Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats

PubMed Central

Manohar, Anitha; Foffani, Guglielmo; Ganzer, Patrick D; Bethea, John R; Moxon, Karen A

2017-01-01

After paralyzing spinal cord injury the adult nervous system has little ability to ‘heal’ spinal connections, and it is assumed to be unable to develop extra-spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rats can thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury. DOI: http://dx.doi.org/10.7554/eLife.23532.001 PMID:28661400

Sim1 is required for the migration and axonal projections of V3 interneurons in the developing mouse spinal cord.

PubMed

Blacklaws, Jake; Deska-Gauthier, Dylan; Jones, Christopher T; Petracca, Yanina L; Liu, Mingwei; Zhang, Han; Fawcett, James P; Glover, Joel C; Lanuza, Guillermo M; Zhang, Ying

2015-09-01

V3 spinal interneurons (INs) are a group of excitatory INs that play a crucial role in producing balanced and stable gaits in vertebrate animals. In the developing mouse spinal cord, V3 INs arise from the most ventral progenitor domain and form anatomically distinctive subpopulations in adult spinal cords. They are marked by the expression of transcription factor Sim1 postmitotically, but the function of Sim1 in V3 development remains unknown. Here, we used Sim1(Cre) ;tdTomato mice to trace the fate of V3 INs in a Sim1 mutant versus control genetic background during development. In Sim1 mutants, V3 INs are produced normally and maintain a similar position and organization as in wild types before E12.5. Further temporal analysis revealed that the V3 INs in the mutants failed to migrate properly to form V3 subgroups along the dorsoventral axis of the spinal cord. At birth, in the Sim1 mutant the number of V3 INs in the ventral subgroup was normal, but they were significantly reduced in the dorsal subgroup with a concomitant increase in the intermediate subgroup. Retrograde labeling at lumbar level revealed that loss of Sim1 led to a reduction in extension of contralateral axon projections both at E14.5 and P0 without affecting ipsilateral axon projections. These results demonstrate that Sim1 is essential for proper migration and the guidance of commissural axons of the spinal V3 INs. © 2015 Wiley Periodicals, Inc.

Positioning and spinal bracing for pain relief in metastatic spinal cord compression in adults.

PubMed

Lee, Siew Hwa; Grant, Robin; Kennedy, Catriona; Kilbride, Lynn

2015-09-24

This is an updated version of the original Cochrane review published in Issue 3 (Lee 2012) on patient positioning (mobilisation) and bracing for pain relief and spinal stability in adults with metastatic spinal cord compression.Many patients with metastatic spinal cord compression (MSCC) have spinal instability, but their clinician has determined that due to their advanced disease they are unsuitable for surgical internal fixation. Mobilising may be hazardous in the presence of spinal instability as further vertebral collapse can occur. Current guidance on positioning (whether a patient should be managed with bed rest or allowed to mobilise) and whether spinal bracing is helpful, is contradictory. To investigate the correct positioning and examine the effects of spinal bracing to relieve pain or to prevent further vertebral collapse in patients with MSCC. For this update, we searched for relevant studies from February 2012 to 31 March 2015. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and MEDLINE In Process, EMBASE, AMED, CINAHL, TRIP, SIGN, NICE, UK Clinical Research Network, National Guideline Clearinghouse and PEDro database. We also searched the metaRegister of Controlled Trials (mRCT), ClinicalTrials.gov, UK Clinical Trials Gateway (UKCTG), WHO International Clinical Trials Registry Platform (ICTRP) and Australia New Zealand Clinical Trials Registry (ANZCTR).For the original version, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, CANCERLIT, NICE, SIGN, AMED, TRIP, National Guideline Clearinghouse, and PEDro database, in February 2012. We selected randomised controlled trials (RCTs) of adults with MSCC of interventions on positioning (mobilisation) and bracing. Two review authors independently assessed each possible study for inclusion and quality. For the original version of the review, we screened 1611 potentially relevant studies. No studies met the inclusion criteria

Full Tensor Diffusion Imaging Is Not Required To Assess the White-Matter Integrity in Mouse Contusion Spinal Cord Injury

