Activation of Shh/Smo is sufficient to maintain oligodendrocyte precursor cells in an undifferentiated state and is not necessary for myelin formation and (re)myelination.

Myelination is the terminal step in a complex and precisely timed program that orchestrates the proliferation, migration and differentiation of oligodendroglial cells. It is thought that Sonic Hedgehog (Shh) acting on Smoothened (Smo) participates in regulating this process, but that these effects are highly context dependent. Here, we investigate oligodendroglial development and remyelination from three specific transgenic lines: NG2-CreERT2 (control), Smofl/fl/NG2-CreERT2 (loss of function), and SmoM2/NG2-CreERT2 (gain of function), as well as pharmacological manipulation that enhance or inhibit the Smo pathway (Smoothened Agonist (SAG) or cyclopamine treatment, respectively). To explore the effects of Shh/Smo on differentiation and myelination in vivo, we developed a highly quantifiable model by transplanting oligodendrocyte precursor cells (OPCs) in the retina. We find that myelination is greatly enhanced upon cyclopamine treatment and hypothesize that Shh/Smo could promote OPC proliferation to subsequently inhibit differentiation. Consistent with this hypothesis, we find that the genetic activation of Smo significantly increased numbers of OPCs and decreased oligodendrocyte differentiation when we examined the corpus callosum during development and after cuprizone demyelination and remyelination. However, upon loss of function with the conditional ablation of Smo, myelination in the same scenarios are unchanged. Taken together, our present findings suggest that the Shh pathway is sufficient to maintain OPCs in an undifferentiated state, but is not necessary for myelination and remyelination.

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part VII, nerves of the lower limb.

OBJECTIVES: To perform a Delphi-based consensus on published evidence on image-guided interventional procedures for peripheral nerves of the lower limb (excluding Morton's neuroma) and provide clinical indications. METHODS: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around peripheral nerves in the lower limb (excluding Morton's neuroma) to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper. RESULTS: Nine statements on image-guided interventional procedures for peripheral nerves of the lower limb have been drafted. All of them received strong consensus. Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. CONCLUSION: Despite the promising results reported by published papers on image-guided interventional procedures for peripheral nerves of the lower limb, there is still a lack of evidence on the efficacy of most procedures. KEY POINTS: • Image-guided pudendal nerve block is safe, effective, and well tolerated with few complications. • US-guided perisciatic injection of anesthetic provides good symptom relief in patients with piriformis syndrome; however, the addition of corticosteroids to local anesthetics still has an unclear role. • US-guided lateral femoral cutaneous nerve block can be used to provide effective post-operative regional analgesia. The volume of local anesthetic affects the size of the blocked sensory area.

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part VI, foot and ankle.

OBJECTIVES: Clarity regarding accuracy and effectiveness for interventional procedures around the foot and ankle is lacking. Consequently, a board of 53 members of the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the published literature to evaluate the evidence on image-guided musculoskeletal interventional procedures around this anatomical region. METHODS: We report the results of a Delphi-based consensus of 53 experts from the European Society of Musculoskeletal Radiology who reviewed the published literature for evidence on image-guided interventional procedures offered around foot and ankle in order to derive their clinical indications. Experts drafted a list of statements and graded them according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus was considered strong when > 95% of experts agreed with the statement or broad when > 80% but < 95% agreed. The results of the Delphi-based consensus were used to write the paper that was shared with all panel members for final approval. RESULTS: A list of 16 evidence-based statements on clinical indications for image-guided musculoskeletal interventional procedures in the foot and ankle were drafted after a literature review. The highest level of evidence was reported for four statements, all receiving 100% agreement. CONCLUSION: According to this consensus, image-guided interventions should not be considered a first-level approach for treating Achilles tendinopathy, while ultrasonography guidance is strongly recommended to improve the efficacy of interventional procedures for plantar fasciitis and Morton's neuroma, particularly using platelet-rich plasma and corticosteroids, respectively. KEY POINTS: • The expert panel of the ESSR listed 16 evidence-based statements on clinical indications of image-guided musculoskeletal interventional procedures in the foot and ankle. • Strong consensus was obtained for all statements. • The highest level of evidence was reached by four statements concerning the effectiveness of US-guided injections of corticosteroid for Morton's neuroma and PRP for plantar fasciitis.

