@article{PaulMiedenLeferingetal.2023,
  author    = {Paul, Mila M. and Mieden, Hannah J. and Lefering, Rolf and Kupczyk, Eva K. and Jordan, Martin C. and Gilbert, Fabian and Meffert, Rainer H. and Sir{\´e}n, Anna-Leena and Hoelscher-Doht, Stefanie},
  title     = {Impact of a femoral fracture on outcome after traumatic brain injury — a matched-pair analysis of the TraumaRegister DGU\(^®\)},
  series = {Journal of Clinical Medicine},
  volume    = {12},
  journal   = {Journal of Clinical Medicine},
  number    = {11},
  issn      = {2077-0383},
  doi       = {10.3390/jcm12113802},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319363},
  year      = {2023},
  abstract  = {Traumatic brain injury (TBI) is the leading cause of death and disability in polytrauma and is often accompanied by concomitant injuries. We conducted a retrospective matched-pair analysis of data from a 10-year period from the multicenter database TraumaRegister DGU\(^®\) to analyze the impact of a concomitant femoral fracture on the outcome of TBI patients. A total of 4508 patients with moderate to critical TBI were included and matched by severity of TBI, American Society of Anesthesiologists (ASA) risk classification, initial Glasgow Coma Scale (GCS), age, and sex. Patients who suffered combined TBI and femoral fracture showed increased mortality and worse outcome at the time of discharge, a higher chance of multi-organ failure, and a rate of neurosurgical intervention. Especially those with moderate TBI showed enhanced in-hospital mortality when presenting with a concomitant femoral fracture (p = 0.037). The choice of fracture treatment (damage control orthopedics vs. early total care) did not impact mortality. In summary, patients with combined TBI and femoral fracture have higher mortality, more in-hospital complications, an increased need for neurosurgical intervention, and inferior outcome compared to patients with TBI solely. More investigations are needed to decipher the pathophysiological consequences of a long-bone fracture on the outcome after TBI.},
  language  = {en}
}
@article{SunBlecharzLangMałeckietal.2022,
  author    = {Sun, Aili and Blecharz-Lang, Kinga G. and Małecki, Andrzej and Meybohm, Patrick and Nowacka-Chmielewska, Marta M. and Burek, Malgorzata},
  title     = {Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro},
  series = {Frontiers in Drug Delivery},
  volume    = {2},
  journal   = {Frontiers in Drug Delivery},
  issn      = {2674-0850},
  doi       = {10.3389/fddev.2022.1027098},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291423},
  year      = {2022},
  abstract  = {The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases.},
  language  = {en}
}
@article{ZwirnerBohnertFrankeetal.2021,
  author    = {Zwirner, Johann and Bohnert, Simone and Franke, Heike and Garland, Jack and Hammer, Niels and M{\"o}bius, Dustin and Tse, Rexson and Ondruschka, Benjamin},
  title     = {Assessing protein biomarkers to detect lethal acute traumatic brain injuries in cerebrospinal fluid},
  series = {Biomolecules},
  volume    = {11},
  journal   = {Biomolecules},
  number    = {11},
  issn      = {2218-273X},
  doi       = {10.3390/biom11111577},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248587},
  year      = {2021},
  abstract  = {Diagnosing traumatic brain injury (TBI) from body fluids in cases where there are no obvious external signs of impact would be useful for emergency physicians and forensic pathologists alike. None of the previous attempts has so far succeeded in establishing a single biomarker to reliably detect TBI with regards to the sensitivity: specificity ratio in a post mortem setting. This study investigated a combination of body fluid biomarkers (obtained post mortem), which may be a step towards increasing the accuracy of biochemical TBI detection. In this study, serum and cerebrospinal fluid (CSF) samples from 30 acute lethal TBI cases and 70 controls without a TBI-related cause of death were evaluated for the following eight TBI-related biomarkers: brain-derived neurotrophic factor (BDNF), ferritin, glial fibrillary acidic protein (GFAP), interleukin 6 (IL-6), lactate dehydrogenase, neutrophil gelatinase-associated lipocalin (NGAL), neuron-specific enolase and S100 calcium-binding protein B. Correlations among the individual TBI biomarkers were assessed, and a specificity-accentuated threshold value analysis was conducted for all biomarkers. Based on these values, a decision tree modelling approach was performed to assess the most accurate biomarker combination to detect acute lethal TBIs. The results showed that 92.45\% of acute lethal TBIs were able to be diagnosed using a combination of IL-6 and GFAP in CSF. The probability of detecting an acute lethal TBI was moderately increased by GFAP alone and considerably increased by the remaining biomarkers. BDNF and NGAL were almost perfectly correlated (p = 0.002; R\(^2\) = 0.944). This study provides evidence that acute lethal TBIs can be detected to a high degree of statistical accuracy using forensic biochemistry. The high inter-individual correlations of biomarkers may help to estimate the CSF concentration of an unknown biomarker, using extrapolation techniques.},
