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BACKGROUND: Knowledge of the body's response to and recovery from exercise is rapidly increasing. State-of-the-art equipment and facilities allow recreationally active adults to seek innovations to enhance performance and shorten recovery time. Myofascial rolling (MR) is a relatively new practice, providing acute benefits for muscle pain and range of motion (ROM). However, there is no consensus on optimal MR duration. PURPOSE: The purpose of this systematic review is to determine the optimal MR duration using a foam roller or a roller massager for muscle pain, ROM, and athletic performance via qualitative review. STUDY DESIGN: Systematic Review of the Literature METHODS: A systematic search was conducted using PubMed, EMBASE, EBSCOHost and PEDro (July 2018). Twenty-two studies met the inclusion criteria and were appraised using the PEDro scale. Studies were grouped by outcome measure, with a total number of subjects of n = 328 for pain/soreness, n = 398 for ROM, and n = 241 for performance. Heterogeneity of data prohibited a formal meta-analysis: studies were manually reviewed and classified as providing evidence for benefit of MR (i.e., significant positive effect) or not (i.e., null or negative effect) for each of the studied outcomes. RESULTS: The most evidence-based benefit of MR is the alleviation of muscle soreness; seven of eight studies assessing pain/soreness resulted in a short-term reduction, and a minimum dose of 90 seconds per muscle appeared beneficial. While ten of 17 studies involving ROM showed acute improvements, the results were inconsistent and highly variable. No significant effects on performance were detected. CONCLUSION: Available data indicate that MR for 90 seconds per muscle group may be the minimal duration to achieve a short-term reduction in pain/soreness, with no upper limit found. Results do not support increases in chronic ROM or performance, and data are insufficient to provide a conclusive recommendation for impacting acute ROM. The heterogeneity of the literature highlights the need for additional research to determine optimal dose of MR. LEVEL OF EVIDENCE: 2a- (Systematic Review with heterogeneity).

Glutamine synthetase, encoded by the gene GLUL, is an enzyme that converts glutamate and ammonia to glutamine. It is expressed by endothelial cells, but surprisingly shows negligible glutamine-synthesizing activity in these cells at physiological glutamine levels. Here we show in mice that genetic deletion of Glul in endothelial cells impairs vessel sprouting during vascular development, whereas pharmacological blockade of glutamine synthetase suppresses angiogenesis in ocular and inflammatory skin disease while only minimally affecting healthy adult quiescent endothelial cells. This relies on the inhibition of endothelial cell migration but not proliferation. Mechanistically we show that in human umbilical vein endothelial cells GLUL knockdown reduces membrane localization and activation of the GTPase RHOJ while activating other Rho GTPases and Rho kinase, thereby inducing actin stress fibres and impeding endothelial cell motility. Inhibition of Rho kinase rescues the defect in endothelial cell migration that is induced by GLUL knockdown. Notably, glutamine synthetase palmitoylates itself and interacts with RHOJ to sustain RHOJ palmitoylation, membrane localization and activation. These findings reveal that, in addition to the known formation of glutamine, the enzyme glutamine synthetase shows unknown activity in endothelial cell migration during pathological angiogenesis through RHOJ palmitoylation. ispartof: NATURE vol:561 issue:7721 pages:63-+ ispartof: location:England status: published

Recovery from acute spinal cord injury (SCI) is characterized by extensive heterogeneity, resulting in uncertain prognosis. Reliable prediction of recovery in the acute phase benefits patients and their families directly, as well as improves the likelihood of detecting efficacy in clinical trials. This issue of heterogeneity is not unique to SCI. In fields such as traumatic brain injury, Parkinson’s disease, and amyotrophic lateral sclerosis, one approach to understand variability in recovery has been to make clinical trial data widely available to the greater research community. We contend that the SCI community should adopt a similar approach in providing open access clinical trial data.

