Search

Background: The arthroscopically assisted stabilization of AC joint dislocations with a suture button system is an established procedure that is widely and successfully used in everyday practice. The main advantages of this one-step method are the minimally invasive procedure and the anatomical reconstruction of the ruptured coracoclavicular ligaments with a permanent implant. With this technical note study, for the first time, the new method of navigated suture button implantation in everyday clinical practice is described with the future goal of further reducing invasiveness and increasing precision. Materials and Methods: The surgical technique is explained using precise descriptions and illustrations, photos, X-rays, and 3D reconstructions based on clinical cases. The step-by-step system setup and patient positioning, AC joint reduction and retention, 3D scan and drill tunnel planning, stab incision and Kirschner wire navigation, and cannulated drilling and implant positioning, as well as closure and documentation are described in detail. Results: The standard coracoclavicular stabilization of AC joint dislocations with the 3D C-arm navigated suture button method is described in detail. Furthermore, the feasibility of an additive horizontal acromioclavicular suture cerclage, the implantation of an additional coracoclavicular suture button system, and the single-stage cannulated screw fixation of non-displaced fractures is demonstrated. Conclusion: The navigated suture button method aims to be simple, safe, minimally invasive, and precise. Prospective clinical studies with a long follow-up should be carried out to determine the clinical and radiological outcome in comparison with current methods.

Abstract Despite advances in the treatment and care of severe physical injuries, trauma remains one of the main reasons for disability-adjusted life years worldwide. Trauma patients often suffer from disturbances in energy utilization and metabolic dysfunction, including hyperglycemia and increased insulin resistance. White adipose tissue plays an essential role in the regulation of energy homeostasis and is frequently implicated in traumatic injury due to its ubiquitous body distribution but remains poorly studied. Initial triggers of the trauma response are mainly damage-associated molecular patterns (DAMPs) such as histones. We hypothesized that DAMP-induced adipose tissue inflammation contributes to metabolic dysfunction in trauma patients. Therefore, we investigated whether histone release during traumatic injury affects adipose tissue. Making use of a murine polytrauma model with hemorrhagic shock, we found increased serum levels of histones accompanied by an inflammatory response in white adipose tissue. In vitro, extracellular histones induced an inflammatory response in human adipocytes. On the molecular level, this inflammatory response was mediated via a MYD88-IRAK1-ERK signaling axis as demonstrated by pharmacological and genetic inhibition. Histones also induced lytic cell death executed independently of caspases and RIPK1 activity. Importantly, we detected increased histone levels in the bloodstream of patients after polytrauma. Such patients might benefit from a therapy consisting of activated protein C and the FDA-approved ERK inhibitor trametinib, as this combination effectively prevented histone-mediated effects on both, inflammatory gene activation and cell death in adipocytes. Preventing adipose tissue inflammation and adipocyte death in patients with polytrauma could help minimize posttraumatic metabolic dysfunction.

Purpose: Since October 2019 a computer software named SPM (surgical process manager) is used in a Level I Trauma center. Workflows were developed for distinct surgical procedures (distal radius fractures, proximal femur fractures, ankle fractures, proximal humerus fractures and vertebral fractures). In addition, these workflows were separated in a shortened „Expert“-versions for consultants and a more detailed „Learner“- versions for residents.This investigation was intended to show, if and what kind of benefits in regard to efficiency (incision to suture and suture to incision time), education and complications a surgery supporting software can bring. Methods: SPM was used in 90 cases during October 2019 to June 2022. A control trial with 108 patients was developed, including patients of the same age, having same kind of injuries, receiving the same surgery technique without using the SPM.The software was installed on the computer in the operation room, projected on head monitors and operated by a foot pedal. Complications could also be documented using the pedal.Groups were divided in surgical procedures and fracture type, qualification of the surgeon, complications and surgery time. Surgery times were taken from the hospital computer system (SAP IS-H). A statistical analysis was performed by using the chi square and Fischer exact test with significance set at a P value

Purpose:. This study examined the leadership development themes that global orthopaedic surgeons in differently resourced countries perceive as essential components and evaluated barriers to attending leadership development programs. Methods:. This multinational, 45-question survey engaged orthopaedic surgeons (one expert per country). The questionnaire collected participants' demographics, perception of effective leadership traits, and valuation of various leadership themes based on importance and interest. Results:. The survey was completed by 110 orthopaedic surgeons worldwide. Respondents most commonly reported holding a leadership position (87%) in hospital settings (62%), clinical settings (47%), and national orthopaedic societies (46%). The greatest proportion of participants reported having never attended a leadership course (42%). Participants regarded “high performing team-building,” “professional ethics,” and “organizational structure and ability to lead” as the most important leadership themes. No significant (P ≤ 0.05) differences were identified among perceived importance or interest in leadership themes between income levels; however, statistically significant differences were identified in the questionnaire; respondents in low- and middle-income countries (LICs/LMICs) demonstrated a stronger interest in attending a leadership course than those in high-income countries (HICs) (98% vs. 79%, P = 0.013), and fewer surgeons in LICs/LMICs had taken personality assessment tests than those in HICs (22% vs. 49%, P = 0.019). The most common barriers to attending leadership courses were lack of opportunities and invitations (57%), difficulty missing work (22%), and cost of course attendance (22%). Conclusions:. These findings can better inform the development of effective curricula and provide a framework for a successful model for the future. Level of Evidence:. V.

Abstract Mental traumatization is associated with long-bone growth retardation, osteoporosis and increased fracture risk. We revealed earlier that mental trauma disturbs cartilage-to-bone transition during bone growth and repair in mice. Trauma increased tyrosine hydroxylase-expressing neutrophils in bone marrow and fracture callus. Here we show that tyrosine hydroxylase expression in the fracture hematoma of patients correlates positively with acknowledged stress, depression, and pain scores as well as individual ratings of healing-impairment and pain-perception post-fracture. Moreover, mice lacking tyrosine hydroxylase in myeloid cells are protected from chronic psychosocial stress-induced disturbance of bone growth and healing. Chondrocyte-specific β2-adrenoceptor-deficient mice are also protected from stress-induced bone growth retardation. In summary, our preclinical data identify locally secreted catecholamines in concert with β2-adrenoceptor signalling in chondrocytes as mediators of negative stress effects on bone growth and repair. Given our clinical data, these mechanistic insights seem to be of strong translational relevance.

