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Primary breast augmentation is one of the most commonly requested aesthetic procedures. Considering the large number of procedures performed in connection with a high demand, it is crucial to prevent complications. For this reason, finding and avoiding possible sources of complications is decisive.Between January 2010 and December 2021, 1625 female patients underwent an aesthetic breast augmentation performed by a single surgeon. The data collected were analyzed through a machine learning technique for binary recursive partitioning. This made it possible to detect unknown sources of a complication and determine a vertex for the various features.When analyzing the data, for most features a high importance score with low entropy was achieved, concluding a high significance. In addition, reproducibility was demonstrated through detailed testing and training accuracies in the algorithm. With this procedure, in addition to known risks such as a high BMI and round implant shape, a larger than A preoperative bra-cup size (OR: 2.7) and a taller body could also be identified as most significant influencing factors for complications.Preoperative breast size plays an exceptionally important role in the occurrence of complications and should be a factor held in a surgeon's considerations. In addition, this study shows ways to transfer artificial intelligence into plastic surgery to increase medical quality.This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Summary Objective Non-invasive Remote Ischemic Conditioning (RIC) offers an approach to reduce tissue damage in various organs/tissues. Besides attenuation of Ischemia-Reperfusion injury (I/R), beneficial effects on cutaneous microcirculation of free microsurgical flaps have been reported. Given the recency of this technique, there are considerable gaps in the current understanding of its mechanism of action. As a result, clinical transfer of RIC is prolongated in several fields. We aimed to optimize the RIC protocol by examination of different RIC-cycle numbers and its effect on changes of cutaneous microcirculation and duration. Methods 80 subjects were divided into groups (1, 3, 5, 7 RIC cycles). RIC was applied via an inflatable tourniquet. Cutaneous microcirculation was continuously assessed at the contralateral anterior lateral thigh utilizing a ©O2C-device continuously. Results RIC caused significant and sustained changes in microcirculation. Four hours after completion of RIC, a maximum increase of +80.8% (CI 1.395–2.221) in blood flow and +23.5% (CI 1.098–1.372) in tissue oxygen saturation was measured (three-cycle group). A higher number of applied cycles was accompanied with significant higher mean pain. Conclusion Acute improvement of cutaneous microcirculation due to RIC lasted for at least 4 h after completion of the RIC-protocol. Dose-dependent effects of RIC are likely. With regard to the increase in pain, we recommend a RIC protocol of 3 cycles for future clinical application.

Mesenchymal stromal cells are promising candidates for regenerative applications upon treatment of bone defects. Bone marrow‐derived stromal cells (BMSCs) are limited by yield and donor morbidity but show superior osteogenic capacity compared to adipose‐derived stromal cells (ASCs), which are highly abundant and easy to harvest. The underlying reasons for this difference on a proteomic level have not been studied yet. Human ASCs and BMSCs were characterized by FACS analysis and tri‐lineage differentiation, followed by an intraindividual comparative proteomic analysis upon osteogenic differentiation. Results of the proteomic analysis were followed by functional pathway analysis. 29 patients were included with a total of 58 specimen analysed. In these, out of 5148 identified proteins 2095 could be quantified in >80% of samples of both cell types, 427 in >80% of ASCs only and 102 in >80% of BMSCs only. 281 proteins were differentially regulated with a fold change of >1.5 of which 204 were higher abundant in BMSCs and 77 in ASCs. Integrin cell surface interactions were the most overrepresented pathway with 5 integrins being among the proteins with highest fold change. Integrin 11a, a known key protein for osteogenesis, could be identified as strongly up‐regulated in BMSC confirmed by Western blotting. The integrin expression profile is one of the key distinctive features of osteogenic differentiated BMSCs and ASCs. Thus, they represent a promising target for modifications of ASCs aiming to improve their osteogenic capacity and approximate them to that of BMSCs.

