Human osteoarthritic cartilage shows reduced in vivo expression of IL-4, a chondroprotective cytokine that differentially modulates IL-1β-stimulated production of chemokines and matrix-degrading enzymes in vitro

open10noThis work was supported by grants from Rizzoli Orthopaedic Institute (Ricerca Corrente); University of Bologna (RFO); MIUR (FIRB-RBAP10KCNS); “Cinque per mille” Funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.BACKGROUND: In osteoarthritis (OA), an inflammatory environment is responsible for the imbalance between the anabolic and catabolic activity of chondrocytes and, thus, for articular cartilage derangement. This study was aimed at providing further insight into the impairment of the anabolic cytokine IL-4 and its receptors in human OA cartilage, as well as the potential ability of IL-4 to antagonize the catabolic phenotype induced by IL-1β. METHODOLOGY/PRINCIPAL FINDINGS: The in vivo expression of IL-4 and IL-4 receptor subunits (IL-4R, IL-2Rγ, IL-13Rα1) was investigated on full thickness OA or normal knee cartilage. IL-4 expression was found to be significantly lower in OA, both in terms of the percentage of positive cells and the amount of signal per cell. IL-4 receptor type I and II were mostly expressed in mid-deep cartilage layers. No significant difference for each IL-4 receptor subunit was noted. IL-4 anti-inflammatory and anti-catabolic activity was assessed in vitro in the presence of IL-1β and/or IL-4 for 24 hours using differentiated high density primary OA chondrocyte also exhibiting the three IL-4 R subunits found in vivo. Chemokines, extracellular matrix degrading enzymes and their inhibitors were evaluated at mRNA (real time PCR) and protein (ELISA or western blot) levels. IL-4 did not affect IL-1β-induced mRNA expression of GRO-α/CXCL1, IL-8/CXCL8, ADAMTS-5, TIMP-1 or TIMP-3. Conversely, IL-4 significantly inhibited RANTES/CCL5, MIP-1α/CCL3, MIP-1β/CCL4, MMP-13 and ADAMTS-4. These results were confirmed at protein level for RANTES/CCL5 and MMP-13. CONCLUSIONS/SIGNIFICANCE: Our results indicate for the first time that OA cartilage has a significantly lower expression of IL-4. Furthermore, we found differences in the spectrum of biological effects of IL-4. The findings that IL-4 has the ability to hamper the IL-1β-induced release of both MMP-13 and CCL5/RANTES, both markers of OA chondrocytes, strongly indicates IL-4 as a pivotal anabolic cytokine in cartilage whose impairment impacts on OA pathogenesis.openAssirelli E.; Pulsatelli L.; Dolzani P.; Platano D.; Olivotto Eleonora .; Filardo G.; Trisolino G.; Facchini A.; Borzì R.M.; Meliconi R.Assirelli E.; Pulsatelli L.; Dolzani P.; Platano D.; Olivotto Eleonora .; Filardo G.; Trisolino G.; Facchini A.; Borzì R.M.; Meliconi R

Deformity progression in congenital posteromedial bowing of the tibia: a report of 44 cases.

Abstract Background Congenital posteromedial bowing of the tibia (CPMBT) is an ultra-rare defect present at birth, characterized by shortened bowed leg, and ankle deformity. We described a single institution experience in the management of CPMBT Methods We identified 44 CPMBT in 44 children. The age at presentation was 5.5 ± 5.6 years and the mean age at the final review was 10.1 ± 4.8 years. Radiographic evaluation included the antero-posterior and lateral inter-physeal angle (AP-IPA and L-IPA), the limb length discrepancy (LLD), the morphology of the distal tibia and the lateral distal tibial angle (LDTA). During the study period, 26 children underwent surgical treatment. Results The estimated curves showed a progressive spontaneous correction of both AP-IPA and L-IPA during growth, but a progressive increase of the LLD. The L-IPA showed a more predictable behaviour while the AP-IPA showed a scattered correction, with a wider variation of the estimated final angle. The final LDTA was 83.4° ± 5.2° and was correlated with the L-IPA. Among the 26 children which underwent surgical treatment, 23 cases had limb lengthening, 1 case had contralateral epiphysiodesis, 1 child underwent tibial osteotomy, 1 patient was treated by hemiepiphysiodesis of the distal tibia to address ankle valgus deformity. Conclusions To date, we reported the largest case series of CPMBT. Nevertheless, further studies are needed to understand which is the best strategy to address this ultra-rare deformity during childhood

