Development and first results of a national databank on care and treatment outcome after traumatic brain injury.

PURPOSE: In absence of comprehensive data collection on traumatic brain injury (TBI), the German Society for Neurosurgery (DGNC) and the German Society for Trauma Surgery (DGU) developed a TBI databank for German-speaking countries. METHODS: From 2016 to 2020, the TBI databank DGNC/DGU was implemented as a module of the TraumaRegister (TR) DGU and tested in a 15-month pilot phase. Since its official launch in 2021, patients from the TR-DGU (intermediate or intensive care unit admission via shock room) with TBI (AIS head ≥ 1) can be enrolled. A data set of > 300 clinical, imaging, and laboratory variables, harmonized with other international TBI data collection structures is documented, and the treatment outcome is evaluated after 6- and 12 months. RESULTS: For this analysis, 318 patients in the TBI databank could be included (median age 58 years; 71% men). Falls were the most common cause of injury (55%), and antithrombotic medication was frequent (28%). Severe or moderate TBI were only present in 55% of patients, while 45% suffered a mild injury. Nevertheless, intracranial pathologies were present in 95% of brain imaging with traumatic subarachnoid hemorrhages (76%) being the most common. Intracranial surgeries were performed in 42% of cases. In-hospital mortality after TBI was 21% and surviving patients could be discharged after a median hospital stay of 11 days. At the 6-and 12 months follow-up, a favorable outcome was achieved by 70% and 90% of the participating TBI patients, respectively. Compared to a European cohort of 2138 TBI patients treated in the ICU between 2014 and 2017, patients in the TBI databank were already older, frailer, fell more commonly at home. CONCLUSION: Within five years, the TBI databank DGNC/DGU of the TR-DGU could be established and is since then prospectively enrolling TBI patients in German-speaking countries. With its large and harmonized data set and a 12-month follow-up, the TBI databank is a unique project in Europe, already allowing comparisons to other data collection structures and indicating a demographic change towards older and frailer TBI patients in Germany.

Cranial CT is a mandatory tool to exclude asymptomatic cerebral hemorrhage in elderly patients on anticoagulation.

Background: Traumatic brain injury (TBI) after falls causes death and disability with immense socioeconomic impact through medical and rehabilitation costs in geriatric patients. Diagnosing TBI can be challenging due to the absence of initial clinical symptoms. Misdiagnosis is particularly dangerous in patients on permanent anticoagulation because minimal trauma might result in severe intracranial hemorrhage. The aim of this study is to evaluate the diagnostic necessity of cranial computed tomography (cCT) to rule out intracranial hemorrhage, particularly in the absence of neurologic symptoms in elderly patients on permanent anticoagulation in their premedication. Patients and methods: Retrospective cohort analysis of elderly trauma patients (≥ 65 years) admitted to the emergency department (ED) of the level-1-trauma center of the University Hospital Frankfurt from 01/2017 to 12/2019. The study included patients who suffered a ground-level fall with suspected TBI and subsequently underwent CT because of preexisting anticoagulation. Results: A total of 227 patients met the inclusion criteria. In 17 of these patients, cCT showed intracranial hemorrhage, of which 14 were subdural hematomas (SDH). In 8 of the patients with bleeding showed no clinical symptoms, representing 5% (n = 160) of all symptom-free patients. Men and women were equally to suffer a post-traumatic hemorrhage. Patients with intracranial bleeding were hospitalized for 14.5 (±10.4) days. Acetylsalicylic acid (ASA) was the most prescribed anticoagulant in both patient cohorts-with or without intracerebral bleeding (70.6 vs. 77.1%, p = 0.539). Similarly, patients taking new oral anticoagulant (NOAC) (p = 0.748), coumarins, or other platelet inhibitors (p > 0.1) did not show an increased bleeding incidence. Conclusion: Acetylsalicylic acid and NOAC use are not associated with increased bleeding risk in geriatric trauma patients (≥ 65 years) after fall-related TBI. Even in asymptomatic elderly patients on anticoagulation, intracranial hemorrhage occurs in a relevant proportion after minor trauma to the head. Therefore, cCT is an obligatory tool to rule out cerebral hemorrhage in elderly patients under anticoagulation.

