Blocking CCN2 Reduces Progression of Sensorimotor Declines and Fibrosis in a Rat Model of Chronic Repetitive Overuse.

Fibrosis may be a key factor in sensorimotor dysfunction in patients with chronic overuse-induced musculoskeletal disorders. Using a clinically relevant rodent model, in which performance of a high demand handle-pulling task induces tissue fibrosis and sensorimotor declines, we pharmacologically blocked cellular communication network factor 2 (CCN2; connective tissue growth factor) with the goal of reducing the progression of these changes. Young adult, female Sprague-Dawley rats were shaped to learn to pull at high force levels (10 min/day, 5 weeks), before performing a high repetition high force (HRHF) task for 3 weeks (2 h/day, 3 days/week). HRHF rats were untreated, or treated in task weeks 2 and 3 with a monoclonal antibody that blocks CCN2 (FG-3019), or a control immunoglobulin G (IgG). Control rats were untreated or received FG-3019, IgG, or vehicle (saline) injections. Mean task reach rate and grasp force were higher in 3-week HRHF + FG-3019 rats, compared with untreated HRHF rats. Grip strength declined while forepaw mechanical sensitivity increased in untreated HRHF rats, compared with controls; changes improved by FG-3019 treatment. The HRHF task increased collagen in multiple tissues (flexor digitorum muscles, nerves, and forepaw dermis), which was reduced with FG-3019 treatment. FG-3019 treatment also reduced HRHF-induced increases in CCN2 and transforming growth factor ß in muscles. In tendons, FG-3019 reduced HRHF-induced increases in CCN2, epitendon thickening, and cell proliferation. Our findings indicate that CCN2 is critical to the progression of chronic overuse-induced multi-tissue fibrosis and functional declines. FG-3019 treatment may be a novel therapeutic strategy for overuse-induced musculoskeletal disorders. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2004-2018, 2019.

Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review.

OBJECTIVE: To produce a best evidence synthesis of the clinical effects of topical glyceryl trinitrate (GTN) in the treatment of tendinopathies. DESIGN: A systematic review of published randomised controlled trials (RCTs) of the use of GTN in patients with tendinopathy. DATA SOURCES: MEDLINE, Embase, Scopus and CINAHL from database inception to January 2018. METHODS: We examined RCTs comparing the effects of topical GTN with either placebo or other treatments on tendinopathy. Overall quality of each eligible study was determined based on a combined assessment of internal validity, external validity and precision. The level of evidence for each assessed parameter was rated based on the system by van Tulder et al. RESULTS: A total of 10 eligible RCTs were identified including patients with tendinopathy of the rotator cuff (n=4), wrist extensors (n=3), Achilles (n=2) and patellar (n=1) tendons. For all tendinopathies, improvements in pain were significant when comparing GTN versus placebo in the short term (<8 weeks; poor evidence). Significant improvements in midterm outcomes for treatment with GTN versus placebo included the following: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence). Patients treated with topical GTN reported a higher incidence of headaches than those who received placebo (moderate evidence). CONCLUSIONS AND RELEVANCE: Treatment of tendinopathies with topical GTN for up to 6 months appears to be superior to placebo and may therefore be a useful adjunct to the treating healthcare professions.

Modulatory effects of taurine on metabolic and oxidative stress parameters in a mice model of muscle overuse.

