Background: We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins.Methods: Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA).Results: A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group.Conclusions: The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced substances, out of which the tachykinins conform to one substance family, may play a role in mediating effects in the tissue in a muscle that is subjected to pronounced overuse.

To describe the incidence and injury distribution of knee injuries in the general population of a European setting.

It is well established that unilateral exercise can produce contralateral effects. However, it is unclear whether unilateral exercise that leads to muscle injury and inflammation also affects the homologous contralateral muscles. To test the hypothesis that unilateral muscle injury causes contralateral muscle changes, an experimental rabbit model with unilateral muscle overuse caused by a combination of electrical muscle stimulation and exercise (EMS/E) was used. The soleus and gastrocnemius muscles of both exercised and non-exercised legs were analyzed with enzyme- and immunohistochemical methods after 1, 3 and 6 weeks of repeated EMS/E. After 1 w of unilateral EMS/E there were structural muscle changes such as increased variability in fiber size, fiber splitting, internal myonuclei, necrotic fibers, expression of developmental MyHCs, fibrosis and inflammation in the exercised soleus muscle. Only limited changes were found in the exercised gastrocnemius muscle and in both non-exercised contralateral muscles. After 3 w of EMS/E, muscle fiber changes, presence of developmental MyHCs, inflammation, fibrosis and affections of nerve axons and AChE production were observed bilaterally in both the soleus and gastrocnemius muscles. At 6 w of EMS/E, the severity of these changes significantly increased in the soleus muscles and infiltration of fat was observed bilaterally in both the soleus and the gastrocnemius muscles. The affections of the muscles were in all three experimental groups restricted to focal regions of the muscle samples. We conclude that repetitive unilateral muscle overuse caused by EMS/E overtime leads to both degenerative and regenerative tissue changes and myositis not only in the exercised muscles, but also in the homologous non-exercised muscles of the contralateral leg. Although the mechanism behind the contralateral changes is unclear, we suggest that the nervous system is involved in the cross-transfer effects.

It is not known whether a glutamate signaling system is involved in muscle inflammation (myositis). In the present study, we examined this question in the soleus muscle in a laboratory model of myositis resulting from repetitive overuse induced by electrical stimulation and injection of pro-inflammatory substances. Sections of rabbit soleus muscle with an induced myositis, i.e., exhibiting infiltration of inflammatory cells, were examined immunohistochemically using antibodies against vesicular glutamate transporter VGluT2 and the glutamate receptor NMDAR1. In situ hybridization for demonstration of VGluT2 mRNA was also performed. Specific reactions for both VGluT2 and NMDAR1 could be observed immunohistochemically in the same cells. In situ hybridization demonstrated the occurrence of VGluT2 mRNA in the cells. Double staining showed that the VGluT2 reactions were detectable in cells marked with T cell/neutrophil marker and in cells expressing eosinophil peroxidase. These data suggest the occurrence of previously unknown glutamate-mediated autocrine/paracrine effects within the inflammatory infiltrates during the development of muscle inflammation.

The higher incidence of fractures in women than in men is generally attributed to the lower areal bone mineral density (areal BMD, g/cm2) of the former. The purpose of the present study was to investigate both areal BMD and injurious falls as risk factors for fractures. In a first cohort, areal BMD was measured in 5,131 men and women (age range 40–95 years). In a second cohort, consisting of 26,565 men and women (age range 40–69 years), a health survey was conducted including questions about lifestyle and medication. Main outcome measures included validated prospective injurious falls and fractures in both cohorts. The higher areal BMD and femoral neck BMD in men compared to women (P < 0.001) were explained by a higher diameter of the femoral neck. Importantly, the diameter of the femoral neck was not associated with fractures in either sex (hazard ratio [HR] 0.94–1.04, P > 0.05 for all), suggesting that a higher areal BMD and lower incidence of osteoporosis in men do not explain their lower incidence of fractures. In contrast, women were more prone to sustain injurious falls than men in both cohorts investigated (HR for women = 1.61 and 1.84, P < 0.001 for both), resulting in a higher incidence of fractures (HR for women = 2.24 and 2.36, P < 0.001 for both). The number of injurious falls and fractures occurring each month during the study period showed a very strong correlation in both women (r = 0.95, P < 0.00001) and men (r = 0.97, P < 0.00001). In summary, low areal BMD, and thus osteoporosis, may not explain the higher fracture incidence in women than in men. Instead, a higher incidence of injurious falls in women was strongly associated with the higher fracture risk.

