Publications by authors named "Miriam Kalbitz"

56 Publications

Early myocardial damage (EMD) and valvular dysfunction after femur fracture in pigs.

Sci Rep 2021 Apr 19;11(1):8503. Epub 2021 Apr 19.

Department of Traumatology, Hand, Plastic and Reconstructive Surgery, Center of Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

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.
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http://dx.doi.org/10.1038/s41598-021-86151-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055677PMC
April 2021

Laboratory Markers in the Management of Pediatric Polytrauma: Current Role and Areas of Future Research.

Front Pediatr 2021 16;9:622753. Epub 2021 Mar 16.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

Severe trauma is the most common cause of mortality in children and is associated with a high socioeconomic burden. The most frequently injured organs in children are the head and thorax, followed by the extremities and by abdominal injuries. The efficient and early assessment and management of these injuries is essential to improve patients' outcome. Physical examination as well as imaging techniques like ultrasound, X-ray and computer tomography are crucial for a valid early diagnosis. Furthermore, laboratory analyses constitute additional helpful tools for the detection and monitoring of pediatric injuries. Specific inflammatory markers correlate with post-traumatic complications, including the development of multiple organ failure. Other laboratory parameters, including lactate concentration, coagulation parameters and markers of organ injury, represent further clinical tools to identify trauma-induced disorders. In this review, we outline and evaluate specific biomarkers for inflammation, acid-base balance, blood coagulation and organ damage following pediatric polytrauma. The early use of relevant laboratory markers may assist decision making on imaging tools, thus contributing to minimize radiation-induced long-term consequences, while improving the outcome of children with multiple trauma.
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http://dx.doi.org/10.3389/fped.2021.622753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010656PMC
March 2021

Increased Presence of Complement Factors and Mast Cells in Alveolar Bone and Tooth Resorption.

Int J Mol Sci 2021 Mar 9;22(5). Epub 2021 Mar 9.

Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany.

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.
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http://dx.doi.org/10.3390/ijms22052759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967164PMC
March 2021

Lower Leg Fractures in Children and Adolescents-Comparison of Conservative vs. ECMES Treatment.

Front Pediatr 2021 4;9:597870. Epub 2021 Mar 4.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

Lower leg fractures are one of the most common fractures in pediatric age. In general, treatment of lower leg fractures is predominantly non-operative, requiring clinical and radiological controls. Nevertheless, it can be observed that in recent years tibial shaft fractures have increasingly been treated surgically. The aim of the present study is to investigate treatment strategies in the context of different fracture types of the lower leg. In this retrospective chart review, we analyzed 168 children with a diaphyseal fracture of the lower leg admitted to a trauma center between 2005 and 2017. The fractures were classified according to the AO Pediatric Comprehensive Classification of Long Bone Fractures (AO-PCCF). The frequency of fractures based on the AO-PCCF classification was as follows: Simple oblique fracture of the tibia (43.5%, = 73), hereof 32 toddler's fractures, multifragmentary oblique fracture of the tibia in 14.3% ( = 24) and simple oblique fracture of both, tibia and fibula in 18 patients (10.7%). Most pediatric fractures were treated conservatively by cast ( = 125). Thirty-seven patients received an ECMES, whereas 3 patients were treated with an external fixator and also 3 fractures were stabilized by plate osteosynthesis. Conservatively treated patients were significantly younger (mean age 6.0) compared to patients treated with ECMES (mean age 10.2) or plate osteosynthesis (PO)/external fixator (EF) (mean age 11.3), even if toddler's fractures (mean age 2.0) are excluded (mean age 7.4). There was no difference in time to full weight-bearing, hospitalization of patients treated with ECMES compared to conservative therapy although ECMES-treated fractures show more instability. The consolidation time was significantly higher in ECMES treated patients compared to conservative therapy. Pediatric patients (≤4 years) with lower leg fractures most often showed simple oblique fractures of the tibia, half of them toddler's fractures, which were treated predominantly by conservative therapy. All in all, the consolidation time was longer in intramedullary nailing (ECMES) than in conservative therapy. Nevertheless, time to full weight bearing and duration of cast was the same in both groups, even though ECMES treated fractures show more instability.
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http://dx.doi.org/10.3389/fped.2021.597870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969713PMC
March 2021

Systemic and local cardiac inflammation after experimental long bone fracture, traumatic brain injury and combined trauma in mice.

J Orthop Translat 2021 May 23;28:39-46. Epub 2021 Feb 23.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Medical Center Ulm, Ulm, Germany.

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.
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http://dx.doi.org/10.1016/j.jot.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906881PMC
May 2021

Trauma, a Matter of the Heart-Molecular Mechanism of Post-Traumatic Cardiac Dysfunction.

