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Background: Late ischemic preconditioning is mediated via nuclear transcription factor signal transducer and activator of transcription 3 (STAT3). Pim-1 kinase reduces infarct size in cardiomyocytes and is regulated by STAT3. We tested the hypothesis that late desflurane-induced preconditioning (DES-SWOP) is mediated via STAT3 and Pim-1.Methods: After institutional approval, pentobarbital-anesthetized male C57BL/6 mice were subjected to 45 min coronary artery occlusion (CAO) and 3 h reperfusion. Control animals received no additional intervention. Desflurane was administered 48 h before CAO either alone or in combination with the janus kinase/STAT3 inhibitor AG-490 (40 μg/g i.p., 20 min before desflurane administration) or the Pim-1 kinase inhibitor II (PIM-Inh.II, 10 μg/g i.p., 15 min before CAO). Infarct size (IS) and area at risk were determined with triphenyltetrazolium chloride and Evans blue, respectively. Additionally, cytosolic and nuclear fractions were separated at two different time points and expression of STAT3, phospho-STAT3(Ser727) , phospho-STAT3(Tyr705) , Pim-1, Bad and phospho-Bad(Ser112) were determined by Western Blot analysis. Data were analyzed with one-way or two-way ANOVA and post hoc Duncan test and are presented as mean ± SEM.Results: IS was 47 ± 2% (n = 7-8 per group) in control animals (CON). DES-SWOP reduced myocardial infarct size to 23 ± 4%* (*P < 0.05 vs. CON). AG-490 alone did not affect myocardial infarct size (44 ± 7%), but abolished DES-SWOP (44 ± 4%). Blockade of Pim-1 did not affect the protection by DES-SWOP (34 ± 4%*). Desflurane reduced cytosolic content and enhanced nuclear content of phospho-STAT(S) (er727) . After 48 h, desflurane enhanced Pim-1 activity, whereas Pim-1 expression remained unchanged.Conclusion: These data suggest that DES-SWOP is mediated by activation and nuclear translocation of STAT3. The impact of Pim-1 in DES-SWOP signaling remains unclear. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemic preconditioning (IPC) and anesthetic-induced preconditioning against myocardial infarction are mediated via protein kinase B. Pim-1 kinase acts downstream of protein kinase B and was recently shown to regulate cardiomyocyte survival. The authors tested the hypothesis that IPC and anesthetic-induced preconditioning are mediated by Pim-1 kinase. METHODS: Pentobarbital-anesthetized male C57Black/6 mice were subjected to 45 min of coronary artery occlusion and 3 h of reperfusion. Animals received no intervention, Pim-1 kinase inhibitor II (10 microg/g intraperitoneally), its vehicle dimethyl sulfoxide (10 microl/g intraperitoneally), or 1.0 minimum alveolar concentration desflurane alone or in combination with Pim-1 kinase inhibitor II (10 microg/g intraperitoneally). IPC was induced by three cycles of 5 min ischemia-reperfusion each, and animals received IPC either alone or in combination with Pim-1 kinase inhibitor II (10 microg/g intraperitoneally). Infarct size was determined with triphenyltetrazolium chloride, and area at risk was determined with Evans blue (Sigma-Aldrich, Taufkirchen, Germany). Protein expression of Pim-1 kinase, Bad, phospho-Bad, and cytosolic content of cytochrome c were measured using Western immunoblotting. RESULTS: Infarct size in the control group was 47 + or - 2%. Pim-1 kinase inhibitor II (44 + or - 2%) had no effect on infarct size. Desflurane (17 + or - 3%) and IPC (19 + or - 2%) significantly reduced infarct size compared with control (both P < 0.05 vs. control). Blockade of Pim-1 kinase completely abrogated desflurane-induced preconditioning (43 + or - 3%), whereas IPC (35 + or - 3%) was blocked partially. Desflurane tended to reduce cytosolic content of cytochrome c, which was abrogated by Pim-1 kinase inhibitor II. CONCLUSION: These data suggest that Pim-1 kinase mediates at least in part desflurane-induced preconditioning and IPC against myocardial infarction in mice. [ABSTRACT FROM AUTHOR]

Abstract Background Septic acute liver and intestinal failure is associated with a high mortality. We therefore investigated the influence of volume resuscitation with different crystalloid or colloid solutions on liver and intestine injury and microcirculation in septic rodents. Methods Sepsis was induced by cecal ligation and puncture (CLP) in 77 male rats. Animals were treated with different crystalloids (NaCl 0.9% (NaCl), Ringer’s acetate (RA)) or colloids (Gelafundin 4% (Gel), 6% HES 130/0.4 (HES)). After 24 h animals were re-anesthetized and intestinal (n = 6/group) and liver microcirculation (n = 6/group) were obtained using intravital microscopy, as well as macrohemodynamic parameters were measured. Blood assays and organs were harvested to determine organ function and injury. Results HES improved liver microcirculation, cardiac index and DO2-I, but significantly increased IL-1β, IL-6 and TNF-α levels and resulted in a mortality rate of 33%. Gel infused animals revealed significant reduction of liver and intestine microcirculation with severe side effects on coagulation (significantly increased PTT and INR, decreased haemoglobin and platelet count). Furthermore Gel showed severe hypoglycemia, acidosis and significantly increased ALT and IL-6 with a lethality of 29%. RA exhibited no derangements in liver microcirculation when compared to sham and HES. RA showed no intestinal microcirculation disturbance compared to sham, but significantly improved the number of intestinal capillaries with flow compared to HES. All RA treated animals survided and showed no severe side effects on coagulation, liver, macrohemodynamic or metabolic state. Conclusions Gelatine 4% revealed devastated hepatic and intestinal microcirculation and severe side effects in CLP induced septic rats, whereas the balanced crystalloid solution showed stabilization of macro- and microhemodynamics with improved survival. HES improved liver microcirculation, but exhibited significantly increased pro-inflammatory cytokine levels. Crystalloid infusion revealed best results in mortality and microcirculation, when compared with colloid infusion.

