Anna L. Sander

Epoxyeicosatrienoic Acids Regulate Trp Channel–Dependent Ca2+ Signaling and Hyperpolarization in Endothelial Cells

Objective—An initial step in endothelium-derived hyperpolarizing factor-mediated responses is endothelial cell hyperpolarization. Here we address the mechanisms by which cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) contribute to this effect in native and cultured endothelial cells. Methods and Results—In native CYP2C-expressing endothelial cells, bradykinin elicited a Ca2+ influx that was potentiated by the soluble epoxide hydrolase inhibitor, 1-adamantyl-3-cyclohexylurea (ACU), and attenuated by CYP inhibition. Similar effects were observed in cultured endothelial cells overexpressing CYP2C9, but not in CYP2C9-deficient cells, and were prevented by the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid as well as by the cAMP antagonist, Rp-cAMPS. The effects on Ca2+ were mirrored by prolongation of the bradykinin-induced hyperpolarization. Ruthenium red and the combination of charybdotoxin and apamin prevented the latter effect, suggesting that Trp channel activation increases Ca2+ influx and prolongs the activation of Ca2+-dependent K+ (KCa) channels. Indeed, overexpression of CYP2C9 enhanced the agonist-induced translocation of a TrpC6-V5 fusion protein to caveolin-1–rich areas of the endothelial cell membrane, which was prevented by Rp-cAMPS and mimicked by 11,12-EET. Conclusions—Elevated EET levels regulate Ca2+ influx into endothelial cells and the subsequent activation of KCa channels, via a cAMP/PKA-dependent mechanism that involves the intracellular translocation of Trp channels.

In vivo effect of hyperbaric oxygen on wound angiogenesis and epithelialization

Hyperbaric oxygen (HBO) therapy is increasingly being used in different areas of medical practice. While demonstrated to be effective in several settings, its mechanism of action is not well understood. In the present study, we determined the effects of HBO on wound epithelialization and neovascularization in an in vivo hairless mouse ear “impaired” wound model. To impair wound healing, macrophages were depleted by pretreatment with iota‐carrageenan. Wound epithelialization and neovascularization were measured using intravital microscopy and computerized planimetry. Metalloproteinase‐2 (MMP‐2), MMP‐9, tissue inhibitor of metalloproteinase‐1 (TIMP‐1), and tumor necrosis factor‐α (TNF‐α) were measured on days 2 and 7 using immunohistochemistry. In nonimpaired healing wounds, the rate of epithelialization and neovascularization was significantly accelerated in the groups treated with HBO. Time to wound closure was significantly delayed in impaired compared with nonimpaired healing wounds and HBO treatment completely reversed this delay. Neither HBO treatment nor macrophage depletion caused significant alterations in MMP‐2 expression in wounds. In contrast, TNF‐α, MMP‐9, and TIMP‐1 were significantly up‐regulated in the impaired healing group receiving HBO treatment. These results show that HBO therapy effectively reversed the negative effect exerted by macrophage reduction on wound epithelialization and neovascularization. This beneficial effect could be due to stimulation of TNF‐α production and, to a lesser degree due to release of metalloproteinases.

Pediatric Polytrauma Management

Caring for pediatric trauma patients requires an understanding of the distinct anatomy and pathophysiology of the pediatric population compared to adult trauma patients. Initial evaluation, management, and resuscitation are performed as a multidisciplinary approach including pediatric physicians, trauma surgeons, and pediatric intensive care physicians. Head injury severity is the principle determinant of outcome and mortality in polytraumatized children. Abdominal injuries rarely require surgery in contrast to adults, but need to be detected. Spine and pelvic injuries as well as injuries of the extremities require age-adapted surgical procedures. However, the degree of recovery in polytraumatized children is often remarkable, even after apparently devastating injuries. Maximal care should, therefore, be rendered under the assumption that a complete recovery will be made.