Spontaneous remyelination occurs after spinal cord injury (SCI), but the extent of myelin repair and identity of the cells responsible remain incompletely understood and contentious. We assessed the cellular origin of new myelin by fate mapping platelet-derived growth factor receptor α (PDGFRα), Olig2+, and P0+ cells following contusion SCI in mice. Oligodendrocyte precursor cells (OPCs; PDGFRα+) produced oligodendrocytes responsible for de novo ensheathment of ∼30% of myelinated spinal axons at injury epicenter 3 months after SCI, demonstrating that these resident cells are a major contributor to oligodendrocyte regeneration. OPCs also produced the majority of myelinating Schwann cells in the injured spinal cord; invasion of peripheral myelinating (P0+) Schwann cells made only a limited contribution. These findings reveal that PDGFRα+ cells perform diverse roles in CNS repair, as multipotential progenitors that generate both classes of myelinating cells. This endogenous repair might be exploited as a therapeutic target for CNS trauma and disease. SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to profound functional deficits, though substantial numbers of axons often survive. One possible explanation for these deficits is loss of myelin, creating conduction block at the site of injury. SCI leads to oligodendrocyte death and demyelination, and clinical trials have tested glial transplants to promote myelin repair. However, the degree and duration of myelin loss, and the extent and mechanisms of endogenous repair, have been contentious issues. Here, we use genetic fate mapping to demonstrate that spontaneous myelin repair by endogenous oligodendrocyte precursors is much more robust than previously recognized. These findings are relevant to many types of CNS pathology, raising the possibility that CNS precursors could be manipulated to repair myelin in lieu of glial transplantation.

Genome editing techniques have facilitated significant advances in our understanding of fundamental biological processes, and the Cre-Lox system has been instrumental in these achievements. Driving Cre expression specifically in injured neurons has not been previously possible: we sought to address this limitation in mice using a Cre-ERT2 construct driven by a reliable indicator of axotomy, activating transcription factor 3 (ATF3). When crossed with reporter mice, a significant amount of recombination was achieved (without tamoxifen treatment) in peripherally-projecting sensory, sympathetic, and motoneurons after peripheral nerve crush in hemizygotes (65–80% by 16 d) and was absent in uninjured neurons. Importantly, injury-induced recombination did not occur in Schwann cells distal to the injury, and with a knock-out-validated antibody we verified an absence of ATF3 expression. Functional recovery following sciatic nerve crush in ATF3-deficient mice (both hemizygotes and homozygotes) was delayed, indicating previously unreported haploinsufficiency. In a proof-of-principle experiment, we crossed the ATF3-CreERT2 line with a floxed phosphatase and tensin homolog (PTEN) line and show significantly improved axonal regeneration, as well as more complete recovery of neuromuscular function. We also demonstrate the utility of the ATF3-CreERT2 hemizygous line by characterizing recombination after lateral spinal hemisection (C8/T1), which identified specific populations of ascending spinal cord neurons (including putative spinothalamic and spinocerebellar) and descending supraspinal neurons (rubrospinal, vestibulospinal, reticulospinal and hypothalamic). We anticipate these mice will be valuable in distinguishing axotomized from uninjured neurons of several different classes (e.g., via reporter expression), and in probing the function of any number of genes as they relate to neuronal injury and regeneration.

