Application of the PANELVIEW instrument to evaluate the guideline development process of the German polytrauma guideline.

BACKGROUND: PANELVIEW is an instrument for evaluating the appropriateness of the process, methods, and outcome of guideline development and the satisfaction of the guideline group with these steps. OBJECTIVE: To evaluate the guideline development process of the German guideline on the treatment of patients with severe/multiple injuries ('German polytrauma guideline') from the perspective of the guideline group, and to identify areas where this process may be improved in the future. METHODS: We administered PANELVIEW to the participants of the 2022 update of the German polytrauma guideline. All guideline group members, including delegates of participating medical societies, steering group members, authors of guideline chapters, the chair, and methodological lead, were invited to participate. Responses were analysed using descriptive statistics. Comments received were categorised by domains/items of the tool. RESULTS: After the first, second, and last consensus conference, the guideline group was invited via email to participate in a web-based survey. Response rates were 36% (n/N = 13/36), 40% (12/30), and 37% (20/54), respectively. The mean scores for items ranged between 5.1 and 6.9 on a scale from 1 (fully disagree) to 7 (fully agree). Items with mean scores below 6.0 were related to (1) administration, (2) consideration of patients' views, perspectives, values, and preferences, and (3) the discussion of research gaps and needs for future research. CONCLUSION: The PANELVIEW tool showed that the guideline group was satisfied with most aspects of the guideline development process. Areas for improvement of the process were identified. Strategies to improve response rates should be explored.

Assessment of patient-reported outcomes after polytrauma - instruments and methods: a systematic review.

OBJECTIVES: We (1) collected instruments that assess health-related quality of life (HRQoL), activities of daily living (ADL) and social participation during follow-up after polytrauma, (2) described their use and (3) investigated other relevant patient-reported outcomes (PROs) assessed in the studies. DESIGN: Systematic Review using the Preferred Reporting Items for Systematic Review and Meta-Analysis guideline. DATA SOURCES: MEDLINE, Embase, CINAHL, PsycINFO, CENTRAL, as well as the trials registers ClinicalTrials.gov and WHO ICTRP were searched from January 2005 to April 2018. ELIGIBILITY CRITERIA: All original empirical research published in English or German including PROs of patients aged 18-75 years with an Injury Severity Score≥16 and/or an Abbreviated Injury Scale≥3. Studies with defined injuries or diseases (e.g. low-energy injuries) and some text types (e.g. grey literature and books) were excluded. Systematic reviews and meta-analyses were excluded, but references screened for appropriate studies. DATA EXTRACTION AND SYNTHESIS: Data extraction, narrative content analysis and a critical appraisal (e.g. UK National Institute for Health and Care Excellence) were performed by two reviewers independently. RESULTS: The search yielded 3496 hits; 54 publications were included. Predominantly, HRQoL was assessed, with Short Form-36 Health Survey applied most frequently. ADL and (social) participation were rarely assessed. The methods most used were postal surveys and single assessments of PROs, with a follow-up period of one to one and a half years. Other relevant PRO areas reported were function, mental disorders and pain. CONCLUSIONS: There is a large variation in the assessment of PROs after polytrauma, impairing comparability of outcomes. First efforts to standardise the collection of PROs have been initiated, but require further harmonisation between central players. Additional knowledge on rarely reported PRO areas (e.g. (social) participation, social networks) may lead to their consideration in health services provision. PROSPERO REGISTRATION NUMBER: CRD42017060825.

Polytrauma outcome: implementation of health-related quality of life assessment into the German Trauma Registry.