Background & Aims: Vitamin D's pleiotropic effects include immune modulation, and its supplementation has been shown to prevent respiratory tract infections. The effectivity of vitamin D as a therapeutic intervention in critical illness remains less defined. The current study analyzed clinical and immunologic effects of vitamin D levels in patients suffering from coronavirus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS)., Methods: This was a single-center retrospective study in patients receiving intensive care with a confirmed SARS-CoV-2 infection and COVID-19 ARDS. 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum levels, pro- and anti-inflammatory cytokines and immune cell subsets were measured on admission as well as after 10-15 days. Clinical parameters were extracted from the patient data management system. Standard operating procedures included the daily administration of vitamin D 3 via enteral feeding., Results: A total of 39 patients with COVID-19 ARDS were eligible, of which 26 were included in this study as data on vitamin D status was available. 96% suffered from severe COVID-19 ARDS. All patients without prior vitamin D supplementation (n = 22) had deficient serum levels of 25-hydroxyvitamin D. Vitamin D supplementation resulted in higher serum levels of 25-hydroxyvitamin D but not did not increase 1,25-dihydroxyvitamin D levels after 10-15 days. Clinical parameters did not differ between patients with sufficient or deficient levels of 25-hydroxyvitamin D. Only circulating plasmablasts were higher in patients with 25-hydroxyvitamin D levels ≥30 ng/ml (p = 0.029). Patients with 1,25-dihydroxyvitamin D levels below 20 pg/ml required longer mechanical ventilation (p = 0.045) and had a worse acute physiology and chronic health evaluation (APACHE) II score (p = 0.048)., Conclusion: The vast majority of COVID-19 ARDS patients had vitamin D deficiency. 25-hydroxyvitamin D status was not related to changes in clinical course, whereas low levels of 1,25-dihydroxyvitamin D were associated with prolonged mechanical ventilation and a worse APACHE II score., Competing Interests: Conflict of interest None., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Dissection reports of large cats (family Felidae) have been published since the late 19th century. These reports generally describe the findings in words, show drawings of the dissection, and usually include some masses of muscles, but often neglect to provide muscle maps showing the precise location of bony origins and insertions. Although these early reports can be highly useful, the absence of visual depictions of muscle attachment sites makes it difficult to compare muscle origins and insertions in living taxa and especially to reconstruct muscle attachments in fossil taxa. Recently, more muscle maps have been published in the primary literature, but those for large cats are still limited. Here, we describe the muscular anatomy of the forelimb of the tiger (Panthera tigris), and compare muscle origins, insertions, and relative muscle masses to other felids to identify differences that may reflect functional adaptations. Our results reiterate the conservative nature of felid anatomy across body sizes and behavioral categories. We find that pantherines have relatively smaller shoulder muscle masses, and relatively larger muscles of the caudal brachium, pronators, and supinators than felines. The muscular anatomy of the tiger shows several modifications that may reflect an adaptation to terrestrial locomotion and a preference for large prey. These include in general a relatively large m. supraspinatus (shoulder flexion), an expanded origin for m. triceps brachii caput longum, and relatively large m. triceps brachii caput laterale (elbow extension), as well as relatively large mm. brachioradialis, abductor digiti I longus, and abductor digiti V. Muscle groups that are well developed in scansorial taxa are not well developed in the tiger, including muscles of the cranial compartment of the brachium and antebrachium, and m. anconeus. Overall, the musculature of the tiger strongly resembles that of the lion (Panthera leo), another large-bodied terrestrial large-prey specialist., (© 2022 Anatomical Society.)

Background: Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT., Methods: This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020., Results: Median age was 61 years (IQR: 51-69). Median PaO 2 /FiO 2 on admission was 122 mmHg (IQR: 87-189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3-10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications., Conclusions: Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications..

