Establishment of a reliable in-vivo model of implant-associated infection to investigate innovative treatment options.

The increasing number of implant-associated infections and of multiresistant pathogens is a major problem in the daily routine. In the field of osteomyelitis, it is difficult to manage a valid clinical study because of multiple influencing factors. Therefore, models of osteomyelitis with a simulation of the pathophysiology to evaluate treatment options for implant-associated infections are necessary. The aim of this study is to develop a standardized and reproducible osteomyelitis model in-vivo to improve treatment options. This study analyses the influence of a post-infectious implant exchange one week after infection and the infection progress afterward in combination with a systemic versus a local antibiotic treatment in-vivo. Therefore, the implant exchange, the exchange to a local drug-delivery system with gentamicin, and the implant removal are examined. Furthermore, the influence of an additional systemic antibiotic therapy is evaluated. An in-vivo model concerning the implant exchange is established that analyzes clinic, radiologic, microbiologic, histologic, and immunohistochemical diagnostics to obtain detailed evaluation and clinical reproducibility. Our study shows a clear advantage of the combined local and systemic antibiotic treatment in contrast to the implant removal and to a non-combined antibiotic therapy. Group genta/syst. showed the lowest infection rate with a percentage of 62.5% concerning microbiologic analysis, which is in accordance with the immunohistochemical, cytochemical, histologic, and radiologic analysis. Our in-vivo rat model has shown valid and reproducible results, which will lead to further investigations regarding treatment options and influencing factors concerning the therapy of osteomyelitis and implant-associated infections.

Use of antibiotic coated intramedullary nails in open tibia fractures: A European medical resource use and cost-effectiveness analysis.

PURPOSE: In patients with open tibial fractures, bone and wound infections are associated with an increased hospital length of stay and higher costs. The infection risk increases with the use of implants. Innovations to reduce this risk include antibiotic-coated implants. This study models whether the use of a gentamicin-coated intramedullary tibial nail is cost-effective for trauma centers managing patients with a high risk of infection. EFFICACY: Absolute infection risk and relative risk reduction, by fracture grade, for antibiotic-coated nails compared to standard nails for patients with open tibial fractures were estimated based on the results of a meta-analysis, which assessed the additional benefit of locally-administered prophylactic antibiotics in open tibia fractures treated with implants. The observed efficacy of antibiotic-coated nails in reducing infections was applied in an economic model. METHODS: The model compared infection rates, inpatient days, theatre usage and costs in high risk patients, with a Gustilo-Anderson (GA) grade III open fracture, for two patient cohorts from a trauma center perspective, with a 1-year time horizon. In one cohort all GAIII patients received a gentamicin-coated nail whilst GAI and GAII patients received a standard nail. All patients in the comparator cohort received a standard nail. Four European trauma centers provided patient-level data (n=193) on inpatient days, procedures and related costs for patients with and without infections. RESULTS: Using the gentamicin-coated nail in patients at high risk of infection (GAIII) was associated with 75% lower rate of infection and cost savings (€477 - €3.263) for all included centers; the higher cost of the implant was offset by savings from fewer infections, inpatient days (-26%) and re-operations (-10%). This result was confirmed by extensive sensitivity analyses. CONCLUSIONS: Analyses demonstrated that infection rates and total costs for in-hospital treatment could be potentially reduced by 75% and up to 15% respectively, by using a gentamicin-coated nail in patients at high risk of infection. Fewer infections, reduced inpatient days and re-operations may be potentially associated with use of antibiotic-coated implants. Results are sensitive to the underlying infection risk, with greatest efficacy and cost-savings when the coated implant is used in high risk patients.

Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study.

BACKGROUND: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. OBJECTIVE: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the 'Stallerpatch' test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. METHODS: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. RESULTS: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. CONCLUSION: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.

[Effect of humor training on stress, cheerfulness and depression in patients with coronary artery disease and refractory angina pectoris]. / Effekt von Humortraining auf Stress, Heiterkeit und Depression bei Patienten mit koronarer Herzkrankheit und therapierefraktärer Angina pectoris.