Early start of thromboprophylaxis does not increase risk of intracranial hematoma progression in multiply injured patients with traumatic brain injury.

BACKGROUND: Venous thromboembolism (VTE) in severely injured patients with severe traumatic brain injury (TBI) is a risk during the clinical course. Data on the safety of an early initiation of pharmacological VTE prophylaxis in severely injured patients with concomitant severe TBI is sparse. METHODS: Admissions to our level-1-trauma center between January 2015 and December 2018 were screened. Patients suffering from severe TBI (Abbreviated Injury Scale (AIS) of the head ≥3) and at least one further AIS ≥ 3 in any other body region were included. Demographic data, thromboembolic events, and progression of the intracranial hemorrhage were extracted from the patient's charts. According to the first application of pharmacological thromboprophylaxis (VTEp), patients were categorized either to the early, the late (later than 24 h) or the no therapy group. RESULTS: In 79 patients (early: n = 35, late: n = 29, no therapy: n = 15) the Injury Severity Score (ISS) was 36.7 ± 12.7 points (AIShead 4.1 ± 0.8). No differences were found regarding the progression of the intracranial hemorrhage after initiation of the VTE prophylaxis (adj. p = 0.8). The VTE rate was low (n = 1, 1.6%). CONCLUSION: In severely injured patients with severe TBI, the early administration of pharmacological thromboprophylaxis did not result in a higher rate of intracranial hematoma progression.

Health Economic Challenge: Geriatric Trauma-An Age-Based Observational Analysis of Treatment Costs and Reimbursement Issues.

Demographic change is having a major impact on the economic and structural development of the healthcare system. People stay active longer and the number of mild traumatic brain injury [mTBI] in patients ≥ 65 years of age consequently increases. The aim of this comparative analysis is to illustrate the impact of demographic change and the increasing treatment of geriatric trauma patients on the cost structure of the health care system using mTBI as an example diagnosis. Patients and Methods: The 12-month retrospective analysis included 220 in-patients treated with mTBI and remunerated under the German Diagnosis Related Group [G-DRG] B80Z. For comparative analysis, the patient population was divided into two study groups according to age [U65 18−64 years, G65 ≥ 65 years]. For the cost and proceeds calculation, itemized cost reports (personnel, supply, material, and equipment costs, etc.) were created. Results: 163 patients U65 and 57 patients G65 were included. In the G65 group, the most frequent accident mechanism was a fall from a short distance (84.1 vs. U65 36.7%; p = 0.007). For the inpatient admission of G65, the use of anticoagulants (p < 0.001) and comorbidity (p = 0.002) played a primary role, while for younger patients it was more neurological symptoms (p < 0.001) and alcohol (p < 0.001) that led to inpatient monitoring. The mean length of hospitalization of G65 patients was significantly longer than that of younger patients (G65 2.4 ± 1.9 days > U65 1.7 ± 0.8 days; p = 0.007) and radiological examinations (G65 94.7% > U65 23.3%; p = 0.013) were performed more frequently. Comparing analysis of the cost and proceeds of U65 vs. G65 results in a proceeds difference of €51,753.91 per year for the G-DRG B80Z compared to U65. Conclusions: It has been shown that there is a difference in costs and proceeds when comparing younger and older patients, resulting in a reimbursement deficit. In view of the demographic development in Europe, flat-rate remuneration will lead to a considerable discrepancy between DRG reimbursement and the coverage of hospitals' running costs. Providing health care to an increasingly aging society represents one of the major personnel and financial challenges for the public health system in the coming decades. Further adaptation of the DRG system to the growing costs caused by older patients is imperative.