Int J Mol Sci 2021 Jan 13;22(2). Epub 2021 Jan 13.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, 86081 Ulm, Germany.

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.
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http://dx.doi.org/10.3390/ijms22020737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828409PMC
January 2021

Early myocardial damage (EMD) and valvular insufficiency result in impaired cardiac function after multiple trauma in pigs.

Sci Rep 2021 Jan 13;11(1):1151. Epub 2021 Jan 13.

Department of Traumatology, Hand, Plastic and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

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.
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http://dx.doi.org/10.1038/s41598-020-80409-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806767PMC
January 2021

Olecranon fractures in children: treatment of a rare entity.

Eur J Trauma Emerg Surg 2020 Nov 24. Epub 2020 Nov 24.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Background: Olecranon fractures are a rare entity in children. The classification and treatment strategies are still discussed controversially.

Methods: A retrospective chart review of all patients < 17 years admitted with an olecranon fracture at a Level I Trauma Center between 2005 and 2017 has been performed. 46 subjects were included. For classification of olecranon fractures in children the AO Pediatric Comprehensive Classification of Long Bone Fractures (AO-PCCF) was used. Fractures were classified along the fracture line, dislocation, joint involvement and affection of the apophysis. For statistical analysis, a comparison of two groups was performed using Student t test. One-way ANOVA and Tukey's multiple comparison test was used to identify differences between more than two groups. For all analysis p ≤ 0.05 was considered statistically significant.

Results: The mean age of the children was 8.5 years (2-16 years). Most children were treated with a conservative therapy (n = 29, 63.0%). 17 patients (36.9%) underwent osteosynthesis (plate or tension band wiring) of which three were initially treated with a conservative therapeutic approach. Children with operative treatment were significantly older compared to children treated conservatively. Interestingly, all patients with luxation were characterized by an oblique fracture line, one of them extraarticular, three intraarticular.

Conclusion: Taken together, this study analyzed one of the largest selections of pediatric patients with olecranon fracture in regard to fracture type and treatment strategy. Based on the assumption that treatment strategies follow a fracture classification, a consistent classification method is needed which should take into account fracture morphology and localization, as considered by the AO-PCCF, and the dislocation as measured by Braque. Surgical treatment is needed in case of dislocation ≥ 5 mm, intra-articular fractures, instable fracture conditions caused by the fracture line, open fractures and the affection of the apophysis. Otherwise, the conservative treatment shows insufficient results in the elbow mobility. The reliable choice of treatments based on our classification was mirrored by the very low rate of conversion of treatment strategies.

Level Of Evidence: Level III-retrospective comparative study.
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http://dx.doi.org/10.1007/s00068-020-01518-7DOI Listing
November 2020

Thirty-Eight-Negative Kinase 1 Is a Mediator of Acute Kidney Injury in Experimental and Clinical Traumatic Hemorrhagic Shock.

Front Immunol 2020 26;11:2081. Epub 2020 Aug 26.

Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany.

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 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. , 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, 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 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.
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http://dx.doi.org/10.3389/fimmu.2020.02081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479097PMC
August 2020

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients.

Front Immunol 2020 2;11:1789. Epub 2020 Sep 2.

Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany.

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, 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 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.
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http://dx.doi.org/10.3389/fimmu.2020.01789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492592PMC
April 2021

Reaming of femoral fractures with different reaming irrigator aspirator systems shows distinct effects on cardiac function after experimental polytrauma.

J Orthop Res 2020 12 1;38(12):2608-2618. Epub 2020 Sep 1.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University Hospital Ulm, Ulm, Germany.

Cardiac injuries are recorded after multiple trauma and are associated with a poor patient outcome. Reaming prior to locked intramedullary nailing is a frequently used technique to stabilize femoral diaphysis fractures. However, in polytraumatized patients, complications such as fat emboli and acute respiratory distress syndrome have been associated with reaming. The reaming irrigator aspirator (RIA) system provides concomitant irrigation and suction of the intramedullary contents, and should, therefore, reduce reaming-associated complications. The aim of the study was to investigate cardiac function after multiple trauma with regard to two different RIA devices (RIAI vs RIAII). 15 male pigs were included in the study. Pigs received either sham treatment or multiple trauma (chest trauma, femur fracture, liver laceration, and hemorrhagic shock), followed by intramedullary nailing after reaming with either the RIAI or RIAII system (RIAII: reduced diameter of the reamer, improved control of irrigation and suction). Cardiac function was assessed by transesophageal echocardiography and systemic inflammation as well as local cardiac damage examined. Pigs of both treatment groups showed impaired cardiac function, valvular insufficiency, and cardiac damage. Systemic inflammation and local cardiac alterations were observed which might contribute to early myocardial damage in vivo. Multiple trauma including long-bone fracture and subsequent intramedullary reaming induces cardiac dysfunction and valvular insufficiency, which might be linked to both mechanical cardiac injury and increased systemic inflammation. 6 hours after trauma there are less differences between RIAI and RIAII treatment with regard to post-traumatic cardiac consequences in multiple injured pigs, indicating no beneficial effect of RIAII over RIAI.
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http://dx.doi.org/10.1002/jor.24830DOI Listing
December 2020

Structural alterations and inflammation in the heart after multiple trauma followed by reamed versus non-reamed femoral nailing.

