Disruption of day-to-night changes in circadian gene expression with chronic tendinopathy.

Overuse injury in tendon tissue (tendinopathy) is a frequent and costly musculoskeletal disorder and represents a major clinical problem with unsolved pathogenesis. Studies in mice have demonstrated that circadian clock-controlled genes are vital for protein homeostasis and important in the development of tendinopathy. We performed RNA sequencing, collagen content and ultrastructural analyses on human tendon biopsies obtained 12 h apart in healthy individuals to establish whether human tendon is a peripheral clock tissue and we performed RNA sequencing on patients with chronic tendinopathy to examine the expression of circadian clock genes in tendinopathic tissues. We found time-dependent expression of 280 RNAs including 11 conserved circadian clock genes in healthy tendons and markedly fewer (23) differential RNAs with chronic tendinopathy. Further, the expression of COL1A1 and COL1A2 was reduced at night but was not circadian rhythmic in synchronised human tenocyte cultures. In conclusion, day-to-night changes in gene expression in healthy human patellar tendons indicate a conserved circadian clock as well as the existence of a night reduction in collagen I expression. KEY POINTS: Tendinopathy is a major clinical problem with unsolved pathogenesis. Previous work in mice has shown that a robust circadian rhythm is required for collagen homeostasis in tendons. The use of circadian medicine in the diagnosis and treatment of tendinopathy has been stifled by the lack of studies on human tissue. Here, we establish that the expression of circadian clock genes in human tendons is time dependent, and now we have data to corroborate that circadian output is reduced in diseased tendon tissues. We consider our findings to be of significance in advancing the use of the tendon circadian clock as a therapeutic target or preclinical biomarker for tendinopathy.

The recovery of muscle function and glycogen levels following game-play in young elite male ice hockey players.

Despite the frequent occurrence of congested game fixtures in elite ice hockey, the postgame recovery pattern has not previously been investigated. The purpose of the present study was therefore to evaluate the acute decrements and subsequent recovery of skeletal muscle glycogen levels, muscle function and repeated-sprint ability following ice hockey game-play. Sixteen male players from the Danish U20 national team completed a training game with muscle biopsies obtained before, postgame and following ~38 h of recovery (day 2). On-ice repeated-sprint ability and muscle function (maximal voluntary isometric [MVIC] and electrically induced low- (20 Hz) and high-frequency (50 Hz) knee-extensor contractions) were assessed at the same time points, as well as ~20 h into recovery (day 1). Muscle glycogen decreased 31% (p < 0.001) postgame and had returned to pregame levels on day 2. MVIC dropped 11%, whereas 50 and 20 Hz torque dropped 21% and 29% postgame, respectively, inducing a 10% reduction in the 20/50 Hz torque ratio indicative of low-frequency force depression (all p < 0.001). While MVIC torque returned to baseline on day 1, 20 and 50 Hz torque remained depressed by 9%-11% (p = 0.010-0.040), hence restoring the pre-exercise 20/50 Hz ratio. Repeated-sprint ability was only marginally reduced by 1% postgame (p = 0.041) and fully recovered on day 1. In conclusion, an elite youth ice hockey game induces substantial reductions in muscle glycogen content and muscle function, but only minor reductions in repeated-sprint ability and with complete recovery of all parameters within 1-2 days postgame.

Muscle-strain injury exudate favors acute tissue healing and prolonged connective tissue formation in humans.

Traumatic strain injury in skeletal muscle is often associated with fluid accumulation at the site of rupture, but the role of this injury exudate (EX) in cellular responses and healing is unknown. We aimed to characterize the EX sampled from human hamstring or calf muscles following a strain injury (n = 12). The cytokine and growth-factor profile, gene expression, and transcriptome analysis of EX-derived cells were compared with blood taken simultaneously from the same individuals. Cellular responses to the EX were tested in 3-dimensional (3D) culture based on primary human fibroblasts and myoblasts isolated from hamstring muscles. The EX contained a highly proinflammatory profile with a substantial expression of angiogenic factors. The proinflammatory profile was present in samples taken early postinjury and in samples aspirated several weeks postinjury, suggesting persistent inflammation. Cells derived from the EX demonstrated an increased expression of fibrogenic, adipogenic, and angiogenesis-related genes in comparison with blood cells. The injury EX stimulated fibroblast proliferation 2-fold compared with plasma, whereas such an effect was not seen for myoblasts. Finally, in 3D cell culture, the EX induced an up-regulation of connective tissue-related genes. In summary, EX formation following a muscle-strain injury stimulates fibroblast proliferation and the synthesis of connective tissue in fibroblasts. This suggests that the EX promotes an acute tissue-healing response but potentially also contributes to the formation of fibrotic tissue in the later phases of tissue repair.-Bayer, M. L., Bang, L., Hoegberget-Kalisz, M., Svensson, R. B., Olesen, J. L., Karlsson, M. M., Schjerling, P., Hellsten, Y., Hoier, B., Magnusson, S. P., Kjaer, M. Muscle-strain injury exudate favors acute tissue healing and prolonged connective tissue formation in humans.

