Metformin shows anti-neoplastic properties by inhibition of oxidative phosphorylation and glycolysis in epidermolysis bullosa-associated aggressive cutaneous squamous cell carcinoma.

BACKGROUND: While most cutaneous squamous cell carcinomas (cSCCs) are treatable, certain high-risk cSCCs, such as those in recessive dystrophic epidermolysis bullosa (RDEB) patients, are particularly aggressive. Owing to repeated wounding, inflammation and unproductive healing, RDEB patients have a 68% cumulative risk of developing life-threatening cSCCs by the age of 35, and a 70% risk of death by the age of 45. Despite aggressive treatment, cSCC represents the leading cause of premature mortality in these patients, highlighting an unmet clinical need. Increasing evidence points to a role of altered metabolism in the initiation and maintenance of cSCC, making metabolism a potential therapeutic target. OBJECTIVES: We sought to determine the feasibility of targeting tumour cell energetics as a strategy to selectively hinder the growth advantage of aggressive cSCC. METHODS: We evaluated the cell energetics profiles of RDEB-SCC cells by analysing available gene expression data against multiple gene signatures and single-gene targets linked to metabolic reprogramming. Additionally, we employed real-time metabolic profiling to measure glycolysis and respiration in these cells. Furthermore, we investigated the anti-neoplastic properties of the metformin against human and murine high-risk cSCCs in vitro and in vivo. RESULTS: Gene expression analyses highlighted a divergence in cell energetics profiles between RDEB-SCC and non-malignant RDEB keratinocytes, with tumour cells demonstrating enhanced respiration and glycolysis scores. Real-time metabolic profiling supported these data and additionally highlighted a metabolic plasticity of RDEB-SCC cells. Against this background, metformin exerted an anti-neoplastic potential by hampering both respiration and glycolysis, and by inhibiting proliferation in vitro. Metformin treatment in an analogous model of fast-growing murine cSCC resulted in delayed tumour onset and slower tumour growth, translating to a 29% increase in median overall survival. CONCLUSIONS: Our data indicate that metformin exerts anti-neoplastic properties in aggressive cSCCs that exhibit high-risk features by interfering with respiration and glycolytic processes.

Litigations in orthopedics and trauma surgery: reasons, dynamics, and profiles.

BACKGROUND: In recent literature, the increasing number of medical litigations, both in terms of the number of cases being filed and the substantive costs associated with lawsuits, has been described. This study aims to provide an overview of the profile of litigation for orthopedic and trauma surgery to describe the differences and the development of the number of cases over time. PATIENTS AND MATERIALS: A retrospective review of all litigations between 2000 and 2017 was conducted using the institutional legal database. The causes of litigation were documented and classified into seven major categories. In addition to plaintiff characteristics, the litigation outcomes and the differences between emergency and elective surgery were analyzed. RESULTS: A total of 230 cases were evaluated. The mean age of the plaintiffs was 44.6 ± 20.1 years, and 56.8% were female. The main reasons for litigation were claimed inappropriate management (46.1%), misdiagnosis (22.6), and poor nursing care (8.3%). Significantly more litigations were filed against surgeons of the orthopedic subspecialty compared with trauma surgeons (78%; p ≤ 0.0001). There were significantly fewer litigations per 1000 cases filed overall in 2009-2017 (65% less; p = 0.003) than in 2000-2008. CONCLUSION: Our results could not confirm the often-stated trend of having more litigations against orthopedic and trauma surgeons. Although the absolute numbers increased, the number of litigations per 1000 patients treated declined. Patients who underwent elective surgery were more likely to file complaints than emergency patients.

Therapeutic assessment of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in reducing periprosthetic joint infection.

