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The present study was aimed at identifying a new scaffold/stem cell combination useful to treat large bone defects. Human amniotic fluid stem cells (AFSCs) were expanded in vitro, labeled with a fluorescent cell-permeable dye (PKH26) and transplanted in vivo in a femoral injured rat model. The femoral defect was left untreated (control rats) or filled with hydroxyapatite (HA; natural nanocrystalline carbonated hydroxyapatite-Orthoss®) scaffold alone or loaded with PKH26-labeled AFSCs. All animals were killed 3 weeks after implantation. Both gross anatomy and histological observations revealed a major bone regenerative response in rat specimens treated with HA scaffold, alone or supplemented with AFSCs. Samples injected with HA plus AFSCs displayed the presence of abundant fibrotic tissue, the formation of periosteal woven bone, and an increased presence of blood vessels in the bone marrow, with still fluorescent AFSCs in close proximity. These observations provide evidence that natural HA plus AFSCs represents a promising alternative therapeutic strategy to autologous bone grafting procedures.

The efficacy of platelet-rich plasma in the treatment for Achilles tendinopathy is debated. Therefore, it is important to know which factors, related to the subjects and/or the disease, are associated with positive or negative outcomes. Aim of this study was to evaluate in a large cohort of patients with Achilles mid-portion tendinopathy which variables were independently associated with a positive outcome after platelet-rich plasma treatment. Eighty-four subjects with Achilles tendinopathy were evaluated by means of VISA-A score and ultrasound and treated with a single platelet-rich plasma injection once a week for 3 weeks. Afterward, a rehabilitation program, based on eccentric training, was implemented. At 3 and 6 months, the relationship between the mean VISA-A score and the following putative predictors was evaluated: sex, age, physical activity, sport, smoking, metabolic risk factors, BMI, symptoms duration, tendon damage, neovessels, adherence to eccentric training. Finally, the percentage of clinically evident positive outcomes (defined as an increase in VISA-A score ≥ 20 points) related to each variable was computed. At final follow-up, using the General Linear Model for Repeated Measures procedure, male sex (0.02), age ≤ 40 (0.05) and adequate eccentric training (0.02) were found to be independently associated with a significant increase in the mean VISA-A score. Moreover, the clinically evident positive outcomes, as previously defined, were significantly associated with male sex (0.01), age ≤ 40 (0.000), BMI ≤ 25 (0.001), symptoms duration ≤ 12 months (0.02) and good adherence to eccentric training (0.004). Younger age, male sex and good adherence to eccentric training can be considered predictors of better results after platelet-rich plasma therapy in Achilles tendinopathy

Background Patients affected by coxarthrosis may be treated surgically with total hip arthroplasty (THA). During the surgical intervention, the hip joint capsule can be completely removed, performing a capsulectomy. Otherwise it's possible to perform a capsulotomy, which allows for capsular conservation. Since there is no scientific evidence demonstrating the superiority of one method over the other, the choice whether to remove or conserve the capsule is at the surgeon's discretion and both procedures are actually accepted. The purpose of our study is to evaluate the differences in functional activities and proprioception in patients who underwent THA and capsulotomy with capsular conservation versus patients who underwent THA with capsulectomy. Methods In order to compare the two surgical techniques of capsulotomy with capsular conservation and capsulectomy, we created a randomized, controlled, double-blind, single-centre, non-pharmacological, interventional, superiority, parallel-group trial. The primary outcome of our study is evaluated using the HOOS scale (Hip disability and Osteoarthritis Outcome Score). Secondary outcomes are: the proprioceptive sensitivity, the postoperative bleeding, the surgical time, the active range of motion, and the ability to walk, sit and stand. The proprioception study is carried out through active and passive repositioning tests. THA is performed through the minimally invasive direct anterior approach. The evaluation tests are carried out in the 15 days preceding the intervention (T0), at 50-day post-operative (T1), and finally at three months after surgery (T2). Discussion Considering that the hip joint capsule is innervated by proprioceptive nerve endings, while the psuedocapsule that replaces the native capsule following a THA with capsulectomy doesn't have any active neurophysiological role, we hypothesize that capsulotomy with capsular conservation at the time of primary THA may lead to better proprioception and therefore better functional recovery. Trial registration ClinicalTrials.gov identifier: NCT02749058. Date of registration: 04/21/2016.

