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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.

Olfactory ensheathing cells (OECs) may support axonal regrowth, and thus might be a viable treatment for spinal cord injury (SCI); however, peripherally-derived OECs remain untested in most animal models of SCI. We have transplanted OECs from the lamina propria (LP) of mice expressing green fluorescent protein (GFP) in all cell types into immunosuppressed rats with cervical or lumbar dorsal root injuries. LP-OECs were deposited into either the dorsal root ganglion (DRG), intact or injured dorsal roots, or the dorsal columns via the dorsal root entry zone (DREZ). LP-OECs injected into the DRG or dorsal root migrated centripetally, and migration was more extensive in the injured root than in the intact root. These peripherally deposited OECs migrated within the PNS but did not cross the DREZ; similarly, large- or small-caliber primary afferents were not seen to regenerate across the DREZ. LP-OEC deposition into the dorsal columns via the DREZ resulted in a laminin-rich injection track: due to the pipette trajectory, this track pierced the glia limitans at the DREZ. OECs migrated centrifugally through this track, but did not traverse the DREZ; axons entered the spinal cord via this track, but were not seen to reenter CNS tissue. We found a preferential association between CGRP-positive small- to medium-diameter afferents and OEC deposits in injured dorsal roots as well as within the spinal cord. In the cord, OEC deposition resulted in increased angiogenesis and altered astrocyte alignment. These data are the first to demonstrate interactions between sensory axons and peripherally-derived OECs following dorsal root injury.

Spinal cord injury is currently incurable and treatment is limited to minimising secondary complications and maximising residual function by rehabilitation. Improved understanding of the pathophysiology of spinal cord injury and the factors that prevent nerve and tissue repair has fuelled a move towards more ambitious experimental treatments aimed at promoting neuroprotection, axonal regeneration, and neuroplasticity. By necessity, these new options are more invasive. However, in view of recent advances in spinal cord injury research and demand from patients, clinicians, and the scientific community to push promising experimental treatments to the clinic, momentum and optimism exist for the translation of candidate experimental treatments to clinical spinal cord injury. The ability to rescue, reactivate, and rewire spinal systems to restore function after spinal cord injury might soon be within reach.

Several options for THz emitters and detectors operated at pump wavelengths around 1560 nm were investigated. Results from photoconductive antennas on In 0.53 Ga 0.47 As-based epilayers as well as DAST crystals are presented. Furthermore, the use of standard LTG GaAs antennas without frequency doubling is explored.

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.

Brain-derived neurotrophic factor (BDNF) has multiple effects on tropomyosin-related receptor kinase B--(TrkB) expressing neurons, including potentiation of spinal nociceptive transmission and stimulation of axon outgrowth. BDNF is upregulated in the spinal cord following dorsal root injury (DRI), a manipulation which elicits both pain and collateral sprouting. Transection of the C7 and C8 dorsal roots (C7/8 DRI) generates cold pain in the ipsilateral forepaw which peaks at 10 days, and resolves within three weeks after injury. In the present study, we investigated the influence of chronic BDNF sequestration, by intrathecal delivery of TrkB-Fc, on the plasticity of nociceptive circuitry and resultant cold pain behaviour following spinal deafferentation. C7/8 DRI resulted in a pronounced deafferentation of the C7 dorsal horn and significant depletion of both peptidergic- and non-peptidergic nociceptive projections. While changes in GAP-43 expression revealed that endogenous BDNF was exerting an overall plasticity-promoting influence on intraspinal axons after DRI, continuous TrkB-Fc treatment stimulated sprouting of nociceptive terminals. DRI stimulated a BDNF-dependent increase in the density of GABAergic interneuronal processes, as indicated by increased vesicular GABA transporter--(VGAT) and neuropeptide Y--(NPY) positive terminal densities. Finally, chronic TrkB-Fc treatment prevented cold pain resolution. These findings demonstrate that endogenous BDNF has both plasticity-promoting and plasticity-suppressing effects on the intrinsic spinal components of nociceptive circuitry, which are likely to underlie cold pain behaviour following C7/8 DRI.

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.

