Trends in Serum Cytokine Expression in Pediatric Skeletal Dysplasia.

The skeletal dysplasias are a heterogeneous group of genetic conditions caused by abnormalities of growth, development, and maintenance of bone and cartilage. Little is known about the roles that cytokines play in the inflammatory and non-inflammatory pathophysiology of skeletal dysplasia. We sought to test our hypothesis that cytokines would be differentially expressed in children with skeletal dysplasia as compared to typically growing controls. Cytokine levels were analyzed using the Cytokine Human Magnetic 25-Plex Panel (Invitrogen, Waltham, MA, USA); 136 growing individuals with skeletal dysplasia and compared to a cohort of 275 healthy pediatric control subjects. We focused on the expression of 12 cytokines across nine dysplasia cohorts. The most common skeletal dysplasia diagnoses were: achondroplasia (58), osteogenesis imperfecta (19), type II collagenopathies (11), multiple epiphyseal dysplasia (MED: 9), diastrophic dysplasia (8), metatropic dysplasia (8), and microcephalic osteodysplastic primordial dwarfism type II (MOPDII: 8). Of the 108 specific observations made, 45 (41.7%) demonstrated statistically significant differences of expression between controls and individuals with skeletal dysplasia. Four of the 12 analyzed cytokines demonstrated elevated expression above control levels in all of the dysplasia cohorts (interleukin 12 [IL-12], IL-13, interferon γ-induced protein 10 kDa [IP-10], regulated on activation, normal T cell expressed and secreted [RANTES]) and two demonstrated expression below control levels across all dysplasia cohorts (monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein-1ß [MIP-1ß]). The highest levels of overexpression were seen in MOPDII, with expression levels of IP-10 being increased 3.8-fold (p < 0.0001). The lowest statistically significant levels of expressions were in type II collagenopathies, with expression levels of MCP-1 being expressed 0.43-fold lower (p < 0.005). With this data, we hope to lay the groundwork for future directions in dysplasia research that will enhance our understanding of these complex signaling pathways. Looking forward, validating these early trends in cytokine expression, and associating the observed variations with trends in the progression of dysplasia may offer new candidates for clinical biomarkers or even new therapeutics. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Identification of potential non-invasive biomarkers in diastrophic dysplasia.

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification.

Collagen X Marker Levels are Decreased in Individuals with Achondroplasia.

Collagen X marker (CXM) is a degradation fragment of collagen type X. It is a real-time biomarker of height velocity with established norms. Plasma C-type natriuretic peptide (CNP) and NTproCNP levels have also been found to correlate with growth velocity in the general population and are elevated in individuals with achondroplasia compared with age- and sex-matched controls. Collagen X marker levels in people with fibroblast growth factor receptor 3 (FGFR3)-opathies have never been systematically measured. The objective of this study was to measure CXM in a population of dwarfism caused by FGFR3-opathies. Using the same cohort in which CNP and NTproCNP levels were previously measured, archived serum aliquots from 63 children with achondroplasia, six with hypochondroplasia, and two with thanatophoric dysplasia had CXM concentrations measured. Results were plotted against age- and sex-specific norms, and standard deviation scores were plotted for comparison between clinical diagnoses. CXM levels were significantly decreased (p < 0.0001) in children with achondroplasia compared with age- and sex-matched controls. Temporal patterns of change in CXM levels were sex-dependent. As the FGFR3 pathway was more constitutively active, CXM levels decreased. New tools are emerging to study impact of skeletal dysplasia on growth plate regulation and function.

Randomized Trial of General Strength and Conditioning Versus Motor Control and Manual Therapy for Chronic Low Back Pain on Physical and Self-Report Outcomes.