Despite many preventive measures, including prophylactic antibiotics, periprosthetic joint infection (PJI) remains a devastating complication following arthroplasty, leading to pain, suffering, morbidity and substantial economic burden. Humans have a powerful innate immune system that can effectively control infections, if alerted quickly. Unfortunately, pathogens use many mechanisms to dampen innate immune responses. The study hypothesis was that immunomodulators that can jumpstart and direct innate immune responses (particularly neutrophils) at the surgical site of implant placement would boost immune responses and reduce PJI, even in the absence of antibiotics. To test this hypothesis, N-formyl-methionyl-leucyl-phenylalanine (fMLP) (a potent chemoattractant for phagocytic leukocytes including neutrophils) was used in a mouse model of PJI with Staphylococcus aureus (S. aureus). Mice receiving intramedullary femoral implants were divided into three groups: i) implant alone; ii) implant + S. aureus; iii) implant + fMLP + S. aureus. fMLP treatment reduced S. aureus infection levels by ~ 2-Log orders at day 3. Moreover, fMLP therapy reduced infection-induced peri-implant periosteal reaction, focal cortical loss and areas of inflammatory infiltrate in mice distal femora at day 10. Finally, fMLP treatment reduced pain behaviour and increased weight-bearing at the implant leg in infected mice at day 10. Data indicated that fMLP therapy is a promising novel approach for reducing PJI, if administered locally at surgical sites. Future work will be toward further enhancement and optimisation of an fMLP-based therapeutic approach through combination with antibiotics and/or implant coating with fMLP.

Fretting-corrosion of CoCr-alloys against TiAl6V4: The importance of molybdenum in oxidative biological environments.

Periprosthetic fluids often contain reactive oxygen species, including H2O2, that are generated during inflammatory processes. Here, we investigated the fretting-corrosion behavior of CoCrX-alloys (X = Mo, Fe) in a complex protein-containing lubricant, with and without the addition of H2O2. Given the known protective role of molybdenum as an alloying element in metal degradation, we considered its effects by designing a two-way factorial experiment. The aim of the study was to investigate tribocorrosive mechanisms in modular joints of knee and hip prostheses. A previously described test-rig was used to run fretting corrosion tests of CoCrX-alloys with (X=Mo) and without (X=Fe) molybdenum against TiAl6V4 in bovine calf serum (BCS) with and without a physiological relevant H2O2 level (3 mM) in gross slip mode (4 Hz, ±50 µm, pmax=0.18 GPa, 37 °C, 50,000 cycles). Two CoCr-pins were pressed against a cylindrical TiAl6V4-rod, forming a line contact. Normal and frictional forces, the displacement, and the open circuit potential (OCP) were measured and recorded continuously. The dissipated frictional work was independent of alloy composition. The addition of H2O2 lowered the dissipated frictional work and increased wear, and this was significant in the absence of Mo. The mean OCP value was lower with Mo-containing than with Mo-free alloy in both pure BCS (p = .042), and BCS ± H2O2 (p < .0005). The wear scar was deeper for the Mo-free alloy, and this was significant (p = .013) in the presence of H2O2. These findings suggest a marked weakening of the passive film in the presence of H2O2, which is mitigated by the availability of Mo.

Microindentation of cartilage before and after articular loading in a bioreactor: assessment of length-scale dependency using two analysis methods.

Background: Microindentation is a technique with high sensitivity and spatial resolution, allowing for measurements at small-scale indentation depths. Various methods of indentation analysis to determine output properties exist. Objective: Here, the Oliver-Pharr Method and Hertzian Method were compared for stiffness analyses of articular cartilage at varying length-scales before and after bioreactor loading. Methods: Using three different conospherical tips with varying radii (20, 100, 793.75 µm), a bioreactor-indenter workflow was performed on cartilage explants to assess changes in stiffness due to articular loading. For all data, both the Oliver-Pharr Method and Hertzian Method were applied for indentation analysis. Results: The reduced moduli calculated by the Hertzian Method were found to be similar to those of the Oliver-Pharr Method when the 20 µm tip size was used. The reduced moduli calculated using the Hertzian Method were found to be consistent across the varying length-scales, whereas for the Oliver-Pharr Method, adhesion/suction led to the largest tip exhibiting an increased average reduced modulus compared to the two smaller tips. Loading induced stiffening of articular cartilage was observed consistently, regardless of tip size or indentation analysis applied. Conclusions: Overall, geometric linearity is preserved across all tip sizes for the Hertzian Method and may be assumed for the two smaller tip sizes using the Oliver-Pharr Method. These findings further validate the previously described stiffening response of the superficial zone of cartilage after articular loading and demonstrate that the finding is length-scale independent.

