Unexpected finding of a marked non-neuronal cholinergic system in human knee joint synovial tissue.

The cholinergic anti-inflammatory pathway is a newly discovered pathway. Another recent concept is the existence of a non-neuronal cholinergic system that has, so far, been defined for human tendons, intestine, airways and urinary bladder. The existence of such a system in joint synovial tissue is yet to be described. We therefore aimed to investigate the expression of choline acetyltransferase (ChAT) at both the protein and mRNA level using immunohistochemistry and in situ hybridisation, in human knee synovial tissue from rheumatoid arthritis (RA) and osteoarthritis (OA) patients. The biopsy samples were collected from patients undergoing knee prosthetic surgery. Our results show that both ChAT protein and mRNA is expressed in fibroblast-like and mononuclear-like cells, and to some extent in blood vessel walls in the synovial tissue. The mononuclear-like cells showing ChAT expression were scattered throughout the synovial tissue or located in association with lymphoid aggregates. Thus, we present the first evidence of the existence of a marked non-neuronal cholinergic system in human synovial tissue. The existence of this system could lead to the development of alternative medications to those currently in use. The system might function as a cholinergic anti-inflammatory pathway in synovial tissue. Our observations show that synovial tissue of patients with marked RA or OA, a tissue in which cholinergic innervation is not proven to exist, is supplied with acetylcholine via production in non-neuronal cells within the tissue.

BDNF in RA: downregulated in plasma following anti-TNF treatment but no correlation with inflammatory parameters.

The involvement of brain-derived neurotrophic factor (BDNF) in rheumatoid arthritis (RA) is largely unknown. The distribution of BDNF and its associated receptors, TrkB and p75, in the synovial tissue of patients with RA was examined and contrasted with that in patients with osteoarthritis (OA). Additionally, levels of BDNF in both synovial tissue and synovial fluid were measured. Furthermore, the effects of anti-tumour necrosis factor (anti-TNF; infliximab) treatment on BDNF levels in the plasma of RA patients were analysed. Cells in the synovium showed immunoreactivity for BDNF and BDNF-, p75- and TrkB-receptor immunoreactions were seen in nerve fibres of nerve fascicles and in association with sensory corpuscles. The levels of BDNF in synovial tissue were not correlated with the number of inflammatory cells observed microscopically or with levels of TNFalpha. Nor did the BDNF levels in synovial fluid correlate with erythrocyte sedimentation rate (ESR) or white blood cell counts. Anti-TNF treatment lead to a decrease in plasma levels of BDNF 14 weeks after the initiation of anti-TNF therapy, i.e., 8 weeks after the last infusion. Higher levels of BDNF were observed in RA patients at baseline compared with those for healthy individuals. However, the levels of BDNF in plasma of patients treated with anti-TNF did not correlate with the changes in ESR or a disease activity score. The clinical significance of this study is that anti-TNF treatment influences plasma levels of BDNF although there was no evidence that BDNF levels correlate with inflammatory parameters in either infliximab-treated or non-infliximab-treated patients with RA. Instead it is likely that sources other than inflammatory cells, including nerve structures, are important sources of BDNF and that the effects of anti-TNF treatment on BDNF levels may be related to effects on circulating and various local cells and/or BDNF-containing neurons.

The role of M. popliteus in unpredictable and in self-initiated balance provocations.

The purpose of this study was to determine whether m. popliteus (POP) activity would contribute to the control of knee joint position in unpredictable and in self-initiated provocations of standing balance. Ten healthy women (age 25.2 +/- 4.5 years, means and SD) without known knee pathology were tested for postural reactions (1) to unpredictable support surface translations in anterior and posterior directions, and (2) in self-initiated balance provocations in a reaction time (RT) forward reach-and-grip task. Electromyographic activity was recorded from POP and other leg muscles plus the deltoid muscle. Three-dimensional kinematics were captured for the knee joint and the body centre of mass was calculated. POP was active first of all the muscles recorded, regardless of translation direction, and knee joint movements elicited were either knee extension or external rotation of the tibia. In the RT task, the POP was active after initiation of reaching movement, and there was little consistency in the kinematic response. POP activity was not direction specific in response to support surface translation, but appeared triggered from reactive knee joint movement. The response to the support-surface translation suggests that POP served to control knee joint position rather than posture. In the RT task, we could not deduce whether POP activity was attributed to knee joint control or to postural control.

