Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1.

Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment and biological processes. The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed endocytic receptor that regulates cellular events by modulating the levels of numerous extracellular molecules via rapid endocytic removal. LRP1 also participates in signalling pathways through this modulation as well as in the interaction with membrane receptors and cytoplasmic adaptor proteins. LRP1 SNPs are associated with several diseases and conditions such as migraines, aortic aneurysms, cardiopulmonary dysfunction, corneal clouding, and bone dysmorphology and mineral density. Studies using Lrp1 KO mice revealed a critical, nonredundant and tissue-specific role of LRP1 in regulating various physiological events. However, exactly how LRP1 functions to regulate so many distinct and specific processes is still not fully clear. Our recent proteomics studies have identified more than 300 secreted proteins that either directly interact with LRP1 or are modulated by LRP1 in various tissues. This review will highlight the remarkable ability of this receptor to regulate secreted molecules in a tissue-specific manner and discuss potential mechanisms underpinning such specificity. Uncovering the depth of these "hidden" specific interactions modulated by LRP1 will provide novel insights into a dynamic and complex extracellular environment that is involved in diverse biological and pathological processes.

iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I.

Proteolytic release of transmembrane proteins from the cell surface, the so called ectodomain shedding, is a key process in inflammation. Inactive rhomboid 2 (iRhom2) plays a crucial role in this context, in that it guides maturation and function of the sheddase ADAM17 (a disintegrin and metalloproteinase 17) in immune cells, and, ultimately, its ability to release inflammatory mediators such as tumor necrosis factor α (TNFα). Yet, the macrophage sheddome of iRhom2/ADAM17, which is the collection of substrates that are released by the proteolytic complex, is only partly known. In this study, we applied high-resolution proteomics to murine and human iRhom2-deficient macrophages for a systematic identification of substrates, and therefore functions, of the iRhom2/ADAM17 proteolytic complex. We found that iRhom2 loss suppressed the release of a group of transmembrane proteins, including known (e.g. CSF1R) and putative novel ADAM17 substrates. In the latter group, shedding of major histocompatibility complex class I molecules (MHC-I) was consistently reduced in both murine and human macrophages when iRhom2 was ablated. Intriguingly, it emerged that in addition to its shedding, iRhom2 could also control surface expression of MHC-I by an undefined mechanism. We have demonstrated the biological significance of this process by using an in vitro model of CD8+ T-cell (CTL) activation. In this model, iRhom2 loss and consequent reduction of MHC-I expression on the cell surface of an Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line dampened activation of autologous CTLs and their cell-mediated cytotoxicity. Taken together, this study uncovers a new role for iRhom2 in controlling cell surface levels of MHC-I by a dual mechanism that involves regulation of their surface expression and ectodomain shedding.

Indications, Associated Procedures, and Results of Ankle Plafond-Plasty for Varus Ankle Osteoarthritis: A Systematic Review and Meta-Analysis.

BACKGROUNDS: Plafond-plasty is a joint-preserving procedure to treat varus ankle osteoarthritis (OA) with asymmetrical joint involvement. The aim of this systematic review and meta-analysis was to evaluate indications, different surgical techniques, associated procedures, and results of plafond-plasty in varus ankle OA and to analyze the level of evidence (LOE) and quality of evidence (QOE) of the included studies. METHODS: A systematic review of the literature was performed using MEDLINE, Embase, and Cochrane. RESULTS: Five studies evaluating 99 ankles were included. A non-rigid varus ankle deformity and an ankle OA Takakura stage 3b or less were the most recommended pre-operative indications. Meta-analysis showed a significant post-operative improvement in clinical and radiological parameters. Many associated surgical procedures have been reported, the most frequent being medial additional supramalleolar osteotomy and lateral ankle ligament reconstruction. The level of evidence and methodological quality assessment of the included studies showed an overall low quality. CONCLUSION: Plafond-plasty seems to be a promising surgical option when managing varus ankle OA with asymmetrical joint involvement, extending the indications for joint sparing surgery. Additional associated procedures should be carefully evaluated case-by-case. LEVELS OF EVIDENCE: IV.