[Treatment-process analysis of orthopaedic trauma surgery patients at an outpatient setting in a university hospital]. / Prozessanalyse der ambulanten Behandlung unfallchirurgischer Patienten an einer universitären Poliklinik.

BACKGROUND: The cost pressure in a competitive environment forces hospitals and physicians to optimize clinical processes. In order to secure competitive advantages, a continuous evaluation of relevant processes is necessary. OBJECTIVE: Administrative and medical processes in a university outpatient department for orthopedics and traumatology were evaluated using the lean method in order to reduce patient waiting times. MATERIAL AND METHODS: Over a period of 2 weeks all patients who were treated in the department for orthopedic and trauma surgery on an outpatient basis were included in the assessment of the process. Personnel in the policlinic were prepared and trained to record times for appointments made by telephone, arrival time at the hospital, first contact, administrative procedure, first contact with the doctor, length of stay in the radiology and anesthesiology departments and completion of treatment. In addition, potential inefficiencies were identified through patient flow analysis and personal interviews with personnel in the administration and outpatient departments as well as residents and senior physicians. RESULTS: A total of 126 patients were enrolled in the study. The average length of stay of patients in the outpatient clinic was 144 min (range 30-371 min). A necessary imaging examination increased the length of stay by an average of 53 min and a necessary premedication by an average of 78 min compared to patients with no further consultations. CONCLUSION: By analyzing the pathways and times of patients, various reasons for waiting times in the university outpatient clinic could be shown. This study shows that a structured application of lean management and a dedicated analysis create added value for patients by reducing waiting times.

[Process optimization in the operating room area]. / Prozessoptimierung im operativen Bereich.

BACKGROUND: The operating room (OR) accounts for the highest fraction of hospital costs and also has the largest proportion of revenue. Classical goals of optimizing OR efficiency are to increase the quality of treatment and economic success. As the reduction of qualified personnel as the largest cost factor was favored for many years, nowadays a shortage of nursing personnel is threatening the surgery departments in many German hospitals. OBJECTIVE: Which improvements are possible while the OR already suffers from restrictions? What are critical resources, what are the critical burdens and how can they be optimized? MATERIAL AND METHODS: An analysis of the OR organization of an orthopedic and traumatology department with reduced OR capacity due to a shortage of OR and anesthesia nursing personnel was performed. This was followed by the evaluation of possible alterations with the corresponding advantages and disadvantages. After selection and implementation, the qualitative and quantitative differences were examined before and after the alterations. RESULTS: Multifaceted problem areas could be identified. The establishment of a fast track OR with concentration of additional resources on many fast points in an OR instead of on a few complex cases was selected and implemented. The installation of a holding area for patients waiting for surgery eliminated transportation delays almost entirely. Alterations in the OR planning and capacity distribution reduced nocturnal operating times. Despite reduction of the OR capacity both the number of operations performed and the incision to suture times could be increased. CONCLUSION: Optimization of the processes in the OR is possible and necessary, despite the lack of personnel. Even only a few structural changes can eliminate bottlenecks, resulting in qualitative and quantitative improvements.

[Medical service providers as bottleneck in orthopedics and trauma surgery : Problems and solution strategies in interdisciplinary collaboration]. / Medizinische Dienstleister als Nadelöhr in Orthopädie und Unfallchirurgie : Probleme und Lösungsstrategien in der interdisziplinären Zusammenarbeit.

BACKGROUND: Due to limited financial and human resources, efficient planning of patient flows, operation preparations and perioperative diagnostics are of great importance. In the present study potential problems and solution strategies in the interdisciplinary collaboration between orthopedic surgeons, trauma surgeons and colleagues in anesthesiology and radiology departments are presented. MATERIAL AND METHODS: After implementation of a process management system, the data were collated and the number of patients, the utilization of external departments in the consultation, waiting times and patient adherence to appointments were analyzed. Patient satisfaction was determined using a questionnaire. In addition, the current literature was searched regarding the topic of process optimization and interdisciplinary cooperation. RESULTS: The waiting time for an appointment in the outpatient clinic consultation in orthopedics and trauma at the University Hospital Bonn was between 9.15 and 11.23 days. Of the patients 10-20% from the consultation presented in the premedication outpatient department. Radiological imaging was performed in 22-28% of the cases. Patient satisfaction was recorded using a questionnaire gathering information on medical treatment, organization and infrastructure as well as treatment success. The importance of an efficient and digitally organized cooperation is generally promoted in the literature; however, there is insufficient data on the subject of process organization and economic interdisciplinary cooperation. CONCLUSION: By implementing a process management, deficiencies in the workflow and interdisciplinary collaboration can be identified and optimized in a structured manner. This also improves patient and employee satisfaction and the quality of treatment.

Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny.

Paternal environmental perturbations including exposure to drugs of abuse can produce profound effects on the physiology and behavior of offspring via epigenetic modifications. Here we show that adult drug-naive male offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity. Reduced levels of the endogenous NMDA receptor co-agonist d-serine were accompanied by increased expression of the d-serine degrading enzyme d-amino acid oxidase (Dao1) in the hippocampus of cocaine-sired male progeny. Increased Dao1 transcription was associated with enrichment of permissive epigenetic marks on histone proteins in the hippocampus of male cocaine-sired progeny, some of which were enhanced near the Dao1 locus. Finally, hippocampal administration of d-serine reversed both the memory formation and synaptic plasticity deficits. Collectively, these results demonstrate that paternal cocaine exposure produces epigenetic remodeling in the hippocampus leading to NMDA receptor-dependent memory formation and synaptic plasticity impairments only in male progeny, which has significant implications for the male descendants of chronic cocaine users.

Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny.

This corrects the article DOI: 10.1038/mp.2017.8.

Fluid collection bags pose a threat for bacterial contamination in primary total hip arthroplasty: a prospective, internally controlled, non-blinded trial.

INTRODUCTION: Surgical equipment, and especially the so-called 'splash basins' that are used intraoperatively, are a potential source of bacterial contamination in primary total hip arthroplasty (THA). With this risk in mind, many commercially available draping kits include plastic bags that can be used to collect fluid or to temporarily store instruments. Following this rationale, we hypothesised that first: the fluid collection bags are a potential reservoir of bacteria and second: there is a time dependency for bacterial contamination. MATERIALS AND METHODS: After ethics approval, we investigated in a prospective, internally controlled, non-blinded trial 43 patients who received primary THA. At the beginning of the surgery, we took deep, representative, intracapsular tissue samples, which served as negative controls. At the end of surgery, tissue samples were taken from the bottom of the 'fluid collection bag' for microbiological analysis. RESULTS: All 86 control samples were negative. Out of the samples taken from the bags, a pathogen could be detected in four patients (9.3%). All pathogens were detected after a surgery time lasting longer than 90 min. CONCLUSION: We were able to show that fluid collection bags are a potential reservoir for bacteria in THA when surgery time was greater than a 90-min threshold. Our data suggest that the risks from fluid collection bags outweigh the advantages of using them. Therefore, we recommend against the use of fluid collection bags intraoperatively in primary THA.

Long-term outcome of total hip arthroplasty in patients with haemophilia.

INTRODUCTION: Besides the target joints (elbow, knee and ankle), the hip is one of the commonly affected joints in haemophilic arthropathy. Hip arthroplasty is the therapy of choice after failure of conservative treatment. There are only limited data on long-term results after primary total hip arthroplasty (THA). AIM: The aim of this retrospective study was to analyse clinical outcome and complication rate after total hip replacement in patients with severe haemophilic arthropathy. METHODS: Forty-three patients with haemophilia (PWH), one patient with von Willebrand disease and one patient with a Factor-VII-deficiency undergoing 49 total hip arthroplasties, were evaluated in a retrospective study. Harris hip score (HHS), range of motion (ROM), pain status (visual analogue scale, VAS) complication rate and patient satisfaction were assessed at a mean follow-up of 11.5 years (range: 3-32). RESULTS: HSS, ROM and VAS improved significantly combined with high patient satisfaction. In total, three (6.1%) periprosthetic infections and five (10.2%) aseptic implant loosenings occurred after THA leading to revision arthroplasty. In two (4.1%) cases, a pseudotumour and one (2.0%) periarticular ossification had to be resected after THA. CONCLUSION: Total hip replacement in PWH leads to a significant increase of function, reduction of pain and a high satisfaction. Due to the relatively high complication rate (infections and aseptic loosening) compared to patients without haemophilia, an individual assessment of the risk-benefit ratio from surgical and haemostaseological point of view is needed.