Introduction: There is evidence that SARS-CoV2 has a particular affinity for kidney tissue and is often associated with kidney failure., Methods: We assessed whether proteinuria can be predictive of kidney failure, the development of chronic kidney disease, and mortality in 37 critically ill COVID-19 patients. We used machine learning (ML) methods as decision trees and cut-off points created by the OneR package to add new aspects, even in smaller cohorts., Results: Among a total of 37 patients, 24 suffered higher-grade renal failure, 20 of whom required kidney replacement therapy. More than 40% of patients remained on hemodialysis after intensive care unit discharge or died (27%). Due to frequent anuria proteinuria measured in two-thirds of the patients, it was not predictive for the investigated endpoints; albuminuria was higher in patients with AKI 3, but the difference was not significant. ML found cut-off points of >31.4 kg/m2 for BMI and >69 years for age, constructed decision trees with great accuracy, and identified highly predictive variables for outcome and remaining chronic kidney disease., Conclusions: Different ML methods and their clinical application, especially decision trees, can provide valuable support for clinical decisions. Presence of proteinuria was not predictive of CKD or AKI and should be confirmed in a larger cohort., Competing Interests: Christoph Wanner received honoraria for steering committee membership and lecturing outside the present work from AstraZeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, Mundipharma, and MSD. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to declare.

Background: Changes in pulmonary hemodynamics and ventilation/perfusion were proposed as hallmarks of Coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). Inhaled nitric oxide (iNO) may overcome these issues and improve arterial oxygenation., Methods: We retrospectively analyzed arterial oxygenation and pulmonary vasoreactivity in seven COVID-19 ARDS patients receiving 20 ppm iNO for 15-30 minutes., Results: The inhalation of NO significantly improved oxygenation. All patients with severe ARDS had higher partial pressures of oxygen and reduced pulmonary vascular resistance. Significant changes in pulmonary shunting were not observed., Conclusion: Overall, iNO could provide immediate help and delay respiratory deterioration in COVID-19-induced moderate to severe ARDS., (© 2020 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients., Competing Interests: PHeu reports grants from German Ministry of Research and Education, German Research Foundation, European Union, Charité—Universitätsmedizin Berlin, Berlin Chamber of Physicians, German Parkinson Society, University Hospital Würzburg, Robert Koch Institute, German Heart Foundation, Federal Joint Committee (G-BA) within the Innovationfond, University Hospital Heidelberg (within RASUNOA-prime; supported by an unrestricted research grant to the University Hospital Heidelberg from Bayer, BMS, Boehringer-Ingelheim, Daiichi Sankyo), Charité—Universitätsmedizin Berlin (within Mondafis; supported by an unrestricted research grant to the Charité from Bayer), University Göttingen (within FIND-AF randomized; supported by an unrestricted research grant to the University Göttingen from Boehringer-Ingelheim), outside the submitted work. SF reports grants from DFG, BMBF, grants and personal fees from Abiomed, Amgen, Akzea, AstraZeneca, Bayer, Berlin-Chemie, Braun, Bristol-Myers Squibb, Boehringer, Daiichi Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, Servier, Siemens, Zoll, outside the submitted work. GE reports grants and personal fees from Bayer, grants and personal fees from Novartis, grants and personal fees from Vifor Pharma Deutschland GmbH, outside the submitted work; PK reports other from FreseniusKabi, personal fees from BBraun, grants, personal fees and other from TEVARatiopharm, other from CSL Behring, other from Pajunk, other from APEPTICO Forschung und Entwicklung GmbH, outside the submitted work; KZ reports personal fees from Aesculap Akademie GmbH, personal fees from Affinites Sante, grants from Ashai Kasai Pharma, grants and personal fees from B. Braun AG, grants and personal fees from B. Braun Avitum AG, personal fees from Bayer AG, grants from Biotest AG, personal fees from Christian Doppler Stiftung, grants and personal fees from CSL Behring GmbH, personal fees from Cyto Sorbents GmbH, personal fees from Edward Lifescience Corporation, personal fees from Executive Insight AG, personal fees from Fresenius Kabi GmbH, personal fees from Fresenius Medical Care, personal fees from Haemonetics Corporation, personal fees from Hartmannbund Landesverband, personal fees from Health Adcances GmbH, personal fees from Heinen + Löwenstein GmbH, personal fees from Hexal AG, grants from INC Research, personal fees from Johnson and Johnson, personal fees from Josef Gassner, personal fees from Maquet GmbH, personal fees from Markus Lücke Kongress Organization, personal fees from Masimo International, personal fees from med Update GmbH, personal fees from Medizin and Markt Gesundheitswerk, personal fees from MSD Sharp and Dohme GmbH, personal fees from Nordic Group, personal fees from Nordic Pharma, grants from Novo Nordisc Pharma GmbH, grants from Pfizer Pharma GmbH, personal fees from Pharmacosmos, personal fees from Ratiopharm GmbH, personal fees from Salvia Medical GmbH, personal fees from Schering Stiftung, personal fees from Schöchl Medical Österreich, personal fees from Serumwerke, personal fees from Verlag für Printmedien und PR, Forum Sanitas, grants and personal fees from Vifor Pharma GmbH, personal fees from Wellington, personal fees from Werfen, outside the submitted work; HK served as a speaker and/or an Advisory Board Member for AbbVie, BMS, Gilead, Hexal, Janssen, MSD, Pfizer, ViiV and has received research funding from AbbVie, Arrowhaed, BMS, Gilead, Janssen, MSD, Novartis, German Liver Foundation, Hector Foundation, Virtual University of Bavaria, Federal Ministry of Education and Research, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Herrmann, Adam, Notz, Helmer, Sonntagbauer, Ungemach-Papenberg, Sanns, Zausig, Steinfeldt, Torje, Schmid, Schlesinger, Rolfes, Reyher, Kredel, Stumpner, Brack, Wurmb, Gill-Schuster, Kranke, Weismann, Klinker, Heuschmann, Rücker, Frantz, Ertl, Muellenbach, Mutlak, Meybohm, Zacharowski and Lotz.)