  language  = {en}
}
@article{HoppAlbertWeissenberger2015,
  author    = {Hopp, Sarah and Albert-Weissenberger, Christiane},
  title     = {The kallikrein-kinin system: a promising therapeutic target for traumatic brain injury},
  series = {Neural Regeneration Research},
  volume    = {10},
  journal   = {Neural Regeneration Research},
  number    = {6},
  doi       = {10.4103/1673-5374.158339},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149416},
  pages     = {885-886},
  year      = {2015},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{SalvadorBurekFoerster2015,
  author    = {Salvador, Ellaine and Burek, Malgorzata and F{\"o}rster, Carola Y.},
  title     = {Stretch and/or oxygen glucose deprivation (OGD) in an in vitro traumatic brain injury (TBI) model induces calcium alteration and inflammatory cascade},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {9},
  journal   = {Frontiers in Cellular Neuroscience},
  number    = {323},
  doi       = {10.3389/fncel.2015.00323},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-148255},
  year      = {2015},
  abstract  = {The blood-brain barrier (BBB), made up of endothelial cells of capillaries in the brain, maintains the microenvironment of the central nervous system. During ischemia and traumatic brain injury (TBI), cellular disruption leading to mechanical insult results to the BBB being compromised. Oxygen glucose deprivation (OGD) is the most commonly used in vitro model for ischemia. On the other hand, stretch injury is currently being used to model TBI in vitro. In this paper, the two methods are used alone or in combination, to assess their effects on cerebrovascular endothelial cells cEND in the presence or absence of astrocytic factors. Applying severe stretch and/or OGD to cEND cells in our experiments resulted to cell swelling and distortion. Damage to the cells induced release of lactate dehydrogenase enzyme (LDH) and nitric oxide (NO) into the cell culture medium. In addition, mRNA expression of inflammatory markers interleukin (I L)-6, IL-1\(\alpha\) chemokine (C-C motif) ligand 2 (CCL2) and tumor necrosis factor (TNF)-\(\alpha\) also increased. These events could lead to the opening of calcium ion channels resulting to excitotoxicity. This could be demonstrated by increased calcium level in OGD-subjected cEND cells incubated with astrocyte-conditioned medium. Furthermore, reduction of cell membrane integrity decreased tight junction proteins claudin-5 and occludin expression. In addition, permeability of the endothelial cell monolayer increased. Also, since cell damage requires an increased uptake of glucose, expression of glucose transporter glut1 was found to increase at the mRNA level after OGD. Overall, the effects of OGD on cEND cells appear to be more prominent than that of stretch with regards to TJ proteins, NO, glutl expression, and calcium level. Astrocytes potentiate these effects on calcium level in cEND cells. Combining both methods to model TBI in vitro shows a promising improvement to currently available models.},
  language  = {en}
}
@phdthesis{Oerter2018,
  author    = {Oerter, Sabrina},
  title     = {Expression von Natrium/Glukose-Cotransportern im menschlichen Gehirn bei Todesf{\"a}llen durch Sch{\"a}del-Hirn-Trauma und Todesf{\"a}llen durch Ersticken},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164093},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Glukosetransporter spielen eine wichtige Rolle in der Versorgung des Gehirns mit N{\"a}hrstoffen und somit f{\"u}r den Erhalt der physiologischen Zellintegrit{\"a}t. Glukose wird {\"u}ber die Blut-Hirn-Schranke (BHS) mittels spezifischen transmembranen Transportproteinen der SLC-Genfamilie (GLUT, SGLT) bef{\"o}rdert. Dabei scheint w{\"a}hrend physiologischen Bedingungen haupts{\"a}chlich der Glukosetransporter GLUT1 (SLC2A1) f{\"u}r die Energieversorgung des Gehirns zust{\"a}ndig