Background Soft tissue sarcomas (STS) of the extremities or trunk often require plastic reconstructive transfer of vital tissue for wound closure after resection. Literature on the oncologic outcome of patients receiving flap closure in comparison with patients receiving primary wound closure is very limited. Methods Patients who underwent resection of a primary extremity or truncal STS without dissemination at our institution between January 2000 until December 2015 were eligible for the study. Patients were divided into two groups based on type of soft tissue closure (primary or flap) while patients receiving skin grafting were excluded. Characteristics, oncologic outcome and prognostic factors of both groups were compared. Results 781 patients could be included, of these 200 had received flap closure and 581 primary wound closure. Tumors receiving flap closure were significantly smaller but were located in distal extremities and showed a trend towards prior neoadjuvant radiotherapy. Incidence of wound and general complications was similar in both groups. 5-year local recurrence free survival (LRFS, 71% vs. 69%) and 5-year disease specific survival (DSS, 84% vs. 88%) did not differ significantly between patients with primary closure and flap closure. Most important predictors in both groups were tumor size and grading with no major differences in analysis of predictors for both endpoints. Conclusion Plastic reconstructive surgery plays an important role in limb-conserving STS treatment. Complication rates of patients with flap coverage are not higher than of patients with primary wound closure and oncologic outcome is similar with no major differences in predictors of LRFS and DSS.

In various oncological conditions, complications correlate with diminished prognosis, however literature on soft tissue sarcomas is limited and inconclusive. The aim of this study was to assess risk factors and the oncologic impact of wound complications in primary extremity soft-tissue sarcomas.Patients with primary extremity soft tissue sarcomas without dissemination and with clear surgical margins (R0) were analyzed. Groups with and without wound complications were compared by univariate and multivariable analysis to identify risk factors. Uni- and multivariable analysis of factors associated with local recurrence free survival (LRFS), metastasis free survival (MFS) and disease specific survival (DSS) were performed.682 patients were included in the study, wound complications occurred in 94 patients (13.7%) within 90 days. Age, ASA-stage, high tumor size and grade, tumor location in the foot, neoadjuvant radiation therapy and operation time represented independent risk factors for wound complications. Patients with wound complications had a significantly worse estimated 5-year LRFS of 49.4 ± 6% versus 78.3 ± 2.1% and 5-year DSS of 77.9 ± 5.4% versus 89.1 ± 1.6%. Wound complications could be identified as an independent risk factor for worse LRFS (HR 2.68[CI 1.83-3.93], p 0.001) and DSS (HR 1.79[CI 1.01-3.16], p = 0.046).Wound complications after soft tissue sarcomas of the extremities are associated with worse local oncological outcome and survival. Patients with high risk of wound complications should be identified and strategies implemented to reduce surgical complications and possibly improve oncologic prognosis.

The aim of the study was to investigate the relationship of BMI and abdominal wall thickness (AWT) with the diameter of the dominant deep inferior epigastric artery perforator (DIEP) as well as DIEA branching pattern in preoperatively performed computed tomography angiography (CTA).We conducted a retrospective study including all patients undergoing DIEP flap breast reconstruction with available CTAs from November 2013 to April 2018 in our department. The caliber-strongest DIEP was detected after passage of the rectus fascia as well as the superficial inferior epigastric artery (SIEA) and correlated with the AWT 5 cm above and below the umbilicus, lateral at the level of the umbilicus and at the level of the anterior superior iliac spine (ASIS), and with BMI.Seventy-seven patients met the inclusion criteria (age: 47.3 ± 8.9 years). We observed a significant relationship (p 0.05) between DIEP (mean ∅ = 2.98 mm) and BMI (r = 0.353), the AWT supra- and infraumbilical (r ≥ 0.32), and the AWT lateral at the level of the umbilicus and ASIS (r ≥ 0.25). In addition, there was a highly significant correlation (p 0.01) between SIEA and BMI (r = 0.389) and between the AWT lateral at the level of ASIS (r ≥ 0.41).We demonstrated a correlation of the diameter of the dominant DIEP with both BMI and AWT. Focusing on the diameter, in patients with a high AWT at the level of the ASIS, the SIEA, if present, may represent an alternative therapeutic option.