The space- and temperature-dependent electron distribution n(r,T) determines optoelectronic properties of disordered semiconductors. It is a challenging task to get access to n(r,T) in random potentials, while avoiding the time-consuming numerical solution of the Schrödinger equation. We present several numerical techniques targeted to fulfill this task. For a degenerate system with Fermi statistics, a numerical approach based on a matrix inversion and one based on a system of linear equations are developed. For a non-degenerate system with Boltzmann statistics, a numerical technique based on a universal low-pass filter and one based on random wave functions are introduced. The high accuracy of the approximate calculations are checked by comparison with the exact quantum-mechanical solutions.

IntroductionGeriatric co-management is known to improve treatment of older adults in various clinical settings, however, widespread application of the concept is limited due to restricted resources. Digitalization may offer options to overcome these shortages by providing structured, relevant information and decision support tools for medical professionals. We present the SURGE-Ahead project (Supporting SURgery with GEriatric co-management and Artificial Intelligence) addressing this challenge.MethodsA digital application with a dashboard-style user interface will be developed, displaying 1) evidence-based recommendations for geriatric co-management and 2) artificial intelligence-enhanced suggestions for continuity of care (COC) decisions. The development and implementation of the SURGE-Ahead application (SAA) will follow the Medical research council framework for complex medical interventions. In the development phase a minimum geriatric data set (MGDS) will be defined that combines parametrized information from the hospital information system with a concise assessment battery and sensor data. Two literature reviews will be conducted to create an evidence base for co-management and COC suggestions that will be used to display guideline-compliant recommendations. Principles of machine learning will be used for further data processing and COC proposals for the postoperative course. In an observational and AI-development study, data will be collected in three surgical departments of a University Hospital (trauma surgery, general and visceral surgery, urology) for AI-training, feasibility testing of the MGDS and identification of co-management needs. Usability will be tested in a workshop with potential users. During a subsequent project phase, the SAA will be tested and evaluated in clinical routine, allowing its further improvement through an iterative process.DiscussionThe outline offers insights into a novel and comprehensive project that combines geriatric co-management with digital support tools to improve inpatient surgical care and continuity of care of older adults.Trial registrationGerman clinical trials registry (Deutsches Register für klinische Studien, DRKS00030684), registered on 21st November 2022.

Abstract Background Among potentially modifiable risk factors for delirium, transfers between wards, hospitals and other facilities have been mentioned with low evidence. TRADE (TRAnsport and DElirium in older people) was set up to investigate i) the impact of transfer and/or discharge on the onset of delirium in older adults and ii) feasibility and acceptance of a developed complex intervention targeting caregiver’s participation during and after hospital discharge or transfer on cognition and the onset of delirium in older adults. Methods The study is designed according to the guidelines of the UK Medical Research Council (MRC) for development and evaluation of complex interventions and comprises two steps: development and feasibility/piloting. The development phase includes i) a multicenter observational prospective cohort study to assess delirium incidence and cognitive decline associated with transfer and discharge, ii) a systematic review of the literature, iii) stakeholder focus group interviews and iv) an expert workshop followed by a Delphi survey. Based on this information, a complex intervention to better and systematically involve family caregivers in discharge and transport was developed. The intervention will be tested in a pilot study using a stepped wedge design with a detailed process and health economic evaluation. The study is conducted at four acute care hospitals in southwest Germany. Primary endpoints are the delirium incidence and cognitive function. Secondary endpoints include prevalence of caregiver companionship, functional decline, cost and cost effectiveness, quality of discharge management and quality of admission management in admitting hospitals or nursing homes. Data will be collected prior to discharge as well as after 3, 7 and 90 days. Discussion TRADE will help to evaluate transfer and discharge as a possible risk factor for delirium. In addition, TRADE evaluates the impact and modifiability of caregiver’s participation during patient’s transfer or discharge on delirium incidence and cognitive decline providing the foundation for a confirmatory implementation study. Trial registration DRKS (Deutsches Register für klinische Studien) DRKS00017828 . Registered on 17th September 2019. Retrospectively registered.

Background: Trauma is the leading cause of death and disability worldwide, especially in the young population. Cardiac injuries are an independent predictor for a poor overall outcome after trauma. The aim of the present study was to analyze systemic inflammation as well as local cardiac inflammation after experimental limb-, neuro- and combined trauma in mice. Methods: Male C57BL/6 mice received either a closed tibia fracture (Fx), isolated traumatic brain injury (TBI) or a combination of both (Fx ​+ ​TBI). Control animals underwent sham procedure. After 6 and 24 ​h, systemic levels of inflammatory mediators were analyzed, respectively. Locally, cardiac inflammation and cardiac structural alterations were investigated in left ventricular tissue of mice 6 and 24 ​h after trauma. Results: Mice showed enhanced systemic inflammation after combined trauma, which was manifested by increased levels of KC, MCP-1 and G-CSF. Locally, mice exhibited increased expression of inflammatory cytokines (IL-1β, TNF) in heart tissue, which was probably mediated via toll-like receptor (TLR) signaling. Furthermore, mice demonstrated a redistribution of connexin 43 in cardiac tissue, which appeared predominantly after combined trauma. Besides inflammation and structural cardiac alterations, expression of glucose transporter 4 (GLUT4) mRNA was increased in the heart early after TBI and after combination of TBI and limb fracture, indicating a modification of energy metabolism. Early after combination of TBI and tibia fracture, nitrosative stress was increased, manifested by elevation of nitrotyrosine in cardiac tissue. Finally, mice showed a trend of increased systemic levels of cardiac troponin I and heart-fatty acid binding protein (HFABP) after combined trauma, which was associated with a significant decrease of troponin I and HFABP mRNA expression in cardiac tissue after TBI and combination of TBI and limb fracture. Conclusion: Mice exhibited early cardiac alterations as well as alterations in cardiac glucose transporter expression, indicating a modification of energy metabolism, which might be linked to increased systemic- and local cardiac inflammation after limb-, neuro- and combined trauma. These cardiac alterations might predispose individuals for secondary cardiac damage after trauma that might compromise cardiac function after TBI and long bone fracture. Translational potential statement: Injuries to the head and extremities frequently occur after severe trauma. In our study, we analyzed the effects of closed tibia fracture, isolated TBI, and the combination of both injuries with regard to the development of post-traumatic secondary cardiac injuries.

