Prospects and challenges of tissue-derived extracellular vesicles.

Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membraned nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit functional responses in recipient cells. To date, studies have often utilized cultured cells or biological fluids as a source for EVs that do not capture local molecular signatures of the tissue microenvironment. Recent work utilizing Ti-EVs has elucidated novel biomarkers for disease and provided insights into disease mechanisms that may lead to the development of novel therapeutic agents. Still, there are considerable challenges facing current studies. This review explores the vast potential and unique challenges for Ti-EV research and provides considerations for future studies that seek to advance this exciting field.

NKCC1 in Neonatal Cochlear Support Cells Reloads Ions Necessary for Cochlear Spontaneous Activity.

In the auditory system, the spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from inner supporting cells (ISCs). This ATP release sets off a cascade, activating purinergic autoreceptors, opening of Ca2+-activated Cl- channel TMEM16A, Cl- efflux and osmotic cell shrinkage. Then, the shrunken ISCs efficiently regain their original volume, suggesting the existence of mechanisms for refilling Cland K+, priming them for subsequent activity. This study explores the potential involvement of NKCCs (Na+-K+-Cl- cotransporters) and KCCs (K+-Cl- cotransporters) in ISC spontaneous activity, considering their capability to transport both Cl- and K+ ions across the cell membrane. Employing a combination of immunohistochemistry, pharmacological interventions, and shRNA experiment, we unveiled the pivotal role of NKCC1 in cochlear spontaneous activity. Immunohistochemistry revealed robust NKCC1 expression in ISCs, persisting until the 2nd postnatal week. Intriguingly, we observed a developmental shift in NKCC1 expression from ISCs to synaptophysin-positive efferent terminals at postnatal day 18, hinting at its potential involvement in modulating synaptic transmission during the post-hearing period. Experiments using bumetanide, a well-known NKCC inhibitor, supported the functional significance of NKCC1 in ISC spontaneous activity. Bumetanide significantly reduced the frequency of spontaneous extracellular potentials (sEP) and spontaneous optical changes (sOCs) in ISCs. NKCC1-shRNA experiments conducted in cultured cochlear tissues further supported these findings, demonstrating a substantial decrease in event frequency and area. Taken together, we revealed the role of NKCC1 in shaping the ISC spontaneous activity that govern auditory pathway development.

T1-VIBE and STIR MRI of lumbar pars interarticularis injuries in elite athletes: fracture characterisation and potential prognostic indicators.

OBJECTIVES: To assess how pars interarticularis fracture characteristics on T1-VIBE and STIR MRI relate to healing and identify anatomical parameters that may impact healing. MATERIALS AND METHODS: A retrospective review of an MRI series of lumbar pars interarticularis injuries in elite athletes over a 3-year period. Fracture configurations, signal intensities and anatomical parameters were recorded by two radiologists. Statistical analysis employed multilevel mixed-effects linear regressions, adjusted for repeated measures and baseline covariates. RESULTS: Forty-seven lumbar pars interarticularis injuries among 31 athletes were assessed. On final scans for each athlete, 15% (7/47) injuries had worsened, 23% (11/47) remained stable, 43% (20/47) partially healed and 19% (9/47) healed completely. Healing times varied, quickest was 49 days for a chronic fracture in a footballer. Bone marrow oedema signal was highest in worsened fractures, followed by improved, and lowest in stable fractures. As healing progressed, T1-VIBE signal at the fracture line decreased. Bone marrow oedema and fracture line signal peaked at 90-120 days before decreasing until 210-240 days. Fractures with smaller dimensions, more vertical orientation and a longer superior articular facet beneath were significantly associated with better healing (p < 0.05). CONCLUSION: Most diagnosed athletic pars interarticularis injuries improve. Normalising T1-VIBE signal at the fracture line is a novel measurable indicator of bony healing. Contrastingly, bone marrow oedema signal is higher in active fractures irrespective of healing or deterioration. Injuries initially perceived as worsening may be exhibiting the normal osteoclastic phase of healing. Better outcomes favour smaller, vertical fractures with a longer superior articular facet beneath.