INTRODUCTION: As a result of improvement in polytrauma management within the last years, more patients survive a significant trauma. Trauma registers, such as the TraumaRegister DGU®, played a role in identifying risk factors of poor outcomes which led to an improvement of survival rates. In recent years the health-related quality of life (HRQoL) after trauma got into the focus of trauma studies. MATERIALS AND METHODS: Under the sponsorship of the German Society of Trauma Surgery (DGU) the members of the Committee on Emergency Medicine, Intensive Care and Trauma Management (Sektion NIS) convened intending to identify an assessment tool for implementation into the TraumaRegister DGU®. RESULTS: After the conduct of a systematic literature review, the working group decided to choose the 12-item Short-Form Health Survey (SF-12) and five more questions, capturing the satisfaction of treatment, work capacity and trauma-related medical treatment. CONCLUSION: The data collection of HRQoL and the additional variables started in 2017 in participating clinics as a part of the regular data collection of the TraumaRegister DGU®.

[Surgery during the SARS-CoV-2 pandemic : Recommendations on operative procedures]. / Chirurgie in der SARS-CoV-2-Pandemie : Empfehlungen zum operativen Vorgehen.

BACKGROUND: In February 2020 Germany was also hit by the SARS-CoV­2 pandemic. Even patients infected by SARS-CoV­2 or COVID-19 may need operative procedures. Currently, no uniform recommendations exist on precautions to be taken when operating on these patients. Furthermore, they may differ from one hospital to another. METHODS: The task force COVID-19 of the emergency, intensive and severely injured section of the German Trauma Society (DGU e. V.) has developed consensus-based recommendations on surgical treatment of patients with SARS-CoV­2 infections. Great importance is placed on the implementation in hospitals at all levels of care. RESULTS: The indications for surgical interventions in patients with COVID-19 infections require an extremely critical evaluation. When indicated these surgical intervention should ideally be performed in a separate operating theater. All personnel involved should wear personal protective equipment with FFP2 masks, face shields and double gloves. The emergency team in the resuscitation bay should generally wear the same personal protective equipment. Special training is mandatory and the exposure of team members should be minimized. CONCLUSION: The recommendations are principally used for all kinds of surgery and comply with the currently available knowledge. Nevertheless, all recommendations represent a compromise between maximum safety of all medical staff and practicability in the routine hospital workflow.

Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

BACKGROUND: Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS: NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS: During systemic inflammation, the expression of the IL-12 receptor ß2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ß receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ß2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION: GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.

Surgical Management of Proximal Interphalangeal Joint Repetitive Stress Epiphyseal Fracture Nonunion in Elite Sport Climbers.

Repetitive stress fracture of the middle phalanx epiphysis is an injury specific to elite adolescent sport climbers. As sport climbing becomes increasingly popular in younger age groups, an increased number of these injuries have been reported in recent years. To date, treatment of these fractures has been nonsurgical, with strict rest and physiotherapy prescribed until fracture union. However, when these patients present in a delayed fashion with an established nonunion, nonsurgical treatment may fail, leading to disabling chronic pain and/or digital deformity in some cases. In this article, we present 2 cases of surgical treatment for finger middle phalanx repetitive stress epiphyseal fracture nonunion, using a percutaneous spot drilling epiphysiodesis technique.

Dendritic Cell-Like Cells Accumulate in Regenerating Murine Skeletal Muscle after Injury and Boost Adaptive Immune Responses Only upon a Microbial Challenge.

Skeletal muscle injury causes a local sterile inflammatory response. In parallel, a state of immunosuppression develops distal to the site of tissue damage. Granulocytes and monocytes that are rapidly recruited to the site of injury contribute to tissue regeneration. In this study we used a mouse model of traumatic skeletal muscle injury to investigate the previously unknown role of dendritic cells (DCs) that accumulate in injured tissue. We injected the model antigen ovalbumin (OVA) into the skeletal muscle of injured or sham-treated mice to address the ability of these DCs in antigen uptake, migration, and specific T cell activation in the draining popliteal lymph node (pLN). Immature DC-like cells appeared in the skeletal muscle by 4 days after injury and subsequently acquired a mature phenotype, as indicated by increased expression of the costimulatory molecules CD40 and CD86. After the injection of OVA into the muscle, OVA-loaded DCs migrated into the pLN. The migration of DC-like cells from the injured muscle was enhanced in the presence of the microbial stimulus lipopolysaccharide at the site of antigen uptake and triggered an increased OVA-specific T helper cell type 1 (Th1) response in the pLN. Naïve OVA-loaded DCs were superior in Th1-like priming in the pLN when adoptively transferred into the skeletal muscle of injured mice, a finding indicating the relevance of the microenvironment in the regenerating skeletal muscle for increased Th1-like priming. These findings suggest that DC-like cells that accumulate in the regenerating muscle initiate a protective immune response upon microbial challenge and thereby overcome injury-induced immunosuppression.