Introduction Many studies have started to search for the perfect aesthetic breast in order to create a pars-pro-toto for reconstruction, but especially for aesthetic surgery. To date, no representative study with anatomically accurate models was performed. Methods In an online based United-States-census-representative survey with 1049 participants, questions regarding the preferred breast were asked utilizing lifelike morphed 3D-generated female models for the first time. Attributes such as breast pole ratio, areola size, breast direction and projection were asked. Results The results show that, contrary to what has been claimed in previous studies, an upper-pole-to-lower-pole ratio of 55:45 is preferred by both female and male participants. When it comes to breast size, on the other hand, there are clear gender-specific differences. While women opted for a cup size around B, the men preferred larger cup sizes. Moreover, the smallest depicted areola size of 30 mm was favored among all groups in the survey. Discussion Most publications used rather detrimental models for their surveys. We therefore opted for computer-generated 3D models and varied their naturalness. This enabled us to ensure a more aesthetic and accurate illustration and thus obtained more comparable and reliable results paired with the representation of the US-population. Taken together this study unveiled unexpected insights into the population favored breast attributes that might change operative planning in breast surgery. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266.

Background: Body image research deals a lot with awareness of the body as an entity. Studies that consider individual anatomical aspects and place them in an intercultural context are rarely present. Methods: For this purpose, general data, body perception and judgment of body images from 2163 (48% female and 52% male) participants from Germany, Nigeria, the USA and Japan were evaluated as part of a survey. Results: There were clear differences in the personal body image of the participants’ own buttocks, the buttocks as a beauty ideal and the way in which dissatisfaction was dealt with in different countries. In addition to sexual well-being (importance score: 0.405 a.u.), the country of origin (0.353), media consumption (0.042) and one’s own weight (0.069) were also identified as influencing factors for satisfaction with one’s own buttocks. A clear evolution could be derived regarding a WHR (waist-to-hip ratio) of well below 0.7, which was consistently favored by the participants but also propagated by influencers through images (p < 0.001). In this context, participants who indicated celebrities as role models for the buttocks showed a correspondingly high level of dissatisfaction with their own buttocks (R = −0.207, p < 0.001, ρ = −0.218). Conclusion: Overall, a highly significant correlation was shown between the consumption frequency of Instagram, TikTok and pornography with the negative perception of women’s own buttocks.

Combined oral contraceptives are one of the most prescribed drugs in the western world. While there is little evidence regarding effects of estrogen or gestagens on muscle metabolism, androgens are well-known for their anabolic characteristics. In this study, we seeked to investigate potential correlations of the myokines GDF-8, IGF-1 and Follistatin with female sexual hormones and likewise possible interactions with combined oral contraceptives (Dienogest and Ethyl Estradiol) intake. We obtained serum samples of young healthy women to measure hormone correlations. Furthermore, we simulated combined oral contraceptive blood circulating hormone concentrations to identify myogenic effects on HSkM

Critical sized defects, especially in long bones, pose one of the biggest problems in orthopedic surgery. By definition, these defects do not heal without further treatment. Different therapeutic options range from autologous bone grafts, for example, free vascularized bone grafts, to commercially available bone allografts. Disadvantages of these bone allografts are related to reduced osteogenesis, since they are solely composed of cell-free bone matrix. The purpose of this study was to investigate the cell seeding efficiency of human adipose-derived stem cells (hASCs) on human bone allografts in vitro and furthermore analyze these optimized seeded allografts in a critical sized defect model in vivo. Cancellous human bone allografts were colonized with human ASCs in vitro. Cell seeding efficiency was evaluated by Cell Counting Kit-8 assay. Thereafter, optimized hASC-seeded bone scaffolds were examined in a murine femur defect model, stabilized with the MouseExFix system. Subsequently, x-ray analysis and histology were performed. Examination of cell seeding efficiency revealed an optimum starting population of 84,600 cells per 100 mm3 scaffold. In addition, scaffolds seeded with hASCs showed increased osteogenesis compared with controls. Histological analysis revealed increased remodeling and elevated new bone formation within hASC-seeded scaffolds. Moreover, immunohistochemical stainings revealed increased proliferation, osteogenesis, and angiogenesis. In this study, we systemically optimized cell/volume ratio of two promising components of tissue engineering: hASCs and human bone allografts. These findings may serve as a basis for future translational studies.

Background: Bromelain-based enzymatic debridement has been introduced as an alternative to surgical excision in deep partial thickness and full thickness burns. We aimed to analyze effectiveness an...