Exercise and spinal manipulative therapy are commonly used for the treatment of chronic low back pain (CLBP) in Australia. Reduction in pain intensity is a common outcome; however, it is only one measure of intervention efficacy in clinical practice. Therefore, we evaluated the effectiveness of two common clinical interventions on physical and self-report measures in CLBP. Participants were randomized to a 6­month intervention of general strength and conditioning (GSC; n = 20; up to 52 sessions) or motor control exercise plus manual therapy (MCMT; n =20; up to 12 sessions). Pain intensity was measured at baseline and fortnightly throughout the intervention. Trunk extension and flexion endurance, leg muscle strength and endurance, paraspinal muscle volume, cardio­respiratory fitness and self-report measures of kinesiophobia, disability and quality of life were assessed at baseline and 3- and 6-month follow-up. Pain intensity differed favoring MCMT between-groups at week 14 and 16 of treatment (both, p = 0.003), but not at 6-month follow­up. Both GSC (mean change (95%CI): -10.7 (-18.7, -2.8) mm; p = 0.008) and MCMT (-19.2 (-28.1, -10.3) mm; p < 0.001) had within-group reductions in pain intensity at six months, but did not achieve clinically meaningful thresholds (20mm) within- or between­group. At 6-month follow-up, GSC increased trunk extension (mean difference (95% CI): 81.8 (34.8, 128.8) s; p = 0.004) and flexion endurance (51.5 (20.5, 82.6) s; p = 0.004), as well as leg muscle strength (24.7 (3.4, 46.0) kg; p = 0.001) and endurance (9.1 (1.7, 16.4) reps; p = 0.015) compared to MCMT. GSC reduced disability (-5.7 (­11.2, -0.2) pts; p = 0.041) and kinesiophobia (-6.6 (-9.9, -3.2) pts; p < 0.001) compared to MCMT at 6­month follow-up. Multifidus volume increased within-group for GSC (p = 0.003), but not MCMT or between-groups. No other between-group changes were observed at six months. Overall, GSC improved trunk endurance, leg muscle strength and endurance, self-report disability and kinesiophobia compared to MCMT at six months. These results show that GSC may provide a more diverse range of treatment effects compared to MCMT.

MRI findings are associated with time to return to play in first class cricket fast bowlers with side strain in Australia and England.

OBJECTIVES: To investigate the reliability of reporting and relationship between MRI parameters at injury and time to return to play (RTP) in first class cricket fast bowlers with side strain in Australia and England. DESIGN: Cohort study. METHODS: Eighty MRI scans of side strain injuries to 57 fast bowlers were sourced. Ten scans were reported by three experienced radiologists to determine intra- and inter-rater reliability. The relationship between six MRI parameters (muscle injured, presence of a muscle tear, rib level of injury, presence of blood fluid products/haematoma, periosteal stripping, rib oedema) and time to RTP was investigated with 39 scans reported by a single radiologist with known intra-rater reliability. The association between parameters and time to RTP was analysed with an ordinal logistic regression model. RESULTS: Recovery time was prolonged with a mean of 39days (standard deviation: 14days) and 44% of bowlers requiring more than 6weeks to RTP. Reliability levels between parameters varied widely. The presence or absence of a muscle tear was the only MRI parameter associated with time to RTP. Players with a muscle tear were 8 times more likely to take more than 6weeks to RTP. The multifactorial model was predictive of recovery time in only 53% of this cohort, leaving 47% of total variance in time to RTP unexplained. CONCLUSIONS: The presence of a muscle tear was associated with time to RTP in cricket fast bowlers with side strain injury in first class cricket in Australia and England.

Ultrasound-Guided Radiofrequency Denervation of the Medial Calcaneal Nerve.

