Chondrogenic potential of IL-10 in mechanically injured cartilage and cellularized collagen ACI grafts.

OBJECTIVE: The application of adjunctive mediators in Autologous chondrocyte implantation (ACI) techniques might be useful for improving the dedifferentiated chondrocyte phenotype, to support neocartilage formation and inhibit post-traumatic cartilage destruction. In this study we examined if (a) interleukin 10 treatment can cause chondrogenic phenotype stabilization and matrix preservation in mechanically injured cartilage and if (b) IL-10 can promote chondrogenesis in a clinically applied collagen scaffold for ACI treatment. MATERIALS AND METHODS: For (a) bovine articular cartilage was harvested, subjected to an axial unconfined injury and treated with bovine IL-10 (1-10,000 pg/ng/ml). For (b) a post-operatively remaining ACI graft was treated with human IL-10. Expression levels of type I/II/X collagen, SOX9 and aggrecan were measured by qPCR (a,b). After 3 weeks cell death was analyzed (nuclear blebbing and TUNEL assay) and matrix composition was determined by GAG measurements and immunohistochemistry (aggrecan, type I/II collagen, hyaluronic acid). STATISTICS: One way ANOVA analysis with Bonferroni's correction. RESULTS: (a) IL-10 stabilized the chondrogenic phenotype after injurious compression and preserved matrix integrity. This was indicated by elevated expression of chondrogenic markers COL2A1, ACAN, SOX9, while COL1A1 and COL10A1 were reduced. An increased GAG content paralleled this and histological staining of type 2 collagen, aggrecan and toluidine blue were enhanced after 3 weeks. (b) IL-10 [100 pg/ml] improved the chondrogenic differentiation of human chondrocytes, which was accompanied by cartilaginous matrix formation after 3 weeks of incubation. CONCLUSION: Interleukin-10 is a versatile adjuvant candidate to control the post-injurious environment in cartilage defects and promote chondrogenesis in ACI grafts.

IL-10 reduces apoptosis and extracellular matrix degradation after injurious compression of mature articular cartilage.

OBJECTIVE: The aim of this study was to examine whether anti-inflammatory interleukin-10 (IL-10) exerts chondroprotective effects in an in vitro model of a single mechanical injury of mature articular cartilage. METHOD: Articular cartilage was harvested from the femoro-patellar groove of adult cows (Bos taurus) and cultured w/o bovine IL-10. After 24 h of equilibration explants were subjected to an axial unconfined compression (50% strain, velocity 2 mm/s, held for 10 s). After 96 h cell death was measured histomorphometrically (nuclear blebbing, NB) and the release of glycosaminoglycans (GAG, DMMB assay) and nitric oxide (NO, Griess-reagent) were analyzed. mRNA levels of matrix degrading enzymes and nitric oxide synthetase were measured by quantitative real time PCR. Differences between groups were calculated using a one-way ANOVA with a Bonferroni post hoc test. RESULTS: Injurious compression significantly increased the number of cells with NB, release of GAG and nitric oxide and expression of MMP-3, -13, ADAMTS-4 and NOS2. Administration of IL-10 significantly reduced the injury related cell death and release of GAG and NO, respectively. Expression of MMP-3, -13, ADAMTS-4 and NOS2 were significantly reduced. CONCLUSION: Joint injury is a complex process involving specific mechanical effects on cartilage as well as induction of an inflammatory environment. IL-10 prevented crucial mechanisms of chondrodegeneration induced by an injurious single compression. IL-10 might be a multipurpose drug candidate for the treatment of cartilage-related sports injuries or osteoarthritis (OA).

[Update on rheuma-orthopedics - role and therapeutic options]. / Update Rheumaorthopädie - Aufgabe und therapeutische Optionen.

