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Background: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored.
Methods: Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h.
Results: Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R.
Conclusions: These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.
Background: Chronic ethanol (EtOH) abuse worsens pathophysiological derangements after hemorrhagic shock and resuscitation (H/R) that induce hepatic injury and strong inflammatory changes via JNK and NF-κB activation. Inhibiting JNK with a cell-penetrating, protease-resistant peptide D-JNKI-1 after H/R in mice with healthy livers ameliorated these effects. Here, we studied if JNK inhibition by D-JNKI-1 in chronically EtOH-fed mice after hemorrhagic shock prior to the onset of resuscitation also confers protection.
Methods: Male mice were fed a Lieber-DeCarli diet containing EtOH or an isocaloric control (ctrl) diet for 4 weeks. Animals were hemorrhaged for 90 min (32 ± 2 mm Hg) and randomly received either D-JNKI-1 (11 mg/kg, intraperitoneally, i. p.) or sterile saline as vehicle (veh) immediately before the onset of resuscitation. Sham animals underwent surgical procedures without H/R and were either D-JNKI-1 or veh treated. Two hours after resuscitation, blood samples and liver tissue were harvested.
Results: H/R induced hepatic injury with increased systemic interleukin (IL)-6 levels, and enhanced local gene expression of NF-κB-controlled genes such as intercellular adhesion molecule (ICAM)-1 and matrix metallopeptidase (MMP)9. c-Jun and NF-κB phosphorylation were increased after H/R. These effects were further increased in EtOH-fed mice after H/R. D-JNKI-1 application inhibited the proinflammatory changes and reduced significantly hepatic injury after H/R in ctrl-fed mice. Moreover, D-JNKI-1 reduces in ctrl-fed mice the H/R-induced c-Jun and NF-κB phosphorylation. However, in chronically EtOH-fed mice, JNK inhibition did not prevent the H/R-induced hepatic damage and proinflammatory changes nor c-Jun and NF-κB phosphorylation after H/R.
Conclusions: These results indicate, that JNK inhibition is protective only in not pre-harmed liver after H/R. In contrast, the pronounced H/R-induced liver damage in mice being chronically fed with ethanol cannot be prevented by JNK inhibition after H/R and seems to be under the control of NF-κB.
Introduction: Current classifications of complete knee dislocations do not capture the extent of the complex concomitant ligamentous and bony injuries, which may have an impact on future outcomes. The purpose of this retrospective study was to evaluate the epidemiology of complete knee dislocations as well as to present an updated classification system based on the author’s experience at a Level-I trauma center.
Materials and methods: Only patients with complete loss of contact of the articulating bones and ≥ 18 years of age who admitted in our level-I trauma center between 2002 and 2019 were included. Patients were identified using a retrospective systematical query in the Hospital Information System (HIS) using the International Statistical Classification of Diseases and Related Health Problems Version10 (ICD-10) codes of the German Diagnosis Related Groups (G-DRG).
Results: Final data included 80 patients, with the majority of patients being male (n = 64; 80.0%). Mean age was 34.9 years (range: 18–70 years). External protective fixation was applied in 32 patients (40.0%). Reconstruction of the posterior cruciate ligament and the anterior cruciate ligament were performed in 56.3% (n = 45) and 55.0% (n = 44) of cases, respectively. The lateral collateral ligament complex was surgically addressed in 47.5% (n = 38), while the medial collateral ligament complex was reconstructed in 40% (n = 32). Surgery of the lateral meniscus and the medial meniscus was needed in 31.1% (n = 25) and 30.0% (n = 24). Neurovascular surgery occurred in 13.8% (n = 11). From the characteristic injury-patterns the authors of this study present a new classification system that ranks the injuries from Grade-A to Grade-D according to their severity.
Conclusion: This retrospective study demonstrates that the historically used classification systems for dislocations of the knee are insufficient for these severe injuries. Concomitant ligamentous, neurovascular, bony, and meniscal injuries were frequent, and required several staged procedures. Consequently, an updated classification system is proposed.
Aim: To evaluate protective immunosuppressive dose and time-dependent effects of ethanol in an in vitro model of acute inflammation in human Chang liver cells.