Introduction: Running is a very popular modality of physical activity, which may help to lose weight and normalize pathological values of blood parameters in subjects suffering from metabolic disorders. Given that both overuse and metabolic pathologies are responsible for the onset of tendon damage, aim of the present study was to evaluate whether the first group of pathogenetic factors or the latter was more responsible for mid-portion Achilles tendinopathy. Method: Thirty-six and 28 subjects with and without mid-portion Achilles tendinopathy, who were regular runners and started running for metabolic disorders, were enrolled, respectively. Information about body weight and blood parameters at baseline was collected. The characteristics of running practice, dietary habits and anthropometric measures were registered. An ultrasound evaluation of the tendon was performed, and the blood metabolic parameters were evaluated. Results: The amount of running years and mileage was equivalent in both groups. A similar weight loss was observed; the subjects with mid-portion Achilles tendinopathy showed a worse metabolic profile (Hb1aC%, p = 0.008; total cholesterol, p = 0.04; HDL cholesterol, p = 0.003; triglycerides, p = 0.009). Conclusions: These findings suggest that the subjects with less evident positive effects of running on metabolism are more exposed to the onset of mid-portion Achilles tendinopathy.

Rationale: Posterior sternoclavicular joint dislocations (PSCJDs) are particularly rare injuries, accounting for 3% to 5% of sternoclavicular joint dislocations. With very few cases reported in the literature, these injuries are often misdiagnosed and imaging is not always clear, thus making physicians often unaware of them. The present case report aims to investigate a rare case involving a clavicular Salter-Harris II fracture with associated posterior displacement of the diaphysis, a term coined a “pseudodislocation.” Patient concerns: We present a case of a 14-year-old adolescent who sustained a traumatic injury to the shoulder while falling during a soccer match. His main concern was about recovery time and the return to daily life activities. Diagnoses: Multiple imaging studies imaging (X-rays, computed tomography, magnetic resonance imaging) revealed a Salter-Harris II fracture of the right clavicle with posterior displacement of the diaphysis. Interventions: The patient underwent primary surgery to reduce the fracture, using an articular locking compression plate, and secondary surgery to remove the hardware. Outcomes: Following the removal of the hardware at 60 days after the initial surgery and a number of cycles of physiotherapy the patient reported a pain-free range of motion with slight limitation at extremes. Full return to recreational and everyday life activities were achieved at 3 months from the initial surgery. Lessons: The PSCJDs are challenging injuries, as they are surrounded by delicate structures inside the mediastinum. Attention must be taken while diagnosing and treating these injuries as the risk of complications and iatrogenic injuries is high. To the author's knowledge, this case is one of the first of its kind described in the literature where we have a Salter-Harrys type II fracture associated with a posterior pseudodislocation of the lateral clavicle. Given the positive results of the case, we recommend the above-mentioned treatment protocol in PSCJD with associated Salter-Harris II fractures in adolescent patients.

Objectives: The efficacy of platelet rich plasma in the treatment of Achilles tendinopathy is controversial. Despite positive results observed in open studies, randomized controlled trials failed to show difference against saline or rehabilitation. Aims of this retrospective observational study were to compare the efficacy of platelet-rich plasma and dry needling and to assess possible differences age and sex-related. Methods: Groups of 46 and 38 patients with non-insertional Achilles tendinopathy were treated with platelet-rich plasma and dry needling (once a week for 3weeks), respectively. At baseline, 3 and 6months, pain and function scores and the percentage of satisfactory outcomes were evaluated. Sub-group analyses were performed according to age and sex. Results: At 3 and 6months no differences in terms of pain and function between groups were observed, but the percentage of subjects reporting satisfactory results, at 6months, was higher in platelet rich plasma group. Better results were observed in younger subjects, with a greater reduction of pain, improvement of function, and accordingly of the percentage of positive outcomes. A trend toward better results was also observed in males. Conclusion: Beneficial effects of platelet rich plasma and dry needling in non-insertional Achilles tendinopathy have been observed only in some subjects, but not in others; platelet rich plasma shows a slight superiority against dry needling, mainly in younger persons; finally, a gender difference in the therapeutic response can be hypothesized.

Background The aim of this retrospective study was to evaluate the outcome of patients with intra-articular calcaneal fractures treated using a minimally invasive locking nail (Calcanail®). Methods Between January 2016 and April 2017, 15 patients (9 men and 6 women) with a calcaneal fracture were consecutively treated with Calcanail®. The Bohler angle was recorded on standard X-rays pre- and post-operatively. The articular reduction of the posterior facet was evaluated with the Goldzak index in a CT scan 3 months post-operatively. The mean age of the patients was 53 years (range, 24–78). Mean final follow-up was 18 months (range, 12–24). Results Six fractures were classified as Sanders II, 7 as Sanders III and 2 as Sanders IV. In 13 out of the 15 patients treated, the post-operative Bohler angle was of more than 20°. Goldzak index was deemed as excellent in 73.5% of the cases (11 patients), good in 20% of cases (3 patients), and poor in 6.5% (1 patient). Post-operative mean AOFAS score was 85 (range, 60–96). Conclusions The Calcanail® provides good restoration of the subtalar joint and the calcaneal angles with the advantages of a minimally invasive approach. It was effectively used in Sanders types II and III, even in the presence of poor cutaneous conditions.