OBJECTIVE: Plantar fasciosis is a common complaint of athletes, particularly for runners. The medial calcaneal nerve (MCN) may play a role in the pain syndrome, and radiofrequency (RF) denervation has been previously reported. The hypothesis is that ultrasound-guided denervation of the MCN results in symptomatic improvement. DESIGN: Retrospective cohort. SETTING: Private practice. PATIENTS: Twenty-nine patients previously receiving ultrasound-guided RF denervation of the MCN, having failed conservative therapy, were assessed in 2 groups, those more than (group 1, n = 16) or less than (group 2, n = 13) 6 months since the procedure. INTERVENTIONS: Ultrasound-guided RF denervation of the MCN. MAIN OUTCOME MEASURES: Pain scores before denervation, as well as at maximal pain relief and the time of the interview. Levels of satisfaction and attitudes toward surgery were also assessed. RESULTS: Pain scores decreased significantly in both groups, for both best and residual pain scores. Group 1 mean pain scores were 8.56 before procedure, 2.81 (P < 0.001 compared to baseline) at best pain score, and 3.75 (P < 0.01) residual pain score. Group 2 mean pain scores were 7.23 before procedure, 3.77 (P < 0.01) at best pain score and 4.92 (P < 0.01) residual pain score. Levels of satisfaction were predominantly positive (69% of group 1% and 54% of group 2 were either somewhat or very satisfied), with attitudes toward surgery unchanged. CONCLUSIONS: For patients with refractory plantar heel pain, ultrasound-guided denervation of the MCN can potentially improve symptoms, although efficacy needs assessing in comparative studies. CLINICAL RELEVANCE: Ultrasound-guided denervation of the MCN provides a further management option for patients with refractory plantar fasciosis.

Normative MRI, ultrasound and muscle functional MRI findings in the forearms of asymptomatic elite rowers.

OBJECTIVES: Forearm injuries are common and debilitating to elite rowers. Chronic exertional compartment syndrome, intersection syndrome and proximal radial bone stress injuries have been documented in this population. This paper explores the imaging findings related to these conditions in asymptomatic elite rowers. DESIGN: Observational study. METHODS: 19 asymptomatic senior elite and under-23 rowers currently competing at National level or above underwent ultrasound (US), Magnetic Resonance Imaging (MRI) and muscle functional MRI evaluation of their forearms. A comprehensive evaluation sheet identifying characteristics of bone stress, intersection syndrome and chronic exertional compartment syndrome was utilised based on a literature search and review by senior clinicians working with this population. RESULTS: Peritendinous fluid of Extensor Carpi Radialis Longus (n=10, 53%) or Extensor Carpi Radialis Brevis (n=6, 32%) was a common finding on US. MRI had a higher rate of identification than US. Extensor Digitorum (Coeff=-1.76, 95%CI -3.04 to -0.49), Flexor Carpi Radialis (Coeff=-2.86, 95%CI -5.35 to -0.38) and Flexor Carpi Ulnaris (Coeff=-3.31, 95%CI -5.30 to -1.32), Pronator Teres (Coeff=-3.94, 95%CI -6.89 to -0.99), and Supinator (Coeff=-168, 95%CI -3.28 to -0.02) showed statistically significant changes immediately post-exercise. Mild proximal radial marrow hyperintensity was present (n=15, 78.9%) with three participants (15.8%) also having mild periosteal oedema of the radius. CONCLUSIONS: Imaging findings commonly seen in symptomatic populations are observed in elite, asymptomatic rowers. Care should be taken when diagnosing bone stress injuries, intersection syndrome and compartment syndrome on imaging findings alone. Data presented can be utilised as a normative dataset for future case studies.

Cell therapy in joint disorders.