Influence of Antibiotic Management on Microbial Selection and Infectious Complications After Trauma.

Background: The inflammatory response and post-traumatic complications like infections play an important role in the pathophysiology of severe injuries. This study examines the microbiological aspects in anti-infective treatment of trauma patients and their inflammatory response in post-traumatic infections complications. Patients and Methods: A retrospective analysis of prospectively collected data in trauma patients (ISS ≥ 16) over a 1-year period (01/2018 to 12/2018) is provided. Patient population was stratified into severely injured patients without post-traumatic infection (inf-PT), and severely injured patients who developed an infection (inf+PT). Results: Of 114 trauma patients, 45 suffered from post-traumatic infection during the first 10 days of hospitalization. Severely injured patients with concomitant traumatic brain injury (PT+TBI) showed the highest rate of post-traumatic infection. Pro-inflammatory reaction was tracked by levels of Interleukin (IL-)6 (day 3: inf+T 190.8 ± 359.4 pg/dL > inf-PT 56.2 ± 57.7 pg/mL (mean ± SD); p = 0.008) and C-Reactive-Protein (CRP, day 3: inf+PT 15.3 mg/dL > inf-PT 6.7 mg/dL, p = 0.001) which were significantly higher in trauma patients who develop an infectious complication and showed a significant positive correlation with the occurrence of infection. The leading entity of infection was pneumonia followed by infections of the urinary tract mainly caused by gram-negative Enterobacteriaceae. 67.5% of all trauma patients received single-shot antibiosis during initial care in trauma bay. The development of secondary colonization was not relevant positively correlated with single-shot antibiosis (r = 0.013, p = 0.895) and prophylactically calculated antibiotic administration (r = 0.066, p = 0.500). Conclusion: Severely injured trauma patients have an increased risk for development of infectious complications, which mainly is pneumonia followed by infection of the urinary tract mainly caused by gram-negative Enterobacteriaceae. Based on the data in this study, the one-time antibiotic and prophylactic calculated use of antibiotics, like Cephalosporins must be critically discussed in terms of their role in the development of post-traumatic infections and microbial selection.

[Admission diagnosis contusion: etiology, epidemiology and cost-causing factors]. / Aufnahmediagnose Prellung: Ätiologie, Epidemiologie und Kostenfaktoren.

BACKGROUND: The admission of patients with minor injuries, such as contusions is a regular practice in acute care hospitals. The pathophysiological changes resulting from the accident are seldom the primary reason for hospitalization. The aim of this retrospective monocentric study was therefore to examine the etiology as well as the cost-causing factors and refinancing on admission. METHODS: Patients were identified due to a retrospective query in the hospital information system (HIS) according to the ICD-10 German modification codes at discharge. A total of 117 patients were enrolled over a period of 2 years. The classification was carried out according to the accident mechanism and the division into age groups. In addition, the cost calculation was based on department and clinic-specific daily rates. RESULTS: In terms of etiology low impact falls in the domestic environment were the most common cause (48.7%), followed by high-energy trauma (22.8%). Within the group with domestic falls, the mean age was 77.8 years. This group also showed the longest length of stay (LOS) with 5.2 days. As part of the calculated costs, the group of domestic falls showed the highest costs of 2596.24 € with an average DRG cost revenue of 1464.51 €. DISCUSSION: The evaluation of the clinic internal data confirmed the subjective perception that the majority of patients admitted with the diagnosis of contusions came from the age group >65 years. Admission is primarily based on the increasing comorbidities and to avert secondary diseases and the consequences of immobilization. It could also be shown that the resulting costs are relevant to health economics and that the treatment does not appear to cover the costs.

Registry-Based Mortality Analysis Reveals a High Proportion of Patient Decrees and Presumed Limitation of Therapy in Severe Geriatric Trauma.