Orthopaedic treatment options for rheumatological patients have been further developed over recent years. For orthopaedic treatment, a range of different interventions are offered: orthoses and special technical aids as well as injections for joints and tendons, or surgery. Surgical interventions cover joint preservation, restitution and arthrodeses. Improvements in equipment and surgical procedures also make minimally invasive interactions possible for rheumatoid diseases. Thus, postoperative morbidity has been reduced significantly. Improvement in function, reduction of pain and prevention of recurrent local inflammation are primary. Considering these aims, arthrodeses are restricted to special indications. Joint preservation and restitution are the predominant measures used. The various procedures are discussed.

[German Acupuncture Trials (gerac) address problems of methodology associated with acupuncture studies]. / Zur Problematik von Akupunkturstudien am Beispiel der Methodik von gerac.

OBJECTIVE: Conflicting or ambivalent findings on the effectiveness of body acupuncture in pain treatment are often attributed to flaws in study methodology. The paper describes the methodology used for the German Acupuncture Trials (gerac), which demonstrates that it is possible to design acupuncture studies in accordance with the standards of good clinical practice. METHOD: Approximately 1000 chronic pain sufferers per indication (migraine, tension-type headache, low back pain (cLBP), or gonarthrosis) are randomly allocated to one of three treatment groups (verum acupuncture, sham acupuncture, or established conservative therapy). Patients are blind to the type of acupuncture. All patients receive ten sessions of treatment (two per week) with an option of adding five more treatments in cases of slight but insufficient improvement (number of headache days or von Korff pain score). Participating physicians are in private practice, representing a variety of specialties. All have completed at least a 140-hour training course in acupuncture. Mandatory and optional verum and sham points are predefined. The point selection is individualized according to the criteria of traditional Chinese medicine (TCM). Primary outcome measures are number of headache days per month, von Korff Graded Chronic Pain Scale or Hannover Functional Ability Questionnaire (cLBP), or WOMAC scores (gonarthrosis). Data are assessed by trained telephone interviewers not involved in treatment and blind to types of acupuncture. PRESENT STATUS: Over 500 participating physicians in ten urban areas of Germany. Patient recruitment for cLBP and gonarthrosis was completed in November 2003 and March 2004 respectively. Recruitment for chronic headaches will be completed in autumn 2004. CONCLUSIONS: The gerac trials prove that it is possible to design and carry out acupuncture studies in accordance to stringent standards of methodology and clinical practice. The results will form a basis for the assessment of acupuncture effectiveness in Germany and abroad.

[Impact of the quality of clinical trials in orthopedics and traumatology on the status of evidence]. / Auswirkungen der Qualität klinischer Studien in der Orthopädie und Unfallchirurgie auf den Erkenntnisstand.

Medical decisions have to be founded on the current scientific state of the art. To evaluate the efficacy of any therapeutical measure, controlled clinical trials are necessary. Firstly, we describe important principles for the design and conduct of controlled clinical trials. Secondly, we list examples from the topical literature and discuss these regarding adherence to the described principles. The accepted quality criteria for clinical trials have insufficiently been transferred to the area of clinical orthopedic and traumatologic research. As a consequence, the evidence for many therapeutical measures is low. We point out frequently occurring flaws in the design and conduct of controlled clinical trials. A brief introduction to the interpretation of clinical trials and meta analyses is given. In orthopedics and traumatology, well designed controlled clinical trials have to be enforced. This is a prerequisite for evaluating therapeutical measures on a scientific basis.

Extracorporeal shock wave therapy in the treatment of lateral epicondylitis : a randomized multicenter trial.