The severity of injury to cardiovascular autonomic pathways following clinical spinal cord injury (SCI) can be evaluated with spectral analyses. Whether this technique provides a translatable assessment of cardiovascular autonomic function in rodent SCI is unknown. Beat-to-beat blood pressure and pulse interval were measured in male rats 1 month after complete T3 or T10 SCI, and in uninjured control animals. Univariate autoregressive spectral analyses were performed and the power of the low frequency (LF), high frequency (HF), and very low frequency (VLF) peaks identified. Frequency domain variables were correlated with the severity of orthostatic hypotension (OH) and the severity of hypertension during autonomic dysreflexia (AD). Total heart rate variability (HRV) and blood pressure variability (BPV) were reduced in animals with T3, but not T10, SCI. VLF and LF HRV were reduced and HF HRV was increased in animals with T3 SCI compared to controls; there were no changes in animals with T10 SCI. BPV in the VLF and LF range was reduced in animals with T3 SCI, but not T10 SCI. In all animals with SCI, severity of OH was positively correlated with LF BPV, and negatively correlated with HF BPV. Severity of AD was positively correlated with HF BPV and HF HRV, and negatively correlated with VLF HRV. Spectral analyses can detect alterations in cardiovascular autonomic function in animals with SCI at rest. These parameters underscore the distinct cardiovascular ramifications of high- versus low-thoracic SCI, and correlate with the severity of AD and OH, clinically-relevant measures of abnormal blood pressure control.

IntroductionRecent studies demonstrate that cardiovascular diseases and associated complications are the leading cause of morbidity and mortality in individuals with spinal cord injury (SCI). Abnormal arterial stiffness, defined by a carotid–to-femoral pulse wave velocity (cfPWV) ≥10 m/s, is a recognised risk factor for heart disease in individuals with SCI. There is a paucity of studies assessing the efficacy of conventional training modalities on arterial stiffness and other cardiovascular outcomes in this population. Therefore, this study aims to compare the efficacy of arm cycle ergometry training (ACET) and body weight-supported treadmill training (BWSTT) on reducing arterial stiffness in individuals with chronic motor complete, high-level (above the sixth thoracic segment) SCI.Methods and analysisThis is a multicentre, randomised, controlled, clinical trial. Eligible participants will be randomly assigned (1:1) into either ACET or BWSTT groups. Sixty participants with chronic (>1 year) SCI will be recruited from three sites in Canada (Vancouver, Toronto and Hamilton). Participants in each group will exercise three times per week up to 30 min and 60 min for ACET and BWSTT, respectively, over the period of 6 months. The primary outcome measure will be change in arterial stiffness (cfPWV) from baseline. Secondary outcome measures will include comprehensive assessments of: (1) cardiovascular parameters, (2) autonomic function, (3) body composition, (4) blood haematological and metabolic profiles, (5) cardiorespiratory fitness and (6) quality of life (QOL) and physical activity outcomes. Outcome measures will be assessed at baseline, 3 months, 6 months and 12 months (only QOL and physical activity outcomes). Statistical analyses will apply linear-mixed modelling to determine the training (time), group (ACET vs BWSTT) and interaction (time × group) effects on all outcomes.Ethics and disseminationEthical approval was obtained from all three participating sites. Primary and secondary outcome data will be submitted for publication in peer-reviewed journals and widely disseminated.Trial registration numberNCT01718977; Pre-results.Trial statusRecruitment for this study began on January 2013 and the first participant was randomized on April 2013. Recruitment stopped on October 2018.

Literature review. To present a comprehensive overview of autonomic assessment in experimental spinal cord injury (SCI). A systematic literature review was conducted using PubMed to extract studies that incorporated functional motor, sensory or autonomic assessment after experimental SCI. While the total number of studies assessing functional outcomes of experimental SCI increased dramatically over the past 27 years, studies with motor outcomes dramatically outnumber those with autonomic outcomes. Within the areas of autonomic dysfunction (cardiovascular, respiratory, gastrointestinal, lower urinary tract, sexual function and thermoregulation), not all aspects have been characterized to the same extent. Studies focusing on bladder and cardiovascular function greatly outnumber those on sexual function, gastrointestinal function and thermoregulation. This review addresses the disparity between well-established motor-sensory testing presently used in experimental animals and the lack of standardized autonomic testing following experimental SCI. Throughout the review, we provide information on the correlation between existing experimental and clinically used autonomic tests. Finally, the review contains a comprehensive set of tables and illustrations to guide the reader through the complexity of autonomic assessment and dysfunctions observed following SCI. A wide variety of techniques exist to evaluate autonomic function in experimental animals with SCI. The incorporation of autonomic assessment as outcome measures in experiments testing treatments or interventions for SCI should be considered a high, clinically relevant priority.