Staurosporine resistance in inflammatory neutrophils is associated with the inhibition of caspase- and proteasome-mediated Mcl-1 degradation.

Apoptosis resistance in activated neutrophils is known to be associated with collateral damage of surrounding tissue, as well as immune and organ dysfunction. Thus, the safe removal of neutrophils by apoptosis induction represents a prerequisite for the resolution of inflammation. Here, we report that intrinsic apoptosis resistance in human neutrophils, isolated from severely injured patients, is based on enhanced stabilization of antiapoptotic myeloid cell leukemia 1 and subsequent impairment of downstream apoptotic pathways. Whereas extrinsic apoptosis induction by the activation of Fas death receptor on inflammatory neutrophils was accompanied by caspase- and proteasome-mediated myeloid cell leukemia 1 degradation, intrinsic apoptosis induction by staurosporine led to a significant stabilization of myeloid cell leukemia 1 protein, which impeded on truncated forms of B cell lymphoma 2-associated X protein and B cell lymphoma 2 homology domain 3-interacting domain death translocation and subsequent cytochrome c release from the mitochondria. We show further that profound inhibition of myeloid cell leukemia 1 degradation is based on the inhibition of caspases and sustained activation of kinases involved in cell survival, such as Akt. Accordingly, impeded myeloid cell leukemia 1 phosphorylation on Ser159 by glycogen synthase kinase 3 and protein ubiquitination has been demonstrated. Inhibition of myeloid cell leukemia 1 activity markedly increased sensitivity to staurosporine-induced cell death. Altogether, these results provide new insights into the mechanisms underlying myeloid cell leukemia 1-mediated apoptosis resistance to staurosporine under inflammatory situations and should be considered for the development of novel therapeutic strategies.

Level of Evidence Analysis for the Latest German National Guideline on Treatment of Patients with Severe and Multiple Injuries and ATLS.

PURPOSE: Advanced Trauma Life Support (ATLS®) is one of the world's best-known training programs for medical providers. Revisions of the ATLS manual have been evidence based for a number of years. In 2011, a level 3 (S3) evidence- and consensus-based guideline on the treatment of patients with severe and multiple injuries was published in Germany. The scope of this study was the systematic comparison of the educational content of the ATLS concept and the interdisciplinary "S3 polytrauma guideline." METHODS: A total of 123 key recommendations of the guideline were compared with the content of the ATLS manual (9th edition). Depending on the level of agreement, the recommendations were classed in the following categories: (1) Agreement. (2) Minor variation. (3) Major variation. RESULTS: An overall 86% conformity was found between the key recommendations of the guideline and the ATLS® manual. The ATLS® primary survey (ABCDE) showed an 85% conformity. The degree of conformity for the individual priorities was as follows: A (Airway) 79%, B (Breathing) 79%, C (Circulation) 86%, D (Disability) 93%, E (Exposure) 100%. The ATLS® secondary survey showed a 94% conformity. The main differences were in the areas of anesthetic induction, fluid administration, and coagulation therapy. CONCLUSIONS: According to our comparison, the educational content and manual of the ATLS are largely compatible with a high level of evidence S3 guideline. However, subsequent editions of both the ATLS® and the S3 guideline should re-examine and reassess a number of aspects.

Lysostaphin-coated titan-implants preventing localized osteitis by Staphylococcus aureus in a mouse model.