VersaBond bone cement prospective randomized study of the clinical properties of a new bone cement in total knee replacement.

VersaBond is a newly developed bone cement. To investigate its clinical performance, VersaBond was compared to Palacos R in a prospective randomized study in total knee replacement. Fifty-nine patients (61 knees) undergoing total knee replacement were randomized to either VersaBond or Palacos R bone cement and followed for 24 months using radiostereometric analysis (RSA). Up to 2 years there were no significant differences in clinical performance between the two cements. The mean/median values for implant migration were very similar for the two bone cements, as were the dispersion, and distribution of outliers. Also the proportion "stable" and "continuously migrating" implants was similar between the two cements. The result of this study indicates that VersaBond bone cement will perform at least equally as well as Palacos R in total knee replacement as regards as aseptic loosening.

The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review.

BACKGROUND: The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting prostaglandin suppression on fracture-healing have been suggested. METHODS: A systematic literature review involving searches of electronic databases and online sources was performed to identify articles exploring the influence of NSAIDs on fracture-healing. RESULTS: A structured search approach identified 316 papers as potentially relevant to the topic, and these were manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with limited control of potentially confounding variables, or presented little key information that was not also present in other studies. CONCLUSIONS: Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing.

Measurements in the Blood of BDNF for RA Patients and in Response to Anti-TNF Treatment Help Us to Clarify the Magnitude of Centrally Related Pain and to Explain the Relief of This Pain upon Treatment.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin with functions related to neuronal survival/proliferation processes and inflammation. BDNF is also an important central pain mediator. The levels of BDNF have been found to be high for RA patients with severe disease and to become lowered in response to anti-TNF treatment. New information says that the levels of BDNF in the blood parallel the BDNF concentrations in the brain and that BDNF can pass the blood-brain barrier. Furthermore, most of the circulating BDNF is produced in the brain. Habitual and regular exercise, in contrast to temporary exercise, does also lead to a lowering of BDNF blood levels. Both anti-TNF treatment and habitual and regular exercise do have pain-relieving effects. It might be that the pain-relieving effect of anti-TNF treatment is related to an affection of central neuronal regions, hereby influencing BDNF production. Measurements of BDNF in the blood help us to clarify the magnitude of centrally related pain for RA patients and help us to explain the relief of this pain in response to anti-TNF treatment.

Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases.

Anti-cholinergic agents are used in the treatment of several pathological conditions. Therapy regimens aimed at up-regulating cholinergic functions, such as treatment with acetylcholinesterase inhibitors, are also currently prescribed. It is now known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various parts of the body. Therefore, interference with the effects of acetylcholine (ACh) brought about by the local production and release of ACh should also be considered. Locally produced ACh may have proliferative, angiogenic, wound-healing, and immunomodulatory functions. Interestingly, cholinergic stimulation may lead to anti-inflammatory effects. Within this review, new findings for the locomotor system of a more widespread non-neuronal cholinergic system than previously expected will be discussed in relation to possible new treatment strategies. The conditions discussed are painful and degenerative tendon disease (tendinopathy/tendinosis), rheumatoid arthritis, and osteoarthritis.

Knee angle and force vector-dependent variations in open and closed kinetic chain for M. popliteus activation.

The popliteus muscle is short and deeply situated in the posterior aspect of the knee, and contributes to control knee joint position. Little is known how activation of the popliteus is controlled. We hypothesized that for the purpose of securing knee joint position, the popliteus would be activated prior to the prime movers of the knee, and that activation would occur earlier and be amplified with increased structural laxity due to joint loading direction and position. Surface and fine wire electromyography (EMG) was used to measure onset and amplitude of muscle activity in the popliteus and three parts of the quadriceps in 10 healthy women (age 25 +/- 4 years). Subjects performed seated isometric knee extensions in 30 degrees and 90 degrees knee flexion in open (OKC) and closed kinetic chain (CKC) in a reaction time task. The popliteus was activated after the quadriceps in all tasks, but with shorter latency relative to the quadriceps in CKC, independent of knee flexion angle. EMG amplitude was greatest for all muscles in OKC in the 30 degrees knee flexion. Biomechanical variables alone do not explain popliteus activation. In addition to biomechanics, behavioral, and habitual aspects need to be considered in further studies.

Mobile bearings do not improve fixation in cemented total knee arthroplasty.

