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Bone grafts, i.e., autologous, allogeneic or synthetic bone substitute materials play an increasing role in reconstructive orthopedic surgery. While the indications and materials differ, it is important to understand the cellular mechanisms regarding their integration and remodeling, which are discussed in this review article. Osteoconductivity describes the new bone growth on the graft, while osteoinductivity represents the differentiation of undifferentiated cells into bone forming osteoblasts. The best case is that both mechanisms are accompanied by osteogenesis, i.e., bone modeling and remodeling of the graft material. Graft incorporation is mediated by a number of molecular pathways that signal the differentiation and activity of osteoblasts and osteoclasts (e.g., parathyroid hormone (PTH) and receptor activator of nuclear factor κβ ligand (RANKL), respectively). Direct contact of the graft and host bone as well as the presence of a mechanical load are a prerequisite for the successful function of bone grafts. Interestingly, while bone substitutes show good to excellent clinical outcomes, their histological incorporation has certain limits that are not yet completely understood. For instance, clinical studies have shown contrasting results regarding the complete or incomplete resorption and remodeling of allografts and synthetic grafts. In this context, a foreign body response can lead to complete material degradation via phagocytosis, however it may also cause a fibrotic reaction to the bone substitute. Finally, the success of bone graft incorporation is also limited by other factors, including the bone remodeling capacities of the host, the material itself (e.g., inadequate resorption, toxicity) and the surgical technique or preparation of the graft.

As organs of photosynthesis, leaves are of vital importance for plants and a source of inspiration for biomimetic developments. Leaves are composed of interconnected functional elements that evolved in concert under high selective pressure, directed toward strategies for improving productivity with limited resources. In this paper, selected basic components of the leaf are described together with biomimetic examples derived from them. The epidermis (the “skin” of leaves) protects the leaf from uncontrolled desiccation and carries functional surface structures such as wax crystals and hairs. The epidermis is pierced by micropore apparatuses, stomata, which allow for regulated gas exchange. Photosynthesis takes place in the internal leaf tissue, while the venation system supplies the leaf with water and nutrients and exports the products of photosynthesis. Identifying the selective forces as well as functional limitations of the single components requires understanding the leaf as an integrated system that was shaped by evolution to maximize carbon gain from limited resource availability. These economic aspects of leaf function manifest themselves as trade-off solutions. Biomimetics is expected to benefit from a more holistic perspective on adaptive strategies and functional contexts of leaf structures.

This study aimed at evaluating the orbital anatomy of patients concerning the relevance of orbital anatomy in the etiology of EO (endocrine orbitopathy) and exophthalmos utilizing a novel approach regarding three-dimensional measurements. Furthermore, sexual dimorphism in orbital anatomy was analyzed. Orbital anatomy of 123 Caucasian patients (52 with EO, 71 without EO) was examined using computed tomographic data and FAT software for 3-D cephalometry. Using 56 anatomical landmarks, 20 angles and 155 distances were measured. MEDAS software was used for performing connected and unconnected t-tests and Spearman´s rank correlation test to evaluate interrelations and differences. Orbital anatomy was highly symmetrical with a mean side difference of 0.3 mm for distances and 0.6° for angles. There was a small albeit statistically significant difference in 13 out of 155 distances in women and 1 in men concerning patients with and without EO. Two out of 12 angles showed a statistically significant difference between female patients with and without EO. Regarding sex, statistically significant differences occurred in 39 distances, orbit volume, orbit surface, and 2 angles. On average, measurements were larger in men. Concerning globe position within the orbit, larger distances to the orbital apex correlated with larger orbital dimensions whereas the sagittal position of the orbital rim defined Hertel values. In this study, little difference in orbital anatomy between patients with and without EO was found. Concerning sex, orbital anatomy differed significantly with men presenting larger orbital dimensions. Regarding clinically measured exophthalmos, orbital aperture anatomy is an important factor which has to be considered in distinguishing between true exophthalmos with a larger distance between globe and orbital apex and pseudoexophthalmos were only the orbital rim is retruded. Thus, orbital anatomy may influence therapy regarding timing and surgical procedures as it affects exophthalmos.