The increasing incidence of implant-associated infections induced by Staphylococcus aureus (SA) in combination with growing resistance to conventional antibiotics requires novel therapeutic strategies. In the current study we present the first application of the biofilm-penetrating antimicrobial peptide lysostaphin in the context of bone infections. In a standardized implant-associated bone infection model in mice beta-irradiated lysostaphin-coated titanium plates were compared with uncoated plates. Coating of the implant was established with a poly(D,L)-lactide matrix (PDLLA) comprising lysostaphin formulated in a stabilizing and protecting solution (SPS). All mice were osteotomized and infected with a defined count of SA. Fractures were fixed with lysostaphin-coated locking plates. Plates uncoated or PDLLA-coated served as controls. All mice underwent debridement and lavage on Days 7, 14, 28 to determine the bacterial load and local immune reaction. Fracture healing was quantified by conventional radiography. On Day 7 bacterial growth in the lavages of mice with lysostaphin-coated plates showed a significantly lower count to the control groups. Moreover, in the lysostaphin-coated plate groups complete fracture healing were observed on Day 28. The fracture consolidation was accompanied by a diminished local immune reaction. However, control groups developed an osteitis with lysis or destruction of the bone and an evident local immune response. The presented approach of terminally sterilized lysostaphin-coated implants appears to be a promising therapeutic approach for low grade infection or as prophylactic strategy in high risk fracture care e.g. after severe open fractures.

Induced hypothermia reduces the hepatic inflammatory response in a swine multiple trauma model.

BACKGROUND: Mild therapeutic hypothermia following trauma has been introduced in several studies to reduce the posttraumatic inflammation and organ injury. In this study, we analyzed the effects of induced mild hypothermia (34°C) on the inflammation of the shock organs liver and kidney. METHODS: In a porcine model of multiple trauma including blunt chest trauma, liver laceration, and hemorrhagic shock followed by fluid resuscitation, the influence of induced hypothermia on hepatic and renal damage and organ-specific inflammation were evaluated. A total of 40 pigs were randomly assigned to four groups, which were sham (anesthesia only) or trauma groups receiving either hypothermia or normothermia. The parameters analyzed were laboratory parameters (aspartate transaminase [AST], lactate dehydrogenase, urea, creatinine) as well as hepatic and renal cytokine expression determined by real-time polymerase chain reaction (interleukin 6 [IL-6], IL-8). Blinded analysis of histologic changes in the liver and kidney was performed. RESULTS: Fifteen and a half hours following combined trauma, hepatic cytokine expression and liver damage were significantly increased in animals with normothermia compared with the respective sham group. Hypothermia, however, resulted in a fivefold reduced hepatic expression of IL-8 (mean ± SE, 2.4 ± 1.3; p = 0.01) when compared with the normothermic trauma group (IL-8, 12.8 ± 4.7). Accordingly, granulocyte infiltration and a histologic, semiquantitative score for liver injury were significantly higher in the normothermic trauma group. Serum AST levels raised significantly after trauma and normothermia compared with the respective sham group, while AST levels showed no difference from the sham groups in the hypothermic trauma group. In contrast, neither trauma nor hypothermia influenced the expression of IL-6 and IL-8 and tissue injury in the kidney. CONCLUSION: Therapeutic hypothermia seems to attenuate the hepatic inflammatory response and the associated liver injury after severe trauma. Therefore, induced hypothermia might represent a potential therapeutic strategy to avoid posttraumatic organ dysfunction.

Implant-associated localized osteitis in murine femur fracture by biofilm forming Staphylococcus aureus: a novel experimental model.