BACKGROUND: Angina pectoris refractory to conventional medical treatment is a common phenomenon in patients with stable coronary artery disease (CAD). Many of these patients suffer from depression and generate substantial costs in the healthcare system. Therefore, the development of new therapeutic concepts is of particular importance. This study investigated whether professional, structured humor training has a positive effect on the symptoms of patients with treatment refractory angina pectoris. METHODS: Between 2013 and 2014 a total of 35 patients with stable CAD were included. Enrolment was possible if patients suffered from treatment refractory angina pectoris (Canadian Cardiovascular Society, CCS grades II-IV) despite optimal antianginal medication and exhaustion of options for myocardial revascularization. Previously, 25.8% of the patients had had a myocardial infarction. In this study, a professional humor coaching was conducted with a duration of 7 weeks. In order to evaluate the effects of the coaching, the following examinations were performed before and after the intervention: exercise stress test (treadmill), hair segment cortisol analysis, Beck Depression Inventory (BDI), the Trier Inventory for the Assessment of Chronic Stress (TICS) and the State-Trait-Cheerfulness Inventory (STCI). RESULTS: Out of the 35 initially recruited patients 31 completed the study. The mean age was 65.5 years and 94.5% were female. There was a significant improvement in cheerfulness (STCI, pre 23.3 ± 5.4, post 27.5 ± 5, p = 0,03). This effect was even stronger in a subgroup analysis in which only female patients were included (pre 23.6 ± 5.5, post 27.7 ± 4.6, p = 0.003). The results of the BDI showed a remarkable improvement in the pre-post analysis (pre 14.6 ± 8.1, post 11.0 ± 6.5, p = 0.064). Analyzing only the female patients, this difference became significant (pre 13.1 ± 6.4, post 9.9 ± 4.6 p = 0,037). The hair segment investigations showed that patients who had a higher cortisol level in the beginning (>25. percentile, n = 22) showed a significant reduction of the cortisol concentration (pre 6.54 pg/mg, 3.78-12.12 pg/mg, post 3.65 pg/mg, 2.82-7.68 pg/mg, p = 0.029). CONCLUSION: Patients with refractory angina pectoris and stable CAD benefit from a professional humor coaching. This effect was shown in a) a significant decrease in cortisol concentrations in the hair segment analysis, b) an improvement in cheerfulness in the STCI and c) a significant difference in the BDI between pre-post values.

Impact of Focal White Matter Damage on Localized Subcortical Gray Matter Atrophy in Multiple Sclerosis: A 5-Year Study.

BACKGROUND AND PURPOSE: It is unclear to what extent subcortical gray matter atrophy is a primary process as opposed to a result of focal white matter damage. Correlations between WM damage and atrophy of subcortical gray matter have been observed but may be partly attributable to indirect relationships between co-occurring processes arising from a common cause. Our aim was to cross-sectionally and longitudinally characterize the unique impact of focal WM damage on the atrophy of connected subcortical gray matter regions, beyond what is explainable by global disease progression. MATERIALS AND METHODS: One hundred seventy-six individuals with MS and 47 healthy controls underwent MR imaging at baseline and 5 years later. Atrophy and lesion-based disruption of connected WM tracts were evaluated for 14 subcortical gray matter regions. Hierarchic regressions were applied, predicting regional atrophy from focal WM disruption, controlling for age, sex, disease duration, whole-brain volume, and T2-lesion volume. RESULTS: When we controlled for whole-brain volume and T2-lesion volume, WM tract disruption explained little additional variance of subcortical gray matter atrophy and was a significant predictor for only 3 of 14 regions cross-sectionally (ΔR2 = 0.004) and 5 regions longitudinally (ΔR2 = 0.016). WM tract disruption was a significant predictor for even fewer regions when correcting for multiple comparisons. CONCLUSIONS: WM tract disruption accounts for a small percentage of atrophy in connected subcortical gray matter when controlling for overall disease burden and is not the primary driver in most cases.

[Adequate anti-infective treatment : Importance of individual dosing and application]. / Adäquate Antiinfektivatherapie : Bedeutung der individuellen Dosierung und Applikation.

Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti-infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine.

[Therapeutic drug monitoring and individual dosing of antibiotics during sepsis : Modern or just "trendy"?] / Therapeutisches Drug Monitoring und individualisierte Dosierung von Antibiotika bei der Sepsis : Modern oder nur "modisch"?

Pharmacokinetic variability of anti-infective drugs due to pathophysiological changes by severe sepsis and septic shock is a well-known problem for critically ill patients resulting in suboptimal serum and most likely tissue concentrations of these agents.To cover a wide range of potential pathogens, high concentrations of broad spectrum anti-infectives have to reach the site of infection. Microbiological susceptibility testing (susceptible, intermediate, resistant) don't take the pharmacokinetic variability into account and are based on data generated by non-critically ill patients. But inter-patient variability in distribution and elimination of anti-infective drugs in ICU patients is extremely high and also highly unpredictable. Drug clearance of mainly renally eliminated drugs and thus the required dose can differ up to 10-fold due to the variability in renal function in patients with severe infections. To assure a timely and adequate anti-infective regime, individual dosing and therapeutic drug monitoring (TDM) seem to be appropriate tools in the setting of pathophysiological changes in pharmacokinetics (PK) and pharmakodynamics (PD) due to severe sepsis. In the case of known minimal inhibitory concentration, PK/PD indices (time or peak concentration dependent activity) and measured serum level can provide an optimal target concentration for the individual drug and patient.Modern anti-infective management for ICU patients includes more than the choice of drug and prompt application. Individual dosing, optimized prolonged infusion time and TDM give way to new and promising opportunities in infection control.

[Disorders of the will in psychopathology]. / Willensstörungen in der Psychopathologie.

At the beginning of modern psychopathology the notion of the will had a high significance. Thus, the works of Eugen Bleuler, Emil Krapelin and Karl Jaspers show an intensive study of disorders of the will, such as abulia, ambivalence or disorders of impulse control. Retrospectively, changes of the scientific paradigms in psychology could be one of the reasons for a break, which led to giving up the concept of the will in psychopathology. With increasing interest in issues of agency and free will, however, a reactivation of this central concept could close a gap in psychopathology as well as in therapeutic practice. Methodologically, a psychopathology of the will may be founded on a differential typological phenomenology. To this purpose, the article first proposes a classification along the structural components of conation, suspension and volition, then gives a temporal analysis of the predecisional, the decisional and the postdecisional phases. The aim of the article is to help identify different disorders of the will, thus also furthering a psychotherapy of will, which can be connected with both cognitive behavioral and psychodynamic approaches.

[Between psyche and brain : State of the art in psychiatry]. / Zwischen Psyche und Gehirn : Zur Standortbestimmung der Psychiatrie.

Since its development around 1800 psychiatry has been oscillating between the poles of the sciences and the humanities, being directed towards subjective experience on the one hand and towards the neural substrate on the other hand. Today, this dualism seems to have been overcome by a naturalism, which identifies subjective experience with neural processes, according to Griesinger's frequently quoted statement "mental diseases are brain diseases". The progress achieved by the neurobiological paradigm on the level of a fundamental science is in contrast to the tendency to isolate mental illnesses from the patients' social relationships and to neglect subjectivity and intersubjectivity in their explanation. What should be searched for is therefore an overarching paradigm that is able to establish psychiatry as a relational medicine in an encompassing sense: as a science and practice of biological, psychological and social relationships and their disorders. Within such a paradigm, the brain may be understood and investigated as the central "relational organ" without reductionist constrictions.

Disinhibition of somatostatin-positive GABAergic interneurons results in an anxiolytic and antidepressant-like brain state.