BackgroundDelayed bone healing, especially in long bones poses one of the biggest problems in orthopeadic and reconstructive surgery and causes tremendous costs every year. There is a need for exploring the causes in order to find an adequate therapy. Earlier investigations of human scaphoid non-union revealed an elevated osteoclast activity, accompanied by upregulated levels of TGF-beta and RANKL. Interestingly, scaphoid non-union seemed to be well vascularized.MethodsIn the current study, we used a murine femur-defect model to study atrophic non unions over a time-course of 10 weeks. Different time points were chosen, to gather insights into the dynamic processes of non-union establishment.ResultsHistological analyses as well as western blots and qRT-PCR indicated enhanced osteoclast activity throughout the observation period, paralleled by elevated levels of TGF-beta, TNF-alpha, MMP9, MMP13 and RANKL, especially during the early phases of non-union establishment. Interestingly, elevated levels of these mediators decreased markedly over a period of 10 weeks, as inflammatory reaction during non-union establishment seemed to wear out. To our surprise, osteoblastogenesis seemed to be unaffected during early stages of non-union establishment.ConclusionTaken together, we gained first insights into the establishment process of atrophic non unions, in which inflammatory processes accompanied by highly elevated osteoclast activity seem to play a leading role.

Impaired bone homeostasis caused by osteomyelitis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. We have previously established a mouse model for post-traumatic osteomyelitis and studied bone regeneration after sufficient debridement. Moreover, we could further characterize the postinfectious inflammatory state of bony defects after debridement with elevated osteoclasts and decreased bone formation despite the absence of bacteria. In this study, we investigated the positive effects of Wnt-pathway modulation on bone regeneration in our previous established mouse model. This was achieved by local application of Wnt3a, a recombinant activator of the canonical Wnt-pathway. Application of Wnt3a could enhance new bone formation, which was verified by histological and μ-CT analysis. Moreover, histology and western blots revealed enhanced osteoblastogenesis and downregulated osteoclasts in a RANKL-dependent manner. Further analysis of Wnt-pathway showed downregulation after bone infections were reconstituted by application of Wnt3a. Interestingly, Wnt-inhibitory proteins Dickkopf 1 (DKK1), sclerostin, and secreted frizzled protein 1 (sFRP1) were upregulated simultaneously to Wnt-pathway activation, indicating a negative feedback for active form of Beta-catenin. In this study, we could demonstrate enhanced bone formation in defects caused by post-traumatic osteomyelitis after Wnt3a application. KEY MESSAGES: Osteomyelitis decreases bone regeneration Wnt3a restores bone healing after infection Canonical Wnt-pathway activation with negative feedback.

BACKGROUND Augmentation mastopexy may be a one- or two-stage procedure. Because of the opposing force vectors in augmentation and in mastopexy, some surgeons advocate a two-stage procedure. The literature appears divided on which operation has a more favorable complication profile. The purpose of this review was to benchmark the outcomes of single-stage augmentation mastopexy against those of a commonly performed aesthetic breast operation (primary breast augmentation). METHODS THE AUTHORS: reviewed electronic patient records of all consecutive female patients who underwent single-stage augmentation mastopexy and primary breast augmentation performed by the first author at our clinic between April of 2009 and May of 2017 with at least a 6-month follow-up. Data from single-stage augmentation mastopexy were benchmarked against the outcomes of primary breast augmentations performed by the same surgeon, for the same period, and at the same clinic. RESULTS ONE HUNDRED FOUR: single-stage augmentation mastopexies and 801 primary breast augmentations were performed during this period, with mean follow-up of 15.4 months and 14.0 months, respectively. Augmentation mastopexy patients were significantly more likely to be older, have a higher body mass index, have more children, and were significantly less likely to use oral contraceptives. There was no statistically significant difference in overall complication rate between the two groups. CONCLUSIONS THE AUTHORS': experience suggests that single-stage augmentation mastopexy has outcomes comparable to those of primary breast augmentation. Smokers were more likely to undergo reoperation because of postoperative complication (seroma), but the rate of implant exchange was not different. CLINICAL QUESTION/LEVEL OF EVIDENCE THERAPEUTIC, III.