Background We have described an unusual sinonasal neoplasm which is a histological mimic of renal cell carcinoma (RCC) and coined the nosological classification “sinonasal renal cell-like adenocarcinoma” (SRCLA) to describe this unusual entity. Since the original description (Zur et al. Otolaryngol Head Neck Surg 128:441–7, 2002), we have reviewed the case reported by Moh’d Hadi et al. (Rhinology 40:44–7, 2002) and have seen two new cases in consultation. Our purpose here is to describe the additional cases and to extend the reported outcome for these patients. Design Four patients were identified. Slides and immunohistochemistry results were reviewed in consultation. Updated clinical follow-up was obtained from the respective clinicians. Results This group consisted of three women, one man, 22–69 years, and mean 46. Three tumors were in the nasal cavity and one was in the nasopharynx. Histologically, these tumors were uniformly composed of clear cells, forming either solid or glandular patterns. The tumor cells were cuboidal to polyhedral; transition to short spindle cells was seen in one case. One case revealed moderate nuclear pleomorphism. No perineural or vascular invasion, or necrosis was seen. No mucin-producing or squamous elements were seen. Immunohistochemistry (IHC) revealed the following staining profile: CK7 + (4/4), CK20 + (focal 1/4), S100 + (1/4), and CD10 + (1/2). No staining was seen for vimentin (0/4), RCC (0/2), thyroglobulin (0/2), actin (0/2), or calponin (0/2). Three patients were treated primarily with surgery, two patients also received adjuvant radiotherapy (RT); the fourth patient was treated with primary RT. All patients are disease-free, based on endoscopy and/or radiography, 2, 4, 5 and 8 years after diagnosis. Renal cell carcinoma has not been identified in any patient. Conclusion Sinonasal renal cell-like adenocarcinoma is a rare and distinct entity noteworthy in its resemblance to RCC. Immunohistochemistry can easily distinguish between these two tumors. No patient developed recurrent or metastatic disease, or was found to have RCC. Greater experience will allow us to fully understand its long-term behavior and arrive at more standardized therapeutic recommendations.

To improve science learning, science educators' teaching tools need to address two major criteria: teaching practice should mirror our current understanding of the learning process; and science teaching should reflect scientific practice. We designed a small-group learning (SGL) model for a fourth year university neurobiology course using these criteria and studied student achievement and attitude in five course sections encompassing the transition from individual work-based to SGL course design. All students completed daily quizzes/assignments involving analysis of scientific data and the development of scientific models. Students in individual work-based (Individualistic) sections usually worked independently on these assignments, whereas SGL students completed assignments in permanent groups of six. SGL students had significantly higher final exam grades than Individualistic students. The transition to the SGL model was marked by a notable increase in 10th percentile exam grade (Individualistic: 47.5%; Initial SGL: 60%; Refined SGL: 65%), suggesting SGL enhanced achievement among the least prepared students. We also studied student achievement on paired quizzes: quizzes were first completed individually and submitted, and then completed as a group and submitted. The group quiz grade was higher than the individual quiz grade of the highest achiever in each group over the term. All students – even term high achievers –could benefit from the SGL environment. Additionally, entrance and exit surveys demonstrated student attitudes toward SGL were more positive at the end of the Refined SGL course. We assert that SGL is uniquely-positioned to promote effective learning in the science classroom.

