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Kurzfassung Sind Russland und China ewige Rivalen oder Partner einer im Entstehen begriffenen Allianz? Und was würde letzteres für die NATO bedeuten? Die NATO reagierte im Jahr 2014 auf die russische hybride Aggression gegen die Ukraine, die aus verdeckter Destabilisierung des Donbass und völkerrechtswidriger Besetzung und Annexion der Krim bestand, mit einem Paradigmenwechsel, der sogenannten „NATO Adaptation.“ Auf dem Gipfeltreffen in Wales 2014 erhöhte sie ihre Reaktionsbereitschaft mit dem Readiness Action Plan, beim Gipfel in Warschau 2016 stärkte sie ihr Abschreckungs- und Verteidigungsdispositiv und richtete 2018 beim Gipfeltreffen in Brüssel ihre Führungsstruktur wieder auf kollektive Verteidigung aus. Obgleich eingebettet in einen „360-Grad-Ansatz“, zielen alle zentralen Verteidigungselemente der NATO-Anpassung seit 2014 in erster Linie auf Russland hin, das seither als potenzielle Bedrohung für die territoriale Integrität der osteuropäischen Mitgliedstaaten gilt. Aber dieser Paradigmenwechsel beruhte zur Gänze auf der Einschätzung, einzig Russland sei eine ernstzunehmende militärische Bedrohung für die Allianz und (abgesehen von Belarus) auf sich allein gestellt. Der Frage, was es bedeuten würde, wenn Russland von einer gleichgesinnten Großmacht wie China unterstützt würde, und ebenso der Frage, welche Folgen zwei gleichzeitige Aggressionen – eine durch Russland in Europa, eine weitere durch China im Indopazifik – für die NATO hätte, wurde bislang keine Beachtung geschenkt. Dabei haben diese beiden Problempunkte in den letzten Jahren rapide an Tragweite für die Anpassung der NATO an die neuen geopolitischen Realitäten gewonnen. Das gilt erst recht in einer abermals veränderten Sicherheitslage, in der Putins Russland aus revisionistischen und imperialen Großmachtmotiven einen unverblümten, brutalen Angriffskrieg gegen sein souveränes Nachbarland Ukraine führt, dabei die europäische Friedensordnung entgegen allen abgeschlossenen Verträgen grundsätzlich in Frage stellt und Unterstützung findet von Xi Jinpings China als „engem Freund und strategischen Partner“, der sich das russische Narrativ zu eigen macht und den USA und der NATO die Schuld für den Konflikt zuweist.

Zusammenfassung Während die Bundesregierung die konzeptionellen Beschlüsse der NATO-Gipfel seit 2014 zur Stärkung der Bündnisverteidigung konstruktiv mitgestaltet hat, lässt ihr Umsetzungsverhalten gravierende Defizite erkennen. Die Realisierung ihrer langfristigen Zusagen droht zu scheitern – und nicht erst seit der Corona-Krise. Es fehlt am politischen Konsens der Koalitionsparteien, bei den wichtigsten Zusagen Wort zu halten – der Erhöhung des Verteidigungshaushalts auf rund 60 Mrd. Euro in 2024 (und damit deutlich in Richtung auf das Zwei-Prozent-Ziel) und an der Bereitstellung kampfkräftiger Land-, Luft- und Seestreitkräfte. Die deutsche Politik muss zum Münchner Konsens größerer Verantwortungsbereitschaft zurückfinden, darf einer weiteren transatlantischen Entfremdung nicht Vorschub leisten und sollte dafür sorgen, dass Deutschland seine angestammte Rolle als Rückgrat der konventionellen Bündnisverteidigung in Europa ausfüllt.

Are Russia and China an emerging alliance or eternal rivals? And what would it mean for NATO? NATO reacted to the Russian aggression against Ukraine with a paradigm shift called “NATO Adaptation.” At the 2014 Wales Summit, it increased its responsiveness with the “Readiness Action Plan,” the 2016 Warsaw Summit strengthened its deterrence and defense posture, and the 2018 Brussels Summit re-designed NATO’s Command Structure toward collective defense. Although embedded in a “360-degree approach,” all key defense elements of NATO’s adaptation have been primarily focused on Russia, which was recognized from March 2014 on as potential threat to the territorial integrity of the Eastern European members. However, this changing of the paradigm was based entirely on the understanding that Russia alone poses a serious military threat to the alliance. There was never any consideration given to the question of what it would mean if Russia were supported by a like-minded great power such as China, nor to the question of what simultaneous aggressions—one by Russia in Europe and another by China in the Indo-Pacific—would mean for NATO. Hence, the answers to these questions are of high relevance to NATO’s further adaptation to the new geopolitical realities.