Summary Background In free tissue transfer, monitoring is paramount to timely detect vascular complications. Although various technical methods have been introduced, clinical flap monitoring and, particularly, capillary refill test (CRT) remain the gold standard. In pale flaps, CRT is challenging as it relies on the color difference between blanched and perfused skin. We proposed a new method of negative pressure-induced hyperemia (NPIH) using handheld electrical negative pressure devices to improve flap monitoring. Methods Forty consecutive patients who received 42 free flaps in our institution were included in the study. Postoperatively, digital photographs were taken during CRT and NPIH, and the color difference (ΔE) was calculated based on the images. Additionally, three surgeons and three nurses evaluated the ease of assessment of capillary refill and NPIH on each flap using five grades. Results NPIH yielded a significantly higher color difference than CRT with a mean ΔE of 10.3 ± 3.3 versus 6.8 ± 4.2. Although for CRT, ΔE of 14 flaps was 5 for NPIH. Subjectively, both surgeons and nurses found NPIH in all flaps to be easier to assess with a mean score of 1.1 ± 0.3 versus 1.8 ± 1.1 for CRT. However, some flaps were found to be challenging or not assessable by CRT. Conclusion NPIH represents a safe, easily applicable, and cheap addition to the established clinical and technical examination methods and may offer advantages over conventional CRT in detecting arterial complications in pale flaps.

Tumors, traumata, burn injuries or surgeries can lead to critical-sized bony defects which need to be reconstructed. Mesenchymal stem cells (MSCs) have the ability to differentiate into multiple cell lineages and thus present a promising alternative for use in tissue engineering and reconstruction. However, there is an ongoing debate whether all MSCs are equivalent in their differentiation and proliferation ability. The goal of this study was to assess osteogenic and adipogenic characteristic changes of adipose-derived stem cells (ASCs) and bone marrow-derived stem cells (BMSCs) upon Myostatin inhibition with Follistatin in vitro and in vivo. We harvested ASCs from mice inguinal fat pads and BMSCs from tibiae of mice. By means of histology, real-time cell analysis, immunohistochemistry, and PCR osteogenic and adipogenic proliferation and differentiation in the presence or absence of Follistatin were analyzed. In vivo, osteogenic capacity was investigated in a tibial defect model of wild-type (WT) mice treated with mASCs and mBMSCs of Myo-/- and WT origin. In vitro, we were able to show that inhibition of Myostatin leads to markedly reduced proliferative capacity in mBMSCs and mASCs in adipogenic differentiation and reduced proliferation in osteogenic differentiation in mASCs, whereas proliferation in mBMSCs in osteogenic differentiation was increased. Adipogenic differentiation was inhibited in mASCs and mBMSCs upon Follistatin treatment, whereas osteogenic differentiation was increased in both cell lineages. In vivo, we could demonstrate increased osteoid formation in WT mice treated with mASCs and mBMSCs of Myo-/- origin and enhanced osteogenic differentiation and proliferation of mASCs of Myo-/- origin. We could demonstrate that the osteogenic potential of mASCs could be raised to a level comparable to mBMSCs upon inhibition of Myostatin. Moreover, Follistatin treatment led to inhibition of adipogenesis in both lineages.

Introduction: Patients experiencing thermal injuries with an extent of over 20% of total body surface area suffer from systemic catabolic disease. The thermal trauma-induced loss of muscle mass causes a higher incidence for comorbidities and subsequently a higher mortality. In this study, we aimed to investigate the role of myostatin in the interplay with follistatin during muscle cachexia. Methods: Patients with burn injuries (>10% total body surface area) between the ages of 18 and 75 were prospectively included within the first 48 h after trauma to determine deviations of parameters connected to muscle catabolism. In the chronic state of burn injury (9–12 months after trauma), we re-evaluated myostatin and follistatin concentrations as well as muscle strength of the non-dominant forearm. Results: We were able to show a time-dependent alteration (9–12 months after burn injury) of myostatin with an initial decrease ( p Conclusion: With regard to the muscle metabolism after thermal trauma, our data suggest an acute anabolic response, presumably to spare muscle mass, which is converted to catabolic conditions accompanied by muscle strength reduction in the chronic phase. Myostatin plays a crucial role in this orchestration and initial myostatin concentration may predict the long-term muscle strength.