Custom-made total ankle arthroplasty with patient-specific instrumentation for severe bone loss conditions: a case series.

PURPOSE: Management of bone loss around the ankle is a challenging condition. This retrospective study describes the design process, the surgical technique, and the preliminary results of custom-made total ankle arthroplasties (TAA) with patient-specific instrumentation (PSI) for different severe bone loss conditions. METHODS: Consecutive patients that underwent custom-made TAA for severe bone loss conditions were included. The primary outcome was to describe the implant design in relation to the bone defect. Moreover, pre-operative and final follow-up clinical scores were compared. RESULTS: Seven patients were included. Post-operative radiographs showed good correspondence between the pre-operative planning and the prosthesis alignment in all patients. Improvement in clinical scores was observed in all patients at the final follow-up. One patient developed a deep infection. CONCLUSION: Short-term results reported herein are encouraging suggesting that custom-made TAA implants with PSI may represent an effective solution for ankle bone loss conditions.

Staged vs concurrent hardware removal in total ankle arthroplasty.

INTRODUCTION: Ankle osteoarthritis is more commonly posttraumatic. Consequently, dealing with hardware removal is quite frequent when performing a total ankle arthroplasty (TAA). The purpose of this study is to compare outcomes regarding either a staged or concurrent hardware removal when performing TAA. MATERIALS AND METHODS: 275 consecutive patients with TAA previously treated with internal fixation were retrospectively reviewed. Finally, 57 patients were enrolled based on exclusion criteria, and were differentiated into two groups considering the timing of hardware removal (staged-group A vs concurrent-group B) to compare: neurovascular and wound complications, time to recover full weight bearing, scar-tissue esthetic, and surgical time. Moreover, a subgroup comparison considering the surgical approach (single approach, minor additional approach, major additional approach) was performed between the group A and group B. RESULTS: No statistically significant difference other that longer surgical time (p < 0.05) was observed between group A and group B. When considering surgical approach subgroups, statistically significant higher surgical wound complications and revision rate were reported in group B (concurrent) major additional approach subgroup, and a statistically significant shorter time to full weight bearing was reported in group A (staged) major additional approach subgroup. CONCLUSIONS: When performing TAA requiring hardware removal, no clear superiority of staged over concurrent hardware removal was observed. However, when considering a subgroup of patients requiring a separate major incision, a staged approach has shown reduced surgical time, less risk of wound complications, and shorter recovery to full weight bearing. LEVEL OF EVIDENCE: III.

Return to sports after total ankle arthroplasty: A systematic review and meta-analysis.

Purpose: Technological developments and implants newer generation allowed to expand the indications for total ankle arthroplasty (TAA) with aim to maintain active lifestyles. This systematic review and meta-analysis examined chance of return to sport, achievable activity level, the type of patients and the sport type after TAA. Methods: A literature search of PubMed, Scopus, and Cochrane databases was performed. Meta-analysis was performed if the same outcomes scores were reported at least by 4 studies. PRISMA guidelines were used. Risk of bias was assessed through the MINORS criteria. Included studies reported data and outcomes related to sport in patients undergoing TAA. Result: Initial search results yielded 483 articles; 11 articles were included in the review process. The chance to return to sport increases after TAA, achieving a mean sport participation rate of 61.9% postoperatively. Until to 92% of patients was able to return to their preoperative level of activity. Meta-analysis showed a significant postoperative improvement in the most represented outcomes scores. Especially, young, male, with lower BMI, and affected by non-inflammatory osteoarthritis were those who returned to sport reporting significantly better outcomes scores. The most frequent postoperative sports included cycling, swimming, hiking and gymnastic. Only few patients practiced impact sport. Conclusions: Current literature does not allow to advise TAA for young and active patient who want to play sports after surgery. Selected patients undergoing TAA can return to sport after surgery, and the most approachable activities are low demanding sport. However, no strong evidence is available to support these findings. Further prospective randomized studies are necessary to establish more accurate expectations concerning sport activity after TAA implantation. Level of evidence: Level II, systematic review.