Here, the authors characterize the spectroscopic and transport properties of heterojunctions composed of quasi-metallic and semiconducting graphene nanoribbons (GNRs) with different widths, showing a predominant quantum tunnelling mechanism. The GNR heterojunctions can also be used to realize adsorbate sensors with high sensitivity.

Abstract Musculoskeletal injuries are the most common reason for surgery in severely injured patients. In addition to direct cardiac damage after physical trauma, there is rising evidence that trauma induces secondary cardiac structural and functional damage. Previous research associates hip fractures with the appearance of coronary heart disease: As 25% of elderly patients developed a major adverse cardiac event after hip fracture. 20 male pigs underwent femur fracture with operative stabilization via nailing (unreamed, reamed, RIA I and a new RIA II; each group n = 5). Blood samples were collected 6 h after trauma and the concentration of troponin I and heart-type fatty acid binding protein (HFABP) as biomarkers for EMD were measured. At baseline and 6 h after trauma, transesophageal ECHO (TOE) was performed; and invasive arterial and left ventricular blood pressure were measured to evaluate the cardiac function after femur fracture. A systemic elevation of troponin I and HFABP indicate an early myocardial damage after femur fracture in pigs. Furthermore, various changes in systolic (ejection fraction and cardiac output) and diastolic (left ventricular end-diastolic pressure, mitral valve deceleration time and E/A ratio) parameters illustrate the functional impairment of the heart. These findings were accompanied by the development of valvular dysfunction (pulmonary and tricuspid valve). To the best of our knowledge, we described for the first time the development of functional impairment of the heart in the context of EMD after long bone fracture in pigs. Next to troponin and HFABP elevation, alterations in the systolic and diastolic function occurred and were accompanied by pulmonary and tricuspid valvular insufficiency. Regarding EMD, none of the fracture stabilization techniques (unreamed nailing, reaming, RIA I and RIA II) was superior.

Abstract One third of multiple trauma patients present abnormal echocardiographic (ECHO) findings. Therefore, ECHO diagnostic after trauma is indicated in case of hemodynamic instability, shock, after chest trauma and after cardiac arrest. 20 male pigs underwent multiple trauma. Blood samples were collected 4 and 6 h after trauma and concentrations of heart-type fatty acid binding protein (HFABP) as a biomarker for EMD were measured. Myocardial damage was evaluated by scoring Hematoxylin–Eosin stained sections. At baseline, 3 and 6 h after trauma, transesophageal ECHO (TOE) was performed, invasive arterial and left ventricular blood pressure were measured to evaluate the cardiac function after multiple trauma. Systemic HFABP concentrations were elevated, furthermore heart injury score in multiple trauma animals was increased determining EMD. A significant decrease of blood pressure in combination with a consecutive rise of heart frequency was observed. Ongoing depression of mean arterial pressure and diastolic blood pressure were accompanied by changes in ECHO-parameters indicating diastolic and systolic dysfunction. Furthermore, a valvular dysfunction was detected. In this study complex myocardial and valvular impairment after multiple trauma in pigs has been observed. Therefore, detection of EMD and progressive valvular dysfunction might be crucial and therapeutically relevant.

Introduction Femoral neck fractures in the elderly are a major event and are rising in incidence over the last decade. Advancing age and numerous comorbidities largely account for high mortality rate and require geriatric expertise. Treatment options are total hip arthroplasty (THA), hemiarthroplasty (HA) or osteosynthesis. Literature suggests THA or HA for better outcomes, although no clear guidelines exist. Material and methods A retrospective chart review was performed of 63 patients (80 ± 11 years; 32 women, 31 men) with Garden one femoral neck fractures treated between June 2018 and June 2020 with either HA or internal fixation with the Femoral Neck System (FNS). Primary outcome measures were surgical and non-surgical complication rates and best achievable mobilization during the hospital stay. Results Thirty four patients were treated with HA, and 29 with the FNS. Mobilization was measured using the Charité Mobility Index (CHARMI). No difference between age, ASA, CCI or preoperative CHARMI was found. The CHARMI was significantly lower in the HA group. No difference in surgical complications was found. The HA cohort showed more non-surgical complications, a longer ICU stay and more blood transfusions. Hospitalization was significant longer in the HA than the FNS cohort (15.1 ± 5.1 vs 9.8 ± 3.8 days). Radiographic controls were performed after 6 and 12 weeks. The FNS group showed a mean shortening of 3.3 mm. 4 of 21 patient had shortening >5 mm. 20 of 21 patients showed radiographic signs of bone healing after 3 months. Conclusion Early results with the FNS show faster recovery than patient with hemiarthroplasty. Internal fixation with the FNS may be an option in non-displaced femoral neck fractures. Further studies should be performed to better evaluate the FNS compared to traditional internal fixation methods and arthroplasty.

