflurane/sufentanil, and during cardiopulmonary bypass (CPB).We studied 30 patients undergoing CS with CPB. All patients received midazolam and sufentanil for induction and isoflurane and sufentanil for maintenance of general anaesthesia. Blood samples were drawn before and after induction of general anaesthesia, after the beginning of surgery, during and after weaning from CPB, and after admission to intensive care unit (ICU) after surgery. Endocannabinoid measurements were performed by HPLC-tandem mass spectrometry.Induction of general anaesthesia led to a significant decline in plasma AEA concentrations [from mean (sd) 0.39 (0.03) to 0.27 (0.03) ng ml(-1), P0.01]. CPB induced a pronounced increase in 2-AG concentrations [from 112.5 (163.5) to 321.0 (120.4) ng ml(-1), P0.01], whereas AEA concentrations remained persistently low until admission to the ICU. 2-AG concentrations returned to preoperative values after surgery.General anaesthesia with isoflurane significantly reduces plasma AEA concentrations. This could be a consequence of stress reduction after loss of consciousness. The significant increase in 2-AG after initiation of CPB may be part of an inflammatory response. These findings suggest that anaesthesia and surgery have differential effects on the ECS which could have substantial clinical consequences.

Severe systemic inflammation (systemic inflammatory response syndrome) associated with cardiac surgery often leads to a worse short-term and long-term outcome. Stress doses of hydrocortisone have been successfully used to improve outcome of CS. The interleukin (IL)-6 to IL-10 ratio is associated with outcome after trauma and major surgery.To evaluate immunologic effects (especially IL-6 to IL-10 ratio) of stress doses of hydrocortisone in a high-risk group of patients after cardiac surgery with cardiopulmonary bypass.Prospective, randomized, double-blinded, placebo-controlled trial.Cardiovascular intensive care unit of a university hospital.High-risk patients (n = 36) undergoing CS.Stress doses of hydrocortisone or placebo.IL-6 to IL-10 ratio and other markers of systemic inflammation at predefined time points; short-term clinical outcome.The two study groups did not differ with regard to demographic data. The patients from the hydrocortisone group (n = 19) had significantly lower levels of IL-6 and higher levels of IL-10, resulting in an attenuated change in IL-6/IL-10 ratio (28.7 [6.4/128.7] vs. 292.8 [6.5/534.6] 4 hours after cardiopulmonary bypass; p0.001). Patients in the hydrocortisone group had a shorter duration of catecholamine support (1 [1/2] vs. 4 [2/4.5] days; p = 0.02), a shorter length of stay in the intensive care unit (2 [2/3] vs. 6 [4/8] days; p = 0.001), and a lower incidence of postoperative atrial fibrillation (26% vs. 59%; p = 0.04).Stress doses of hydrocortisone attenuate the evolution of IL-6/IL-10 ratio in patients with systemic inflammatory response syndrome after CS, which seems to be associated with an improved outcome. The immunologic effects of hydrocortisone may thus be both, inhibitory (IL-6) and permissive (IL-10), regarding the immune response.

Extensive evidence indicates that the basolateral complex of the amygdala (BLA) modulates the consolidation of memories for emotionally arousing experiences, an effect that involves the activation of the glucocorticoid system. Because the BLA expresses high densities of cannabinoid CB1 receptors, the present experiments investigated whether the endocannabinoid system in the BLA influences memory consolidation and whether glucocorticoids interact with this system. The CB1 receptor agonist WIN55,212-2 (5–50 ng per 0.2 μL per side), infused bilaterally into the BLA of male Sprague–Dawley rats immediately after inhibitory avoidance training, induced dose-dependent enhancement of 48-h retention. Conversely, the CB1 receptor antagonist AM251 (0.07–0.28 ng per 0.2 μL per side) administered after training into the BLA induced inhibitory avoidance retention impairment. Furthermore, intra-BLA infusions of a low and nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory enhancement induced by concurrent administration of WIN55,212-2. Delayed infusions of WIN55,212-2 or AM251 administered into the BLA 3 h after training or immediate posttraining infusions of these drugs into the adjacent central amygdala did not significantly alter retention performance. Last, intra-BLA infusions of a low and otherwise nonimpairing dose of AM251 (0.14 ng per 0.2 μL per side) blocked the memory-enhancing effect induced by systemic administration of corticosterone (3 mg/kg, s.c.). These findings indicate that endocannabinoids in the BLA enhance memory consolidation and suggest that CB1 activity within this brain region is required for enabling glucocorticoid effects on memory consolidation enhancement.

Survivors of the acute respiratory distress syndrome (ARDS) often report traumatic memories from the intensive care unit (ICU) and display a high incidence of post-traumatic stress disorder (PTSD). As it is known that subjects with PTSD often show sustained reductions in circulating cortisol concentrations, we examined the relationship between serum cortisol, traumatic memories and PTSD in patients after ARDS. We evaluated 33 long-term survivors of ARDS (7.5 +/- 2.9 years after discharge from the ICU) for pre-defined categories of traumatic memory from the ICU, hypothalamic-pituitary-adrenocortical aids reactivity to corticotropin and PTSD (by psychiatric interview). During evaluation, patients with multiple traumatic memories had significantly lower basal serum cortisol levels when compared to patients with no or only I category of traumatic memory, with no differences in peak cortisol. levels after corticotropin stimulation between both subgroups. There was a significant negative correlation between basal cortisol levels and the number of traumatic memories present. PTSD symptom scores correlated with the number of traumatic memories but not with cortisol levels. These findings indicate that lower baseline cortisol levels in long-term survivors of ARDS are associated with an increased incidence of traumatic memories from the ICU, and that more traumatic memories are related to a higher incidence and intensity of PTSD symptoms. (C) 2009 Elsevier B.V. All rights reserved.