BACKGROUND: On the basis of observational trials, numerous investigators have recommended extracorporeal shock wave therapy as an alternative treatment for chronic lateral epicondylitis of the elbow. However, there has been no evidence of its efficacy from well-designed randomized clinical trials. The objective of this study was to find out whether extracorporeal shock wave therapy in combination with local anesthesia was superior to placebo therapy in combination with local anesthesia. METHODS: A randomized multicenter trial with a parallel-group design was conducted. Following administration of local anesthesia, either extracorporeal shock wave therapy with three treatments of 2000 pulses each and a positive energy flux density (ED+) of 0.07 to 0.09 mJ/mm (2) or placebo therapy was applied on an outpatient basis. Treatment allocation was blinded for patients and for observers. The primary end point was based on the rate of success, as determined with the Roles and Maudsley score and whether additional treatment was required, twelve weeks after the intervention. Crossover was possible after assessment of the primary end point. Secondary end points were the Roles and Maudsley score, subjective pain rating, and grip strength after six and twelve weeks and after twelve months. The planned number of 272 patients was included in the study. RESULTS: The primary end point could be assessed for 90.8% of the patients. The success rate was 25.8% in the group treated with extracorporeal shock wave therapy and 25.4% in the placebo group, a difference of 0.4% with a 95% confidence interval of -10.5% to 11.3%. Similarly, there was no relevant difference between groups with regard to the secondary end points. Improvement was observed in two-thirds of the patients from both groups twelve months after the intervention. Few side effects were reported. CONCLUSIONS: Extracorporeal shock wave therapy as applied in the present study was ineffective in the treatment of lateral epicondylitis. The previously reported success of this therapy appears to be attributable to inappropriate study designs. Different application protocols might improve clinical outcome. We recommend that extracorporeal shock wave therapy be applied only in high-quality clinical trials until it is proved to be effective.

[Effect of extracorporeal shockwave therapy on vascular regulation. Infrared thermography in epicondylitis humeri radialis]. / Einfluss der Extrakorporalen Stosswellentherapie auf die Gefässregulation. Infrarotthermographie bei Epicondylitis humeri radialis.

BACKGROUND: Extracorporeal shockwave therapy (ESWT) is recommended as an alternative treatment for lateral epicondylitis (LE). An influence on the blood perfusion is considered to be one possible effect. Infrared thermography is used in this trial to measure effects of ESWT on the thermal regulation in the target area. METHODS: 33 patients with chronic LE were examined in a prospective, placebo-controlled single blind study with an independent observer. 3 x 2000 impulses of an energy flux density ED+ 0.22 mJ/mm2 were applied under local anaesthesia as verum-ESWT. Placebo-ESWT was performed under the same conditions. One elbow was treated, the other served as control. Before and after each shockwave application and after 12 weeks skin temperature was measured on both elbows at three predefined points by infrared thermography. RESULTS: While a significant decrease in the skin temperature was found on the treated and sham-treated sides opposed to the contralateral side, there was no difference between the real shockwave treatment and placebo therapy. Responder and Non-responder to the treatment could not be distinguished during the therapy. DISCUSSION: Infrared thermography was proved to be a valuable additional technical instrument for diagnosis of LE, but is not an appropriate instrument to predict the clinical outcome in patients treated with ESWT. A noted reduction of skin temperature on the treated side is not due to specific effects of the shockwaves. It is unlikely that ESWT as applied has an influence on thermal regulation in the target area. These findings are supported by negative results of experimental and clinical trials.

[Physical-technical principles of extracorporeal shockwave therapy (ESWT)]. / Physikalisch-technische Grundlagen der extrakorporalen Stosswellentherapie (ESWT).

Extracorporeal shock waves in orthopaedics are currently applied in the treatment of chronic enthesiopathies such as lateral epicondylitis, plantar heel spur, as well as in calcifying tendinitis of the shoulder or in bony nonunions. Detailed knowledge of physical parameters and properties of shock waves appear to be necessary to determine clinically relevant dose-effect relations and to make shock wave devices, clinical results, and basic science in shock wave therapy more comparable. This study gives an overview of physical parameters and properties in shock wave therapy. Measurement technologies, types of shock wave devices, and mechanisms of shock waves are also described.

[Extracorporeal shockwave therapy (ESWT) in epicondylitis humeri radialis. A review of the literature]. / Extrakorporale Stosswellentherapie (ESWT) bei Epicondylitis humeri radialis. Eine Literaturübersicht.