Role of tissue perfusion, muscle strength recovery, and pain in rehabilitation after acute muscle strain injury: A randomized controlled trial comparing early and delayed rehabilitation.

Muscle strain injuries disrupt the muscle-tendon unit, early rehabilitation is associated with a faster return to sports (RTS), but the time course of tissue healing remains sparsely described. The purpose was to examine tissue regeneration and the effectiveness of early versus delayed rehabilitation onset on functional and structural recovery after strain injuries. A total of 50 recreational athletes with a severe acute strain injury in their thigh or calf muscles were randomized to early or delayed rehabilitation onset. Magnetic resonance imaging (MRI) was obtained initially, 3 and 6 months postinjury, and dynamic contrast-enhanced MRI (DCE-MRI) estimated tissue inflammation initially and after 6 months. Muscle strength was determined 5 weeks, 3 months, and 6 months postinjury, and a questionnaire determined soreness, pain, and confidence. DCE-MRI microvascular perfusion was higher in the injured compared to an uninjured muscle acutely (P < 0.01) and after 6 months (P < 0.01), for both groups (P > 0.05) and unrelated to RTS (P > 0.05). Total volume of the injured muscle decreased from the acute to the 3-month scan, and to the 6-month scan (P < 0.01) in both groups. Muscle strength was similar in both groups at any time. There was a nonsignificant trend (P ≤ 0.1) toward less pain and higher confidence with early rehabilitation. One reinjury was recorded. In conclusion, our data showed prolonged tissue repair with the initial response linked to muscle atrophy but did not explain why early rehabilitation onset accelerated recovery considering that structural and functional recovery was similar with early and delayed rehabilitation.

High prevalence of daily and multi-site pain--a cross-sectional population-based study among 3000 Danish adolescents.

BACKGROUND: Daily pain and multi-site pain are both associated with reduction in work ability and health-related quality of life (HRQoL) among adults. However, no population-based studies have yet investigated the prevalence of daily and multi-site pain among adolescents and how these are associated with respondent characteristics. The purpose of this study was to investigate the prevalence of self-reported daily and multi-site pain among adolescents aged 12-19 years and associations of almost daily pain and multi-site pain with respondent characteristics (sex, age, body mass index, HRQoL and sports participation). METHODS: A population-based cross-sectional study was conducted among 4,007 adolescents aged 12-19 years in Denmark. Adolescents answered an online questionnaire during physical education lessons. The questionnaire contained a mannequin divided into 12 regions on which the respondents indicated their current pain sites and pain frequency (rarely, monthly, weekly, more than once per week, almost daily pain), characteristics, sports participation and HRQoL measured by the EuroQoL 5D. Multivariate regression was used to calculate the odds ratio for the association between almost daily pain, multi-site pain and respondent characteristics. RESULTS: The response rate was 73.7%. A total of 2,953 adolescents (62% females) answered the questionnaire. 33.3% reported multi-site pain (pain in > 1 region) while 19.8% reported almost daily pain. 61% reported current pain in at least one region with knee and back pain being the most common sites. Female sex (OR: 1.35-1.44) and a high level of sports participation (OR: 1.51-2.09) were associated with increased odds of having almost daily pain and multi-site pain. Better EQ-5D score was associated with decreased odds of having almost daily pain or multi-site pain (OR: 0.92-0.94). CONCLUSION: In this population-based cohort of school-attending Danish adolescents, nearly two out of three reported current pain and, on average, one out of three reported pain in more than one body region. Female sex, and high level of sports participation were associated with increased odds of having almost daily pain and multi-site pain. The study highlights an important health issue that calls for investigations to improve our understanding of adolescent pain and our capacity to prevent and treat this condition.

Care-seeking behaviour of adolescents with knee pain: a population-based study among 504 adolescents.