Probiotics in Orthopedics: From Preclinical Studies to Current Applications and Future Perspective.

In recent years, probiotics have been emerging as an attractive therapeutic strategy for several diseases. In orthopedics, probiotics seem to be a promising supplementation for treatment of osteoporosis, osteoarthritis, muscle loss-related disease, wound and ulcer issues, and prevention of surgical antibiotic prophylaxis side effects. Although probiotics are still not included in guidelines for these conditions, several studies have reported theoretical benefits of their administration. Further high-level clinical trials are necessary to convert research into solid clinical practice. However, probiotics represent a cost-effective future perspective and may play a role in association with traditional orthopedic therapies.

First Metatarsal Hemiepiphysiodesis for the Treatment of Juvenile Hallux Valgus: A Systematic Review.

INTRODUCTION: Juvenile hallux valgus (JHV) is a pediatric deformity characterized by the varus deviation of the first metatarsal and valgus deviation of the proximal phalanx. Among the several surgical techniques available, hemiepiphysiodesis consists of the unilateral growth arrest of the first metatarsal physis. Despite this technique has been proposed over 70 years ago, only a few studies including clinical and radiological outcomes have been published, making the procedure unclear in terms of results. This systematic review aimed to evaluate the outcomes of hemiepiphysiodesis of the first metatarsal in the treatment of JHV. METHODS: Google Scholar, Embase, PubMed, and Cochrane databases were searched for all the articles reporting on clinical and radiological results of hemiepiphysiodesis of the first metatarsal in the treatment of JHV. The selected articles were reviewed to extract demographic data, surgical techniques, complications, clinical outcomes, and radiological parameters. RESULTS: Six articles were included in the qualitative analysis. A total of 85 patients with 144 halluces valgus were treated through hemiepiphysiodesis of the first metatarsal. The mean age at surgery was 10.7 years (range 5 to 15). The mean follow-up was 2.7 years (range 1 to 7.5). Hemiepiphysiodesis was performed through 2 different techniques. Eighteen (12.5%) complications occurred. The mean American Orthopaedic Foot and Ankle Society (AOFAS) score increased from 70.6 (range 49 to 93) preoperatively to 89.4 (range 72 to 100) postoperatively. The mean HVA improved from 28.3 (range 14 to 46) to 24.03 degrees (range 0 to 54), and the mean IMA improved from 13 (range 8 to 33) to 10.9 degrees (range 8 to 33). CONCLUSIONS: This review showed that hemiepiphysiodesis of the first metatarsal is a safe treatment for JHV. Improvement in both clinical and radiological results has been observed in all the studies, sometimes being statistically significant. Despite the improvement, mean postoperative radiological angles remained altered and consistent with mild-moderate hallux valgus. This suggests that hemiepiphysiodesis plays a bigger role in preventing the worsening of the deformity rather than correcting it. Randomized controlled trials with longer follow-up and a larger number of patients are needed to further investigate the efficacy and safety of this treatment.

Hallux Valgus Plantar Pressure Distribution Before and After Surgery.

Hallux valgus is a common foot deformity that may cause pain and functional limitation, and often requires surgical correction. Clinical and radiographic parameters are typically used to assess postoperative outcomes. Plantar pressure distribution systems represent an innovative additional tool to evaluate hallux functional outcome after surgery. A systematic review of the current literature was performed to assess evaluation systems used for plantar pressure analysis and differences before and after hallux valgus surgery, and a possible relationship between different surgical techniques and clinical and radiographic results. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used for this review. Initial search results yielded 40 studies. Two additional studies were found through cross-reference. Twenty-five studies were screened. A total of 10 articles were included in the review process. Two main plantar pressure analysis systems were identified. Hallux function restoration based on plantar pressure measurement did not always occur. No relevant relationships between plantar pressure distribution data and different surgical techniques were established. All patients achieved satisfactory clinical and radiographic outcomes, regardless of surgical techniques used; however, no clear relationships were observed between clinical and radiographic results and the change in foot plantar pressure patterns. The current literature on this topic showed several methodologic limitations. Therefore, it is not possible to provide sufficiently supported evidence-based data regarding plantar pressure distribution rebalance after surgery using current plantar pressure analysis systems. Further investigations are needed to fill these gaps in evidence.

