A bifunctional role for group IIA secreted phospholipase A2 in human rheumatoid fibroblast-like synoviocyte arachidonic acid metabolism.

Human group IIA-secreted phospholipase A(2) (sPLA(2)-IIA) is an important regulator of cytokine-mediated inflammatory responses in both in vitro and in vivo models of rheumatoid arthritis (RA). However, treatment of RA patients with sPLA(2)-IIA inhibitors shows only transient benefit. Using an activity-impaired sPLA(2)-IIA mutant protein (H48Q), we show that up-regulation of TNF-dependent PGE(2) production and cyclooxygenase-2 (COX-2) induction by exogenous sPLA(2)-IIA in RA fibroblast-like synoviocytes (FLSs) is independent of its enzyme function. Selective cytosolic phospholipase A(2)-α (cPLA(2)-α) inhibitors abrogate TNF/sPLA(2)-IIA-mediated PGE(2) production without affecting COX-2 levels, indicating arachidonic acid (AA) flux to COX-2 occurs exclusively through TNF-mediated activation of cPLA(2)-α. Nonetheless, exogenous sPLA(2)-IIA, but not H48Q, stimulates both AA mobilization from FLSs and microparticle-derived AA release that is not used for COX-2-dependent PGE(2) production. sPLA(2)-IIA-mediated AA production is inhibited by pharmacological blockade of sPLA(2)-IIA but not cPLA(2)-α. Exogenous H48Q alone, like sPLA(2)-IIA, increases COX-2 protein levels without inducing PGE(2) production. Unlike TNF, sPLA(2)-IIA alone does not rapidly mobilize NF-κB or activate phosphorylation of p38 MAPK, two key regulators of COX-2 protein expression, but does activate the ERK1/2 pathway. Thus, sPLA(2)-IIA regulates AA flux through the cPLA(2)-α/COX-2 pathway in RA FLSs by up-regulating steady state levels of these biosynthetic enzymes through an indirect mechanism, rather than direct provision of substrate to the pathway. Inhibitors that have been optimized for their potency in enzyme activity inhibition alone may not adequately block the activity-independent function of sPLA(2)-IIA.

Operation Sumatra Assist: surgery for survivors of the tsunami disaster in Indonesia.

The tsunami of 26 December 2004 was one of the deadliest natural disasters recorded, with the Indonesian province of Aceh being the most devastated region. As part of the Australian Government's response to the disaster, the Australian Defence Force deployed personnel from the Sydney-based 1st Health Support Battalion to Banda Aceh, the capital of the province. This unit joined with medical personnel from the New Zealand Defence Force to form the ANZAC field hospital. The mission of this unit as part of Operation Sumatra Assist was to provide medical and surgical care to the people of Aceh during the critical stages of rebuilding of the tsunami-devastated region. Surgical teams of the ANZAC field hospital were some of the first to provide definitive surgical care to the critically injured survivors of the disaster. During the first 4 weeks of the deployment, 173 surgical procedures were carried out for 71 patients in this facility. Thirty patients underwent 119 procedures (69% of total) for injuries sustained in the tsunami. Most of these patients required debridements, dressing changes and wound management procedures for the management of severe soft tissue infections. Three amputations were carried out. The remaining 41 patients underwent 54 procedures (31%) for emergent surgical conditions unrelated to the disaster.

A single-centre prospective study of clinical and haemostatic risk factors for venous thromboembolism following lower limb arthroplasty.

