Die UVB-abhängige Induktion des Vaskulären Endothelialen Wachstumsfaktors (VEGF) wird in epidermalen Zellen autokrin durch den Transformierenden Wachstumsfaktor alpha (TGF@) reguliert: Bedeutung für die UVB-induzierte

Ein Zusammenhang zwischen chronischer Sonnenexposition der Haut und vermehrter Bildung von Gefäßen bei der Photoalterung und Photokarzinogenese der Haut mit vorzeitiger Alterung und Ausbildung nicht-melanozytärer und melanozytärer Tumoren der Haut kann als wissenschaftlich gesichert angesehen werden. Teleangiektasien, die durch eine Zunahme und Vergrößerung kutaner Blutgefäße gekennzeichnet sind, und die Entwicklung stark vaskularisierter Hauttumoren sind charakteristische Endpunkte einer chronisch sonnenexponierten und sonnengeschädigten Haut. Die zugrundeliegenden molekularen Mechanismen der UV-induzierten pathophysiologischen Angiogenese sind weitgehend unbekannt. In der Tumorprogression sind Angiogenesefaktoren wie der vaskuläre endotheliale Wachstumsfaktor VEGF, ein multifunktionales Zytokin mit mitogener Aktivität für Endothelzellen, von zentraler Bedeutung, da Tumorwachstum und -metastasierung von der Ausbildung eines tumorversorgenden Blutgefäßsystems abhängig sind. In der vorliegenden Arbeit sollte mit molekularbiologischen und zellbiologischen Methoden untersucht werden, ob und in welcher Form solare UVB-Strahlung als schädigende Komponente des Sonnenlichts auf der Erdoberfläche die Regulation von VEGF beeinflußt. Es konnte gezeigt werden, daß UVB-Bestrahlung den Angiogenesefaktor VEGF in epidermalen Zellen auf Proteinebene mit biphasischer Expression nach 4 bzw. 24 h maximal induziert. In Untersuchungen der UVB-induzierten VEGF-Promotoraktivität wurde durch transiente Transfektionen von HaCaT-Zellen mit Deletionskonstrukten des humanen VEGF-Promotors und in Experimenten unter Verwendung neutralisierender Antikörper der transformierende Wachstumsfaktor alpha (TGF) als Mediator der sekundären VEGF-Expression nach UVBBestrahlung identifiziert. Die primäre Induktion von VEGF und die Synthese von TGF sind abhängig von der UVB-Aktivierung des EGF-Rezeptors (EGF-R) und konnten durch den EGF-R-spezifischen Tyrosinkinase-Inhibitor PD 153035 signifikant inhibiert werden. Die UVB-abhängige VEGF-Expression wurde in vivo in menschlicher Haut immunohistologisch bestätigt. Durch die signifikante Verminderung der UVB-abhängig gesteigerten Angiogenese in der Epidermis repetitiv bestrahlter haarloser Mäuse konnte nach intraperitonealer Injektion neutralisierender Antikörper gegen VEGF die kausale Bedeutung von VEGF in vivo im Mausmodell belegt werden. Zusammengefaßt konnten in dieser Arbeit in vitro und in vivo die Bedeutung von VEGF für angiogenetische Prozesse nach UVB-Exposition herausgearbeitet und wesentliche Wege seiner Signaltransduktion identifiziert werden

Evaluation of range of motion restriction within the hip joint

In Total Hip Arthroplasty, determining the impingement free range of motion requirement is a complex task. This is because in the native hip, motion is restricted by both impingement as well as soft tissue restraint. The aim of this study is to determine a range of motion benchmark which can identify motions which are at risk from impingement and those which are constrained due to soft tissue. Two experimental methodologies were used to determine motions which were limited by impingement and those motions which were limited by both impingement and soft tissue restraint. By comparing these two experimental results, motions which were limited by impingement were able to be separated from those motions which were limited by soft tissue restraint. The results show motions in extension as well as flexion combined with adduction are limited by soft tissue restraint. Motions in flexion, flexion combined with abduction and adduction are at risk from osseous impingement. Consequently, these motions represent where the maximum likely damage will occur in femoroacetabular impingement or at most risk of prosthetic impingement in Total Hip Arthroplasty

Use of antagonist muscle EMG in the assessment of neuromuscular health of the low back