Objective: Current treatments for blast-induced lung injury are limited to supportive procedures including mechanical ventilation. The study aimed to investigate the role of post-trauma-induced oedema generation in the function of time and trauma intensity and the probable role of beta 2-adrenergic receptors (β2-ARs) agonists on pulmonary oedema. The study is conducted using an ex vivo model after an experimental in vivo blast-induced thorax trauma in rats. Methods: Rats were randomised and divided into two groups, blast and sham. The blast group were anaesthetised and exposed to the blast wave (3.16 ± 0.43 bar) at a distance of 3.5 cm from the thorax level. The rats were sacrificed 10 min after the blast, the lungs explanted and treated with terbutaline, formoterol, propranolol or amiloride to assess the involvement of sodium transport. Other groups of rats were exposed to distances of 5 and 7 cm from the thorax to reduce the intensity of the injury. Further, one group of rats was studied after 180 min and one after 360 min after a 3.5 cm blast injury. Sham controls were exposed to identical procedures except for receiving blast overpressure. Results: Lung injury and oedema generation depended on time after injury and injury intensity. Perfusion with amiloride resulted in a further increase in oedema formation as indicated by weight gain (p < 0.001), diminished tidal volume (Tv) (p < 0.001), and increased airway resistance (p < 0.001). Formoterol caused a significant increase in the Tv (p < 0.001) and a significant decrease in the airway resistance (p < 0.01), while the lung weight was not influenced. Trauma-related oedema was significantly reduced by terbutaline in terms of lung weight gain (p < 0.01), Tv (p < 0.001), and airway resistance (p < 0.01) compared to control blast-injured lungs. Terbutaline-induced effects were completely blocked by the β-receptor antagonist propranolol (p < 0.05). Similarly, amiloride, which was added to terbutaline perfusion, reversed terbutaline-induced weight gain reduction (p < 0.05). Conclusions: β2-adrenoceptor stimulation had a beneficial impact by amiloride-dependent sodium and therefore, fluid transport mechanisms on the short-term ex vivo oedema generation in a trauma-induced in vivo lung injury of rats.

Traumatic brain injury (TBI) represents a major determining factor of outcome in severely injured patients. However, reliable brain-damage-monitoring markers are still missing. We therefore assessed brain-specific beta-synuclein as a novel blood biomarker of synaptic damage and measured the benchmarks neurofilament light chain (NfL), as a neuroaxonal injury marker, and glial fibrillary acidic protein (GFAP), as an astroglial injury marker, in patients after polytrauma with and without TBI. Compared to healthy volunteers, plasma NfL, beta-synuclein, and GFAP were significantly increased after polytrauma. The markers demonstrated highly distinct time courses, with beta-synuclein and GFAP peaking early and NfL concentrations gradually elevating during the 10-day observation period. Correlation analyses revealed a distinct influence of the extent of extracranial hemorrhage and the severity of head injury on biomarker concentrations. A combined analysis of beta-synuclein and GFAP effectively discriminated between polytrauma patients with and without TBI, despite the comparable severity of injury. Furthermore, we found a good predictive performance for fatal outcome by employing the initial plasma concentrations of NfL, beta-synuclein, and GFAP. Our findings suggest a high diagnostic value of neuronal injury markers reflecting distinct aspects of neuronal injury for the diagnosis of TBI in the complex setting of polytrauma, especially in clinical surroundings with limited imaging opportunities.

Initially underestimated as platelet dust, extracellular vesicles are continuously gaining interest in the field of inflammation. Various studies addressing inflammatory diseases have shown that microvesicles (MVs) originating from different cell types are systemic transport vehicles carrying distinct cargoes to modulate immune responses. In this study, we focused on the clinical setting of multiple trauma, which is characterized by activation and dysfunction of both, the fluid-phase and the cellular component of innate immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a, we hypothesized that increased C5a production induces alterations in MV shedding of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation. In a mono-centered prospective clinical study with polytraumatized patients, we found significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1, CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1 on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory neutrophil functions. Furthermore, in vitro exposure of human neutrophils (from healthy volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils, which could be blocked using the C5aR1 antagonist PMX53. Mechanistic analyses revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV were exposed to a complex ex vivo whole blood model significant pro-inflammatory properties (NADPH activity, ROS and MPO generation) of the MVs became evident. C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion. These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding from neutrophils results in decreased C5aR1 surface expression on the one hand, on the other hand it leads to profound inflammatory signals which likely are both key drivers of the neutrophil dysfunction which is regularly observed in patients suffering from multiple traumatic injuries.

Trauma represents a major socioeconomic burden worldwide. After a severe injury, hemorrhagic shock (HS) as a frequent concomitant aspect is a central driver of systemic inflammation and organ damage. The kidney is often strongly affected by traumatic-HS, and acute kidney injury (AKI) poses the patient at great risk for adverse outcome. Recently, thirty-eight-negative kinase 1 (TNK1) was proposed to play a detrimental role in organ damage after trauma/HS. Therefore, we aimed to assess the role of TNK1 in HS-induced kidney injury in a murine and a post hoc analysis of a non-human primate model of HS comparable to the clinical situation. Mice and non-human primates underwent resuscitated HS at 30 mmHg for 60 min. 5 h after the induction of shock, animals were assessed for systemic inflammation and TNK1 expression in the kidney. In vitro, murine distal convoluted tubule cells were stimulated with inflammatory mediators to gain mechanistic insights into the role of TNK1 in kidney dysfunction. In a translational approach, we investigated blood drawn from either healthy volunteers or severely injured patients at different time points after trauma (from arrival at the emergency room and at fixed time intervals until 10 days post injury; identifier: NCT02682550, https://clinicaltrials.gov/ct2/show/NCT02682550). A pronounced inflammatory response, as seen by increased IL-6 plasma levels as well as early signs of AKI, were observed in mice, non-human primates, and humans after trauma/HS. TNK1 was found in the plasma early after trauma-HS in trauma patients. Renal TNK1 expression was significantly increased in mice and non-human primates after HS, and these effects with concomitant induction of apoptosis were blocked by therapeutic inhibition of complement C3 activation in non-human primates. Mechanistically, in vitro data suggested that IL-6 rather than C3 cleavage products induced upregulation of TNK1 and impaired barrier function in renal epithelial cells. In conclusion, these data indicate that C3 inhibition in vivo may inhibit an excessive inflammatory response and mediator release, thereby indirectly neutralizing TNK1 as a potent driver of organ damage. In future studies, we will address the therapeutic potential of direct TNK1 inhibition in the context of severe tissue trauma with different degrees of additional HS.