BACKGROUND: The treatment of severely injured patients, especially in older age, is complex, and based on strict guidelines. METHODS: We conducted a retrospective study by analyzing our internal registry for mortality risk factors in deceased trauma patients. All patients that were admitted to the trauma bay of our level-1-trauma center from 2014 to 2018, and that died during the in-hospital treatment, were included. The aim of this study was to carry out a quality assurance concerning the initial care of severely injured patients. RESULTS: In the 5-year period, 135 trauma patients died. The median (IQR) age was 69 (38-83) years, 71% were male, and the median (IQR) Injury Severity Score (ISS) was 25 (17-34) points. Overall, 41% of the patients suffered from severe traumatic brain injuries (TBI) (AIShead ≥ 4 points). For 12.7%, therapy was finally limited owing to an existing patient's decree; in 64.9% with an uncertain prognosis, a 'therapia minima' was established in consensus with the relatives. CONCLUSION: Although the mortality rate was primarily related to the severity of the injury, a significant number of deaths were not exclusively due to medical reasons, but also to a self-determined limitation of therapy for severely injured geriatric patients. The conscientious documentation concerning the will of the patient is increasingly important in supporting medical decisions.

miR-142-3p Expression Is Predictive for Severe Traumatic Brain Injury (TBI) in Trauma Patients.

BACKGROUND: Predictive biomarkers in biofluids are the most commonly used diagnostic method, but established markers in trauma diagnostics lack accuracy. This study investigates promising microRNAs (miRNA) released from affected tissue after severe trauma that have predictive values for the effects of the injury. METHODS: A retrospective analysis of prospectively collected data and blood samples of n = 33 trauma patients (ISS ≥ 16) is provided. Levels of miR-9-5p, -124-3p, -142-3p, -219a-5p, -338-3p and -423-3p in severely injured patients (PT) without traumatic brain injury (TBI) or with severe TBI (PT + TBI) and patients with isolated TBI (isTBI) were measured within 6 h after trauma. RESULTS: The highest miR-423-3p expression was detected in patients with severe isTBI, followed by patients with PT + TBI, and lowest levels were found in PT patients without TBI (2-∆∆Ct, p = 0.009). A positive correlation between miR-423-3p level and increasing AIShead (p = 0.001) and risk of mortality (RISC II, p = 0.062) in trauma patients (n = 33) was found. ROC analysis of miR-423-3p levels revealed them as statistically significant to predict the severity of brain injury in trauma patients (p = 0.006). miR-124-3p was only found in patients with severe TBI, miR-338-3p was shown in all trauma groups. miR-9-5p, miR-142-3p and miR-219a-5p could not be detected in any of the four groups. CONCLUSION: miR-423-3p expression is significantly elevated after isolated traumatic brain injury and predictable for severe TBI in the first hours after trauma. miR-423-3p could represent a promising new biomarker to identify severe isolated TBI.

Severe Traumatic Brain Injury (TBI) Modulates the Kinetic Profile of the Inflammatory Response of Markers for Neuronal Damage.

The inflammatory response plays an important role in the pathophysiology of multiple injuries. This study examines the effects of severe trauma and inflammatory response on markers of neuronal damage. A retrospective analysis of prospectively collected data in 445 trauma patients (Injury Severity Score (ISS) ≥ 16) is provided. Levels of neuronal biomarkers (calcium-binding Protein B (S100b), Enolase2 (NSE), glial fibrillary acidic protein (GFAP)) and Interleukins (IL-6, IL-10) in severely injured patients (with polytrauma (PT)) without traumatic brain injury (TBI) or with severe TBI (PT+TBI) and patients with isolated TBI (isTBI) were measured upon arrival until day 5. S100b, NSE, GFAP levels showed a time-dependent decrease in all cohorts. Their expression was higher after multiple injuries (p = 0.038) comparing isTBI. Positive correlation of marker level after concomitant TBI and isTBI (p = 0.001) was noted, while marker expression after PT appears to be independent. Highest levels of IL-6 and -10 were associated to PT und lowest to isTBI (p < 0.001). In all groups pro-inflammatory response (IL-6/-10 ratio) peaked on day 2 and at a lower level on day 4. Severe TBI modulates kinetic profile of inflammatory response by reducing interleukin expression following trauma. Potential markers for neuronal damage have a limited diagnostic value after severe trauma because undifferentiated increase.

