[Reorientation of Medical Procedures Covered by Statutory Accident Insurance]. / Neuausrichtung der Heilverfahren der Gesetzlichen Unfallversicherung.

As of 01/01/2014, the German Statutory Accident Insurance (DGUV) has reorganized inpatient medical procedures. The central element of reorientation is the reorganization of the catalogue of types of accidents and type of medical procedures of hospitalized injured patients in 3 care stages. In addition, the reorientation also concentrates on hospitals with the highest performance and the best qualification and also focuses on severe and most severe injuries.This reorientation is also based on the White Paper of the German Society for Trauma Surgery (DGU), especially on the Trauma Network DGU. The new regulations will be implemented by the state associations of the German Statutory Accident Insurance.The hierarchy of care depends on established admission criteria and the severity of injury. This structuring also refers to special competence in the field of rehabilitation and will lead to the strengthening of multidisciplinary rehabilitation management and workplace-related modules of the healthcare. Overall, the accident insurance institution will place increased demands on their network partners.

AT-101 simultaneously triggers apoptosis and a cytoprotective type of autophagy irrespective of expression levels and the subcellular localization of Bcl-xL and Bcl-2 in MCF7 cells.

The effects of autophagy on cell death are highly contextual and either beneficial or deleterious. One prime example for this dual function of autophagy is evidenced by the cell responses to the BH3 mimetic AT-101 that is known to induce either apoptotic or autophagy-dependent cell death in different settings. Based on previous reports, we hypothesized that the expression levels of pro-survival Bcl-2 family members may be key determinants for the respective death mode induced by AT-101. Here we investigated the role of autophagy in the response of MCF7 breast cancer cells to AT-101. AT-101 treatment induced a prominent conversion of LC3-I to LC3-II and apoptotic cell death characterized by the appearance of Annexin-positive/PI-negative early apoptotic cells and PARP cleavage. Inhibition of the autophagy pathway, either through application of 3-MA or by lentiviral knockdown of ATG5, strongly potentiated cell death, indicating a pro-survival function of autophagy. Overexpression of wild type Bcl-xL significantly diminished the net amount of AT-101-induced cell death, but failed to alter the death-enhancing effects of the ATG5 knockdown. This was also observed with the organelle-specific variants Bcl-xL-ActA and Bcl-2-ActA (mitochondrial) as well as Bcl-xL-cb5 and Bcl-2-cb5 (ER) which all reduced AT-101-induced cell death, but did not affect the death-enhancing effects of 3-MA. Collectively, our data indicate that in apoptosis-proficient MCF7 cells, AT-101 triggers Bcl-2- and Bcl-xL-dependent apoptosis and a cytoprotective autophagy response that is independent of the expression and subcellular localization of Bcl-xL and Bcl-2.

[Significance of Helicopter Emergency Medical Service in Prehospital Trauma Care]. / Bedeutung der Luftrettung bei der präklinischen Traumaversorgung.

BACKGROUND: In the late 1960s, the helicopter emergency medical service (HEMS) was established in Germany because of an increasing number of severe injuries in traffic accidents. To get a doctor quickly on scene was the initial intention, rather than transporting the patient. Today, rescue helicopters cover the entire field of emergency medicine and are an important transportation device for polytrauma patients. MATERIAL AND METHODS: The importance of the HEMS for the treatment of severely injured patients was examined by an analysis of the databases of the leading air rescue organisations ADAC and DRF Luftrettung (2005-2011). RESULTS: Traumatological cases, albeit with large regional differences, make up 35 % of all uses of the helicopter emergency services. CONCLUSIONS: For the multiply injured patient in particular, in over 40 % of the cases there is a joint patient care involving both helicopter- and ambulance-based emergency services. The HEMS undertakes especially the rapid, if necessary, even transregional transport to specialised trauma centres.

[Importance of air ambulances for the care of the severely injured]. / Bedeutung der Luftrettung für die Schwerverletztenversorgung.

BACKGROUND: In the late 1960s, helicopter emergency medical services (HEMS) were established because of the increasing number of severely injured in road traffic accidents. It was initially thought to bring the doctor to the patient quickly. AIM: Today, the rescue helicopter covers the entire field of emergency medicine. By analyzing the databases of the TraumaRegister DGU® (2005-2011), the importance of the HEMS for the treatment of the severely injured was examined. RESULTS: The results showed that around 30 % of severely injured are allocated to hospitals by HEMS. In addition to regional differences, the level of the hospital also plays a particularly important role. The combination of the transfer by HEMS and treatment in a level I trauma center has a significantly positive effect on the survival rate of the patient, especially in patients with traumatic brain injury (TBI).