OBJECTIVE: The aim of this study was to investigate the regulatory effects of taurine on the biochemical parameters of muscle injury by overuse. METHODS: Male Swiss mice were divided into four groups: control (Ctrl), overuse (Ov), taurine (Tau), and overuse plus taurine (OvTau). High-intensity exercise sessions were administered for 21 d with concomitant subcutaneous injections of taurine (150 mg/kg). The mice were then sacrificed. The quadriceps muscles were surgically removed for subsequent histologic analysis and evaluation of mitochondrial function, oxidative stress parameters, tissue repair, and DNA damage markers. RESULTS: The Ov group showed significant differences compared with the Ctrl group (all P <0.05). The fiber area decreased by 49.34%, whereas the centralized nuclei contents (Ctrl = 1.33%; Ov = 28.67%), membrane potential (Ctrlsuc = 179.05 arbitrary fluorescence units (AFUs), Ctrlsuc+ADP = 198.11 AFUs; Ovsuc = 482.95 AFUs, Ovsuc+ADP = 461.6 AFUs), complex I activity (Ctrl = 20.45 nmol ⋅ min ⋅ mg protein, Ov = 45.25 nmol ⋅ min ⋅ mg protein), hydrogen peroxide (Ctrlsuc = 1.08 relative fluorescence unit (RFU) ⋅ sec ⋅ mg protein, Ctrlsuc+ADP = 0.23 RFU ⋅ sec ⋅ mg protein; Ovsuc = 5.02 RFU ⋅ sec ⋅ mg protein, Ovsuc+ADP = 0.26 RFU ⋅ sec ⋅ mg protein) and malondialdehyde (Ctrl = 0.03 nmol ⋅ mg ⋅ protein, Ov = 0.06 nmol ⋅ mg ⋅ protein) levels, and DNA damage (Ctrlfreq = 7.17%, Ovfreq = 31.17%; Ctrlindex = 4.17, Ovindex = 72.5) were increased. Taurine administration reduced the number of centralized nuclei (OvTau = 5%), hydrogen peroxide levels (OvTausuc = 2.81 RFU ⋅ sec ⋅ mg protein, OvTaussuc+ADP = 1.54 RFU ⋅ sec ⋅ mg protein), membrane potential (OvTausuc = 220.18 AFUs, OvTaussuc+ADP = 235.28 AFUs), lipid peroxidation (OvTau = 0.02 nmol/mg protein), and DNA damage (OvTaufreq = 21.33%, OvTauindex = 47.83) and increased the fiber area by 54% (all P <0.05). CONCLUSION: Taken together, these data suggest that taurine supplementation modulates various cellular remodeling parameters after overuse-induced muscle damage, and that these positive effects may be related to its antioxidant capacity.

GABAB Receptor Agonist R-Baclofen Reverses Social Deficits and Reduces Repetitive Behavior in Two Mouse Models of Autism.

Autism spectrum disorder (ASD) is diagnosed by two core behavioral criteria, unusual reciprocal social interactions and communication, and stereotyped, repetitive behaviors with restricted interests. Excitatory/inhibitory imbalance is a prominent hypothesis for the etiology of autism. The selective GABAB receptor agonist R-baclofen previously reversed social deficits and reduced repetitive behaviors in a mouse model of Fragile X syndrome, and Arbaclofen improved some clinical symptoms in some Fragile X and ASD patients. To evaluate R-baclofen in a broader range of mouse models of ASD, we tested both the R-baclofen enantiomer and the less potent S-baclofen enantiomer in two inbred strains of mice that display low sociability and/or high repetitive or stereotyped behaviors. R-baclofen treatment reversed social approach deficits in BTBR T+ Itpr3tf/J (BTBR), reduced repetitive self-grooming and high marble burying scores in BTBR, and reduced stereotyped jumping in C58/J (C58), at nonsedating doses. S-baclofen produced minimal effects at the same doses. These findings encourage investigations of R-baclofen in other preclinical model systems. Additional clinical studies may be warranted to further evaluate the hypothesis that the GABAB receptor represents a promising pharmacological target for treating appropriately stratified subsets of individuals with ASD.

Astroglial glutamate transporter deficiency increases synaptic excitability and leads to pathological repetitive behaviors in mice.

An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette's syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST(CreERT2/+)/GLT1(flox/flox), iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.

Multidisciplinary management of Paget-Schroetter syndrome. A case series of eight patients.

Paget-Schroetter syndrome (PSS) in the context of upper extremity deep venous thrombosis (DVT) is an uncommon but potentially very serious condition affecting young, healthy adults, in which secondary post-thrombotic syndrome (PTS) can be a complication with major implications. The best treatment option remains controversial, with current guidelines recommending anticoagulation for at least 3 months. However, an incidence of PTS of approximately 50% after 6 months, 30% after 1 year and 25% after 2 years has been found using this therapeutic approach. Consequently, specialized units recommend local thrombolysis and early decompressive surgery. We describe a series of eight cases treated in this way. None of the patients showed signs of complications, and an early return to regular activities with no PTS was observed in 90% of cases.

Hypothenar hammer syndrome from ice hockey stick-handling.