zu sein. Die Erforschung der SGLT-Expression ist in den letzten Jahren ein wichtiger Ansatzpunkt f{\"u}r neue Behandlungsstrategien vieler Erkrankungen, wie Diabetes Mellitus, maligne Neoplasien oder eines Herzinfarkts, geworden. Jedoch ist {\"u}ber deren Expression und Funktion im menschlichen Gehirn nur wenig bekannt. Besonders die Lokalisation entlang der BHS bleibt fraglich. Ein Großteil bisheriger Forschungsarbeiten besch{\"a}ftigt sich haupts{\"a}chlich mit der Expressionsanalyse des Transporters SGLT1 im tierischen Gehirn in vivo (Poppe et al. 1997; Balen et al. 2008; Yu et al. 2013). Es konnte aufgezeigt werden, dass SGLT1 mRNA exklusiv in Neuronen und nicht an der BHS exprimiert wird. Dies wird durch in vitro Analysen einer humanen Hirnendothelzelllinie best{\"a}tigt. Demnach kann kein SGLT1 unter physiologischen Bedingungen nachgewiesen werden (Sajja et al. 2014). Im menschlichen Hirngewebe besitzen SGLTs somit keine zentrale Funktion f{\"u}r den Glukosetransport an der BHS. Im Gegensatz dazu konnte eine Expression von SGLT sowohl in vivo als auch in vitro w{\"a}hrend hypoglyk{\"a}mischen Bedingungen belegt werden (Vemula et al. 2009; Sajja et al. 2014). Die Expression der SGLT-Transporter w{\"a}hrend einer isch{\"a}mischen Hypoglyk{\"a}mie f{\"u}hrt zu der Annahme, dass diese Transporter f{\"u}r die Aufrechterhaltung der Energieversorgung des gesch{\"a}digten Hirngewebes notwendig sind. Um die physiologischen Mechanismen nach einem Glukosemangel zu untersuchen, wurden SHT-Modelle etabliert (Salvador et al. 2013). In einem experimentellen Modell des Sch{\"a}del-Hirn-Traumas im Rahmen eines DFG-gef{\"o}rdertes Projekts ist ein Expressionsverlauf von Glukosetransportern im Maushirn und in Hirnendothelzellen erarbeitet worden (Wais 2012; Salvador et al. 2015). Somit k{\"o}nnten SGLTs als Ansatzpunkt f{\"u}r den Nachweis der {\"U}berlebenszeit nach einem SHT fungieren. Die vorliegende Arbeit fokussiert sich auf die Expression der Natrium-abh{\"a}ngigen Glukosetransporter SGLT1 und SGLT2 im menschlichen Gehirn. Hierbei liegt das Hauptaugenmerk auf der Lokalisation dieser Transporter an der menschlichen BHS von post mortalem Hirngewebe. Weiterhin wird untersucht ob die Expressionsst{\"a}rke von SGLT1 und SGLT2 eine Aussage {\"u}ber die {\"U}berlebenszeit von Verstorbenen nach einer traumatisch bedingten Hirnver{\"a}nderung zul{\"a}sst. Die Lokalisation von SGLT1 und SGLT2 an der menschlichen BHS konnte durch die Etablierung eines Protokolls zur Isolation von Hirnkapillaren erfolgen. Vorab wurden alle verwendeten Antik{\"o}rper auf ihre Spezifit{\"a}t mittels siRNA Transfektion und Blockierung der Immunfluoreszenzsignale mittels immunisierten Peptids getestet. Somit ist die Spezifit{\"a}t der detektierten SGLT1- und SGLT2-Expression in menschlichen Hirnkapillaren gew{\"a}hrleistet. Anschließend wird untersucht, in welchen zeitlichem Verlauf nach einer traumatisch bedingten Hirnver{\"a}nderung die verschiedenen Formen der Glukosetransporter exprimiert werden und ob ggf. der Umfang und die Verteilung von SGLT1, SGLT2 und GLUT1 sowie das Verh{\"a}ltnis zueinander Ausk{\"u}nfte {\"u}ber eine vitale bzw. postmortale Entstehung eines Traumas bzw. dessen {\"U}berlebenszeit zul{\"a}sst. Hierf{\"u}r wird ein Expressionsschema der Glukosetransporter generiert, abh{\"a}ngig von Todeszeitpunkt und Todesursache. Es konnte festgestellt werden, dass GLUT1 nicht als Target f{\"u}r die Ermittlung der {\"U}berlebenszeit nach einem Trauma geeignet ist. Dahingegen zeigen SGLT1 und SGLT2 eine signifikante {\"A}nderung der Expressionsst{\"a}rke im contusionalen Gewebe in Abh{\"a}ngigkeit von der {\"U}berlebenszeit. Obwohl diese vorl{\"a}ufigen Daten einen neuen Ansatzpunkt f{\"u}r die forensische Fragestellung aufzeigen, m{\"u}ssen weitere Experimente mit einem erh{\"o}hten Umfang der Probenanzahl und k{\"u}rzere Zeitspannen der {\"U}berlebenszeitr{\"a}ume durchgef{\"u}hrt werden.},
  subject      = {Sodium-Glucose Transporter 2},
  language  = {de}
}
@article{MinnerupSutherlandBuchanetal.2012,
  author    = {Minnerup, Jens and Sutherland, Brad A. and Buchan, Alastair M. and Kleinschnitz, Christoph},
  title     = {Neuroprotection for Stroke: Current Status and Future Perspectives},
  series = {International Journal of Molecular Science},
  volume    = {13},
  journal   = {International Journal of Molecular Science},
  number    = {9},
  doi       = {10.3390/ijms130911753},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134730},
  pages     = {11753-11772},
  year      = {2012},
