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Purpose: The Masquelet technique for the treatment of large bone defects is a two-stage procedure based on an induced membrane. Compared to mature periosteum, the induced membrane differs significantly. However, both play a crucial role in bone regeneration. As part of a histological and radiological post-evaluation of an earlier project, we analyzed the influence of the granule size of the bone void filler Herafill® on development of periosteum regrowth in a critical size defect.
Methods: We compared three different sizes of Herafill® granules (Heraeus Medical GmbH, Wehrheim) in vivo in a rat femoral critical size defect (10 mm) treated with the induced membrane technique. After 8 weeks healing time, femurs were harvested and taken for histological and radiological analysis.
Results: A significantly increased regrowth of periosteum into the defect was found when small granules were used. Large granules showed significantly increased occurrence of bone capping. Small granules lead to significant increase in callus formation in the vicinity to the membrane.
Conclusion: The size of Herafill® granules has significant impact on the development of periosteal-like structures around the defect using Masquelet’s induced membrane technique. Small granules show significantly increased regrowth of periosteum and improved bone formation adjacent to the induced membrane.
The Masquelet technique for the treatment of large bone defects is a two‐stage procedure based on an induced membrane. The size of a scaffold is reported to be a critical factor for bone healing response. We therefore aimed to investigate the influence of the granule size of a bone graft substitute on bone marrow derived mononuclear cells (BMC) supported bone healing in combination with the induced membrane. We compared three different sizes of Herafill® granules (Heraeus Medical GmbH, Wehrheim) with or without BMC in vivo in a rat femoral critical size defect. A 10 mm defect was made in 126 rats and a membrane induced by a PMMA‐spacer. After 3 weeks, the spacer was taken out and membrane filled with different granule sizes. After 8 weeks femurs were taken for radiological, biomechanical, histological, and immunohistochemical analysis. Further, whole blood of the rat was incubated with granules and expression of 29 peptide mediators was assessed. Smallest granules showed significantly improved bone healing compared to larger granules, which however did not lead to an increased biomechanical stability in the defect zone. Small granules lead to an increased accumulation of macrophages in situ which could be assigned to the inflammatory subtype M1 by majority. Increased release of chemotactic respectively proangiogenic active factors in vitro compared to syngenic bone and beta‐TCP was observed. Granule size of the bone graft substitute Herafill® has significant impact on bone healing of a critical size defect in combination with Masquelet's technique in terms of bone formation and inflammatory.
Introduction: It has been proposed that individual genetic variation contributes to the course of severe infections and sepsis. Recent studies of single nucleotide polymorphisms (SNPs) within the endotoxin receptor and its signaling system showed an association with the risk of disease development. This study aims to examine the response associated with genetic variations of TLR4, the receptor for bacterial LPS, and a central intracellular signal transducer (TIRAP/Mal) on cytokine release and for susceptibility and course of severe hospital acquired infections in distinct patient populations. Methods: Three intensive care units in tertiary care university hospitals in Greece and Germany participated. 375 and 415 postoperative patients and 159 patients with ventilator associated pneumonia (VAP) were included. TLR4 and TIRAP/Mal polymorphisms in 375 general surgical patients were associated with risk of infection, clinical course and outcome. In two prospective studies, 415 patients following cardiac surgery and 159 patients with newly diagnosed VAP predominantly caused by Gram-negative bacteria were studied for cytokine levels in-vivo and after ex-vivo monocyte stimulation and clinical course. Results: Patients simultaneously carrying polymorphisms in TIRAP/Mal and TLR4 and patients homozygous for the TIRAP/Mal SNP had a significantly higher risk of severe infections after surgery (odds ratio (OR) 5.5; confidence interval (CI): 1.34 - 22.64; P = 0.02 and OR: 7.3; CI: 1.89 - 28.50; P < 0.01 respectively). Additionally we found significantly lower circulating cytokine levels in double-mutant individuals with ventilator associated pneumonia and reduced cytokine production in an ex-vivo monocyte stimulation assay, but this difference was not apparent in TIRAP/Mal-homozygous patients. In cardiac surgery patients without infection, the cytokine release profiles were not changed when comparing different genotypes. Conclusions: Carriers of mutations in sequential components of the TLR signaling system may have an increased risk for severe infections. Patients with this genotype showed a decrease in cytokine release when infected which was not apparent in patients with sterile inflammation following cardiac surgery.