Background: The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS)., Methods: This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay., Results: Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009)., Conclusions: COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity., Competing Interests: T. Schlesinger, B. Weißbrich, F. Wedekink, Q. Notz, J. Herrmann, M. Krone, M. Sitter, B. Schmid, L. Dölken, P. Kranke, C. Lotz have nothing to disclose. M. Kredel reports personal fees from Pfizer, outside the submitted work. J. Wischhusen reports personal fees from CatalYm GmbH, outside the submitted work. P. Meybohm reports grants from B. Braun Melsungen, grants from CSL Behring, grants from Fresenius Kabi, grants from Vifor Pharma, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Pharmacological interventions reducing myocardial ischemia and reperfusion (I/R) injury include the administration of anesthetics. Both sevoflurane as well as propofol have been shown to elicit cardiac protection via distinct molecular mechanisms. We investigated the hypothesis that sevoflurane in contrary to propofol anesthesia elicits cardiac protection against I/R-injury via mitochondrial mechanisms of disease., Methods: Male New Zealand white rabbits (n = 42) were subjected 30 min of coronary artery occlusion followed by 3 h of reperfusion. After induction with pentobarbital, the animals either received sevoflurane or propofol to maintain general anesthesia. Infarct size was determined gravimetrically after triphenyltetrazolium chlorid-staining. Cardiac mitochondria were isolated and mitochondrial oxygen consumption was measured using a Clark electrode. Mitochondrial respiratory chain complex activities (I-IV) were analyzed utilizing specific assays. Data are mean ± SD., Results: Sevoflurane anesthesia significantly decreased the resulting myocardial infarct size compared to propofol anesthesia (p = 0.0275 vs. propofol). Mitochondria from animals receiving propofol anesthesia showed a significantly reduced mitochondrial respiratory control ratio (p = 0.01909 vs. sham) and impaired activities of respiratory complex I (p = 0.0147 vs. sham; p < 0.01 vs. sevoflurane) as well as respiratory complex IV (p = 0.0181 vs. sham). Mitochondrial dysfunction was absent in sevoflurane anesthesized animals. Furthermore, a significantly higher portion of complex I was found to be in its deactive form during I/R-injury in animals receiving sevoflurane anesthesia (p = 0.0123 vs. propofol)., Conclusions: Sevoflurane as opposed to propofol anesthesia preserved mitochondrial respiration and elicited cardiac protection against I/R-injury., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Cyclooxygenase (COX)-2 mediates ischemic pre- and postconditioning as well as anesthetic-induced preconditioning. However, the role of COX-1 and -2 in anesthetic-induced postconditioning has not been investigated. We evaluated the role of COX-1 and -2 in sevoflurane-induced postconditioning in vivo. Pentobarbital-anaesthetized male C57BL/6 mice were subjected to 45 minutes of coronary artery occlusion and 3 hours of reperfusion. Animals received either no intervention, the vehicle dimethyl sulfoxide (DMSO, 10 µL/g intraperitoneally), acetylsalicylic acid (ASA, 5 µg/g intraperitoneally), the selective COX-1 inhibitor SC-560 (10 µg/g intraperitoneally), or the selective COX-2 inhibitor NS-398 (5 µg/g intraperitoneally). 1.0 MAC (minimum alveolar concentration) sevoflurane was administered for 18 minutes during early reperfusion either alone or in combination with ASA, SC-560, and NS-398. Infarct size was determined with triphenyltetrazolium chloride. Statistical analysis was performed using 1-way and 2-way analyses of variance with post hoc Duncan testing. The infarct size in the control group was 44% ± 9%. DMSO (42% ± 7%), ASA (36% ± 6%), and NS-398 (44% ± 18%) had no effect on infarct size. Sevoflurane (17% ± 4%; P < .05) and SC-560 (26% ± 10%; P < .05) significantly reduced the infarct size compared with control condition. Sevoflurane-induced postconditioning was not abolished by ASA (16% ± 5%) and SC-560 (22% ± 4%). NS-398 abolished sevoflurane-induced postconditioning (33% ± 14%). It was concluded that sevoflurane induces postconditioning in mice. Inhibition of COX-1 elicits a myocardial infarct size reduction and does not abolish sevoflurane-induced postconditioning. Blockade of COX-2 abolishes sevoflurane-induced postconditioning. These results indicate that sevoflurane-induced postconditioning is mediated by COX-2., (© The Author(s) 2014.)