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part V, knee.

OBJECTIVES: Interventional procedures around the knee are widely adopted for treating different musculoskeletal conditions. A panel of experts from the Ultrasound and Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) reviewed the existing literature to assess the evidence on image-guided musculoskeletal interventional procedures around the knee, with the goal of highlighting some controversies associated with these procedures, specifically the role of imaging guidance, as well as the efficacy of the medications routinely injected. METHODS: We report the results of a Delphi-based consensus of 53 experts in musculoskeletal radiology, who reviewed the published literature for evidence on image-guided interventional procedures around the knee to derive a list of pertinent clinical indications. RESULTS: A list of 10 statements about clinical indications of image-guided procedures around the knee was created by a Delphi-based consensus. Only two of them had the highest level of evidence; all of them received 100% consensus. CONCLUSIONS: Ultrasonography guidance is strongly recommended for intra-articular and patellar tendinopathy procedures to ensure the precision and efficacy of these treatments. Prospective randomized studies remain warranted to better understand the role of imaging guidance and assess some of the medications used for interventional procedures around the knee. KEY POINTS: • A list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the knee was produced by an expert panel of the ESSR. • Strong consensus with 100% agreement was obtained for all statements. • Two statements reached the highest level of evidence, allowing us to strongly recommend the use of ultrasonography to guide intra-articular and patellar tendon procedures to ensure higher accuracy and efficacy of these treatments.

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part IV, hip.

OBJECTIVES: Image-guided musculoskeletal interventional procedures around the hip are widely used in daily clinical practice. The need for clarity concerning the actual added value of imaging guidance and types of medications to be offered led the Ultrasound and the Interventional Subcommittees of the European Society of Musculoskeletal Radiology (ESSR) to promote, with the support of its Research Committee, a collaborative project to review the published literature on image-guided musculoskeletal interventional procedures in the lower limb in order to derive a list of clinical indications. METHODS: In this article, we report the results of a Delphi-based consensus of 53 experts who reviewed the published literature for evidence on image-guided interventional procedures offered in the joint and soft tissues around the hip in order of their clinical indications. RESULTS: Ten statements concerning image-guided treatment procedures around the hip have been collected by the panel of ESSR experts. CONCLUSIONS: This work highlighted that there is still low evidence in the existing literature on some of these interventional procedures. Further large prospective randomized trials are essential to better confirm the benefits and objectively clarify the role of imaging to guide musculoskeletal interventional procedures around the hip. KEY POINTS: • Expert consensus produced a list of 10 evidence-based statements on clinical indications of image-guided interventional procedures around the hip. • The highest level of evidence was only reached for one statement. • Strong consensus was obtained for all statements.

Myeloid-derived suppressor cells support remyelination in a murine model of multiple sclerosis by promoting oligodendrocyte precursor cell survival, proliferation, and differentiation.

The most frequent variant of multiple sclerosis (MS) is the relapsing-remitting form, characterized by symptomatic phases followed by periods of total/partial recovery. Hence, it is possible that these patients can benefit from endogenous agents that control the inflammatory process and favor spontaneous remyelination. In this context, there is increasing interest in the role of myeloid-derived suppressor cells (MDSCs) during the clinical course of experimental autoimmune encephalomyelitis (EAE). MDSCs speed up infiltrated T-cell anergy and apoptosis. In different animal models of MS, a milder disease course is related to higher presence/density of MDSCs in the periphery, and smaller demyelinated lesions in the central nervous system (CNS). These observations lead us to wonder whether MDSCs might not only exert an anti-inflammatory effect but might also have direct influence on oligodendrocyte precursor cells (OPCs) and remyelination. In the present work, we reveal for the first time the relationship between OPCs and MDSCs in EAE, relationship that is guided by the distance from the inflammatory core. We describe the effects of MDSCs on survival, proliferation, as well as potent promoters of OPC differentiation toward mature phenotypes. We show for the first time that osteopontin is remarkably present in the analyzed secretome of MDSCs. The ablation of this cue from MDSCs-secretome demonstrates that osteopontin is the main MDSC effector on these oligodendroglial cells. These data highlight a crucial pathogenic interaction between innate immunity and the CNS, opening ways to develop MDSC- and/or osteopontin-based therapies to promote effective myelin preservation and repair in MS patients.