Individual fascicles of the ankle lateral ligaments and the lateral fibulotalocalcaneal ligament complex can be identified on 3D volumetric MRI.

PURPOSE: Lateral ligament ankle sprains are common and the anatomy on imaging studies is vital for accurate diagnosis. The lateral fibulotalocalcaneal ligament (LFTCL) complex consists of the inferior fascicle of the anterior talofibular ligament (ATFL) which is connected by arciform fibres with the calcaneofibular ligament (CFL). The superior fascicle of ATFL is an independent structure that should be assessed individually. MRI evaluation of these distinct fascicles and the arciform fibres has not been described. The aim of this study is to identify the anatomical relationship of these components of the LFTCL complex in healthy individuals on MRI. METHODS: Thirty ankles from healthy volunteers were imaged using 3D volumetric MRI. The ATFL fascicles and size were evaluated. Presence of arciform fibres connecting the inferior ATFL fascicle and CFL to form the LFTCL complex and anatomical relationship around the lateral ligament complex were assessed. RESULTS: Both the superior and inferior ATFL fascicles were observed in 26 (86.7%) ankles. The superior ATFL fascicle was significantly larger in all specimens (39% longer and 80.7% wider). For the specimens with a single fascicle, this was similar in size to the superior fascicle observed in the other 26 specimens. These measurements were not affected by age or gender. Arciform fibres of the LFTCL complex were identified in 22 (84.6%) specimens with two ATFL fascicles and three (75%) ankles with a single ATFL fascicle. Connecting fibres from the ATFL to PTFL were observed in 19 (63.3%) ankles while connections between the CFL and PTFL were identified in 21 (70%) ankles. Five ankles had a perforating artery visualized in the intervening space between the superior and inferior ATFL fascicles (a branch of the lateral tarsal artery of the dorsalis pedis artery). CONCLUSION: Two distinct ATFL fascicles may be identified in the majority of ankles on MRI. Isolated injury to the superior fascicle identified on MRI may be useful when diagnosing patients presenting with symptoms of subtle instability without overt ankle laxity on clinical examination. The current study is the first to identify the arciform fibres of the LFTCL complex supporting isolated ATFL repair in the presence of intact LFTCL complex. LEVEL OF EVIDENCE: Level III.

Rupture of the peroneus quartus tendon in a professional rugby player.

The peroneus quartus is one of a variety of described accessory peroneal muscles, most commonly an incidental finding on MRI or ultrasound of the ankle. We present the only described case in the literature of a peroneus quartus tendon rupture in a professional rugby player as well as the MRI findings.

Image guided injection therapies in athletes-Do they work and what should we be using?

In the modern management of the injured elite athlete, the goals of guided injection therapies have extended beyond simple reduction of pain to enhancement of tissue healing and accelerated return to competition, faster than natural healing can allow. This article will review the injection therapies which are frequently used in elite sports injury management and describe other less commonly used injection therapies that are available to the treating clinician and athlete. The evidence base, where available, for each treatment option will be summarised.

Percutaneous Release Procedures: Trigger Finger and Carpal Tunnel.

Trigger digit and carpal tunnel syndrome are both conditions traditionally treated with open surgery but are potentially amenable to curative treatment using percutaneous techniques. The advantages of minimally invasive techniques are lower risk of wound breakdown and infection, quicker healing, reduced postprocedural pain, reduced complications, and a quicker return to normal activity. The advent of high-resolution ultrasound has allowed percutaneous release procedures for these conditions to be developed and performed with a potential for a reduced risk of complications and an increased likelihood of success. This article reviews the literature as well as our institutional experience in performing ultrasound-guided percutaneous release for trigger digit and carpal tunnel syndrome.

MRI findings and return to play in football: a prospective analysis of 255 hamstring injuries in the UEFA Elite Club Injury Study.