Objectives: Nitric oxide synthases (NOSs) mediate the first window of anesthetic-induced preconditioning (APC). The authors tested the hypothesis that endothelial NOS (eNOS) mediates the first window and inducible NOS (iNOS) mediates the second window of APC., Design: Randomized, prospective, blinded laboratory investigation., Setting: Experimental laboratory., Participants: Mice., Interventions: Mice were subjected to a 45-minute coronary artery occlusion (CAO) and a 180-minute reperfusion. C57BL/6 mice received desflurane, 1.0 minimum alveolar concentration, for 30 minutes or 12, 24, 48, or 96 hours before CAO. In eNOS(-/-) and iNOS(-/-) mice, desflurane was given 30 minutes and 48 hours before CAO. In the control groups, no desflurane was administered. Myocardial infarct size (IS) was determined after staining with Evans blue and triphenyltetrazolium chloride., Measurements and Main Results: The second window of APC was detectable at 48 hours but not at 12, 24, and 96 hours after preconditioning. In the control groups, IS was not different among the wild-type (50 ± 10%), eNOS(-/-) (52 ± 14%), and iNOS(-/-) (46 ± 10%) mice. The IS decreased significantly (p < 0.05) when desflurane was administered 30 minutes (10 ± 6%) or 48 hours (16 ± 7%) before CAO in wild-type mice, 48 hours (21 ± 13%) before CAO in eNOS(-/-) mice, and 30 minutes (13 ± 6%) before CAO in iNOS(-/-) mice. Desflurane given 30 minutes before CAO in eNOS(-/-) mice (60 ± 10%) and 48 hours before CAO in iNOS(-/-) mice (48 ± 21%) did not decrease the IS significantly compared with controls., Conclusions: Endothelial NOS and iNOS work independently to mediate the first and second windows of APC, respectively. Endothelial NOS is not necessary to trigger the second window of APC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The volatile anesthetic desflurane (DES) effectively reduces cardiac infarct size following experimental ischemia/reperfusion injury in the mouse heart. We hypothesized that endogenous estrogens play a role as mediators of desflurane-induced preconditioning against myocardial infarction. In this study, we tested the hypothesis that desflurane effects local estrogen synthesis by modulating enzyme aromatase expression and activity in the mouse heart. Aromatase metabolizes testosterone to 17β- estradiol (E2) and thereby significantly contributes to local estrogen synthesis. We tested aromatase effects in acute myocardial infarction model in male mice. The animals were randomized and subjected to four groups which were pre-treated with the selective aromatase inhibitor anastrozole (A group) and DES alone (DES group) or in combination (A+DES group) for 15 minutes prior to surgical intervention whereas the control group received 0.9% NaCl (CON group). All animals were subjected to 45 minutes ischemia following 180 minutes reperfusion. Anastrozole blocked DES induced preconditioning and increased infarct size compared to DES alone (37.94 ± 15.5% vs. 17.1 ± 3.62%) without affecting area at risk and systemic hemodynamic parameters following ischemia/reperfusion. Protein localization studies revealed that aromatase was abundant in the murine cardiovascular system with the highest expression levels in endothelial and smooth muscle cells. Desflurane application at pharmacological concentrations efficiently upregulated aromatase expression in vivo and in vitro. We conclude that desflurane efficiently regulates aromatase expression and activity which might lead to increased local estrogen synthesis and thus preserve cellular integrity and reduce cardiac damage in an acute myocardial infarction model.

Objectives: The authors tested the hypothesis that ischemic and desflurane-induced preconditioning are blocked by propofol., Design: A prospective, randomized, vehicle-controlled study., Setting: A university research laboratory., Subjects: New Zealand white rabbits (n = 52)., Methods: Pentobarbital-anesthetized rabbits were subjected to 30 minutes of coronary artery occlusion followed by 3 hours of reperfusion. Rabbits received 0.0 (control) or 1.0 minimum alveolar concentration of desflurane (30 minutes' duration and a 30-minute memory period) or ischemic preconditioning (5 minutes of ischemia and a 30-minute memory period) in the absence or presence of propofol (10 mg/kg/h intravenously) or its vehicle (10% Intralipid emulsion; B Braun, Melsungen, Germany). The myocardial infarct size was measured with triphenyltetrazolium staining. Statistical analysis was performed with 1-way and 2-way analysis of variance when appropriate, followed by a post hoc Duncan test. Data are mean ± standard deviation., Results: Myocardial infarct size was 56% ± 8% in control animals (n = 7). Desflurane significantly (p < 0.05) reduced the infarct size to 37% ± 6% (n = 7). Desflurane-induced preconditioning was blocked by propofol (65% ± 10%, n = 7) but not by its vehicle (45% ± 11%, n = 5). Propofol and its vehicle alone had no effect on the infarct size (62% ± 8% [n = 6] and 58% ± 3% [n=5], respectively). Ischemic preconditioning reduced infarct size in the absence or presence of propofol to 24% ± 7% (n = 7) and 29% ± 12% (n = 6)., Conclusion: Desflurane-induced preconditioning markedly reduced infarct size and was blocked by propofol, whereas ischemic preconditioning was not blocked by propofol. The results suggest an important interference between propofol and anesthetic-induced preconditioning and might explain some contradictory findings in studies in humans., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The second window of anaesthetic-induced preconditioning (APC) is afforded by the interplay of multiple signalling pathways, whereas a similar protective response is mediated by peroxisome-proliferator-activated receptor γ (PPARγ) agonists. However, a possible role of this nuclear receptor during APC has not been studied to date. We investigated the hypothesis that the second window of APC is mediated by the activation of PPARγ. New Zealand White rabbits (n = 48) were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. The animals received desflurane (1.0 minimal alveolar concentration), the PPARγ antagonist GW9662, as well as the combined application of both, respectively, 24 h prior to coronary artery occlusion. Infarct size was determined gravimetrically; tissue levels of 15-deoxy-(12,14)-prostaglandin J(2) (15d-PGJ(2)) and nitrite/nitrate (NO(x)), as well as PPAR DNA binding were measured using specific assays. Data are presented as means ± s.e.m. Desflurane led to a reduced myocardial infarct size (41.7 ± 2.5 versus 61.8 ± 2.8%, P < 0.05), accompanied by significantly increased PPAR DNA binding (289.9 ± 33 versus 102.9 ± 18 relative light units, P < 0.05), as well as elevated tissue levels of 15d-PGJ(2) (224.4 ± 10.2 versus 116.9 ± 14.2 pg ml(-1), P < 0.05) and NO(x) (14.9 ± 0.7 versus 5.4 ± 0.7 μm, P < 0.05). Pharmacological inhibition of PPARγ abolished these protective effects, resetting the infarct size (56.5 ± 2.9%), as well as PPAR DNA-binding activity (91.2 ± 31 relative light units) and NO(x) tissue levels (5.9 ± 0.9 μm) back to control levels. Desflurane governs a second window of APC by increasing the production of 15d-PGJ(2), subsequently activating PPARγ, resulting in a diminished myocardial infarct size by increasing the downstream availability of NO.