Effects of acute ethanol gavage on intestinal integrity after hemorrhage/resuscitation

Abstract Background. In hemorrhagic shock with subsequent resuscitation (H/R), increased pro-inflammatory changes contribute to tissue injury and mortality in rodent models. Ethanol (EtOH) is assumed to modulate the inflammatory response and the subsequent organ injury after H/R. Therefore, we determined the contribution of acute ethanol gavage on intestinal inflammation and injury as well as survival after H/R in rats. Methods. Fourteen hours before H/R, female LEWIS rats were gavaged with single dose of EtOH or saline (5 g/kg, 30% EtOH, H/R_EtOH group or H/R_ctrl group). Then, rats were hemorrhaged to a mean arterial blood pressure of 30 ± 2 mmHg for 60 min and resuscitated. Control groups underwent surgical procedures and gavage without H/R (sham_ctrl group and sham_EtOH group). Tissue was harvested 2 h after resuscitation. Mortality was assessed 72 h after H/R. Results. Ethanol gavage increased survival after H/R from 20% to 80%, but amplified plasma alanineaminotransferase (ALT) release compared to saline gavage (2847 ± 406 vs. 1159 ± 200 IU/L, p < 0.05). Intestinal mucosal damage index, intestinal permeability, ileal myeloperoxidase levels as indicators of polymorphonuclear leukocyte (PMNL) infiltration and systemic IL-6 levels as well as ileal IL-6 and TNF gene expressions after H/R were reduced and partly restored after ethanol gavage when compared to the saline gavaged group after H/R. Conclusions. Taken together, we propose that acute ethanol gavage prior to H/R 1) did not enhance intestinal mucosa injury after H/R and 2) suppressed the H/R-induced inflammatory response. Both findings seem to contribute to the ethanol-induced survival benefit after H/R in our model.

A Clinically Useful Classification of Traumatic Intervertebral Disk Lesions

OBJECTIVE Lesions of the intervertebral disk accompanying vertebral fractures are the subject of controversy regarding the extent of surgical intervention, in part due to the lack of a comprehensive classification. The purpose of this study is to present a novel and clinically useful classification system for traumatic disk lesions after vertebral fractures. MATERIALS AND METHODS MRI of 204 disks in 102 patients with trauma-induced single-level thoracolumbar fractures referred to our trauma center between 2007 and 2011 were analyzed retrospectively. Exclusion criteria were malignant vertebral collapse, spondylodiskitis, osteoporotic fractures, and degenerative disk disease in the uninjured disks. Morphologic changes and signal alterations of the adjacent disks were determined using routine MRI of these patients and a grading system was developed. Disks were divided according to their signals into four categories from grade 0 to grade 3. Intra- and interobserver reliabilities were measured by calculating the Cohen kappa coefficient. RESULTS Of the 204 disks studied, 28.9% (59/204) were determined to be grade 0 (uninjured), 4.9% (10/204) grade 1 (disk edema), 25.5% (52/204) grade 2 (bleeding/rupture), and 40.7% (83/204) grade 3 (displacement). The kappa value for the intra- and interobserver agreement was 0.96. CONCLUSION This novel classification may improve communication between spine surgeons and radiologists as well as facilitate clinical decision making in spine surgery. Further studies need to be conducted to verify clinical relevance.

