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BackgroundFilament perforation is a widely-used method to induce subarachnoid hemorrhage (SAH) in mice. Whereas the perforation site has been assumed to be in the branching of middle cerebral artery (MCA) and anterior cerebral artery (ACA), we recently observed more proximal perforations.MethodsFilament perforation was performed in CD1- (n = 10) and C57Bl/6N-mice (n = 9) ex vivo. The filament was left in place and the perforation site was microscopically assessed. Digital subtraction angiography (DSA) was performed in CD1- (n = 9) and C57Bl/6J-mice (n = 29) and anatomical differences of the internal carotid artery (ICA) were determined.ResultsWhereas in C57Bl/6N-mice perforation occurred in the proximal intracranial ICA in 89% (n = 8), in CD1-mice the perforation site was in the proximal ICA in 50% (n = 5), in the branching between MCA and ACA in 40% (n = 4), and in the proximal ACA in 10% (n = 1). DSA revealed a stronger angulation (pweight/angle= 0.757) and CD1-mice (r = -0.468, pweight/angle= 0.242).ConclusionFilament perforation in mice occurs not only at the hitherto presumed branching between MCA and ACA, but seems to depend on mouse strain and anatomy as the proximal intracranial ICA may also be perforated frequently.

Background Mechanical thrombectomy is the standard treatment for acute ischemic stroke in patients with large vessel occlusion and can be performed up to 24h after symptom onset. Despite high recanalization rates, embolism in new territories has been reported in 8.6% of the cases. Causes for this could be clot abruption during stent retrieval into the smaller opening of a standard distal access catheter, and antegrade blood flow via collaterals despite proximal balloon protection. A funnel-shaped tip with a larger internal diameter was developed to increase the rate of first-pass recanalization and to improve the safety and efficacy of mechanical thrombectomy. Methods This in vitro study compared the efficacy of a funnel-shaped tip with a standard tip in combination with different clot compositions. Mechanical thrombectomy was performed 80 times for each tip, using two stent retrievers (Trevo XP ProVue 3/20 mm, 4/20 mm) and four different clot types (hard vs. soft clots, 0–24h vs. 72h aged clots). Results Significantly higher first-pass recanalization rates (mTICI 3) were observed for the funnel-shaped tip, 70.0% versus 30.0% for the standard tip (absolute difference, 32; relative difference 57.1%; P < .001), regardless of the clot type and stent retriever. Recanalization could be increased using harder Chandler loop clots versus softer statically generated clots, as well as 0–24h versus 72h aged clots, respectively. Conclusion The funnel-shaped tip achieved higher first-pass recanalization rates than the smaller standard tip and lower rates of clot abruption at the tip. Clot compositions and aging times impacted recanalization rates.

Longitudinal in vivo imaging studies characterizing subarachnoid hemorrhage (SAH)-induced large artery vasospasm (LAV) in mice are lacking. We developed a SAH-scoring system to assess SAH severity in mice using micro CT and longitudinally analysed LAV by intravenous digital subtraction angiography (i.v. DSA). Thirty female C57Bl/6J-mice (7 sham, 23 SAH) were implanted with central venous ports for repetitive contrast agent administration. SAH was induced by filament perforation. LAV was assessed up to 14 days after induction of SAH by i.v. DSA. SAH-score and neuroscore showed a highly significant positive correlation (rsp = 0.803, p sp = −0.71, p max = 30.5%, p max = 21.2%, p = 0.014), middle cerebral (Δmax = 28.16%, p max = 23.49%, p Pe = −0.54, p = 0.04). Arterial diameter of the left MCA correlated negatively with cerebral perfusion on day 3 (rPe = −0.72, p = 0.005). In addition, pseudoaneurysms arising from the filament perforation site were visualized in three mice using i.v. DSA. Thus, micro-CT and DSA are valuable tools to assess SAH severity and to longitudinally monitor LAV in living mice.