Background Chronic ankle instability is defined by an instability lasting more than 6 months, in those cases where a comprehensive conservative treatment fails a surgical stabilization is required. Several surgical techniques have been proposed for the management of the chronic lateral instability of the ankle and even after 50 years, the Brostrom–Gould technique is still considered the gold standard for the treatment of this pathology. Recently, many authors have developed completely arthroscopic lateral ligament repair and the use of these procedures is rapidly increasing. The aim of this review is to provide an updated overview of open and new arthroscopic lateral ligament repair techniques in order to summarize and compare the effectiveness of these strategies. Methods A systematic literature review using PubMed/Medline databases was performed (July 1972–July 2015). Clinical results, satisfaction rate and complications of both patient populations were recorded and statistically analyzed. Results The total ankles treated with an open Brostrom ATFL repair in the 13 studies was 505 with a mean follow up of 73.4 months (range 9 months–27.9 years). Postoperative AOFAS score was reported in 11 studies, with a mean value of 90.1 (range, 60–100), patient's satisfaction rate was 91.7%. Surgery-related complications occurred in 40 (7.92%) out of 505 treated ankles. The total number of ankles treated within the 6 arthroscopic studies was 216 with a mean follow up of 37.2 months (range 6 months–14 years). Five studies reported a mean postoperative AOFAS score of 92.48 (range, 44–100) with a patient's satisfaction rate of 96.4%. Surgery-related complications were observed in 33 (15.27%) cases. Conclusions The results of this review show the excellent efficacy of open and arthroscopic surgical procedures in the treatment of the chronic ankle instability. The higher complication rate of arthroscopic procedures respect to the open ones represents the major issue: however, this does not seem to affect the patient's satisfaction. Because of statistical heterogeneity observed no definitive conclusions can be statistically drawn. Finally, to definitively validate the effectiveness of arthroscopic procedures prospective and comparative studies are needed.

PURPOSE:Platelet rich plasma and high volume image guided injections of saline have been used in the treatment of patellar tendinopathy with positive results. As the different mechanisms of action do not interfere each other, it can be hypothesized that they can be used in combination. Aim of this study was twofold: first, to evaluate the efficacy of these two treatments in the management of patellar tendinopathy; second, to verify whether the combination of these therapies could provide further advantages.METHODS:Fifty-four patients suffering from patellar tendinopathy were enrolled. After clinical (VAS and VISA-P) and sonographic evaluation, two ultrasound guided injections (2 weeks apart) of platelet rich plasma, high-volume image-guided injections of saline, or both in association were performed. The VAS and VISA-P scores obtained from the three treatments groups (18 patients in each group) were compared across the different follow-up times (3 and 6 months).RESULTS:In the short term both treatments showed comparable efficacy, whereas in the medium term the positive effects of high-volume image-guided injections gradually diminished and platelet rich plasma showed greater efficacy. Better results (reduced pain, improved function and increased number of subjects who exhibited optimal recovery [> 20 points in VISA-P score]) were observed when both procedures were associated.CONCLUSIONS:The contemporaneous administration of platelet rich plasma and high volume image guided injections of saline treatments, which influence tendon repair by means of different mechanisms, grants a greater improvement for patellar tendinopathy. This finding has clinical relevance, given that this condition has a substantial impact on sports and work performance.LEVEL OF EVIDENCE: III.

A fit 26 year-old-man presented to our Department with an open fracture of the left tibial shaft (AO 42-C3). The fracture was initially treated with an External Fixator, which was replaced by an intramedullary Grosse Kempf nail after 4 months. In the following year he developed an atrophic non-union and we witnessed the increasing bone resorption at the fracture site which led to the nail breakage. An accurate CT pre-operative planning was made and a revision surgery was successfully performed: the broken nail was removed and intercalary allograft reconstruction was made, using a compressible intramedullary nail. Whereas in literature it is well described how intercalary allografts can be used to fill the massive diaphyseal defects after tumor resections, we assumed it could also be an adequate technique to treat a large bone defect at a non-union site.