[Biological downsizing : Acetabular defect reconstruction in revision total hip arthroplasty]. / Biologisches Downsizing : Azetabuläre Knochendefekte in der Hüftrevisionsendoprothetik.

BACKGROUND: Periacetabular bony defects remain a great challenge in revision total hip arthroplasty. After assessment and classification of the defect and selection of a suitable implant the primary stable fixation and sufficient biological reconstitution of a sustainable bone stock are essential for long term success in acetabular revision surgery. Biological defect reconstruction aims for the down-sizing of periacetabular defects for later revision surgeries. TECHNIQUE: In the field of biological augmentation several methods are currently available. Autologous transplants feature a profound osseointegrative capacity. However, limitations such as volume restrictions and secondary complications at the donor site have to be considered. Structural allografts show little weight bearing potential in the long term and high failure rates. In clinical practice, the usage of spongious chips implanted via impaction bone grafting technique in combination with antiprotrusio cages for the management of contained defects have shown promising long time results. Nevertheless, when dealing with craniolateral acetabular and dorsal column defects, the additional implantation of macroporous metal implants or augments should be considered since biological augmentation has shown little clinical success in these particular cases. PROSPECT: This article provides an overview of the current clinically available biological augmentation methods of peri-acetabular defects. Due to the limitations of autologous and allogeneic bone transplants in terms of size and availability, the emerging field of innovative implantable tissue engineering constructs gains interest and will also be discussed in this article.

Memory and PTPIP51--a new protein in hippocampus and cerebellum.

Previously the expression of Protein Tyrosine Phosphatase Interacting Protein 51 (PTPIP51) in mouse brain was reported. Here, we investigated PTPIP51 mRNA and protein in two of the brain regions namely the hippocampus and the cerebellum of mouse brains. On a cellular level both the protein and the mRNA were related to the pyramidal cells of the hippocampal formation, the granular cells of the dentate gyrus and the cells of the adjacent strata. In the cerebellum PTPIP51 was traced in Purkinje cells, the cells of the molecular layer and the granular layer. On a subcellular level only partial co-localization was seen for the endoplasmic reticulum, but not with mitochondria. In addition the interactome of PTPIP51 was analysed. In hippocampal cells a strong interaction with PTP1B and vesicle-associated membrane protein-associated protein B (VAPB) was detected. A somewhat differing interaction profile was found in the cerebellum, where high interaction levels were found for 14-3-3, diacylglycerol kinase α (DGKα), NFκB and PTP1B. These interaction partners represent specific signalling pathways linked to building memory. PTPIP51 can be associated with nerve growth factor signalling, dendritic and axonal growth, synaptogenesis, and all processes needed for memory formation. Moreover, in HT-22 mouse hippocampal cells PTPIP51 expression was induced by administrating the fibroblast growth factor 1 (FGF-1), which is known to take part in learning/memory processes. Knocking down p38-MAPK also led to an up-regulation of PTPIP51 probably resembling a compensative mechanism. Thus, a possible connection to the processing of memories can be anticipated. Differences in the interaction profile in both regions may be attributed to the actual/local differences in memory formation.

Human genome-wide expression analysis reorients the study of inflammatory mediators and biomechanics in osteoarthritis.