Ultrastructural modifications of human meniscus under different conditions

Human meniscus presents two cell populations [1]. The main cell type present in its inner and middle part is the fibrochondrocyte, a round or oval shaped cell, while in outer zone fibroblast-like cells within a dense connective tissue [2] are mostly observable. The aim of this work is to study a variety of pathological conditions. We have analized samples of meniscus obtained from 3 multiorgan donors (63 median age, years), 5 patients with traumatic meniscal tear (40 median age, years) and from 3 patients undergoing total knee replacement for osteoartritis (OA) (73 median age, years). In elderly menisci we observed a progression of chromatin margination, and a partial cytoplasmic organelle conservation, but for the presence of occasional autophagic vacuoles. Both after trauma and in OA, an increasing chromatin condensation, organelle degeneration and cytoplasmic vacuolization appear. In OA, similarly to elderly, autophagic vacuoles, which probably represent a cellular self-protection mechanism, appeared in the cytoplasm. The most evident ultrastructural changes have been observed when intervention takes place long time after trauma. In this case a high chromatin condensation, a large cytoplasmic vacuolization with degeneration of organelles and several necrotic cells appear. Calcification areas occur in all conditions. In particular, specimens from traumatic menisci have a structure similar to OA ones, especially if trauma has not been surgically repaired at appropriate times. In all there is disorganization of collagen fibers, and their replacement with proteoglycans. We can conclude that trauma and OA induce an increasing meniscal degeneration, comparable to physiological aging. When surgery takes place long time after trauma we observed most evident menisci degeneration. In all pathological conditions apoptotic like features appeared [3]

Inflammatory molecules produced by meniscus and synovium in early and end-stage osteoarthritis: a coculture study

The aim of this study was to identify the molecules and pathways involved in the cross-talk between meniscus and synovium that may play a critical role in osteoarthritis (OA) pathophysiology. Samples of synovium and meniscus were collected from patients with early and end-stage OA and cultured alone or cocultured. Cytokines, chemokines, metalloproteases, and their inhibitors were evaluated at the gene and protein levels. The extracellular matrix (ECM) changes were also investigated. In early OA cultures, higher levels of interleukin-6 (IL-6) and IL-8 messenger RNA were expressed by synovium and meniscus in coculture compared with meniscus cultured alone. RANTES release was significantly increased when the two tissues were cocultured compared with meniscus cultured alone. Increased levels of matrix metalloproteinase-3\ua0(MMP-3) and MMP-10 proteins, as well as increased release of glycosaminoglycans and aggrecan CS846 epitope, were observed when synovium was cocultured with meniscus. In end-stage OA cultures, increased levels of IL-8 and monocyte chemoattractant\ua0protein-1\ua0(MCP-1) proteins were released in cocultures compared with cultures of meniscus alone. Chemokine (C-C motif) ligand 21 (CCL21) protein release was higher in meniscus cultured alone and in coculture compared with synovium cultured alone. Increased levels of MMP-3 and 10 proteins were observed when tissues were cocultured compared with meniscus cultured alone. Aggrecan CS846 epitope release was increased in cocultures compared with cultures of either tissue cultured alone. Our study showed the production of inflammatory molecules by synovium and meniscus which could trigger inflammatory signals in early OA patients, and induce ECM loss in the progressive and final stages of OA pathology

Virtual Surgical Planning, 3D-Printing and Customized Bone Allograft for Acute Correction of Severe Genu Varum in Children

Complex deformities of lower limbs are frequent in children with genetic or metabolic skeletal disorders. Early correction is frequently required, but it is technically difficult and burdened by complications and recurrence. Herein, we described the case of a 7-year-old girl affected by severe bilateral genu varum due to spondyloepiphyseal dysplasia. The patient was treated by patient-specific osteotomies and customized structural wedge allograft using Virtual Surgical Planning (VSP) and 3D-printed patient-specific instrumentation (PSI). The entire process was performed through an in-hospital 3D-printing Point-of-Care (POC). VSP and 3D-printing applied to pediatric orthopedic surgery may allow personalization of corrective osteotomies and customization of structural allografts by using low-cost in-hospital POC. However, optimal and definitive alignment is rarely achieved in such severe deformities in growing skeleton through a single operation