PubMed Central

Tu, Tsang-Wei; Kim, Joong H.; Wang, Jian

2010-01-01

Abstract In vivo diffusion tensor imaging (DTI) derived indices have been demonstrated to quantify accurately white-matter injury after contusion spinal cord injury (SCI) in rodents. In general, a full diffusion tensor analysis requires the acquisition of diffusion-weighted images (DWI) along at least six independent directions of diffusion-sensitizing gradients. Thus, DTI measurements of the rodent central nervous system are time consuming. In this study, diffusion indices derived using the two-direction DWI (parallel and perpendicular to axonal tracts) were compared with those obtained using six-direction DTI in a mouse model of SCI. It was hypothesized that the mouse spinal cord ventral-lateral white-matter (VLWM) tracts, T8–T10 in this study, aligned with the main magnet axis (z) allowing the apparent diffusion coefficient parallel and perpendicular to the axis of the spine to be derived with diffusion-weighting gradients in the z and y axes of the magnet coordinate respectively. Compared with six-direction full tensor DTI, two-direction DWI provided comparable diffusion indices in mouse spinal cords. The measured extent of spared white matter after injury, estimated by anisotropy indices, using both six-direction DTI and two-direction DWI were in close agreement and correlated well with histological staining and behavioral assessment. The results suggest that the two-direction DWI derived indices may be used, with significantly reduced imaging time, to estimate accurately spared white matter in mouse SCI. PMID:19715399

The contribution of mouse models to understanding the pathogenesis of spinal muscular atrophy

PubMed Central

Sleigh, James N.; Gillingwater, Thomas H.; Talbot, Kevin

2011-01-01

Spinal muscular atrophy (SMA), which is caused by inactivating mutations in the survival motor neuron 1 (SMN1) gene, is characterized by loss of lower motor neurons in the spinal cord. The gene encoding SMN is very highly conserved in evolution, allowing the disease to be modeled in a range of species. The similarities in anatomy and physiology to the human neuromuscular system, coupled with the ease of genetic manipulation, make the mouse the most suitable model for exploring the basic pathogenesis of motor neuron loss and for testing potential treatments. Therapies that increase SMN levels, either through direct viral delivery or by enhancing full-length SMN protein expression from the SMN1 paralog, SMN2, are approaching the translational stage of development. It is therefore timely to consider the role of mouse models in addressing aspects of disease pathogenesis that are most relevant to SMA therapy. Here, we review evidence suggesting that the apparent selective vulnerability of motor neurons to SMN deficiency is relative rather than absolute, signifying that therapies will need to be delivered systemically. We also consider evidence from mouse models suggesting that SMN has its predominant action on the neuromuscular system in early postnatal life, during a discrete phase of development. Data from these experiments suggest that the timing of therapy to increase SMN levels might be crucial. The extent to which SMN is required for the maintenance of motor neurons in later life and whether augmenting its levels could treat degenerative motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), requires further exploration. PMID:21708901

Transspinal direct current stimulation modulates migration and proliferation of adult newly born spinal cells in mice.

PubMed

Samaddar, Sreyashi; Vazquez, Kizzy; Ponkia, Dipen; Toruno, Pedro; Sahbani, Karim; Begum, Sultana; Abouelela, Ahmed; Mekhael, Wagdy; Ahmed, Zaghloul