Complex-Valued Phase Transmittance RBF Neural Networks for Massive MIMO-OFDM Receivers.

Multi-input multi-output (MIMO) transmission schemes have become the techniques of choice for increasing spectral efficiency in bandwidth-congested areas. However, the design of cost-effective receivers for MIMO channels remains a challenging task. The maximum likelihood detector can achieve excellent performance-usually, the best performance-but its computational complexity is a limiting factor in practical implementation. In the present work, a novel MIMO scheme using a practically feasible decoding algorithm based on the phase transmittance radial basis function (PTRBF) neural network is proposed. For some practical scenarios, the proposed scheme achieves improved receiver performance with lower computational complexity relative to the maximum likelihood decoding, thus substantially increasing the applicability of the algorithm. Simulation results are presented for MIMO-OFDM under 5G wireless Rayleigh channels so that a fair performance comparison with other reference techniques can be established.

Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography.

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.

The proportion of myeloid-derived suppressor cells in the spleen is related to the severity of the clinical course and tissue damage extent in a murine model of multiple sclerosis.

Multiple Sclerosis (MS) is the second cause of paraplegia among young adults, after all types of CNS traumatic lesions. In its most frequent relapsing-remitting form, the severity of the disease course is very heterogeneous, and its reliable evaluation remains a key issue for clinicians. Myeloid-Derived sSuppressor Cells (MDSCs) are immature myeloid cells that suppress the inflammatory response, a phenomenon related to the resolution or recovery of the clinical symptoms associated with experimental autoimmune encephalomyelitis (EAE), the most common model for MS. Here, we establish the severity index as a new parameter for the clinical assessment in EAE. It is derived from the relationship between the maximal clinical score and the time elapsed since disease onset. Moreover, we relate this new index with several histopathological hallmarks in EAE and with the peripheral content of MDSCs. Based on this new parameter, we show that the splenic MDSC content is related to the evolution of the clinical course of EAE, ranging from mild to severe. Indeed, when the severity index indicates a severe disease course, EAE mice display more intense lymphocyte infiltration, demyelination and axonal damage. A direct correlation was drawn between the MDSC population in the peripheral immune system, and the preservation of myelin and axons, which was also correlated with T cell apoptosis within the CNS (being these cells the main target for MDSC suppression). The data presented clearly indicated that the severity index is a suitable tool to analyze disease severity in EAE. Moreover, our data suggest a clear relationship between circulating MDSC enrichment and disease outcome, opening new perspectives for the future targeting of this population as an indicator of MS severity.

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part I, shoulder.

BACKGROUND: Image-guided interventional procedures around the shoulder are commonly performed in clinical practice, although evidence regarding their effectiveness is scarce. We report the results of a Delphi method review of evidence on literature published on image-guided interventional procedures around the shoulder with a list of clinical indications. METHODS: Forty-five experts in image-guided musculoskeletal procedures from the ESSR participated in a consensus study using the Delphic method. Peer-reviewed papers regarding interventional procedures around the shoulder up to September 2018 were scored according to the Oxford Centre for Evidence-based Medicine levels of evidence. Statements on clinical indications were constructed. Consensus was considered as strong if more than 95% of experts agreed and as broad if more than 80% agreed. RESULTS: A total of 20 statements were drafted, and 5 reached the highest level of evidence. There were 10 statements about tendon procedures, 6 about intra-articular procedures, and 4 about intrabursal injections. Strong consensus was obtained in 16 of them (80%), while 4 received broad consensus (20%). CONCLUSIONS: Literature evidence on image-guided interventional procedures around the shoulder is limited. A strong consensus has been reached for 80% of statements. The ESSR recommends further research to potentially influence treatment options, patient outcomes, and social impact. KEY POINTS: • Expert consensus produced a list of 20 evidence-based statements on clinical indications of image-guided interventional procedures around the shoulder. • The highest level of evidence was reached for five statements. • Strong consensus was obtained for 16 statements (80%), while 4 received broad consensus (20%).

Clinical indications for image-guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-Part II, elbow and wrist.