BACKGROUND: Knee pain is common during adolescence. Adolescents and their parents may think that knee pain is benign and self-limiting and therefore avoid seeking medical care. However, long-term prognosis of knee pain is not favourable and treatment seems to offer greater reductions in pain compared to a "wait-and-see" approach. The purpose of this study was to describe the determinants of care-seeking behaviour among adolescents with current knee pain and investigate what types of treatment are initiated. METHODS: An online questionnaire was forwarded to 2,846 adolescents aged 15-19 in four upper secondary schools. The questionnaire contained questions on age, gender, height, weight, currently painful body regions, frequency of knee pain, health-related quality of life measured by the EuroQol 5-dimensions, sports participation and if they had sought medical care. Adolescents who reported current knee pain at least monthly or more frequently were telephoned. The adolescents were asked about pain duration, onset of knee pain (traumatic or insidious) and if they were currently being treated for their knee pain. RESULTS: 504 adolescents currently reported at least monthly knee pain. 59% of these had sought medical care and 18% were currently under medical treatment . A longer pain duration and higher pain severity increased the odds of seeking medical care. Females with traumatic onset of knee pain were more likely to have sought medical care than females with insidious onset of knee pain. Females with traumatic onset of knee pain and increased pain severity were more likely to be undergoing medical treatment. The most frequently reported treatments were the combination of exercises and orthotics (68% of those undergoing medical treatment). CONCLUSION: Females with insidious onset of knee pain do not seek medical care as often as those with traumatic onset and adolescents of both genders with insidious onset are less likely to be under medical treatment. These findings are important as knee pain with insidious onset has similar consequences as knee pain with traumatic onset regarding pain severity, pain duration and reductions in health-related quality of life.

Assessment of the Psychometric Properties of the Danish VISA-P.

Purpose: The objective of the current study was to conduct a rigorous assessment of the psychometric properties of the Victorian Institute of Sports Assessment-patellar tendinopathy (VISA-P). Methods: Rasch analysis, confirmatory factor analysis (CFA), and multivariable linear regression were used to assess the psychometric properties of the VISA-P questionnaire in 184 Danish patients with patellar tendinopathy who had symptoms ranging from under 3 months to over 1 year. A group of 100 healthy Danish persons was included as a reference for known-group validation. Results: The analyses revealed that the 8-item VISA-P did not fit a unidimensional model, yielded at best a 3-factor model, and exhibited differential item functioning (DIF) across healthy subjects versus people with patellar tendinopathy. Conclusion: VISA-P in its present form does not satisfy a measurement model and is not a robust scale for measuring patellar tendinopathy. A new PROM for patellar tendinopathy should be developed and appropriately validated, and meanwhile, simple pain scoring (e.g., numeric rating scales) and functional tests are suggested as more appropriate outcome measures for studies of patellar tendinopathy.

Early intervention for adolescents with patellofemoral pain syndrome--a pragmatic cluster randomised controlled trial.

BACKGROUND: Self-reported knee pain is highly prevalent among adolescents. As much as 50% of the non-specific knee pain may be attributed to Patellofemoral Pain Syndrome (PFPS). In the short term, exercise therapy appears to have a better effect than patient education consisting of written information and general advice on exercise or compared with placebo treatment. But the long-term effect of exercise therapy compared with patient education is conflicting. The purpose of this study is to examine the short- and long-term effectiveness of patient education compared with patient education and multimodal physiotherapy applied at a very early stage of the condition among adolescents. METHODS/DESIGN: This study is a single blind pragmatic cluster randomised controlled trial. Four upper secondary schools have been invited to participate in the study (approximately 2500 students, aged 15-19 years). Students are asked to answer an online questionnaire regarding musculoskeletal pain. The students who report knee pain are contacted by telephone and offered a clinical examination by a rheumatologist. Subjects who fit the inclusion criteria and are diagnosed with PFPS are invited to participate in the study. A minimum of 102 students with PFPS are then cluster-randomised into two intervention groups based on which school they attend. Both intervention groups receive written information and education. In addition to patient education, one group receives multimodal physiotherapy consisting primarily of neuromuscular training of the muscles around the foot, knee and hip and home exercises. The students with PFPS fill out self-reported questionnaires at baseline, 3, 6, 12 and 24 months after inclusion in the study. The primary outcome measure is perception of recovery measured on a 7-point Likert scale ranging from "completely recovered" to "worse than ever" at 12 months. DISCUSSION: This study is designed to investigate the effectiveness of patient education compared with patient education combined with multimodal physiotherapy. If patient education and multimodal physiotherapy applied at an early stage of Patellofemoral Pain Syndrome proves effective, it may serve as a basis for optimising the clinical pathway for those suffering from the condition, where specific emphasis can be placed on early diagnosis and early treatment. TRIAL REGISTRATION: clinicaltrials.gov reference: NCT01438762.