Objectives: Myocardial ischemia is accompanied by a rapid activation of adenosine-monophosphate-activated protein kinase (AMPK). However, it is unclear whether this represents a potentially beneficial or detrimental event in the course of ischemic injury. The role of AMPK activation in the cardioprotective setting of desflurane-induced preconditioning has not been investigated to date. Hence, the current study was undertaken to address the role of AMPK activation during desflurane-induced preconditioning in vivo., Design: A prospective randomized vehicle-controlled study., Setting: A university research laboratory., Subjects: Male New Zealand white rabbits (n = 44)., Interventions: The animals were subjected to a 30-minute coronary artery occlusion (CAO) followed by 3 hours of reperfusion. Desflurane (1.0 minimum alveolar concentration) was administered for 30 minutes and discontinued 30 minutes prior to CAO. Different groups of animals received the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-riboside (AICAR), alone or in combination with desflurane. Infarct size was determined gravimetrically; AMPK activity and myocardial glycogen content were measured using specific assays. Phosphorylation of the AMPK substrate, acetyl-CoA carboxylase, was assessed by immunoblotting. Data are mean ± standard error of the mean., Results: Desflurane significantly reduced the myocardial infarct size (36.7 ± 1.9%, p < 0.05) compared with the control group (61.6% ± 3.0%), concomitant with increased myocardial tissue levels of glycogen (2.09 ± 0.07 μg, p < 0.05). Activation of the AMPK by AICAR alone did not protect against ischemic injury (65% ± 3.3), but did abolish the cardioprotection elicited by desflurane (61.8% ± 4.2%) at the same time as increasing myocardial glycogen consumption (1.42 ± 0.15 μg/mL)., Conclusions: The results obtained show that the pharmacologic activation of AMPK abolishes cardioprotection elicited by desflurane., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Remote ischemic preconditioning (remote IPC) elicits a protective cardiac phenotype against myocardial ischemic injury. The remote stimulus has been hypothesized to act on major signaling pathways; however, its molecular targets remain largely undefined. We hypothesized that remote IPC exerts its effects by activating the peroxisome-proliferator-activated receptors (PPARs) α and γ, which have been previously implicated in cardioprotective signaling. Male New Zealand white rabbits (n = 78) were subjected to a 30-min coronary artery occlusion followed by three hours of reperfusion. Three cycles of remote IPC consisting of 10-min renal ischemia/reperfusion were performed. The animals either received the PPARα-antagonist GW6471 or the PPARγ-antagonist GW9662 alone or combined with remote IPC. Infarct size was determined gravimetrically. Tissue levels of 15d-prostaglandin J(2) (15d-PGJ(2)), as well as the PPAR DNA binding were measured using specific assays. Reverse transcriptase polymerase chain reaction was used to analyze changes in endothelial nitric oxide synthase or inducible nitric oxide synthase (iNOS) mRNA expression in relative quantity (RQ). Data are mean ± SD. As a result, remote IPC significantly reduced the myocardial infarct size (42.2 ± 4.9%* versus 61 ± 1.9%), accompanied by an increased PPAR DNA-binding (189.6 ± 19.8RLU* versus 44.4 ± 9RLU), increased iNOS expression (3.5 ± 1RQ* versus 1RQ), as well as 15d-PGJ(2) levels (179.7 ± 7.9 pg/mL* versus 127.9 ± 7.6 pg/mL). The protective response elicited by remote IPC, as well as the accompanying molecular changes were abolished by inhibiting PPARα (56.8 ± 4.7%; 61.1 ± 14.2RLU; and 1.91 ± 0.96RQ, respectively) or PPARγ (57.4 ± 3.3%; 52.7 ± 16.9RLU; and 1.54 ± 0.25RQ, respectively). (*Significantly different from control P < 0.05). In conclusion, the obtained results indicate that both PPARα and PPARγ play an essential role in remote IPC against myocardial infarction, impinging on the transcriptional control of iNOS expression.