AIM: The present study evaluated whether the MRI parameters of hamstring injuries in male professional football players correlate with time to return to play (RTP). METHODS: 46 elite European football teams were followed prospectively for hamstring injuries between 2007 and 2014. Club medical staff recorded individual player exposure and time-loss after hamstring injury. MRI parameters were evaluated by two independent radiologists and correlated with the RTP data. RESULTS: A total of 255 grade 1 and 2 injuries were evaluated in this study. RTP was longer for grade 2 than grade 1 injuries (24±13, 95% CI 21 to 26 days vs 18±15, 95% CI 16 to 20 days; mean difference: 6, 95% CI 2 to 9 days, p=0.004, d=0.39). 84% of injuries affected the biceps femoris (BF) muscle, whereas 12% and 4% affected the semimembranosus (SM) and semitendinosus (ST), respectively. No difference in lay-off time was found for injuries to the three different muscles (BF 20±15 days, SM 18±11 days, ST 23±14 days; p=0.83). The recurrence rate was higher for BF injuries than for SM and ST injuries combined (18% vs 2%, p=0.009). The size of the oedema weakly correlated with time to RTP (r(2)=6-12%). No correlation was found between location of injury and time to RTP. The majority of the intramuscular injuries affected the MT junction (56% in grade 1 and 2 injuries), but no difference in lay-off time was found between the different types of injuries. CONCLUSIONS: The radiological grade and size of the oedema correlate with time to RTP for both, grade 1 and 2 injuries. No correlations were found between time to RTP and the location and type of injury.

The Use of Sonographically Guided Botulinum Toxin Type A (Dysport) Injections Into the Tensor Fasciae Latae for the Treatment of Lateral Patellofemoral Overload Syndrome.

BACKGROUND: Pain in the anterior and lateral parts of the knee during exercise is a common clinical problem for which current management strategies are often unsuccessful. PURPOSE: To investigate the effect of an ultrasound-guided botulinum toxin (BT) injection into the tensor fasciae latae (TFL), followed by physical therapy, in patients classified with lateral patellofemoral overload syndrome (LPOS) who failed to respond to conventional treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 45 patients (mean ± SD age, 32.4 ± 8.6 years) who met the inclusion criteria of (1) activity-related anterolateral knee symptoms, (2) symptoms lasting longer than 3 months, (3) a pathological abnormality confirmed by magnetic resonance imaging, and (4) previous failed physical therapy received an ultrasound-guided injection of BT into the TFL followed by physical therapy. Patient-reported outcomes were collected at 5 intervals: before the injection; at 1, 4, and 12 weeks after the injection; and at a mean 5 years after the injection. In 42 patients, relative iliotibial band (ITB) length changes were assessed using the modified Ober test at the first 4 time points. A computational model was run to simulate the effect of TFL weakening on gluteus medius (GMed) activity. Statistical analysis was undertaken using 1-way analysis of variance and paired t tests with Bonferroni post hoc correction. RESULTS: There was a significant improvement in Anterior Knee Pain Scale scores from before the injection (61 ± 15) to 1 (67 ± 15), 4 (70 ± 16), and 12 weeks (76 ± 16) after the injection and in 87% of patients (39/45 patients available for follow-up) at approximately 5 years (from 62.9 ± 15.4 to 87.0 ± 12.5) after the injection (all P < .010). A significant effect on the modified Ober test was identified as a result of the intervention, with an increase in leg drop found at 1 (3° ± 5°), 4 (4° ± 5°), and 12 (7° ± 6°) weeks after the injection compared with before the injection (all P < .010). Simulating a progressive reduction in TFL strength resulted in corresponding increases in GMed activity during gait. CONCLUSION: An injection of BT into the TFL, combined with physical therapy, resulted in a significant improvement of symptoms in patients with LPOS, which was maintained at 5-year follow-up. This may result from reduced lateral TFL/ITB tension or to an increase in GMed activity in response to inhibition of the TFL.

Spinal muscular atrophy: from tissue specificity to therapeutic strategies.