Objective To determine whether there are objective findings of tendinosis in a rabbit tendinopathy model on exercised and contralateral (non-exercised) Achilles tendons.Design Four groups of six New Zealand white rabbits per group were used. The animals of one (control) group were not subjected to exercise/stimulation.Interventions Animals were subjected to a protocol of electrical stimulation and passive flexion-extension of the right triceps surae muscle every second day for 1, 3 or 6 weeks.Main Outcome Measures Tenocyte number and vascular density were calculated. Morphological evaluations were also performed as well as in-situ hybridisation for vascular endothelial growth factor (VEGF) messenger RNA.Results There was a significant increase in the tenocyte number after 3 and 6 weeks of exercise, but not after 1 week, in comparison with the control group. This was seen in the Achilles tendons of both legs in experimental animals, including the unexercised limb. The pattern of vascularity showed an increase in the number of tendon blood vessels in rabbits that had exercised for 3 weeks or more, compared with those who had exercised for 1 week or not at all. VEGF-mRNA was detected in the investigated tissue, with the reactions being more clearly detected in the tendon tissue with tendinosis-like changes (6-week rabbits) than in the normal tendon tissue (control rabbits).Conclusions There were bilateral tendinosis-like changes in the Achilles tendons of rabbits in the current model after 3 weeks of training, suggesting that central neuronal mechanisms may be involved and that the contralateral side is not appropriate as a control.

Background Tenocytes produce substance P (SP), and its receptor (neurokinin-1 receptor (NK-1R)) is expressed throughout the tendon tissue, especially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these changes.Objectives To test whether development of tendinosis-like changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of exercise with local administration of SP in an established Achilles tendinopathy model.Methods Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous inflammation, were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1R were conducted.Results There was a significant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a finding not seen in NaCl-injected controls or in uninjected, exercised animals. Paratendinous inflammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, inflammatory cells and tenocytes.Conclusions SP accelerated the development of tendinosis-like changes in the rabbit Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to paratendinitis.

BACKGROUND: In previous studies we found evidence favouring that human Achilles tendon cells (tenocytes) are capable of producing the neuropeptide substance P (SP). Furthermore, the preferred recep ...

ObjectiveA rabbit model for investigating the effects of muscle overuse affecting the triceps surae muscle, including examinations on the magnitude of a neuropeptide which can have pro‐inflammatory properties (substance P [SP]), was used.MethodA “kicking machine” was used for New Zealand white rabbits during 1, 3 and 6 weeks of exercise (2h of exercise every second day). Electrical stimulation was given in the plantar flexion phase. Specimens from the experimental (exercised) side as well as from the contralateral side were taken. Morphologic evaluations, immunohistochemistry and ELISA were applied.ResultsThe muscle morphology was affected in response to the exercise in the muscles of both legs. SP immunoreactions were noted for inflammatory cells and neurokinin‐1 receptor was expressed in inflammatory cells and necrotic muscle fibers. ELISA analyses revealed that the SP levels in the soleus muscle part were significantly increased in both the exercised and the non‐exercised leg after 3 and 6 weeks of training, as compared to non‐exercised animals.ConclusionsMuscle overuse via this model leads to changes also in the muscle on the contralateral side. The observations show that examining the contralateral side in this animal model is defenetely not optimal when evaluating the response to the exercise. The occurrence of bilateral changes may be related to effects that are inforced via the nervous system.

Neurotrophins are substances that have been shown to be important in growth and remodelling phases in different types of tissue. There is no information concerning the possible occurrences of neurotrophins and their receptors in tendons. In this study, sections of both chronic painful (tendinosis) and pain-free (non-tendinosis) human Achilles tendons were immunohistochemically stained with antibodies against the neurotrophins NGF and BDNF, and their receptors TrkA, TrkB and p75. There were marked immunoreactions for NGF and BDNF in the tendon cells (tenocytes) of both tendinosis and non-tendinosis specimens. The tenocytes were also reactive for the receptor p75, but not for the receptors TrkA and TrkB. In addition, p75 immunoreactions were seen in nerve fascicles and in the walls of arterioles. This is the first study to identify neurotrophins in the tenocytes of human tendon. It is clear from this study that the local cells of tendons are sources of neurotrophins. The neurotrophins may play an important role in the tendon through their interaction with the receptor p75 in the tenocytes. These interactions may regulate tropic modulatory, and apoptotic effects. In conclusion, the observations show a new concept concerning production and function of neurotrophins, namely in the tenocytes of tendons.

Sclerosing polidocanol injections targeting the area with vasculo/neural ingrowth on the ventral side of the tendon have previously been demonstrated to give good clinical results in patients with chronic painful midportion Achilles tendinosis. In this study, 20 consecutive patients (9 men and 11 women, mean age 46 years) with chronic painful midportion Achilles tendinosis were treated with either sclerosing polidocanol injections (Group A) or open surgical revision of the area with vasculo/neural ingrowth on the ventral side of the Achilles tendon (Group B). Before treatment, all patients had structural tendon changes and increased blood flow-neovascularisation demonstrated with US and colour Doppler. Under US and colour Doppler-guidance, both the injections and the surgical revision targeted the area with neovessels just outside the ventral part of the tendon. A maximum of two sclerosing injection treatments, with 6-8 weeks in-between, were given. For evaluation, the patients recorded the severity of Achilles tendon pain during tendon loading activity (their recreational or sport activity), before and after treatment, on a VAS. Patient global satisfaction with treatment was also assessed. At the 3 months follow-up 6/9 (one patient was excluded) patients in Group A, and 8/10 patients in Group B, were satisfied with the treatment and had a significantly reduced level of tendon pain (Group A VAS from 76 to 24, P < 0.05, Group B VAS from 75 to 21, P < 0.05). There was one deep infection in Group B. At the 6 months follow-up, 6/9 patients in Group A, and 10/10 patients in Group B were satisfied. In summary, both treatment with sclerosing polidocanol injections and open surgical revision outside the ventral Achilles midportion show promising short-term clinical results.

