microRNAs in nociceptive circuits as predictors of future clinical applications

Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals. \ua9 2013 Kress, H\ufcttenhofer, Landry, Kuner, Favereaux, Greenberg, Bednarik, Heppenstall, Kronenberg, Malcangio, Rittner, c\ue7eyler, Trajanoski, Mouritzen, Birklein, Sommer and Soreq

Degenerative Cervical Myelopathy: Development and Natural History [AO Spine RECODE-DCM Research Priority Number 2].

Study design: Narrative review. Objectives: To discuss the current understanding of the natural history of degenerative cervical myelopathy (DCM). Methods: Literature review summarizing current evidence pertaining to the natural history and risk factors of DCM. Results: DCM is a common condition in which progressive arthritic disease of the cervical spine leads to spinal cord compression resulting in a constellation of neurological symptoms, in particular upper extremity dysfunction and gait impairment. Anatomical factors including cord-canal mismatch, congenitally fused vertebrae and genetic factors may increase individuals\u27 risk for DCM development. Non-myelopathic spinal cord compression (NMSCC) is a common phenomenon with a prevalence of 24.2% in the healthy population, and 35.3% among individuals \u3e60 years of age. Clinical radiculopathy and/or electrophysiological signs of cervical cord dysfunction appear to be risk factors for myelopathy development. Radiological progression of incidental Ossification of the Posterior Longitudinal Ligament (OPLL) is estimated at 18.3% over 81-months and development of myelopathy ranges between 0-61.5% (follow-up ranging from 40 to 124 months between studies) among studies. In patients with symptomatic DCM undergoing non-operative treatment, 20-62% will experience neurological deterioration within 3-6 years. Conclusion: Current estimates surrounding the natural history of DCM, particularly those individuals with mild or minimal impairment, lack precision. Clear predictors of clinical deterioration for those treated with non-operative care are yet to be identified. Future studies are needed on this topic to help improve treatment counseling and clinical prognostication

A New Framework for Investigating the Biological Basis of Degenerative Cervical Myelopathy [AO Spine RECODE-DCM Research Priority Number 5]: Mechanical Stress, Vulnerability and Time

Study design: Literature Review (Narrative). Objective: To propose a new framework, to support the investigation and understanding of the pathobiology of DCM, AO Spine RECODE-DCM research priority number 5. Methods: Degenerative cervical myelopathy is a common and disabling spinal cord disorder. In this perspective, we review key knowledge gaps between the clinical phenotype and our biological models. We then propose a reappraisal of the key driving forces behind DCM and an individual\u27s susceptibility, including the proposal of a new framework. Results: Present pathobiological and mechanistic knowledge does not adequately explain the disease phenotype; why only a subset of patients with visualized cord compression show clinical myelopathy, and the amount of cord compression only weakly correlates with disability. We propose that DCM is better represented as a function of several interacting mechanical forces, such as shear, tension and compression, alongside an individual\u27s vulnerability to spinal cord injury, influenced by factors such as age, genetics, their cardiovascular, gastrointestinal and nervous system status, and time. Conclusion: Understanding the disease pathobiology is a fundamental research priority. We believe a framework of mechanical stress, vulnerability, and time may better represent the disease as a whole. Whilst this remains theoretical, we hope that at the very least it will inspire new avenues of research that better encapsulate the full spectrum of disease

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Vertigo in Patients with Degenerative Cervical Myelopathy

(1) Background: Cervical vertigo (CV) represents a controversial entity, with a prevalence ranging from reported high frequency to negation of CV existence. (2) Objectives: To assess the prevalence and cause of vertigo in patients with a manifest form of severe cervical spondylosis–degenerative cervical myelopathy (DCM) with special focus on CV. (3) Methods: The study included 38 DCM patients. The presence and character of vertigo were explored with a dedicated questionnaire. The cervical torsion test was used to verify the role of neck proprioceptors, and ultrasound examinations of vertebral arteries to assess the role of arteriosclerotic stenotic changes as hypothetical mechanisms of CV. All patients with vertigo underwent a detailed diagnostic work-up to investigate the cause of vertigo. (4) Results: Symptoms of vertigo were described by 18 patients (47%). Causes of vertigo included: orthostatic dizziness in eight (22%), hypertension in five (14%), benign paroxysmal positional vertigo in four (11%) and psychogenic dizziness in one patient (3%). No patient responded positively to the cervical torsion test or showed significant stenosis of vertebral arteries. (5) Conclusions: Despite the high prevalence of vertigo in patients with DCM, the aetiology in all cases could be attributed to causes outside cervical spine and related nerve structures, thus confirming the assumption that CV is over-diagnosed