Functional re-innervation of target neurons following neurological damage such as spinal cord injury is an essential requirement of potential therapies. There are at least two avenues by which this can be achieved: (a) through the regeneration of injured axons and (b) through promoting plasticity of those spared by the initial insult. There are several reasons why the latter approach may be more feasible, not the least of which are the inhibitory character of the glial scar, the often long distances over which injured axons must regrow, and the fact that spared axons are often already in the vicinity of denervated targets. The challenge is to unveil the well-recognized intrinsic plasticity of spared axons in a way that avoids complications, such as pain or autonomic dysfunction. One approach that we as well as others have taken is to target growth-suppressing signaling pathways initiated in spared axons by myelin-derived proteins. This article reviews models used for the study of spinal axon plasticity and describes the anatomical and behavioral effects of interfering with myelinderived proteins, their receptors, and components of their intracellular signaling cascades.

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.

International Collaboration on Repair Discoveries, University of British Columbia,Vancouver, British Columbia V6T 1Z4, CanadaABSTRACTBridging of a lesion site and minimizing local damage to create an environment permis-sive for regeneration are both primary components of a successful strategy to repair spinalcord injury (SCI). Olfactory ensheathing cells (OECs) are prime candidates for autologoustransplantation to bridge this gap, but little is known currently about their mechanism ofaction. In addition, OECs from the accessible lamina propria (LP) of the olfactory mucosa area more viable source in humans but have yet to be tested for their ability to promoteregeneration in established SCI models. Here, mouse LP-OECs expressing green fluorescentprotein (GFP) transplanted directly into both rat and mouse dorsolateral spinal cord lesionsites demonstrate limited migration but interact with host astrocytes to develop a newtransitional zone at the lesion border. LP-OECs also promote extensive migration of hostSchwann cells into the central nervous system repair zone and stimulate angiogenesis toprovide a biological scaffold for repair. This novel environment created by transplanted andhost glia within the spinal cord inhibits cavity and scar formation and promotes extensivesprouting of multiple sensory and motor axons into and through the lesion site. Sixty daysafter rat SCI, serotonin- and tyrosine hydroxylase-positive axons sprouted across the lesioninto the distal cord, although axotomized rubrospinal axons did not. Thus, even in a xeno-transplant paradigm, LP-OECs work collaboratively with host glial cells to create an envi-ronment to ameliorate local damage and simultaneously promote a regenerative response inmultiple axonal populations. J. Comp. Neurol. 473:1–15, 2004.

Melanin pigmentation of the oral cavity among tobacco smokers, "smoker's melanosis", was first described by Hedin in 1977. Studies performed on dark skinned ethnic groups found that although nearly all non-tobacco users had oral melanin pigmentation; tobacco smokers had significantly more oral surfaces pigmented than non-tobacco users. We present a case of oral smokers melanosis involving the tongue of a 37-year-old black female.

The keratoameloblastoma is a rare histologic variant of the ameloblastoma. Review of the English language literature revealed five case reports of keratoameloblastoma. We report the sixth case of this tumor. The tumor developed in the right posterior maxilla of a 26-year-old African-American man and demonstrated aggressive clinical behavior, analogous to conventional ameloblastoma. The initial biopsy specimen showed extensive cyst formation, which histologically resembled odontogenic keratocyst. However, the lining epithelium varied in thickness and there was separation and edema between the basal cells and the rest of the epithelium. The basal cells were strongly adherent to the underlying stroma unlike the basal layer of the odontogenic keratocyst, where cleavage often occurs in this area. Additionally, although the basal cells were palisaded and demonstrated nuclear polarization in areas, they were cuboidal rather than columnar. The excision specimen revealed more of a solid ameloblastic component in addition to the cystic component seen on the initial biopsy. Nevertheless, it is possible that the ameloblastoma had developed in an odontogenic keratocyst. Alternatively, it can be postulated that the keratoameloblastoma consists of both cystic and solid components, the former being analogous to the cysts of the conventional ameloblastoma.

The glandular odontogenic cyst is a rare jawbone cyst of odontogenic origin, first described in 1988 by Gardner et al. We describe a previously unreported case of a combined cyst composed of glandular odontogenic cyst and ghost cell keratinization that was present for 33 years. We also reviewed the published 38 cases of glandular odontogenic cyst found in the world literature and add this additional case.