We report the efficacy of the ultrasound-guided percutaneous treatment in the management of elbow extensor tendons calcific tendinopathy. The ultrasound-guided percutaneous treatment is broadly used with positive results in patients suffering from rotator cuff calcific tendinopathy. However, this interventional method has been reported only in one patient in the medical literature. A 34 years-old female who complained pain, swelling and severe functional limitation of the right elbow was referred to our unit. Elbow radiographs and ultrasound examination showed a soft-fluid calcification above the origin of the extensor tendons. Ultrasound-guided percutaneous treatment was therefore performed. After one year, the patient reported no pain and regained complete range of elbow motion. This method, in well trained hands, is an alternative treatment in the management of the uncommon elbow calcific deposit.

Distal humerus fractures are uncommon injuries requiring specific clinical and radiographic analysis in order to plan the optimal therapeutic strategy. In particular, bicolumnar distal humerus fractures (Type A2, A3 and C) are complex fractures. In the last years, double plating fixation became the standard treatment: this procedure helped surgeons to obtain a stable and anatomical fixation and an early mobilization, which is the main outcome for obtaining valuable functional results. In this retrospective study, we evaluated the use of open bicolumnar 90-90 plating for fixation of acute fragility fractures of the distal humerus in elderly patients, using the olecranon osteotomy as surgical approach.

OBJECTIVE: Rotator cuff tendon tears increase with age, but no study has specifically addressed prevalence changes in women from premenopause to postmenopause. The aims of this study were to evaluate the prevalence of rotator cuff asymptomatic tears in postmenopausal women and to study their relationship with anthropometric and metabolic measures. METHODS: Premenopausal and postmenopausal women who were free from shoulder pain/functional impairment were enrolled. Body mass index (BMI), fasting glucose, triglycerides, total cholesterol, and high-density lipoprotein (HDL) cholesterol were evaluated. Both shoulders were examined by ultrasound imaging. For the purposes of this study, only full-thickness tears (classified as small, large, or massive) were taken into account. RESULTS: The prevalence of full-thickness tears (mainly localized in the supraspinatus tendon of the dominant side) was significantly higher in the postmenopausal group (8.9\% vs 3.1\%), with small, medium, and large tears in 60\%, 20\%, and 20\% of cases, respectively. In women with tears, intragroup comparison showed significantly higher values for BMI and fasting glucose, and lower levels of HDL cholesterol; no difference was found for triglycerides and total cholesterol in premenopausal and postmenopausal women, respectively. On multiple logistic regression analysis, the probability of detecting a tear in both groups was positively related to high values of BMI and lower levels of HDL cholesterol. CONCLUSIONS: The prevalence of asymptomatic full-thickness tears is increased in the postmenopausal period, and there is an association between tears and metabolic disorders. Because asymptomatic tears have a great potential to evolve into symptomatic painful shoulder, a precocious discovery of this pathology may allow the planning of preventive and therapeutic measures.

Several epidemiological and clinical observations have definitely demonstrated that obesity has harmful effects on tendons. The pathogenesis of tendon damage is multi-factorial. In addition to overload, attributable to the increased body weight, which significantly affects load-bearing tendons, systemic factors play a relevant role. Several bioactive peptides (chemerin, leptin, adiponectin and others) are released by adipocytes, and influence tendon structure by means of negative activities on mesenchymal cells. The ensuing systemic state of chronic, sub-clinic, low-grade inflammation can damage tendon structure. Metabolic disorders (diabetes, impaired glucose tolerance, and dislipidemia), frequently associated with visceral adiposity, are concurrent pathogenetic factors. Indeed, high glucose levels increase the formation of Advanced Glycation End-products, which in turn form stable covalent cross-links within collagen fibers, modifying their structure and functionality. Sport activities, so useful for preventing important cardiovascular complications, may be detrimental for tendons if they are submitted to intense acute or chronic overload. Therefore, two caution rules are mandatory: first, to engage in personalized soft training program, and secondly to follow regular check-up for tendon pathology.

Previous research has shown that plantar fascia and Achilles tendon thickness is increased in diabetes. The aims of present study were to assess whether tendon changes can occur in the early stages of the disease and to evaluate the extent of the influence of body mass index (BMI). The study population included 51 recent-onset type II diabetic subjects, who were free from diabetic complications, divided according to BMI into three groups (normal weight, overweight, and obese). Eighteen non-diabetic, normal-weight subjects served as controls. Plantar fascia and Achilles tendon thickness was measured by means of sonography. The groups were well balanced for age and sex. In all the diabetic subjects, plantar fascia and Achilles tendon thickness was increased compared to the controls (p < 0.001, p = 0.01, p = 0.003, respectively). A significant relationship was found between plantar fascia thickness and BMI values (r = 0.749, p < 0.0001), while the correlation between BMI and Achilles tendon was weaker (r = 0.399, p = 0.004). This study shows that plantar fascia and Achilles tendon thickness is increased in the early stages of type II diabetes and that BMI is related more to plantar fascia than Achilles tendon thickness. Further longitudinal studies are needed to evaluate whether these early changes can overload the metatarsal heads and increase the stress transmitted to plantar soft tissues, thus representing an additional risk factor for foot ulcer development.