Analgesic use in adolescents with patellofemoral pain or Osgood-Schlatter Disease: a secondary cross-sectional analysis of 323 subjects.

OBJECTIVES: The prevalence of pain medication use for adolescent knee pain and factors associated with use are not well understood. This study aimed to determine the self-reported use of pain medication for knee pain and identify factors associated with use in adolescents (age 10-19) with longstanding knee symptoms. METHODS: In this exploratory cross-sectional study, we performed a secondary analysis of data previously collected in 323 adolescents with longstanding knee pain. Factors associated with pain medication use were assessed using multivariable logistic regressions. Analyses were repeated with stratification by age, sex, sport participation frequency, knee pain duration, and knee pain intensity. RESULTS: Among 323 adolescents (mean age 14.4 ± 2.5, 73% female), 84% had patellofemoral pain, (peri- or retro-patellar pain during loaded bending of the knee) and 16% had Osgood-Schlatter Disease (apophysitis with swelling and localized pain at the tibial tuberosity). Twenty-one percent (95% CI 16-25%) of adolescents reported pain medication use for their knee pain, with no difference in usage between those ≤ vs. > 15 years of age (21%, 95% CI 16-27% vs. 20%, 95% CI 13-29%). Adolescents with patellofemoral pain reported greater usage than their counterparts with Osgood-Schlatter Disease (22%, 95% CI 17-28% vs. 12%, 95% CI 4.5-24.3%). The most consistent factor associated with use was knee-related symptoms, observed in both the overall (OR 0.97, 95% CI 0.94-0.99) and stratified analyses (ORs ranged from 0.89 to 0.96). CONCLUSIONS: Approximately one in five adolescents with longstanding knee pain reported pain medication use, particularly in adolescents with patellofemoral pain. Knee-related symptoms most consistently associated with the use of pain medications in this population. Future longitudinal studies with data collected at multiple time-points are needed to validate these findings. IMPLICATIONS: Self-reported pain medication use is common in adolescents with longstanding knee pain, even though whether pharmacological therapy is the best pain management option at this young age is debatable. Reliance on pain medication at an early age could potentially hamper the development of healthy pain coping strategies and increase the risk of dependence and misuse later in life. Future studies should assess the safety, efficacy, and risks of long-term use of pain medications for adolescent knee pain.

No Treatment Benefits of Local Administration of Insulin-like Growth Factor-1 in Addition to Heavy Slow Resistance Training in Tendinopathic Human Patellar Tendons: A Randomized, Double-Blind, Placebo-Controlled Trial With 1-Year Follow-up.

BACKGROUND: Heavy slow resistance (HSR) training is currently recommended as part of the treatment of patellar tendon tendinopathy. However, treatment success is not reached in all patients, and combinations of different treatments could be beneficial. Local administration of insulin-like growth factor-1 (IGF-1) in humans has been shown to quickly stimulate tendon collagen synthesis. PURPOSE: To study whether IGF-1 injections combined with HSR training enhance tendon synthesis, tissue structure, and patient satisfaction versus saline injection combined with HSR training in patients with patellar tendinopathy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Forty patients (age 18-50 years) with unilateral patellar tendinopathy undertook HSR training (3 times a week for 12 weeks) and received intratendinous IGF-1 injections (1 mg IGF-1 per dose) or isotonic saline injections (sham injections) at baseline and after 1 and 2 weeks of training. The primary outcome was collagen synthesis parameters after 12 weeks (primary endpoint). The secondary outcomes were patient-reported outcomes (scores on the Victorian Institute of Sport Assessment-Patella [VISA-P] and visual analog scale [VAS] for pain) and structural changes before the initiation of treatment and at week 3, week 12, and 1 year after the initiation of treatment. RESULTS: Analysis of the patellar tendon biopsy specimens at 12 weeks showed that collagen mRNA and total RNA were increased in the tendinopathic tendons compared with the contralateral healthy tendons regardless of treatment with IGF-1 or saline. Similarly, no difference between the groups was seen in tendon thickness and Doppler activity at week 12 or at 1-year follow-up. The combination of HSR training and IGF-1 injections significantly improved VISA-P and VAS pain scores after 3 weeks, whereas the overall responses after 12 weeks and at 1-year follow-up were identical in the 2 groups. CONCLUSION: Although a small, immediate clinical response to IGF-1 injections was seen when combined with training, no additional long-term effect of intratendinous IGF-1 was observed on structural and clinical outcomes in patients with patellar tendinopathy. REGISTRATION: NCT01834989 (ClinicalTrials.gov identifier).