  abstract  = {Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.},
  language  = {en}
}
@article{AlbertWeissenbergerMenclSchuhmannetal.2014,
  author    = {Albert-Weissenberger, Christiane and Mencl, Stine and Schuhmann, Michael K. and Salur, Irmak and G{\"o}b, Eva and Langhauser, Friederike and Hopp, Sarah and Hennig, Nelli and Meuth, Sven G. and Nolte, Marc W. and Sir{\´e}n, Anna-Leena and Kleinschnitz, Christoph},
  title     = {C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00269},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119263},
  pages     = {269},
  year      = {2014},
  abstract  = {Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75\% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.},
  language  = {en}
}
@article{NeuhausGaiserMahringeretal.2014,
  author    = {Neuhaus, Winfried and Gaiser, Fabian and Mahringer, Anne and Franz, Jonas and Riethm{\"u}ller, Christoph and F{\"o}rster, Carola},
  title     = {The pivotal role of astrocytes in an in vitro stroke model of the blood-brain barrier},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00352},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118297},
  pages     = {352},
  year      = {2014},
  abstract  = {Stabilization of the blood-brain barrier during and after stroke can lead to less adverse outcome. For elucidation of underlying mechanisms and development of novel therapeutic strategies validated in vitro disease models of the blood-brain barrier could be very helpful. To mimic in vitro stroke conditions we have established a blood-brain barrier in vitro model based on mouse cell line cerebEND and applied oxygen/glucose deprivation (OGD). The role of astrocytes in this disease model was investigated by using cell line C6. Transwell studies pointed out that addition of astrocytes during OGD increased the barrier damage significantly in comparison to the endothelial monoculture shown by changes of transendothelial electrical resistance as well as fluorescein permeability data. Analysis on mRNA and protein levels by qPCR, western blotting and immunofluorescence microscopy of tight junction molecules claudin-3,-5,-12, occludin and ZO-1 revealed that their regulation and localisation is associated with the functional barrier breakdown. Furthermore, soluble factors of astrocytes, OGD and their combination were able to induce changes of functionality and expression of ABC-transporters Abcb1a (P-gp), Abcg2 (bcrp), and Abcc4 (mrp4). Moreover, the expression of proteases (matrixmetalloproteinases MMP-2, MMP-3, MMP-9, and t-PA) as well as of their endogenous inhibitors (TIMP-1, TIMP-3, PAI-1) was altered by astrocyte factors and OGD which resulted in significant changes of total MMP and t-PA activity. Morphological rearrangements induced by OGD and treatment with astrocyte factors were confirmed at a nanometer scale using atomic force microscopy. In conclusion, astrocytes play a major role in blood-brain barrier breakdown during OGD in vitro.},
  language  = {en}
}
@article{AlbertWeissenbergerMenclHoppetal.2014,
  author    = {Albert-Weissenberger, Christiane and Mencl, Stine and Hopp, Sarah and Kleinschnitz, Christoph and Siren, Anna-Leena},
  title     = {Role of the kallikrein-kinin system in traumatic brain injury},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00345},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118226},
  pages     = {345},
  year      = {2014},
  abstract  = {Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite improvements in acute intensive care, there are currently no specific therapies to ameliorate the effects of TBI. Successful therapeutic strategies for TBI should target multiple pathophysiologic mechanisms that occur at different stages of brain injury. The kallikrein-kinin system is a promising therapeutic target for TBI as it mediates key pathologic events of traumatic brain damage, such as edema formation, inflammation, and thrombosis. Selective and specific kinin receptor antagonists and inhibitors of plasma kallikrein and coagulation factor XII have been developed, and have already shown therapeutic efficacy in animal models of stroke and TBI. However, conflicting preclinical evaluation, as well as limited and inconclusive data from clinical trials in TBI, suggests that caution should be taken before transferring observations made in animals to humans. This review summarizes current evidence on the pathologic significance of the kallikrein-kinin system during TBI in animal models and, where available, the experimental findings are compared with human data.},
  language  = {en}
}