[ATLS® and TDSC®: how it fits together : A treatment concept for mass casualty and terrorist-related mass casualty situations, life-threatening and special scenarios]. / ATLS® und TDSC®: How it fits together : Ein Behandlungskonzept für MANV und TerrorMANV, lebensbedrohliche oder besondere Lagen.

Terrorist-related mass casualty incidents represent a medical and organizational challenge for all hospitals. The main reasons are the special patterns of injuries, the onset and development of the scenario, the lack of information at the beginning, the overall number of casualties and the number of uninjured but involved patients presenting at the hospital.Due to these circumstances and the high percentage of penetrating injuries with a permanent risk of uncontrollable bleeding and other life-threatening complications, a strategic and tactical initial surgical care is necessary.For these special terrorist-related mass casualty (MasCal) situations, the Terror and Disaster Surgical Care (TDSC®) course was developed and imparts special medical and surgical knowledge as well as a scenario-based training in surgical decision-making. The TDSC® course focusses on the scenario-related provision of surgical care and distribution of the limited resources to enable survival for as many patients as possible.To improve individualized trauma care course formats, such as the Advanced Trauma Life Support (ATLS®) were established and are nowadays widespread in Germany. It could be shown that standardized approaches and algorithm-based treatment could improve the outcome of trauma victims. Faced with the present day permanent risk of a possible terrorist-related MasCal situation, the question arises how and to what extent elements and principles of both course formats (TDSC® and ATLS®) could be used to improve and organize the initial care in a terrorist-linked MasCal incident.For the first time it is shown that the key elements of both courses (primary survey of the ATLS® and the TDSC® principles: categorization, prioritization, disposition and realization) could be established and integratively used to structure the initial intrahospital medical and surgical care.

[Update on gunshot wounds to extremities]. / Update zu Schussverletzungen der Extremitäten.

Due to recent rampage and terror attacks in Europe, gunshot wounds have become a focus of attention even though they are still rare in Europe. Approximately 50% of gunshot wounds affect the extremities and to understand the sequelae, a basic knowledge of wound ballistics is indispensable. The energy transmitted from the bullet to the tissue is responsible for the severity of the injury and is dependent on the type of weapon and ammunition. A differentiation is made between low-energy injuries caused, e.g. by pistols and high-energy injuries mostly caused by rifles. The higher energy transfer to the tissue in high-energy injuries, results in a temporary wound cavity in addition to the permanent wound channel with extensive soft tissue damage. High-energy gunshot fractures are also more extensive compared to those of low energy injuries. Debridement seems to be necessary for almost all gunshot wounds. Fractures should be temporarily stabilized with an external fixator due to contamination.

[The Summer School of the German Society for Orthopaedics and Traumatology - A Success Story]. / Die Summer School der Deutschen Gesellschaft für Orthopädie und Unfallchirurgie ­ eine Erfolgsgeschichte.

Background: It has been known for several years that orthopaedic and trauma clinics suffer from a shortage of young people, due to the substantial loss in attractiveness. The Youth Forum OU has been addressing this problem for many years, by initiating many projects such as the Summer School to counteract this trend. The purpose of this research is to evaluate the success of Summer Schools since 2009. Methods: The Youth Forum OU performed a survey in December 2014 to answer the research question on the basis of an internet-based poll of the student participants in all Summer Schools between 2009 and 2014. Following data cleansing, 121 students and former students were included in the survey. Results: Seventy-two completed questionnaires were collected and included in the evaluation. The survey included 40 % of Summer School participants, with a mean age of 27.3 years (SD ± 2.95); 50 % were female. Participation in the Summer School helped 50 % of the respondents to decide to start advanced study in orthopaedics and/or traumatology (OU). One third of these Summer School participants had already finished a university degree; 100 % are now residents in orthopaedics and/or traumatology. Regardless of prior plans, 87.2 % of participants are now residents in OU. Thirty-three are still students: 78.8 % have already decided to work in OU. The survey also served to identify the factors positively and negatively associated with OU. Unfavourable factors included the reputation of OU, and the difficulty of reconciling family and work. Favourable factors included surgical work and personal experience during university studies. Discussion: The aim of this study was to evaluate whether the efforts of the Youth Forum OU, the German Society for Orthopaedics and Traumatology (DGOU) and the local hospitals lead to increased interest in OU. The answer to this question is positive. This is particularly true for those students who did not plan to become an orthopaedic or trauma surgeon before participating in a Summer School. In conclusion, the efforts to recruit residents for OU by using Summer Schools were successful. Moreover, this research offers approaches to counteract the loss of attractiveness of OU.

Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy.

[The young resident between work and family. Status quo and approaches to a solution in orthopedics and traumatology]. / Der junge Arzt zwischen Beruf und Familie. Status quo und Lösungsansätze im Fach Orthopädie und Unfallchirurgie.