Septic arthritis of the wrist is a serious condition, yet little is known about its long-term outcome. A retrospective analysis of 22 patients treated for bacterial septic arthritis of the wrist was conducted with subsequent follow-up of 18 patients with a median period of 44 months to assess functional results via DASH-Score and clinical examination. Arthrotomy was used to treat all patients; in 19 patients, multiple operations were needed to cure the infection. Follow-up revealed a mean DASH-score of 34 (SD 22) and a significant correlation with needed surgical radicality and number of needed operations. The range of motion of the wrist and grip strength of the affected side was 49% (SD 20%) and 70% (SD 28%) of the contralateral side, respectively. In conclusion, septic arthritis of the wrist leads to long-term functional restrictions with a strong correlation with the stage of the disease. Hence, early diagnosis and treatment are paramount.

Breast adenocarcinoma continues to be the most frequently diagnosed tumor entity. Despite established therapy options, mortality for breast cancer remains to be as high as 40,000 patients in the US annually. Thus, a need to develop a patient-oriented, targeted therapy exists. In this study, we investigated the interaction of breast adenocarcinoma with the ubiquitously present protein Follistatin and subsequently the GDF8/11 pathway. We analyzed primary histological samples from adenocarcinoma patients for expression of Follistatin and GDF8/11. Furthermore, expression levels of Follistatin and GDF8/11 in MCF7 were compared with MCF10a cells. From the resulting data, GDF8 and Follistatin were used as chemotherapeutic agents in MCF7 cells and their migratory, proliferative behavior and viability were measured. From the experiments, we were able to detect a significantly increased expression of Follistatin and GDF8/11 in the low malignant breast adenocarcinoma (G1) as compared to benign breast fibroadenoma. Interestingly, a decrease was demonstrated in higher grade malignancies. These findings were accompanied by the clinical observation that increased expression of Follistatin and GDF8 is associated with a higher overall survival rate of breasts cancer patients. Substitution of GDF8 and Follistatin reduces the viability of the MCF7 cells and disrupts the migrative and proliferative potential. In summary, MCF7 cells show high chemosensitivity to Follistatin and especially GDF8 and both proteins might serve as targets to improve systemic treatment in breast cancer. In contrast to most established chemotherapy regimens Follistatin and GDF8 show no cytotoxicity to other organs.

Osteomyelitis is a frequent consequence of open fractures thus representing a common bone infection with subsequent alteration of bone regeneration. Impaired bone homeostasis provokes serious variations in the bone remodeling process, thereby involving multiple inflammatory cytokines to activate bone healing. Our previously established mouse model of posttraumatic osteomyelitis provides the chance to study regulation of selected cytokines after surgical debridement of osteomyelitis thus illustrating the course of initial infectious recovery. An inflammatory cytokine array revealed specifically upregulated cytokines in debrided animals after bone infection, that were verified by Western blot analysis, identifying increased levels of CCL2, CCL3, and CXCL2. Increased osteoclastogenesis after debridement of osteomyelitis was demonstrated by Calcitonin-receptor and RANKL detection via immunohistochemical and -fluorescence stainings. The substantial protein analysis was complemented by uncovering diminished osteogenesis and proliferation in debrided group, tracking Osteocalcin, RUNX2, and PCNA expression. Interestingly TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Additional flow cytometry analysis proved elevated B cell activity, subsequently increased osteoclast activity and accelerated bone resorption. Based on the variety of severely altered cytokines, we propose a RANKL-dependent osteoclastogenesis after debridement of osteomyelitis coinciding with elevated B cells and simultaneously decreased osteogenesis. A comprehensive understanding of these mechanisms provides new therapeutic options of osteomyelitis cure and is of great importance in prospective medical treatment. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2425-2434, 2017.