The complications of spinal cord injury (SCI) increase in number and severity with the level of injury. A recent survey of SCI researchers reveals that animal models of high SCI are essential. Despite this consensus, most laboratories continue to work with mid- or low-thoracic SCI. The available data on cervical SCI in animals characterize incomplete injuries; for example, nearly all studies published in 2009 examine discrete, tract-specific lesions that are not clinically-relevant. A primary barrier to developing animal models of severe, higher SCI is the challenge of animal care, a critical determinant of experimental outcome. Currently, many of these practices vary substantially between laboratories, and are passed down anecdotally within institutions. The care of animals with SCI is complex, and becomes much more challenging as the lesion level ascends. In our experience, the care of animals with high-thoracic (T3) SCI is much more demanding than the care of animals with low-thoracic SCI, even though both injuries result in paraplegia. We have developed an animal care regimen for rats with complete high-thoracic SCI. Our practices have been refined over the past 7 years, in collaboration with animal care centre staff and veterinarians. During this time, we have cared for more than 300 rats with T3 complete transection SCI, with experimental end-points of up to 3 months. Here we provide details of our animal care procedures, including acclimatization, housing, diet, antibiotic prophylaxis, surgical procedures, post-operative monitoring, and prevention of complications. In our laboratory, this comprehensive approach consistently produces good outcomes following T3 complete transection SCI: using body weight as an objective indicator of animal health, we have found that our rats typically return to pre-operative weights within 10 days of T3 complete SCI. It is our hope that the information provided here will improve care of experimental animals, and facilitate adoption of models that directly address the complications associated with higher level injuries.

Cardiometabolic risk factors are sorely underreported after spinal cord injury (SCI), despite the high prevalence of metabolic disorders and cardiovascular mortality in this population. Body-composition analysis and serum-lipid profiling are two assessments that are beginning to be more widely used to document metabolic changes after clinical SCI. Individuals with SCI have been reported to carry increased visceral fat and to exhibit altered serum-lipid levels. However, little is known about the development of these cardiometabolic risk factors in animal models. Using a combination of magnetic resonance imaging (MRI) and adipose tissue dissection, we show that visceral and subcutaneous adipose tissue were both increased at 1 month, but not at 1 week, after complete T3 SCI in rats. Additionally, at 1 month post injury, T3 SCI rats exhibited nonfasting serum hypertriglyceridemia, a result obtained using both standard clinical methods and a home cholesterol monitoring device (CardioChek). Interestingly, at 1 month post injury, rats with complete T10 SCI did not show an increase in either visceral adiposity or serum triglyceride levels. The fact that complete high-thoracic SCI disrupts lipid metabolism and perturbs fat storage in the subacute period, while low-thoracic SCI does not, suggests that differences in descending sympathetic control of adipose tissue might play a role in these changes. These results provide the first evidence of cardiometabolic risk factors in experimental animals with SCI, and are a starting point for investigations of the etiology of obesity and metabolic dysfunctions that often accompany SCI.

Ras-mediated signaling pathways participate in multiple aspects of neural development and function. For example, Ras signaling lies downstream of neurotrophic factors and Trk family receptor tyrosine kinases to regulate neuronal survival and morphological differentiation, including axon extension and target innervation. Neurofibromin, the protein encoded by the tumor suppressor gene Nf1, is a negative regulator of Ras [Ras-GAP (GTPase-activating protein)], and we previously demonstrated that Nf1 null embryonic sensory and sympathetic neurons can survive and differentiate independent of neurotrophin support. In this report, we demonstrate that Nf1 loss in adult sensory neurons enhances their intrinsic capacity for neurite outgrowth and collateral branching in vitro and in vivo after dorsal root injury. In contrast to the permanent sensory deficits observed in control mice after dorsal rhizotomy, neuron-specific Nf1 mutant mice spontaneously recover proprioceptive function. This phenomenon appears to be mediated both by a cell-autonomous capacity of spared Nf1−/− DRG neurons for increased axonal sprouting, and by non-cell-autonomous contribution from Nf1−/− neurons in the denervated spinal cord.