Previous studies report conflicting results concerning the potential significance of thrombophilic genotypes in postarthroplasty venous thromboembolism (VTE). This study assessed thrombophilic genotypes, haemostatic and clinical variables as independent risk factors for VTE postarthroplasty. A total number of 569 patients undergoing elective lower limb arthroplasty at a single centre were prospectively studied. All patients were interviewed and had blood samples collected preoperatively. Bilateral lower limb ultrasonography was performed at day 7 +/- 2 postoperatively in all patients (ventilation/perfusion lung scanning in symptomatic patients only). The incidence of inhospital postoperative VTE was 26%. In univariate analysis - increased age, knee arthroplasty, recent surgery, general anaesthesia, shorter operation time, non-receipt of blood transfusion and differences in surgical practice (including use of pneumatic calf compression, surgical drains and postoperative bandaging techniques) were significantly associated with VTE. Factor V Leiden, prothrombin G20210A and MTHFR C677T mutations were not significant risk factors for VTE, and of all haemostatic variables tested, only median activated partial thromboplastin time showed significant difference between VTE and non-VTE patients (34 s vs. 33 s). Multiple logistic regression analysis demonstrated that increased age, knee arthroplasty and individual surgeon's routine practices were the only significant independent risks for VTE; hence routine preoperative blood screening for a potential hypercoaguable state is not indicated in this surgical setting.

Selection of patients for inpatient rehabilitation or direct home discharge following total joint replacement surgery: a comparison of health status and out-of-pocket expenditure of patients undergoing hip and knee arthroplasty for osteoarthritis.

OBJECTIVES: To analyse the differences in patient health outcomes and out-of-pocket costs following hip and knee joint replacement for osteoarthritis between patients who went home immediately after the acute care hospital stay and those who were admitted to inpatient rehabilitation care before going home. METHODS: One hundred and eighteen patients undergoing total hip or knee replacement in Sydney, Australia completed cost diaries, SF-36 and WOMAC Index, pre-operatively and for one year post-operatively. RESULTS: The health status of all groups improved significantly from before surgery to 12 months post-surgery. No significant difference in health status at 12 months post-surgery was seen between home and rehabilitation patients for either hip or knee replacement. Both hip replacement home and rehabilitation patients and knee replacement home patients reported lower out-of-pocket expenditure from before surgery to 1 year post-surgery. DISCUSSION: The majority of total joint replacement patients can be discharged directly home and achieve excellent outcomes at 12 months post-surgery. We would recommend more focused randomized studies to explore the most suitable patient selection for rehabilitation.

Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients.

BACKGROUND: The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention. METHODS: In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively. RESULTS: Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010). CONCLUSIONS: The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia.

Cost of joint replacement surgery for osteoarthritis: the patients' perspective.

OBJECTIVE: To address costs of total joint replacement surgery from the patients' perspective by determining patient out-of-pocket costs during the first year following joint replacement, and to explore whether health status presurgery or in the immediate 3 months postsurgery were determinants of costs. In light of the different outcomes experienced by patients with total knee replacement (TKR) and total hip replacement (THR), any differences in costs between the 2 groups were also explored. METHODS: Patients with osteoarthritis (OA) scheduled for primary unilateral TKR or THR surgery at 3 Sydney hospitals were approached. Patients completed questionnaires preoperatively to record expenses during the previous 3 months and health status immediately prior to surgery. Patients then maintained detailed prospective cost diaries and completed SF-36 and WOMAC Index every 3 months for the first postoperative year. Arthritis-specific cost inforrmation obtained in the diary included medications (prescription and nonprescription), visits to health professionals, tests (radiographs, scans, blood tests, etc), special equipment, alterations to house, and the use of private or community services. RESULTS: Ninety-eight TKR and 76 THR patients provided cost details for their first postoperative year. For both THR and TKR patients, out-of-pocket costs fell considerably over the first postoperative year, and during the year the proportion of patients who experienced no out-of-pocket costs increased, as did the proportion who made no use of health services such as medical tests or visits to health professionals. Regression analysis for THR patients showed that pension status, preoperative SF-36 Physical Component Score, and 3-month postoperative WOMAC Function were significant independent predictors of postoperative costs. Regression analysis for TKR patients showed that presurgery WOMAC Stiffness and pension status were significant independent predictors of postoperative costs, indicating that those with greater stiffness had greater postsurgery costs and those on a pension had lower costs. CONCLUSION: OA patients undergoing THR and TKR have substantial out-of-pocket costs presurgery, which fall dramatically over the first postoperative year. Poorer presurgery health status predicted greater expenditure during the first postoperative year, which might be taken into consideration when patients are making a choice about the timing of joint surgery.