Therapieprinzipien distaler Unterarmfrakturen im Kindesalter

Fractures of the forearm in children represent one of the most frequent injuries. Most are monotraumatic occurring during sport or leisure activities. Diagnosis can be made by conventional X-ray examination in 2 planes. Distal forearm fractures are classified into epiphyseolysis and epiphyseal fractures, metaphyseal greenstick and buckle fractures, complete distal radius and forearm fractures as well as Galeazzi lesions. The vast majority of cases without relevant dislocation can be treated with immobilization employing a cast. The remaining fractures have to be repositioned and restored depending on age and degree of dislocation.The state of the art in surgical therapy is the Kirschner wire osteosynthesis after closed reduction. Especially meta-diaphyseal fractures can alternatively be stabilized with plate osteosynthesis or external fixation. Following these therapeutic principles, prognosis is excellent and most of the injuries heal without any functional impairment.ZusammenfassungUnterarmfrakturen im Wachstumsalter sind häufige Verletzungen. Meist handelt es sich um ein Monotrauma im Rahmen von Sport- und Freizeitverletzungen. Die Diagnose wird mittels konventioneller Röntgendiagnostik in zwei Ebenen gestellt. Als Hauptgruppen finden sich Epiphysenlösungen und -frakturen, metaphysäre Grünholzfrakturen und Wulst-/Stauchungsfrakturen, komplette distale Radius- oder Unterarmfrakturen sowie als Sonderform Galeazzi-Verletzungen. Therapie der Wahl ist bei dem überwiegenden Anteil dieser Frakturen die konservative Behandlung mittels Ruhigstellung. Altersabhängig muss bei relevanter Dislokation eine Reposition sowie Retention durchgeführt werden.Methode der Wahl bei operativem Vorgehen ist die Kirschner-Draht-Osteosynthese nach geschlossener Reposition. Insbesondere bei Frakturen des metadiaphysären Überganges kann auf eine alternative Technik der Retention mittels Plattenosteosynthese oder Fixateur externe zur Stabilisierung des Radius ausgewichen werden. Bei adäquater Therapie ist die Prognose jedoch hervorragend und die überwiegende Anzahl dieser Verletzungen heilt folgenlos aus.AbstractFractures of the forearm in children represent one of the most frequent injuries. Most are monotraumatic occurring during sport or leisure activities. Diagnosis can be made by conventional X-ray examination in 2 planes. Distal forearm fractures are classified into epiphyseolysis and epiphyseal fractures, metaphyseal greenstick and buckle fractures, complete distal radius and forearm fractures as well as Galeazzi lesions. The vast majority of cases without relevant dislocation can be treated with immobilization employing a cast. The remaining fractures have to be repositioned and restored depending on age and degree of dislocation.The state of the art in surgical therapy is the Kirschner wire osteosynthesis after closed reduction. Especially meta-diaphyseal fractures can alternatively be stabilized with plate osteosynthesis or external fixation. Following these therapeutic principles, prognosis is excellent and most of the injuries heal without any functional impairment.

Delayed wound repair in sepsis is associated with reduced local pro-inflammatory cytokine expression.

Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.

Frakturen der Halswirbelsäule

ZusammenfassungBei Verletzungen der Halswirbelsäule (HWS) ist auch aufgrund der hohen Inzidenz an neurologischen Begleitverletzungen eine sorgfältige klinische und radiologische Abklärung obligat. Bei Verdacht auf das Vorliegen einer diskoligamentären Verletzung sollte eine kernspintomographische Untersuchung oder eine gehaltene Funktionsaufnahme durch den Chirurgen eingesetzt werden. Die drei wesentlichen Säulen in der Behandlung von HWS-Verletzungen stellen die Indikation, der Zugang und das gewählte Implantat dar. Dennoch wird häufig abhängig vom Frakturtyp trotz konsequenter und adäquater Therapie ein persistierendes Funktionsdefizit beibehalten. Diese Arbeit beinhaltet eine Übersicht über die häufigsten Frakturformen der HWS mit den entsprechenden Therapieregimen.AbstractDue to the high incidence of concomitant neurological lesions, standardized clinical and radiologic diagnostic procedures in cervical spine injuries are mandatory. Magnetic resonance imaging or a stress X-ray should be performed when discoligamentous injuries are suspected. The three most important pillars in the treatment of cervical spine injuries are the surgical indication, the surgical approach and the choice of implant. However, despite prompt and appropriate therapy many of these injuries lead to permanent functional impairment depending on the type of fracture. This article summarizes the most frequent fracture types of the cervical spine, as well as the corresponding therapeutic options and outcome.Due to the high incidence of concomitant neurological lesions, standardized clinical and radiologic diagnostic procedures in cervical spine injuries are mandatory. Magnetic resonance imaging or a stress X-ray should be performed when discoligamentous injuries are suspected. The three most important pillars in the treatment of cervical spine injuries are the surgical indication, the surgical approach and the choice of implant. However, despite prompt and appropriate therapy many of these injuries lead to permanent functional impairment depending on the type of fracture. This article summarizes the most frequent fracture types of the cervical spine, as well as the corresponding therapeutic options and outcome.