Kurzfassung: Die NATO war für zwei Jahrzehnte primär eine politische Allianz, die Russland als Partnerstaat ansah. Mit der Annexion der Krim durch Russland sowie der hybriden Aggression gegen die Ost-Ukraine hat sich ein Paradigmenwechsel vollzogen, bei dem es darum geht, einerseits Verteidigungsfähigkeit herzustellen, andererseits aber auch die Dialogbereitschaft zu erhalten. Der Beitrag zeichnet den Weg der NATO seither nach und befasst sich mit der Frage, was der Paradigmenwechsel der NATO – an dessen Zustandekommen die Bundesregierung maßgebend beteiligt war – für die deutsche Sicherheitspolitik und die Bundeswehr bedeutet. Dabei wird vor allem auf die Zusagen Deutschlands eingegangen, ambitionierte NATO-Fähigkeitenziele zu erfüllen und das Verteidigungsinvestitionsversprechen von Wales einzuhalten. Außerdem wird Deutschlands Rolle als Rahmennation behandelt. Abschließend werden weitergehende Perspektiven einer wieder stärker an Abschreckung und Bündnisverteidigung orientierten NATO aufgezeigt.

Pressure overload induces cardiac remodeling involving both the contractile machinery and intercalated disks (IDs). Filamin C (FlnC) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapters localizing in IDs of higher vertebrates. Knockout of the gene encoding Xin (Xirp1) in mice leads to a mild cardiac phenotype with ID mislocalization. In order to amplify this phenotype, we performed transverse aortic constriction (TAC) on control and Xirp1-deficient mice. TAC induced similar left ventricular hypertrophy in both genotypes, suggesting that the lack of Xin does not lead to higher susceptibility to cardiac overload. However, in both genotypes, FlnC appeared in "streaming" localizations across multiple sarcomeres proximal to the IDs, suggesting a remodeling response. Furthermore, FlnC-positive areas of remodeling, reminiscent of sarcomeric lesions previously described for skeletal muscles (but so far unreported in the heart), were also observed. These adaptations reflect a similarly strong effect of the pressure induced by TAC in both genotypes. However, 2 weeks post-operation TAC-treated knockout hearts had reduced levels of connexin43 and slightly increased incidents of ventricular tachycardia compared to their wild-type (WT) counterparts. Our findings highlight the FlnC-positive sarcomeric lesions and ID-proximal streaming as general remodeling responses in cardiac overload-induced hypertrophy.

Prolonged breath-hold causes complex compensatory mechanisms such as increase in blood pressure, redistribution of blood flow, and bradycardia. We tested whether apnea induces an elevation of catecholamine-concentrations in well-trained apneic divers. 11 apneic divers performed maximal dry apnea in a horizontal position. Parameters measured during apnea included blood pressure, ECG, and central, in addition to peripheral hemoglobin oxygenation. Peripheral arterial hemoglobin oxygenation was detected by pulse oximetry, whereas peripheral (abdominal) and central (cerebral) tissue oxygenation was measured by Near Infrared Spectroscopy (NIRS). Exhaled O2 and CO2, plasma norepinephrine and epinephrine concentrations were measured before and after apnea. Averaged apnea time was 247±76 s. Systolic blood pressure increased from 135±13 to 185±25 mmHg. End-expiratory CO2 increased from 29±4 mmHg to 49±6 mmHg. Norepinephrine increased from 623±307 to 1 826±984 pg ml−1 and epinephrine from 78±22 to 143±65 pg ml−1 during apnea. Heart rate reduction was inversely correlated with increased norepinephrine (correlation coefficient −0.844, p=0.001). Central (cerebral) O2 desaturation was time-delayed compared to peripheral O2 desaturation as measured by NIRSabdominal and SpO2. Increased norepinephrine caused by apnea may contribute to blood shift from peripheral tissues to the CNS and thus help to preserve cerebral tissue O2 saturation longer than that of peripheral tissue.