Thyroid eye disease (TED) is a common extrathyroidal manifestation of hyperthyroidism, typically associated with Graves’ disease (GD). This condition can cause severe functional limitations as well as significant aesthetic concerns. Treatment for TED patients aims to restore functionality and address aesthetic concerns. Surgical TED treatment is usually performed by orbital wall resection, which effectively decompresses intraorbital tissues and corrects the orbital/ocular disorders. Several different scenarios of surgical TED treatment including one-, two-, and three-wall resections are known. More recently, a new minimally invasive technique, the so-called lateral valgization (LAVA) of the orbital wall, was reported to show promising results comparable to conventional wall resection techniques. Due to the relatively limited data on TED treatment, only a few quantitative investigations of alternative TED surgery scenarios exist. In this feasibility study, we estimate the soft tissue outcome of LAVA treatment using computational simulation. Our experimental results show that the amount of intraorbital tissue released into the extraorbital space by LAVA treatment is comparable with the outcome of two-wall resection. Our computational simulation confirms previously reported isolated clinical findings suggesting that the minimally invasive LAVA approach represents an attractive alternative to conventional wall resection approaches for surgical TED treatment.

Key Points Lamellipodial protrusion depends on the force generated by actin polymerization. Actin polymerization is the sum of the activities of nucleators — for example, the actin-related protein 2/3 (ARP2/3) complex — and elongators — formins and ENA/VASP proteins. Small GTPases, such as RAC and CDC42, control both actin nucleators and actin elongators; RAC activates the WASP family verprolin-homologous protein (WAVE) complex upstream of the ARP2/3 complex independently of the activation of the formin FMNL2 by CDC42, but RAC may coordinate ARP2/3 with ENA/VASP proteins by inducing a complex between WAVE and lamellipodin. The speed of cell migration depends on the turnover of actin branched junctions and on the elongation of actin networks. An intrinsic instability of lamellipodia is due to ARP2/3 inhibitory proteins, such as Arpin, which is also activated downstream of RAC. The persistence of lamellipodia is the major controller of cell directionality. Directional persistence (that is, the characteristic time during which a cell sustains its migration in the same direction) is the combinatory result of several intertwined positive- and negative-feedback loops that sustain or stop actin polymerization at the leading edge. Lamellipodial protrusion is powered by actin polymerization that is mediated through the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. These processes are regulated by positive and negative feedback loops centred around the GTPase RAC, and the balance between them determines lamellipodial and directional persistence during cell migration. Membrane protrusions at the leading edge of cells, known as lamellipodia, drive cell migration in many normal and pathological situations. Lamellipodial protrusion is powered by actin polymerization, which is mediated by the actin-related protein 2/3 (ARP2/3)-induced nucleation of branched actin networks and the elongation of actin filaments. Recently, advances have been made in our understanding of positive and negative ARP2/3 regulators (such as the SCAR/WAVE (SCAR/WASP family verprolin-homologous protein) complex and Arpin, respectively) and of proteins that control actin branch stability (such as glial maturation factor (GMF)) or actin filament elongation (such as ENA/VASP proteins) in lamellipodium dynamics and cell migration. This Review highlights how the balance between actin filament branching and elongation, and between the positive and negative feedback loops that regulate these activities, determines lamellipodial persistence. Importantly, directional persistence, which results from lamellipodial persistence, emerges as a critical factor in steering cell migration.

Endocytosis mediates the cellular uptake of micronutrients and the turnover of plasma membrane proteins. Clathrin-mediated endocytosis is the major uptake pathway in resting cells 1 , but several clathrin-independent endocytic routes exist in parallel 2 , 3 . One such pathway, fast endophilin-mediated endocytosis (FEME), is not constitutive but triggered upon activation of certain receptors, including the β 1 adrenergic receptor 4 . FEME activates promptly following stimulation as endophilin is pre-enriched by the phosphatidylinositol-3,4-bisphosphate-binding protein lamellipodin 4 , 5 . However, in the absence of stimulation, endophilin foci abort and disassemble after a few seconds. Looking for additional proteins involved in FEME, we found that 20 out of 65 BAR domain-containing proteins tested colocalized with endophilin spots. Among them, FBP17 and CIP4 prime the membrane of resting cells for FEME by recruiting the 5′-lipid phosphatase SHIP2 and lamellipodin to mediate the local production of phosphatidylinositol-3,4-bisphosphate and endophilin pre-enrichment. Membrane-bound GTP-loaded Cdc42 recruits FBP17 and CIP4, before being locally deactivated by RICH1 and SH3BP1 GTPase-activating proteins. This generates the transient assembly and disassembly of endophilin spots, which lasts 5–10 seconds. This mechanism periodically primes patches of the membrane for prompt responses upon FEME activation. Chan Wah Hak et al. show how plasma membrane patches are primed for fast endophilin-mediated endocytosis and disassembly, in the absence of receptor stimulation, through FBP17 and CIP4 binding to SHIP2 and lamellipodin.