BACKGROUND: Although image-guided interventional procedures of the elbow and wrist are routinely performed, there is poor evidence in the literature concerning such treatments. Our aim was to perform a Delphi-based consensus on published evidence on image-guided interventional procedures around the elbow and wrist and provide clinical indications on this topic. METHODS: A board of 45 experts in image-guided interventional musculoskeletal procedures from the European Society of Musculoskeletal Radiology were involved in this Delphi-based consensus study. All panelists reviewed and scored published papers on image-guided interventional procedures around the elbow and wrist updated to September 2018 according to the Oxford Centre for Evidence-based Medicine levels of evidence. Consensus on statements drafted by the panelists about clinical indications was considered as "strong" when more than 95% of panelists agreed and as "broad" if more than 80% agreed. RESULTS: Eighteen statements were drafted, 12 about tendon procedures and 6 about intra-articular procedures. Only statement #15 reached the highest level of evidence (ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement). Seventeen statements received strong consensus (94%), while one received broad consensus (6%). CONCLUSIONS: There is still poor evidence in published papers on image-guided interventional procedures around the elbow and wrist. A strong consensus has been achieved in 17/18 (94%) statements provided by the panel on clinical indications. Large prospective randomized trials are needed to better define the role of these procedures in clinical practice. KEY POINTS: • The panel provided 18 evidence-based statements on clinical indications of image-guided interventional procedures around the elbow and wrist. • Only statement #15 reached the highest level of evidence: ultrasound-guided steroid wrist injections result in greater pain reduction and greater likelihood of attaining clinically important improvement. • Seventeen statements received strong consensus (94%), while broad consensus was obtained by 1 statement (6%).

Clinical indications for image guided interventional procedures in the musculoskeletal system: a Delphi-based consensus paper from the European Society of Musculoskeletal Radiology (ESSR)-part III, nerves of the upper limb.

BACKGROUND: Image-guided interventional procedures of the nerves are commonly performed by physicians from different medical specialties, although there is a lack of clinical indications for these types of procedures. This Delphi-based consensus provided a list of indications on image-guided interventional procedures for nerves of the upper limb based on updated published evidence. METHODS: An expert panel of 45 members of the Ultrasound and Interventional Subcommittees of the ESSR participated in this Delphi-based consensus study. After revision of the published papers on image-guided interventional procedures for nerves of the upper limb updated to September 2018, the experts drafted a list of statements according to the Oxford Centre for evidence-based medicine levels of evidence. Consensus on statements regarding clinical indications was considered as strong when more than 95% of experts agreed, and broad if more than 80% agreed. RESULTS: Ten statements were drafted on procedures for nerves of the upper limb. Only two statements reached the highest level of evidence (ultrasound guidance is a safe and effective method for brachial plexus block; ultrasound-guided non-surgical approaches are safe and effective methods to treat carpal tunnel syndrome in the short term, but there is sparse evidence on the mid- and long-term effectiveness of these interventions). Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%). CONCLUSIONS: This Delphi-based consensus study reported poor evidence on image-guided interventional procedures for nerves of the upper limb. Sixty percent of statements on clinical indications provided by the expert board reached a strong consensus. KEY POINTS: • An expert panel of the ESSR provided 10 evidence-based statements on clinical indications for image-guided interventional procedures for nerves of the upper limb • Two statements reached the highest level of evidence • Strong consensus was obtained on 6/10 statements (60%), while 4/10 statements reached broad consensus (40%).

R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System.

Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1-/- and R-Ras2-/--null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1-/- and/or R-Ras2-/- mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.SIGNIFICANCE STATEMENT In this study, we show that R-Ras1 and R-Ras2 play essential roles in regulating myelination in vivo and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination in main CNS tracts. In vivo electrophysiology recordings demonstrate a slower conduction velocity of nerve impulses in the absence of R-Ras1 and R-Ras2. Therefore, R-Ras1 and R-Ras2 are essential for proper axonal myelination and accurate neural transmission.