In order to promote the accessibility of biodiversity data in historic and contemporary literature, we introduce a new interdisciplinary project called BIOfid (FID=Fachinformationsdienst, a service for providing specialized information). The project aims at a mobilization of data available in print only by combining digitization of scientific biodiversity literature with the development of innovative text mining tools for complex, eventually semantic searches throughout the complete text corpus. A major prerequisite for the development of such search tools is the provision of sophisticated anatomy ontologies on the one hand, and of complete lists of species names (currently considered valid as well as all synonyms) at a global scale on the other hand. In the initial stage, we chose examples from German publications of the past 250 years dealing with the geographic distribution and ecology of vascular plants (Tracheophyta), birds (Aves), as well as moths and butterflies (Lepidoptera) in Germany. These taxa have been prioritized according to current demands of German research groups (about 50 sites) aiming at analyses and modeling of distribution patterns and their changes through time. In the long term, we aim at providing data and open source software applicable for any taxon and geographic region. For this purpose, a platform for open access journals for long-term availability of professional e-journals will be established. All generated data will also be made accessible through GFBio (German Federation for Biological Data). BIOfid is supported by the LIS-Scientific Library Services and Information Systems program of the German Research Foundation (DFG).
CROWDFUNDING PLATFORMS HAVE BECOME A VALUABLE ALTERNATIVE TO TRADITIONAL SOURCES OF FINANCING. HOWEVER, SOME PHENOMENA ON CROWDFUN DING PLATFORMS CAUSE UNDESIRABLE EXTERNAL EFFECTS THAT CAN ADVERSELY INFLUENCE THE FUNDING SUCCESS OF PROJECTS. ONE SUCH PHENOMENON IS PROJECT OVERFUNDING. IN ORDER TO INTERNALIZE THE EXTERNALITIES OF OVER FUNDING, WE PROPOSE A FUNDING REDISTRIBUTION APPROACH FOR IMPROVING OVERALL FUNDING RESULTS. TO EVALUATE THIS CONCEPT, WE DEVELOP AND DEPLOY AN AGENT-BASED MODEL.
Crowdfunding platforms offer project initiators the opportunity to acquire funds from the Internet crowd and, therefore, have become a valuable alternative to traditional sources of funding. However, some processes on crowdfunding platforms cause undesirable external effects that influence the funding success of projects. In this context, we focus on the phenomenon of project overfunding. Massively overfunded projects have been discussed to overshadow other crowdfunding projects which in turn receive less funding. We propose a funding redistribution mechanism to internalize these overfunding externalities and to improve overall funding results. To evaluate this concept, we develop and deploy an agent-based model (ABM). This ABM is based on a multi-attribute decision-making approach and is suitable to simulate the dynamic funding processes on a crowdfunding platform. Our evaluation provides evidence that possible modifications of the crowdfunding mechanisms bear the chance to optimize funding results and to alleviate existing flaws.
Immunosuppression is a typical hallmark of cancer and frequently includes perturbations of the NKG2D tumor recognition system as well as impaired signaling by other activating NK cell receptors. Several in vitro studies suggested that sustained engagement of the NKG2D receptor, as it is occurring in the tumor microenvironment, not only impairs expression and function of NKG2D but also impacts signaling by other activating NK receptors. Here, we made use of a transgenic mouse model of ubiquitous NKG2D ligand expression (H2-Kb-MICA mice) to investigate consequences of chronic NKG2D engagement in vivo for functional responsiveness by other activating NK receptors such as NKp46 and Ly49D. Unexpectedly, we found no evidence for an impairment of NKp46 expression and function in H2-Kb-MICA mice, as anticipated from previous in vitro experiments. However, we observed a marked downregulation and dysfunction of the activating receptor Ly49D in activated NK cells from H2-Kb-MICA mice. Ly49D shares the adaptor proteins DAP10 and DAP12 with NKG2D possibly explaining the collateral impairment of Ly49D function in situations of chronic NKG2D engagement. Altogether, our results demonstrate that persistent engagement of NKG2D in vivo, as often observed in tumors, can selectively impair functions of unrelated NK receptors and thereby compromise NK responsiveness to third-party antigens.