2017-02-01

Direct current electrical fields have been shown to be a major factor in the regulation of cell proliferation, differentiation, migration, and survival, as well as in the maturation of dividing cells during development. During adulthood, spinal cord cells are continuously produced in both animals and humans, and they hold great potential for neural restoration following spinal cord injury. While the effects of direct current electrical fields on adult-born spinal cells cultured ex vivo have recently been reported, the effects of direct current electrical fields on adult-born spinal cells in vivo have not been characterized. Here, we provide convincing findings that a therapeutic form of transspinal direct current stimulation (tsDCS) affects the migration and proliferation of adult-born spinal cells in mice. Specifically, cathodal tsDCS attracted the adult-born spinal cells, while anodal tsDCS repulsed them. In addition, both tsDCS polarities caused a significant increase in cell number. Regarding the potential mechanisms involved, both cathodal and anodal tsDCS caused significant increases in expression of brain-derived neurotrophic factor, while expression of nerve growth factor increased and decreased, respectively. In the spinal cord, both anodal and cathodal tsDCS increased blood flow. Since blood flow and angiogenesis are associated with the proliferation of neural stem cells, increased blood flow may represent a major factor in the modulation of newly born spinal cells by tsDCS. Consequently, we propose that the method and novel findings presented in the current study have the potential to facilitate cellular, molecular, and/or bioengineering strategies to repair injured spinal cords. NEW & NOTEWORTHY Our results indicate that transspinal direct current stimulation (tsDCS) affects the migratory pattern and proliferation of adult newly born spinal cells, a cell population which has been implicated in learning and memory. In addition, our results suggest a

The increased prevalence of cervical spondylosis in patients with adult thoracolumbar spinal deformity.

PubMed

Schairer, William W; Carrer, Alexandra; Lu, Michael; Hu, Serena S

2014-12-01

Retrospective cohort study. To assess the concomitance of cervical spondylosis and thoracolumbar spinal deformity. Patients with degenerative cervical spine disease have higher rates of degeneration in the lumbar spine. In addition, degenerative cervical spine changes have been observed in adult patients with thoracolumbar spinal deformities. However, to the best of our knowledge, there have been no studies quantifying the association between cervical spondylosis and thoracolumbar spinal deformity in adult patients. Patients seen by a spine surgeon or spine specialist at a single institution were assessed for cervical spondylosis and/or thoracolumbar spinal deformity using an administrative claims database. Spinal radiographic utilization and surgical intervention were used to infer severity of spinal disease. The relative prevalence of each spinal diagnosis was assessed in patients with and without the other diagnosis. A total of 47,560 patients were included in this study. Cervical spondylosis occurred in 13.1% overall, but was found in 31.0% of patients with thoracolumbar spinal deformity (OR=3.27, P<0.0001). Similarly, thoracolumbar spinal deformity was found in 10.7% of patients overall, but was increased at 23.5% in patients with cervical spondylosis (OR=3.26, P<0.0001). In addition, increasing severity of disease was associated with an increased likelihood of the other spinal diagnosis. Patients with both diagnoses were more likely to undergo both cervical (OR=3.23, P<0.0001) and thoracolumbar (OR=4.14, P<0.0001) spine fusion. Patients with cervical spondylosis or thoracolumbar spinal deformity had significantly higher rates of the other spinal diagnosis. This correlation was increased with increased severity of disease. Patients with both diagnoses were significantly more likely to have received a spine fusion. Further research is warranted to establish the cause of this correlation. Clinicians should use this information to both screen and counsel patients

Terminations of reticulospinal fibers originating from the gigantocellular reticular formation in the mouse spinal cord.

PubMed

Liang, Huazheng; Watson, Charles; Paxinos, George

2016-04-01

The present study investigated the projections of the gigantocellular reticular nucleus (Gi) and its neighbors--the dorsal paragigantocellular reticular nucleus (DPGi), the alpha/ventral part of the gigantocellular reticular nucleus (GiA/V), and the lateral paragigantocellular reticular nucleus (LPGi)--to the mouse spinal cord by injecting the anterograde tracer biotinylated dextran amine (BDA) into the Gi, DPGi, GiA/GiV, and LPGi. The Gi projected to the entire spinal cord bilaterally with an ipsilateral predominance. Its fibers traveled in both the ventral and lateral funiculi with a greater presence in the ventral funiculus. As the fibers descended in the spinal cord, their density in the lateral funiculus increased. The terminals were present mainly in laminae 7-10 with a dorsolateral expansion caudally. In the lumbar and sacral cord, a considerable number of terminals were also present in laminae 5 and 6. Contralateral fibers shared a similar pattern to their ipsilateral counterparts and some fibers were seen to cross the midline. Fibers arising from the DPGi were similarly distributed in the spinal cord except that there was no dorsolateral expansion in the lumbar and sacral segments and there were fewer fiber terminals. Fibers arising from GiA/V predominantly traveled in the ventral and lateral funiculi ipsilaterally. Ipsilaterally, the density of fibers in the ventral funiculus decreased along the rostrocaudal axis, whereas the density of fibers in the lateral funiculus increased. They terminate mainly in the medial ventral horn and lamina 10 with a smaller number of fibers in the dorsal horn. Fibers arising from the LPGi traveled in both the ventral and lateral funiculi and the density of these fibers in the ventral and lateral funiculi decreased dramatically in the lumbar and sacral segments. Their terminals were present in the ventral horn with a large portion of them terminating in the motor neuron columns. The present study is the first demonstration