Dorsal root injury (DRI) disrupts the flow of sensory information to the spinal cord. Although primary afferents do not regenerate to their original targets, spontaneous recovery can, by unknown mechanisms, occur after DRI. Here, we show that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), but not nerve growth factor or neurotrophin-4, are upregulated in the spinal gray matter after DRI. Because endognous BDNF and NT-3 have well established roles in synaptic and axonal plasticity, we hypothesized that they contributed to spontaneous recovery after DRI. We first developed a model of DRI-induced mechanosensory dysfunction: rat C7/8 DRI produced a deficit in low-threshold cutaneous mechanosensation that spontaneously improved within 10 d but did not recover completely. To determine the effects of endogenous BDNF and NT-3, we administered TrkB-Fc or TrkC-Fc fusion proteins throughout the recovery period. To our surprise, TrkB-Fc stimulated complete recovery of mechanosensation by 6 d after DRI. It also stimulated mechanosensory axon sprouting but prevented deafferentation-induced serotonergic sprouting. TrkC-Fc had no effect on low-threshold mechanosensory behavior or axonal plasticity. There was no mechanosensory improvement with single-bolus TrkB-Fc infusions at 10 d after DRI (despite significantly reducing rhizotomy-induced cold pain), indicating that neuromodulatory effects of BDNF did not underlie mechanosensory recovery. Continuous infusion of the pan-neurotrophin antagonist K252a also stimulated behavioral and anatomical plasticity, indicating that these effects of TrkB-Fc treatment occurred independent of signaling by other neurotrophins. These results illustrate a novel, plasticity-suppressing effect of endogenous TrkB ligands on mechanosensation and mechanosensory primary afferent axons after spinal deafferentation.

Here we review mechanisms and molecules that necessitate protection and oppose axonal growth in the injured spinal cord, representing not only a cast of villains but also a company of therapeutic targets, many of which have yet to be fully exploited. We next discuss recent progress in the fields of bridging, overcoming conduction block and rehabilitation after spinal cord injury (SCI), where several treatments in each category have entered the spotlight, and some are being tested clinically. Finally, studies that combine treatments targeting different aspects of SCI are reviewed. Although experiments applying some treatments in combination have been completed, auditions for each part in the much-sought combination therapy are ongoing, and performers must demonstrate robust anatomical regeneration and/or significant return of function in animal models before being considered for a lead role.

Dorsal rhizotomy results in primary deafferentation of the dorsal horn with concomitant sprouting of spared intraspinal monoaminergic axons. Because descending monoaminergic systems are thought to mitigate nociceptive transmission from the periphery and because dorsal rhizotomy can result in neuropathic pain, we sought to determine whether the rhizotomy-induced sprouting response could be further augmented. Because myelin-derived molecules mask endogenous plasticity of CNS axons and because myelin-inhibitory signaling occurs through the Rho-GTPase pathway, we inhibited Rho-pathway signaling after cervical dorsal rhizotomy in rats. An increase in the density of serotonergic- and tyrosine hydroxylase-positive fibers was seen in the dorsal horn 1 week after septuple rhizotomy, and axon density continued to increase for at least 1 month. One week after septuple rhizotomy, administration of intrathecal Y-27632, an antagonist of Rho-kinase (ROCK), increased the density of both fiber types over vehicle-treated controls. To examine behavioral effects of both cervical rhizotomy and ROCK inhibition, we examined responses to evoked pain: mechanical and thermal allodynia and cold hyperalgesia in the forepaw were examined after single, double, and quadruple rhizotomies of dorsal roots of the brachial plexus. The most notable behavioral outcome was the development of cold hyperalgesia in the affected forepaw after rhizotomies of the C7 and C8 dorsal roots. Application of Y-27632 both attenuated cold hyperalgesia and induced monoaminergic plasticity after C7/8 rhizotomy. Thus, inhibition of Rho-pathway signaling both promoted the sprouting of intact supraspinal monoaminergic fibers and alleviated pain after dorsal rhizotomy.

Background Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. Results We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. Conclusions This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.