PLoS One 2020 25;15(6):e0235220. Epub 2020 Jun 25.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

Background: Approximately 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 Approach: 15 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.

Results: After 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.

Discussion: Multiple 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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316303PMC
September 2020

Toll-Like Receptor-Mediated Cardiac Injury during Experimental Sepsis.

Mediators Inflamm 2020 10;2020:6051983. Epub 2020 Jan 10.

Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, Center of Surgery, University of Ulm, 89081 Ulm, Germany.

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. , protein expression of connexin43 and -actinin was decreased after the onset of polymicrobial sepsis, whereas in HL-1 cells, mRNA expression of , , and was increased in the presence of LPS. Expression of TJ proteins was not affected 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.
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http://dx.doi.org/10.1155/2020/6051983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199613PMC
January 2020

Effects of Circulating HMGB-1 and Histones on Cardiomyocytes-Hemadsorption of These DAMPs as Therapeutic Strategy after Multiple Trauma.

J Clin Med 2020 May 11;9(5). Epub 2020 May 11.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm, 89081 Ulm, Germany.

Background And Purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction.

Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients.

Key Results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage.

Conclusion And Implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.
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http://dx.doi.org/10.3390/jcm9051421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291040PMC
May 2020

Different classifications concerning fractures of the lateral humeral condyle in children.

Eur J Trauma Emerg Surg 2020 Apr 23. Epub 2020 Apr 23.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Purpose: Fractures of the lateral condyle are the second most frequent elbow fractures in children. Although the pathobiomechanism is well known and different fracture classifications exist, there are still adverse clinical results. This raises the questions how precise classifications predict fracture stability, especially in the context of choosing the best therapy. It also remains unclear how these classifications can be applied in practice.

Methods: Seventy-five patients with a fracture of the lateral condyle were analyzed in this retrospective study. We included all patients with an age ≤ 14 years admitted at a German Level I Trauma Center between 2005 and 2017. Different classifications according to Jakob, Finnbogason, Song and Hasler/v. Laer have been applied.

Results: Seventy-five patients with fractures of the lateral condyle were analyzed thereof 53 treated operatively and 22 conservatively. In sum, 6 out of 75 fractures showed no lateralization (Jakob: stable) in the first X-ray, but the same wide of the fracture gap medial as lateral (Finnbogason and Song: unstable). In 2 out of 75 patients, fracture instability occurred although it was not detected by the classification of Jakob, Finnbogason, Song and Hasler/v. Laer.

Conclusion: Classifying fractures according to the Jakob-Classification has limitations if notable rotation without lateral displacement occurs. Hasler/v. Laer's classification appears most adequate but can sometimes not be applied due to missing X-ray 4 days after trauma. The Finnbogason- and Song-Classification performs best in prediction of instability based on the X-ray at the time of accident because of considering the fracture pathobiomechanism. All in all, we recommend the classification of Hasler and v. Laer, because it is the best predictive classification.
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http://dx.doi.org/10.1007/s00068-020-01349-6DOI Listing
April 2020

A novel mouse model to study fracture healing of the proximal femur.

J Orthop Res 2020 10 4;38(10):2131-2138. Epub 2020 Apr 4.

Department of Orthopaedic Surgery, Orthopaedic Trauma Institute, University of California, San Francisco, California.