Walk and Run Test in Patients with Degenerative Compression of the Cervical Spinal Cord

Impaired gait is one of the cardinal symptoms of degenerative cervical myelopathy (DCM) and frequently its initial presentation. Quantitative gait analysis is therefore a promising objective tool in the disclosure of early cervical cord impairment in patients with degenerative cervical compression. The aim of this cross-sectional observational cohort study was to verify whether an objective and easily-used walk and run test is capable of detecting early gait impairment in a practical proportion of non-myelopathic degenerative cervical cord compression (NMDCC) patients and of revealing any correlation with severity of disability in DCM. The study group consisted of 45 DCM patients (median age 58 years), 126 NMDCC subjects (59 years), and 100 healthy controls (HC) (55.5 years), all of whom performed a standardized 10-m walk and run test. Walking/running time/velocity, number of steps and cadence of walking/running were recorded; analysis disclosed abnormalities in 66.7% of NMDCC subjects. The DCM group exhibited significantly more pronounced abnormalities in all walk/run parameters when compared with the NMDCC group. These were apparent in 84.4% of the DCM group and correlated closely with disability as quantified by the modified Japanese Orthopaedic Association scale. A standardized 10-m walk/run test has the capacity to disclose locomotion abnormalities in NMDCC subjects who lack other clear myelopathic signs and may provide a means of classifying DCM patients according to their degree of disability

Walk and Run Test in Patients with Degenerative Compression of the Cervical Spinal Cord

Impaired gait is one of the cardinal symptoms of degenerative cervical myelopathy (DCM) and frequently its initial presentation. Quantitative gait analysis is therefore a promising objective tool in the disclosure of early cervical cord impairment in patients with degenerative cervical compression. The aim of this cross-sectional observational cohort study was to verify whether an objective and easily-used walk and run test is capable of detecting early gait impairment in a practical proportion of non-myelopathic degenerative cervical cord compression (NMDCC) patients and of revealing any correlation with severity of disability in DCM. The study group consisted of 45 DCM patients (median age 58 years), 126 NMDCC subjects (59 years), and 100 healthy controls (HC) (55.5 years), all of whom performed a standardized 10-m walk and run test. Walking/running time/velocity, number of steps and cadence of walking/running were recorded; analysis disclosed abnormalities in 66.7% of NMDCC subjects. The DCM group exhibited significantly more pronounced abnormalities in all walk/run parameters when compared with the NMDCC group. These were apparent in 84.4% of the DCM group and correlated closely with disability as quantified by the modified Japanese Orthopaedic Association scale. A standardized 10-m walk/run test has the capacity to disclose locomotion abnormalities in NMDCC subjects who lack other clear myelopathic signs and may provide a means of classifying DCM patients according to their degree of disability

TUT-DIS3L2 is a mammalian surveillance pathway for aberrant structured non-coding RNAs

Uridylation of various cellular RNA species at the 3' end has been generally linked to RNA degradation. In mammals, uridylated pre-let-7 miRNAs and mRNAs are targeted by the 3' to 5' exoribonuclease DIS3L2. Mutations in DIS3L2 have been associated with Perlman syndrome and with Wilms tumor susceptibility. Using in vivo cross-linking and immunoprecipitation (CLIP) method, we discovered the DIS3L2-dependent cytoplasmic uridylome of human cells. We found a broad spectrum of uridylated RNAs including rRNAs, snRNAs, snoRNAs, tRNAs, vault, 7SL, Y RNAs, mRNAs, lncRNAs, and transcripts from pseudogenes. The unifying features of most of these identified RNAs are aberrant processing and the presence of stable secondary structures. Most importantly, we demonstrate that uridylation mediates DIS3L2 degradation of short RNA polymerase II-derived RNAs. Our findings establish the role of DIS3L2 and oligouridylation as the cytoplasmic quality control for highly structured ncRNAs