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

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

Neglected Fractures of the Lateral Humeral Condyle in Children; Which Treatment for Which Condition?

Background: Neglected fractures of the lateral humeral condyle (LHC) are misdiagnosed or insufficiently treated fractures, presenting later than 3 weeks after injury. The management of neglected LHC fractures in children remains controversial. Methods: Twenty-seven children were included in this retrospective study. Charts and medical records were investigated for demographics, time interval between injury and treatment, and type of treatment. Baseline radiographs were assessed for fracture grading and displacement. Final radiographs were investigated for bone healing, avascular necrosis, elbow deformities and growth disturbances. Complications were classified by the Clavien–Dindo–Sink (CDS) system. Outcomes were assessed according to the Dhillon Score (DhiS) and Mayo Elbow Performance Score (MEPS). Results: The mean time from injury to presentation was 27 months. Treatments included nonoperative management (6 patients), “in-situ” fixation (7 patients), open reduction and internal fixation (11 patients) and corrective osteotomy (3 patients). The mean follow-up was 7 years (range: 2–16). Overall, we observed complications in 16 patients (59%); six complications were considered major (22%) and occurred in Weiss Grade 3 fractures, with lateral displacement ≥5 mm. At the latest follow-up, pain and functional scores improved in 23 of 27 patients (85%). Mean MEPS increased from an average of 62 points preoperatively to 98 points postoperatively, while mean DhiS improved on average from 5 to 8 points. CDS score and time interval between injury and treatment were independent predictors of MEPS and DhiS. Conclusion: Our study describes outcomes from a cohort of children undergoing different treatments for neglected LHC fractures. Prolonged time interval between injury and treatment and perioperative major complications negatively impacted the treatment outcomes. Our findings strengthen the requirement for widely agreed guidelines of surgical management in neglected LHC fractures