Spinal muscular atrophy (SMA) is the most frequent genetic cause of death in infants and toddlers. All cases of spinal muscular atrophy result from reductions in levels of the survival motor neuron (SMN) protein, and so SMN upregulation is a focus of many preclinical and clinical studies. We examine four issues that may be important in planning for therapeutic success. First, neuromuscular phenotypes in the SMNΔ7 mouse model closely match those in human patients but peripheral disease manifestations differ, suggesting that endpoints other than mouse lifespan may be more useful in predicting clinical outcome. Second, SMN plays important roles in multiple central and peripheral cell types, not just motor neurons, and it remains unclear which of these cell types need to be targeted therapeutically. Third, should SMN-restoration therapy not be effective in all patients, blocking molecular changes downstream of SMN reduction may confer significant benefit, making it important to evaluate therapeutic targets other than SMN. Lastly, for patients whose disease progression is slowed, but who retain significant motor dysfunction, additional approaches used to enhance regeneration of the neuromuscular system may be of value.

British athletics muscle injury classification: a new grading system.

The commonly used muscle injury grading systems based on three grades of injury, representing minor, moderate and complete injuries to the muscle, are lacking in diagnostic accuracy and provide limited prognostic information to the clinician. In recent years, there have been a number of proposals for alternative grading systems. While there is recent evidence regarding the prognostic features of muscle injuries, this evidence has not often been incorporated into the grading proposals. The British Athletics Muscle Injury Classification proposes a new system, based on the available evidence, which should provide a sound diagnostic base for therapeutic decision-making and prognostication. Injuries are graded 0-4 based on MRI features, with Grades 1-4 including an additional suffix 'a', 'b' or 'c' if the injury is 'myofascial', 'musculo-tendinous' or 'intratendinous'. Retrospective and prospective studies in elite track and field athletes are underway to validate the classification for use in hamstring muscle injury management. It is intended that this grading system can provide a suitable diagnostic framework for enhanced clinical decision-making in the management of muscle injuries and assist with future research to inform the development of improved prevention and management strategies.

ABA renewal involves enhancements in both GluA2-lacking AMPA receptor activity and GluA1 phosphorylation in the lateral amygdala.

Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.

Hamstring muscle injuries in professional football: the correlation of MRI findings with return to play.

BACKGROUND: Hamstring injury is the single most common injury in professional football. MRI is commonly used to confirm the diagnosis and provide a prognosis of lay-off time. OBJECTIVE: To evaluate the use of MRI as a prognostic tool for lay-off after hamstring injuries in professional football players and to study the association between MRI findings and injury circumstances. METHODS: Prospective cohort study where 23 European professional teams, were followed between 2007 and 2011. Team medical staffs recorded individual player exposure and time-loss injuries. Radiological grading was performed using a modified Peetrons classification into four grades where grades 2 and 3 represent fibre disruption. RESULTS: In total, 516 hamstring injuries occurred and 58% of these were examined by MRI. Thirteen per cent were grade 0 injuries, 57% grade 1, 27% of grade 2 and 3% of grade 3. Grade 0 and 1 injuries accounted for 56% (2141/3830 days) of the total lay-off. The lay-off time differed between all four radiological grades of injury (8±3, 17±10, 22±11 and 73±60 days, p<0.0001). Eighty-three per cent of injuries affected the biceps femoris while 11% and 5% occurred to the semimembranosus and semitendinosus, respectively. Re-injuries (N=34/207) constituted 16% of injuries. All re-injuries occurred to the biceps femoris. CONCLUSION: MRI can be helpful in verifying the diagnosis of a hamstring injury and to prognosticate lay-off time. Radiological grading is associated with lay-off times after injury. Seventy per cent of hamstring injuries seen in professional football are of radiological grade 0 or 1, meaning no signs of fibre disruption on MRI, but still cause the majority of absence days.

Imaging in the assessment and management of Achilles tendinopathy and paratendinitis.