LJM is frequently observed in young subjects with insulin-dependent diabetes mellitus (IDDM). Aim of this study was to evaluate whether non-insulin-dependent diabetes mellitus (NIDDM) increases the risk of LJM in elderly subjects. Thirty patients (15 males, 15 females, mean age 73.93 ± 12.72 years) with NIDDM in good glycemic control were compared with thirty non-diabetic elderly, well matched for sex and age (15 males, 15 females, mean age 74.3 ± 4.24 years), and with ten young normal subjects (5 males, 5 females, mean age 26.3 ± 1.56 years). In these subjects, the range of motion (ROM) of ankle, knee, hip, elbow and shoulder were measured with a double-armed goniometer. Moreover, abnormalities of supraspinatus, patellar and Achilles tendons were evaluated with a standardized ultrasound (US) procedure. A significant reduction in the mobility of all joints was found in elderly subjects, compared to younger ones, with exception for the knee and elbow flexion. Elderly patients with diabetes, compared with their age-matched counterpart, showed LJM for ankle dorso- and plantar flexion, hip flexion and adduction, shoulder abduction and flexion. Moreover, tendons sonographic abnormalities were more frequently observed in diabetics. Our data confirm that diabetes worsens the LJM in the elderly, increasing the cross-linking of collagen by the non-enzymatic advanced glycation end products formation.

Rare side-effects of fluoroquinolone therapy are tendinitis and tendon rupture. Many reports have demonstrated that the concomitant use of corticosteroids, in patients aged 60 years or older, increase the risk substantially. We present a case of spontaneous bilateral Achilles tendon rupture induced by ciprofloxacin and methylprednisolone. A 61-year-old woman was diagnosed with Bronchiolitis Obliterans with Organizing Pneumonia (BOOP) and was started on oral ciprofloxacin 500 mg twice daily for 3 weeks and on oral methylprednisolone 16 mg twice daily for 2 weeks. The diagnosis was made after doctors, rather than stop drug therapy and advise complete rest, had mistakenly prescribed for the woman to undergo physiotherapy and local NSAIDs, thus favoring the onset of tendon ruptures and resulting in surgical and legal implications. Inspired by this case, we also submit a brief review on professional liability in Orthopaedics. Copyright © by BIOLIFE, s.a.s.

The need for bone grafting procedures to replace skeletal defects has become more considerable because of increased opportunities to save major bone loss. We report our experience and a critical analysis about the role of bone grafts and bone graft substitutes in prosthetic hip surgery replacement.

Relapses are frequently observed in subjects with chronic tendinopathies. Corticosteroid injections are usually performed with positive results, but are uncomfortable for the patient and not free from side effects. The aim of this pilot study is to evaluate the short-term efficacy and tolerability of an occlusive Betamethasone Valerate medicated Plaster (BMVP). Fifteen subjects with relapses of chronic tendinopathies (clinical and ultrasound diagnosis) were enrolled, and treated according to RICE (Rest - Ice - Compression - Elevation) protocol. An BMVP plaster was also applied on the affected tendon. Clinical examination, at baseline and after 7, 14, 21 and 28 days, included pain (VAS at rest and during activities) and functional evaluation. Local side effects on the area and drop-outs were also recorded. Pain, both at rest and during activities, significantly decreased at 28 days (from 3.7 ± 2.7 to 1.1 ± 1.7 [p < 0.01], and from 7.3 ± 1.7 to 3.3 ± 1.4 [p < 0.0000], respectively). Moreover, the patients reported a significant improvement in the functional limitation. Five subjects dropped out of the study. No side effects were reported. The release of the steroid in pharmacologically-active concentrations over 12–24 hours and the good penetration of the drug in subcutaneous tissues explain the positive results. BMVP application may be considered a reliable first therapeutic approach in relapses of chronic tendinopathies.