CONTEXT: Articular cartilage possesses poor natural healing mechanisms, and a variety of non-cell-based and cell-based treatments aim to promote regeneration of hyaline cartilage. DATA SOURCES: A review of the literature to December 2013 using PubMed with search criteria including the keywords stem cell, cell therapy, cell transplantation, cartilage, chondral, and chondrogenic. STUDY SELECTION: Forty-five articles were identified that employed local mesenchymal stem cell (MSC) therapy for joint disorders in humans. Nine comparative studies were identified, consisting of 3 randomized trials, 5 cohort studies, and 1 case-control study. STUDY TYPE: Clinical review. LEVEL OF EVIDENCE: Level 4. DATA EXTRACTION: Studies were assessed for stem cell source, method of implantation, comparison groups, and concurrent surgical techniques. RESULTS: Two studies comparing MSC treatment to autologous chondrocyte implantation found similar efficacy. Three studies reported clinical benefits with intra-articular MSC injection over non-MSC controls for cases undergoing debridement with or without marrow stimulation, although a randomized study found no significant clinical difference at 2-year follow-up but reported better 18-month magnetic resonance imaging and histologic scores in the MSC group. No human studies have compared intra-articular MSC therapy to non-MSC techniques for osteoarthritis in the absence of surgery. CONCLUSION: Mesenchymal stem cell-based therapies appear safe and effective for joint disorders in large animal preclinical models. Evidence for use in humans, particularly, comparison with more established treatments such as autologous chondrocyte implantation and microfracture, is limited.

Ultrasound-guided radiofrequency ablation in the management of interdigital (Morton's) neuroma.

OBJECTIVE: To identify the benefits of ultrasound-guided radiofrequency ablation of Morton's neuroma as an alternative to surgical excision. MATERIALS AND METHODS: We studied a consecutive cohort of surgical candidates for Morton's neurectomy who we referred, instead, for radiofrequency ablation (RFA). Under local anaesthetic, RFA was performed under ultrasound guidance, by a single radiologist. This out-patient procedure was repeated after 4 weeks if necessary. We followed patients for a minimum of 6 months to assess their change in visual analogue pain scores (VAS), symptom improvement, complications and progression to surgical excision. RESULTS: Thirty feet in 25 patients were studied. There were 4 men and 21 women with an average age of 55 years (range 33-73 years). All had tried previous methods of conservative management. Forty percent presented with 2nd space neuromas and 60% with 3rd space ones. The average number of treatment sessions was 1.6 (range 1-3, mode 1). Prior to treatment, all patients had pain on activity (VAS average: 6.0, range 3-9). Post-treatment there was a statistically significant reduction in pain scores (post-RFA VAS average: 1.7, range 0-8, p < 0.001). The average overall symptom improvement was 76%. There was one minor complication of temporary nerve irritation. Three neuromas (10%) have progressed to surgical excision; 1 patient has ongoing, unchanged pain with no obvious cause. At 6 months, 26 out of 30 feet had a satisfactory outcome. CONCLUSION: Ultrasound-guided RFA has successfully alleviated patients' symptoms of Morton's neuroma in >85% of cases. Only 10% have proceeded to surgical excision in the short term.

Medium to long-term results of the UNIX uncemented unicompartmental knee replacement.

INTRODUCTION: We report the first non-designer study of the Unix uncemented unicompartmental knee prosthesis. MATERIALS AND METHODS: Eighty-five consecutive UKRs were carried out with sixty-five available for follow-up. Oxford Knee Scores, WOMAC questionnaire and radiological assessment were completed. RESULTS: The mean Oxford Knee Score was thirty-eight and WOMAC Score was twenty. Overall Kaplan Meier survival estimate is 76% (95% confidence interval 60%-97%) at 12years and 88% (95% confidence interval 76-100%) with aseptic loosening as the endpoint. Radiographic assessment showed lysis in the tibia in 6% of patients with no lysis evident around the central fin. DISCUSSION: Survivorship is comparable to other published series of UKRs. We suggest the central fin design is key to dissipating large forces throughout the proximal tibia, resulting in low levels of tibial loosening. Level of evidence IV.

Neurological complications of foot and ankle surgery.

Postoperative neurological complications following foot and ankle surgery are common. This article reviews the structural architecture of peripheral nerves and innervation patterns around the foot and ankle; describes the pathophysiology of surgery-related nerve injury; and illustrates the postoperative neurological complications using specific case examples.

Skin-derived tenocyte-like cells for the treatment of patellar tendinopathy.