Chronic Sequelae After Muscle Strain Injuries: Influence of Heavy Resistance Training on Functional and Structural Characteristics in a Randomized Controlled Trial.

BACKGROUND: Muscle strain injury leads to a high risk of recurrent injury in sports and can cause long-term symptoms such as weakness and pain. Scar tissue formation after strain injuries has been described, yet what ultrastructural changes might occur in the chronic phase of this injury have not. It is also unknown if persistent symptoms and morphological abnormalities of the tissue can be mitigated by strength training. PURPOSE: To investigate if heavy resistance training improves symptoms and structural abnormalities after strain injuries. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 30 participants with long-term weakness and/or pain after a strain injury of the thigh or calf muscles were randomized to eccentric heavy resistance training of the injured region or control exercises of the back and abdominal muscle. Isokinetic (hamstring) or isometric (calf) muscle strength was determined, muscle cross-sectional area measured, and pain and function evaluated. Scar tissue ultrastructure was determined from biopsy specimens taken from the injured area before and after the training intervention. RESULTS: Heavy resistance training over 3 months improved pain and function, normalized muscle strength deficits, and increased muscle cross-sectional area in the previously injured region. No systematic effect of training was found upon pathologic infiltration of fat and blood vessels into the previously injured area. Control exercises had no effect on strength, cross-sectional area, or scar tissue but a positive effect on patient-related outcome measures, such as pain and functional scores. CONCLUSION: Short-term strength training can improve sequelae symptoms and optimize muscle function even many years after a strain injury, but it does not seem to influence the overall structural abnormalities of the area with scar tissue. REGISTRATION: NCT02152098 (ClinicalTrials.gov identifier).

Ultrasonographic assessment of patellar tendon thickness at 16 clinically relevant measurement sites - A study of intra- and interrater reliability.

OBJECTIVES: To determine intra- and interrater reliability of ultrasonographic imaging (USI) measurements of patellar tendon (PT) thickness using 16 measurement sites covering the entire tendon. DESIGN: Reliability study. SETTING: Physiotherapy outpatient clinic. PARTICIPANTS: Twenty healthy and physically active volunteers (9 women). Mean age: 24 years (SD ±â€¯2.73). Mean body mass: 75.8 kg (SD ±â€¯11.8). MAIN OUTCOME MEASURES: Intraclass correlation coefficient (ICC) and 95% limits of agreement (LOA) in cm and in percentage relative to the mean PT thickness. RESULTS: Intrarater reliability ranged from 0.59 to 0.87 and 0.59 to 0.93 for examiners I and II, respectively. Interrater reliability ranged from 0.37 to 0.89. Measurement precision for examiner I ranged from 0.05 to 0.09 cm (17.5%-26.7%) while ranging from 0.04 to 0.13 cm (13.3%-38.7%) for examiner II. Interrater measurement precision ranged from 0.07 to 0.15 cm (19.1%-42.5%). CONCLUSION: In an attempt to replicate daily clinical USI practice, this was the first study extensively assessing reliability throughout the full range of the patellar tendon - revealing a considerable variation in intra- and interrater reliability as well as measurement precision throughout the 16 individual PT sites. In a clinical context, the low interrater reliability and precision found at the proximal tendon insertion site may have implications for USI of the symptomatic PT, as this is the site mainly associated with underlying pathologic changes. Further reliability studies are needed to clarify the region-specific reliability of the full length PT.

Protein-containing nutrient supplementation following strength training enhances the effect on muscle mass, strength, and bone formation in postmenopausal women.