Background: Non-specific low back pain (LBP) has been one of the most frequently occurring musculoskeletal problems. Impairment in the mechanical stability of the lumbar spine has been known to lower the safety margin of the spine musculature and can result in the occurrence of pain symptoms of the low back area. Previously, changes in spinal stability have been identified by investigating recruitment patterns of low back and abdominal muscles in laboratory experiments with controlled postures and physical activities that were hard to conduct in daily life. The main objective of this study was to explore the possibility of developing a reliable spine stability assessment method using surface electromyography (EMG) of the low back and abdominal muscles in common physical activities. Methods: Twenty asymptomatic young participants conducted normal walking, plank, and isometric back extension activities prior to and immediately after maintaining a 10-min static upper body deep flexion on a flat bed. EMG data of the erector spinae, external oblique, and rectus abdominals were collected bilaterally, and their mean normalized amplitude values were compared between before and after the static deep flexion. Changes in the amplitude and co-contraction ratio values were evaluated to understand how muscle recruitment patterns have changed after the static deep flexion. Results: Mean normalized amplitude of antagonist muscles (erector spinae muscles while conducting plank; external oblique and rectus abdominal muscles while conducting isometric back extension) decreased significantly (P < 0.05) after the 10-min static deep flexion. Normalized amplitude of agonist muscles did not vary significantly after deep flexion. Conclusions: Results of this study suggest the possibility of using surface EMG in the evaluation of spinal stability and low back health status in simple exercise postures that can be done in non-laboratory settings. Specifically, amplitude of antagonist muscles was found to be more sensitive than agonist muscles in identifying changes in the spinal stability associated with the 10-min static deep flexion. Further research with various loading conditions and physical activities need to be performed to improve the reliability and utility of the findings of the current study.open0

Comparison of Functional and Clinical Outcomes between Minimally-Invasive and Conventional Approaches after Total Hip Replacement

Background: Total Hip Arthroplasty (THA) is one of the most commonly performed and successful orthopaedic surgeries. At the same time, the issue about the best surgical approach for THA remains controversial. This systematic review aims to evaluate the current evidence for the use of Minimally-Invasive Surgery (MIS) in THA. Methods: A systematic literature search of PubMed, Medline and Embase was conducted. Randomised controlled trials, comparative studies, and cohort studies were included in this systematic review. Main outcome measurements included incision length, blood loss, operating time, length of stay, complications, postoperative pain on a Visual Analogue Scale (VAS), Short Form 36/12 Health Survey (SF 36/12), Harris Hip Score (HHS) and cup inclination. Results: A total of 30 studies met the inclusion criteria. There was no significant difference between MIS and conventional approaches for THA with regards to complication rates and implant inclination angle. The average operating time in 10/24 (41%) studies was significantly (p<0.05) longer in the MIS group. MIS THA lead to an improvement, patient-centered results with reduced blood loss in 9/16 (56%), reduced use of analgesics in 4/4 (100%) and reduced myoglobin correlated muscle trauma in 3/4 (75%) of the analysed studies. Additionally, 10/10 (100%) studies reported less postoperative pain after MIS THA, 16/19 (84%) studies detected an improved postoperative Harris Hip score and 7/7 (100%) studies an improved SF36/12 score respectively. This resulted a reduced length of stay in 10/10 (100%) of the studies when compared to THA utilizing a conventional approach. Conclusion: MIS in THA is nowadays no longer seen as just cosmetically attractive but rather as a real improvement for the clinical outcome. There is evidence for improved patient related outcome following MIS THA

Insights into ionic medicine: Cerium reduces the presence of reactive oxygen species and favors osteogenic over adipogenic differentiation in human mesenchymal stromal cells

The guided application of metallic ions in bone tissue engineering (BTE) has recently gained popularity being described as one important example of ionic medicine (IM). BTE aims to enhance osteogenic differentiation of precursor cells like bone-marrow-derived mesenchymal stromal cells (BMSCs) and, by that, regenerate bone tissue. BMSCs however can also differentiate into adipogenic lineage. It is known that elevated levels of reactive oxygen species (ROS) stimulate BMSC towards (undesired) adipogenic differentiation. One ion, that is particularly interesting for application in IM-guided BTE is cerium (Ce) since it acts as a self-regenerating ROS-scavenger and has already been successfully incorporated in biomaterials. Ce has demonstrated pro-osteogenic, anti-adipogenic and anti-oxidative effects before, however, so far, there is no direct comparative study available that analyzes these effects on human BMSCs in one and the same setting. Therefore, in this study, the influence of Ce nitrate (CeN) on the expression of osteogenic, adipogenic and ROS-scavenging genes in BMSCs was evaluated as well as its impact on formation of an osseous extracellular matrix (ECM), lipid formation and physical ROS presence. The presence of CeN improved BMSCs viability, enhanced proliferation, and reduced ROS-levels. Furthermore, CeN suppressed adipogenesis while osteogenic differentiation and the formation and maturation of the ECM were enhanced. The presence of CeN reduced the physical presence of ROS and the gene expression patterns shifted towards an anti-oxidant profile. Ce therefore constitutes an attractive ion for application in IM-guided BTE. Further research is necessary to clarify the biological mechanisms and pathways that are involved in the Ce-mediated modulation of BMSC differentiation