Ulnar artery thrombosis and hypothenar hammer syndrome are rare vascular complications that could potentially occur with repeated blows or trauma to the hand. Although initially reported as an occupational hazard among laborers and craftsmen, it has been observed more recently among recreationalists and athletes. Until now, it has never been reported as a complication in ice hockey players. In this case report, a 26-year-old Canadian professional ice hockey player presented with acute dominant right hand paleness, coolness, and pain with hand use. The patient used a wooden hockey stick with a large knob of tape at the end of the handle, which he regularly gripped in the palm of his right hand to help with face-offs and general stick-handling. Sonographic evaluation demonstrated no arterial flow in the distal right ulnar artery distribution, and ulnar artery occlusion with no aneurysmal degeneration was confirmed by magnetic resonance angiogram. Intraarterial thrombolytic therapy was initiated, and subsequent serial angiograms demonstrated significant improvement in distal ulnar artery flow as well as recanalization of right hand deep palmar arch and digital arteries. The patient's symptoms resolved, and he was maintained on therapeutic anticoagulation for 3 months prior to returning to playing ice hockey professionally, but with a padded glove and no tape knob at the handle tip. This case highlights a unique presentation of hockey stick-handling causing ulnar artery thrombosis that was likely from repeated palmar hypothenar trauma. Appropriate diagnostic imaging, early intraarterial thrombolysis, and postoperative surveillance and follow-up were crucial for the successful outcome in this patient.

Overuse injuries of the lower extremity.

Overuse injuries are a common and important cause of morbidity in elite and recreational athletes. They are increasingly recognized in the sedentary population. This article reviews the major classes of overuse injuries of the lower extremity. The underlying pathologic condition is correlated with the imaging appearances, and the often variable relationship between the imaging appearances and patients' symptoms are reviewed. Attempts at imaged-based grading systems and the ability of imaging to predict patients' prognosis are considered. Image-guided injection therapy for tendinopathy is an important and rapidly changing area; the indications, risks, and potential benefits of these interventions are reviewed.

Effect of dehydroepiandrosterone administration on recovery from mix-type exercise training-induced muscle damage.

This study aimed to determine the role of DHEA-S in coping against the exercise training mixing aerobic and resistance components. During 5-day successive exercise training, 16 young male participants (19.2 ± 1.2 years) received either a placebo (flour capsule) or DHEA (100 mg/day) in a double-blinded and placebo-controlled design. Oral DHEA supplementation significantly increased circulating DHEA-S by 2.5-fold, but a protracted drop (~35 %) was observed from Day 3 during training. In the Placebo group, only a minimal DHEA-S reduction (~17 %) was observed. Changes in testosterone followed a similar pattern as DHEA-S. Muscle soreness was elevated significantly on Day 2 for both groups to a similar extent. Lower muscle soreness was observed in the DHEA-supplemented group on Day 3 and Day 6. In the Placebo group, training increased circulating creatine kinase (CK) levels by approximately ninefold, while only a threefold increase was observed in the DHEA-supplemented group. This mix-type exercise training improved glucose tolerance in both groups, while lowering the insulin response to the glucose challenge, but no difference between treatments was observed. Our results suggest that DHEA-S may play a role in protecting skeletal muscle from exercise training-induced muscle damage.

Ultrasound-guided injections of hyperosmolar dextrose for overuse patellar tendinopathy: a pilot study.

PURPOSE: To evaluate whether ultrasound-guided injection of hyperosmolar dextrose for treatment of patellar tendinopathy decreases pain scores and normalises the appearance of the patellar tendon on ultrasound. METHODS: Subjects were referred from primary care clinics and failed conservative treatment. Subjects received a diagnostic ultrasound examination, then ultrasound-guided injection of 25% dextrose with lidocaine into the area of tendinopathy until they were satisfied with treatment. The primary outcome measure was a three-part visual analogue scale (VAS; baseline and mean of 45 weeks after start of treatment) for pain at rest, activities of daily living (ADL) and during sport. Secondary outcomes included segmental ultrasound examinations assessing tendon hypoechogenicity (area and severity score), neovascularity (severity score) and the presence or absence of intratendinous tearing and calcification, irregularities of cortical bone and thickness. RESULTS: 47 consecutive referrals were included. Subjects received a mean of four (± 3) injection sessions. At mean 45 weeks post-enrollment, subjects reported a reduction in pain across the three VAS items (rest 38.4 ± 25-18.7 ± 18.4; ADL 51.1 ± 22.9-25.8 ± 20.1; sport 78.1 ± 15.7-38.8 ± 26.1; p<0.01). There was improvement in neovascularity following the dextrose injection. A significant correlation between hypoechogenicity severity scores and pain at follow-up is reported. CONCLUSION: There was a reduction in pain and an improvement in ultrasound appearance following ultrasound-guided dextrose injections for refractory patellar tendinopathy. An improved hypoechoic appearance of the tendon was associated with decreased pain scores, suggesting that dextrose injections may modify patellar tendinopathy at the tissue level and that fibrillar changes may play a role in tendon nociception.