Identification of membrane proteins regulated by ADAM15 by SUSPECS proteomics.

ADAM15 is a member of the disintegrin-metalloproteinase family of sheddases, which plays a role in several biological processes including cartilage homeostasis. In contrast with well-characterized ADAMs, such as the canonical sheddases ADAM17 and ADAM10, little is known about substrates of ADAM15 or how the enzyme exerts its biological functions. Herein, we used "surface-spanning enrichment with click-sugars (SUSPECS)" proteomics to identify ADAM15 substrates and/or proteins regulated by the proteinase at the cell surface of chondrocyte-like cells. Silencing of ADAM15 by siRNAs significantly altered membrane levels of 13 proteins, all previously not known to be regulated by ADAM15. We used orthogonal techniques to validate ADAM15 effects on 3 of these proteins which have known roles in cartilage homeostasis. This confirmed that ADAM15-silencing increased cell surface levels of the programmed cell death 1 ligand 2 (PDCD1LG2) and reduced cell surface levels of vasorin and the sulfate transporter SLC26A2 through an unknown post-translational mechanism. The increase of PDCD1LG2 by ADAM15 knockdown, a single-pass type I transmembrane protein, suggested it could be a proteinase substrate. However, shed PDCD1LG2 could not be detected even by a data-independent acquisition mass spectrometry, a highly sensitive method for identification and quantification of proteins in complex protein samples, suggesting that ADAM15 regulates PDCD1LG2 membrane levels by a mechanism different from ectodomain shedding.

Surgical management of clubfoot overcorrection: a case series.

INTRODUCTION: Overcorrection is a possible complication of clubfoot treatment, whose prevalence varies from 5 to 67%. Overcorrected clubfoot usually presented as a complex flatfoot with different degrees of hindfoot valgus, flat top talus, dorsal bunion, and dorsal navicular subluxation. The management of clubfoot overcorrection is challenging, and both conservative and surgical treatments are available. This study aims to present our experience in the surgical management of overcorrected clubfoot and to provide an overview of actual treatment options for each specific sub-deformity. MATERIALS AND METHODS: A retrospective cohort study of patients surgically treated for an overcorrected clubfoot from 2000 to 2015 at our Institution was conducted. Surgical procedures were tailored to the type and symptomatology of the deformity. A medializing calcaneal osteotomy or subtalar arthrodesis was performed for hindfoot valgus. Subtalar and/or midtarsal arthrodesis were considered in cases of dorsal navicular subluxation. The first metatarsus elevatus was addressed through a proximal plantarflexing osteotomy, sometimes associated with a tibialis anterior tendon transfer. Clinical scores and radiographic parameters were obtained pre-operatively and at the last follow-up. RESULTS: Fifteen consecutive patients were enrolled. The series included 4 females and 11 males, with a mean age at surgery of 33,1 (18-56) years, and a mean follow-up of 4,46 (2-10) years. Seven medializing calcaneal osteotomies, 5 subtalar arthrodesis, 11 first metatarsal plantarflexing osteotomies, and 7 anterior tibialis tendon transfers were performed. A statistically significant improvement in both clinical and radiographic scores was observed. CONCLUSIONS: Management of overcorrected clubfoot involves many surgical techniques because of the high interpersonal variability of the deformities. The surgical approach showed positive results, as long as the indication is based on clinical symptoms and functional impairment rather than morphological alterations and radiographic findings.

Patient Reported Outcome Measures (PROMs) in Surgery: Evaluation after Minimally Invasive Reduction and Percutaneous K-Wires Fixation for Intra-Articular Calcaneal Fractures.