[Importance of the correct placement of the pelvic binder for stabilisation of haemodynamically compromised patients]. / Bedeutung der korrekten Positionierung eines Beckengurts zur temporären Stabilisierung von Beckenringverletzungen.

A 36-year-old motorcyclist sustained multiple severe injuries in a motorcycle accident. The leading injury was a type B open-book pelvic fracture, resulting in a relevant haemodynamic instability. Due to an initial misplacement of the pelvic binder (Samsling®) by the paramedics in the field, a sufficient compression of the fracture and stabilisation of the haemodynamic situation could not be obtained. After repositioning of the pelvic binder in the emergency room, the pelvis was adequately stabilised, leading to a transient stabilisation of the haemorrhagic shock. This example illustrates the benefit of a simple and effective tool for the initial stabilisation of pelvic fractures in haemodynamically compromised patients and in particular the importance of the correct placement of the pelvic binder.

[Web-based evidence of treatment capacity. An instrument for optimizing the interface between prehospital and hospital management]. / Web-basierter Versorgungskapazitätsnachweis. Ein Instrument zur Schnittstellenoptimierung zwischen Präklinik und Klinik.

BACKGROUND: The outcome of injured patients depends on intrastractural circumstances as well as on the time until clinical treatment begins. A rapid patient allocation can only be achieved occur if informations about the care capacity status of the medical centers are available. Considering this an improvement at the interface prehospital/clinical care seems possible. MATERIAL AND METHOD: In 2010 in Frankfurt am Main the announcement of free capacity (positive proof) was converted to a web-based negative proof of interdisciplinary care capacities. So-called closings are indicated in a web portal, recorded centrally and registered at the local health authority and the management of participating hospitals. RESULTS: Analyses of the allocations to hospitals of all professional disciplines from the years 2009 and 2010 showed an optimized use of the resources. A decline of the allocations by the order from 261 to 0 could be reached by the introduction of the clear care capacity proof system. The health authorities as the regulating body rarely had to intervene (decline from 400 to 7 cases). Surgical care in Frankfurt was guaranteed at any time by one of the large medical centers. CONCLUSION: The web-based care capacity proof system introduced in 2010 does justice to the demand for optimum resource use on-line. Integration of this allocation system into the developing trauma networks can optimize the process for a quick and high quality care of severely injured patients. It opens new approaches to improve allocation of high numbers of casualties in disaster medicine.

The death associated protein (DAP) kinase homologue Dlk/ZIP kinase induces p19ARF- and p53-independent apoptosis.

Dlk/ZIP kinase is one of five members of the death associated protein (DAP) kinase family. DAP kinase is able to induce apoptosis in a p19ARF/p53-dependent manner. We elucidated the potential role of the p19ARF/p53 pathway in Dlk/ZIP kinase-triggered cell death. Overexpression of a constitutively pro-apoptotic form of Dlk/ZIP kinase induced apoptosis in rat fibroblast cells which express wild-type p19ARF and p53. Cell death was characterised by apoptotic membrane blebbing, mitochondrial depolarisation, cytochrome c release and activation of caspase-3. However, Dlk/ZIP kinase-triggered cell death was also observed in p19ARF-deficient and p53-deficient mouse fibroblast cells. Quantitative analysis revealed that the status of p53 had no major influence on cellular susceptibility to Dlk/ZIP kinase-triggered cell death. Loss of p53 did not prevent Dlk/ZIP kinase-induced mitochondrial membrane depolarisation and release of cytochrome c. Furthermore, overexpression of Dlk/ZIP kinase did not lead to an increased expression of pro-apoptotic p53 target genes in either cell line. These data suggest that Dlk/ZIP kinase is able to trigger the mitochondrial apoptosis pathway independent of the p19ARF/p53 signalling pathway.

Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway.

Dlk/ZIP kinase is a member of the Death Associated Protein (DAP) kinase family of pro-apoptotic serine/threonine kinases that have been implicated in regulation of apoptosis and tumour suppression. Expression of both Dlk/ZIP kinase and its interaction partner Par-4 is maintained in four medulloblastoma cell lines investigated, whereas three of seven neuroblastoma cell lines have lost expression of Par-4. Overexpression of a constitutively pro-apoptotic deletion mutant of Dlk/ZIP kinase induced significant apoptosis in D283 medulloblastoma cells. Cell death was characterized by apoptotic membrane blebbing, and a late stage during which the cells had ceased blebbing and were drastically shrunken or disrupted into apoptotic bodies. Over-expression of the anti-apoptotic Bcl-xL protein had no effect on Dlk/ZIP kinase-induced membrane blebbing, but potently inhibited Dlk/ZIP kinase-induced cytochrome c release and transition of cells to late stage apoptosis. Treatment with caspase inhibitors delayed, but did not prevent entry into late stage apoptosis. These results demonstrate that Dlk/ZIP kinase-triggered apoptosis involves the mitochondrial apoptosis pathway. However, cell death proceeded in the presence of caspase inhibitors, suggesting that Dlk/ZIP kinase is able to activate alternative cell death pathways. Alterations of signal transduction pathways leading to Dlk/ZIP kinase induced apoptosis or loss of expression of upstream activators could play important roles in tumour progression and metastasis of neural tumours.