Autologous periosteal transplantation (without chondrocyte cell transplantation) for treating traumatic articular cartilage defects of the patella gives pain relief in uncontrolled clinical studies. To study the whole transplanted area macroscopically and microscopically, animal studies are motivated. In this pilot study, we reproduce the surgical technique for periosteum transplantation on human patella to a rabbit model. A full-thickness cartilage defect of the whole patella was created in eight adult female rabbits. The defect was treated with autologous periosteal transplantation. After surgery, the rabbits were allowed free activity. This is the difference compared to the treatment in humans, where our group uses CPM for 5 days and non-weight-bearing for 12 weeks. After 21 weeks, there was a diffuse synovitis in all transplanted knees, and in five of eight knees there were signs of osteoarthritis in the patello-femoral joint. Histologically, in three animals, small islands of hyaline cartilage surrounded by fibrocartilage were seen in the transplanted area. In the other five animals, fibrocartilage was the predominant tissue. In contrast to previous experimental studies using a rabbit model, we did not achieve hyaline cartilage resurfacing.

Integrated surface electromyograms of the three superficial parts of the quadriceps and isokinetic knee extensor maximum torque and power production were recorded simultaneously and at different angular velocities in both legs in 11 male subjects with unilateral tear of the anterior cruciate ligament. The cross-sectional area (CSA) of the thigh and its muscular components were measured by computerized tomography. The principal findings were a small but significant decrease in quadriceps CSA on the affected side; a decreased active, but not passive, range of movement; decreased mechanical output, whether or not corrected for differences in CSA; and decreased electrornyographic activity — particularly in rectus femoris. These findings suggest that the reason for the decreased maximum and total knee extensor performance seen in these patients is a change in knee joint receptor afferent inflow.

Several studies have reported estimations of the total number of fibres in a muscle, e.g. before and after training or before and after inactivity. In those investigations a combination of computed tomographic estimations of muscle size and morphological studies of fibre size has most often been used. There have been doubts about the reliability of those studies on pennate muscles, since changes in muscle fibre size have been said to alter fibre angulation and thus the number of fibres that will cross a section. If such an alteration in fibre angulation takes place with an increase in fibre size, there ought to be some correlation between fibre size and fibre angulation. The present study was designed to test whether repetitive estimations of muscle fibre angulation could be performed in vivo and if any such correlation could be found between fibre size and fibre angulation. A group of 15 women volunteered to take part in the study. Repeated ultrasonographic recordings were made on five subjects on 3 consecutive days to test the repeatability of ultrasonographic measurement of fibre angulation. Both muscle morphological analyses and ultrasonographic measurements of fibre angulation were performed on the other 10 subjects. Ultrasonographic measurement of fibre angulation was found to be reproducible since no variation between measurements made on different days was found. When trying to correlate muscle fibre size to the muscle fibre angulation, measured ultrasonographically, no significant correlation was found. In conclusion, the study showed that ultrasonographic recordings of fibre angulation are reproducible when performed on different days; furthermore, our results did not reveal any correlation between fibre angulation and fibre size which would have indicated that fibre angulation was dependent on fibre size.

Injuries involving the Achilles tendon and manifested as chronic tendon pain are common, especially among recreational athletes. In a pilot study on a small group of patients with chronic painful mid-portion Achilles tendinosis, eccentric calf-muscle training was shown to give good clinical results. The aim of this prospective study was to investigate if the previously achieved good clinical results could be reproduced in a larger group of patients, and also to investigate the effects of eccentric calf-muscle training in patients with chronic insertional Achilles tendon pain. Seventy-eight consecutive patients, having chronic painful Achilles tendinosis at the mid-portion (2-6 cm level) in a total of 101 tendons (55 unilateral and 23 bilateral), and thirty consecutive patients with chronic insertional Achilles tendon pain in 31 tendons (29 unilateral and one bilateral) were treated with eccentric calf-muscle training for 12 weeks. Most patients were recreational athletes. Evaluation of the amount of tendon pain during activity was recorded on a visual analogue scale (VAS), before and after treatment. In 90 of the 101 Achilles tendons (89%) with chronic painful mid-portion Achilles tendinosis, treatment was satisfactory and the patients were back on their pre-injury activity level after the 12-week training regimen. In these patients, the amount of pain during activity, registered on the VAS-scale (mean+/-SD), decreased significantly from 66.8+/-19.4 to 10.2+/-13.7. On the contrary, in only ten of the tendons (32%) with chronic insertional Achilles tendon pain was treatment satisfactory, with a significant decrease on the VAS-scale (mean+/-SD), from 68.3+/-7.0 to 13.3+/-13.2. Our conclusion is that treatment with eccentric calf-muscle training produced good clinical results in patients with chronic painful mid-portion Achilles tendinosis, but not in patients with chronic insertional Achilles tendon pain.