Method: The study was performed in 2016 and 2017 in the research laboratory of the Department of Trauma, Hand and Reconstructive Surgery, the University Hospital of the Goethe-University Frankfurt. Chang liver cells were stimu - lated with either interleukin (IL)-1β or IL-6 and subsequent - ly treated with low-dose ethanol (85 mmol/L) or high-dose ethanol (170 mmol/L) for one hour (acute exposure) or 72 hours (subacute exposure). IL-6 and IL-1β release were de - termined by enzyme-linked immunosorbent assay. Neu - trophil adhesion to Chang liver monolayers, production of reactive oxygen species, and apoptosis or necrosis were analyzed.
Results: Contrary to high-dose ethanol, acute low-dose ethanol exposure significantly reduced IL-1β-induced IL-6 and IL-6-induced IL-1β release ( P <0.05). Subacute etha - nol exposure did not change proinflammatory cytokine release. Acute low-dose ethanol exposure significantly decreased inflammation-induced formation of reactive oxygen species ( P <0.05) and significantly improved cell survival ( P <0.05). Neither acute nor subacute high-dose ethanol exposure significantly changed inflammationinduced changes in reactive oxygen species or survival. Acute and subacute ethanol exposure, independently of the dose, significantly decreased neutrophil adhesion to inflamed Chang liver cells ( P <0.05).
Conclusion: Acute treatment of inflamed Chang liver cells with ethanol showed its immunosuppressive potential. However, the observed effects were limited to low-dose setting, indicating the relevance of ethanol dose in the modulation of inflammatory cell response.
Background/Aims: Alcohol (ethanol, EtOH) as significant contributor to traumatic injury is linked to suppressed inflammatory response, thereby influencing clinical outcomes. Alcohol-induced immune-suppression during acute inflammation (trauma) was linked to nuclear factor-kappaB (NF-ĸB). Here, we analyzed alcohol`s effects and mechanisms underlying its influence on NF-ĸB-signaling during acute inflammation in human lung epithelial cells. Methods: A549-cells were stimulated with interleukin (IL)-1β, or sera from trauma patients (TP) or healthy volunteers, with positive/negative blood alcohol concentrations (BAC), and subsequently exposed to EtOH (170 Mm, 1h). IL-6-release and neutrophil adhesion to A549 were analyzed. Specific siRNA-NIK mediated downregulation of non-canonical, and IKK-NBD-inhibition of canonical NF-ĸB signaling were performed. Nuclear levels of activated p50 and p52 NF-ĸB-subunits were detected using TransAm ELISA. Results: Both stimuli significantly induced IL-6-release (39.79±4.70 vs. 0.58±0.8 pg/ml) and neutrophil adhesion (132.30±8.80 vs. 100% control, p<0.05) to A549-cells. EtOH significantly decreased IL-6-release (22.90±5.40, p<0.05) and neutrophil adherence vs. controls (105.40±14.5%, p<0.05). IL-1β-induced significant activation of canonical/p50 and non-canonical/p52 pathways. EtOH significantly reduced p50 (34.90±23.70 vs. 197.70±36.43, p<0.05) not p52 activation. Inhibition of canonical pathway was further increased by EtOH (less p50-activation), while p52 remained unaltered. Inhibition of non-canonical pathway was unchanged by EtOH. Conclusion: Here, alcohol`s anti-inflammatory effects are mediated via decreasing nuclear levels of activated p50-subunit and canonical NF-ĸB signaling pathway.
Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.
Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits.
Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
Oxidative stress attenuates the NO-cGMP pathway, e.g. in the vascular system, through scavenging of free NO radicals by superoxide O2•-, by inactivation of soluble guanylyl cyclase (sGC) via oxidation of its central Fe2+ ion, and by down-regulation of sGC protein levels. While the former pathways are well established, the molecular mechanisms underlying the latter are still obscure. Using oxidative sGC inhibitor ODQ we demonstrate rapid down-regulation of sGC protein in mammalian cells. Co-incubation with proteasomal inhibitor MG132 results in accumulation of ubiquitinated sGC whereas sGC activator BAY 58–2667 prevents ubiquitination. ODQ-induced down-regulation of sGC is mediated through selective ubiquitination of its b subunit, and BAY 58–2667 abrogates this effect. Ubiquitination of sGC-b is dramatically enhanced by E3 ligase CHIP. Our data indicate that oxidative stress promotes ubiquitination of sGC b subunit through E3 ligase CHIP, and that sGC activator 58–2667 reverts this effect, most likely through stabilization of the heme-free b subunit. Thus the deleterious effects of oxidative stress can be counter-balanced by an activator of a key enzyme of vascular homeostasis.