A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3 × 5 or 3 × 8 Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n = 15/group, ntotal = 90). Tumors were assigned to volumes receiving 90–107%, 50–90%, 5–50%, and n = 26) rather than 5–50% (n = 7) of the target dose. Latency was significantly shortened only after 3 × 8 Gy vs. controls (p p = 0.29) and latency (218 vs. 189 days; p = 0.17) of radiation-associated tumors were similar after VMAT vs. AP/PA. LOH was strongly associated with sarcoma but not with treatment. The results do not support the hypothesis that IMRT increases the risk of second cancer. Thus the current practice of withholding dose-sparing IMRT from young patients may need to be re-evaluated.

Clot-retrieval failure and embolism in new territories (ENT) are complications reducing the efficacy of mechanical thrombectomy (MT). Reasons for these problems are clot abruption during stent retriever retraction into the cylindrical tip of a standard distal access catheter (DAC), and antegrade blood flow during retrieval. To overcome these complications, a funnel-shaped tip catheter model was developed and tested. Using an experimental in vitro setup, this study compared the efficacy of a funnel-shaped tip with a standard cylindrical tip in combination with different clot compositions. Mechanical thrombectomy was performed 80 times for each tip, using two stent retrievers (Trevo XP ProVue 3/20 mm and 4/20 mm) and four different clot types (mechanical vs. static preparation, 0-24h vs. 72h clot aging times). Significantly higher first-pass recanalization rates were observed for the funnel-shaped tip, which reached 70.0% vs. 30.0% for the standard tip (absolute difference, 32; relative difference 20.0%, P

One limitation of mechanical thrombectomy (MT) is clot migration during procedure. This might be caused by abruption of the trapped thrombus at the distal access catheter (DAC) tip during stent-retriever retraction due to the cylindrical shaped tip of the DAC. Aiming to solve this problem, this study evaluates the proof-of-concept of a new designed funnel-shaped tip, in an experimental in vitro setting. Two catheter models, one with a funnel-shaped tip and one with a cylindrical-shaped tip, were compared in an experimental setup. For MT a self-made vessel model and thrombi generated from pig’s blood were used. MT was performed 20 times for each device using two different stent-retrievers, 10 times respectively. For the funnel-shaped model: for both stent-retrievers (Trevo XP ProVue 3/20 mm; Trevo XP ProVue 4/20 mm) MT was successful at first pass in 9/10 (90%), respectively. For the cylindrical-shaped model: MT was successful at first pass in 5/10 (50%) with the smaller stent-retriever and in 6/10 (60%) with the larger stent-retriever. The experiments show a better recanalization rate for funnel-shaped tips, than for cylindrical-shaped tips. These results are indicating a good feasibility for this new approach, thus the development of a prototype catheter seems reasonable.

Mobile information and communication technologies are increasingly used in nursing. In a new plasma-supported treatment for patients with chronic wounds in outpatient nursing settings, the LiveCity camera can be used as an innovative mobile communication technology. It enables rapid and high quality exchange of information between remotely located doctors and nursing staff. This procedure promises to deliver positive outcomes regarding the quality of the treatment and patient safety while avoiding additional hospitalisation and saving time and costs. This is achieved by rapidly confirming diagnoses and agreeing on a joint treatment appropriate for the current wound status. Thus, complications in wound healing can be promptly identified and countermeasures initiated through quick and easy access to medical and nursing expertise.