Staphylococcus aureus (SA) is the most common causative agent for implant-associated osteitis. The present study characterizes a novel model of a low grade acute SA osteitis with bone defect in the femur which is stabilized by a titanium locking plate. Wild-type Balb/c mice were osteotomized, fixed by a locking plate and infected with SA. Mice underwent debridement 7 and 14 days later and were sacrificed at Day 28. At Days 7, 14, and 28 after inoculation local and systemic cell populations and IL-6 were analyzed. Fracture healing was quantified by radiography. The control group underwent the same procedure without infection. The bacterial load of implant-associated osteitis with biofilm formation was quantified by counting CFU and real-time PCR. Fracture healing determined by radiography was delayed in infected compared to non-infected mice. Throughout the investigation period CFU and leukocyte counts, as well as IL-6 levels were found to be significantly elevated in infected mice at the infection site but not systemically. Our murine model allows the detailed investigation of implant associated localized osteitis with biofilm producing SA and its influence on fracture healing. The model provides a tool to analyze therapeutic or prophylactic approaches to the problem of biofilm-associated osteitis.

Induced hypothermia does not impair coagulation system in a swine multiple trauma model.

BACKGROUND: Accidental hypothermia, acidosis, and coagulopathy represent the lethal triad in severely injured patients. Therapeutic hypothermia however is commonly used in transplantations, cardiac and neurosurgical surgery, or after cardiac arrest. However, the effects of therapeutic hypothermia on the coagulation system following multiple trauma need to be elucidated. METHODS: In a porcine model of multiple trauma including blunt chest injury, liver laceration, and hemorrhagic shock followed by fluid resuscitation, the influence of therapeutic hypothermia on coagulation was evaluated. A total of 40 pigs were randomly assigned to sham (only anesthesia) or trauma groups receiving either hypothermia or normothermia. Each group consisted of 10 pigs. Analyzed parameters were cell count (red blood cells, platelets), pH, prothrombin time (PT), fibrinogen concentration, and analysis with ROTEM and Multiplate. RESULTS: Trauma and consecutive fluid resuscitation resulted in impaired coagulation parameters (cell count, pH, PT, fibrinogen, ROTEM, and platelet function). During hypothermia, coagulation parameters measured at 37°C, such as PT, fibrinogen, thrombelastometry measurements, and platelet function, showed no significant differences between normothermic and hypothermic animals in both trauma groups. Additional analyses of thrombelastometry at 34°C during hypothermia showed significant differences for clotting time and clot formation time but not for maximum clot firmness. We were not able to detect macroscopic or petechial bleeding in both trauma groups. CONCLUSION: Based on the results of the present study we suggest that mild hypothermia can be safely performed after stabilization following major trauma. Mild hypothermia has effects on the coagulation system but does not aggravate trauma-induced coagulopathy in our model. Before hypothermic treatment can be performed in the clinical setting, additional experiments with prolonged and deeper hypothermia to exclude detrimental effects are required.

The impact of arterial hypertension on polytrauma and traumatic brain injury.

BACKGROUND: Pre-hospital hypotension in trauma patients is associated with high mortality. Especially for patients with severe traumatic brain injury (TBI), arterial normotension or even hypertension (AHT) is considered an important mechanism for sustaining adequate cerebral perfusion pressure. The effect of pre-hospital arterial hypertension (pAHT) on in-hospital mortality after trauma has not been studied to date. METHODS: We retrospectively analyzed data in the trauma registry of the German Society for Trauma Surgery (DGU) on all trauma patients in Germany from 1993 to 2008 who were 16 to 80 years old at the time of the trauma and had an injury severity score (ISS) of 9 or above (total, 42 500 patient data sets). For the analysis, we divided the patients into two groups: those with and those without TBI. We further divided the TBI patients into five subgroups depending on the course of their systolic blood pressure up to the moment of their arrival at the hospital. We also analyzed the patients' demographic data, patterns of injury, and accident mechanisms. RESULTS: Trauma patients with TBI and pAHT (142 of 561 patients) had a significantly higher mortality than normotensive TBI patients (25.3% vs. 13.5%, p<0.001). Arterial hypertension that either rises or falls before the patient reaches the hospital is associated with higher in-hospital mortality. A logistical regression analysis of 5384 patients revealed that patients with pAHT (n = 561) had an odds ratio of 1.9 (95% confidence interval, 1.4 to 1.6) for death in the hospital compared to normotensive patients (n = 6020). CONCLUSION: Systolic blood pressure values above 160 mm Hg before arrival in the hospital worsen the outcome of trauma patients with TBI.

Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice.

INTRODUCTION: Although the formation of neutrophil (PMN) extracellular traps (NETs) has been detected during infection and sepsis, their role in vivo is still unclear. This study was performed in order to evaluate the influence of NETs depletion by administration of recombinant human (rh)DNase on bacterial spreading, PMN tissue infiltration and inflammatory response in a mouse model of polymicrobial sepsis. METHODS: In a prospective controlled double-armed animal trial, polymicrobial sepsis was induced by cecal ligation and puncture (CLP). After CLP, mice were treated with rhDNase or phosphate buffered saline, respectively. Survival, colony forming unit (CFU) counts in the peritoneal cavity, lung, liver and blood were determined. PMN and platelet counts, IL-6 and circulating free (cf)-DNA/NETs levels were monitored. PMN infiltration, as well as organ damage, was analyzed histologically in the lungs and liver. Capability and capacity of PMN to form NETs were determined over time. RESULTS: cf-DNA/NETs were found to be significantly increased 6, 24, and 48 hours after CLP when compared to the levels determined in sham and naïve mice. Peak levels after 24 hours were correlated to enhanced capacity of bone marrow-derived PMN to form NETs after ex vivo stimulation with phorbol-12-myristate-13-acetate at the same time. rhDNase treatment of mice resulted in a significant reduction of cf-DNA/NETs levels 24 hours after CLP (P < 0.001). Although overall survival was not affected by rhDNase treatment, median survival after 24 hours was significantly lower when compared with the CLP group (P < 0.01). In mice receiving rhDNase treatment, CFU counts in the lung (P < 0.001) and peritoneal cavity (P < 0.05), as well as serum IL-6 levels (P < 0.001), were found to be already increased six hours after CLP. Additionally, enhanced PMN infiltration and tissue damage in the lungs and liver were found after 24 hours. In contrast, CFU counts in mice without rhDNase treatment increased later but more strongly 24 hours after CLP (P < 0.001). Similarly, serum IL-6 levels peaked after 24 hours (P < 0.01). CONCLUSIONS: This study shows, for the first time, that depletion of NETs by rhDNase administration impedes the early immune response and aggravates the pathology that follows polymicrobial sepsis in vivo.

Facts and fiction: the impact of hypothermia on molecular mechanisms following major challenge.

Numerous multiple trauma and surgical patients suffer from accidental hypothermia. While induced hypothermia is commonly used in elective cardiac surgery due to its protective effects, accidental hypothermia is associated with increased posttraumatic complications and even mortality in severely injured patients. This paper focuses on protective molecular mechanisms of hypothermia on apoptosis and the posttraumatic immune response. Although information regarding severe trauma is limited, there is evidence that induced hypothermia may have beneficial effects on the posttraumatic immune response as well as apoptosis in animal studies and certain clinical situations. However, more profound knowledge of mechanisms is necessary before randomized clinical trials in trauma patients can be initiated.

Coagulation management of bleeding trauma patients is changing in German trauma centers: an analysis from the trauma registry of the German Society for Trauma Surgery.