Fibromyalgia (FM) is a common stress-related painful disorder. There is considerable evidence of neuroimmunologic alterations in FM which may be the consequence of chronic stress and pain or causally involved in the development of this disorder. The endocannabinoid system has been shown to play a pivotal role in mammalian nociception, is activated under stressful conditions and can be an important signaling pathway for immune modulation. The endocannabinoid system could therefore be involved in the complex pathophysiology of FM. We tested this hypothesis by evaluating the effects of stress hormones and the endocannabinoid anandamide on neutrophil function in patients with FM. We determined plasma levels of catecholamines, cortisol and anandamide in 22 patients with primary FM and 22 age- and sex-matched healthy controls. Neutrophil function was characterized by measuring the hydrogen peroxide (H2O2) release (oxidative stress) and the ingestion capabilities of neutrophils (microbicidal function). FM patients had significantly higher norepinephrine and anandamide plasma levels. Neutrophils of FM patients showed an elevated spontaneous H2O2 production. The ability of neutrophils to adhere was negatively correlated with serum cortisol levels. Adhesion and phagocytosis capabilities of neutrophils correlated positively with anandamide plasma levels. In conclusion, patients with FM might benefit from pharmacologic manipulation of endocannabinoid signaling which should be tested in controlled studies.

Background: Endogenous ligands of cannabinoid receptors ( endocannabinoids), in particular anandamide ( arachidonylethanolamide), have been recognized as being of crucial importance in a variety of physiological functions. Plasma concentrations of anandamide have been measured in a number of investigations; however, discrepant data on "normal'' anandamide plasma concentrations were reported. Since this might be caused by pre-analytical variables, we investigated the impact of different sample handling conditions on measured plasma anandamide concentrations. Methods: Blood samples were taken from healthy volunteers in EDTA- or heparin-containing tubes; whole blood samples were kept at +4 degrees C, room temperature, or 37 degrees C, respectively, for up to 120 min before obtaining plasma by centrifugation. Plasma anandamide concentrations were measured by an isotope-dilution liquid chromatography tandem mass spectrometry ( LC-MS/MS) method. Results: A marked time- and temperature-dependent increase in plasma anandamide concentrations ex vivo was observed in both EDTA- and heparin-containing tubes. Mean anandamide concentrations approximately doubled when EDTA samples were kept at 4 degrees C for 60 min before centrifugation {[}immediately centrifuged, 1.3 mg/L ( SD 0.3 mg/L); 2.8 mg/L ( SD 0.5 mg/L) after storage for 60 min; n=12). After storage of heparinized whole-blood samples for 120 min at 37 degrees C, a mean plasma anandamide concentration of 11.9 mg/L ( SD 1.8 mg/L) was found. In cell-free plasma, no increase in anandamide concentrations was found. Conclusion: Anandamide is released from blood cells ex vivo at a very high rate; therefore, strictly standardized pre-analytical protocols have to be applied for plasma anandamide determination.

Background The endocannabinoid system includes G-protein-coupled cannabinoid receptors, the endocannabinoids N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and multiple enzymes involved in the biosynthesis and degradation of endocannabinoids, including the anandamide metabolizing enzyme fatty acid amide hydrolase. Endocannabinoids play an important role in the physiologic control of sleep, pain processing, and emesis. The authors therefore investigated the effects of general anesthesia on the endocannabinoid system in humans. Methods The authors measured whole blood levels of anandamide in 12 patients after induction of general anesthesia with etomidate (an agent shown to have no effect on anandamide levels) and maintenance of anesthesia with the volatile agent sevoflurane as well as in 12 patients undergoing total intravenous anesthesia with propofol, a known inhibitor of fatty acid amide hydrolase in the mouse brain. Anandamide levels were measured using high-performance liquid chromatography-tandem mass spectrometry at four time points (before and at 10, 20, 30, and 40 min after induction of anesthesia). Results Patients of the sevoflurane group showed a significant decline in anandamide levels from induction of anesthesia to 40 min after induction, whereas anandamide levels in patients of the propofol group remained unchanged (type III sum of squares = 1725.66, F = 162.60, P < 0.001, repeated-measures analysis of variance). Conclusion General anesthesia influences the endocannabinoid system in a drug-dependent way, which may explain side effects of general anesthetics such as psychomimetic and antiemetic properties of propofol and the high incidence of postoperative nausea and vomiting after volatile anesthetics. These findings suggest new targets for anesthetic drug development.

BACKGROUND: A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V) during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS) represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation. METHODOLOGY/PRINCIPAL FINDINGS: We studied the activity of the ECS in human volunteers (n = 21) during parabolic flight maneuvers (PFs). During PFs, microgravity conditions (

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