The compatibility between the family and the medical profession requires a new challenge of leadership in hospitals, politics and medical societies. The generation change in the medical profession needs the implementation of modern framework conditions in the departments of orthopedics and traumatology. Topics such as work organisation, family support and programs to assist the return to work need to be discussed and should be used as a competitive advantage. Employees of generation y need a gender-independent role model in the field of modern management methods in employee leadership.

[How many generalists and how many specialists does orthopedics and traumatology need?]. / Wie viel Generalist und wie viel Spezialist braucht die Orthopädie und Unfallchirurgie?

The training in orthopedic and trauma surgery has changed significantly with the introduction of the new residency program. The contents taught have already been reduced in breadth and the current developments in the outpatient and particularly in the clinical landscape also contribute to increasing specialization. This trend favors structures in which comprehensive medical care for the population in Germany in orthopedic and trauma surgery appears to be endangered and in which the future efforts for e.g. polytraumatised patients need to be questioned. The Young Forum of the German Society for Orthopedics and Traumatology actively accompanies a discussion about the necessity and value of generalists to ensure the level of care in Germany in addition to the specialists.

Cytokeratin 8 interacts with clumping factor B: a new possible virulence factor target.

Staphylococcus aureus is a human pathogen of growing clinical significance, owing to its increasing levels of resistance to most antibiotics. Infections range from mild wound infections to severe infections such as endocarditis, osteomyelitis and septic shock. Adherence of S. aureus to human host cells is an important step, leading to colonization and infection. Adherence is mediated by a multiplicity of proteins expressed on the bacterial surface, including clumping factor B. In this study, we aimed to identify new targets of clumping factor B in human keratinocytes by undertaking a genome-wide yeast two-hybrid screen of a human keratinocyte cDNA library. We show that clumping factor B is capable of binding cytokeratin 8 (CK8), a type II cytokeratin. Using a domain-mapping strategy we identified amino acids 437-464 as necessary for this interaction. Recombinantly expressed fragments of both proteins were used in pull-down experiments and confirmed the yeast two-hybrid studies. Analysis with S. aureus strain Newman deficient in clumping factor B showed the clumping factor B-dependence of the interaction with CK8. We postulate that the clumping factor B-CK8 interaction is a novel factor in S. aureus infections.

[Do meniscus injuries affect postural stability?]. / Beeinträchtigen Meniskusverletzungen den stabilen Stand?

BACKGROUND: Meniscal lesions are known to cause a loss of proprioception, which plays an important role in the regulation of postural stability. It is unclear, however, whether meniscus injuries adversely affect not only the sense of joint position but also postural control. The objective of this study was to investigate the influence of meniscal lesions on postural stability. MATERIAL AND METHODS: In this prospective study, postural stability was assessed by posturography in 27 patients with unilateral meniscal lesions. Both the injured and uninjured legs were tested and compared for significant differences using a t-test. RESULTS: Despite the presence of an arthroscopically confirmed meniscal lesion, none of the stability indexes that we calculated revealed significant differences in postural stability between the injured and uninjured sides. CONCLUSIONS: It was surprising to note that the loss of proprioception in patients with meniscus injuries did not influence postural stability. Patients with functional knee instability must therefore be examined for the presence of further injuries because a meniscal lesion alone cannot explain instability symptoms.

[Spectrum of surgical procedures performed in German rescue centers and the field hospital in Afghanistan in 2008]. / Spektrum der Operationen in deutschen Sanitätseinrichtungen in Afghanistan im Jahr 2008.

From the military perspective detailed knowledge about the spectrum of operations undertaken abroad is of particular interest to provide indications of the skills that will be required by the surgeons. Therefore, all surgical reports produced in 2008 in the operation theatres of Mazar-e-Sharif, Feyzabad and Kunduz were reviewed. The overview shows that a total of 799 operations were performed equivalent to 0.4-1.6 operations/day. Most of the patients who underwent surgery were local civilians and most of these operations involved osteosynthesis, débridement and soft tissue procedures. Of the surgical procedures 11% involved patients who were German service personnel of which 85% were urgent or emergency procedures and 25% of these involved treatment of combat injuries. When civilian patients with life-threatening injuries or diseases are referred to the medical facilities there is little opportunity to make decisions with regard to acceptance. Often it may be necessary for surgeons to perform procedures which are outside their field of specialization. In order to ensure a favorable outcome in acute situations surgeons mainly required skills in emergency surgery of the body cavities (visceral and thoracic surgery).

[Patterns and causes of injuries in a contemporary combat environment]. / Verletzungsmuster und -ursachen in modernen Kriegen.