The presence and suppressive activity of myeloid-derived suppressor cells are potentiated after interferon-ß treatment in a murine model of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the human central nervous system (CNS), mainly affecting young adults. Among the immunomodulatory disease modifying treatments approved up to date to treat MS, IFN-ß remains to be one of the most widely prescribed for the Relapsing-Remitting (RR) variant of the disease, although its mechanism of action is still partially understood. RR-MS variant is characterized by phases with increasing neurological symptoms (relapses) followed by periods of total or partial recovery (remissions), which implies the existence of immunomodulatory agents to promote the relapsing-to-remitting transition. Among these agents, it has been described the immunosuppressive role of a heterogeneous population of immature myeloid cells, namely the myeloid-derived suppressor cells (MDSCs) during the clinical course of the experimental autoimmune encephalomyelitis (EAE), the most used MS model to study RRMS. However, it is still unknown how the current MS disease modifying treatments, e.g. IFN- ß, affects to MDSCs number or activity. Our present results show that a single injection of IFN-ß at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas. Moreover, the single dose of IFN-ß promotes MDSC immunosuppressive activity both in vivo and in vitro, augmenting T cell apoptosis. Finally, we show that IFN-ß preserves MDSC immaturity, preventing their differentiation to mature and less suppressive myeloid cell subsets. Taking together, all these data add new insights into the mechanism of IFN-ß treatment in EAE and point to MDSCs as a putative endogenous mediator of its beneficial role in this animal model of MS.

2-AG limits Theiler's virus induced acute neuroinflammation by modulating microglia and promoting MDSCs.

The innate immune response is mediated by primary immune modulators such as cytokines and chemokines that together with immune cells and resident glia orchestrate CNS immunity and inflammation. Growing evidence supports that the endocannabinoid 2-arachidonoylglycerol (2-AG) exerts protective actions in CNS injury models. Here, we used the acute phase of Theiler's virus induced demyelination disease (TMEV-IDD) as a model of acute neuroinflammation to investigate whether 2-AG modifies the brain innate immune responses to TMEV and CNS leukocyte trafficking. 2-AG or the inhibition of its hydrolysis diminished the reactivity and number of microglia at the TMEV injection site reducing their morphological complexity and modulating them towards an anti-inflammatory state via CB2 receptors. Indeed, 2-AG dampened the infiltration of immune cells into the CNS and inhibited their egress from the spleen, resulting in long-term beneficial effects at the chronic phase of the disease. Intriguingly, it is not a generalized action over leukocytes since 2-AG increased the presence and suppressive potency of myeloid derived suppressor cells (MDSCs) in the brain resulting in higher apoptotic CD4+ T cells at the injection site. Together, these data suggest a robust modulatory effect in the peripheral and central immunity by 2-AG and highlight the interest of modulating endogenous cannabinoids to regulate CNS inflammatory conditions.

Clinical indications for musculoskeletal ultrasound updated in 2017 by European Society of Musculoskeletal Radiology (ESSR) consensus.

OBJECTIVES: To update the 2012 European Society of Musculoskeletal Radiology (ESSR) clinical consensus guidelines for musculoskeletal ultrasound referral in Europe. METHODS: Twenty-one musculoskeletal imaging experts from the ESSR participated in a consensus study based on a Delphic process. Two independent (non-voting) authors facilitated the procedure and resolved doubtful issues. Updated musculoskeletal ultrasound literature up to July 2017 was scored for shoulder, elbow, wrist/hand, hip, knee, and ankle/foot. Scoring of ultrasound elastography was included. The strength of the recommendation and level of evidence was scored by consensus greater than 67% or considered uncertain when the consensus was consensus less than 67%. RESULTS: A total of 123 new papers were reviewed. No evidence change was found regarding the shoulder. There were no new relevant articles for the shoulder, 10 new articles for the elbow, 28 for the hand/wrist, 3 for the hip, 7 for the knee, and 4 for the ankle/foot. Four new evidence levels of A were determined, one for the hip (gluteal tendons tears), one for the knee (meniscal cysts), one for the ankle (ankle joint instability), and one for the foot (plantar plate tear). There was no level A evidence for elastography, although for Achilles tendinopathy and lateral epicondylitis evidence level was B with grade 3 indication. CONCLUSIONS: Four new areas of level A evidence were included in the guidelines. Elastography did not reach level A evidence. Whilst ultrasound is of increasing importance in musculoskeletal medical practice, the evidence for elastography remains moderate. KEY POINTS: • Evidence and expert consensus shows an increase of musculoskeletal ultrasound indications. • Four new A evidence levels were found for the hip, knee, ankle, and foot. • There was no level A evidence for elastography.

Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.

The "Big-Bang" for modern glial biology: Translation and comments on Pío del Río-Hortega 1919 series of papers on microglia.

The word "glia" was coined in the mid-19th century and defined as "the nerve glue". For decades, it was assumed to be a uniform matrix, until cell theorists raised the "neuron doctrine" which stipulated that nervous tissue was composed of individual cells. The term "astrocytes" was introduced in the late 19th century as a synonym for glial cells, but it was Santiago Ramón y Cajal who defined a "third element" distinct from glial cells (astrocytes) and neurons. It was not until 1919 when Pío del Río-Hortega, an alumnus of the Cajal School, introduced the modern terms we use today, and thoroughly described both "oligodendrocytes" and "microglia" to clearly distinguish them from astrocytes. In a series of four papers published that year in Spanish, Río-Hortega described the distribution and morphological phenotype of microglia. He also noted that these cells were the origin of the rod cells described earlier in pathologic tissue, and recognized that resting microglia transformed into an ameboid phenotype in different types of brain diseases and pathologies. He also noted the mesodermal origin of these cells and recognized their phagocytic capacity. We here provide the first English translation of these landmark series of papers, which paved the way for modern glial research. To heighten the value and accessibility of these classic papers and their original figures, an introduction to this critical period of neuroscience is provided, along with unpublished photographs. By adding comments to the translated text, we provide sufficient context so that contemporary scientists may fully appreciate it. GLIA 2016;64:1801-1840.

Differential expression of sema3A and sema7A in a murine model of multiple sclerosis: Implications for a therapeutic design.

We characterised the expression of semaphorin (sema)3A, sema7A and their receptors in the immune and the central nervous system (CNS) at different stages of experimental autoimmune encephalomyelitis (EAE). We also studied their expression in neonatal and adult oligodendrocyte progenitor cell (OPC) and in mature oligodendrocyte cultures. Our results show that sema3A is increased in the CNS and decreased in the immune system upon EAE induction. However, sema7A expression is increased in both the CNS and the immune system during EAE. We also detected sema3A, sema7A and their receptors in neonatal and adult OPCs and in mature oligodendrocytes. These data suggest that sema3A and sema7A are involved in the pathogenesis of EAE, in the modulation of the immune response and in the neurodegeneration that take place in the CNS. Sema7A may represent an intriguing potential therapeutic target for the treatment of both the neurodegenerative and immune-mediated disease processes in MS.

ERK1/2 signaling is essential for the chemoattraction exerted by human FGF2 and human anosmin-1 on newborn rat and mouse OPCs via FGFR1.

Signaling through fibroblast growth factor receptors (FGFRs) is essential for many cellular processes including proliferation and migration, as well as differentiation events such as myelination. Anosmin-1 is an extracellular matrix (ECM) glycoprotein that interacts with the fibroblast growth factor receptor 1 (FGFR1) to exert its biological actions through this receptor, although the intracellular pathways underlying anosmin-1 signaling remain largely unknown. This protein is defective in the X-linked form of Kallmann syndrome (KS) and has a prominent role in the migration of neuronal and oligodendroglial precursors. We have shown that anosmin-1 exerts a chemotactic effect via FGFR1 on neuronal precursors from the subventricular zone (SVZ) and the essential role of the ERK1/2 signaling. We report here the positive chemotactic effect of FGF2 and anosmin-1 on rat and mouse postnatal OPCs via FGFR1. The same effect was observed with the truncated N-terminal region of anosmin-1 (A1Nt). The introduction in anosmin-1 of the missense mutation F517L found in patients suffering from KS annulled the chemotactic activity; however, the mutant form carrying the disease-causing mutation E514K also found in KS patients, behaved as the wild-type protein. The chemoattraction exhibited by FGF2 and anosmin-1 on OPCs was blocked by the mitogen-activated protein kinase (MAPK) inhibitor U0126, suggesting that the activation of the ERK1/2 MAPK signaling pathway following interaction with the FGFR1 is necessary for FGF2 and anosmin-1 to exert their chemotactic effect. In fact, both proteins were able to induce the phosphorylation of the ERK1/2 kinases after the activation of the FGFR1 receptor.