The majority of fractures, especially in elderly and osteoporotic patients, occurs in metaphyseal bone. However, only a few experimental models exist to study metaphyseal bone healing in mice. Currently used mouse models of metaphyseal fracture healing are either based on drill hole defects, lacking adequate biomechanical stimulation at the site of fracture and therefore endochondral ossification in the fracture callus, or are introduced into the distal part of the mouse femur stabilized by a locking plate, which is challenging due to the small specimen size. Therefore, the aim of the current study was to develop a new mouse model to study metaphyseal fracture healing of the proximal femur. We chose a combination between an open osteotomy and a closed intramedullary stabilization. A 24 G needle was inserted into the femur in a closed manner, then an osteotomy was made with a 0.4-mm Gigli wire saw between the third and the lesser trochanter of the femur using an open approach. Fractured femurs were analyzed using microcomputed tomography and histology at days 14 and 21 after surgery. No animals were lost due to surgery or anesthesia. All animals displayed normal limb loading and a physiological gait pattern within the first three days after fracture. We found robust endochondral ossification during the fracture healing process with high expression of late chondrocyte and early osteogenic markers at day 14 (d14). By day 21 (d21), all fractures had a bony bridging score of 3 or more, indicating successful healing. Callus volume significantly decreased from d14 to d21, whereas high numbers of osteoclasts appeared at the fracture callus until d21, indicating that callus remodeling had already started at d21. In conclusion, we successfully developed a novel mouse model to study endochondral fracture healing of the proximal femur. This model might be useful for future studies using transgenic animals to unravel molecular mechanisms of osteoporotic metaphyseal fracture healing.
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http://dx.doi.org/10.1002/jor.24677DOI Listing
October 2020

Systemic and Cardiac Alterations After Long Bone Fracture.

Shock 2020 12;54(6):761-773

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

The purpose of this study was to reveal possible consequences of long-bone fracture on cardiac tissue and to analyze the role of systemically elevated danger associated molecular patterns, complement anaphylatoxins and cytokines. Blood samples of mice, pigs, and humans after a fracture were analyzed by ELISAs for complement component 5a (C5a), tumor necrosis factor (TNF), and extracellular histones. In vivo results were completed by in vitro experiments with human cardiomyocytes treated with TNF and extracellular histones. The influence of histones and human plasma after fracture on isolated human polymorphonuclear leukocytes (PMNs) was investigated. An elevation of TNF, C5a, and extracellular histones after long bone fracture was measured. Moreover, the appearance of systemic troponin I levels was observed and structural changes in connexin 43 and desmin were detected. Further, the presence of TNF leads to elevation of reactive oxygen species, troponin I release, and histone appearance in supernatant of human cardiomyocytes. Incubation of human PMNs with histones and plasma of patients after fracture lead to formation of neutrophil extracellular traps. Present results suggest that structural alterations in the heart might be consequences of the complement activation, the release of extracellular histones, and the systemic TNF elevation in the context of a long bone fracture.
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http://dx.doi.org/10.1097/SHK.0000000000001536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664958PMC
December 2020

Complement Activation and Organ Damage After Trauma-Differential Immune Response Based on Surgical Treatment Strategy.

Front Immunol 2020 31;11:64. Epub 2020 Jan 31.

Department of Traumatology, Hand-, Plastic- and Reconstructive Surgery, University of Ulm, Ulm, Germany.

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 and . Moreover, the impact of reamed vs. non-reamed intramedullary nailing was examined with regard to the complement activation after multiple trauma in pigs. 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 after trauma. Human cardiomyocytes were exposed to C3a or C5a and analyzed regarding calcium signaling and mitochondrial respiration. 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 left ventricles. C3a and C5a acted detrimentally on human cardiomyocytes by affecting their functionality and their mitochondrial respiration . After multiple trauma, an early activation of the complement system is triggered, affecting the heart as well as , 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.
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http://dx.doi.org/10.3389/fimmu.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025487PMC
April 2021

The Prognostic Value of Troponin in Pediatric Polytrauma.

Front Pediatr 2019 20;7:477. Epub 2019 Nov 20.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University Hospital of Ulm, Ulm, Germany.

Severe trauma accounts for a great number of deaths among children and adolescents. The diagnostic value of troponin serum levels of severely injured patients has been reported for adults, but data on pediatric polytrauma (PT) are scarce. Therefore, we conducted a retrospective monocentered study analyzing the prognostic value of troponin T (TnT) in pediatric trauma patients at the time point of hospital admission. Data of 88 polytraumatized pediatric patients admitted to the emergency room of the University Hospital of Ulm, Germany, between 2007 and 2016 were analyzed retrospectively. The data source was the written and digital patient records. Interleukin-6 (IL-6), creatine kinase activity (CK activity), and lactate and TnT levels were measured by a certified clinical diagnostic laboratory; and patients were stratified for the Injury Severity Score (ISS). The prognostic value for lung contusion, organ dysfunction, and fatal outcome was statistically explored. The study was approved by the independent ethical committee of the University of Ulm (#44/18). TnT levels were significantly increased in patients after severe PT compared with mild or moderate trauma severity as assessed by ISS values. Patients with TnT levels above the cutoff showed significantly increased levels of IL-6 and CK activity and a significantly prolonged stay in the intensive care unit. However, TnT levels did not correlate with absolute ISS values. TnT levels were significantly increased in patients with chest trauma and lung contusion. The incidence of lung contusion was associated with elevation of TnT. So was the onset of organ dysfunction, defined as a Sequential Organ Failure Assessment (SOFA) score ≥ 2 and fatal outcome, with a significant enhancement of plasma levels in children with organ dysfunction and in non-survivors. These descriptive data suggest that evaluation of TnT on admission of multiply injured children may help in predicting severity of injury and mortality in the clinical course after trauma and thus may be a useful addition to established prognostic parameters in the future.
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http://dx.doi.org/10.3389/fped.2019.00477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879657PMC
November 2019

Functional immune monitoring in severely injured patients-A pilot study.