BackgroundApproximately 30,000 patients with blunt cardiac trauma are recorded each year in the United States. Blunt cardiac injuries after trauma are associated with a longer hospital stay and a poor overall outcome. Organ damage after trauma is linked to increased systemic release of pro-inflammatory cytokines and damage-associated molecular patterns. However, the interplay between polytrauma and local cardiac injury is unclear. Additionally, the impact of surgical intervention on this process is currently unknown. This study aimed to determine local cardiac immunological and structural alterations after multiple trauma. Furthermore, the impact of the chosen fracture stabilization strategy (reamed versus non-reamed femoral nailing) on cardiac alterations was studied.Experimental approach15 male pigs were either exposed to multiple trauma (blunt chest trauma, laparotomy, liver laceration, femur fracture and haemorrhagic shock) or sham conditions. Blood samples as well as cardiac tissue were analysed 4 h and 6 h after trauma. Additionally, murine HL-1 cells were exposed to a defined polytrauma-cocktail, mimicking the pro-inflammatory conditions after multiple trauma in vitro.ResultsAfter multiple trauma, cardiac structural changes were observed in the left ventricle. More specifically, alterations in the alpha-actinin and desmin protein expression were found. Cardiac structural alterations were accompanied by enhanced local nitrosative stress, increased local inflammation and elevated systemic levels of the high-mobility group box 1 protein. Furthermore, cardiac alterations were observed predominantly in pigs that were treated by non-reamed intramedullary reaming. The polytrauma-cocktail impaired the viability of HL-1 cells in vitro, which was accompanied by a release of troponin I and HFABP.DiscussionMultiple trauma induced cardiac structural alterations in vivo, which might contribute to the development of early myocardial damage (EMD). This study also revealed that reamed femoral nailing (reamed) is associated with more prominent immunological cardiac alterations compared to nailing without reaming (non-reamed). This suggests that the choice of the initial fracture treatment strategy might be crucial for the overall outcome as well as for any post-traumatic cardiac consequences.

Sepsis is associated with global cardiac dysfunction and with high mortality rate. The development of septic cardiomyopathy is due to complex interactions of damage-associated molecular patters, cytokines, and complement activation products. The aim of this study was to define the effects of sepsis on cardiac structure, gap junction, and tight junction (TJ) proteins. Sepsis was induced by cecal ligation and puncture in male C57BL/6 mice. After a period of 24 h, the expression of cardiac structure, gap junction, and TJ proteins was determined. Murine HL-1 cells were stimulated with LPS, and mRNA expression of cardiac structure and gap junction proteins, intracellular reactive oxygen species, and troponin I release was analyzed. Furthermore, pyrogenic receptor subtype 7 (P2X7) expression and troponin I release of human cardiomyocytes (iPS) were determined after LPS exposure. In vivo, protein expression of connexin43 and α-actinin was decreased after the onset of polymicrobial sepsis, whereas in HL-1 cells, mRNA expression of connexin43, α-actinin, and desmin was increased in the presence of LPS. Expression of TJ proteins was not affected in vivo during sepsis. Although the presence of LPS and nigericin resulted in a significant troponin I release from HL-1 cells. Sepsis affected cardiac structure and gap junction proteins in mice, potentially contributing to compromised cardiac function.

Background: The complement system is part of the innate immunity, is activated immediately after trauma and is associated with adult respiratory distress syndrome, acute lung injury, multiple organ failure, and with death of multiply injured patients. The aim of the study was to investigate the complement activation in multiply injured pigs as well as its effects on the heart in vivo and in vitro. Moreover, the impact of reamed vs. non-reamed intramedullary nailing was examined with regard to the complement activation after multiple trauma in pigs.Materials and Methods: Male pigs received multiple trauma, followed by femoral nailing with/without prior conventional reaming. Systemic complement hemolytic activity (CH-50 and AH-50) as well as the local cardiac expression of C3a receptor, C5a receptors1/2, and the deposition of the fragments C3b/iC3b/C3c was determined in vivo after trauma. Human cardiomyocytes were exposed to C3a or C5a and analyzed regarding calcium signaling and mitochondrial respiration.Results: Systemic complement activation increased within 6 h after trauma and was mediated via the classical and the alternative pathway. Furthermore, complement activation correlated with invasiveness of fracture treatment. The expression of receptors for complement activation were altered locally in vivo in left ventricles. C3a and C5a acted detrimentally on human cardiomyocytes by affecting their functionality and their mitochondrial respiration in vitro.Conclusion: After multiple trauma, an early activation of the complement system is triggered, affecting the heart in vivo as well as in vitro, leading to complement-induced cardiac dysfunction. The intensity of complement activation after multiple trauma might correlate with the invasiveness of fracture treatment. Reaming of the femoral canal might contribute to an enhanced “second hit” response after trauma. Consequently, the choice of fracture treatment might imply the clinical outcome of the critically injured patients and might be therefore crucial for their survival.

Background and Purpose: Post-traumatic cardiac dysfunction often occurs in multiply injured patients (ISS ≥ 16). Next to direct cardiac injury, post-traumatic cardiac dysfunction is mostly induced by the release of inflammatory biomarkers. One of these is the heparin-binding factor Midkine, which is elevated in humans after fracture, burn injury and traumatic spinal cord injury. Midkine is associated with cardiac pathologies but the exact role of Midkine in the development of those diseases is ambiguous. The systemic profile of Midkine after multiple trauma, its effects on cardiomyocytes and the association with post-traumatic cardiac dysfunction, remain unknown.Experimental Approach: Midkine levels were investigated in blood plasma of multiply injured humans and pigs. Furthermore, human cardiomyocytes (iPS) were cultured in presence/absence of Midkine and analyzed regarding viability, apoptosis, calcium handling, metabolic alterations, and oxidative stress. Finally, the Midkine filtration capacity of the therapeutic blood absorption column CytoSorb ®300 was tested with recombinant Midkine or plasma from multiply injured patients.Key Results: Midkine levels were significantly increased in blood plasma of multiply injured humans and pigs. Midkine acts on human cardiomyocytes, altering their mitochondrial respiration and calcium handling in vitro. CytoSorb®300 filtration reduced Midkine concentration ex vivo and in vitro depending on the dosage.Conclusion and Implications: Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes in vitro. Further examinations are required to determine whether the application of CytoSorb®300 filtration in patients after multiple trauma is a promising therapeutic approach to prevent post-traumatic cardiac disfunction.

