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Background Ectopic ossifications (EO) following total hip replacement are possible and known post-operative complications, developing in about 60% of patients during the first 4-12 weeks after implantation. There is no treatment but surgery, therefore preventive measures are considered to be indispensible. Proven and sufficient measures to prevent EO are radiation treatment or treatment with non-steroidal anti-inflammatory drugs (NSAIDs). These measures are able to reduce EO to occur in about 10% of prophylactically treated patients. Objectives The objective of this retrospective study was to evaluate our practice of treating patients postoperatively with the NSAID proglumetacina molecular combination of indomethacin with the gastroprotective substance proglumidand to compare the success rate with that of competitive preventive treatments. Methods During the years from 1995 to 1997 there were 560 patients in our orthopaedic department who underwent total hip replacement, in most of them because of osteoarthritis of the hip. Other reasons for surgery were femur head necrosis, rheumatoid arthritis, femoral neck fractures or loosening of an already existing hip endoprosthesis. Immediately after surgery, 2 weeks and again 2 months later, and, if possible, also 6 months later, control X-rays were performed. Signs of ossification were objectified using the Brooker classification. Results 545 of these patients (573 women, 188 men; mean age: 66.8 ± 9.7 years; body weight: 75.6 ± 13.2 kg; body length: 167.3 ± 8.5 cm) were postoperatively treated for 3 weeks with proglumetacin. X-ray films of all patients after surgery showed no ossification, just as after 2 weeks the films of 506, after 2 months of 473, and after 6 months of 263 (of 329 re-examined) patients. Clinically not relevant ossifications (class I or II according to Brooker) were seen after 2 weeks in 37 patients (6.8%), after 2 months in 57 patients (10.5%) and after 6 months in 65 (11.9%) patients. Of all patients treated for at least one week no one (0.0%) showed a clinically relevant ossification (class III or IV). Two patients showing class III ossification were prophylactically treated only for 6 and 4 days, respectively. Concerning EO occurrence, in our patients there was no correlation with gender, kind of prosthesis or anaesthesia, duration of hip disease, or risk factors like already performed total hip replacement and diabetes mellitus, respectively.Concerning safety only 43 patients (7.9%) complained of minor or increasing gastric adverse drug reactions, requiring additional gastroprotective drug therapy or even stop of treatment. Conclusion In conclusion, the non-steroidal anti-inflammatory drug proglumetacin is very safe and at least as effective as other preventive measures and very safe. In our view, proglumetacin therefore represents a favourable and economic alternative treatment.

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Chaperonins have classically been thought of as intracellular molecules involved in the correct folding of proteins. Their expression is upregulated during times of stress such as heat (hence their common nomenclature as heat shock proteins [HSP]), anoxia, hypoglycaemia and reactive oxygen species [1]. These are conditions found in infected tissues or in tissues with chronic inflammation such as the rheumatoid synovium. In their intracellular location they protect the cell from apoptotic death due to stress. Increasingly chaperonins have been recognised to subserve extracellular functions for which they have received the name 'chaperokines' since they bind to specific receptors on the cell surface and activate cells of the innate immune system to secrete inflammatory cytokines, chemokines and small molecular weight mediators such as prostaglandins [2]. Indeed, an early event in inflammation is cell stress/necrosis leading to the release of HSP60 and HSP70 that binds via a CD14-mediated mechanism to Toll-like receptors 2 and 4 [2] as part of the 'danger' signal [3]. The secretion of tumour necrosis factor alpha, IL-1, IL-12 and other chemokines prepares the environment for a TH1 adaptive immune response. It is now recognised that some chaperonins, such as BiP and HSP27, may activate the innate immune system to secrete anti-inflammatory cytokines, such as IL-10 [4,5] that may skew the adaptive immune response to TH2. Recent work by our group has shown that BiP can not only prevent but also treat ongoing collagen-induced arthritis in DBA/1 mice [6], suggesting that chaperonins may down modulate ongoing TH1 responses. Thus, it may be possible to suppress rheumatoid inflammation by administration of appropriate chaperonins such as BiP. Finally, chaperonins may be important system regulators determining the outcome between TH1 and Th2 immune responses. References 1. Pockley AG: Heat shock proteins as regulators of the immune response. Lancet 2003, 362:469-476. 2. Asea A: Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 2003, 9:25-33. 3. Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305. 4. De AK, Kodys KM, Yeh BS, Miller-Graziano C: Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heatshock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.

STAT3, SOCS1 and SOCS3. Results The primary inflammation lasted for a week in both strains. In wt mice this inflammation became chronic until the end of the experiments at week 4, while it decreased rapidly in IL-6-/-mice. In wt mice STAT3 became activated from day 1 until the end of the experiments. Also the level of STAT3 mRNA and protein increased. STAT1 in contrast only became activated during the chronic phase after day7. During the arthritis there was an increase of SOCS1 and SOCS3 mRNA expression. In IL-6-/-mice STAT3 only became activated at day 1. No activation of STAT1 occurred in IL-6-/-mice. Conclusion STAT3 activation occurred during both the primary and chronic inflammation in wildtype mice. During the first week IL-6-/-mice also developed a primary inflammation. IL-6 is not the only cytokine that activates STAT3, explaining STAT3 activation at day 1 in IL-6-/-mice. Lack of further STAT3 activation during the primary inflammation suggests a major role for IL-6 in STAT3 activation. STAT1 only became activated in the chronic phase. Arthritis increased expression of SOCS1 and 3, but this seemed not enough to inhibit STAT activation. Future research will have to address the importance of activated STAT1 and 3 for chronic synovitis and the possibility of inhibiting these signalling molecules in the inflamed synovium.