RANTES (regulated on activation, normal T cell-expressed and secreted) is a CC chemokine appearing to be involved in the recruitment of leukocytes at inflammation sites. RANTES is produced by CD8+ T cells, epithelial cells, fibroblasts, and platelets. It acts in vitro in leukocyte activation and human immunodeficiency virus suppression, but its role in vivo is still uncertain. In our study, we established the involvement of RANTES in an in vivo model of chronic inflammation induced by potassium permanganate, leading to calcified granulomas. In our rat model, RANTES expression (mRNA and protein) was significantly upregulated in granulomatous tissue; RANTES expression was further increased upon i.p. injection of lipopolysaccharide (LPS), while it was kept at basal levels by dexamethasone (Dex) given 18 hours before sacrifice. LPS and Dex increased and decreased, respectively, the recruitment of mononuclear cells in granulomatous tissue compared with control granulomas from phosphate-buffered saline (PBS)-treated animals. In granuloma tissue, levels of RANTES were higher in LPS-treated rats and lower in the Dex group compared to controls. RANTES was also found in the conditioned medium of granuloma tissue from treated (LPS or Dex) and untreated (PBS) rats. When LPS was added in vitro for 18 hours, RANTES was further increased, except in the Dex group (P > 0.05). On serum analysis, RANTES levels were higher in the LPS group and lower in the Dex group compared to controls. This study shows for the first time that RANTES is produced in vivo in chronic, experimental inflammatory states, an effect increased by LPS and inhibited by Dex.

Purpose: Femoroacetabular impingement may predispose to the development of hip osteoarthritis. Conservative treatments are effective in the short term, but surgery is often required. Aim of this paper was to report the short-term results on hip pain and function after ultrasound-guided injections of hyaluronic acid. Methods: In this open prospective trial, twenty patients suffering from mild femoroacetabular impingement were enrolled. Each patient received a 2-ml intra-articular ultrasound-guided injection of hyaluronic acid at baseline and after 40 days; the same dosing schedule was repeated after 6 months. The clinical evaluation was performed at baseline and after 6 and 12 months of follow-up. Pain score, Lequesne Index, Harris Hip Score and anti-inflammatory medication consumption were measured. Adverse events were also registered. Results: Twenty-three hips (3 bilateral cases) were treated. Pain decreased from 6.7 ± 1.3 to 3.7 ± 1.8 and to 1.7 ± 1.8 after 6 and 12 months, respectively; Lequesne Index was reduced and the mean Harris Hip Score improved from 83.3 ± 6 before treatment to 88.2 ± 4.7 at 12 months. Consumption of anti-inflammatory drugs was also reduced, from 14 to 4 subjects and from 3.6 ± 2.2 to 1.3 ± 1.3 tablets/week. Local side effects after injection were observed only in 2 cases. Conclusions: Hyaluronic acid is safe and effective in the treatment of mild femoroacetabular impingement, with significant pain reduction and function improvement. Level of evidence: IV. © 2013 Springer-Verlag Berlin Heidelberg.

Mast cells, which derive from a bone marrow progenitor and mature in tissues, are important for allergic reactions, but also in inflammation, autoimmunity, and T-cell-mediated immune responses. The addition of certain cytokines to human umbilical cord blood-derived cultured mast cells have been shown to augment IgE-induced production of distinct cytokines, without histamine secretion. CCL2/MCP-1 is a beta chemokine capable of attracting and activating lymphocytes, macrophages, memory T cells and basophilic cells, but not neutrophils. CCL2/MCP-1 regulates the recruitment of inflammatory cells into tissue during inflammation and allergy. IL-33 belongs to the IL-1 family and binds to the ST2 receptor which has high homology to IL-1 receptor and has biological activities. IL-33, causes allergic inflammation and exerts significant biological effects both in vivo and in vitro. IL-33 induces expression of several cytokines and chemokines, resulting in severe inflammatory and allergic diseases. However, our knowledge regarding the effects of these cytokines on human mast cell functions is limited. Here, using human umbilical cord blood mast cells (HUCBMCs) as a valid model, we found that IL-33 induces CCL2/MCP-1 release in HUCBMCs. The release was higher at 24 h incubation compared with 12 h. This study documents the ability of IL-33 to directly stimulate Human umbilical cord blood mast cells (UCBMCs) to produce CCL2/MCP-1. We show that IL-33 is a strong activator of human mast cells capable of inducing CCL2/MCP-1 released at translational level. The present data describe an additional biological activity of IL-33, suggesting that this cytokine may have an important effect on the recruitment of inflammatory cells in allergic diseases. Copyright © by BIOLIFE, s.a.s.

Tendinopathies are very common in athletes and in people practicing sport activities. The experimental evidence that growth factors (GFs), present in platelets, enhance the recruitment, proliferation and differentiation of cells involved in tissue regeneration, has prompted the use of platelet rich plasma (PRP) preparations in the treatment of these diseases. However, at present, a sound demonstration of the clinical efficacy of PRP is still lacking. Several theoretical and practical reasons can explain the failure of the treatment: a) animal experiments have been carried out on normal tendons submitted to surgical lesions, and it is questionable whether these models may best mimic human pathology; b) the pathway of chronic tendinopathies is very complex, involving, besides GFs, many other pathogenetic factors, which operate at different stages of the disease; c) several methods have been used to produce PRP, which can result in a large variation in GF content, and in kinetics of release. Therefore, further research is desirable. As a preliminary step, it is necessary to standardize PRP preparation, and to establish the modalities of its activation and administration. Secondly, prospective, randomized, double-blind studies are needed, selecting subjects with homogenous forms of tendinopathies: load-bearing and non-load-bearing tendons, midportion and insertional tendinopathies, with or without neovascularization. Finally, new strategies in PRP use should be exploited: among them, the association of PRP with autologous stem cells or the administration of selective GFs (fibroblast growth factor, vascular endothelial growth factor, or anti-angiogenic factors), which could be better options in specific situations.