Background Angiotensin-converting enzyme (ACE) inhibitors (ACEis) are beneficial in patients with heart failure, yet their role after heart transplantation (HTx) remains ambiguous. Particularly, the effects of ACEis on plasma and cardiac metabolites of the "classical" and "alternative" renin-angiotensin system (RAS) in HTx patients are unknown. Methods This cross-sectional study used a novel mass spectrometry–based approach to analyze plasma and tissue RAS regulation in homogenates of heart biopsy specimens from 10 stable HTx patients without RAS blockade and in 15 patients with ACEi therapy. Angiotensin (Ang) levels in plasma and Ang formation rates in biopsy tissue homogenates were measured. Results Plasma Ang II formation is exclusively ACE dependent, whereas cardiac Ang II formation is primarily chymase dependent in HTx patients. ACEi therapy substantially increased plasma Ang-(1–7), the key effector of the alternative RAS, leaving plasma Ang II largely intact. Importantly, neprilysin and prolyl-carboxypeptidase but not angiotensin converting enzyme 2 are essential for cardiac tissue Ang-(1–7) formation. Conclusion ACE is the key enzyme for the generation of plasma Ang II, whereas chymase is responsible for cardiac tissue production of Ang II. Furthermore, our findings reveal that neprilysin and prolyl-carboxypeptidase are the essential cardiac enzymes for the alternative RAS after HTx. These novel insights into the versatile regulation of the RAS in HTx patients might affect future therapeutic avenues, such as chymase and neprilysin inhibition, beyond classical Ang II blockade.

\(\bf{Introduction}\) Bone infections after trauma, \(\textit{i.e.}\) posttraumatic osteomyelitis, pose one of the biggest problems of orthopedic surgery. Even after sufficient clinical therapy including vast debridement of infected bone and antibiotic treatment, regeneration of postinfectious bone seems to be restricted. One explanation includes the large sized defects resulting from sufficient debridement. Furthermore, it remains unclear if inflammatory processes after bone infection do affect bone regeneration. For continuing studies in this field, an animal model is needed where bone regeneration after sufficient treatment can be studied in detail. \(\bf{Methods}\) For this purpose we created a stable infection in murine tibiae by \(\textit{Staphylococcus aureus}\) inoculation. Thereafter, osteomyelitic bones were debrided thoroughly and animals were subsequently treated with antibiotics. Controls included debrided, non-infected, as well as infected animals exclusively treated with antibiotics. To verify sufficient treatment of infected bone, different assessments detecting \(\textit{S. aureus}\) were utilized: agar plates, histology and RT-qPCR. \(\bf{Results}\) All three detection methods revealed massive reduction or eradication of \(\textit{S.aureus}\) within debrided bones 1 and 2 weeks postoperatively, whereas sole antibiotic therapy could not provide sufficient treatment of osteomyelitic bones. Debrided, previously infected bones showed significantly decreased bone formation, compared to debrided, non-infected controls. \(\bf{Discussion}\) Thus, the animal model presented herein provides a reliable and fascinating tool to study posttraumatic osteomyelitis for clinical therapies.

Scaphoid bones have a high prevalence for non‐union. Even with adequate treatment, bone regeneration may not occur in certain instances. Although this condition is well described, the molecular pathology of scaphoid non‐unions is still poorly defined. In this study, gene expression of osteogenic and angiogenic growth and transcription factors as well as inflammatory mediators were analysed in human scaphoid non‐unions and intraindividually compared to adjacent autologous cancellous bone from the distal radius. In addition, histology and immunohistochemical stainings were performed to verify qRT‐PCR data. Gene expression analysis revealed a significant up‐regulation of RANKL, ALP, CYCLIN D1, MMP‐13, OPG, NFATc1, TGF‐β and WNT5A in scaphoid non‐unions. Interestingly, RANKL and NFATc1, both markers for osteoclastogenesis, were significantly induced in non‐unions. Moreover, WNT5A was highly up‐regulated in all non‐union samples. TRAP staining confirmed the observation of induced osteoclastogenesis in non‐unions. With respect to genes related to osteogenesis, alkaline phosphatase was significantly up‐regulated in scaphoid non‐unions. No differences were detectable for other osteogenic genes such as RUNX‐2 or BMP‐2. Importantly, we did not detect differences in angiogenesis between scaphoid non‐unions and controls in both gene expression and immunohistochemistry. Summarized, our data indicate increased osteoclast activity in scaphoid non‐unions possibly as a result of the alterations in RANKL, TGF‐β and WNT5A expression levels. These data increase our understanding for the reduced bone regeneration capacity present in scaphoid non‐unions and may translate into the identification of new therapeutic targets to avoid secondary damages and prevent occurrence of non‐unions to scaphoid bones.