This review article evaluates therapeutic procedures and clinical findings of extracorporeal shock wave therapy (ESWT) when used for lateral epicondylitis (LE) based on systematic research of the literature. A total of 20 studies were identified, 2 of which had been carried out as prospective, randomized, and controlled studies; the biometric quality of the remaining is clearly inferior. The inclusion and exclusion criteria used in the studies tallied well. In the more recent literature, important ESWT parameters such as energy used, number of impulses and treatment sessions, and locating methods also tallied in part. The studies reported only occasional side effects that could be evaluated as harmless. When evaluating the clinical success of ESWT, it was stated that about 40-80% of the patients achieved a good or very good result at follow-up examinations after 3-12 months. However, in the single placebo-controlled and blinded study with an independent observer, the same therapy results were achieved in the control group where a local anesthetic was used as in the ESWT group. For this reason, it has been concluded that up to now no clinically relevant efficacy has been proven for the use of ESWT for LE. It should no longer be applied clinically as a matter of course, but only as part of high-quality studies with an adequate control group and blinding of patients and follow-up examiners. Due to the pain incurred when applying ESWT and the risk of uncovering the masking, the blinding of the patients must be checked in each further controlled ESWT study.

[Extracorporeal shockwave therapy (ESWT) as therapeutic option in supraspinatus tendon syndrome? One year results of a placebo controlled study]. / Die extrakorporale Stosswellentherapie (ESWT) als therapeutische Option beim Supraspinatussehnensyndrom? Ein-Jahres-Ergebnisse einer placebokontrollierten Studie.

Extracorporeal shock wave therapy (ESWT) is seen as a therapeutic option in the treatment of chronic supraspinatus tendinitis by some authors. To test whether ESWT comprising 3 x 2000 pulses with the positive energy flux density ED+ of 0.33 mJ/mm2 is clinically superior to a sham ESWT treatment, a prospective, randomized, single-blinded, placebo-controlled study with an independent observer was performed. Forty patients were treated either by verum ESWT or sham ESWT under local anesthesia. Target criteria were the age-corrected Constant score, pain at rest and during activity on a visual analogue scale, and subjective improvement. Patients who reported no subjective improvement after 12 weeks were deblinded and received verum ESWT if they had belonged to the placebo group (partial crossover). The results of the verum group lie within the range of results for ESWT published by other authors. Patients in the placebo group with local anesthetic showed equally good results. At 12 weeks, and 1 year after intervention, no difference could be found between the verum and placebo groups regarding Constant score, pain, shoulder function, or subjective improvement. The nonresponders to the placebo ESWT continued to show no improvement after receiving verum ESWT. This contradicts a specific ESWT effect. Based on the results of this placebo-controlled study, ESWT appears to have no clinically relevant effect on supraspinatus tendinitis. The study underlines the importance of a control group in evaluating new treatment methods for diseases with unknown natural history.

[Acupuncture in diseases of the locomotor system. Status of research and clinical applications]. / Akupunktur bei Erkrankungen des Bewegungsapparates. Stand der Forschung und Situation der klinischen Anwendung.

Acupuncture has been used for over 2000 years for a wide variety of complaints with minimal side effects. Based on the experience in Chinese medicine and the anticipated positive effects, acupuncture has been widely accepted in Western medicine as well. Some clinical evidence supports the efficacy of acupuncture treatment, but randomized controlled trials have been conducted for only a few of all possible locomotive disorder indications, and the results have been equivocal. Other indications have not yet been systematically studied, and application is based on clinical experience and consensus among practitioners. One of the outcomes on which consensus appears to exist is that 10-20 sessions are generally necessary, and that initial improvement can be expected to occur by the 10th treatment. Rigorous trials should be conducted to improve clinical validity and provide scientific proof of the efficacy of acupuncture. Clinical trials like the German Acupuncture Trials (gerac), funded by the German health insurance companies, have been launched with the aim of furthering knowledge in this area.

[Musculoskeletal shock wave therapy--current database of clinical research]. / Muskuloskeletale Stosswellenapplikation - Aktueller Stand der klinischen Forschung zu den Standardindikationen.