Objectives: The authors tested the hypothesis that volatile anesthetic-induced preconditioning (APC) follows a similar time pattern as that described for ischemic preconditioning and that delayed APC is mediated by nitric oxide., Design: A prospective randomized vehicle-controlled study., Setting: A university research laboratory., Subjects: New Zealand white rabbits (n = 75)., Methods: Rabbits were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute coronary artery occlusion (CAO) and 3 hours of reperfusion. Desflurane (1.0 minimum alveolar concentration) was administered for 30 minutes and was discontinued 0.5 hours, 2 hours, 3 hours, 12 hours, 24 hours, 48 hours, 72 hours, and 96 hours before CAO, respectively. In 2 separate experimental groups, the nitric oxide synthase inhibitor N-omega-nitro-L-arginine (L-NA) was administered 72 hours after the administration of 0.0 or 1.0 minimum alveolar concentration of desflurane. The infarct size was determined gravimetrically. Data are mean +/- standard deviation., Results: Desflurane significantly (p < 0.05) reduced the infarct size compared with the control (63% +/- 12%, n = 7) when administered 0.5 hours (35% +/- 5%, n = 7), 2 hours (35% +/- 9%, n = 7), 24 hours (31% +/- 8%, n = 7), 48 hours (30% +/- 11%, n = 6), and 72 hours (39% +/- 5%, n = 6) before CAO. However, when desflurane was administered 3 hours (53% +/- 9%, n = 7), 12 hours (71% +/- 6%, n = 7), or 96 hours (66% +/- 5%, n = 7) before CAO, the myocardial infarct size was not reduced. The second window (72 hours) of preconditioning was abolished by the NOS inhibitor L-NA (52% +/- 16%, n = 7). L-NA alone had no effect on infarct size (64% +/- 11%, n = 7)., Conclusions: Desflurane induces a first (0.5-2 hours) and second window of preconditioning (24-72 hours) in the rabbit model of acute myocardial infarction. The second window of APC is mediated by nitric oxide., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objectives: The authors tested the hypothesis that desflurane-induced cardioprotection depends on the timing of application and whether desflurane-induced postconditioning is mediated by nitric oxide., Design: A prospective randomized vehicle-controlled study., Setting: A university research laboratory., Subjects: New Zealand White rabbits (N = 56)., Interventions: Rabbits were instrumented and subjected to a 30-minute coronary artery occlusion (CAO) and 3 hours of reperfusion. Animals were randomized to 8 groups (n = 7) and received 0.0 or 1.0 minimum alveolar concentration desflurane for 30 minutes before CAO (PRE), during CAO (ISCH), after CAO (POST), before and after CAO (PRE + POST), or continuously for 90 minutes starting 30 minutes before CAO (PRE + ISCH + POST). In 2 separate experimental groups, the nitric oxide synthase inhibitor N-omega-nitro-L-arginine (L-NA) was administered before reperfusion in the presence or absence of desflurane. Data are mean +/- standard deviation., Results: Infarct size was 68% +/- 14% in control experiments. Desflurane significantly (p < 0.05) reduced infarct size in the PRE (43% +/- 9%) and POST groups (49% +/- 12%) but not in the ISCH group (69% +/- 9%). The PRE + ISCH + POST and PRE + POST groups produced similar reductions in infarct size to 47% +/- 12% and 43% +/- 9%, respectively. L-NA alone had no effect on infarct size (61% +/- 9%) but blocked postconditioning completely (L-NA + POST, 68% +/- 10%)., Conclusions: Desflurane induces pre- and postconditioning but does not confer cardioprotection during ischemia in rabbits. The combination of pre- and postconditioning or continuous application does not provide additional cardioprotection. Furthermore, desflurane-induced postconditioning is mediated by nitric oxide.

Objective: An optimal administration protocol to induce a maximal effect of anesthetic preconditioning has not been evaluated to date. In this study, desflurane preconditioning was characterized with respect to its threshold, dose dependency, and continuous versus repetitive application. Furthermore, the role of beta(2)-adrenergic receptors in anesthetic preconditioning was tested., Design: A randomized controlled study., Setting: Laboratory study in a University hospital., Subjects: New Zealand white rabbits in vivo., Interventions: Systemic hemodynamics were continuously measured. Rabbits were subjected to 30 minutes of coronary artery occlusion and 3 hours of reperfusion. Animals received desflurane continuously for 30 minutes at 0.5, 1.0, or 1.5; desflurane for 90 minutes at 0.5 or 1.5 MAC; or repetitively for three 10-minute periods at 0.5, 1.0, or 1.5 MAC before coronary occlusion. The beta(2)-adrenergic receptor blocker ICI 118,551 (0.2 mg/kg) or saline placebo was given in the absence or presence of 1.0 MAC desflurane. Myocardial infarct size was measured with triphenyltetrazolium staining., Measurements and Main Results: Myocardial infarct size was 61% +/- 5% in control experiments. Desflurane, administered continuously at 0.5 MAC for 30 minutes (52% +/- 4%) or 90 minutes (56% +/- 8%) had no effect, whereas 0.5 MAC of desflurane given repetitively reduced infarct size to 36% +/- 7%. Desflurane administered continuously for 30 minutes at 1.0 or 1.5 MAC reduced infarct size to 35% +/- 5% and 39% +/- 4%, respectively. Repetitive application at 1.0 MAC (37% +/- 6%) or 1.5 MAC (29% +/- 4%) and continuous administration of 1.5 MAC for 90 minutes (32% +/- 6%) did not result in further infarct size reduction. ICI 118,551 did not affect infarct size (53% +/- 2%) but abolished desflurane preconditioning (51% +/- 5%)., Conclusion: beta(2)-Adrenergic receptors mediate desflurane-induced preconditioning. Desflurane-induced preconditioning has a threshold that can be lowered by repetitive administration.