Scand J Immunol 2020 Feb 3;91(2):e12837. Epub 2019 Nov 3.

Department of Orthopaedic and Trauma Surgery, University Hospital Erlangen, Erlangen, Germany.

After severe trauma, the resulting excessive inflammatory response is countered by compensatory anti-inflammatory mechanisms. The systemic inflammatory response to trauma enhanced by inappropriately timed surgical second hits may be detrimental for the patient. On the other hand, overwhelming anti-inflammatory mechanisms may put patients at increased risk from secondary local and systemic infections. The ensuing sepsis and organ dysfunction due to immune dysregulation remain the leading causes of death after injury. To date, there are no clinically applicable techniques to monitor the pro-/anti-inflammatory immune status of the patients and the remaining ability to react to microbial stimuli. Therefore, in the present study, we used a highly standardized and easy-to-use system to draw peripheral whole blood from polytraumatized patients (ISS ≥ 32, n = 7) and to challenge it with bacterial lipopolysaccharide. Secreted cytokines were compared with those in samples from healthy volunteers. We observed a significant decrease in the release of monocyte-derived mediators. Surprisingly, we detected stable or even increased concentrations of cytokines related to T cell maturation and function. For clinical practicability, we reduced the incubation time before supernatants were collected. Even after an abbreviated stimulation period, a stable release of almost all analysed parameters in patient blood could be detected. In conclusion, the data are indicative of a clinically well-applicable approach to monitor the immune status in severely injured patients in a short time. This may be used to optimize the timing of necessary surgical interventions to avoid a boost of proinflammation and reduce risk of secondary infections.
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http://dx.doi.org/10.1111/sji.12837DOI Listing
February 2020

Midkine Is Elevated After Multiple Trauma and Acts Directly on Human Cardiomyocytes by Altering Their Functionality and Metabolism.

Front Immunol 2019 21;10:1920. Epub 2019 Aug 21.

Department of Traumatology, Hand, Plastic, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

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. 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. 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 . CytoSorb®300 filtration reduced Midkine concentration and depending on the dosage. Midkine is elevated in human and porcine plasma after multiple trauma, affecting the functionality and metabolism of human cardiomyocytes . 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.
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http://dx.doi.org/10.3389/fimmu.2019.01920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736577PMC
October 2020

Modeling trauma in rats: similarities to humans and potential pitfalls to consider.

J Transl Med 2019 09 5;17(1):305. Epub 2019 Sep 5.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm Medical School, Albert-Einstein-Allee 23, 89081, Ulm, Germany.

Trauma is the leading cause of mortality in humans below the age of 40. Patients injured by accidents frequently suffer severe multiple trauma, which is life-threatening and leads to death in many cases. In multiply injured patients, thoracic trauma constitutes the third most common cause of mortality after abdominal injury and head trauma. Furthermore, 40-50% of all trauma-related deaths within the first 48 h after hospital admission result from uncontrolled hemorrhage. Physical trauma and hemorrhage are frequently associated with complex pathophysiological and immunological responses. To develop a greater understanding of the mechanisms of single and/or multiple trauma, reliable and reproducible animal models, fulfilling the ethical 3 R's criteria (Replacement, Reduction and Refinement), established by Russell and Burch in 'The Principles of Human Experimental Technique' (published 1959), are required. These should reflect both the complex pathophysiological and the immunological alterations induced by trauma, with the objective to translate the findings to the human situation, providing new clinical treatment approaches for patients affected by severe trauma. Small animal models are the most frequently used in trauma research. Rattus norvegicus was the first mammalian species domesticated for scientific research, dating back to 1830. To date, there exist numerous well-established procedures to mimic different forms of injury patterns in rats, animals that are uncomplicated in handling and housing. Nevertheless, there are some physiological and genetic differences between humans and rats, which should be carefully considered when rats are chosen as a model organism. The aim of this review is to illustrate the advantages as well as the disadvantages of rat models, which should be considered in trauma research when selecting an appropriate in vivo model. Being the most common and important models in trauma research, this review focuses on hemorrhagic shock, blunt chest trauma, bone fracture, skin and soft-tissue trauma, burns, traumatic brain injury and polytrauma.
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http://dx.doi.org/10.1186/s12967-019-2052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728963PMC
September 2019

Transthoracic Echocardiography of the Neonatal Laboratory Piglet.