Aims The pathogenesis of myocardial ischemia-reperfusion injury (MI/R) involves an inflammatory response. Since the four-and-a-half LIM domain-containing protein 2 (Fhl2) has been observed to modulate immune cell migration, we aimed to study the consequences of Fhl2−/− under MI/R with respect to immune reaction, scar formation, and hemodynamic performance. Material and methods In a closed chest model of 1 h MI/R, immune cell invasion of phagocytic monocytes was characterized by flow cytometry and immunohistochemistry. In addition, infarct size was assessed by triphenyltetrazolium chloride/Masson trichrome staining 24 h/21 days after reperfusion and a set of hemodynamic parameters was recorded by catheterisation in Fhl2−/− mice and controls. Key findings While flow cytometry did not reveal differences in myocardial CD45high immune cell infiltrate, histological analysis showed that infiltrating immune cells in Fhl2−/− animals were preferentially located in the perivascular area, whereas in wild type, immune cells were well dispersed within the area at risk. After 24 h and 21 days of reperfusion, infarct size was significantly reduced in Fhl2−/− compared to WT animals. In addition, hemodynamic performance was better in Fhl2−/− mice, compared to WT mice up to day 21 of reperfusion. The loss of Fhl2 leads to an altered immune response to myocardial ischemia, which results in smaller infarcts and better hemodynamic performance up to 21 days after myocardial ischemia reperfusion. Significance Immune cell invasion plays a pivotal role in the context of MI/R. Fhl2 significantly influences immune cell function and immune cell interaction with injured cardiac tissue leading to altered scar composition.

Background and goal of the study Pulmonary inflammation, increased vascular permeability, and pulmonary edema, occur in response to primary pulmonary infections like pneumonia but are also evident in endotoxemia or sepsis. Mechanical ventilation augments pre-existing lung injury and inflammation resulting from exposure to microbial products. The objective of this study was to test the hypothesis that low-tidal-volume prevent ventilation induced lung injury in sepsis. Materials and methods 10–12-week-old male C57BL/6N-mice received an intraperitoneal (i.p.) injection with equipotent dosages of LPS, 1668-thioate, 1612-thioate, or PBS. 120 min after injection, mice were randomized to low- (LV, 7 ± 1 ml/kg) or high-tidal-volume (HV, 25 ± 1 ml/kg) ventilation. Hemodynamic and ventilatory parameters were recorded and inflammatory markers were analyzed form BAL that was generated after 90 minute ventilation. Results and discussion Arterial blood pressures declined during mechanical ventilation in all groups. pO2 decreased in LPS injected and CO2 increased in sham, LPS, and 1612-thioate administered mice at 45 min and in 1668-thioate injected mice after 90 minute LV ventilation compared to respective HV groups. BAL protein concentrations increased in HV ventilated and 1668- or 1612-thioat pre-treated mice. BAL TNF-α protein concentrations increased in both LPS- and 1668-thioate-injected and IL-1β protein concentrations only in LPS-injected and HV ventilated mice. Most notably, no increased protein concentrations were observed in any of the LV ventilated groups. Conclusion We conclude that low-tidal-volume ventilation may be a potential strategy for the prevention of ventilator induced lung injury in a murine model of systemic TLR agonist induced lung injury.

Aims In contrast to the membrane bound adenylyl cyclases, the soluble adenylyl cyclase (sAC) is activated by bicarbonate and divalent ions including calcium. sAC is located in the cytosol, nuclei and mitochondria of several tissues including cardiac muscle. However, its role in cardiac pathology is poorly understood. Here we investigate whether sAC is involved in hypertrophic growth using two different model systems. Methods and results In isolated adult rat cardiomyocytes hypertrophy was induced by 24 h β1-adrenoceptor stimulation using isoprenaline (ISO) and a β2-adrenoceptor antagonist (ICI118,551). To monitor hypertrophy cell size along with RNA/DNA- and protein/DNA ratios as well as the expression level of α-skeletal actin were analyzed. sAC activity was suppressed either by treatment with its specific inhibitor KH7 or by knockdown. Both pharmacological inhibition and knockdown blunted hypertrophic growth and reduced expression levels of α-skeletal actin in ISO/ICI treated rat cardiomyocytes. To analyze the underlying cellular mechanism expression levels of phosphorylated CREB, B-Raf and Erk1/2 were examined by western blot. The results suggest the involvement of B-Raf, but not of Erk or CREB in the pro-hypertrophic action of sAC. In wild type and sAC knockout mice pressure overload was induced by transverse aortic constriction. Hemodynamics, heart weight and the expression level of the atrial natriuretic peptide were analyzed. In accordance, transverse aortic constriction failed to induce hypertrophy in sAC knockout mice. Mechanistic analysis revealed a potential role of Erk1/2 in TAC-induced hypertrophy. Conclusion Soluble adenylyl cyclase might be a new pivotal player in the cardiac hypertrophic response either to long-term β1-adrenoceptor stimulation or to pressure overload.