Zusammenfassung. Hintergrund: Aufgrund der demografischen und epidemiologischen Entwicklung wird die Vermittlung adäquater pflegerischer Kompetenzen in der pflegerischen Ausbildung zunehmend diskutiert. Kompetenzen sind in den Examina angemessen zu überprüfen. Hierfür haben sich international OSCEs bewährt. Ziel: Ziel der vorliegenden Analyse war die Ermittlung von Kompetenzen, die in pflegerischen Erstausbildungen mit OSCEs überprüft werden. Methodik: In internationalen Datenbanken wurden einschlägige Publikationen recherchiert. Analyse-Einschlusskriterium war die Nennung mindestens einer überprüften Kompetenz. Die Kompetenzen wurden – in Anlehnung an den «Fachqualifikationsrahmen Pflege für die hochschulische Bildung» – nach Wissen, Fertigkeiten und Haltung kategorisiert. Ergebnisse: 36 Artikel erfüllten das Einschlusskriterium. Relevante Studien stammen mehrheitlich aus Großbritannien (UK), Kanada und Australien. Es wurden insgesamt n = 166 Kompetenzen in allen Kategorien identifiziert, die anhand verschiedener Methoden gemessen wurden. Am häufigsten wurden Fertigkeiten überprüft. Dabei wurde der sichere Umgang mit Medikamenten am häufigsten thematisiert. Weitere wichtige Themen waren die Kommunikationskompetenz in Bezug auf PatientInnen und die Fähigkeit zur Selbsteinschätzung. Diskussion: Es werden sehr unterschiedliche Kompetenzen mit differenten Formaten per OSCE gemessen. OSCE ermöglichen eine Überprüfung sowohl auf individueller als auch institutioneller Ebene, also sowohl für die Lehre als auch das Gelernte. Weiterer Forschungsbedarf wird festgestellt.

Subarachnoid hemorrhage (SAH) is a subtype of hemorrhagic stroke. Cerebral vasospasm that occurs in the aftermath of the bleeding is an important factor determining patient outcome and is therefore frequently taken as a study endpoint. However, in small animal studies on SAH, quantification of cerebral vasospasm is a major challenge. Here, an ex vivo method is presented that allows quantification of volumes of entire vessel segments, which can be used as an objective measure to quantify cerebral vasospasm. In a first step, endovascular casting of the cerebral vasculature is performed using a radiopaque casting agent. Then, cross-sectional imaging data are acquired by micro computed tomography. The final step involves 3-dimensional reconstruction of the virtual vascular tree, followed by an algorithm to calculate center lines and volumes of the selected vessel segments. The method resulted in a highly accurate virtual reconstruction of the cerebrovascular tree shown by a diameter-based comparison of anatomical samples with their virtual reconstructions. Compared with vessel diameters alone, the vessel volumes highlight the differences between vasospastic and non-vasospastic vessels shown in a series of SAH and sham-operated mice.

Mobile information and communication technologies are increasingly used in nursing. In a new plasma-supported treatment for patients with chronic wounds in outpatient nursing settings, the LiveCity camera can be used as an innovative mobile communication technology. It enables rapid and high quality exchange of information between remotely located doctors and nursing staff. This procedure promises to deliver positive outcomes regarding the quality of the treatment and patient safety while avoiding additional hospitalisation and saving time and costs. This is achieved by rapidly confirming diagnoses and agreeing on a joint treatment appropriate for the current wound status. Thus, complications in wound healing can be promptly identified and countermeasures initiated through quick and easy access to medical and nursing expertise.

Plasma-supported wound care is a new and innovative approach for the treatment of chronic wounds. Plasma-supported wound care could be implemented by nursing personnel. This chapter will describe what roles and tasks nursing personnel have in plasma-supported wound care and which specific competencies they must acquire for its application.

Optical coherence tomography (OCT) is a clinical standard in ophthalmology. Currently, its application in dentistry is gaining increasing interest. In this study, we tested the possibility to use a modified commercially available spectral domain OCT (SD-OCT) to assess the layer thickness of orthodontic surface sealants. Reference samples of surface sealants for calibration and repeatability testing were measured using a micrometer screw. SD-OCT measurements were compared with micro-CT and light microscopic analyses. After validating the calibration of the SD-OCT, surface sealant layer thickness after aging (thermo cycling) and simulation of professional tooth cleaning (PTC) was assessed using the SD-OCT on 45 extracted teeth assigned to three test groups (n = 15 each): Light Bond™ Sealant, Pro Seal®, and Opal® Seal. SD-OCT showed excellent repeatability and accuracy for measurements of surface sealant layer thickness. Compared with micro-CT, SD-OCT showed better accordance with the reference measurements. The analysis of surface sealants after thermo cycling and PTC revealed poor resistance of Light Bond after only aging and demonstrated substantial wear of all sealants after aging and PTC. Imaging using commercially available ophthalmic SD-OCT might represent a suitable non-invasive methodology for longitudinal assessments of surface sealant layer thickness in vitro and in vivo. SD-OCT might be a suitable non-invasive method for longitudinal assessments of surface sealant durability in clinical trials.