Limited joint mobility is frequently observed in elderly people and in patients suffering from diabetes, who represent a growing segment of the population of western countries. Our review wishes to offer the “state of art” about this interesting topic, which may have important clinical implications, leading to impairment of both basic and instrumental activities of daily living. The main causes of a reduced range of motion are degenerative joint diseases and increased stiffness of collagen tissue. The main biochemical abnormality, common to aging and diabetes, is the non-enzymatic glycosilation of collagen, with advanced glycation end product (AGE) formation, which in turn leads to an increase of collagen cross-links. The most extensive accumulation of AGEs occurs in tissues that contain proteins with low turnover, such as the collagen in the extracellular matrix of articular capsule, ligaments and muscle-tendon units. The increase in collagen cross-linking alters the mechanical properties of these tissues with a decrease in elasticity and tensile strength, and an increase in mechanical stiffness. Besides this, AGEs react with specific cell surface receptors (RAGEs). The engagement of the ligand by RAGEs triggers cell-specific signalling, resulting in enhanced generation of reactive oxygen species and sustained up-regulation of pro-inflammatory mediators and adhesion molecules. An appropriate control of the glucose levels and a diet rich in antioxidant agents are recommended in patients with diabetes. Stretching and strengthening programmes are widely used, in order to prevent and to reduce joint stiffness, but the improvements with physiotherapy are little and short-lasting. Several drugs, which can interfere with AGE formation and removal, or with the cellular effects of AGEs, are under study (among them pyridoxamine, an active form of Vitamin B6, AGE-breaker compounds, glucosamine, rutin and derivatives, soluble RAGE isoforms, and statins). In experimental animal models, these drugs are effective in reducing diabetic complications due to AGE formation; however, further study is necessary before their extensive use in the clinical setting.

IL-32 is onae of the last important cytokines discovered, produced mainly by T cells, natural killer cells, and epithelial cells. Probably many other different cells are a source of IL-32, which has been found to be a powerful pro-inflammatory mediator. Here we studied the effect of IL-32 on histamine release by human-derived cord-blood mast cells. In these studies we found that IL-32 significantly stimulates the release of histamine only at high concentrations (100 ng/ml) while at 10 or 50 ng/ml it had no effect. These results were found for the first time and demonstrate that IL-32 may play an important role in allergic and inflammatory diseases. Copyright © by BIOLIFE, s.a.s.

Background: Viscosupplementation (VS) with hyaluronic acid (HA) is largely used for knee osteoarthritis therapy, but the evidences for its usefulness in hip osteoarthritis (OA) are limited. Methods: In this review, an extensive search of published trials on VS in hip OA was performed. From the selected papers the following data were extracted: sample size, inclusion / exclusion criteria, treatment procedures, evaluation methods, follow-up duration and clinical outcomes. Results: The level of evidence was low in quite all the trials (no placebo controlled groups). A reduction of pain and an improvement of function after 3 months, persistent in the long term (12 - 18 months), was observed. Patients with mild morphological alterations responded better to therapy. Side effects were negligible, and were limited to pain and a sensation of heaviness in the injection site. No clear differences among Low (LMW) and High Molecular Weight (HMW) HA preparations were found in the clinical outcomes. However, for HMW-HA preparations, a lower number of injections was, in general, necessary in order to reach the therapeutic effect. Conclusions: Despite the initial promising results, some questions still remain open : 1) the characteristics of responders must be more precisely defined; 2) the treatment schedules, at present mainly based on the individual clinical experience, need a proper and accepted standardization. Finally, larger and placebo controlled trials are necessary to confirm the efficacy of VS in hip OA.