What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study

Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 and TBX4, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in PITX1 and TBX4 in Italian patients with idiopathic clubfoot. PITX1 and TBX4 genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in TBX4, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on PITX1 and TBX4. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same TBX4-PITX1 axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors

The fingerprint of the summer 2018 drought in Europe on ground-based atmospheric CO2 measurements

During the summer of 2018, a widespread drought developed over Northern and Central Europe. The increase in temperature and the reduction of soil moisture have influenced carbon dioxide (CO2) exchange between the atmosphere and terrestrial ecosystems in various ways, such as a reduction of photosynthesis, changes in ecosystem respiration, or allowing more frequent fires. In this study, we characterize the resulting perturbation of the atmospheric CO2 seasonal cycles. 2018 has a good coverage of European regions affected by drought, allowing the investigation of how ecosystem flux anomalies impacted spatial CO2 gradients between stations. This density of stations is unprecedented compared to previous drought events in 2003 and 2015, particularly thanks to the deployment of the Integrated Carbon Observation System (ICOS) network of atmospheric greenhouse gas monitoring stations in recent years. Seasonal CO2 cycles from 48 European stations were available for 2017 and 2018.The UK sites were funded by the UK Department of Business, Energy and Industrial Strategy (formerly the Department of Energy and Climate Change) through contracts TRN1028/06/2015 and TRN1537/06/2018. The stations at the ClimaDat Network in Spain have received funding from the ‘la Caixa’ Foundation, under agreement 2010-002624

Comparison between modified Dunn procedure and in situ fixation for severe stable slipped capital femoral epiphysis: A retrospective study of 29 hips followed for 2–7 years

Background and purpose — The best treatment option for severe slipped capital femoral epiphysis (SCFE) is still controversial. We compared clinical and radiographic outcomes of modified Dunn procedure (D) and in situ fixation (S) in severe SCFE. Patients and methods — We retrospectively compared D and S, used for severe stable SCFE (posterior sloping angle (PSA) > 50°) in 29 patients (15 D; 14 S). Propensity analysis and inverse probability of treatment weights (IPTW) to adjust for baseline differences were performed. Patients were followed for 2–7 years. Results — Avascular necrosis (AVN) occurred in 3 patients out of 15, after D, causing conversion to total hip replacement (THR) in 2 cases. In S, 1 hip developed chondrolysis, requiring THR 3 years after surgery. 3 symptomatic femoroacetabular impingements (FAI) occurred after S, requiring corrective osteotomy in 1 hip, and osteochondroplasty in another case. The risk of early re-operation was similar between the groups. The slippage was corrected more accurately and reliably by D. The Nonarthritic Hip Score was similar between groups, after adjusting for preoperative and postoperative variables. Interpretation — Although D was superior to S in restoring the proximal femoral anatomy, without increasing the risk of early re-operation, some concern remains regarding the potential risk of AVN in group D

Congenital Pseudarthrosis of the Clavicle in Children: A Systematic Review

(1) Background: Congenital pseudoarthrosis of the clavicle is a rare condition due to the failure of the union process of the ossification nuclei of the clavicle. The aim of this study was to conduct a systematic review of relevant case series about the argument to find an up-to-date base of evidence for treatment choice. (2) Methods: an electronic literature research of Ovid, MEDLINE and the Cochrane Library databases was conducted, and articles were selected based on inclusion criteria. Demographic data, clinical features, treatment options, outcomes and complications were analyzed. (3) Results: 21 articles met the inclusion criteria, showing a poor overall study quality; 231 pediatric patients (240 clavicles) were analyzed. The condition was typically right sided, showed no sex predominance and no clear predisposing factors. 156 patients underwent surgical treatment, mainly open debridement and refresh of bony ends, fixation with pin or plate and bone graft, with a successful union rate of 87.4%. The nonunion rate was significantly higher in the allograft group (44.4%, p = 0.019). (4) Conclusions: this paper presents an updated systematic review about treatment of congenital pseudoarthrosis of the clavicle. We confirm the generally satisfactory results of surgery, demonstrating that successful union is achievable in 87.4% of cases with a prevalence of 15.7% of major complications. Nonetheless our results should be interpreted with caution due to several limitations