Achilles tendinopathy is a common overuse injury in patients engaged in athletic activities. Tendon degeneration is often accompanied by paratendinitis. Radiologists are frequently asked to use imaging techniques to evaluate patients with problems at or around the Achilles tendon. The main imaging modalities used in the assessment of Achilles tendon disorders are plain radiography, ultrasound, and magnetic resonance imaging. In recent years, ultrasound has also been used to guide minimally invasive local treatments for Achilles tendinopathy, which may prevent the need for surgery if conservative treatments have failed. In this article, we review the imaging features of Achilles tendinopathy and consider the relative strengths and weaknesses of the various imaging techniques. The role of imaging in directing patient management is also discussed, with particular focus on ultrasound-guided treatments.

Ultrasound-guided treatments for chronic Achilles tendinopathy: an update and current status.

Minimally-invasive treatments for chronic Achilles tendinopathy may prevent the need for surgery when conservative methods have failed. Whilst injections have traditionally been used to manage symptoms, recently described therapies may also have disease-modifying potential. Ultrasound provides the ability to guide therapeutic interventions, ensuring that treatment is delivered to the exact site of pathology. Treatments can be broadly categorised according to their intended therapeutic targets, although some may act through several possible mechanisms. In this article, we review the ultrasound-guided techniques currently used to treat chronic Achilles tendinopathy, with reference to the available literature. There is strong pilot-level evidence supporting the use of many of these techniques, although large definitive trials are lacking. An approach towards the management of chronic Achilles tendinopathy is suggested.

Ultrasound-guided percutaneous release of the annular pulley in trigger digit.

The purpose of this study was to describe and evaluate a new technique for ultrasound-guided percutaneous release of the annular pulley in trigger digit using a modified hypodermic needle. A total of 35 ultrasound-guided percutaneous releases were performed on 25 patients diagnosed and referred by hand surgeons in our institution over 16 months from October 2006. Inclusion criteria were as follows: adulthood, triggering present for at least 4 months, failure to respond to conservative management or steroid injections, no previous history of pulley release in the affected digit. Under ultrasound guidance, the affected pulley was released using a standard 19-gauge hypodermic needle bent at two points as the cutting device. Follow-up took place at 12 weeks and 6 months with improvement in triggering and clinically graded pain. At follow-up, no complications had occurred and all patients demonstrated improvement in their triggering, with complete resolution in 32 digits (91%), good improvement in 2 digits (6%) and some improvement in 1 digit (3%). This new technique uses a widely available and safe cutting device and is safe and can be used to provide definitive management for trigger finger, allowing the procedure to be performed in a variety of clinical settings.

Normal sonographic anatomy of the posterolateral corner of the knee.

OBJECTIVE: The posterolateral corner of the knee comprises a group of structures that are important to knee stability. MRI is currently the standard imaging technique, but visualization of individual structures is often incomplete. Sonography allows rapid real-time assessment of these superficial structures, but knowledge of the anatomy is essential to allow accurate examination. CONCLUSION: We present an illustrated review of the sonographic anatomy of the posterolateral corner of the knee with MRI correlation.

Posterior impingement syndromes of the ankle.

Acute, or repetitive, compression of the posterior structures of the ankle may lead to posterior ankle impingement (PAI) syndrome, posteromedial ankle impingement (PoMI) syndrome, or Haglund's syndrome. The etiology of each of these conditions is quite different. Variations in posterior ankle osseous and soft tissue anatomy contribute to the etiology of PAI and Haglund's syndromes. The presence of an os trigonum or Stieda process is classically associated with PAI syndrome, whereas a prominent posterosuperior tubercle of the os calcis or Haglund's deformity is the osseous predisposing factor in Haglund's syndrome. PoMI has no defined predisposing anatomical variants but typically follows an inversion-supination injury of the ankle joint. This article discusses the biomechanics, clinical features, imaging, and management of each of these conditions. Magnetic resonance imaging (MRI) provides the optimal tool in posterior ankle assessment, and this review focuses on the MRI findings of each of the conditions just listed.