BACKGROUND: Recent research of lateral elbow tendinopathy has led to the use of laboratory-amplified tenocyte-like cells. HYPOTHESIS: Ultrasound-guided injection of autologous skin-derived tendon-like cells are effective compared with other injectable therapies for the treatment of refractory patellar tendinosis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: From 60 patellar tendons in 46 patients with refractory patellar tendinopathy, a 4-mm skin biopsy was sampled to grow tenocyte-like collagen-producing cells. Patients were allocated into 2 groups: (1) injection with laboratory-prepared, amplified collagen-producing cells derived from dermal fibroblasts and suspended in autologous plasma from centrifuged autologous whole blood or (2) injection with autologous plasma alone. Injections were made into the sites of hypoechogenicity, intrasubstance tears, and fibrillar discontinuity within the patellar tendon. The Victorian Institute of Sport Assessment (VISA) score was used to assess pain, severity, and functional disability. Ultrasound was performed to assess structural and blood flow changes, evaluating 4 criteria: tendon thickness, hypoechogenicity, intrasubstance tears, and neovascularity. RESULTS: In the cell group, mean VISA scores improved from 44 ± 15 before treatment to 75 ± 17 at 6 months; in the plasma group, from 50 ± 18 to 70 ± 14. Estimated average difference between groups was 8.1, a significantly higher score in the cell group. Patients treated with collagen-producing cells also had significantly faster improvement and a highly significant effect of treatment, with the difference between groups estimated as 2.5 per unit increase in 1/√time. One patient treated with cell therapy had a late rupture and progressed to surgery; histopathology showed normal tendon structure. CONCLUSION: Ultrasound-guided injection of autologous skin-derived tendon-like cells can be safely used in the short term to treat patellar tendinopathy, with faster response of treatment and significantly greater improvement in pain and function than with plasma alone.

The Achilles tendon.

Achilles tendon disorders are among the most common conditions seen by sports medicine physicians. The request for radiological assessment and for radiologically assisted therapy is on the steady increase. Thus understanding the anatomy and biomechanics of the Achilles tendon is crucial to the effective radiological diagnosis and thus the management of such conditions.

Skeletal muscle: functional anatomy and pathophysiology.

Muscle is generally divided into three subtypes-skeletal, cardiac, and smooth-but because this edition focuses on the musculoskeletal system, this article concentrates on skeletal muscle. We review ultrastructure and function and then look at the latest scientific ideas concerning the physiological basis of muscle contraction. It is important to appreciate the different muscle types and how they act with respect to muscle growth and adaptation. Finally, what happens to muscle cells when they are damaged and the reparative response is considered.

Lateral elbow tendinopathy: correlation of ultrasound findings with pain and functional disability.

BACKGROUND: Lateral elbow tendinopathy is a common condition often diagnosed by ultrasound. Debate exists regarding which ultrasound findings correlate with disease severity and prognosis. HYPOTHESIS: Sonographic predictors for tendon healing in patients with lateral elbow tendinopathy can be found by correlating initial ultrasound findings with subsequent changes in pain and functional disability scores after a period of nonoperative management. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Sixty-two elbows (34 right, 28 left) in 62 patients (30 male, 32 female) with a clinical diagnosis of lateral elbow tendinopathy underwent sonographic evaluation of the common extensor origin after assessment with a validated outcome measure, the Patient-Rated Tennis Elbow Evaluation (PRTEE). After 6 months of nonoperative standardized treatment (physiotherapy with eccentric loading), the PRTEE questionnaire was repeated. RESULTS: The mean pretreatment PRTEE was 78 (range, 51-97) and posttreatment score was 29 (range, 0-91). This difference in means was found to be significant (P < .0001). A positive correlation was identified between the presence of a lateral collateral ligament tear (P < .0001) and the size of the largest intrasubstance tear (P < .0001) and poor outcome. A negative correlation was identified with amount of hypoechogenicity (P = .0009). No correlation was found with age, sex, side, duration of symptoms, thickness of tendon, or amount of neovascularity. CONCLUSION: The size of intrasubstance tears and presence of a lateral collateral ligament tear on ultrasound can be used to assess lateral elbow tendinopathy severity, indicate those who may not respond to nonoperative therapy, and potentially guide more invasive treatment. Those patients with a large intrasubstance tear or tears identified on ultrasound are less likely to respond to nonoperative treatment. Presence of neovascularity has little correlation with change in pain severity or functional disability and may be a poor predictor of prognosis.

