Kardioprotektiver Effekt von Cytosin-Phosphoguanin-Oligonucleotiden in einem murinen „Closed Chest“ Modell

Einleitung: Zur Begrenzung eines Reperfusionsschadens nach einem Herzinfarkt wurden Therapieoptionen in einem operativen Mausmodell untersucht. Im Rahmen der myokardialen Postkonditionierung wurde die kardioprotektive Wirkung des Toll-artigen Rezeptor 9 Liganden CpG-ODN (1668-Thioat, bakterielle DNA) an einem Ischämie/Reperfusions (I/R) Modell analysiert.Methode: Im „closed chest“ Modell wurde in einer Initialoperation, über einen interkostalen Zugang, ein Okkluder auf den Ramus interventricularis anterior platziert. Nach 5 Tagen Rekonvaleszenz wurde mittels Zug am Okkluder eine Ischämie von 30 oder 60 Minuten mit anschließender Reperfusion von 2 oder 24 Stunden durchgeführt. 5 Minuten vor der Reperfusion wurden CpG-ODN oder die Kontrollsubstanz PBS intraperitoneal injiziert. Eine weitere Gruppe wurde mit drei Zyklen Ischämie/Reperfusion ischämisch postkonditioniert (IPC). Die Infarktgrößen wurden nach 2 oder 24 Stunden vermessen und kardiale Zytokine mittels RT-PCR nach 2 Stunden Reperfusion quantifiziert. Das „closed chest“ Modell ermöglichte die Analyse der Zytokinexpression, die nur durch die I/R und nicht durch das Trauma der Instrumentierung verursacht wurde.Ergebnisse: Der postkonditionierende Effekt wurde anhand der Infarktgröße und der Expression sowohl pro- als auch antiinflammatorischer Zytokine im Mausherz bestimmt und quantifiziert. Es kam nach der Postkonditionierung mit CpG-ODN zur ausgeprägten Infarktreduktion im Vergleich zu unserer Kontrollgruppe PBS. Das Ausmaß der Infarktreduktion durch CpG-ODN war vergleichbar mit der Infarktreduktion durch die ischämische Postkonditionierung, die in der Literatur als Goldstandard gilt. Die Verlängerung der Ischämiezeit hob den kardioprotektiven Effekt sowohl von CpG-ODN, als auch der ischämischen Postkonditionierung auf. Jede Postkonditionierung führte zu einer differenzierten Immunantwort im Myokard. In der CpG-ODN Gruppe imponierte die Expression des antiinflammatorischen Zytokins IL-10. Fazit: Die Resultate demonstrieren die kardioprotektive Wirkung von CpG-ODN im Rahmen der myokardialen Postkonditionierung. Die Verwendung von CpG-ODN könnte ein innovativer Therapieansatz in der Behandlung des Reperfusionsschades nach einem Herzinfarkt sein

Digital Online Patient Informed Consent for Anesthesia before Elective Surgery-Recent Practice in Europe

BACKGROUND: Digitalization in the health system is a topic that is rapidly gaining popularity, and not only because of the current pandemic. As in many areas of daily life, digitalization is becoming increasingly important in the medical field amid the exponential rise in the use of computers and smartphones. This opens up new possibilities for optimizing patient education in the context of anesthesia. The main aim of this study was to assess the implementation of remote consent in Europe.METHODS: An online survey entitled "Digital online Patient Informed Consent for Anesthesia before Elective Surgery. Recent practice in Europe," with a total of 27 questions, was sent by the European Society of Anesthesiology and Intensive Care (ESAIC) to their members in 47 European countries. To assess the effect of the economy on digitalization and legal status with regard to anesthesia consent, data were stratified based on gross domestic product per capita (GDPPC).RESULTS: In total, 23.1% and 37.2% of the 930 participants indicated that it was possible to obtain consent online or via telephone, respectively. This observation was more often reported in countries with high GDPPC levels than in countries with low GDPPC levels. Furthermore, 27.3% of the responses for simple anesthesia, 18.7% of the responses for complex anesthesia, and 32.2% of the responses for repeated anesthesia indicated that remote consent was in accordance with the law, and this was especially prevalent in countries with high GDPPC. Concerning the timing of consent, patients were informed at least one day before in 67.1% of cases for simple procedures and in 85.2% of cases for complex procedures.CONCLUSION: Even European countries with high GDPPC use remote informed consent only in a minority of cases, and most of the time for repeated anesthetic procedures. This might reflect the inconsistent legal situation and inhomogeneous medical technical structures across Europe.</p

