Background: Polymethylmethacrylate (PMMA) is a potent stimulant of inflammatory response. This study investigated the role of Prostaglandin E2 (PGE2), Platelet activating factor (PAF) and histamine and their specific antagonists in bone changes. Materials: 120 white-male-wistar rats were divided into ten groups. Using sterile technique, a 2mm drill hole was made in the tibia 1cm distal to the knee joint bilaterally. The left tibia was filled with Simplex particulate cement polymer (PMMA) and the right tibia was used as control. The first nine groups respectively received terfenadine 1mg/kg, 10mg/kg and 25mg/kg, alprazolam 0.08mg/kg, 0.32mg/kg and 0.64mg/kg, and naproxen 1mg/kg, 5mg/kg and 25mg/kg; however, the tenth group received no drug and served as control. The animals were killed after 16 weeks and implant areas were harvested aseptically and studied by one pathologist. Results: Our study revealed that the cellular reaction in the left side was statistically more than the right one in all cases (p< 0.05). Also, a significant decrease in histiocytes and giant cells was seen just in those groups that had received 10mg/kg and 25mg/kg of terfenadine, 0.32mg/kg and 0.64mg/kg of alprazolam and 5mg/kg and 25mg/kg of naproxen (P< 0.05) while administration of 1mg/kg naproxen resulted in significant decrease only in giant cells (P< 0.05) but not in histiocytes. Discussion: Previous studies have suggested that particulate debris, PGE2 production and inflammatory response are associated with arthroplasty loosening. This experiment has demonstrated that the increased cellular reaction by the membrane surrounding particulate cement polymer can be suppressed by administration of PGE2, PAF and histamine specific inhibitors. The use of these agents may be indicated in retarding the bone loss associated with early prosthetic loosening

Background and aim: Clear cell sarcoma is a rare tumor with melanocytic features and is associated with tendons and aponeuroses. 18 cases were registered between 1986 and 1996 in the Scandinavian Sarcoma Group central registry. The aim was to investigate if histamine enhances the antitumor effect of dacarbazine (DTIC) and docetaxel. Methods: Human clear cell sarcoma tumor tissue was maintained by serial s.c. transplantations in nude mice. DTIC (200mg/kg, i.p.) 3 times with an interval of 2 days, docetaxel (20 mg/kg, i.p.) single dose and histamine (4 mg/kg, s.c.) daily, 5 days per week was administered in tumorbearing nude mice. DTIC and docetaxel was given separately or in combination with histamine. The tumor volumes were compared with a control group (given saline i.p.). The antitumor effect is considered signiþcant when Treatment/Control-ratio ≤ 0.4 Results: In the DTIC group the lowest TC-ratio was noted at day 21 (0.54) and in the histamine-DTIC group (0.37). Corrresponding results were 0.39 in the docetaxel-group and 0.33 in the combination docetaxel-histamine at day 13. The TC-ratio was reduced at all measuring occasions when histamine was given in adjunction with DTIC and docetaxel. Conclusions: Histamine seems to enhance the antitumor effect of dacarbazine and docetaxel in this clear cell sarcoma tumor model