Aims The incidence of secondary systemic fungal infections has sharply increased in bacterial septic patients. Antimycotics exhibit immunomodulatory properties, yet these effects are incompletely understood in secondary systemic fungal infections following bacterial sepsis. We investigated a model of systemic inflammation to determine whether antimycotics (liposomal amphotericin B (L-AMB), itraconazol (ITC), and anidulafungin (ANI)) modulate the gene and protein expression as well as the phagocytic activity of lipopolysaccharide (LPS)-stimulated human monocytes. Main methods THP-1 monocytes were incubated with L-AMB, ITC or ANI and LPS. Gene expression levels of cytokines (TNF- , IL-1 , IL-6, and IL-10) were measured after 2 h, 6 h, and 24 h. Cytokine protein levels were evaluated after 24 h and phagocytic activity was determined following co-incubation with Escherichia coli. Key findings All antimycotics differentially modulated the gene and protein expression of cytokines in sepsis-like conditions. In the presence of LPS, we identified L-AMB as immunosuppressive, whereas ITC demonstrated pro-inflammatory properties. Both compounds induced remarkably less phagocytosis. Significance Our study suggests that antimycotics routinely used in septic patients alter the immune response in sepsis-like conditions by modulating cytokine gene and protein expression levels and phagocytic activity. Future treatment strategies should consider the immune status of the host and apply antimycotics accordingly in bacterial septic patients with secondary fungal infections.

Conventional antibiotics exhibit immunomodulatory properties beneficial in the treatment of sepsis. Antibiotic-resistant Gram-positive bacteria have become a problem in sepsis therapy, giving rise to increased use of last-resort antibiotics; for example, linezolid (LIN), vancomycin (VAN) and daptomycin (DAP). As the immunomodulatory properties of these antibiotics in treating sepsis are unknown, this study examined the effect of VAN, LIN and DAP on the immune response under sepsis-like conditions in vitro. Lipopolysaccharide (LPS)-activated THP-1 monocytes were incubated with LIN, VAN or DAP. Gene expression of cytokines (TNFα, IL-1β, IL-6, IL-10) and Toll-like receptors (TLR1, 2, 4, 6, 7 and 9) was monitored and phagocytosis was determined following coincubation with E. coli. The antibiotics differentially modulated the gene expression of the investigated cytokines. While LIN and VAN upregulated the expression of all TLRs, DAP downregulated mRNA levels of TLR1, TLR2 and TLR6, which recognize pathogen-associated molecular patterns from Gram-positive bacteria. In addition, LIN inhibited, whereas VAN promoted the phagocytic activity of monocytes. Our results suggest that LIN and VAN possess pro-inflammatory properties, whereas DAP might reduce the immune response to Gram-positive bacteria in sepsis. Furthermore, VAN might be beneficial in the prevention of Gram-negative infections by increasing the phagocytosis of E. coli.

In this study we investigated the responsiveness of near-infrared spectroscopy (NIRS) recordings measuring regional cerebral tissue oxygenation (rSO2) during hypoxia in apneic divers. The goal was to mimic dynamic hypoxia as present during cardiopulmonary resuscitation, laryngospasm, airway obstruction, or the "cannot ventilate cannot intubate" situation. Ten experienced apneic divers performed maximal breath hold maneuvers under dry conditions. SpO2 was measured by Masimo™ pulse oximetry on the forefinger of the left hand. NIRS was measured by NONIN Medical's EQUANOX™ on the forehead or above the musculus quadriceps femoris. Following apnea median cerebral rSO2 and SpO2 values decreased significantly from 71 to 54 and from 100 to 65%, respectively. As soon as cerebral rSO2 and SpO2 values decreased monotonically the correlation between normalized cerebral rSO2 and SpO2 values was highly significant (Pearson correlation coefficient = 0.893). Prior to correlation analyses, the values were normalized by dividing them by the individual means of stable pre-apneic measurements. Cerebral rSO2 measured re-saturation after termination of apnea significantly earlier (10 s, SD = 3.6 s) compared to SpO2 monitoring (21 s, SD = 4.4 s) [t(9) = 7.703, p < 0.001, r(2) = 0.868]. Our data demonstrate that NIRS monitoring reliably measures dynamic changes in cerebral tissue oxygen saturation, and identifies successful re-saturation faster than SpO2. Measuring cerebral rSO2 may prove beneficial in case of respiratory emergencies and during pulseless situations where SpO2 monitoring is impossible.