Because of its highly bioactive properties sphingosine 1-phosphate (S1P) is an attractive target for the treatment of several diseases. Since the expression of sphingosine kinases as well as S1P receptors was demonstrated in the kidney, questions about the physiological and pathophysiological functions of S1P in this organ have been raised. In this review, we summarize the current state of knowledge about S1P-mediated functions in the kidney. A special focus is put on S1P modulated signal transduction in renal glomerular and tubular cells and consequences for the development and treatment of several kidney diseases, diabetic nephropathy, glomerulonephritis, ischemia-reperfusion injury, as well as for Wilms tumor progression.
Introduction: Systemic inflammation (e.g. following surgery) involves Toll-like receptor (TLR) signaling and leads to an endocrine stress response. This study aims to investigate a possible influence of TLR2 and TLR4 single nucleotide polymorphisms (SNPs) on perioperative adrenocorticotropic hormone (ACTH) and cortisol regulation in serum of cardiac surgical patients. To investigate the link to systemic inflammation in this context, we additionally measured 10 different cytokines in the serum. Methods: 338 patients admitted for elective cardiac surgery were included in this prospective observational clinical cohort study. Genomic DNA of patients was screened for TLR2 and TLR4 SNPs. Serum concentrations of ACTH, cortisol, interferon (IFN)-, interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)- and granulocyte macro-phage-colony stimulating factor (GM-CSF) were determined before surgery, immediately post surgery and on the first postoperative day. Results: 13 patients were identified as TLR2 SNP carrier, 51 as TLR4 SNP carrier and 274 pa-tients as non-carrier. Basal levels of ACTH, cortisol and cytokines did not differ between groups. In all three groups a significant, transient perioperative rise of cortisol could be ob-served. However, only in the non-carrier group this was accompanied by a significant ACTH rise, TLR4 SNP carriers had significant lower ACTH levels compared to non-carriers ((mean[95% confidence intervals]) non-carriers: 201.9[187.7 to 216.1]pg/ml; TLR4 SNP car-riers: 149.9[118.4 to 181.5]pg/ml; TLR2 SNP carriers: 176.4[110.5 to 242.3]pg/ml). Compared to non-carriers, TLR4 SNP carriers showed significant lower serum IL-8, IL-10 and GM-CSF peaks ((mean[95% confidence intervals]): IL-8: non-carriers: 42.6[36.7 to 48.5]pg/ml, TLR4 SNP carriers: 23.7[10.7 to 36.8]pg/ml; IL-10: non-carriers: 83.8[70.3 to 97.4]pg/ml, TLR4 SNP carriers: 54.2[24.1 to 84.2]pg/ml; GM-CSF: non-carriers: 33.0[27.8 to 38.3]pg/ml, TLR4 SNP carriers: 20.2[8.6 to 31.8]pg/ml). No significant changes over time or between the groups were found for the other cytokines. Conclusions: Regulation of the immunoendocrine stress response during systemic inflamma-tion is influenced by the presence of a TLR4 SNP. Cardiac surgical patients carrying this ge-notype showed decreased serum concentrations of ACTH, IL-8, IL-10 and GM-CSF. This finding might have impact on interpreting previous and designing future trials on diagnosing and modulating immunoendocrine dysregulation (e.g. adrenal insufficiency) during systemic inflammation and sepsis.
Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.