Unusual onset of adult still's disease due to a systemic reaction to artificial breast implants.

In this manuscript, we report an exceptional observation study of a young woman suffering from an autoimmune syndrome induced by adjuvants (ASIA). Until today only seven cases of adult-onset Still's disease (AOSD) induced by breast implants have been published. This may be due to the fact that this illness itself is very rare; however, the reason might also be that the community is not sensitized to the case-specific symptoms. Within this article, we show for the first time highly detailed diagnostic test procedures such as PET-CT scans and specific histological staining of the breast tissue, displaying proinflammatory macrophages that are a well-known activator and booster of autoimmune diseases. We hope to give new insights into the clinical picture and pathogenesis of AOSD in order to improve the challenging diagnosis.

Targeted therapies and checkpoint inhibitors in sarcoma.

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

Tissue substitutes with improved angiogenic capabilities: an in vitro investigation with endothelial cells and endothelial progenitor cells.

The use of implantable biomaterials, such as artificial skin substitutes used for dermal defects, remains limited by the low angiogenic potential of these products. The rapid in vivo degradation of growth factors contributes to the limiting of angiogenesis in biomaterials. Here, we report on collagen sponges in which vascular endothelial growth factor (VEGF) was immobilized through physical binding to heparin, covalently incorporated in the matrix via cross-linking with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide. The in vitro release of VEGF over time and endothelial cell proliferation were investigated in matrices modified at varying heparin to EDC ratios either nonloaded or loaded with VEGF. ELISA demonstrated a significantly slower in vitro release of VEGF over a period of 5 days from heparinized matrices as compared to their unmodified and cross-linked counterparts. The effects of these modifications on the proliferation of endothelial cells and endothelial progenitor cells were evaluated after 1, 3 and 5 days either according to the bromodeoxyuridine assay or total cell counting with a Neubauer chamber. The endothelial and endothelial progenitor cells cultured in contact with heparinized matrices loaded with VEGF revealed both the highest rate of DNA synthesis and the highest total cell count. Furthermore, these results show that the cross-linking of collagen matrices - both in the presence and absence of heparin - leads to increases of the proliferative activities. We can assume that these changes lead to matrices with increased angiogenic capabilities.

[Wnt signaling in cutaneous wound healing]. / Wnt-Signalwege bei kutaner Wundheilung.

Human skin is an efficient barrier that protects the organism from noxious substances. Wounds destroy this barrier. Wound healing is a phased physiological regeneration of the destroyed tissue that ideally leads to occlusion of a wound, in particular by regeneration of connective tissue and capillaries. The Wnt signaling pathway is a highly conserved signal transduction cascade across the animal kingdom that controls basic cellular interactions in multicellular organisms. Accordingly, through the Wnt signaling path many processes, e. g. as the balance between proliferation and differentiation or apoptosis, coordinated. Wnt signaling is activated by a wound and participates in each subsequent phase of the healing process, beginning with inflammatory control and programmed cell death, to the mobilization of stem cells within the wound. Endogenous Wnt signaling is an attractive therapeutic approach to assist in the repair of skin wounds, as the complex mechanisms of the Wnt signaling pathway have become increasingly understood over the years. This review summarizes current data to clarify the role of Wnt signaling in the wound healing process of the skin.

A new tool for the early diagnosis of carbon monoxide intoxication.

Invasive measurement of carboxyhemoglobin (COHb) by blood gas analysis (BGA) is accepted as the standard diagnostic procedure in diagnosis of inhalation injury and carbon monoxide (CO) intoxications. The main disadvantage of BGA with COHb testing is the unavailability in pre-hospital rescue conditions. The non-invasive SpCO analysis using pulse CO oximetry (Rad57, Masimo Corp., USA) represents an easy-to-handle device to facilitate the diagnosis of CO intoxication. Between January 2006 and August 2008, 20 patients who were admitted with CO intoxication to our burn centre were included in this study. Blood gas analysis including COHb testing was performed on the first day, hourly. At the same time, SpCO was determined using the Rad57 pulse CO oximeter. Patients received inhalative oxygen according to the parameters of blood gas analysis or hyperbaric oxygenation if COHb > 10%. Five young healthy volunteers served as control group. The SpCO of the volunteers was cross-checked against their COHb levels, which were measured by blood gas analysis. Results of pulse CO oximetry revealed a mean error of approximately 3.15% from the results achieved by blood gas analysis. If COHb resulted in values higher than 10%, the bias remained approximately the same (3.43%/precision 2.362%). When different blood gas analyzers in our department were tested with the same patient sample, a mean error of 2.4% was found. This is only 1% lower compared to the mean error of pulse CO oximetry. Therefore, pulse CO oximetry represents a reliable measurement technique that is easy to handle and could facilitate the early diagnosis of CO intoxication in pre-hospital rescue conditions.