During the past decade application of extracorporal shock waves became an established procedure for the treatment of various musculoskeletal diseases in Germany. Up to now the positive results of prospective randomised controlled trials have been published for the treatment of plantar fasciitis, lateral elbow epicondylitis (tennis elbow), and of calcifying tendinitis of the rotator cuff. Most recently, contradicting results of prospective randomised placebo-controlled trials with adequate sample size calculation have been reported. The goal of this review is to present information about the current clinical database on extracorporeal shock wave treatment (ESWT).

Side-effects of extracorporeal shock wave therapy (ESWT) in the treatment of tennis elbow.

Apart from a few observational reports, there are no studies on the side-effects of extracorporeal shock wave therapy (ESWT) in the treatment of insertion tendopathies. Within the framework of a randomised, placebo-controlled, single-blind, multicentre study to test the effectiveness of ESWT in the case of lateral epicondylitis (LE), side-effects were systematically recorded. A total of 272 patients from 15 centres was allocated at random to active ESWT (3 x 2000 pulses, energy flux density ED(+) 0.04 to 0.22 mJ/mm(2) under local anaesthesia) or placebo ESWT. In all, 399 ESWT and 402 placebo treatments were analysed. More side-effects were documented in the ESWT group (OR = 4.3, CI = [2.9; 6.3]) than in the placebo group. Most frequently, transitory reddening of the skin (21.1%), pain (4.8%) and small haematomas (3.0%) were found. Migraine was registered in four and syncopes in three instances after ESWT. ESWT for LE with an energy flux density of ED(+) 0.04 to 0.22 mJ/mm(2) is a treatment method which has very few side-effects. The possibility of migraine being triggered by ESWT and the risk of a syncope should be taken into account in the future. No physical shock wave parameters could be definitely identified as the cause of the side-effects observed.

[Acupuncture in the treatment of locomotive disorders - status of research and situation regarding clinical application]. / Akupunktur bei Erkrankungen des Bewegungsapparates. Stand der Forschung und Situation der klinischen Anwendung.

Acupuncture has been used for over 2000 years for a wide variety of complaints with minimal side effects. Based on the experience in Chinese medicine and the anticipated positive effects, acupuncture has been widely accepted in Western medicine as well. Some clinical evidence supports the efficacy of acupuncture treatment, but randomized controlled trials have been conducted for only a few of all possible locomotive disorder indications, and the results have been equivocal. Other indications have not yet been systematically studied, and application is based on clinical experience and consensus among practitioners. One of the outcomes on which consensus appears to exist is that 10-20 sessions are generally necessary, and that initial improvement can be expected to occur by the 10th treatment. Rigorous trials should be conducted to improve clinical validity and provide scientific proof of the efficacy of acupuncture. Clinical trials like the German Acupuncture Trials (gerac), funded by the German health insurance companies, have been launched with the aim of furthering knowledge in this area.

[Comparison of extracorporeal shockwave therapy (ESWT) with roentgen irradiation in supraspinatus tendon syndrome--a prospective randomized single-blind parallel group comparison]. / Vergleich der extrakorporalen Stosswellentherapie (ESWT) mit der Röntgenreizbestrahlung beim Supraspinatussehnensyndrom--Ein prospektiver randomisierter einfachblinder Parallelgruppenvergleich.

AIM: Extracorporal shock wave therapy (FSWT) is applied in the case of supraspinatus tendinitis if conservative therapies have failed. So far there has been no controlled study comparing the effectiveness of ESWT with an established conservative method of therapy such as X-ray stimulation radiotherapy. METHOD: Thirty patients with chronic supraspinatus tendinitis were admitted into the prospective randomised study. After randomisation, the patients were treated either three times with 2000 pulses (energy flux density ED+ 0.33 mJ/mm2) with a Storz Minilith SL1 after one week, or with X-ray stimulation radiotherapy with 6 x 0.5 Gy on the ICRU reference point (1 neutral fraction/day) with cobalt 60 gamma rays. Primary endpoint was the age-corrected constant score. RESULTS: In the ESWT group the average age-corrected constant score rose from 50.1 points before ESWT to 91.5 points after 12 weeks and to 97.8 after 52 weeks. In the radiotherapy group it improved from 47.6 through 79.5 points to 87.4 points. CONCLUSION: No statistically significant differences were proven between ESWT and radiotherapy. ESWT appears to be at least equivalent to radiotherapy in treating chronic supraspinatus tendinitis syndrome and can avoid a dose of radiation for patients and staff. A comprehensive randomised study is, however necessary to ensure the equivalence of ESWT.