Periodontitis is the inflammatory destruction of the tooth-surrounding and -supporting tissue, resulting at worst in tooth loss. Another locally aggressive disease of the oral cavity is tooth resorption (TR). This is associated with the destruction of the dental mineralized tissue. However, the underlying pathomechanisms remain unknown. The complement system, as well as mast cells (MCs), are known to be involved in osteoclastogenesis and bone loss. The complement factors C3 and C5 were previously identified as key players in periodontal disease. Therefore, we hypothesize that complement factors and MCs might play a role in alveolar bone and tooth resorption. To investigate this, we used the cat as a model because of the naturally occurring high prevalence of both these disorders in this species. Teeth, gingiva samples and serum were collected from domestic cats, which had an appointment for dental treatment under anesthesia, as well as from healthy cats. Histological analyses, immunohistochemical staining and the CH-50 and AH-50 assays revealed increased numbers of osteoclasts and MCs, as well as complement activity in cats with TR. Calcifications score in the gingiva was highest in animals that suffer from TR. This indicates that MCs and the complement system are involved in the destruction of the mineralized tissue in this condition.

Trauma remains a leading global cause of mortality, particularly in the young population. In the United States, approximately 30,000 patients with blunt cardiac trauma were recorded annually. Cardiac damage is a predictor for poor outcome after multiple trauma, with a poor prognosis and prolonged in-hospitalization. Systemic elevation of cardiac troponins was correlated with survival, injury severity score, and catecholamine consumption of patients after multiple trauma. The clinical features of the so-called “commotio cordis” are dysrhythmias, including ventricular fibrillation and sudden cardiac arrest as well as wall motion disorders. In trauma patients with inappropriate hypotension and inadequate response to fluid resuscitation, cardiac injury should be considered. Therefore, a combination of echocardiography (ECG) measurements, echocardiography, and systemic appearance of cardiomyocyte damage markers such as troponin appears to be an appropriate diagnostic approach to detect cardiac dysfunction after trauma. However, the mechanisms of post-traumatic cardiac dysfunction are still actively being investigated. This review aims to discuss cardiac damage following trauma, focusing on mechanisms of post-traumatic cardiac dysfunction associated with inflammation and complement activation. Herein, a causal relationship of cardiac dysfunction to traumatic brain injury, blunt chest trauma, multiple trauma, burn injury, psychosocial stress, fracture, and hemorrhagic shock are illustrated and therapeutic options are discussed.

ORTHOUNION is a multicentre, open, comparative, three-arm, randomized clinical trial (EudraCT number 2015-000431-32) to compare the efficacy, at one and two years, of autologous human bone marrow-derived expanded mesenchymal stromal cell (hBM-MSC) treatments versus iliac crest autograft (ICA) to enhance bone healing in patients with diaphyseal and/or metaphysodiaphyseal fracture (femur, tibia, and humerus) status of atrophic or oligotrophic nonunion (more than 9 months after the acute fracture, including recalcitrant cases after failed treatments). The primary objective is to determine if the treatment with hBM-MSCs combined with biomaterial is superior to ICA in obtaining bone healing. If confirmed, a secondary objective is set to determine if the dose of 100 × 106 hBM-MSCs is noninferior to that of 200 × 106 hBM-MSCs. The participants (n=108) will be randomly assigned to either the experimental low dose (n=36), the experimental high dose (n=36), or the comparator arm (n=36) using a central randomization service. The trial will be conducted in 20 clinical centres in Spain, France, Germany, and Italy under the same clinical protocol. The confirmation of superiority for the proposed ATMP in nonunions may foster the future of bone regenerative medicine in this indication. On the contrary, absence of superiority may underline its limitations in clinical use.

Severe blunt chest trauma in humans is associated with high mortality rates. Whereas lung tissue damage and lung inflammation after blunt chest trauma have extensively been investigated, the traumatic and posttraumatic effects on the heart remain poorly understood. Therefore, the purpose of this study was to define cardiac injury patterns in an experimental blunt chest trauma model in rats.Experimental blunt chest trauma was induced by a blast wave in rats, with subsequent analysis of its effects on the heart. The animals were subjected either to a sham or trauma procedure. Systemic markers for cardiac injury were determined after 24 h and 5 days. Postmortem analysis of heart tissue addressed structural injury and inflammation 24 h and 5 days after trauma.Plasma levels of extracellular histones were elevated 24 h and 5 days after blunt chest trauma compared to sham-treated animals. In the heart, up-regulation of interleukin-1β 24 h after trauma and increased myeloperoxidase activity 24 h and 5 days after trauma were accompanied by reduced complement C5a receptor-1 expression 24 h after trauma. Histological analysis revealed extravasation of erythrocytes and immunohistochemical analysis alteration of the pattern of the gap-junction protein connexin 43. Furthermore, a slight reduction of α-actinin and desmin expression in cardiac tissue was found after trauma together with a minor increase in sarcoplasmatic/endoplasmatic reticlulum calcium-ATPase (SERCA) expression.The clinically highly relevant rat model of blast wave-induced blunt chest trauma is associated with cardiac inflammation and structural alterations in cardiac tissue.