[Inpatient treatment costs, cost-driving factors and potential reimbursement problems due to fall-related fractures in patients with Parkinson's disease]. / Stationäre Versorgungskosten, kostenverursachende Faktoren und potenzielle Vergütungsprobleme bei durch Morbus Parkinson bedingten Frakturen.

BACKGROUND: In an increasingly economically oriented healthcare system the analysis of disease-specific costs is becoming more and more relevant, especially in chronic diseases with long duration of hospitalization. As a frequent neurodegenerative disease idiopathic Parkinson's disease (IPD) causes high healthcare costs. The pathognomonic affection of mobility and equilibrium often leads to fall-related fractures in the course of the disease, which cause further costs through hospitalization and possibly surgical treatment. OBJECTIVE: The aim of the study was the calculation of inpatient treatment costs of fall-related fractures in IPD as well as the analysis of relevant cost-causing factors. In addition, an alternative calculation of the treatment costs was carried out with the question of potential remuneration problems in the current diagnosis-related groups (DRG) system. METHODS: The basis of this retrospective, single center analysis was the actual revenue of 95 patients treated between January 2011 and January 2018 at the University Hospital Frankfurt am Main. The proceeds were systematically reviewed for relevant demographic, healthcare and disease-related aspects and statistically analyzed for cost-related factors using univariate analysis. The alternative calculation of the treatment costs was carried out according to commonly used health economics methods. RESULTS: The median revenue per patient and injury was 9295 € (±8038 €, median 7148 €) with a mean length of stay of 13.5 days (±7.2 days, median 13 days). The alternative calculation of treatment costs per patient was an average of 9789 € (±6423 €, median 8906 €). High treatment costs were associated with age >75 years (p = 0.028), surgical treatment (p = 0.004), intensive care unit (ICU) stay (p = 0.004), limb fractures (p = 0.028) and an advanced stage of IPD (p = 0.028). Significant differences between actual revenue and calculated costs were found for hospital stays ≥14 days (p = 0.009) and advanced stages of disease (p = 0.036). CONCLUSION: The costs of care in patients with IPD and fall-related fractures are high and relevant to health economics. In general, remuneration based on the DRG system seems to largely cover the costs; however, compensation problems arise especially for patients with a long duration of hospitalization or advanced IPD.

Simvastatin exerts anticancer effects in osteosarcoma cell lines via geranylgeranylation and c-Jun activation.

Osteosarcoma is the leading primary bone cancer in young adults and exhibits high chemoresistance rates. Therefore, characterization of both alternative treatment options and the underlying mechanisms is essential. Simvastatin, a cholesterol-lowering drug, has among its pleiotropic effects anticancer potential. Characterizing this potential and the underlying mechanisms in osteosarcoma is the subject of the present study. Human osteosarcoma cells (SaOS-2 and U2OS) were treated with simvastatin (4-66 µM) for 48 or 72 h. The effects of downstream substrate mevalonate (MA) or substrates for isoprenylation farnesyl pyrophosphate (FPP) and geranylgeranyl-pyrophosphate (GGPP) were evaluated using add-back experiments. Tumour growth using MTT assay, apoptosis, cell cycle and signalling cascades involved in simvastatin-induced manipulation were analysed. The results revealed that simvastatin dose-dependently inhibited cell growth. Simvastatin significantly induced apoptosis, increased the Bax/Bcl-2 ratio, and cleavage of caspase-3 and PARP protein. Simvastatin impaired cell cycle progression as shown by significantly increased percentages of cells in the G0/G1 phase and lower percentages of cells in the S phase. Gene expression levels of cell cycle-regulating genes (TP53, CDKN1A and CDK1) were markedly altered. These effects were not completely abolished by FPP, but were reversed by MA and GGPP. JNK and c-Jun phosphorylation was enhanced after simvastatin treatment, while those were abolished when either MA or GGPP were added. In conclusion, simvastatin acts primarily by reducing prenylation to induce apoptosis and reduce osteosarcoma cell growth. Particularly enhanced activation of c-Jun seems to play a pivotal role in osteosarcoma cell death.