BACKGROUND: The optimal surgical treatment of intra-articular calcaneal fractures (IACF) is still under debate. In the literature, results are based on clinical or radiographical findings. Few studies have evaluated the effect of patient expectations on patient-reported outcomes after surgery and little is known about outcomes directly reported by the patient who experienced it. Patient reported outcome measures (PROMs) may represent a viable and useful tool for evaluating the efficacy of the procedure and can be considered as an indicators of health-care quality. The aim of this study is to evaluate PROMs after minimally invasive reduction and percutaneous Kirschner-wires fixation for IACF, and to compare PROMs to pre-operative and last follow-up radiographic findings. METHODS: 33 consecutive patients with IACF treated with minimally invasive reduction and percutaneous K-wires fixation were included. Data collection included demographics, pre-operative and last available Böhler and Gissane angle X-rays, foot function index (FFI), and foot and ankle outcome score (FAOS). RESULTS: At a mean follow up of 36.7 months, the mean FFI score was 24.3 ± 19.9 and the mean FAOS score was 68 ± 24.8. Patients with better Gissane angle showed better activity limitations FFI subscores. Moreover, worse pre-operative Gissane and Böhler angle were significantly associated with a worse total FAOS score and subscores. CONCLUSIONS: Minimally invasive reduction and percutaneous K-wires fixation provided satisfactory PROMs. Despite these results, prospective randomized studies are required to confirm the validity and reliability of PROMs in evaluating different treatments.

Retrograde intramedullary nail entry point for tibio-talo-calcaneal arthrodesis: a review of anatomical studies.

PURPOSE: Tibio-talo-calcaneal arthrodesis (TTCA) is considered a safe and valuable option for end-stage tibiotalar and subtalar arthritis, and usually is performed with a retrograde intramedullary nail. Although the good results reported, potential complications may be related to retrograde nail entry point. Aim of this systematic review is to analyze in cadaveric studies the risk of iatrogenic injuries related to different entry points and different retrograde intramedullary nail design when performing TTCA. METHODS: According to PRISMA, a systematic review of the literature was performed on PubMed, EMBASE and SCOPUS databases. A subgroup analysis comparing different entry point location (anatomical or fluoroscopic guided) and different nail design (straight vs. valgus curved nails) was performed. RESULTS: Five studies were included, for a total of 40 specimens. Superiority of anatomical landmark-guided entry points was observed. Different nail designs did not seem to influence nor iatrogenic injuries neither hindfoot alignment. CONCLUSION: Retrograde intramedullary nail entry point should be placed in the lateral half of the hindfoot in order to minimize the risk of iatrogenic injuries.

Growth Performance and Recovery of Nosocomial Aspergillus spp. in Blood Culture Bottles.

Theoretically, Aspergillus spp. grow in culture media, but frequently, blood cultures of patients with invasive Aspergillosis are negative, even if until now, the reasons are not clear. This aspect underlines the lack of a good strategy for the cultivation and isolation of Aspergillus spp. In order to develop a complete analytical method to detect Aspergillus in clinical and pharmaceutical samples, we investigated the growth performance of two blood culture systems versus the pharmacopeia standard method. At <72 h, all test systems showed comparable sensitivity, about 1−2 conidia. However, the subculture analysis showed a suboptimal recovery for the methods, despite the positive growth and the visualization of the "Aspergillus balls" in the culture media. To investigate this issue, we studied three different subculture approaches: (i) the use of a sterile subculture unit, (ii) the use of a sterile subculture unit and the collection of a larger aliquot (100 µL), following vigorous agitation of the vials, and (iii) to decapsulate the bottle, withdrawing and centrifuging the sample, and aliquot the pellet onto SDA plates. Our results showed that only the third procedure recovered Aspergillus from all positive culture bottles. This work confirmed that our strategy is a valid and faster method to culture and isolate Aspergillus spp. from blood culture bottles.

A top-down approach to uncover the hidden ligandome of low-density lipoprotein receptor-related protein 1 in cartilage.