A major objective of this article is to examine the research implications of recently available genome-wide expression profiles of cartilage from human osteoarthritis (OA) joints. We propose that, when viewed in the light of extensive earlier work, this novel data provides a unique opportunity to reorient the design of experimental systems toward clinical relevance. Specifically, in the area of cartilage explant biology, this will require a fresh evaluation of existing paradigms, so as to optimize the choices of tissue source, cytokine/growth factor/nutrient addition, and biomechanical environment for discovery. Within this context, we firstly discuss the literature on the nature and role of potential catabolic mediators in OA pathology, including data from human OA cartilage, animal models of OA, and ex vivo studies. Secondly, due to the number and breadth of studies on IL-1ß in this area, a major focus of the article is a critical analysis of the design and interpretation of cartilage studies where IL-1ß has been used as a model cytokine. Thirdly, the article provides a data-driven perspective (including genome-wide analysis of clinical samples, studies on mutant mice, and clinical trials), which concludes that IL-1ß should be replaced by soluble mediators such as IL-17 or TGF-ß1, which are much more likely to mimic the disease in OA model systems. We also discuss the evidence that changes in early OA can be attributed to the activity of such soluble mediators, whereas late-stage disease results more from a chronic biomechanical effect on the matrix and cells of the remaining cartilage and on other local mediator-secreting cells. Lastly, an updated protocol for in vitro studies with cartilage explants and chondrocytes (including the use of specific gene expression arrays) is provided to motivate more disease-relevant studies on the interplay of cytokines, growth factors, and biomechanics on cellular behavior.

Utilizing weak pump depletion to stabilize squeezed vacuum states.

We propose and demonstrate a pump-phase locking technique that makes use of weak pump depletion (WPD) - an unavoidable effect that is usually neglected - in a sub-threshold optical parametric oscillator (OPO). We show that the phase difference between seed and pump beam is imprinted on both light fields by the non-linear interaction in the crystal and can be read out without disturbing the squeezed output. In our experimental setup we observe squeezing levels of 1.96 ± 0.01 dB, with an anti-squeezing level of 3.78 ± 0.02 dB (for a 0.55 mW seed beam at 1064 nm and 67.8 mW of pump light at 532 nm). Our new locking technique allows for the first experimental realization of a pump-phase lock by reading out the pre-existing phase information in the pump field. There is no degradation of the detected squeezed states required to implement this scheme.

Pollen-derived nonallergenic substances enhance Th2-induced IgE production in B cells.

BACKGROUND: B cells play a central role in IgE-mediated allergies. In damaged airway epithelium, they are exposed directly to aeroallergens. We aimed to assess whether direct exposure of B cells to pollen constituents affects allergic sensitization. METHODS: B cells from murine splenocytes and from blood samples of healthy donors were incubated for 8 days under Th2-like conditions with aqueous ragweed pollen extracts (Amb-APE) or its constituents. Secreted total IgM, IgG, and IgE was quantified by ELISA. Additionally, birch, grass, or pine-pollen extracts were tested. The number of viable cells was evaluated by ATP measurements. B-cell proliferation was measured by CFSE staining. IgE class switch was analyzed by quantitation of class switch transcripts. In an OVA/Alum i.p.-sensitization mouse model, Amb-APE was intranasally instilled for 11 consecutive days. RESULTS: Upon Th2 priming of murine B cells, ragweed pollen extract caused a dose-dependent increase in IgE production, while IgG and IgM were not affected. The low-molecular-weight fraction and phytoprostane E1 (PPE1) increased IgE production, while Amb a 1 did not. PPE1 enhanced IgE also in human memory B cells. Under Th1 conditions, Amb-APE did not influence immunoglobulin secretion. The IgE elevation was not ragweed specific. It correlated with proliferation of viable B cells, but not with IgE class switch. In vivo, Amb-APE increased total IgE and showed adjuvant activity in allergic airway inflammation. CONCLUSIONS: Aqueous pollen extracts, the protein-free fraction of Amb-APE, and the pollen-contained substance PPE1 specifically enhance IgE production in Th2-primed B cells. Thus, pollen-derived nonallergenic substances might be responsible for B-cell-dependent aggravation of IgE-mediated allergies.

Pollen-derived adenosine is a necessary cofactor for ragweed allergy.