Outcome of Traumatic Intervertebral Disk Lesions After Stabilization by Internal Fixator

OBJECTIVE The optimal treatment of intervertebral disk lesions accompanying thoracolumbar fractures remains controversial. To evaluate short- and medium-term progression of intervertebral disk lesions accompanying vertebral fractures, MRI scans obtained after trauma were compared with scans obtained at an average follow-up of 1 year, by means of our clinically useful classification of traumatic intervertebral disk lesions. MATERIALS AND METHODS MRI scans of 54 disks in patients with trauma-induced single-level thoracolumbar fractures were analyzed retrospectively. All patients underwent posterior stabilization using a titanium internal fixator. Exclusion criteria were malignant vertebral collapse, spondylodiskitis, osteoporotic fractures, and degenerative disk disease in the uninjured disks. Morphologic changes and signal alterations of the adjacent disks were compared using routine MRI scans obtained after trauma and at an average follow-up of 1 year. Disks were divided according to their signals into four categories, from grade 0 to grade 3. RESULTS Of the disks studied after trauma (n = 54), 27.8% were determined to be grade 0, 31.5% were grade 2, and 40.7% were grade 3. In the follow-up examination, MRI detected grade 0 in 13% of disks. Hence, more than 50% of the disks with grade 0 after trauma changed into grade 2 lesions, resulting in 46.3% grade 2 lesions. Grade 3 disk lesions (40.7%) remained the same without any sign of recovery. CONCLUSION In the current study, we found progressive disk degradation and creeping in instrumented and nonfused segments in thoracolumbar fractures. For further validation, randomized controlled long-term outcome investigations seem mandatory as the next step in future clinical research.

Traumatische Wirbelsäulenfrakturen und Osteoporose

ZusammenfassungDie traumatischen Wirbelsäulenfrakturen bei vorliegender Osteoporose müssen obligat von der osteoporotischen Sinterungsfraktur in Bezug auf Entstehung, Klassifikation und operative Behandlung abgegrenzt werden. Das Therapiekonzept umfasst immer eine suffiziente analgetische Therapie, eine antiosteoporotische Medikation und eine angepasste Trainingstherapie. Kommt es bei A1-Frakturen sowie A2.1-/A2.2-Frakturen bei konservativem Behandlungsansatz zu einer Chronifizierung der Schmerzen oder einer sekundären Kyphosierung haben sich minimal-invasive Zementaugmentationsverfahren etabliert. Alle anderen Frakturformen, insbesondere instabile Frakturen, Frakturen mit vorliegendem neurologischem Defizit sowie relevante Stenosen des Spinalkanals erfordern trotz erhöhtem Risiko und Aufwand eine konventionelle operative Versorgung. Unter Einbeziehung der veränderten Knochenqualität und Biomechanik des osteoporotischen Knochens haben sich eigene Techniken und Strategien – Zementaugmentation der Pedikelschrauben, additive Zementaugmentation des Wirbelkörpers (Hybridverfahren) – zur Versorgung dieser komplexen traumatischen Wirbelkörperfrakturen etabliert.AbstractTraumatic vertebral body fractures are different from the osteoporotic vertebral sintering fractures with regard to accruement, classification and surgical treatment. The standard therapeutic regimen for traumatic vertebral fracture implies sufficient analgetic as well as antiosteoporotic medication and physiotherapy. In cases of A1 fractures and A2.1/A2.2 fractures, minimally invasive treatment strategies have proven to be appropriate treatment options when conservative treatment fails. Unstable fractures, the presence of neurological deficits or stenosis of the canal require conventional operative treatment. Due to reduced bone quality and age-dependent biomechanical changes, distinct operative procedures and strategies – cement augmentation of pedicle screws, additional cement augmentation of the fractured vertebra – for complex traumatic vertebral fractures have been established.Traumatic vertebral body fractures are different from the osteoporotic vertebral sintering fractures with regard to accruement, classification and surgical treatment. The standard therapeutic regimen for traumatic vertebral fracture implies sufficient analgetic as well as antiosteoporotic medication and physiotherapy. In cases of A1 fractures and A2.1/A2.2 fractures, minimally invasive treatment strategies have proven to be appropriate treatment options when conservative treatment fails. Unstable fractures, the presence of neurological deficits or stenosis of the canal require conventional operative treatment. Due to reduced bone quality and age-dependent biomechanical changes, distinct operative procedures and strategies - cement augmentation of pedicle screws, additional cement augmentation of the fractured vertebra - for complex traumatic vertebral fractures have been established.