The low-density lipoprotein receptor-related protein 1 (LRP1) is a cell-surface receptor ubiquitously expressed in various tissues. It plays tissue-specific roles by mediating endocytosis of a diverse range of extracellular molecules. Dysregulation of LRP1 is involved in multiple conditions including osteoarthritis (OA) but little information is available about the specific profile of direct binding partners of LRP1 (ligandome) for each tissue, which would lead to a better understanding of its role in disease states. Here, we investigated adult articular cartilage where impaired LRP1-mediated endocytosis leads to tissue destruction. We used a top-down approach involving proteomic analysis of the LRP1 interactome in human chondrocytes, direct binding assays using purified LRP1 and ligand candidates, and validation in LRP1-deficient fibroblasts and human chondrocytes, as well as a novel Lrp1 conditional knockout (KO) mouse model. We found that inhibition of LRP1 and ligand interaction results in cell death, alteration of the entire secretome and transcriptional modulations in human chondrocytes. We identified a chondrocyte-specific LRP1 ligandome consisting of more than 50 novel ligand candidates. Surprisingly, 23 previously reported LRP1 ligands were not regulated by LRP1-mediated endocytosis in human chondrocytes. We confirmed direct LRP1 binding of HGFAC, HMGB1, HMGB2, CEMIP, SLIT2, ADAMTS1, TSG6, IGFBP7, SPARC and LIF, correlation between their affinity for LRP1 and the rate of endocytosis, and some of their intracellular localization. Moreover, a conditional LRP1 KO mouse model demonstrated a critical role of LRP1 in regulating the high-affinity ligands in cartilage in vivo. This systematic approach revealed the specificity and the extent of the chondrocyte LRP1 ligandome and identified potential novel therapeutic targets for OA.

High-Resolution Secretome Analysis of Chemical Hypoxia Treated Cells Identifies Putative Biomarkers of Chondrosarcoma.

Chondrosarcoma is the second most common bone tumor, accounting for 20% of all cases. Little is known about the pathology and molecular mechanisms involved in the development and in the metastatic process of chondrosarcoma. As a consequence, there are no approved therapies for this tumor and surgical resection is the only treatment currently available. Moreover, there are no available biomarkers for this type of tumor, and chondrosarcoma classification relies on operator-dependent histopathological assessment. Reliable biomarkers of chondrosarcoma are urgently needed, as well as greater understanding of the molecular mechanisms of its development for translational purposes. Hypoxia is a central feature of chondrosarcoma progression. The hypoxic tumor microenvironment of chondrosarcoma triggers a number of cellular events, culminating in increased invasiveness and migratory capability. Herein, we analyzed the effects of chemically-induced hypoxia on the secretome of SW 1353, a human chondrosarcoma cell line, using high-resolution quantitative proteomics. We found that hypoxia induced unconventional protein secretion and the release of proteins associated to exosomes. Among these proteins, which may be used to monitor chondrosarcoma development, we validated the increased secretion in response to hypoxia of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme well-known for its different functional roles in a wide range of tumors. In conclusion, by analyzing the changes induced by hypoxia in the secretome of chondrosarcoma cells, we identified molecular mechanisms that can play a role in chondrosarcoma progression and pinpointed proteins, including GAPDH, that may be developed as potential biomarkers for the diagnosis and therapeutic management of chondrosarcoma.

Quantitative Proteomics Reveals That ADAM15 Can Have Proteolytic-Independent Functions in the Steady State.