[Antibiotic treatment of infections in burn patients - a systematic review]. / Antibiotikatherapie von Infektionen bei Verbrennungspatienten ­ Eine systematische Übersichtsarbeit.

BACKGROUND: Due to the loss of the natural skin barrier function with reduced immune competence as a result of a plasma loss and the numerous intensive care interventions, burn patients are particularly at risk for infection. STUDY DESIGN: systematic review METHODS: A systematic review of German and English literature between 1990 and 2018 analyzes the epidemiological and diagnostic aspects as well as the therapeutic use of antibiotics in infections of burn patients in clinical trials. RESULTS: A total number of 53 randomized controlled clinical trials met the inclusion criteria. Various types / forms of application of antibiotic prophylaxis in burn wounds were investigated: topically, systemically (generally), systemically (perioperatively), nonabsorbable antibiotics (= selective intestinal decontamination), locally (inhaled) and all forms of administration versus control. Early postburn prophylaxis was studied in low-severity patients (six studies) and severe burn patients (seven studies). Antimicrobial prophylaxis has shown no effectiveness in the prevention of toxic shock syndrome in low grade burns, but can be useful in patients with severe burns in need for mechanical ventilation. Perioperative prophylaxis has been studied in ten studies. CONCLUSION: The benefit of long-term systemic antibiotic prophylaxis in the majority of burn patients is not evident. Mild infections in stable clinical conditions should be closely monitored, while in severe infections, international sepsis guidelines and the Tarragona principle are recommended.

[Regulation of bone metabolism by the Wnt signaling pathway]. / Regulation des Knochenstoffwechsels durch den Wnt-Signalweg.

The development and homeostasis of multicellular organisms depends on a complex cellular interaction between proliferation, migration, differentiation, adhesion, and cell death. Wnt signaling pathways coordinate these different cellular responses. Wnt signaling plays a role as a regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. The Wnt signaling pathway is an attractive therapeutic target with the potential to directly modulate stem cells responsible for the regeneration of skeletal tissue. Recent studies indicate that Wnt ligands are capable of promoting bone growth, suggesting that Wnt factors could be used to stimulate bone healing in osteogenic disorders.

Management, clinical outcomes, and complications of acute cannula-related peripheral vein phlebitis of the upper extremity: A retrospective study.

OBJECTIVE: Acute phlebitis due to peripheral vein catheter use is frequently observed in clinical practice, and requires surgical therapy in severe cases. In this retrospective study, we aimed to increase awareness, evaluate current treatment options, and develop recommendations to optimize treatment outcomes. METHODS: A total of 240 hospitalized patients with a diagnosis of upper extremity phlebitis from 2006 to 2011 were evaluated in terms of initial clinical features, parameters, co-morbidities and treatment regimes. Severity of phlebitis was graded according to the Baxter scale by assessing clinical symptoms such as pain, erythema, induration, swelling, or palpable venous cord (grade 0-5). Patients were divided in two subgroups: conservative (n = 132) and operative (n = 108) treatment. RESULTS: Surgical intervention rates and severity were higher for cannula insertion in the cubital fossa region than for cannula insertion in the forearm and hand region (p < 0.05). Baxter scale grades were higher in the surgical treatment group than in the conservative treatment group (4.47 vs. 2.67, respectively). CONCLUSIONS: The cubital fossa region is vulnerable to severe phlebitis and is not recommended as the first site of choice for cannulation. Phlebitis of Baxter scale grade 4 or 5 should be considered for early surgical intervention.