We evaluated the response of various muscle and bone adaptation parameters with 24 wk of strength training in healthy, early postmenopausal women when a nutrient supplement (protein, carbohydrate, calcium, and vitamin D) or a placebo supplement (a minimum of energy) was ingested immediately following each training session. At inclusion, each woman was randomly and double-blindedly assigned to a nutrient group or a placebo (control) group. Muscle hypertrophy was evaluated from biopsies, MRI, and dual-energy X-ray absorptiometry (DEXA) scans, and muscle strength was determined in a dynamometer. Bone mineral density (BMD) was measured using DEXA scans, and bone turnover was determined from serum osteocalcin and collagen type I cross-linked carboxyl terminal peptide. The nutrient group improved concentric and isokinetic (60 degrees /s) muscle strength from 6 to 24 wk by 9 +/- 3% (P < 0.01), whereas controls showed no change (1 +/- 2%, P > 0.05). Only the nutrient group improved lean body mass (P < 0.05) over the 24 wk. BMD responded similarly at the lumbar spine but changed differently in the two groups at the femoral neck (P < 0.05) [control: 0.943 +/- 0.028 to 0.930 +/- 0.024 g/mm(3) (-1.0 +/- 1.4%); nutrient group: 0.953 +/- 0.051 to 0.978 +/- 0.043 g/mm(3) (3.8 +/- 3.4%)] when adjusted for age, body mass index, and BMD at inclusion. Bone formation displayed an interaction (P < 0.05), mainly caused by increased osteocalcin at 24 wk in the nutrient group. In conclusion, we report that nutrient supplementation results in superior improvements in muscle mass, muscle strength, femoral neck BMD, and bone formation during 24 wk of strength training. The observed differences following such a short intervention emphasize the significance of postexercise nutrient supply on musculoskeletal maintenance.

Exercise therapy, patient education, and patellar taping in the treatment of adolescents with patellofemoral pain: a prospective pilot study with 6 months follow-up.

BACKGROUND: Patellofemoral pain (PFP) is the most common knee condition among adolescents, with a prevalence of 6-7% resulting in reduced function and quality of life. Exercise therapy is recommended for treating PFP, but has only been tested in older adolescents (15-19 years). This pilot study aimed to investigate the adherence to, and clinical effects of, exercise and patient education in young adolescents (12-16 years), with PFP. METHODS: Twenty adolescents (16 females) with PFP were recruited from a population-based cohort to undergo a 3-month multimodal intervention. This comprised of a 30-min patient education and group-based exercise therapy. Exercises included supervised lower extremity strength exercises three times per week, in addition to similar home-based strength exercises. Outcomes included a 7-point global rating of change scale (ranging from "completely recovered" to "worse than ever"), the Knee injury and Osteoarthritis Outcome Score (KOOS), physical activity scale (PAS), weekly sports participation and health-related quality of life measured by European Quality of Life 5 dimensions Youth (EQ-5DY) and isometric knee and hip muscle strength. Pain was measured on a visual analogue scale (VAS), and satisfaction treatment was measured on a five-point Likert scale ranging from "highly satisfied" to "not satisfied at all". These were collected at 3- and 6-month follow-ups. Adherence to supervised exercise was measured as session attendance, and adolescent self-reported adherence to home-based exercises. RESULTS: Adherence to the exercise therapy was poor, with adolescents participating in a median of 16 (IQR 5.5-25) out of 39 possible supervised training session. Five out of 18 adolescents had a successful outcome after both 3 and 6 months. There were no relevant changes in isometric muscle strength. CONCLUSION: This was the first study to investigate adherence to, and clinical effects of, exercise therapy and patient education in young adolescents with patellofemoral pain. Adherence to the exercise therapy was low with little to no clinical effects making a full clinical trial impractical. Future studies need to explore how an intervention can be successfully tailored to young adolescents with patellofemoral pain to obtain good adherence while improving pain and function.

Exercise-dependent IGF-I, IGFBPs, and type I collagen changes in human peritendinous connective tissue determined by microdialysis.