Front Pediatr 2019 31;7:318. Epub 2019 Jul 31.

Division of Neonatology and Pediatric Critical Care, Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany.

Newborn piglets are commonly used in biomedical research. However, cardiovascular imaging of this species is quite challenging. For point of care diagnostics of heart function transthoracic echocardiography may be used, which appears to differ comparing newborn piglets with adult pigs. To date, there are few data or studies on the feasibility and quality of measurement of functional echocardiographic parameters in very small neonatal piglets. To study the feasibility of transthoracic echocardiography in very small newborn piglets in supine position. In 44 anesthetized and intubated newborn piglets, positioned in supine position [age 32 h (12-44 h), weight 1,220 g (1,060-1,495 g), median (IQR)] transthoracic echocardiography was performed using a point of care ultrasound device (M-Turbo, FujiFilm SonoSite BV, Amsterdam, Netherlands), and a standard ultrasound transducer. Using 2D- and M-mode-imaging left- and right-sided heart structures were accessible to transthoracic echocardiography in neonatal piglets. Diameters of the interventricular septum, the left ventricle, and the posterior wall were measured and ejection fraction and shortening fraction was calculated. Both left and right ventricular outflow tract could be imaged, and ventricular filling and systolic function could be evaluated. Furthermore, we were able to assess shunts of fetal circulation, such as patent ductus arteriosus, structure of the heart valves and congenital heart defects including ventricular septal defect. In summary, transthoracic echocardiography is feasible for assessment of cardiovascular function even in very small newborn laboratory piglets in supine position.
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http://dx.doi.org/10.3389/fped.2019.00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684740PMC
July 2019

Tissue damage in the heart after cardiac arrest induced by asphyxia and hemorrhage in newborn pigs.

Pediatr Res 2019 12 23;86(6):709-718. Epub 2019 Jul 23.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

Background: Asphyxia of newborns is a severe and frequent challenge of the peri- and postnatal period.

Methods: Forty-four neonatal piglets underwent asphyxia and hemorrhage (AH), followed by resuscitation with blood or crystalloid transfusion. In this study, 15 piglets (blood n = 9, NaCl n = 6, mean age 31 h) were randomly chosen. Four hours after return of spontaneous circulation, heart tissue and blood were collected. Analyses of heart fatty acid binding protein (HFABP), cardiac troponin I (TnI) levels, and activation of the complement system were performed. Histological staining for connexin 43 (Cx43) and complement C5a receptor 1 (C5aR1) was performed.

Results: Following AH, systemic elevation of cardiac TnI and HFABP revealed cardiac damage in both groups. Systemic activation of the complement system and the appearance of extracellular histones in plasma of the blood transfusion group were observed. The Cx43 was translocated from the intercalated discs to the cytosol after AH. Cardiac glycogen concentration was reduced in both groups. A significant reduction of C5aR1 in the left ventricle and a significant elevation of the heart injury score were investigated after blood transfusion.

Conclusion: AH leads to alteration of the heart, particularly in Cx43 and glycogen reserves, as well as local inflammation.
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http://dx.doi.org/10.1038/s41390-019-0505-6DOI Listing
December 2019

Cardiac Glucose and Fatty Acid Transport After Experimental Mono- and Polytrauma.

Shock 2020 05;53(5):620-629

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.

Objective: The aim of this study was to define the influence of trauma on cardiac glucose and fatty acid transport. The effects were investigated in vivo in a porcine mono- and polytrauma model and in vitro in human cardiomyocytes, which were treated simultaneously with different inflammatory substances, mimicking posttraumatic inflammatory conditions.

Methods And Results: In the porcine fracture- and polytrauma model, blood glucose concentrations were measured by blood gas analysis during an observation period of 72 h. The expression of cardiac glucose and fatty acid transporters in the left ventricle was determined by RT-qPCR and immunofluorescence. Cardiac and hepatic glycogen storage was examined. Furthermore, human cardiomyocytes were exposed to a defined trauma-cocktail and the expression levels of glucose- and fatty acid transporters were determined. Early after polytrauma, hyperglycemia was observed. After 48 and 72 h, pigs with fracture- and polytrauma developed hypoglycemia. The propofol demand significantly increased posttrauma. The hepatic glycogen concentration was reduced 72 h after trauma. Cardiac glucose and fatty acid transporters changed in both trauma models in vivo as well as in vitro in human cardiomyocytes in presence of proinflammatory mediators.