Osteoarthritis (OA) is no longer considered a cartilage-centric disease with remodelling of other joint tissues now recognized. While understudied, entheseal pathology is considered a secondary OA feature. A pivotal role for proteinase-activated receptor 2 (PAR2) in OA has been demonstrated previously in cartilage and subchondral bone at early time points, however the entheseal role of PAR2 has not been reported. OA was induced by destabilization of the medial meniscus (DMM) in wild type (WT) and PAR2 deficient (KO) animals. At 4 weeks and one year post surgery, knee joints were harvested for histological analysis. Medial collateral ligament (MCL) width was measured by 2D planimetry analysis. Immunohistochemistry was used to characterize the MCL and anterior cruciate ligament (ACL). Data were expressed as mean±SEM (n=4–6/group) and analysed using Student's t-test, with p<0.05 as the criterion of significance. MCL width increased between 4 weeks and 1 year in WT DMM (0.24 ±0.07 vs 0.40 ±0.008mm respectively, p<0.001). Interestingly, a significant reduction in MCL was observed in KO compared with WT at 1 year (0.23 ±0.005 vs 0.40 ±0.008mm respectively, p <0.001) post-DMM. Further characterization of DMM WT MCL and ACL at 4 weeks showed the presence of F4/80. +. cells in addition to IL-33 and histamine. At one year post-surgery, a cellular infiltrate was observed in MCL DMM WT but absent in KO mice. Histological evaluation revealed an absence of F4/80. +. cells but the presence of a PAR2. +. population, subsequently identified as hypertrophic-like chondrocytes (RUNX2) and chondrocytes-like cells (SOX9). Deletion of PAR2 affords long-term protection against ligament remodelling and demonstrates a critical role for this receptor in both OA joint pathology and ligament injuries. While PAR2 appears to be a credible therapeutic target in OA entheseal pathology, further understanding of the molecular mechanism regulated by this receptor will be required

Purpose. Congenital insensitivity to pain is a rare autosomal recessive condition that leads to varying degrees of sensory and autonomic neuropathy. The aim of the study was to explore the common orthopaedic presentations of congenital insensitivity to pain and provide guidance on their treatment and complications. Methods. This study presents the results of fifteen patients with congenital insensitivity to pain, which were referred and treated at our supra-regional referral centre. Intradermal histamine tests and quantitative sweat tests were performed on all fifteen patients. Results. The average age of presentation was 13.2 years (range, two to 28 years). Eight patients presented with Charcot arthropathies and joint dislocations, which involved the foot/ankle (n=4), knee (n=2) or spine (n=2). Four patients presented with fractures or avascular necrosis affecting the tarsal bones and three patients presented with recurrent infections of the lower limbs. Patient education regarding appropriate shoe ware, pedal hygiene, periods of non-weight bearing, spinal bracing and close follow-up within the multi-disciplinary team was the mainstay of treatment. Patients with infection underwent cultures, aspiration, magnetic resonance imaging and treatment with antibiotics. Only one patient required joint washout for septic arthritis of the ankle. Conclusions. Congenital insensitivity to pain presents with both acute and chronic pathology affecting the weight-bearing joints. Treatment should be aimed at off-loading the pressure on these joints and preventing the development of further complications. Surgical intervention should be reserved for patients not responding to conservative treatment or those requiring debridement/washout for extensive infection

Introduction: Histamine is an integral mediator following traumatic injury. Histamine-2 receptors have previously been identified on lymphocytes and monocytes. Materials and methods: Two rodent models (1) Bilateral femoral fracture and intramedullary nailing, with resulting indirect lung injury (n=30). (2) In vivo model of orthopaedic implant contaminated by Staphylococcus epidermidis (n=36). Animals were randomised to receive ranitidine or placebo (saline). Results: Markers of lung injury (MPO activity, BAL proteins and wet:dry ratios) increased 24 hours following bilateral femoral fracture, but were reduced if ranitidine was administered systemically after the injury. Production of Th-1 cytokines was blocked by ranitidine, whilst Th-2 cytokine production remained unaffected by ranitidine. These suggest an anti-inflammatory effect of ranitidine, blocking the early (Th-1) pro-inflammatory response following major injury. Ranitidine’s effect on implant infection rates showed higher rates (44% versus 17%, relative risk 1.8 (95% CI 1.0 to 3.3)) when systemic ranitidine was delivered peri-operatively, suggesting an immunosuppressive effect. Conclusions: The findings highlight the complex balance in vivo, a double-edged sword: the risk of increasing implant infection versus reducing indirect lung injury following major injury. The administration of ranitidine in major trauma patients with severe pro-inflammatory responses may block and reduce early multi-organ dysfunction and improve survival. However, owing to infection, the peri-operative administration of ranitidine should be avoided in elective cases