Extracorporeal shockwave therapy (ESWT) in the treatment of plantar fasciitis--a biometrical review.

The application of extracorporeal shockwave therapy (ESWT) as a treatment for conservatively unsuccessfully treated plantar fasciitis has experienced a rapid increase over the last years. However, the efficacy of ESWT has not yet been established unequivocally, as published studies have led to inconsistent results. Furthermore, reviews on clinical trials on ESWT are either not up to date, incomplete, or methodologically inadequate. As a consequence, a systematic literature search was conducted which yielded 21 relevant articles on ESWT in the treatment of plantar fasciitis. These were rated according to biometrical criteria for the conduct of therapeutic trials based on international guidelines. None of the rated trials fulfilled all of the criteria, and it is concluded that at this point the efficacy of ESWT can be neither confirmed nor excluded. Randomised and controlled clinical trials are required to adequately estimate the value of ESWT as a treatment for plantar fasciitis.

Specific inhibition of interleukin-4-dependent Stat6 activation by an intracellularly delivered peptide.

The transcription factor Stat6 (signal transducer and activator of transcription 6) is activated following stimulation with interleukin (IL)-4 or IL-13. Stat6 binds via a single SH2 domain first to tyrosine-phosphorylated motifs in the IL-4Ralpha chain, and then to another Stat6 molecule, which results in the formation of active dimers. We show here that a peptide derived from the Stat6-binding region of IL-4Ralpha (Stat6BP) is an effective inhibitor when it is delivered into cells by coupling with a membrane-permeable peptide. Stat6BP completely inhibited IL-4 dependent phosphorylation of Stat6, as well as basal and IL-4 stimulated transcription from a reporter gene construct with a Stat6-dependent promoter, while IL-3 and IL-4 dependent phosphorylation of Stat5 was not affected. The inhibitory effect of Stat6BP was transient, but could be prolonged by treating the cells with the phosphatase inhibitor pervanadate.

Low-energy extracorporeal shock-wave treatment (ESWT) for tendinitis of the supraspinatus. A prospective, randomised study.

We have performed a controlled, randomised study to analyse the effects of low-energy shock-wave therapy (ESWT) on function and pain in tendinitis of the supraspinatus without calcification. There were 20 patients in the treatment group and 20 in the control group. The former group received 6,000 impulses (energy flux density, 0.11 mJ/mm2) in three sessions after local anaesthesia. The control group had 6000 impulses of sham ESWT after local anaesthesia. The patients were examined at six and 12 weeks after treatment by an independent observer who evaluated the Constant score and level of pain. We found an increase in function and a reduction of pain in both groups (p < or = 0.001). Statistical analysis showed no difference between the groups for the Constant score and for pain. We therefore do not recommend ESWT for the treatment of tendinitis of supraspinatus.

Absence of spinal response to extracorporeal shock waves on the endogenous opioid systems in the rat.

Extracorporeal shock wave therapy (ESWT) seems to be a new therapeutic strategy for chronic pain due to tendopathies. Neurophysiological mechanisms of action for pain relief following ESWT are still unknown. The aim of this study was to investigate if the analgesic effect of ESWT is caused by modulation of the endogenous spinal opioid system. Rats were treated with two different energy flux densities (0.04 and 0.11mJ/mm(2)) and immunohistochemical analysis of met-enkephalin (MRGL) and dynorphin (Dyn) was performed at 4 or 72 h after ESWT. ESWT had no modulatory influence on the expression of the spinal opioid systems. Different energy doses or repetitive treatment did not alter MRGL or Dyn immunoreactivity in the spinal cord. Furthermore, a delayed effect of ESWT at 72 h after treatment was not detectable. We conclude from these findings that the analgesic effects of ESWT treatment are not supported by endogenous opioids.