BACKGROUND: Most antiepileptic drugs (AEDs) inhibit seizure generation by acting on voltage-dependent ion channels. Voltage-dependent sodium and calcium channels are commonly expressed in brain and heart, suggesting that AEDs may have considerable cardiodepressive effects, thereby facilitating sudden cardiac death as a potential cause of sudden unexpected death in epilepsy (SUDEP). Here, we investigated the effects of carbamazepine (CBZ), lamotrigine (LTG) and levetiracetam (LEV) alone and in combination on the shortening properties of isolated ventricular cardiomyocytes of wild type mice. METHODS: Properties of murine cardiomyocytes were determined by recording the sarcomere shortening with a video imaging system before, during and after administration of AEDs in different concentrations and combinations. We assessed (i) the number of successful shortenings during continuous electrical stimulation (electromechanical coupling) and (ii) the shortening amplitude as well as other shortening-related properties upon repetitive electrical stimulation at 4 Hz. Data are given as mean±SEM. RESULTS: At 100 µM, CBZ (10 cells), LTG (11 cells) and LEV (11 cells) alone had no effect on the electromechanical coupling, but reversibly reduced shortening amplitudes by 15±4 %, 24±3 % and 11±3 %, respectively. Increasing the LTG concentration to 250 (21 cells) and 500 µM (4 cells) reversibly inhibited the electromechanical coupling in 62 % and 100 % of the experiments. Importantly, simultaneous application of CBZ, LTG and LEV at 100 µM also impaired the electromechanical coupling in 8 of 19 cardiomyocytes (42 %) and reduced the shortening amplitude by 21±4 %. CONCLUSION: Our data show that AEDs reversibly impair cardiac excitation and contraction. Importantly, the blocking effect on electromechanical coupling appears to be additive when different AEDs are simultaneously applied. The translational value of these experimental findings into clinical practice is limited. Our results, however, suggest that rationale AED-therapy may be important with respect to cardiac side-effects and potential facilitation of serious cardiac dysfunction especially when AEDs are used in combination or at very high doses.

Aims Toll-like receptor (TLR)9 ligand CpG-oligodeoxynucleotide (CpG-ODN) exerts preconditioning in myocardial ischemia/reperfusion. We hypothesized a postconditioning effect of CpG-ODN in a murine closed-chest model of myocardial infarction. Materials and Methods C57BL/6 (12 weeks, male, WT) mice were instrumented at the left anterior descending artery, then allowed 5d of recovery before 30 min ischemia. Treatments comprised: 1) PBS: 250 μl phosphate buffer solution intraperitoneally 5 min before reperfusion and 2) IPC (ischemic postconditioning): 3 twenty-second reperfusion and occlusion episodes at the end of ischemia 3) CpG-ODN: 1668 thioate 0.2 μmol/kg BW intraperitoneally 5 min before reperfusion. Infarct size was assessed via triphenyltetrazolium chloride (TTC) staining after 2 and 24 h reperfusion. Myocardial mRNA-expression of cytokines was measured using real-time PCR after 2 h reperfusion. Phosphatidylinositol-3 kinase (PI3K)-inhibitor wortmannin was injected intraperitoneally in WT 15 min before postconditioning and PBS in each group. Cardiac function in WT was assessed with a left-ventricular pressure-volume catheter at 24 h reperfusion. Key findings Following 30 min ischemia and 2 h reperfusion, infarct size was diminished by 90% in WT postconditioned with CpG-ODN (2.4 ± 1.55 IS/AAR%) and IPC (1.98 ± 1.03 IS/AAR%) compared to PBS mice (23.2 ± 3.97 IS/AAR%). Infarct size increased following 24 h reperfusion but the differences remained robust. Expression of TNF-α and IL-10 was increased in CpG-ODN. Wortmannin abolished the postconditioning effect of CpG-ODN and IPC. Ejection fraction and preload-recruitable stroke work were significantly greater in CpG-ODN mice. Significance CpG-ODN confers postconditioning via activation of TLR9. Cardiac function is preserved following CpG-ODN postconditioning. The PI3K -inhibitor wortmannin attenuates CpG-ODN postconditioning.

Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1363-2) contains supplementary material, which is available to authorized users.