Major depressive disorder (MDD) is associated with reduced concentrations of γ-aminobutyric acid (GABA) that are normalized by antidepressant therapies. Moreover, depressive-like phenotypes of GABAA receptor mutant mice can be reversed by treatment with conventional antidepressants drugs, as well as by subanesthetic doses of ketamine. Thus GABAergic deficits may causally contribute to depressive disorders, while antidepressant therapies may enhance GABAergic synaptic transmission. Here we tested the hypothesis that sustained enhancement of GABAergic transmission alone is sufficient to elicit antidepressant-like behavior, using disinhibition of GABAergic interneurons. We focused on somatostatin-positive (SST+) GABAergic interneurons because of evidence that their function is compromised in MDD. To disinhibit SST+ interneurons, we inactivated the γ2 subunit gene of GABAA receptors selectively in these neurons (SSTCre:γ2f/f mice). Loss of inhibitory synaptic input resulted in increased excitability of SST+ interneurons. In turn, pyramidal cell targets of SST+ neurons showed an increased frequency of spontaneous inhibitory postsynaptic currents. The behavior of SSTCre:γ2f/f mice mimicked the effects of anxiolytic and antidepressant drugs in a number of behavioral tests, without affecting performance in a spatial learning- and memory-dependent task. Finally, brain extracts of SSTCre:γ2f/f mice showed decreased phosphorylation of the eukaryotic elongation factor eEF2, reminiscent of the effects of ketamine. Importantly, these effects occurred without altered activity of the mammalian target of rapamycin pathway nor did they involve altered expression of SST. However, they were associated with reduced Ca2+/calmodulin-dependent auto-phosphorylation of eEF2 kinase, which controls the activity of eEF2 as its single target. Thus enhancing GABAergic inhibitory synaptic inputs from SST+ interneurons to pyramidal cells and corresponding chronic reductions in the synaptic excitation:inhibition ratio represents a novel strategy for antidepressant therapies that reproduces behavioral and biochemical end points of rapidly acting antidepressants.

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Contact system revisited: an interface between inflammation, coagulation, and innate immunity.

The contact system is a plasma protease cascade initiated by factor XII (FXII) that activates the proinflammatory kallikrein-kinin system and the procoagulant intrinsic coagulation pathway. Anionic surfaces induce FXII zymogen activation to form proteolytically active FXIIa. Bacterial surfaces also have the ability to activate contact system proteins, indicating an important role for host defense using the cooperation of the inflammatory and coagulation pathways. Recent research has shown that inorganic polyphosphate found in platelets activates FXII in vivo and can induce coagulation in pathological thrombus formation. Experimental studies have shown that interference with FXII provides thromboprotection without a therapy-associated increase in bleeding, renewing interest in the FXIIa-driven intrinsic pathway of coagulation as a therapeutic target. This review summarizes how the contact system acts as the cross-road of inflammation, coagulation, and innate immunity.

[Psychopathology and film: a valuable interaction?]. / Psychopathologie en film: een waardevolle interactie?

BACKGROUND: Film or film fragments are often used in psychopathology education. However, so far there have been very few articles that have discussed the benefits and limitations of using films to explain or illustrate psychopathology. Although numerous films involves psychopathology in varying degrees, it is not clear how we can use films for psychopathology education. AIM: To examine the advantages, limitations and possible methods of using film as a means of increasing our knowledge and understanding of psychiatric illnesses. METHOD: We discuss five examples that illustrate the interaction of film and psychopathology. On the one hand we explain how the psychopathological concepts are used in each film and on the other hand we explain which aspects of each film are valuable aids for teaching psychopathology. RESULTS: The use of film makes it possible to introduce the following topics in psychopathological teaching programme: holistic psychiatric reasoning, phenomenology and the subjective experience, the recognition of psychopathological prototypes and the importance of context. CONCLUSION: There is undoubtedly an analogy between the method we have chosen for teaching psychopathology with the help of films and the holistic approach of the psychiatrist and his or her team. We believe psychopathology education can benefit from films and we would recommend our colleagues to use it in this way.

[Implant augmentation in pelvic surgery. Options and technique]. / Implantataugmentation am Becken. Optionen und Technik.