Early decreased TLR2 expression on monocytes is associated with their reduced phagocytic activity and impaired maturation in a porcine polytrauma model.

In their post-traumatic course, trauma patients suffering from multiple injuries have a high risk for immune dysregulation, which may contribute to post-injury complications and late mortality. Monocytes as specific effector cells of the innate immunity play a crucial role in inflammation. Using their Pattern Recognition Receptors (PRRs), notably Toll-Like Receptors (TLR), the monocytes recognize pathogens and/or pathogen-associated molecular patterns (PAMPs) and organize their clearance. TLR2 is the major receptor for particles of gram-positive bacteria, and initiates their phagocytosis. Here, we investigated the phagocytizing capability of monocytes in a long-term porcine severe trauma model (polytrauma, PT) with regard to their TLR2 expression. Polytrauma consisted of femur fracture, unilateral lung contusion, liver laceration, hemorrhagic shock with subsequent resuscitation and surgical fracture fixation. After induction of PT, peripheral blood was withdrawn before (-1 h) and directly after trauma (0 h), as well as 3.5 h, 5.5 h, 24 h and 72 h later. CD14+ monocytes were identified and the expression levels of H(S)LA-DR and TLR2 were investigated by flow cytometry. Additionally, the phagocytizing activity of monocytes by applying S. aureus particles labelled with pHrodo fluorescent reagent was also assessed by flow cytometry. Furthermore, blood samples from 10 healthy pigs were exposed to a TLR2-neutralizing antibody and subsequently to S. aureus particles. Using flow cytometry, phagocytizing activity was determined. P below 0.05 was considered significant. The number of CD14+ monocytes of all circulating leukocytes remained constant during the observational time period, while the percentage of CD14+H(S)LA-DR+ monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of TLR2+ expressing cells out of all monocytes significantly decreased directly, 3.5 h and 5.5 h after trauma. The percentage of phagocytizing monocytes decreased immediately and remained lower during the first 3.5 h after trauma, but increased after 24 h. Antagonizing TLR2 significantly decreased the phagocytizing activity of monocytes. Both, decreased percentage of activated as well as TLR2 expressing monocytes persisted as long as the reduced phagocytosis was observed. Moreover, neutralizing TLR2 led to a reduced capability of phagocytosis as well. Therefore, we assume that reduced TLR2 expression may be responsible for the decreased phagocytizing capacity of circulating monocytes in the early post-traumatic phase.

Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway.

BACKGROUND/AIMS: Alcohol (ethanol, EtOH) as significant contributor to traumatic injury is linked to suppressed inflammatory response, thereby influencing clinical outcomes. Alcohol-induced immune-suppression during acute inflammation (trauma) was linked to nuclear factor-kappaB (NF-ĸB). Here, we analyzed alcohol`s effects and mechanisms underlying its influence on NF-ĸB-signaling during acute inflammation in human lung epithelial cells. METHODS: A549-cells were stimulated with interleukin (IL)-1ß, or sera from trauma patients (TP) or healthy volunteers, with positive/negative blood alcohol concentrations (BAC), and subsequently exposed to EtOH (170 Mm, 1h). IL-6-release and neutrophil adhesion to A549 were analyzed. Specific siRNA-NIK mediated downregulation of non-canonical, and IKK-NBD-inhibition of canonical NF-ĸB signaling were performed. Nuclear levels of activated p50 and p52 NF-ĸB-subunits were detected using TransAm ELISA. RESULTS: Both stimuli significantly induced IL-6-release (39.79±4.70 vs. 0.58±0.8 pg/ml) and neutrophil adhesion (132.30±8.80 vs. 100% control, p<0.05) to A549-cells. EtOH significantly decreased IL-6-release (22.90±5.40, p<0.05) and neutrophil adherence vs. controls (105.40±14.5%, p<0.05). IL-1ß-induced significant activation of canonical/p50 and non-canonical/p52 pathways. EtOH significantly reduced p50 (34.90±23.70 vs. 197.70±36.43, p<0.05) not p52 activation. Inhibition of canonical pathway was further increased by EtOH (less p50-activation), while p52 remained unaltered. Inhibition of non-canonical pathway was unchanged by EtOH. CONCLUSION: Here, alcohol`s anti-inflammatory effects are mediated via decreasing nuclear levels of activated p50-subunit and canonical NF-ĸB signaling pathway.