Conclusions: Monotrauma as well as polytrauma changed the cardiac energy transport by altering the expression of glucose and fatty acid transporters. In vitro data suggest that human cardiomyocytes shift to a state alike myocardial hibernation preferring glucose as primary energy source to maintain cardiac function.
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http://dx.doi.org/10.1097/SHK.0000000000001400DOI Listing
May 2020

Lung injury after asphyxia and hemorrhagic shock in newborn piglets: Analysis of structural and inflammatory changes.

PLoS One 2019 5;14(7):e0219211. Epub 2019 Jul 5.

Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Baden-Württemberg, Germany.

Objective: Asphyxia of newborns is a severe and frequent challenge of the peri- and postnatal period. The purpose of this study was to study early morphological, immunological and structural alterations in lung tissue after asphyxia and hemorrhage (AH).

Methods: 44 neonatal piglets (age 32 hrs) underwent asphyxia and hemorrhage (AH) and were treated according to the international liaison committee of resuscitation (ILCOR) guidelines. For this study, 15 piglets (blood transfusion (RBC) n = 9; NaCl n = 6, mean age 31 hrs) were randomly picked. 4 hours after ROSC (return of spontaneous circulation), lung tissue and blood samples were collected.

Results: An elevation of myeloperoxidase (MPO) activity was observed 4 hrs after AH accompanied by an increase of surfactant D after RBC treatment. After AH tight junction proteins Claudin 18 and junctional adhesion molecule 1 (JAM1) were down-regulated, whereas Occludin was increased. Furthermore, after AH and RBC treatment dephosphorylated active form of Connexin 43 was increased.

Conclusions: AH in neonatal pigs is associated with early lung injury, inflammation and alterations of tight junctions (Claudin, Occludin, JAM-1) and gap junctions (Connexin 43) in lung tissue, which contributes to the development of lung edema and impaired function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219211PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611609PMC
February 2020

Inflammatory response of mesenchymal stromal cells after in vivo exposure with selected trauma-related factors and polytrauma serum.

PLoS One 2019 14;14(5):e0216862. Epub 2019 May 14.

Institute of Transfusion Medicine, Ulm University Medical Center, Ulm, Germany.

Polytrauma (PT) is a life-threatening disease and a major global burden of injury. Mesenchymal stromal cells (MSC) might be a therapeutic option for PT patients due to their anti-inflammatory and regenerative potential. We hypothesised that the inflammatory response of MSC is similar after exposure to selected trauma-relevant factors to sera from PT patients (PTS). Therefore, we investigated the effects of a mixture of defined factors, supposed to play a role on MSC in the early phase of PT. Additionally, in a translational approach we investigated the effect of serum from PT patients on MSC in vitro. MSC were incubated with a PT cocktail in physiological (PTCL) and supra-physiological (PTCH) concentrations or PTS. The effect on gene expression and protein secretion of MSC was analysed by RNA sequencing, ELISA and Multiplex assays of cell culture supernatant. Stimulation of MSC with PTCH, PTCL or IL1B led to significant up- or downregulation of 470, 183 and 469 genes compared to unstimulated MSC at 6 h. The intersection of differentially expressed genes in these groups was very high (92% overlap with regard to the PTCL group; treated for 6 h). Cytokine secretion profile of MSC revealed that IL1B mimics the effect of a more complex PT cocktail as well. However, there was only a minor proportion of overlapping differentially expressed genes between the MSC group stimulated with early times of PTS and the MSC group stimulated with PTCH, PTCL and IL1B. In conclusion, the effect of sera from PT patients on MSC activation cannot be simulated by the chosen trauma-relevant factors. Furthermore, we conclude that while IL1B might be useful to prime MSC prior to therapeutic application, it might not be as useful for the in vitro study of functional properties of MSC in the context of PT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216862PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516676PMC
January 2020

Sensory contact to the stressor prevents recovery from structural and functional heart damage following psychosocial trauma.

Brain Behav Immun 2019 08 11;80:667-677. Epub 2019 May 11.

Laboratory for Molecular Psychosomatics, Department of Psychosomatic Medicine and Psychotherapy, University of Ulm, Ulm, Germany. Electronic address:

Cardiovascular disorders (CVD) and posttraumatic stress disorder (PTSD) are highly comorbid, but the underlying mechanisms are not fully understood. Chronic psychosocial stress was induced in male mice by chronic subordinate colony housing (CSC), a pre-clinically validated mouse model for PTSD. Cardiac structure and function were assessed on day 20 of the CSC paradigm. Following CSC, mice were kept in different sensory contact modalities to the last aggressor for 30 days, and development of cardiac function and behavioral aspects were determined. Here we show that psychosocial trauma affects heart structure by disturbing cell-to-cell integrity of cardiomyocytes, causes tachycardia, disturbance of diurnal heart rate rhythmicity and behavioral deficits in a mouse model for PTSD. Structural and functional alterations were also found in cardiomyocytes upon in vitro treatment with pro-inflammatory cytokines typically increased after psychosocial trauma. Interestingly, sensory contact to the aggressor subsequent to psychosocial trauma prohibits functional and structural heart recovery, while isolation was beneficial for cardiac but detrimental for mental health. These findings contribute to our understanding of potential mechanisms underlying the high comorbidity of CVD and PTSD.
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http://dx.doi.org/10.1016/j.bbi.2019.05.013DOI Listing
August 2019

Distinct Dynamics of Stem and Progenitor Cells in Blood of Polytraumatized Patients.