Objective: Clostridial gas gangrene (GG) or clostridial myonecrosis is a very rare but life‐threatening necrotizing soft tissue infection (NSTI) caused by anaerobic, spore‐forming, and gas‐producing clostridium subspecies. It is the most rapidly spreading and lethal infection in humans, also affecting muscle tissue. The high mortality, of up to 100%, in clostridial GG is mediated by potent bacterial exotoxins. Necrotizing fasciitis (NF) is an important differential diagnosis, most often caused by group A streptococci, primarily not affecting musculature but the subcutaneous tissue and fascia. In the early stages of the infection, it is difficult to distinguish between GG and NF. Therefore, we compare both infection types, identify relevant differences in initial clinical presentation and later course, and present the results of our patients in a retrospective review.
Methods: Patients diagnosed with GG from 2008 to 2018 in our level one trauma center were identified. Their charts were reviewed retrospectively and data analyzed in terms of demographic information, microbiological and histological results, therapeutic course, outcome, and mortality rates. The laboratory risk indicator for NF (LRINEC) score was applied on the first blood work acquired. Results were compared to those of a second group diagnosed with NF.
Results: Five patients with GG and nine patients with NF were included in the present study. Patients with GG had a mortality rate of 80% compared to 0% in patients with NF. In eight patients with NF, affected limbs could be salvaged; one NF underwent amputation. LRINEC did not show significant differences between the groups; however, C‐reactive protein was significantly increased (P = 0.009) and hemoglobin (Hb) was significantly decreased (P = 0.02) in patients with GG. Interleukin‐6 and procalcitonin levels did not show significant difference. Patients with GG were older (70.2 vs 50 years). Of the isolated bacteria, 86% were sensitive to the initial calculated antibiotic treatment with ampicillin‐sulbactam or imipenem plus metronidazole plus clindamycin.
Conclusion: Both GG and NF need full‐scale surgical, antibiotic, and intensive care treatment, especially within the first days. Among patients with NSTI, those with clostridial GG have a significantly increased mortality risk due to early septic shock caused by clostridial toxins. In the initial stages, clinical differences are hardly detectable. Immediate surgical debridement is the key to successful therapy for NSTI and needs to be performed as early as possible. However, patients should be treated in a center with an experienced interdisciplinary intensive care team based on a predetermined treatment plan.
Purpose: Fractures of the humerus account for 5%–8% of all fractures. Nonunion is found with an incidence of up to 15%, depending on the location of the fracture. In case of a manifest nonunion the surgeon faces a challenging problem and has to conceive a therapy based on the underlying pathology. The aim of this study was to describe our treatment concepts for this entity and present our results of the last five years.
Methods: Twenty-six patients were treated for nonunion of the humerus between January 2013 and December 2017. Their charts were reviewed retrospectively and demographic data, pathology, surgical treatment and outcome were assessed.
Results: The most frequent location for a nonunion was the humeral shaft, with the most common trauma mechanism being multiple falls. Most often atrophic nonunion (n = 14), followed by hypertrophic and infection-caused nonunion (each n = 4), were found. Our treatment concept could be applied in 19 patients, of which in 90% of those who were available for follow-up consolidation could be achieved.
Conclusion: Humeral nonunion is a heterogeneous entity that has to be analyzed precisely and be treated correspondingly. We therefore present a treatment concept based on the underlying pathology.
A central motivation for the development of x-ray free-electron lasers has been the prospect of time-resolved single-molecule imaging with atomic resolution. Here, we show that x-ray photoelectron diffraction—where a photoelectron emitted after x-ray absorption illuminates the molecular structure from within—can be used to image the increase of the internuclear distance during the x-ray-induced fragmentation of an O2 molecule. By measuring the molecular-frame photoelectron emission patterns for a two-photon sequential K-shell ionization in coincidence with the fragment ions, and by sorting the data as a function of the measured kinetic energy release, we can resolve the elongation of the molecular bond by approximately 1.2 a.u. within the duration of the x-ray pulse. The experiment paves the road toward time-resolved pump-probe photoelectron diffraction imaging at high-repetition-rate x-ray free-electron lasers.