Hypophosphatasia is a hereditary disease that can present as premature exfoliation of deciduous dentition in young children. We present a case of a 32-month-old female with a history of skeletal problems who spontaneously exfoliated three mandibular primary teeth. It was the premature exfoliation of her mandibular teeth that led to the diagnosis of childhood hypophosphatasia.

Hairy leukoplakia, often seen in patients with acquired immunodeficiency syndrome, is strongly associated with Epstein-Barr virus (EBV) infection and questionably associated with human papillomavirus (HPV) infection. To date, most in situ hybridization (ISH) studies suggest that the EBV is localized only to the superficial squamous layers, favoring the theory of lingual infection by saliva rather than by reactivation of latent lingual infection. We describe 11 formalin-fixed, paraffin-embedded specimens from patients with lingual hairy leukoplakia that we examined for the presence of the EBV, HPV, cytomegalovirus, and human immunodeficiency virus. We used standard DNA ISH for the EBV and cytomegalovirus and polymerase chain reaction ISH for the EBV, HPV, and human immunodeficiency virus. The EBV was present in all 11 specimens according to polymerase chain reaction ISH studies but in only seven specimens according to conventional DNA ISH. Polymerase chain reaction ISH localized the EBV to the basal and parabasal layers in addition to the strong localization in the upper epithelial layers. No evidence for HPV or cytomegalovirus DNA was found. The human immunodeficiency virus was focally localized to rare superficial squamous cells in seven specimens. The presence of EBV DNA in basal and parabasal lingual cells, as well as localization of latency-associated proteins in these layers, suggests that hairy leukoplakia in patients with acquired immunodeficiency syndrome might represent a reactivation of latent lingual infection accompanied by a dramatic increase in viral copy number in the more mature, superficial, squamous cells. The human immunodeficiency virus was also found in seven specimens, but the significance of this new finding is uncertain and requires further study. There is no evidence to suggest that the HPV is involved in the development of hairy leukoplakia.

Steroid ketones were found to react with diethyl cyanomethylphosphonate in the presence of dimsyl anion and dimethyl sulfoxide at room temperature forming conjugated nitriles. Ketones at positions 2,4,6,7,12, and 15 readily afforded unsaturated nitriles. The yield of Δ 4 -3-cyano-methylene steroids from Δ 4 -3-ketosteroids was high under these conditions. The sterically hindered ketone from lanosterol also could be converted to an unsaturated nitrile. Ketones at positions 1 and 11 were found to be unreactive even when dimsyl anion and dimethyl sulfoxide were used. 16-Ketoprogesterone did not react, probably because it is a β -diketone.

A synthesis of ⨿-lactams has been achieved using intramolecular Michael addition of a substituted acrylamide of type IV. The scope of the reaction has been studied and the possibility of retro-Michael reaction has been investigated.

Thirty-five infants born over a two-year period to mothers participating in a methadone-maintenance treatment program were studied The average birthweight was normal (3240 gms) for infants born to mothers who conceived while taking methadone, and 465 gms less (2775 gms) for infants conceived while their mothers were taking heroin (p less than .01). Sixty percent of the infants demonstrated mild or no symptoms and 40% developed moderate or severe symptoms. The infants whose symptoms were most severe were born to mothers who had documented histories of polydrug abuse. Many infants were slow to gain weight in the neonatal period. Thereafter growth and development have remained generally within the normal range.

Under the conditions of this study, tritiated pilocarpine was topically applied to rabbits, and the activity in the aqueous humor was measured at selected times. It was found that higher pH affords greater pilocarpine penetration. At pH 7.5, for example, penetration into the aqueous was twice as great as at pH 4.

Under the conditions of this study, systemically or topically applied thimerosal was found to have no teratogenic effect even when given in concentrations approaching the 50% lethal dose of these compounds. A comparison of topical and subcutaneous administration of thimerosal to rabbits shows that a substantial concentration of mercury was present in blood and tissues of the treated animals and their offspring. Thimerosal was found to cross the blood-brain and placenta barriers.