A disintegrin and metalloproteinase 15 (ADAM15) is a member of the ADAM family of sheddases. Its genetic ablation in mice suggests that ADAM15 plays an important role in a wide variety of biological functions, including cartilage homeostasis. Nevertheless, while the substrate repertoire of other members of the ADAM family, including ADAM10 and ADAM17, is largely established, little is known about the substrates of ADAM15 and how it exerts its biological functions. Herein, we used unbiased proteomics to identify ADAM15 substrates and proteins regulated by the proteinase in chondrocyte-like HTB94 cells. ADAM15 silencing did not induce major changes in the secretome composition of HTB94 cells, as revealed by two different proteomic approaches. Conversely, overexpression of ADAM15 remodeled the secretome, with levels of several secreted proteins being altered compared to GFP-overexpressing controls. However, the analysis did not identify potential substrates of the sheddase, i.e., transmembrane proteins released by ADAM15 in the extracellular milieu. Intriguingly, secretome analysis and immunoblotting demonstrated that ADAM15 overexpression increased secreted levels of tissue inhibitor of metalloproteinases 3 (TIMP-3), a major regulator of extracellular matrix turnover. An inactive form of ADAM15 led to a similar increase in the inhibitor, indicating that ADAM15 regulates TIMP-3 secretion by an unknown mechanism independent of its catalytic activity. In conclusion, high-resolution quantitative proteomics of HTB94 cells manipulated to have increased or decreased ADAM15 expression did not identify canonical substrates of the proteinase in the steady state, but it revealed that ADAM15 can modulate the secretome in a catalytically-independent manner.

Patient-specific instrumentation in total ankle arthroplasty.

The recent increase in the adoption of total ankle arthroplasty (TAA) reflects the improvements in implant designs and surgical techniques, including the use of preoperative navigation system and patient-specific instrumentation (PSI), such as custom-made cutting guides. Cutting guides are customized with respect to each patient's anatomy based on preoperative ankle computed tomography scans, and they drive the saw intra-operatively to improve the accuracy of bone resection and implant positioning. Despite some promising results, the main queries in the literature are whether PSI improves the reliability of achieving neutral ankle alignment and more accurate implant sizing, whether it is actually superior over standard techniques, and whether it is cost effective. Moreover, the advantages of PSI in clinical outcomes are still theoretical because the current literature does not allow to confirm its superiority. The purpose of this review article is therefore to assess the current literature on PSI in TAA with regard to current implants with PSI, templating and preoperative planning strategies, alignment and sizing, clinical outcomes, cost analysis, and comparison with standard techniques.

Traumatic Cuboid Dislocation. The Potential Role of Plantar Ligaments Integrity in Facilitating Reduction: A Case Report.

CASE: A 56-year-old male patient sustained a traumatic cuboid medioplantar dislocation associated with a lateral cuneiform fracture. The patient was treated with open reduction and fixation using 2 temporary Kirschner wires. During surgery, the plantar ligament apparatus was found to be almost intact and the reduction was easily performed. At the last follow-up visit, the patient's functional outcomes were excellent. CONCLUSIONS: Traumatic cuboid medioplantar dislocation associated with lateral cuneiform fracture usually requires surgical treatment. The authors conclude the integrity of the plantar ligament apparatus may play a role in facilitating the reduction.

Quantitative Proteomics Reveals Changes Induced by TIMP-3 on Cell Membrane Composition and Novel Metalloprotease Substrates.

Ectodomain shedding is a key mechanism of several biological processes, including cell-communication. Disintegrin and metalloproteinases (ADAMs), together with the membrane-type matrix metalloproteinases, play a pivotal role in shedding transmembrane proteins. Aberrant shedding is associated to several pathological conditions, including arthritis. Tissue inhibitor of metalloproteases 3 (TIMP-3), an endogenous inhibitor of ADAMs and matrix metalloproteases (MMPs), has been proven to be beneficial in such diseases. Thus, strategies to increase TIMP-3 bioavailability in the tissue have been sought for development of therapeutics. Nevertheless, high levels of TIMP-3 may lead to mechanism-based side-effects, as its overall effects on cell behavior are still unknown. In this study, we used a high-resolution mass-spectrometry-based workflow to analyze alterations induced by sustained expression of TIMP-3 in the cell surfaceome. In agreement with its multifunctional properties, TIMP-3 induced changes on the protein composition of the cell surface. We found that TIMP-3 had differential effects on metalloproteinase substrates, with several that accumulated in TIMP-3-overexpressing cells. In addition, our study identified potentially novel ADAM substrates, including ADAM15, whose levels at the cell surface are regulated by the inhibitor. In conclusion, our study reveals that high levels of TIMP-3 induce modifications in the cell surfaceome and identifies molecular pathways that can be deregulated via TIMP-3-based therapies.