Arginase impairs hypoxic pulmonary vasoconstriction in murine endotoxemia

Background: Hypoxic pulmonary vasoconstriction (HPV) optimizes the match between ventilation and perfusion in the lung by reducing blood flow to poorly ventilated regions. Sepsis and endotoxemia impair HPV. We previously showed that nitric oxide synthase 2 (NOS2) is required, but not sufficient, for the effect of endotoxin on HPV. The aim of the current study was to identify additional factors that might contribute to the impairment of HPV during endotoxemia. Methods: Gene expression profiling was determined using pulmonary tissues from NOS2-deficient (NOS2−/−) and wild-type mice subjected to endotoxin or saline challenge (control). HPV was accessed as the percentage increase in left pulmonary vascular resistance (LPVR) in response to left main bronchus occlusion (LMBO) in wild-type mice. Results: Among the 22,690 genes analyzed, endotoxin induced a greater than three-fold increase in 59 and 154 genes in the lungs of wild-type and NOS2−/− mice, respectively. Of all the genes induced by endotoxin in wild-type mice, arginase 1 (Arg1) showed the greatest increase (16.3-fold compared to saline treated wild-type mice). In contrast, endotoxin did not increase expression of Arg1 in NOS2−/− mice. There was no difference in the endotoxin-induced expression of Arg2 between wild-type and NOS2-deficient mice. We investigated the role of arginase in HPV by treating the mice with normal saline or the arginase inhibitor Nω-hydroxy-nor-L-arginine (norNOHA). In control mice (in the absence of endotoxin) treated with normal saline, HPV was intact as determined by profound LMBO-induced increase in LPVR (121 ± 22% from baseline). During endotoxemia and treatment with normal saline, HPV was impaired compared to normal saline treated control mice (33 ± 9% vs. 121 ± 22%, P &lt; 0.05). HPV was restored in endotoxin-exposed mice after treatment with the arginase inhibitor norNOHA as shown by the comparison to endotoxemic mice treated with normal saline (113 ± 29% vs, 33 ± 9%, P &lt; 0.05) and to control mice treated with normal saline (113 ± 29% vs, 121 ± 22%, P = 0.97). Conclusions: The results of this study suggest that endotoxemia induces Arg1 and that arginase contributes to the endotoxin-induced impairment of HPV in mice

Digital Online Anaesthesia Patient Informed Consent before Elective Diagnostic Procedures or Surgery: Recent Practice in Children&mdash;An Exploratory ESAIC Survey (2021)

Background: One undisputed benefit of digital support is the possibility of contact reduction, which has become particularly important in the context of the COVID-19 pandemic. However, to the best of our knowledge, there is currently no study assessing the Europe-wide use of digital online pre-operative patient information or evaluation in the health sector. The aim of this study was to give an overview of the current status in Europe. Methods: A web-based questionnaire covering the informed consent process was sent to members of the European Society of Anaesthesia and Intensive Care Medicine (ESAIC) in 47 European countries (42,433 recipients/930 responses). Six questions related specifically to the practice in paediatrics. Results: A total of 70.2% of the respondents indicated that it was not possible to obtain informed consent via the Internet in a routine setting, and 67.3% expressed that they did not know whether it is in line with the legal regulations. In paediatric anaesthesia, the informed consent of only one parent was reported to be sufficient by 77.6% of the respondents for simple interventions and by 63.8% for complex interventions. Just over 50% of the respondents judged that proof of identity of the parents was necessary, but only 29.9% stated that they ask for it in clinical routine. In the current situation, 77.9% would favour informed consent in person, whereas 60.2% could imagine using online or telephone interviews as an alternative to a face-to-face meeting if regulations were changed. Only 18.7% participants reported a change in the regulations due to the current pandemic situation. Conclusion: Whether informed consent is obtained either online or on the telephone in the paediatric population varies widely across Europe and is not currently implemented as standard practice. For high-risk patients, such as the specific cohort of children with congenital heart defects, wider use of telemedicine might provide a benefit in the future in terms of reduced contact and reduced exposure to health risks through additional hospital stays

Leigh Syndrome Mouse Model Can Be Rescued by Interventions that Normalize Brain Hyperoxia, but Not HIF Activation

Leigh syndrome is a devastating mitochondrial disease for which there are no proven therapies. We previously showed that breathing chronic, continuous hypoxia can prevent and even reverse neurological disease in the Ndufs4 knockout (KO) mouse model of complex I (CI) deficiency and Leigh syndrome. Here, we show that genetic activation of the hypoxia-inducible factor transcriptional program via any of four different strategies is insufficient to rescue disease. Rather, we observe an age-dependent decline in whole-body oxygen consumption. These mice exhibit brain tissue hyperoxia, which is normalized by hypoxic breathing. Alternative experimental strategies to reduce oxygen delivery, including breathing carbon monoxide (600 ppm in air) or severe anemia, can reverse neurological disease. Therefore, unused oxygen is the most likely culprit in the pathology of this disease. While pharmacologic activation of the hypoxia response is unlikely to alleviate disease in vivo, interventions that safely normalize brain tissue hyperoxia may hold therapeutic potential.status: publishe

A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells

Sickle cell disease is an inherited disorder of hemoglobin (Hb). During a sickle cell crisis, deoxygenated sickle hemoglobin (deoxyHbS) polymerizes to form fibers in red blood cells (RBCs), causing the cells to adopt “sickled” shapes. Using small molecules to increase the affinity of Hb for oxygen is a potential approach to treating sickle cell disease, because oxygenated Hb interferes with the polymerization of deoxyHbS. We have identified a triazole disulfide compound (4,4′-di­(1,2,3-triazolyl)­disulfide, designated TD-3), which increases the affinity of Hb for oxygen. The crystal structures of carboxy- and deoxy-forms of human adult Hb (HbA), each complexed with TD-3, revealed that one molecule of the monomeric thiol form of TD-3 (5-mercapto-1H-1,2,3-triazole, designated MT-3) forms a disulfide bond with β-Cys93, which inhibits the salt-bridge formation between β-Asp94 and β-His146. This inhibition of salt bridge formation stabilizes the R-state and destabilizes the T-state of Hb, resulting in reduced magnitude of the Bohr effect and increased affinity of Hb for oxygen. Intravenous administration of TD-3 (100 mg/kg) to C57BL/6 mice increased the affinity of murine Hb for oxygen, and the mice did not appear to be adversely affected by the drug. TD-3 reduced in vitro hypoxia-induced sickling of human sickle RBCs. The percentage of sickled RBCs and the <i>P</i>₅₀ of human SS RBCs by TD-3 were inversely correlated with the fraction of Hb modified by TD-3. Our study shows that TD-3, and possibly other triazole disulfide compounds that bind to Hb β-Cys93, may provide new treatment options for patients with sickle cell disease