Epidemiological analyses of injury patterns and mechanisms help to identify the expertise military surgeons need in a combat setting and accordingly help to adjust infrastructure and training requirements. Therefore, a MEDLINE search (1949-2009), World Wide Web search (keywords "combat, casualties, war, military, wounded and neurosurgery") and an analysis of deaths among allied war casualties in Afghanistan and Iraq were performed. Up to 10th December 2009 there had been 4,688 allied military deaths in Iraq and 1,538 in Afghanistan. Of these 22% died in non-hostile action, 33% in direct combat situations and the majority of 45% in indirect combat actions. The leading causes of injury were explosive devices (70%) and gunshot wounds. Chest or abdominal injuries (40%) and traumatic brain injuries (35%) were the main causes of death for soldiers killed in action. The case fatality rate in Iraq is approximately half that of the Vietnam War, whereas the killed-in-action rate in Afghanistan (18.7%) is similar to the Vietnam War (20%); however, the amputation rate is twice as high in modern conflicts. Approximately 8-15% of the fatal injuries seem to be potentially survivable.Military surgeons must have an excellent expertise in a wide variety of surgical specialties. Life saving emergency care, especially in the fields of thoracic, visceral and vascular surgery as well as practical skills in the fields of neurosurgery and oral and maxillofacial surgery are required. Additionally, it is of vital importance to ensure the availability of sufficient tactical and strategic medical evacuation capabilities for the wounded.

Limited humoral immunoglobulin E memory influences serum immunoglobulin E levels in blood.

The switch of B cells expressing membrane-bound Igs, which serve as antigen receptors, to antibody-secreting plasmablasts and finally to non-dividing, long-lived plasma cells (PCs) lacking an antigen receptor, marks the terminal differentiation of a B cell. Antibody-secreting PCs represent the key cell type for the maintenance of a proactive humoral immunological memory. Although some populations of long-lived PCs persist in the spleen, most of them return to their 'place of birth' and travel to the bone marrow or invade inflamed tissues, where they survive up to several months in survival niches as resident, immobile cells. Existing data strongly support the notion that isotype-specific receptor signalling influences the migration behaviour of plasmablasts to the bone marrow. The recent observation in the murine system that the immigration of plasmablasts and the final differentiation to long-lived PCs in the bone marrow is dependent on the expressed B-cell isotype and the related expression of chemokine receptors leads to the conclusion that during a T-helper type 2 (Th2)-mediated immune response in wild type mice, IgE plasmablasts do not have the same chance to contribute to long-lived PC memory as IgG1 plasmablasts. The overall limited humoral IgE memory additionally restricts the quantity of IgE Igs in the serum.

AllergoOncology: the role of IgE-mediated allergy in cancer.

Epidemiological studies have suggested inverse associations between allergic diseases and malignancies. As a proof of concept for the capability of immunoglobulin E (IgE) to destruct tumor cells, several experimental strategies have evolved to specifically target this antibody class towards relevant tumor antigens. It could be demonstrated that IgE antibodies specific to overexpressed tumor antigens have been superior to any other immunoglobulin class with respect to antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) reactions. In an alternative approach, IgE nonspecifically attached to tumor cells proved to be a powerful adjuvant establishing tumor-specific immune memory. Active Th2 immunity could also be achieved by applying an oral immunization regimen using mimotopes, i.e. epitope mimics of tumor antigens. The induced IgE antibodies could be cross-linked by live tumor cells leading to tumoricidic mediator release. Thus, IgE antibodies may not only act in natural tumor surveillance, but could possibly also be exploited for tumor control in active and passive immunotherapy settings. Thereby, eosinophils, mast cells and macrophages can be armed with the cytophilic IgE and become potent anti-tumor effectors, able to trace viable tumor cells in the tissues. It is strongly suggested that the evolving new field AllergoOncology will give new insights into the role of IgE-mediated allergy in malignancies, possibly opening new avenues for tumor therapy.

Molecular and cellular targets of anti-IgE antibodies.

Immunoglobulin E (IgE) was the last of the immunoglobulins discovered. It is present in very low amounts (nano- to micro-gram per ml range) in the serum of normal healthy individuals and normal laboratory mouse strains and has a very short half-life. This contrasts with the other immunoglobulin classes, which are present in much higher concentrations (micro- to milligram per ml range) and form a substantial component of serum proteins. Immunoglobulins play a role in homeostatic mechanisms and they represent the humoral arm of defence against pathogenic organisms. Since IgE antibodies play a key role in allergic disorders, a number of approaches to inhibit IgE antibody production are currently being explored. In the recent past the use of nonanaphylactic, humanized anti-IgE antibodies became a new therapeutic strategy for allergic diseases. The therapeutic rational beyond the idea derives from the ability of the anti-IgE antibodies to bind to the same domains on the IgE molecule that interact with the high-affinity IgE receptor, thereby interfering with the binding of IgE to this receptor without cross-linking the IgE on the receptor (nonanaphylactic anti-IgE antibodies). Treatment with anti-IgE antibodies leads primarily to a decrease in serum IgE levels. As a consequence thereof, the number of high-affinity IgE receptors on mast cells and basophils decreases, leading to a lower excitability of the effector cells reducing the release of inflammatory mediator such as histamine, prostaglandins and leukotrienes. Experimental studies in mice indicate that injection of some monoclonal anti-IgE antibodies also inhibited IgE production in vivo. The biological mechanism behind this reduction remains speculative. A possible explanation may be that these antibodies can also interact with membrane bound IgE on B cells, which could interfere the IgE production.