BACKGROUND: Ragweed (Ambrosia artemisiifolia) is a strong elicitor of allergic airway inflammation with worldwide increasing prevalence. Various components of ragweed pollen are thought to play a role in the development of allergic responses. The aim of this study was to identify critical factors for allergenicity of ragweed pollen in a physiological model of allergic airway inflammation. METHODS: Aqueous ragweed pollen extract, the low molecular weight fraction or the major allergen Amb a 1 was instilled intranasally on 1-11 consecutive days, and allergic airway inflammation was evaluated by bronchoalveolar lavage, lung histology, serology, gene expression in lung tissue, and measurement of lung function. Pollen-derived adenosine was removed from the extract enzymatically to analyze its role in ragweed-induced allergy. Migration of human neutrophils and eosinophils toward supernatants of ragweed-stimulated bronchial epithelial cells was analyzed. RESULTS: Instillation of ragweed pollen extract, but not of the major allergen or the low molecular weight fraction, induced specific IgG1 , pulmonary infiltration with inflammatory cells, a Th2-associated cytokine signature in pulmonary tissue, and impaired lung function. Adenosine aggravated ragweed-induced allergic lung inflammation. In vitro, human neutrophils and eosinophils migrated toward supernatants of bronchial epithelial cells stimulated with ragweed extract only if adenosine was present. CONCLUSIONS: Pollen-derived adenosine is a critical factor in ragweed-pollen-induced allergic airway inflammation. Future studies aim at therapeutic strategies to control these allergen-independent pathways.

Total ankle replacement in patients with von Willebrand disease: mid-term results of 18 procedures.

von Willebrand disease (VWD) is a recognized cause of secondary ankle osteoarthritis (OA). Few studies have examined orthopaedic complications and outcomes in VWD patients treated for end-stage ankle OA with total ankle replacement (TAR). To determine the clinical presentation, intraoperative and postoperative complications and evaluate the mid-term outcome in VWD patients treated with TAR. Eighteen patients with VWD with mean age 47.3 years (range = 34.0-68.7) were treated for end-stage ankle OA with TAR. The mean duration of follow-up was 7.5 years (range = 2.9-13.2). Intraoperative and perioperative complications were recorded. Component stability was assessed with weight-bearing radiographs. Clinical evaluation included range of motion (ROM) tests using a goniometer and under fluoroscopy using a lateral view. Clinical outcomes were analysed by a visual analogue scale, the American Orthopaedic Foot and Ankle Society hindfoot score and Short Form (36) Health Survey (SF-36) health survey. One patient sustained an intraoperative medial malleolar fracture. In two patients delayed wound healing was observed. Two secondary major surgeries were performed. Pain level decreased from 8.2 ± 0.9 (range = 7-10) preoperatively to 1.1 ± 1.2 (range = 0-4) postoperatively. Significant functional improvement including ROM was observed. All categories of SF-36 score showed significant improvement in quality of life. Mid-term results of TAR in patients with VWD are encouraging. The total rate of intraoperative and postoperative complications was 33.3%. However, longer term outcomes are necessary to fully understand the clinical benefit of TAR in patients with VWD.

PTPIP51 levels in glioblastoma cells depend on inhibition of the EGF-receptor.

Protein tyrosine phosphatase interacting protein 51 (PTPIP51) is upregulated in glioblastoma multiforme (GBM) and expression levels correlate with the grade of malignancy in gliomas. A similar correlation was reported for its interacting partner 14-3-3ß, which has been shown to facilitate the interaction of PTPIP51 with cRAF (Raf1). Since the interaction of these signalling partners stimulates growth factor signalling downstream of the epidermal growth factor receptor (EGFR), a major drug target in GBM, we here investigated the impact of EGFR inhibition by small molecule inhibitors or monoclonal antibody on PTPIP51. The effect of EGFR inhibition on PTPIP51 mRNA, protein expression and its interaction profile in GBM was analyzed using the U87 cell line as model system. The transferability of the results to in vivo conditions was evaluated in cultured tumour cells from GBM patients. Cells were treated either to the small molecule tyrosine kinase inhibitor of EGFR Gefitinib or the monoclonal antibody Cetuximab in a time and dose dependent manner. Gefitinib treatment decreased the proliferation rate and induced apoptosis in U87 and primary tumour cells. The PTPIP51 interaction profile changed in correlation to the applied Gefitinib. Despite unchanged mRNA levels PTPIP51 protein was reduced. In contrast, treatment with Cetuximab had no effects on PTPIP51 expression. In conclusion, our results demonstrate the impact of EGFR inhibition by Gefitinib on PTPIP51 protein expression, a downstream regulator of MAPK signalling. These data will serve as a basis to unravel the precise role of PTPIP51-mediated signalling in GBM and its potential implications for Gefitinib-mediated therapy in future studies.