The murine in vivo model of acute myocardial infarction is increasingly used to investigate anesthetic-induced preconditioning (APC) and postconditioning (APOST). However, in mice the potency of different volatile anesthetics to reduce myocardial infarct size (IS) has never been investigated systematically nor in a head to head comparison with regard to ischemic preconditioning (IPC) and postconditioning (IPOST). Male C57BL/6 mice were subjected to 45 min of coronary artery occlusion (CAO) and 180 min of reperfusion. To induce APC, 1.0 MAC isoflurane (ISO), sevoflurane (SEVO) or desflurane (DES) was administered 30 min prior to CAO for 15 min. In an additional group, ISO was administered 45 min prior to CAO for 30 min. To induce APOST, 1.0 MAC ISO, SEVO or DES was administered for 18 min starting 3 min prior to the end of CAO. IPC was induced by 3 or 6 cycles of 5 min ischemia/reperfusion, 40 or 60 min prior to CAO, respectively. IPOST was induced by 3 cycles of 30 sec reperfusion/ischemia at the beginning of reperfusion. Area at risk (AAR) and IS were determined with Evans Blue and TTC staining, respectively. IS (IS/AAR) was 50 +/- 4% (mean +/- SEM) in the control group and was significantly (*P < 0.05) reduced by 3x5 IPC (26 +/- 3%*), 6 x 5 IPC (26 +/- 4%*), IPOST (20 +/- 2%*), ISO APOST (19 +/- 1%*), SEVO APOST (15 +/- 1%*), DES APOST (14 +/- 2%*) and SEVO APC (27 +/- 6%*). ISO APC significantly reduced IS compared to control when administered 30 min (33 +/- 4%*), but not when administered 15 min (48 +/- 6%). DES APC significantly reduced IS compared to control and to SEVO APC (7 +/- 1%*). Within the paradigm of preconditioning, the potency of volatile anesthetics to reduce myocardial infarct size in mice significantly increases from ISO over SEVO to DES, whereas within the paradigm of postconditioning the potency of these volatile anesthetics to reduce myocardial infarct size in mice is similar.

Background: Anesthetic preconditioning is mediated by beta-adrenergic signaling. This study was designed to elucidate the role of beta-adrenergic signaling in desflurane-induced postconditioning., Methods: Pentobarbital-anesthetized New Zealand White rabbits were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion and were randomly assigned to receive vehicle (control), 1.0 minimum alveolar concentration of desflurane, esmolol (30 mg x kg(-1) x h(-1)) for the initial 30 min of reperfusion or throughout reperfusion, the beta2-adrenergic receptor blocker ICI 118,551 (0.2 mg/kg), the protein kinase A inhibitor H-89 (250 microg/kg), or the calcium/calmodulin-dependent protein kinase II inhibitor KN-93 (300 microg/kg) in the presence or absence of desflurane. Protein expression of protein kinase B, calcium/calmodulin-dependent protein kinase II, and phospholamban was measured by Western immunoblotting. Myocardial infarct size was assessed by triphenyltetrazolium staining., Results: Infarct size was 57 +/- 5% in control. Desflurane postconditioning reduced infarct size to 36 +/- 5%. Esmolol given during the initial 30 min of reperfusion had no effect on infarct size (54 +/- 4%) but blocked desflurane-induced postconditioning (58 +/- 5%), whereas esmolol administered throughout reperfusion reduced infarct size in the absence or presence of desflurane to 42 +/- 6% and 41 +/- 7%, respectively. ICI 118,551 and KN-93 did not affect infarct size (62 +/- 4% and 62 +/- 6%, respectively) but abolished desflurane-induced postconditioning (57 +/- 5% and 64 +/- 3%, respectively). H-89 decreased infarct size in the absence (36 +/- 5%) or presence (33 +/- 5%) of desflurane., Conclusions: Desflurane-induced postconditioning is mediated by beta-adrenergic signaling. However, beta-adrenergic signaling displays a differential role in cardioprotection during reperfusion.

In a 50-year-old man without bronchopulmonary symptoms a round mass lesion close to the hilum of the right lung was detected in a routine chest x-ray and confirmed by computed tomography. Histological examination of two biopsy specimens did not result in a definitive diagnosis. Therefore thoracotomy with enucleation of the focus was performed. The histological picture of the lesion is characterized by connective tissue proliferation, multinucleated giant cells, ossification, localised hemorrhage, deposits of hemosiderin and foci of foam cells. The findings are interpreted as a giant cell granuloma of the lung.