Shockwave therapy for the treatment of chronic proximal hamstring tendinopathy in professional athletes.

BACKGROUND: Chronic proximal hamstring tendinopathy is an overuse syndrome that is usually managed by nonoperative methods. Shockwave therapy has proved to be effective in many tendinopathies. HYPOTHESIS: Shockwave therapy may be more effective than other nonoperative treatments for chronic proximal hamstring tendinopathy. STUDY DESIGN: Randomized controlled clinical study; Level of evidence, 1. METHODS: Forty professional athletes with chronic proximal hamstring tendinopathy were enrolled between February 1, 2004, and September 30, 2006. Patients were randomly assigned to receive either shockwave therapy, consisting of 2500 impulses per session at a 0.18 mJ/mm² energy flux density without anesthesia, for 4 weeks (SWT group, n = 20), or traditional conservative treatment consisting of nonsteroidal anti-inflammatory drugs, physiotherapy, and an exercise program for hamstring muscles (TCT group, n = 20). Patients were evaluated before treatment, and 1 week and 3, 6, and 12 months after the end of treatment. The visual analog scale (VAS) score for pain and Nirschl phase rating scale (NPRS) were used as primary outcome measures. RESULTS: The patients were observed for a mean of 10.7 months (range, 1-12 months). Six patients were lost to follow-up because they underwent a surgical intervention: 3 (all in TCT group) were lost at 3 months; 2 (1 in each group), at 6 months; and 1 (in the TCT group), at 12 months. Primary follow-up was at 3 months after the beginning of treatment. The VAS scores in the SWT and TCT groups were 7 points before treatment (P = .84), and 2 points and 5 points, respectively, 3 months after treatment (P < .001). The NPRS scores in the SWT and TCT groups were 5 points in either group before treatment (P = .48), and 2 points and 6 points, respectively, 3 months after treatment (P < .001). At 3 months after treatment, 17 of the 20 patients (85%) in the SWT group and 2 of the 20 patients (10%) in the TCT group achieved a reduction of at least 50% in pain (P < .001). There were no serious complications in the SWT group. CONCLUSION: Shockwave therapy is a safe and effective treatment for patients with chronic proximal hamstring tendinopathy.

Suprascapular nerve entrapment in a patient with a spinal cord injury.

STUDY DESIGN: Case report. OBJECTIVES: To describe a case of suprascapular nerve entrapment (SNE) in a patient with a spinal cord injury (SCI) as a cause of shoulder pain. SETTING: Physical Medicine and Rehabilitation Institute, Nancy, France. REPORT: Six months after the occurrence of acute paraplegia T9 ASIA, a 45-year-old man complained of pain in the posterior and lateral areas of the left shoulder. A clinical assessment found an atrophy of the infraspinatus muscle and a muscular weakness during external shoulder rotation. SNE was suggested as a cause of pain and confirmed by nerve conduction recording. Magnetic resonance imaging excluded any compressive cyst. SNE at the spinoglenoid notch, related to upper limb overuse, was suggested. A gluco-corticoid injection in the proximity of the suprascapular nerve eliminated the pain in a few hours. Two months after the injection, the pain had not reappeared, the infraspinatus muscle atrophy was resolved, and supraspinal nerve conduction was normalized. CONCLUSION: Shoulder pain is common in individuals with paraplegia, but this is the first time that SNE has been reported as a cause of pain. This micro-traumatic pathology, well known in athletes, is probably under-diagnosed in patients with SCI who overuse their upper limbs for wheelchair propulsion and body transfers.