Targeting Bone Tumours with 45S5 Bioactive Glass

Despite advances in treatment modalities, bone tumour therapies still face significant challenges. Severe side effects of conventional approaches, such as chemo- and radiation therapy, result in poor survival rates and high tumour recurrence rates, which are the most common issues that need to be improved upon. The aim of this study was to evaluate the therapeutic properties of 45S5 bioactive glass (BG) for targeting bone tumours. The viability of the cells derived from osteosarcoma, chondrosarcoma, and giant cell tumours was significantly reduced in the presence of 45S5-BG. In contrast, the viability of non-malignant osteoblast-like cells, chondrocytes, and bone marrow-derived stromal cells was not or only slightly affected. While alterations to the particle surface induced by heat treatment, acid etching, or incubation in a simulated body fluid had only minor effects on cytotoxicity, reducing the particle size or sintering the material significantly improved the cytotoxic effect of 45S5-BG. Further, using a chicken chorioallantoic membrane assay, the co-transplantation of 45S5-BG resulted in a significant reduction in tumour formation in vivo. Given the known positive effects of BGs on bone regeneration, our findings suggest that 45S5-BG holds great potential for the development of new and effective bone tumour therapies, with minimal side effects on non-malignant cells and simultaneous contribution to bone healing.This study was supported by a grant from “Deutsche Krebshilfe e.V.” (grant number: 70115225). We acknowledge financial support for the publication fee by the “Open Access Publikationsfonds” of the Heidelberg University.Deutsche Krebshilfe e.V.“Open Access Publikationsfonds” of the Heidelberg Universit

In vitro and in ovo impact of the ionic dissolution products of boron-doped bioactive silicate glasses on cell viability, osteogenesis and angiogenesis

Due to the pivotal role of angiogenesis in bone regeneration, the angiogenic properties of biomaterials are of high importance since they directly correlate with the biomaterials’ osteogenic potential via ‘angiogenic-osteogenic coupling’ mechanisms. The impact of bioactive glasses (BGs) on vascularization can be tailored by incorporation of biologically active ions such as boron (B). Based on the ICIE16-BG composition (in mol%: 49.5 SiO2, 36.3 CaO, 6.6 Na2O, 1.1 P2O5, 6.6 K2O), three B-doped BGs have been developed (compositions in mol%: 46.5/45.5/41.5 SiO2, 36.3 CaO, 6.6 Na2O, 1.1 P2O5, 6.6 K2O, 3/4/8 B2O3). The influence of B-doping on the viability, cellular osteogenic differentiation and expression of osteogenic and angiogenic marker genes of bone marrow-derived mesenchymal stromal cells (BMSCs) was analyzed by cultivating BMSCs in presence of the BGs’ ionic dissolution products (IDPs). Furthermore, the influence of the IDPs on angiogenesis was evaluated in ovo using a chorioallantoic membrane (CAM) assay. The influence of B-doped BGs on BMSC viability was dose-dependent, with higher B concentrations showing limited negative effects. B-doping led to a slight stimulation of osteogenesis and angiogenesis in vitro. In contrast to that, B-doping significantly enhanced vascularization in ovo, especially in higher concentrations. Differences between the results of the in vitro and in ovo part of this study might be explained via the different importance of vascularization in both settings. The implementation of new experimental models that cover the ‘angiogenic-osteogenic coupling’ mechanisms is highly relevant, for instance via extending the application of the CAM assay from solely angiogenic to angiogenic and osteogenic purposes.Open Access funding enabled and organized by Projekt DEAL.Universitätsklinikum Heidelberg (8914

CTCF induces histone variant incorporation, erases the H3K27me3 histone mark and opens chromatin

Insulators functionally separate active chromatin domains frominactive ones. The insulator factor, CTCF, has been found to bind to boundaries and to mediate insulator function. CTCF binding sites are depleted for the histone modification H3K27me3 and are enriched for the histone variant H3.3. In order to determine whether demethylation of H3K27me3 and H3.3 incorporation are a requirement for CTCF binding at domain boundaries or whether CTCF causes these changes, we made use of the LacI DNA binding domain to control CTCF binding by the Lac inducer IPTG. Here we show that, in contrast to the related factor CTCFL, the N-terminus plus zinc finger domain of CTCF is sufficient to open compact chromatin rapidly. This is preceded by incorporation of the histone variant H3.3, which thereby removes the H3K27me3 mark. This demonstrates the causal role for CTCF in generating the chromatin features found at insulators. Thereby, spreading of a histone modification from one domain through the insulator into the neighbouring domain is inhibited