Purpose: Congenital insensitivity to Pain (CIP) is a rare peripheral neuropathy which may affect various sensory pathways and often affects the autonomic nervous system. Musculoskeletal manifestations include infections, fractures, growth disturbances, avascular necrosis, Charcot arthropathy, joint dislocations and heterotopic ossification. The purpose of the study was to review the orthopaedic problems in patients with Congenital Insensitivity to Pain and make treatment recommendations. Methods: Thirteen patients from eight families were examined and all charts and radiographs were reviewed. A quantitative sweat test was performed in five patients and an intradermal histamine test in ten. DNA was prepared in all patients and examined for specific mutations. Results: Three clinical presentations were found:. Type A – Five patients presented with multiple infections requiring many surgical procedures ranging from local debridement to below knee amputation. Type B – Three patients presented with fractures and growth disturbances of the lower limbs as well as avascular necrosis of the talus or femoral condyle. Two patients underwent corrective osteotomies due to deformities. Type C – Five patients presented with Charcot arthropathies, joint dislocations, fractures and infections. Four of them were mentally retarded. Patients underwent multiple surgical procedure to control infections. Attempts surgical stabilization of joints were unsuccessful. Mutations were found in four patients. Conclusions. Patient education, shoe ware and periods of non weight bearing are important in prevention and early treatment of decubitus ulcers. Differentiation between fractures and infections is difficult and should be based on aspiration and cultures in order to prevent unnecessary surgery. Established infections should be treated by wide surgical debridement. Deformities should be treated by corrective osteotomies and shortening should be treated with shoe lifts or epiphysiodesis. Joint dislocations should be treated non-operatively as attempts at surgical stabilization gave poor results

Introduction: Bradykinin (BK) exerts its effects directly via B2 receptors but also indirectly through release of factors such as prostaglandins, cytokines, or histamine. During in vitro and preclinical in vivo studies, the B2 receptor inhibitor icatibant (ITB) has been shown to be a potent inhibitor of BK effects. Recently it has been found that a single injection of 90 μg of ITB significantly reduced pain in patients with knee OA, and this effect lasted for about 1 week. The aim of the present study was to determine whether ITB, by multiple dosing, may exert long-lasting clinically relevant effects on OA pain. Objectives:. To compare the onset, extent and duration of pain relief (pain during activity, at rest and at night) in the affected knee between 2 dose groups of ITB and placebo by using a visual analogue scale (VAS). To compare ITB and placebo for safety and the efficacy variables: Western Ontario McMaster Universities OA index (WOMAC), and time until need of rescue medication. Study design: Randomised, double-blind, placebo-controlled, 3-arm, parallel-group, 12-week multi-centre study to compare the effect of intra-articular injections of 2 doses of ITB (500 μg and 2000 μg) and placebo in patients with symptomatic unilateral knee OA. Subjects were treated 3 times in weekly intervals and then followed-up for 10 weeks. Assessments of pain and intake of rescue medication was followed with an electronic patient diary on a daily basis. Functional assessment of the affected knee joint was performed by answering the WOMAC questionnaire at several visits following the last injection. Statistical analysis included the Chi-square test, differences in means, Wilcoxon-test, the trapezoid rule and Kaplan-Meier curves, using analysis of variance without and with covariates (ANOVA, ANCOVA). Results: 340 subjects were screened, and 266 were randomised and treated: 90 with placebo, 86 with 500 μg and 90 with 2000 μg ITB. Treatment-emergent adverse events were experienced by 13 subjects treated with placebo, 8 with 500 μg and 17 treated with 2000 μg ITB. After 3 injections, long-lasting reduction in pain up to 12 weeks after start of treatment could be observed in all treatment groups. Onset of pain relief by _ 10 units was fast and had been reported already 4 hours after start of injection. Both ITB groups consistently demonstrated greater effects on pain when compared to the placebo group; however, there was no difference between the 500 μg and 2000 μg dose groups. Conclusion: The outcome of the present study demonstrates ITB as an analgesic with fast onset and long-lasting pain relief, which could be differentiated against placebo. Its extent of pain relief, together with its excellent safety profile, qualifies ITB as a promising alternative for intervention in acute and chronic pain