UNLABELLED: Mobile bearings were introduced to improve wear and knee kinematics. By uncoupling the forces generated at the articulation from the implant-bone interface this would, theoretically, also improve the fixation of the implant to bone. We did this study to evaluate whether mobile bearings improve the fixation of the tibial component to bone. Fifty-two consecutive knees in 47 patients (average age, 72 years; range, 62-84 years) with primary osteoarthrosis were randomized into two groups to receive a cemented total knee arthroplasty with either a fixed-bearing or mobile-bearing tibial component. The quality of fixation was analyzed with radiostereometric analysis for up to 2 years. Mobile bearings did not improve fixation. Both magnitudes and directions of component rotations were similar, and the number of implants with continuous migration was almost identical. Both implant types had a combination of subsidence and lift-off, but where the mobile bearing implants displayed more of subsidence, the fixed bearing knees showed more lift-off. It might be that the somewhat stiffer cobalt-chromium baseplate or the different joint conformity used in the mobile-bearing knees counteracts any potential effects of the mobile bearing. LEVEL OF EVIDENCE: Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence.

Uncemented HA-coated implant is the optimum fixation for TKA in the young patient.

UNLABELLED: Fixation of the tibial component in total knee arthroplasty in younger patients remains controversial. We evaluate the results of three different types of fixation of the Profix total knee arthroplasty in a randomized controlled trial of 97 consecutive knees (85 patients) with osteoarthrosis or inflammatory arthritis with 2-year followup of all patients. We randomized patients to three different types of fixation of the tibial component: cemented, uncemented (HA coated) with screws, or uncemented (HA coated) without screws. We performed clinical evaluations and radiostereometric analysis at 6 weeks, and 3, 6, 12 and 24 months postoperatively. The knees in the uncemented groups migrated more than those in the cemented group during the first 3 months, but at 2 years we observed no differences. The uncemented implants displayed all migration within the first 3 months. The cemented implants did not stabilize but had continuously increasing migration during the followup. Cementless implants without screws did not migrate more than implants with screws and displayed similar pattern of migration, indicating screws do not improve fixation. Uncemented fixation using hydroxyapatite-coated implants without screws seems to be the best solution for the younger patient. LEVEL OF EVIDENCE: Therapeutic Level I. See the Guidelines for Authors for a complete description of levels of evidence.

Patients with and without rheumatoid arthritis benefit equally from preoperative epoetin-alpha treatment.

BACKGROUND: Preoperative epoetin-alpha administration is said to have a limited effect in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA), due to lower iron availability. We studied the effects of preoperative epoetin-alpha treatment in orthopedic surgery patients in a daily life setting in which iron supplementation was assured, and compared the effects in RA and non-RA patients. METHODS: In an open, naturalistic, randomized controlled trial, 695 orthopedic surgery patients with preoperative hemoglobin (Hb) values of 10-13 g/dL, either with RA (113) or without RA (582), received either preoperative epoetin-alpha treatment added to standard care, or standard care alone. Hb values and transfusions were evaluated from entry into the study until 4-6 weeks after surgery. RESULTS: Both in RA and non-RA patients, perioperative Hb values were significantly higher and transfusion requirements were significantly lower in epoetin-alpha treated patients than in control patients (p < 0.001). In RA patients, the outcomes regarding Hb values were not significantly or relevantly different from non-RA patients. INTERPRETATION: Just as with orthopedic patients in general, RA patients benefit from preoperative epoetin-alpha treatment in combination with iron supplementation. We postulate that iron supplementation during epoetin-alpha therapy in RA patients is important for optimal efficacy.

Fever and autologous blood retransfusion after total knee arthroplasty: a prospective study of 40 autotransfusion events in 21 patients.

The commonest adverse reaction of autotransfusion of drain blood is an increase in temperature, probably due to a cytokine-mediated inflammatory reaction. We recorded body temperature in 21 patients operated on with a total knee prosthesis prospectively during the first 18 postoperative hours. The patients had been given an autotransfusion of autologous filtered drain blood (40 events) within the first 8-9 hours. They all had hypothermia at the end of operation, with a continuous increase in temperature during the first 12 hours whereafter the temperature slowly fell. No additional increase in temperature was seen during the first 2 hours after an autologous retransfusion. Autotransfusion of filtered drain blood within the first 8 postoperative hours after arthroplasty thus did not seem to cause an additional increase in temperature above that due to spontaneous recovery after postoperative hypothermia and surgical trauma.