Main symptom of mucopolysaccharidosis type IVa (MPS IVa) is progressive systemic skeletal dysplasia. This is routinely monitored by cerebral and spinal MRI. The vascular system is generally not in the primary focus of interest. In our population of MPS IVa patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before.MRI-datasets of 26 patients with MPS IVa acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. The vessel length and angle of the basilar artery (BA) and both vertebral arteries (VA) were analyzed. A deflection angle between 90° and 130° in the vessel course was defined as tortuosity, less than 90° as kinking. The results were compared to a matched control group of 23 patients not suffering from MPS.The deflection angle [°] of the VA and BA was significantly decreased in the majority (85%) of MPS IVa patients compared to the control group: BA 132±24 vs. 177±6, BA/VA transition 113±21 vs. 152±13, right VA 108±23 vs. 156±13, left VA 110± 22 vs. 157±14 (all p0.005). Likewise, vessels of MPS IVa patients were significantly longer compared to the control group: BA 27±4 vs. 21±2, right VA 20±6 vs. 10±1, left VA 18±5 vs. 11±2 (all p0.005).MPS IVa is associated with significantly increased tortuosity of vertebrobasilar arteries. Therefore the vascular system of MPS IVa patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events.

Purpose As result of the current demographic changes, osteoporosis and osteoporotic fractures are becoming an increasing social and economic burden. In this experimental study, extracorporeal shock wave therapy (ESWT), was evaluated as a treatment option for the improvement of osteoporotic fracture healing. Methods A well-established fracture model in the metaphyseal tibia in the osteoporotic rat was used. 132 animals were divided into 11 groups, with 12 animals each, consisting of one sham-operated group and 10 ovariectomized (osteoporotic) groups, of which 9 received ESWT treatment. Different energy flux intensities (0.15 mJ/mm2, 0.35 mJ/mm2, or 0.55 mJ/mm2) as well as different numbers of ESWT applications (once, three times, or five times throughout the 35-day healing period) were applied to the osteoporotic fractures. Fracture healing was investigated quantitatively and qualitatively using micro-CT imaging, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, histomorphometric analysis and biomechanical analysis. Results The results of this study show a qualitative and quantitative improvement in the osteoporotic fracture healing under low-energy (energy flux intensity: 0,15 mJ/mm2) ESWT and with fewer treatment applications per healing period. Conclusion In conclusion, low-energy ESWT seems to exhibit a beneficial effect on the healing of osteoporotic fractures, leading to improved biomechanical properties, enhanced callus-quantity and -quality, and an increase in the expression of bone specific transcription factors. The results suggest that low-energy ESWT, as main treatment or as adjunctive treatment in addition to a surgical intervention, may prove to be an effective, simple to use, and cost-efficient option for the qualitative and quantitative improvement of osteoporotic fracture healing.