The adult spinal cord injury without radiographic abnormalities syndrome: magnetic resonance imaging and clinical findings in adults with spinal cord injuries having normal radiographs and computed tomography studies.

PubMed

Kasimatis, Georgios B; Panagiotopoulos, Elias; Megas, Panagiotis; Matzaroglou, Charalambos; Gliatis, John; Tyllianakis, Minos; Lambiris, Elias

2008-07-01

Spinal cord injury without radiographic abnormalities (SCIWORA) is thought to represent mostly a pediatric entity and its incidence in adults is rather underreported. Some authors have also proposed the term spinal cord injury without radiologic evidence of trauma, as more precisely describing the condition of adult SCIWORA in the setting of cervical spondylosis. The purpose of the present study was to evaluate adult patients with cervical spine injuries and radiological-clinical examination discrepancy, and to discuss their characteristics and current management. During a 16-year period, 166 patients with a cervical spine injury were admitted in our institution (Level I trauma center). Upper cervical spine injuries (occiput to C2, 54 patients) were treated mainly by a Halo vest, whereas lower cervical spine injuries (C3-T1, 112 patients) were treated surgically either with an anterior, or posterior procedure, or both. Seven of these 166 patients (4.2%) had a radiologic-clinical mismatch, i.e., they presented with frank spinal cord injury with no signs of trauma, and were included in the study. Magnetic resonance imaging was available for 6 of 7 patients, showing intramedullary signal changes in 5 of 6 patients with varying degrees of compression from the disc and/or the ligamentum flavum, whereas the remaining patient had only traumatic herniation of the intervertebral disc and ligamentum flavum bulging. Follow-up period was 6.4 years on average (1-10 years). This retrospective chart review provides information on adult patients with cervical spinal cord injuries whose radiographs and computed tomography studies were normal. It furthers reinforces the pathologic background of SCIWORA in an adult population, when evaluated by magnetic resonance imaging. Particularly for patients with cervical spondylosis, special attention should be paid with regard to vascular compromise by predisposing factors such as smoking or vascular disease, since they probably contribute in

GDNF and NGF family members and receptors in human fetal and adult spinal cord and dorsal root ganglia.

PubMed

Josephson, A; Widenfalk, J; Trifunovski, A; Widmer, H R; Olson, L; Spenger, C

2001-11-12

We describe the expression of mRNA encoding ligands and receptors of members of the GDNF family and members of the neurotrophin family in the adult human spinal cord and dorsal root ganglia (DRG). Fetal human spinal cord and ganglia were investigated for the presence of ligands and receptors of the neurotrophin family. Tissues were collected from human organ donors and after routine elective abortions. Messenger RNA was found encoding RET, GFR alpha-1, BDNF, trkB, and trkC in the adult human spinal cord and BDNF, NT-3, p75, trkB, and trkC in the fetal human spinal cord. The percentage of adult human DRG cells expressing p75, trkA, trkB, or trkC was 57, 46, 29, and 24%, respectively, and that of DRG cells expressing RET, GFR alpha-1, GFR alpha-2, or GFR alpha-3 was 79, 20, 51, and 32%, respectively. GFR alpha-2 was expressed selectively in small, GFR alpha-3 principally in small and GFR alpha-1 and RET in both large and small adult human DRG neurons. p75 and trkB were expressed by a wide range of DRG neurons while trkA was expressed in most small diameter and trkC primarily in large DRG neurons. Fetal DRG cells were positive for the same probes as adult DRG cells except for NT-3, which was only found in fetal DRG cells. Messenger RNA species only expressed at detectable levels in fetal but not adult spinal cord tissues included GDNF, GFR alpha-2, NT-3, and p75. Notably, GFR alpha-2, which is expressed in the adult rat spinal cord, was not found in the adult human spinal cord. Copyright 2001 Wiley-Liss, Inc.