The activation of monocytes/macrophages by several stimuli is an initial event in the inflammatory response. To ascertain the importance of LTB(4) and 5-lypoxigenase in the inflammatory site, we isolated and stimulated rat adherent granuloma macrophages (RAGMs) with calcium ionophore in the presence or absence of regulated on activation, normal T expressed and secreted (RANTES) [CCL5] at different concentrations. We tested the hypothesis that RANTES may influence the production of LTB(4) stimulated by calcium ionophore A23187 (2.5 microM/ml) in rat adherent granuloma macrophages derived from granuloma induced by potassium permanganate diluted 1:40 saturated solution. To test this hypothesis, we measured LTB(4) production, in rat granuloma macrophages stimulated with A23187 (2.5 microM) alone and in combination with RANTES at different concentrations. In these studies, the cell-free supernatant of stimulated RAGMs with the ionophore A23187, resulted in a drastic increase of LTB(4). However, when the cells were treated with the combination RANTES plus A23187 the stimulatory effect was more pronounced than A23187 alone. LTB(4) production was quantitated. The calcium ionophore A23187 directly induced LTB(4) in macrophages, this production was markedly enhanced when the cells were pretreated with RANTES. However, the addition of RANTES in the absence of calcium ionophore A23187 did not directly induce LTB(4) release, nor was lypoxigenase expression augmented. Preincubation of RAGMs with NDGA (nordihydroguiaretic acid) (10(-5)M) completely abolished the production of LTB4 on RAGMSs challenged with A23187 in combination with RANTES or A23187 alone in the supernatants. Similar effects were obtained when the cells were pretreated with dexamethasone. These data suggest, for the first time, that RANTES may stimulate the release of LTB(4), only when it is associated to other stimuli and for this reason we conclude that RANTES modulates inflammatory diseases, and may require other stimuli to be effective in amplifying its spectrum of action(s).

Knowledge of post-operative clinical and laboratory changes in the uncomplicated course of ACL reconstruction could assist orthopaedic surgeons in making a timely diagnosis of septic arthritis. A total of 58 candidates to ACL reconstruction were enrolled in this study according to inclusion/exclusion criteria. Pre- and post-operative changes on 1st, 3rd, 7th, 15th, and 30thday were collected for skin body temperature (SBT), knee pain (KP), white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP). Post-operative joint effusion was recorded when inhibiting quadriceps contraction. The post-operative changes were compared with baseline values at each time point in the whole sample and in the subgroups of patients receiving bone-patellar-tendon-bone (BPTP) or hamstring tendon (HT) autograft. Follow-up at six month was considered adequate to rule out surgery-related septic arthritis. Mean SBT significantly increased on 1st, 3rdand 7thpost-operative day and returned to values not differing from baseline on 15thand 30thday. Median KP was significantly elevated during the first month. Joint effusion was observed on 7thpost-operative day in 52% of patients. Mean WBC count significantly increased on 1st, 7thand 15thday while no difference from baseline was observed on 3rdand 30thday. Mean ESR was significantly elevated on 1stday, increased on 3rdday and peaked on 7thday. ESR decreased on 15thand 30thday but remained significantly higher than baseline. Mean CRP significantly increased on 1stday, peaked on 3rdday and decreased on 7thday, while levels on 15thand 30thday did not differ from baseline. The SBT, KP, WBC count, ESR and CRP changes stratified in relation to the type of autograft showed the same variation trend as in the whole sample. Close clinical surveillance may be advisable when SBT, occurrence of joint effusion and CRP levels deviate from the described reference trend two weeks after surgery.

Purpose: Mast cells play an important role in innate and acquired immunity and are thought to be the cellular origin of most proteases and cytokines. Substance P (SP) and its receptor, NK-1R, play critical roles in immune regulation in human and animal models of inflammation. Methods: We used mature human cord blood mast cells (HCBMC) differentiated from cord blood CD34+ precursor activated with SP in culture. Results: Our data indicate that Substance P strongly activates mature HCBMC in releasing CXCL8 expression and secretion (Control: 1.200 ± 1.0; SP: 4.10 ± 0.90; P < 0.01). Moreover, in a RT-PCR, HCBMC expressed CXCL8 mRNA after Substance P activation. Since calcium ionophore A23187 is a pharmacological activator that raises cytosolic free calcium ion concentraion and stimulates mast cells in the production and secretion of proinflammatory compounds, it was used as positive control. In addition, we found that HCBMCs generate the transcription of histidine decarboxylase (HDC), the enzyme responsible for the generation of histamine from histidine, after SP treatment. Since CXCL8 is a member of the CXC chemokine subfamily with potent chemotactic activity and is a primary inflammatory cytokine we conclude that our results, obtained from HCBMC cultures, a good and valid model in vitro, support the concept that the neurogenic system modulates inflammatory events by Substance P-mediated HCBMC chemokine CXCL8 release. Conclusion: The expression, synthesis and release of CXCL8 suggest an increase of inflammatory process in vivo mediated by the recruitment and infiltration of inflammatory cells in inflamed tissues.