Background: Interprofessional teamwork has become increasingly important to provide patient centered care. Physicians and nurses as two major professions are needed to be adequately qualified. Interprofessional Education (IPE) is an eligible approach. Nevertheless, there is a lack of the impact for both professions. Therefore, we implemented and evaluated simulation training and a collaborative working sequence on a training ward. The aim was to analyze the course structure and assess learning effects to evaluate the suitability for IPE. Methods: A mixed methods study with a sequential explanatory design was conducted. A total of five medical and five nursing students were involved. Students completed questionnaire based interviews after IPE lectures. Two group discussions were conducted to specify and expand quantitative evaluation results. For descriptive statistics, we used the software package SPSS. Both group discussions were analyzed by a qualitative content analysis using the software MAXQDA. Results: Students rated IPE predominantly positive. The learning contents broadness and the links between theory and practice. Students identified six core learning effects: (1) Realization of the importance for collaborative working; (2) Gaining knowledge about the roles of both professions; (3) Realization, that interprofessional care facilitates work; (4) Practicing communication between physicians and nurses; (5) Improving collaborative communication with the patient; and (6) Understanding chances and challenges of joint decision making. Nevertheless, students suggested improvements, e.g., the scenarios of the simulation training should be expanded. Conclusion: The results provide clear evidence that IPE by simulation training and a training ward is feasible and well accepted by students in a German medical school. Results can be used to adapt IPE lectures and to implement them for a larger number of students. The next step is to generalize findings and to sustainably implement IPE in both curricula.

PLoS ONE 10(6), e0130661 (2015). doi:10.1371/journal.pone.0130661, Published by PLoS, Lawrence, Kan.

Purpose There is an increasing need for small animal in vivo imaging in murine orthotopic glioma models. Because dedicated small animal scanners are not available ubiquitously, the applicability of a clinical CT scanner for visualization and measurement of intracerebrally growing glioma xenografts in living mice was validated. Materials and Methods 2.5x106 U87MG cells were orthotopically implanted in NOD/SCID/ᵞc-/- mice (n = 9). Mice underwent contrast-enhanced (300 μl Iomeprol i.v.) imaging using a micro-CT (80 kV, 75 μAs, 360° rotation, 1,000 projections, scan time 33 s, resolution 40 x 40 x 53 μm) and a clinical CT scanner (4-row multislice detector; 120 kV, 150 mAs, slice thickness 0.5 mm, feed rotation 0.5 mm, resolution 98 x 98 x 500 μm). Mice were sacrificed and the brain was worked up histologically. In all modalities tumor volume was measured by two independent readers. Contrast-to-noise ratio (CNR) and Signal-to-noise ratio (SNR) were measured from reconstructed CT-scans (0.5 mm slice thickness; n = 18). Results Tumor volumes (mean±SD mm3) were similar between both CT-modalities (micro-CT: 19.8±19.0, clinical CT: 19.8±18.8; Wilcoxon signed-rank test p = 0.813). Moreover, between reader analyses for each modality showed excellent agreement as demonstrated by correlation analysis (Spearman-Rho >0.9; p