BACKGROUND: Osteoporotic fractures of the pelvis are an increasing problem in trauma surgery. Sufficient implant anchorage is reduced due to the poor bone stock; however, early mobilization is especially necessary for geriatric patients in order to prevent additional complications. MATERIAL AND METHODS: Implant augmentation may be one technique to increase implant anchorage and stability in osteoporotic bone. This procedure is currently used in the treatment of osteoporotic fractures of the dorsal pelvic ring. Beside the augmentation of iliosacral screws in the treatment of sacral insufficiency fractures, cement augmentation with lumbar or sacral pedicle screws is used for increased stability. INDICATIONS AND RISKS: Implant augmentation in pelvic surgery should be indicated crucially due to the specific risks of the procedure. Cement leakage and heat generation during cement curing (when PMMA--polymethylmetacrylate--cement is used) can compromise neurovascular structures. Potential complications like cement embolism are possible. CONCLUSION: The use of special implants (cannulated and perforated screws) as well as intraoperative navigation and 3D imaging increase patient safety and help to make implant augmentation a low risk procedure.

Factor XII: a novel target for safe prevention of thrombosis and inflammation.

Plasma protein factor XII (FXII) activates the procoagulant and proinflammatory contact system that drives both the kallikrein-kinin system and the intrinsic pathway of coagulation. When zymogen FXII comes into contact with negatively charged surfaces, it auto-activates to the serine proteaseactivated FXII (FXIIa). Recently, various in vivo activators of FXII have been identified including heparin, misfolded protein aggregates, polyphosphate and nucleic acids. Murine models have established a central role of FXII in arterial and venous thrombosis. Despite its central function in thrombosis, deficiency in FXII does not impair haemostasis in animals and humans. In a preclinical cardiopulmonary bypass system in large animals, the FXIIa-blocking antibody 3F7 prevented thrombosis; however, in contrast to traditional anticoagulants, bleeding was not increased. In addition to its function in thrombosis, FXIIa initiates formation of the inflammatory mediator bradykinin. This mediator increases vascular leak, causes vasodilation, and induces chemotaxis with implications for septic, anaphylactic and allergic disease states. Therefore, targeting FXIIa appears to be a promising strategy for thromboprotection without associated bleeding risks but with anti-inflammatory properties.

Mechanical characterization between room temperature and 1000 °C of SiC free-standing thin films by a novel high-temperature micro-tensile setup.

A novel high-temperature micro-tensile setup allows the characterization of the elastic and plastic as well as creep behavior of free-standing thin films at temperatures of up to 1000 °C. Correspondingly, a new layout for free-standing thin film tensile test structures has been developed, enabling accurate self-alignment upon loading. Furthermore, a differential optical strain measurement technique as well as optimizations of the optical path has been implemented, providing a strain resolution of well below 1 × 10(-4) at 1000 °C. Two different polycrystalline SiC free-standing thin films have been investigated in tension to acquire stress-strain data and corresponding Young's modulus at up to 1000 °C. The high sensitivity of the strain measurement technique makes it also possible to identify creep strains in the high-temperature regime.

Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies.

BACKGROUND: Acute thrombotic microangiopathies (TMAs) are characterized by excessive microvascular thrombosis and are associated with markers of neutrophil extracellular traps (NETs) in plasma. NETs are composed of DNA fibers and promote thrombus formation through the activation of platelets and clotting factors. OBJECTIVE: The efficient removal of NETs may be required to prevent excessive thrombosis such as in TMAs. To test this hypothesis, we investigated whether TMAs are associated with a defect in the degradation of NETs. METHODS AND RESULTS: We show that NETs generated in vitro were efficiently degraded by plasma from healthy donors. However, NETs remained stable after exposure to plasma from TMA patients. The inability to degrade NETs was linked to a reduced DNase activity in TMA plasma. Plasma DNase1 was required for efficient NET degradation and TMA plasma showed decreased levels of this enzyme. Supplementation of TMA plasma with recombinant human DNase1 restored NET-degradation activity. CONCLUSIONS: Our data indicate that DNase1-mediated degradation of NETs is impaired in patients with TMAs. The role of plasma DNases in thrombosis is, as of yet, poorly understood. Reduced plasma DNase1 activity may cause the persistence of pro-thrombotic NETs and thus promote microvascular thrombosis in TMA patients.