According to recent estimates, around 6,000 people – mostly children under five – die every day from diseases caused by inappropriate water and sanitation (WS) services. Much of the academic and political debate surrounding this issue has focused on private sector participation. By shifting the attention towards the influence of governance, Krause examines the political and sectoral institutions that are essential for the provision of WS services. Utilizing data from sixty-nine developing countries, Matthias Krause demonstrates that the level of democracy has a statistically significant positive impact on access to WS services and that low-quality governance of sub-national governments compromises the internal efficiency of providers and the widespread access to services. This book makes a critical contribution to the water and sanitation research and will help academics and policy-makers to rethink the way in which they deal with water issues. Matthias Krause is an economist at the German Development Institute in Bonn, Germany. He has several years of research and working experience in Latin America (among others in Chile, Brazil and Colombia). His main research activities lie within the fields of private sector participation in infrastructure, political economy of regulation, and private sector development. 1. Introduction 2. Normative and problem-oriented framework for assessing WS policies 3. Political-economic framework for analysing the relation between governance and the provision of WS services 4. Political governance and access to WS services: A cross-country regression analysis 5. The role of governance and PSP for the provision of WS services: Case study on Colombia 6. Summary and conclusions. Appendix.

Treatment of complex tibial plateau fractures remains a challenging task in clinical practice. Sufficient and appropriate preoperative decision making is essential for optimal treatment success and ultimately influences patient outcomes. Recently, the novel technique of 3D printing has proven to be beneficial for the preoperative management in other joint regions. To investigate the impact of point-of-care 3D printing on the preoperative management of tibial plateau fractures, we asked 5 students, 10 surgical residents, 3 junior surgeons and 4 senior surgeons, to simulate the preoperative planning of 22 tibial plateau fractures (11 AO B and 11 AO C fractures) regarding the treatment concept, patient positioning, operative approach and implant selection and positioning. First with CT scans only, second with 3D volumetric reconstructions, and finally with 3D printed fracture models. We analyzed the inter- and intraobserver agreement and the subjective perceived confidence of the rater regarding his decision with the different imaging modalities across the different levels of professional experience. Statistics were performed using kappa values, percentage match (PM) analysis and a univariate one-way analysis of variance. The use of 3D printing had no effect on the interobserver reliability of treatment concept selection (PM CT 83% > 3DCT 83% > 3D 82%). However, descriptively higher kappa and percentage match values increased for agreement on patient positioning and surgical approach using 3D printed fracture models. In addition, the raters selected the implants that were actually used to treat the fractures in 63% of the cases. The subjective perceived certainty of the raters increased with the use of 3D printing technology from 45% (CT and 3DCT) to 60% (3D). Additionally, raters changed their treatment plan in 36% of the cases and gained additional information 76% of the time when using the 3D printed specimen. The use of 3D printed fracture models showed a trend toward higher interrater reliability of patient positioning and surgical approach for medical students and surgical residents, while experienced surgeons show less benefit. In addition, 3D-printed models supported implant pre-selection and increased subjective confidence, positively influencing preoperative planning.

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P 3 . Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P 3 -deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. The regulatory role of calcitonin in bone homeostasis is well studied, yet its molecular activity is poorly understood. The authors show that calcitonin regulates bone cells function by inhibiting the osteoclast secretion of sphingosine 1-phosphate, a lipid mediator of osteoclast–osteoblast crosstalk.