Tenosynovitis caused by texting: an emerging disease.

De Quervain tenosynovitis is characterized by pain that overlies the radial aspect of the wrist and that is aggravated by ulnar deviation of the hand. The most common cause of de Quervain tenosynovitis is overuse of the thumb musculature. The authors report a case of bilateral de Quervain tenosynovitis observed in a woman aged 48 years at a rural outpatient primary care office. The condition was induced by the patient's excessive use of the text messaging feature on her cellular telephone. Treatment, including naproxen, cock-up wrist splints, and limitation of texting, resulted in complete recovery of the patient. The authors urge physicians to be aware of the potential association between a patient's tenosynovitis symptoms and excessive texting.

Analgesics and anti-inflammatory medications in sports: use and abuse.

Both acute and overuse musculoskeletal injuries are common in adolescent athletes. Pharmacologic agents including nonsteroidal anti-inflammatory drugs, acetaminophen, and topical over-the-counter agents have been shown to be effective in controlling pain, but data regarding their efficacy in expediting healing and time to recovery continue to be debated. Studies indicate that adolescents consume analgesic agents on their own and may be unaware of their potential toxicities. Data also indicate that adolescent athletes use medications in hopes of alleviating pain and allowing continuation of sports without adequate time for healing. This article reviews the mechanisms, toxicity, drug interactions, efficacy, and abuse potential of commonly used analgesic and anti-inflammatory drugs.

Low-dose amitriptyline for treatment of persistent arm pain due to repetitive use.

Amitriptyline is sometimes used to treat arm pain related to repetitive use, but rigorous evidence of its benefit is lacking. This randomized controlled trial investigated whether amitriptyline provided greater pain relief or improved arm function than a placebo pill in adults with arm pain associated with repetitive use that had persisted for at least 3 months. Participants (N=118) were randomly assigned to receive 25mg of amitriptyline or a placebo pill for 6 weeks. The primary outcome was intensity of pain (10-point numerical rating scale) and secondary outcomes were arm symptoms, arm function, grip strength, mood, and sleep. Assessments were done at baseline, 3 and 6 weeks of treatment, and 1 month after the treatment ended. Changes in arm pain were not statistically significant. However, the amitriptyline group improved more than the placebo group in arm function (p=0.023) and sense of well being (p=0.034). In a longitudinal analysis, the amitriptyline group's arm function score improved 0.45 points per week faster than placebo after adjusting for subject characteristics (p=0.015). At the treatment's midpoint, the amitriptyline group reported more "troublesome side-effects" than the placebo group (52.5% vs. 27.1%, p=0.005), but this difference decreased by the end of the treatment (30.5% vs. 22.0%, p=0.30). The most frequent side effect was drowsiness. In conclusion, this study found that low-dose amitriptyline did not significantly decrease arm pain among these participants but did significantly improve arm function and well being. Future research is needed to explore the effects of higher doses and longer duration of treatment.

Botulinum toxin injection to facilitate rehabilitation of muscle imbalance syndromes in sports medicine.

Intramuscular injection of Botulinum toxin to produce reduction of focal muscle overactivity, and localized muscle spasm, has been utilized therapeutically for almost two decades. Muscle overactivity in neurologically normal muscle, where an imbalance exists between a relatively overactive muscle and its less active synergist or antagonist, can inhibit control of the antagonist producing a functional muscle imbalance. This brief review provides an overview of the role of muscle imbalance in sports-related pain and dysfunction, and outlines the potential for intramuscular injection of Botulinum toxin to be used as an adjunct to specific muscle re-education and functional rehabilitation in this patient group. A comprehensive understanding of normal movement and the requirements of the sporting activity are essential to allow accurate diagnosis of abnormal motor patterns and to re-educate more appropriate movement strategies. Therapeutic management of co-impairments may include stretching of tight soft tissues, specific re-education aimed at isolation of the non-dominant weak muscles and improvement in their activation, 'unlearning' of faulty motor patterns, and eventual progression onto functional exercises to anticipate gradual return to sporting activity. Intramuscular injection of Botulinum toxin, in carefully selected cases, provides short term reduction of focal muscle overactivity, and may facilitate activation of relatively 'inhibited' muscles and assist the restoration of more appropriate motor patterns.