Cancers that grow in bone, such as myeloma and breast cancer metastases, cause devastating osteolytic bone destruction. These cancers hijack bone remodeling by stimulating osteoclastic bone resorption and suppressing bone formation. Currently, treatment is targeted primarily at blocking bone resorption, but this approach has achieved only limited success. Stimulating osteoblastic bone formation to promote repair is a novel alternative approach. We show that a soluble activin receptor type IIA fusion protein (ActRIIA.muFc) stimulates osteoblastogenesis ( p < .01), promotes bone formation ( p < .01) and increases bone mass in vivo ( p < .001). We show that the development of osteolytic bone lesions in mice bearing murine myeloma cells is caused by both increased resorption ( p < .05) and suppression of bone formation ( p < .01). ActRIIA.muFc treatment stimulates osteoblastogenesis ( p < .01), prevents myeloma-induced suppression of bone formation ( p < .05), blocks the development of osteolytic bone lesions ( p < .05), and increases survival ( p < .05). We also show, in a murine model of breast cancer bone metastasis, that ActRIIA.muFc again prevents bone destruction ( p < .001) and inhibits bone metastases ( p < .05). These findings show that stimulating osteoblastic bone formation with ActRIIA.muFc blocks the formation of osteolytic bone lesions and bone metastases in models of myeloma and breast cancer and paves the way for new approaches to treating this debilitating aspect of cancer. ß

Total knee arthroplasty (TKA) is one of the most successful orthopaedic procedures that alleviates pain and restores function in patients with degenerative knee joint diseases. Arthrofibrosis, abnormal scarring in which dense fibrous tissue prevents normal range of motion, develops in ~3–10% of TKA patients. No prophylactic intervention is available and treatment is restricted to aggressive physiotherapy or revision surgery. Tissue was collected from patients undergoing primary (n = 30) or revision (n = 27) TKA. Revision patients were stratified as non-arthrofibrotic and arthrofibrotic. Tissue was macroscopically and histologically compared to improve our understanding of the pathophysiology of arthrofibrosis. Macroscopically, tissue from primary TKA presents as homogenous, fatty tissue whereas tissue from revision TKA presents as dense, pigmented tissue. Histologically, there was dramatic tissue remodelling, increased collagen deposition and increased (myo)fibroblast staining in tissue from revision TKA. Significantly, tissue architecture was similar between revision patients regardless of clinically diagnosis. There are significant differences in architecture and composition of tissue from revision TKA over primary TKA. Surprisingly, whether revision TKA were clinically diagnosed as arthrofibrotic or non-arthrofibrotic there were still significant differences in fibrotic markers compared to primary TKA suggesting an ongoing fibrotic process in all revision knees.

Objective: To identify the incidence, etiology, and risk factors for fevers in individuals with traumatic spinal cord injury (SCI).Design: A retrospective review of the medical records of consecutive adult traumatic SCI patients over a 2-year period was performed. Setting:The study was performed at a tertiary care, Level I trauma center.Participants: Consecutive adult traumatic SCI admissions to acute care (n ¼ 48) and rehabilitation (n ¼ 40) were included in the study.Main Outcome Measures: Incidence, etiology, mean maximum temperature elevation, and duration of fevers (temperature .99.9 F) were measured.Results: The incidence of fever was 60.4% and 50% (acute care and rehabilitation, respectively). Total number of fevers was 58 and 66, acute and rehabilitation, respectively. Respiratory and urinary tract were the most common identifiable fever etiologies. Unidentified fever etiologies were numerous in both the acute and rehabilitation groups, representing 66% and 56% of cases, respectively. Significant differences (P , 0.05) were found between identified vs unidentified fever etiology groups for mean maximal temperature (102.58F vs 101.18F on acute and 101.58F vs 100.78F on rehabilitation), duration of fever (10.3 days vs 2.2 on acute and 2.8 days vs 1.3 on rehabilitation), fevers above 101.48F (75% vs 29% on acute and 40% vs 8% on rehabilitation), cause of injury (gunshot wound on acute care) and completeness of injury (American Spinal Injury Association classification A on rehabilitation).Conclusions: This study suggests that fevers occur commonly in patients with SCI, with respiratory and genitourinary system etiologies most commonly identified. Unidentified etiologies were common and were associated with lower temperature elevation and shorter fever duration. Injury etiology and completeness of injury may comprise additional risk factors. These factors should be taken into account when initiating costefficient fever workup in individuals with SCI.

Arthrofibrosis is a fibroproliferative disease characterised by excessive deposition of extracellular matrix components intra-articularly leading to pain and restricted range of movement. Although frequently observed following total knee arthroplasty (TKA) no therapeutic options exist. A pilot study demonstrated that intra-articular injection of Anakinra, an IL-1R antagonist, improved range of movement and pain in patients with arthrofibrosis however the mechanism of action is unknown. We hypothesise that IL-1α/β will drive an inflammatory phenotype in fibroblasts isolated from the knee, therefore identifying a potential mechanism of action for Anakinra in arthrofibrosis following TKA. Fibroblasts isolated from synovial membranes and infra-patellar fat pad of patients undergoing TKA express high levels of IL-1R1. Stimulation with IL-1α/β induced a pro-inflammatory phenotype characterised by increased secretion of GMCSF, IL-6 and IL-8. No significant difference in the inflammatory response was observed between fibroblasts isolated from synovial membrane or infra-patellar fat pad. IL-1α/β treatments induced a pro-inflammatory phenotype in fibroblasts from both synovial membrane and infra-patellar fat pad and therefore Anakinra can likely have an inhibitory effect on fibroblasts present in both tissues in vivo. It is also likely that fibroblast responses in the tissues are controlled by IL-1α/β availability and not their ability to respond to it.