Dermal application of nitric oxide in vivo: kinetics, biological responses, and therapeutic potential in humans.

Many local hemodynamic and vascular disorders may be the result of impaired bioavailability of nitric oxide (NO). Previous findings point to a therapeutic potential of dermal NO application in the treatment of hemodynamic disorders, but no reliable data are available on the mechanisms, kinetics, or biological responses relating to cutaneous exposure to NO in humans in vivo. Here we show that, owing to its excellent diffusion capacity, cutaneously applied NO rapidly penetrates the epidermal barrier in significant amounts, strongly enriching skin tissue and blood plasma with its vasoactive derivates. In parallel, it significantly increased vasodilatation and blood flow and reduced thrombocyte aggregation capacity. Data presented here for the first time show that, in humans, dermal application of NO has strong potential for use in the therapy of local hemodynamic disorders arising from insufficient availability of NO or its bioactive derivates.

The mobilisation of mononuclear cells and endothelial progenitor cells after burn injury in a porcine model.

BACKGROUND: Mononuclear blood cells (MNCs) consist of heterogeneous cell populations, for example, CD34+ cells and endothelial progenitor cells (EPCs). EPCs are involved in vasculogenesis, but little is known about their role during burn trauma. AIM: This study investigates the role of MNCs and their subpopulations during and after burn injury in an experimental porcine setting. METHODS: Eighteen 8-week-old German land pigs were scalded by immersion in 70 degrees C hot water for 3 min, resulting in a 30% total body surface area (TBSA) full-thickness burn. Vascular endothelial growth factor (VEGF) serum concentrations and MNC, EPC and CD34+ cell counts were measured at eight different time points up to 48 h following trauma. RESULTS: The experimental porcine setting made it possible to determine the cell counts of MNCs, EPCs and CD34+ cells directly during burn trauma, which has not been described before. The data revealed a fulminant drop in MNC and EPC during burn trauma, whereas the CD34+ cell fraction rose. Besides significant changes in the VEGF serum concentration, a correlation between VEGF and EPC was also observed. CONCLUSION: The results show that MNCs and their subpopulations are significantly affected by burn trauma and underpin their potential diagnostic and therapeutic importance during and after burn injury.

Enhancing angiogenesis in collagen matrices by covalent incorporation of VEGF.

Since the survival of ingrowing cells in biomaterials for regenerative processes largely depends on the supply of nutrients and oxygen, angiogenesis plays an important role in the development of new materials for tissue engineering. In this study we investigated the possibility of enhancing the angiogenic properties of collagen matrices by covalent incorporation of the vascular endothelial growth factor (VEGF). In a previous paper we already reported the use of homo- and heterobifunctional cross-linking agents for modifying collagen matrices [1]. In the present work the angiogenic growth factor was linked to the collagen with the homobifunctional cross-linker disuccinimidyldisuccinatepolyethyleneglycol (SS-PEG-SS) in a two step procedure. The efficiency of the first reaction step-the reaction of SS-PEG-SS with VEGF--was evaluated by western blot analysis. After 10 minutes virtually all of the dimeric molecules VEGF were on average modified by conjugation with 1 cross-linking molecule. The biological activity of the conjugate was investigated by exposing endothelial cells to non-modified VEGF and to VEGF conjugated to the cross-linker. The conjugation only had a limited effect on the mitogenic activity of VEGF. We therefore applied the cross-linking reaction to the VEGF-collagen system. In a first approach the changes were evaluated by the in vitro exposure of HUVECs to non-modified matrices, to matrices in which the VEGF was simply admixed and to matrices in which the VEGF was covalently incorporated. The angiogenic properties were evaluated in vivo with the chorioallantois membrane model. In this assay the chorioallantois membrane of the chicken embryo was exposed to the same set of matrices. The covalent incorporation of VEGF has a small but significant effect both on the formation of microvessels in the chorioallantois membrane and the tissue ingrowth into the implant. The covalent incorporation of angiogenic growth factors may thus be considered as a promising approach for enhancing the angiogenic capabilities of collagen matrices. Also the cross-linking with the homobifunctional cross-linking agent has a positive effect on the angiogenic potential of the collagen matrices.