Impaired Surface Expression of HLA-DR, TLR2, TLR4, and TLR9 in Ex Vivo-In Vitro Stimulated Monocytes from Severely Injured Trauma Patients.

Objective. Trauma patients (TP) frequently develop an imbalanced immune response that often causes infectious postinjury complications. Monocytes show a diminished capability of both producing proinflammatory cytokines and antigen presentation after trauma. TLR2, TLR4, and TLR9 recognize pathogens and subsequently activate monocytes. While there are conflictive data about TLR2 and TLR4 expression after trauma, no studies about the expression of TLR2, TLR4, TLR9, and HLA-DR on monocytes from TP after their secondary ex vivo-in vitro "hit" have been reported. Methods/Results. Ex vivo-in vitro lipopolysaccharide- (LPS-) stimulated blood from TP showed diminished interleukin- (IL-) 1ß-release in TP for five postinjury days compared to healthy volunteers (HV). The recovery was observed at day 5. In parallel, monocytes from TP showed an impaired capability of TLR2, TLR4, and TLR9 expression after secondary stimulation compared to HV, while the measurement of unstimulated samples showed significant reduction of TLR4 and TLR9 at ED. Furthermore, HLA-DR decreased after trauma and was even more profound by stimulation of monocytes. Ratio of monocytes to leukocytes was significantly increased at days 6 and 7 after trauma compared to HV. Conclusion. Impaired expression of TLRs and HLA-DR in acute inflammatory conditions may be responsible for the well-described monocyte paralysis after severe trauma.

Simvastatin Reduces Cancerogenic Potential of Renal Cancer Cells via Geranylgeranyl Pyrophosphate and Mevalonate Pathway.

Simvastatin is a cholesterol-lowering drug, inhibiting 3-hydroxy-3-methylglutaryl-coenzyme CoA (HMG-CoA) reductase. Previous studies have indicated the anticancerous effects of simvastatin. Here, we evaluated the anticancerous potential of simvastatin in renal cell carcinoma (RCC) cell lines. RCC occurs with an incidence of 2-3% of all cancer entities with high chemoresistance rate. Therefore, the understanding of underlying mechanisms for RCC activity and the development of alternative therapies are essential. Human RCC cell lines Caki-1 and KTC-26 were treated with simvastatin (16 or 33 µM) for 48 or 72 h. The effects of the downstream substrates mevalonate (MA), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) were evaluated using add-back experiments. Cell growth was assessed using MTT assay. Apoptosis and cell cycle were analyzed by flow cytometry. Apoptosis-involved proteins were evaluated by Western blot. Simvastatin caused dose- and time-dependent inhibition of RCC cell growth by cell cycle arrest and apoptosis induction. Substitution of MA or GGPP abolished these effects to a large extent. These findings suggest that the antiproliferative effects of simvastatin are not only mediated through cholesterol deprivation but also by prenylation-associated mechanisms, thereby providing new insights into tumor-suppressive ability of simvastatin and into novel additive treatment options in the management of RCC.