Multiple kinetics of mitochondrial cytochrome c release in drug-induced apoptosis.

We investigated cytochrome c release kinetics in response to three apoptosis-inducing agents (tumor necrosis factor-alpha, staurosporine, and valinomycin) in MCF-7/Casp-3 cells stably transfected with enhanced green fluorescent protein (EGFP)-tagged cytochrome c. All three agents induced significant caspase activation in the cultures determined by monitoring the cleavage of fluorigenic caspase substrates in extracts from drug-treated MCF-7/Casp-3 cells, albeit the valinomycin-induced activation was less pronounced. Time-lapse confocal microscopy showed that tumor necrosis factor-alpha and staurosporine caused rapid, one- or multiple-step release of cytochrome c-EGFP from mitochondria. In contrast, valinomycin-induced cytochrome c-EGFP release occurred slowly over several hours. Unlike staurosporine, the valinomycin-induced cytochrome c release was not associated with translocation of the proapoptotic Bax protein to the mitochondria, and was not accompanied by co-release of the proapoptotic Smac protein. Immunoprecipitation experiments revealed that cytochrome c was also released out of the cell into the extracellular space before loss of plasma membrane integrity. Our data indicate the existence of multiple kinetics of cytochrome c release in drug-induced apoptosis.

Ca(2+)-induced inhibition of apoptosis in human SH-SY5Y neuroblastoma cells: degradation of apoptotic protease activating factor-1 (APAF-1).

During apoptotic and excitotoxic neuron death, challenged mitochondria release the pro-apoptotic factor cytochrome c. In the cytosol, cytochrome c is capable of binding to the apoptotic protease-activating factor-1 (APAF-1). This complex activates procaspase-9 in the presence of dATP, resulting in caspase-mediated execution of apoptotic neuron death. Many forms of Ca(2+)-mediated neuron death, however, do not lead to prominent activation of the caspase cascade despite significant release of cytochrome c from mitochondria. We demonstrate that elevation of cytosolic Ca(2+) induced prominent degradation of APAF-1 in human SH-SY5Y neuroblastoma cells and in a neuronal cell-free apoptosis system. Loss of APAF-1 correlated with a reduced ability of cytochrome c to activate caspase-3-like proteases. Ca(2+) induced the activation of calpains, monitored by the cleavage of full-length alpha-spectrin into a calpain-specific 150-kDa breakdown product. However, pharmacological inhibition of calpain activity indicated that APAF-1 degradation also occurred via calpain-independent pathways. Our data suggest that Ca(2+) inhibits caspase activation during Ca(2+)-mediated neuron death by triggering the degradation of the cytochrome c-binding protein APAF-1.

Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis.

Exposure of rat hippocampal neurons or human D283 medulloblastoma cells to the apoptosis-inducing kinase inhibitor staurosporine induced rapid cytochrome c release from mitochondria and activation of the executioner caspase-3. Measurements of cellular tetramethylrhodamine ethyl ester fluorescence and subsequent simulation of fluorescence changes based on Nernst calculations of fluorescence in the extracellular, cytoplasmic, and mitochondrial compartments revealed that the release of cytochrome c was preceded by mitochondrial hyperpolarization. Overexpression of the anti-apoptotic protein Bcl-xL, but not pharmacological blockade of outward potassium currents, inhibited staurosporine-induced hyperpolarization and apoptosis. Dissipation of mitochondrial potassium and proton gradients by valinomycin or carbonyl cyanide p-trifluoromethoxy-phenylhydrazone also potently inhibited staurosporine-induced hyperpolarization, cytochrome c release, and caspase activation. This effect was not attributable to changes in cellular ATP levels. Prolonged exposure to valinomycin induced significant matrix swelling, and per se also caused release of cytochrome c from mitochondria. In contrast to staurosporine, however, valinomycin-induced cytochrome c release and cell death were not associated with caspase-3 activation and insensitive to Bcl-xL overexpression. Our data suggest two distinct mechanisms for mitochondrial cytochrome c release: (1) active cytochrome c release associated with early mitochondrial hyperpolarization, leading to neuronal apoptosis, and (2) passive cytochrome c release secondary to mitochondrial depolarization and matrix swelling.