BACKGROUND: Recent findings have emphasized the need for early and aggressive coagulation support in bleeding trauma patients. This study aimed to examine whether blood component transfusion and hemostatic drug administration during acute trauma care have changed in daily practice during the recent years. METHODS: The multicenter trauma registry of the German Society for Trauma was retrospectively analyzed for primarily admitted patients older than 16 years with an Injury Severity Score ≥ 16 who had received at least five red blood cell (RBC) units between emergency room arrival and intensive care unit admission. Administration of fresh frozen plasma and platelet units has been documented since 2002, and use of hemostatic drugs since 2005. RESULTS: From 2002 until 2009 (n = 2,813), the fresh frozen plasma:RBC ratio increased from 0.65 to 0.75 (p = 0.02) and the platelet:RBC ratio from 0.04 to 0.09 (p < 0.0001). A constant increase was also observed regarding the overall use of hemostatic drugs (n = 1,811; 2005-2009) as these were administered to 43.4% of the patients in 2005 and to 60.7% in 2009 (p < 0.0001). Especially, the administration of fibrinogen concentrate (2005: 17.0%, 2009: 45.6%; p < 0.0001) and recombinant factor VIIa (2005: 1.9%, 2009: 6.3%; p = 0.04) showed a marked increase. However, mortality rates remained unchanged during the 8-year study period. CONCLUSIONS: The therapy of bleeding trauma patients has changed in Germany during the recent years toward more aggressive coagulation support. This development continues although grades of evidence are still low regarding most of the changes reported in our study. Randomized controlled trials are needed with respect to blood component therapy using predefined ratios and to the administration of hemostatic drugs commonly used for the severely injured.

Molecular mechanisms underlying delayed apoptosis in neutrophils from multiple trauma patients with and without sepsis.

Delayed neutrophil apoptosis and overshooting neutrophil activity contribute to organ dysfunction and subsequent organ failure in sepsis. Here, we investigated apoptotic signaling pathways that are involved in the inhibition of spontaneous apoptosis in neutrophils isolated from major trauma patients with uneventful outcome as well as in those with sepsis development. DNA fragmentation in peripheral blood neutrophils showed an inverse correlation with the organ dysfunction at d 10 after trauma in all patients, supporting the important role of neutrophil apoptosis regulation for patient's outcome. The expression of the antiapoptotic Bcl-2 protein members A1 and Mcl-1 were found to be diminished in the septic patients at d 5 and d 10 after trauma. This decrease was also linked to an impaired intrinsic apoptosis resistance, which has been previously shown to occur in neutrophils during systemic inflammation. In patients with sepsis development, delayed neutrophil apoptosis was found to be associated with a disturbed extrinsic pathway, as demonstrated by reduced caspase-8 activity and Bid truncation. Notably, the expression of Dad1 protein, which is involved in protein N-glycosylation, was significantly increased in septic patients at d 10 after trauma. Taken together, our data demonstrate that neutrophil apoptosis is regulated by both the intrinsic and extrinsic pathway, depending on patient's outcome. These findings might provide a molecular basis for new strategies targeting cell death pathways in apoptosis-resistant neutrophils during systemic inflammation.

Adipocyte-secreted factors increase osteoblast proliferation and the OPG/RANKL ratio to influence osteoclast formation.

Several studies have reported a positive relationship of the body fat mass and bone density. However, it is not clear whether adipocyte-derived signaling molecules directly act on osteoblasts or osteoclasts. Therefore, we investigated the effect of fat cell-secreted factors on the proliferation and differentiation of preosteoblasts and the molecular mechanisms involved. This stimulation led to an increased proliferation of MC3T3-E1 and primary preosteoblastic cells (2.8-fold and 1.5-fold, respectively; p<0.0001), which could be reduced with inhibitors of protein tyrosine kinases, FGFR1 and PI3K. Concordantly, we found human adipocytes to secrete bFGF and bFGF to mimic the effect of adipocyte-secreted factors. The ratio of OPG/RANKL secretion in primary human preosteoblasts increased 9-fold (mRNA and protein) when stimulated with adipocyte-secreted factors. Moreover, osteoblasts which were prestimulated with adipocyte-secreted factors inhibited the formation of osteoclasts. In conclusion, human adipocytes secrete factors that directly act on preosteoblasts and alter their crosstalk with osteoclasts. These in vitro findings reflect the higher bone mass in obese people and attribute it to effects of adipocyte-secreted factors on bone formation.