Microdialysis studies indicate that mechanical loading of human tendon during exercise elevates type I collagen production in tendon. However, the possibility that the insertion of microdialysis fibers per se may increase the local collagen production due to trauma has not been explored. Insulin-like growth factor I (IGF-I) and its binding proteins (IGFBPs), which are known to stimulate collagen production in animal tendons, may regulate the translation of mechanical loading to collagen synthesis. Systemic and tissue levels of IGF-I, IGFBP, and type I collagen metabolism markers [procollagen I COOH-terminal propeptide (PICP) and COOH-terminal telopeptide of type I collagen] were measured by microdialysis in peritendinous tissue of the human Achilles tendon in an exercise group (performing a 36-km run, n = 6) and a control group (no intervention, n = 6). An increase in local PICP concentration was seen in both groups after 72 h and stayed elevated in the exercise group at 96 h (P < 0.05). IGFBP-1 in both serum and dialysate increased in the exercise group immediately after exercise (P < 0.05), whereas IGFBP-3 decreased systemically (P < 0.05). Elevation of local IGFBP-4 was observed in both the control and exercise groups after 48 h (P < 0.05). Total IGF-I did not change in locally or systemically in either group. Our results indicate an increased local production of PICP in human peritendinous tissue in response to prolonged mechanical loading with part of the increase due to trauma from the sampling technique. Care must therefore be emphasized to minimize the numbers of insertions with microdialysis. We demonstrated an elevation of IGFBP-1 both systemically and peritendinously in response to prolonged acute exercise. The local increased collagen synthesis was preceded by an elevation of local concentration of IGFBP-4, suggesting that IGFBP-4 may have a key role in the IGF-axis effect on the human collagen synthesis in vivo.

Tendon collagen synthesis at rest and after exercise in women.

In general, there is a higher incidence of musculoskeletal injuries during physical activity in women than in men. We hypothesized that in women rates of tendon collagen synthesis would be lower than in men at rest and after exercise, especially in the later luteal phase when estrogen and progesterone concentrations are higher than the early follicular phase. We studied tendon collagen fractional synthesis rate (FSR) in 15 young, healthy female subjects in either the early follicular (n = 8) or the late luteal phase (n = 7) 72 h after an acute bout of one-legged exercise (60 min kicking at 67% workload maximum) (72 h) and compared the results with those previously obtained for men. Samples were taken from the patellar tendon in both the exercised and rested legs to determine collagen FSR by the incorporation of [15N]proline into tendon collagen hydroxyproline. There was no effect of menstrual phase on tendon collagen synthesis either at rest or after exercise. However, there was a significant difference between women and men at rest (women = 0.025 +/- 0.002%/h, men = 0.045 +/- 0.008%/h; P < 0.05) and 72 h after exercise (women = 0.027 +/- 0.005%/h; men = 0.058 +/- 0.008%/h). Furthermore, rest and 72-h tendon collagen synthesis were not different in women, whereas in men tendon collagen synthesis remained significantly elevated 72 h after exercise. It is concluded that both in the resting state and after exercise, tendon collagen FSR is lower in women than in men, which may contribute to a lower rate of tissue repair after exercise.

Expression of insulin-like growth factor I, insulin-like growth factor binding proteins, and collagen mRNA in mechanically loaded plantaris tendon.

Insulin-like growth factor I (IGF-I) is known to exert an anabolic effect on tendon fibroblast production of collagen. IGF-I's regulation is complex and involves six different IGF binding proteins (IGFBPs). Of these, IGFBP-4 and -5 could potentially influence the effect of IGF-I in the tendon because they both are produced in fibroblast; however, the response of IGFBP-4 and -5 to mechanical loading and their role in IGF-I regulation in tendinous tissue are unknown. A splice variant of IGF-I, mechano-growth factor (MGF) is upregulated and known to be important for adaptation in loaded muscle. However, it is not known whether MGF is expressed and upregulated in mechanically loaded tendon. This study examined the effect of mechanical load on tendon collagen mRNA in relation to changes in the IGF-I systems mRNA expression. Data were collected at 2, 4, 8 and 16 days after surgical removal of synergistic muscle to the plantaris muscle of the rat, thus increasing the load to plantaris muscle and tendon. Nearly a doubling of the tendon mass was observed after 16 days of loading. A rapid rise in tendon procollagen III mRNA was seen after 2 days whereas the increase in procollagen I mRNA was significant from day 8. MGF was expressed and upregulated in loaded tendon tissue with a faster response than IGF-I, which was increased from day 8. Finally, IGFBP-4 mRNA was increased with a time pattern similar to procollagen III, whereas IGFBP-5 decreased at day 8. In conclusion, loading of tendon tissue results in an upregulation of IGF-I, IGFBP-4, and procollagen and is associated with an increase in tendon mass. Also, MGF is expressed with an early upregulation in loaded tendon tissue. We suggest that the IGF-I system could be involved in collagen synthesis in tendon in response to mechanical loading.

Self-reported Recovery is Associated With Improvement in Localized Hyperalgesia Among Adolescent Females With Patellofemoral Pain: Results From a Cluster Randomized Trial.