Mice are extensively used for experimental bone-healing studies. However, there are few established nondestructive in vivo techniques for longitudinal fracture-healing analysis in mice, including in vivo micro-computed tomography (μCT) and radiography. Importantly, none of the established methods can discriminate between non-mineralized fibrous tissue and cartilage in the soft fracture callus. Therefore, the objective was to establish high-resolution in vivo magnetic resonance imaging (MRI) for the longitudinal assessment of soft callus formation during bone healing in mice. C57BL/6J mice received a femur osteotomy stabilized using an external fixator and were randomly assigned to five groups. Group 1 mice were scanned three times longitudinally during fracture healing using an optimized MRI scanning protocol to establish an algorithm to characterize the different fracture-callus tissues. Mice of groups 2-4 were scanned once on day 10, 14 or 21, respectively, euthanized after scanning and their femurs subjected to ex vivo μCT and histomorphometric analysis to compare the data assessed by MRI with μCT and histology. Control group 5 mice were not scanned. After 28 days, mice of groups 1 and 5 were euthanized and the fracture-healing outcome was evaluated by bending-test, μCT and histology to determine whether the repeated anesthesia, handling and the MRI measurements themselves influenced fracture healing. The callus-tissue values determined by MRI were mostly comparable to those obtained by μCT and histomorphometric analysis. However, at time points characterized by small relative bone or cartilage areas, MRI measurements were weakly comparable to histomorphometric data, possibly due to the inferior spatial resolution. Importantly, at the early and intermediate phases of healing, cartilage and fibrous-tissue values obtained by MRI were highly accurate. Furthermore, repeated anesthesia, handling and MRI scans did not impact bone healing. Therefore, we demonstrated the feasibility of high-resolution in vivo MRI for longitudinal assessment of soft callus formation during murine endochondral fracture healing.

Evidence is emerging that systemic inflammation after trauma drives structural and functional impairment of cardiomyocytes and leads to cardiac dysfunction, thus worsening the outcome of polytrauma patients. This study investigates the structural and molecular changes in heart tissue 4 h after multiple injuries with additional hemorrhagic shock using a clinically relevant rodent model of polytrauma. We determined mediators of systemic inflammation (keratinocyte chemoattractant, macrophage chemotactic protein 1), activated complement component C3a and cardiac troponin I in plasma and assessed histological specimen of the mouse heart via standard histomorphology and immunohistochemistry for cellular and subcellular damage and ongoing apoptosis. Further we investigated spatial and quantitative changes of connexin 43 by immunohistochemistry and western blotting. Our results show significantly increased plasma levels of both keratinocyte chemoattractant and cardiac troponin I 4 h after polytrauma and 2 h after induction of hypovolemia. Although we could not detect any morphological changes, immunohistochemical evaluation showed increased level of tissue high-mobility group box 1, which is both a damage-associated molecule and actively released as a danger response signal. Additionally, there was marked lateralization of the cardiac gap-junction protein connexin 43 following combined polytrauma and hemorrhagic shock. These results demonstrate a molecular manifestation of remote injury of cardiac muscle cells in the early phase after polytrauma and hemorrhagic shock with marked disruption of the cardiac gap junction. This disruption of an important component of the electrical conduction system of the heart may lead to arrhythmia and consequently to cardiac dysfunction.

Following bone fracture, the repair process starts with an inflammatory reaction at the fracture site. Fracture healing is disturbed when the initial inflammation is increased or prolonged, whereby, a balanced inflammatory response is anticipated to be crucial for fracture healing, because it may induce down-stream responses leading to tissue repair. However, the impact of the immune response on fracture healing remains poorly understood. Here, we investigated bone healing in NOD/scid-IL2Rγcnull mice, which exhibit severe defects in innate and adaptive immunity, by biomechanical testing, histomorphometry and micro-computed tomography. We demonstrated that NOD/scid-IL2Rγcnull mice exhibited normal skeletal anatomy and a mild bone phenotype with a slightly reduced bone mass in the trabecular compartment in comparison to immunocompetent Balb/c mice. Fracture healing was impaired in immunodeficient NOD/scid-IL2Rγcnull mice. Callus bone content was unaffected during the early healing stage, whereas it was significantly reduced during the later healing period. Concomitantly, the amount of cartilage was significantly increased, indicating delayed endochondral ossification, most likely due to the decreased osteoclast activity observed in cells isolated from NOD/scid-IL2Rγcnull mice. Our results suggest that--under aseptic, uncomplicated conditions--the immediate immune response after fracture is non-essential for the initiation of bone formation. However, an intact immune system in general is important for successful bone healing, because endochondral ossification is delayed in immunodeficient NOD/scid-IL2Rγcnull mice.

Severe blunt chest trauma is associated with high mortality. Sepsis represents a serious risk factor for mortality in acute respiratory distress syndrome (ARDS). In septic patients with ARDS complement activation products were found to be elevated in the plasma. In single models like LPS or trauma complement has been studied to some degree, however in clinically highly relevant double hit models such as the one used here little data is available. Here, we hypothesized that absence of C5 is correlated with a decreased inflammatory response in trauma induced septic acute lung injury.12 hrs after DH in mice the local and systemic cytokines and chemokines were quantified by multiplex bead array or ELISA, activated caspase-3 by western blot. Data were analyzed using one-way ANOVA followed by post-hoc Sidak's multiple comparison test (significance, p≤ 0.05).In lung tissue interleukin (IL)-6, monocyte chemo attractant protein-1 (MCP-1) and granulocyte-colony stimulating factor (G-CSF) was elevated in both C5-/- mice and wildtype littermates (wt), whereas caspase-3 was reduced in lungs after DH in C5-/- mice. Systemically, reduced keratinocyte-derived chemokine (KC) levels were observed after DH in C5-/- compared to wt mice. Locally, lung myeloperoxidase (MPO), protein, IL-6, MCP-1 and G-CSF in brochoalveolar lavage fluid (BALF) were elevated after DH in C5-/- compared to wt.In the complex but clinically relevant DH model the local and systemic inflammatory immune response features both, C5-dependent and C5-independent characteristics. Activation of caspase-3 in lung tissue after DH was C5-dependent whereas local inflammation in lung tissue was C5-independent.

