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Between 1972 and 1989 angulation osteotomy was performed on 61 patients with long humeral stumps at the Orthopaedic Hospital of Heidelberg University. Marquardt's surgical technique was used to improve function in patients who had undergone above-elbow amputation and in children with a risk of terminal osseous overgrowth. Thirty-one patients with 43 angulation osteotomies were followed up. Of the 10 adults followed up, the osteotomy had not straightened, whereas with the 33 angulation osteotomies in children, one had straightened out within 6 months, seven within 12 months and a further 12 up to 24 months after surgery. The only recognizable reason for this difference was the patient's age depending on whether humeral growth was not yet completed. Marquardt's angulation osteotomy, however, is still the only surgical technique that improves humeral stump function, providing a rotation-stable humeral prosthesis and a free-moving shoulder joint. [ABSTRACT FROM AUTHOR]

The protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a non-canonical, phosphorylation-independent 14-3-3 interaction site that encompasses all known TOC mutations. Disruption of this site dysregulates ADAM17 activity. The larger cub deletion also includes the TOC site and thus also dysregulated ADAM17 activity. The cub deletion, but not the TOC mutation, also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, demonstrating the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences, and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17., (© 2024. The Author(s).)

In the lung, pulmonary epithelial cells undergo mechanical stretching during ventilation. The associated cellular mechanoresponse is still poorly understood at the molecular level. Here, we demonstrate that activation of the mechanosensitive cation channel Piezo1 in a human epithelial cell line (H441) and in primary human lung epithelial cells induces the proteolytic activity of the metalloproteinases ADAM10 and ADAM17 at the plasma membrane. These ADAMs are known to convert cell surface expressed proteins into soluble and thereby play major roles in proliferation, barrier regulation and inflammation. We observed that chemical activation of Piezo1 promotes cleavage of substrates that are specific for either ADAM10 or ADAM17. Activation of Piezo1 also induced the synthesis and ADAM10/17-dependent release of the growth factor amphiregulin (AREG). In addition, junctional adhesion molecule A (JAM-A) was shed in an ADAM10/17-dependent manner resulting in a reduction of cell contacts. Stretching experiments combined with Piezo1 knockdown further demonstrated that mechanical activation promotes shedding via Piezo1. Most importantly, high pressure ventilation of murine lungs increased AREG and JAM-A release into the alveolar space, which was reduced by a Piezo1 inhibitor. Our study provides a novel link between stretch-induced Piezo1 activation and the activation of ADAM10 and ADAM17 in lung epithelium. This may help to understand acute respiratory distress syndrome (ARDS) which is induced by ventilation stress and goes along with perturbed epithelial permeability and release of growth factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Several membrane-anchored signal mediators such as cytokines (e.g. TNFα) and growth factors are proteolytically shed from the cell surface by the metalloproteinase ADAM17, which, thus, has an essential role in inflammatory and developmental processes. The membrane proteins iRhom1 and iRhom2 are instrumental for the transport of ADAM17 to the cell surface and its regulation. However, the structure-function determinants of the iRhom-ADAM17 complex are poorly understood. We used AI-based modelling to gain insights into the structure-function relationship of this complex. We identified different regions in the iRhom homology domain (IRHD) that are differentially responsible for iRhom functions. We have supported the validity of the predicted structure-function determinants with several in vitro, ex vivo and in vivo approaches and demonstrated the regulatory role of the IRHD for iRhom-ADAM17 complex cohesion and forward trafficking. Overall, we provide mechanistic insights into the iRhom-ADAM17-mediated shedding event, which is at the centre of several important cytokine and growth factor pathways., (© 2023. The Author(s).)

Objective: To test the response of Osteopontin levels in patients with knee/hip Osteoarthritis undergoing a replacement surgery., Method: Plasma samples of 30 (16 with knee Osteoarthritis and 14 with hip Osteoarthritis) patients have been collected before and 3 month after a knee/hip replacement in order to investigate the above stated aim of this study., Result: Osteopontin levels did not decrease after 3 months of the surgery., Conclusion: Osteopontin levels showed no significant reduction and therefore do not respond to replacement treatment.

Introduction: A diagnostic evaluation of the severity and progression of hip osteoarthritis (OA) using biochemical markers is lacking in the current medical literature. Osteopontin (OPN) has been proved to correlate with the progression and severity of knee OA. Therefore, the examination of plasma OPN levels in patients with idiopathic hip OA and its correlation with disease severity and progression was necessary., Methods: Our study included 21 patients displaying symptomatic severe idiopathic hip OA; the diagnosis of the disease was based on the checklist of the American College of Rheumatology and the severity was evaluated according to the K-L grading (Kellgran and Lawrence score)., Results: 14 patients showed radiological changes according K-L grade 3 (66.66%), and 7 patients showed radiological changes according K-L grade 4 (33.33%). We observed a highly statistically significant increase of plasma OPN levels in comparison with normal referenced values, the cut off value for differentiating between normal people and patients with hip OA was 193.6 ng/ml. Furthermore, the mean of plasma OPN levels in idiopathic hip osteoarthritis patients with K-L grade 4 (362.51 ± 83.31 ng/mL) was greater than those with K-L grade 3 (283.41 ± 56.31 ng/mL), the difference being statistically significant., Conclusions: plasma OPN levels are increased in idiopathic hip OA and are correlated with the severity of the disease.