Shock 2019 04;51(4):430-438

Institute of Molecular Medicine, Ulm University, Ulm, Germany.

Endogenously mobilized stem and progenitor cells (SPCs) or exogenously provided SPCs are thought to be beneficial for trauma therapy. However, still little is known about the synchronized dynamics of the number of SPCs in blood after severe injury and parameters like cytokine profiles that correlate with these numbers. We determined the number of hematopoietic stem cells, common myeloid progenitors, granulocyte-macrophage progenitors, and mesenchymal stem/stromal cells in peripheral blood (PB) 0 to 3, 8, 24, 48, and 120 h after polytrauma in individual patients (injury severity score ≥ 21). We found that the number of blood SPCs follows on average a synchronous, inverse bell-shaped distribution, with an increase at 0 to 3 h, followed by a strong decrease, with a nadir in SPC numbers in blood at 24 or 48 h. The change in numbers of SPCs in PB between 48 h and 120 h revealed two distinct patterns: Pattern 1 is characterized by an increase in the number of SPCs to a level higher than normal, pattern 2 is characterized by an almost absent increase in the number of SPCs compared to the nadir. Changes in the concentrations of the cytokines CK, MDC, IL-8, G-CSF Gro-α, VEGF, and MCP-1 correlated with changes in the number of SPCs in PB or were closely associated with Pattern 1 or Pattern 2. Our data provide novel rationale for investigations on the role of stem cell mobilization in polytraumatized patients and its likely positive impact on trauma outcome.
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http://dx.doi.org/10.1097/SHK.0000000000001198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407807PMC
April 2019

Successful Resuscitation in a Model of Asphyxia and Hemorrhage to Test Different Volume Resuscitation Strategies. A Study in Newborn Piglets After Transition.

Front Pediatr 2018 10;6:192. Epub 2018 Jul 10.

Division of Neonatology and Pediatric Critical Care, Department of Pediatrics and Adolescent Medicine, Ulm University, Ulm, Germany.

Evidence for recommendations on the use of volume expansion during cardiopulmonary resuscitation in newborn infants is limited. To develop a newborn piglet model with asphyxia, hemorrhage, and cardiac arrest to test different volume resuscitation on return of spontaneous circulation (ROSC). We hypothesized that immediate red cell transfusion reduces time to ROSC as compared to the use of an isotonic crystalloid fluid. Forty-four anaesthetized and intubated newborn piglets [age 32 h (12-44 h), weight 1,220 g (1,060-1,495g), Median (IQR)] were exposed to hypoxia and blood loss until asystole occurred. At this point they were randomized into two groups: (1) Crystalloid group: receiving isotonic sodium chloride ( = 22). (2) Early transfusion group: receiving blood transfusion ( = 22). In all other ways the piglets were resuscitated according to ILCOR 2015 guidelines [including respiratory support, chest compressions (CC) and epinephrine use]. One hour after ROSC piglets from the crystalloid group were randomized in two sub-groups: late blood transfusion and infusion of isotonic sodium chloride to investigate the effects of a late transfusion on hemodynamic parameters. All animals achieved ROSC. Comparing the crystalloid to early blood transfusion group blood loss was 30.7 ml/kg (22.3-39.6 ml/kg) vs. 34.6 ml/kg (25.2-44.7 ml/kg), Median (IQR). Eleven subjects did not receive volume expansion as ROSC occurred rapidly. Thirty-three animals received volume expansion (16 vs. 17 in the crystalloid vs. early transfusion group). 14.1% vs. 10.5% of previously extracted blood volume in the crystalloid vs. early transfusion group was infused before ROSC. There was no significant difference in time to ROSC between groups [crystalloid group: 164 s (129-198 s), early transfusion group: 163 s (162-199 s), Median (IQR)] with no difference in epinephrine use. Early blood transfusion compared to crystalloid did not reduce time to ROSC, although our model included only a moderate degree of hemorrhage and ROSC occurred early in 11 subjects before any volume resuscitation occurred.
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http://dx.doi.org/10.3389/fped.2018.00192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048263PMC
July 2018