Review: imaging of groin pain in the athlete.

Chronic groin pain is a common entity in the sporting population and causes considerable morbidity. The differential diagnosis is wide, and this article presents a review of the common causes with particular reference to anatomy, ultrasound and magnetic resonance imaging (MRI) findings.

Os peroneum friction syndrome complicated by sesamoid fatigue fracture: a new radiological diagnosis? Case report and literature review.

Injuries to the peroneal tendons are relatively common worldwide but tendon rupture without significant trauma is uncommon. Ankle mechanics can be seriously affected by disruption of one or both of the peroneal tendons although complete rupture can also remain asymptomatic. Accessory ossicles are sesamoid bones and are common findings in routine radiology of the foot and ankle. Although in the vast majority these "os" are normal variants of anatomy, they can lead to painful syndromes and suffer fractures and even undergo degenerative changes in response to overuse and trauma. Although similar syndromes have been discussed in the surgical literature, there is a lack of literature describing the use of modern imaging in the accurate diagnosis and its subsequent assistance towards appropriate management of os peroneum friction syndrome complicated by sesamoid fatigue syndrome. This article presents the plain film, sonographic and magnetic resonance imaging findings in a case of os peroneum friction syndrome complicated by a sesamoid fatigue fracture as well as reviewing the pertinent literature.

Imaging of entrapment and compressive neuropathies.

Although the subject of entrapment and compressive neuropathies is huge, with dedicated textbooks on the subject, this article attempts to provide an up-to-date overview of the role of imaging in the diagnosis of nerve entrapment and compression syndromes. Entrapment and compressive neuropathies are a group of distinct syndromes secondary to physical constriction or irritation affecting peripheral nerves at specific anatomical sites in the body. Most nerve entrapment and compressive syndromes derive from an injury to the neurovascular components in a narrow anatomical passage. Because of their etiological diversity, which includes pressure, angulation, stretch, and friction, the pathophysiology of individual nerve entrapment syndromes differs widely. Neuropathy can result in considerable morbidity. Although the mainstay of achieving diagnosis is with clinical acumen and electrophysiological investigations, the increasing use of modern high-resolution imaging studies is of particular value in confirming physical findings and enabling determination of the extent of injury. Knowledge and familiarity of pertinent anatomy and appropriate choice of imaging modality is important for the radiologist to allow accurate interpretation of site and etiology of nerve entrapment and compression as well as ascertaining possible alternative diagnoses.

Treatment of Morton's neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases.

OBJECTIVE: Morton's neuroma is a common cause of forefoot pain. For this study, we assessed the efficacy of a series of sonographically guided alcohol injections into the lesion. SUBJECTS AND METHODS: One hundred one consecutive patients with Morton's neuroma were included in this prospective series. An average of 4.1 treatments per person were administered, and follow-up images were obtained at a mean of 21.1 months after the last treatment (range, 13-34 months). RESULTS: Technical success was 100%. Partial or total symptom improvement was reported by 94% of the patients, with 84% becoming totally pain-free. The median visual assessed pain score decreased from 8 before treatment to 0 after treatment (p < 0.001). Transitory increased local pain occurred in 17 cases (16.8%). There were no major complications. Thirty patients underwent sonography at 6 months after the last injection and showed a 30% decrease in the size of the neuroma. CONCLUSION: We conclude that alcohol injection of Morton's neuroma has a high success rate and is well tolerated. The results are at least comparable to surgery, but alcohol injection is associated with less morbidity and surgical management may be reserved for nonresponders.