Postmenopausal females display a chronic inflammatory phenotype with higher levels of circulating pro-inflammatory cytokines. Furthermore, the inflammatory response to injury may be altered under estrogen-deficiency, because it was shown previously that estrogen-deficient mice displayed increased levels of the inflammatory cytokines Midkine (Mdk) and Interleukin-6 (IL-6) in the early fracture hematoma. Because a balanced immune response to fracture is required for successful bone regeneration, this might contribute to the delayed fracture healing frequently observed in osteoporotic, postmenopausal fracture patients. In this study, we aimed to investigate whether further cytokines in addition to Mdk and IL-6 might be affected by estrogen-deficiency after fracture in mice and whether these cytokines are also relevant during human fracture healing. Additionally, we aimed to investigate whether serum from male vs. female fracture patients affects osteogenic differentiation of human mesenchymal stem cells (MSCs). To address these questions, female mice were either sham-operated or ovariectomized (OVX) and subjected to standardized femur osteotomy. A broad panel of pro- and anti-inflammatory cytokines was determined systemically and locally in the fracture hematoma. In a translational approach, serum was collected from healthy controls and patients with an isolated fracture. Mdk and IL-6 serum levels were determined at day 0, day 14 and day 42 after fracture. Subgroup analysis was performed to investigate differences between male and female fracture patients after menopause. In an in vitro approach, human MSCs were cultured with the collected patient serum and osteogenic differentiation was assessed by qPCR and alkaline-phosphatase staining. Our results suggest an important role for the pro-inflammatory cytokines Mdk and IL-6 in the response to fracture in estrogen-deficient mice among all of the measured inflammatory mediators. Notably, both cytokines were also significantly increased in the serum of patients after fracture. However, only Mdk serum levels differed significantly between male and female fracture patients after menopause. MSCs cultivated with serum from female fracture patients displayed significantly reduced osteogenic differentiation, which was attenuated by Mdk-antibody treatment. In conclusion, our study demonstrated increased Mdk levels after fracture in OVX mice and female fracture patients after menopause. Because Mdk is a negative regulator of bone formation, this might contribute to impaired osteoporotic fracture healing.

Severe tissue trauma-induced systemic inflammation is often accompanied by evident or occult blood-organ barrier dysfunctions, frequently leading to multiple organ dysfunction. However, it is unknown whether specific barrier molecules are shed into the circulation early after trauma as potential indicators of an initial barrier dysfunction. The release of the barrier molecule junctional adhesion molecule-1 (JAM-1) was investigated in plasma of C57BL/6 mice 2 h after experimental mono- and polytrauma as well as in polytrauma patients (ISS ≥ 18) during a 10-day period. Correlation analyses were performed to indicate a linkage between JAM-1 plasma concentrations and organ failure. JAM-1 was systemically detected after experimental trauma in mice with blunt chest trauma as a driving force. Accordingly, JAM-1 was reduced in lung tissue after pulmonary contusion and JAM-1 plasma levels significantly correlated with increased protein levels in the bronchoalveolar lavage as a sign for alveolocapillary barrier dysfunction. Furthermore, JAM-1 was markedly released into the plasma of polytrauma patients as early as 4 h after the trauma insult and significantly correlated with severity of disease and organ dysfunction (APACHE II and SOFA score). The data support an early injury- and time-dependent appearance of the barrier molecule JAM-1 in the circulation indicative of a commencing trauma-induced barrier dysfunction.

There is increasing evidence that complement may play a role in bone development. Our previous studies demonstrated that the key complement receptor C5aR was strongly expressed in the fracture callus not only by immune cells but also by bone cells and chondroblasts, indicating a function in bone repair. To further elucidate the role of complement in bone healing, this study investigated fracture healing in mice in the absence of the key complement molecules C3 and C5. C3(-/-) and C5(-/-) as well as the corresponding wildtype mice received a standardized femur osteotomy, which was stabilized using an external fixator. Fracture healing was investigated after 7 and 21 days using histological, micro-computed tomography and biomechanical measurements. In the early phase of fracture healing, reduced callus area (C3(-/-): -25%, p=0.02; C5(-/-): -20% p=0.052) and newly formed bone (C3(-/-): -38%, p=0.01; C5(-/-): -52%, p=0.009) was found in both C3- and C5-deficient mice. After 21 days, healing was successful in the absence of C3, whereas in C5-deficient mice fracture repair was significantly reduced, which was confirmed by a reduced bending stiffness (-45%; p=0.029) and a smaller callus volume (-17%; p=0.039). We further demonstrated that C5a was activated in C3(-/-) mice, suggesting cleavage via extrinsic pathways. Our results suggest that the activation of the terminal complement cascade in particular may be crucial for successful fracture healing.

Background. The molecular mechanisms of the immune response after polytrauma are highly complex and far from fully understood. In this paper, we characterize a new standardized polytrauma model in rats based on the early molecular inflammatory and apoptotic response. Methods. Male Wistar rats (250 g, 6–10/group) were anesthetized and exposed to chest trauma (ChT), closed head injury (CHI), or Tib/Fib fracture including a soft tissue trauma (Fx + STT) or to the following combination of injuries: (1) ChT; (2) ChT + Fx + STT; (3) ChT + CHI; (4) CHI; (5) polytrauma (PT = ChT + CHI + Fx + STT). Sham-operated rats served as negative controls. The inflammatory response was quantified at 2 hours and 4 hours after trauma by analysis of “key” inflammatory mediators, including selected cytokines and complement components, in serum and bronchoalveolar (BAL) fluid samples. Results. Polytraumatized (PT) rats showed a significant systemic and intrapulmonary release of cytokines, chemokines, and complement anaphylatoxins, compared to rats with isolated injuries or selected combinations of injuries. Conclusion. This new rat model appears to closely mimic the early immunological response of polytrauma observed in humans and may provide a valid basis for evaluation of the complex pathophysiology and future therapeutic immune modulatory approaches in experimental polytrauma.

We present a detailed derivation of the Gutzwiller density functional theory (DFT) that covers all conceivable cases of symmetries and Gutzwiller wave functions. The method is used in a study of ferromagnetic nickel where we calculate ground state properties (lattice constant, bulk modulus, spin magnetic moment) and the quasi-particle band structure. Our method resolves most shortcomings of an ordinary density functional calculation on nickel. However, the quality of the results strongly depends on the particular choice of the double-counting correction. This constitutes a serious problem for all methods that attempt to merge DFT with correlated-electron approaches based on Hubbard-type local interactions.