OBJECTIVES: Adolescent females with patellofemoral pain (PFP) have localized (around the knee) and distal (tibialis anterior muscle) hyperalgesia assessed by decreased pressure pain thresholds (PPT). This may have implications for treating PFP as both localized and central pain mechanisms may contribute to the manifestations of pain. The objective of this study was to compare the change in localized and distal hyperalgesia among female adolescents with PFP deeming themselves recovered compared with those not recovered 3 months after patient education with or without exercise therapy. METHODS: This is an ancillary analysis of a cluster randomized controlled trial investigating the effect of patient education with or without exercise therapy on self-reported recovery in 121 adolescents with PFP. PPTs were measured at 4 sites around the knee and on tibialis anterior in a random subsample of 57 female adolescents. Changes in localized and distal hyperalgesia from baseline to follow-up were compared with self-reported recovery. Adolescents were categorized as recovered if they rated themselves as "completely recovered" or "strongly recovered" on a 7-point Likert scale. RESULTS: Thirty-nine adolescents (68%) were available for follow-up at 3 months and 10 adolescents reported being recovered. Recovered adolescents had a 68 kPa (95% CI, 1, 136; P=0.047) larger improvement in PPT around the knee and a 76 kPa (95% CI, -29, 181; P=0.16) nonsignificant improvement in PPT on the tibialis anterior compared with adolescents not recovered. CONCLUSIONS: Female adolescents with PFP who rated themselves as recovered had a larger reduction in localized hyperalgesia compared with those not recovered.

Is Knee Pain During Adolescence a Self-limiting Condition? Prognosis of Patellofemoral Pain and Other Types of Knee Pain.

BACKGROUND: The prevalence of adolescent knee pain is 33%, and patellofemoral pain (PFP) is the most common diagnosis with a nontraumatic onset. The 2-year prognosis of adolescent PFP compared with other types of knee pain is unknown. PURPOSE: To investigate the 2-year prognosis of knee pain among adolescents with and without a diagnosis of PFP. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: In 2011, a cohort of 2200 adolescents aged 15 to 19 years answered an online questionnaire on musculoskeletal pain. Of these, 504 reported knee pain, and 153 of these were clinically diagnosed with PFP. After 2 years, the 504 adolescents, as well as 252 randomly selected adolescents who did not report knee pain in 2011, were contacted again. Primary outcome at follow-up was the proportion of adolescents with knee pain during the last week prior to follow-up. RESULTS: Overall, 55.9% (95% CI, 50.8%-60.9%) of those reporting knee pain at baseline also reported pain 2 years later. Adolescents diagnosed with PFP had a 1.26 (95% CI, 1.05-1.50) higher relative risk (RR) of knee pain at follow-up compared with other types of knee pain. Adolescents with PFP were significantly more likely to reduce or stop sports participation compared with adolescents with other types of knee pain. Of those without knee pain at baseline, 12.8% (95% CI, 8.4%-17.2%) reported knee pain at follow-up in 2013. Adolescents with knee pain at baseline had a 4.51 (95% CI, 3.15-6.45) higher RR of knee pain at follow-up compared with adolescents without knee pain at baseline. CONCLUSION: Knee pain during adolescence, and PFP in particular, is in most cases present after 2 years and thus may not be self-limiting. A greater focus on early detection and prevention of knee pain during adolescence is needed.

Effect of exercise therapy on neuromuscular activity and knee strength in female adolescents with patellofemoral pain-An ancillary analysis of a cluster randomized trial.

BACKGROUND: Female adolescents with patellofemoral pain are characterized by altered neuromuscular knee control and reduced maximal quadriceps torque. The purpose of this study is to investigate whether exercise therapy and patient education are associated with larger improvements in neuromuscular knee control and maximal quadriceps torque compared with patient education alone. METHODS: This is an ancillary analysis of a cluster randomized controlled trial investigating the effect of patient education and exercise therapy on self-reported recovery in 121 adolescents with patellofemoral pain. A random subsample of 57 female adolescents was included and tested at baseline and after 3months. Neuromuscular control of the knee was quantified as the complexity of surface electromyography of the vastus lateralis and vastus medialis during stair descent. Secondary outcomes were complexity of knee flexion/extension kinematics and maximal quadriceps torque. FINDINGS: There was an 8-15% greater decrease in the complexity of surface electromyography suggesting an improvement in neuromuscular knee control among those randomized to exercise therapy (0.08