Immunoglobulin E-binding and skin test reactivity to hydrophobin HCh-1 from Cladosporium herbarum, the first allergenic cell wall component of fungi.

BACKGROUND: For many years, fungal spores have been recognized as potential causes of respiratory allergies. All fungal allergens cloned so far represent either secreted or cytoplasmatic proteins, but nothing is known about the involvement of fungal surface proteins in allergic diseases. METHODS: A phage surface displayed cDNA-library from the mould Cladosporium herbarum was constructed and phage displaying IgE-binding proteins were selectively enriched with immobilized serum IgE from C. herbarum-sensitized individuals. Inserts encoding putative allergens were sequenced, subcloned and used to produce recombinant proteins. Allergenicity of the proteins was evaluated by IgE binding in Western blots, enzyme-linked immunosorbent assay (ELISA) and skin prick test in a total of 84 patients sensitized to either C. herbarum or Aspergillus fumigatus and three healthy controls. RESULTS: After four rounds of affinity selection, the cDNA-library was enriched for clones displaying IgE-binding molecules. Sequencing of inserts showed that one clone contained an open reading frame predicting a protein of 105 amino acids and a calculated molecular weight of 10.5 kDa showing the classical signature of members of the hydrophobin family. The recombinant protein, termed HCh-1, was able to bind IgE from six patients sensitized to fungi in vitro. Two of those patients were also included in a skin prick test survey and showed strong type I skin reactions to HCh-1, demonstrating the allergenic nature of C. herbarum hydrophobin and indicating a prevalence of sensitization in the range of 8-9%. In contrast, the hydrophobin HYP1 from Aspergillus fumigatus was not recognized by the sera of the same patients and controls investigated with HCh-1. CONCLUSION: C. herbarum hydrophobin represents the first component of the cell wall of fungi demonstrated to act as a rare but clinically relevant allergen in vitro and in vivo.

Somatic diversity of the immunoglobulin repertoire is controlled in an isotype-specific manner.

We have studied two aspects of the IgE immune response. First, we have compared the kinetics of the IgE response to the T cell-dependent antigen ph-Ox coupled to ovalbumin with that of the IgG1 response and we have assessed the quality of the IgE response. Second, we have studied the generation of somatic diversity, understood as the combined effect of somatic mutation and the selection of D(iversity) and J(oining) elements, in germinal center B cells at the molecular level, using the germ-line sequence of the prototype anti-ph-Ox heavy chain variable element V(H)Ox1 as reference. We evaluated sequences derived from mu-, gamma 1- and epsilon-variable elements and showed that somatic diversification was different for all isotypes studied. We further compared the IgE responses of wild-type mice with those of mice expressing a truncated cytoplasmic IgE tail (IgE(KVK Delta tail)). IgE(KVK Delta tail) mice showed a more diverse sequence pattern. We corroborated previous results suggesting that short CDR3 regions are indicative for high-affinity antibodies by measuring relative affinities of phage-expressed Fab fragments with prototype long and short CDR3 regions. Therefore, the composition of the antigen-receptor is responsible for the selection process and the expansion of antigen-specific cells, leading to an isotype-specific antibody repertoire.

The IgE antigen receptor: a key regulator for the production of IgE antibodies.

Immunoglobulins in general form a substantial component of serum proteins, and play a role in homeostatic mechanisms, a first line of defense against pathogenic organisms and in immunological memory. In the secreted form, immunoglobulins represent the effector arm of the humoral immune system. However, immunoglobulins are not only secreted, but can also be expressed on the surface of a B lymphocyte (membrane immunoglobulin), and, in this physical state, most likely convey signals to steer the B cell along its differentiation pathway. A step forward in the understanding of the role of membrane immunoglobulins other than membrane IgM or IgD was achieved with two mouse lines with mutations in the epsilon heavy chain gene. In IgE(DeltaM1M2) mice serum IgE is reduced to less than 10% of normal mice, while IgE(KVKDeltatail) mice show a reduction of 50%, reflecting a serious impairment of the IgE-mediated immune response. We think that the cytoplasmic tail of IgE is involved in a signal transduction which leads to the expression of high quantities and qualities of secreted IgE immunoglobulins.