Background: Patients with actively replicating human immunodeficiency virus (HIV) are highly radiosensitive and exhibit adverse reactions even at low irradiation doses. A major underlying cause is high intra- and extracellular levels of a virus-encoded peptide termed viral protein R (Vpr). As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined whether it may be utilized as a drug in the treatment of glioblastoma multiforme (GBM). Methods: Four glioblastoma-derived cell lines with and without lentivirus-mediated Methylguanine-DNA methyltransferase (MGMT) overexpression (U251, U87, U251-MGMT, U87-MGMT) were exposed to Vpr, temozolomide (TMZ), conventional photon irradiation (2-6 Gy) or to combinations. Caspase assays were employed to detect apoptosis. Colony formation assays were used to analyse clonogenic survival. Dose escalation was performed using n = 12 NOD/SCID/γc−/− (NSG) mice in a classical 3+3 manner. This strain was also used as an orthotopic implant model of glioma using luciferase-expressing U87 cells (n = 18). Continuous Vpr administration was achieved using osmotic pumps, irradiation (3×5 Gy) was performed using a small-animal irradiation device and intracerebral tumor growth was monitored using repetitive contrast-enhanced micro CT scans. Results: Vpr showed high rates of acute toxicities with a LD50 of 4.0±1.1 μM for U251 and a LD50 of 15.7±7.5 μM for U87 cells. Caspase assays revealed Vpr-induced apoptosis in U251 but not in U87 cells. Vpr also efficiently inhibited clonogenic survival both in U251 and U87 cells and showed additive effects with irradiation. In contrast to TMZ, Vpr acted independently of the MGMT expression status. Dose escalation in mice (n = 12) was feasible and resulted in no evident renal or liver toxicity. Similar to irradiation with 3 × 5 Gy (n = 8), Vpr treatment of orthotopically implanted NSG mice (n = 5) delayed tumor growth and significantly (p = 0.041; log-rank test) prolonged overall survival compared to untreated animals (n = 5). Conclusion: The HIV-encoded peptide Vpr exhibits all properties of an effective chemotherapeutic drug and may be a useful agent in the treatment of GBM. Citation Format: Jens Kuebler, Stefanie Kirschner, Linda Hartmann, Grit Welzel, Maren Engelhardt, Carsten Herskind, Marlon R. Veldwijk, Christian Schultz, Manuela Felix, Gerhard Glatting, Patrick Maier, Frederik Wenz, Marc A. Brockmann, Frank A. Giordano. The HIV-derived protein Vpr52-96 has anti-glioma activity in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4458. doi:10.1158/1538-7445.AM2015-4458

BACKGROUND AND PURPOSE: Patients with actively replicating human immunodeficiency virus (HIV) are highly radiosensitive and exhibit adverse reactions even at low irradiation doses. One of the major underlying causes are high intra- and extracellular levels of a virus-encoded peptide termed viral protein R (Vpr). As Vpr efficiently crosses the blood-brain barrier and accumulates in astrocytes, we examined whether its active subunit (Vpr52-96) may be utilized as drug in the treatment of glioblastoma multiforme. MATERIAL AND METHODS: Four glioblastoma-derived cell lines with and without lentivirus-mediated MGMT-overexpression (U251, U87MG, U251-MGMT, U87-MGMT) were exposed to Vpr52-96, 100 µM of temozolomide (TMZ), conventional photon irradiation (2-6 Gy) or to combinations of the three. Acute toxicities and LD50 were examined using the MTT proliferation assay. Apoptosis was detected using a luminescent reaction measuring caspase-3 and -7 activities (Caspase Glo®). Clonogenic survival (survival fraction, SF) was determined using the colony-forming assay. RESULTS: Treatment of U251 cells with 1, 10 and 20 µM of medium-dissolved Vpr52-96 yielded cell viability rates of 82.4 ± 3.2%, 32.6 ± 9.1% and 10.5 ± 4.8% respectively, corresponding to a LD50 of 4.0 ± 1.1 µM. For U87MG, the corresponding viability rates were 89.3 ± 4.4%, 61.2 ± 12.4% and 43.6 ± 17.8%, resulting in an LD50 of 15.7 ± 7.5 µM. Combined treatment (Vpr + RT and/or TMZ) showed additive, but not synergistic effects in MTT assays. Vpr induced apoptosis in all cell lines within 6-12 hours in a dose-dependent fashion. Clonogenic assays also revealed an additive effect but no sensitization towards irradiation. Vpr alone efficiently inhibited clonogenic survival (SF at 10 µM Vpr: 0.24 ± 0.06 for U251 and 0.35 ± 0.09 for U87MG). In contrast to TMZ, it acts independently from the MGMT expression status (SF of U251-MGMT at 10 µM Vpr: 0.2 vs. 0.9 at 100 µM TMZ; SF of U87-MGMT at 10 µM Vpr: 0.3 vs. 0.7 at 100 µM TMZ). SUMMARY: Vpr52-96 exhibits all traits of a chemotherapeutic drug that may be employed for the treatment of glioblastoma multiforme. The protein acts additively to current standard therapies and shows undiminished antiproliferative activity in MGMT-overexpressing cells.