Deletion of atrophy enhancing genes fails to ameliorate the phenotype in a mouse model of spinal muscular atrophy.

PubMed

Iyer, Chitra C; McGovern, Vicki L; Wise, Dawnne O; Glass, David J; Burghes, Arthur H M

2014-05-01

Spinal muscular atrophy (SMA) is an autosomal recessive disease causing degeneration of lower motor neurons and muscle atrophy. One therapeutic avenue for SMA is targeting signaling pathways in muscle to ameliorate atrophy. Muscle Atrophy F-box, MAFbx, and Muscle RING Finger 1, MuRF1, are muscle-specific ubiquitin ligases upregulated in skeletal and cardiac muscle during atrophy. Homozygous knock-out of MAFbx or MuRF1 causes muscle sparing in adult mice subjected to atrophy by denervation. We wished to determine whether blockage of the major muscle atrophy pathways by deletion of MAFbx or MuRF1 in a mouse model of SMA would improve the phenotype. Deletion of MAFbx in the Δ7 SMA mouse model had no effect on the weight and the survival of the mice while deletion of MuRF1 was deleterious. MAFbx(-/-)-SMA mice showed a significant alteration in fiber size distribution tending towards larger fibers. In skeletal and cardiac tissue MAFbx and MuRF1 transcripts were upregulated whereas MuRF2 and MuRF3 levels were unchanged in Δ7 SMA mice. We conclude that deletion of the muscle ubiquitin ligases does not improve the phenotype of a Δ7 SMA mouse. Furthermore, it seems unlikely that the beneficial effect of HDAC inhibitors is mediated through inhibition of MAFbx and MuRF1. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterization of Proliferating Neural Progenitors after Spinal Cord Injury in Adult Zebrafish

PubMed Central

Hui, Subhra Prakash; Nag, Tapas Chandra; Ghosh, Sukla

2015-01-01

Zebrafish can repair their injured brain and spinal cord after injury unlike adult mammalian central nervous system. Any injury to zebrafish spinal cord would lead to increased proliferation and neurogenesis. There are presences of proliferating progenitors from which both neuronal and glial loss can be reversed by appropriately generating new neurons and glia. We have demonstrated the presence of multiple progenitors, which are different types of proliferating populations like Sox2+ neural progenitor, A2B5+ astrocyte/ glial progenitor, NG2+ oligodendrocyte progenitor, radial glia and Schwann cell like progenitor. We analyzed the expression levels of two common markers of dedifferentiation like msx-b and vimentin during regeneration along with some of the pluripotency associated factors to explore the possible role of these two processes. Among the several key factors related to pluripotency, pou5f1 and sox2 are upregulated during regeneration and associated with activation of neural progenitor cells. Uncovering the molecular mechanism for endogenous regeneration of adult zebrafish spinal cord would give us more clues on important targets for future therapeutic approach in mammalian spinal cord repair and regeneration. PMID:26630262

Postnatal maturation of mouse medullo-spinal cerebrospinal fluid-contacting neurons.

PubMed

Orts-Del'Immagine, Adeline; Trouslard, Jérôme; Airault, Coraline; Hugnot, Jean-Philippe; Cordier, Baptiste; Doan, Thierry; Kastner, Anne; Wanaverbecq, Nicolas

2017-02-20

The central canal along the spinal cord (SC.) and medulla is characterized by the presence of a specific population of neurons that contacts the cerebrospinal fluid (CSF). These medullo-spinal CSF-contacting neurons (CSF-cNs) are identified by the selective expression of the polycystin kidney disease 2-like 1 ionic channel (PKD2L1 or polycystin-L). In adult, they have been shown to express doublecortin (DCX) and Nkx6.1, two markers of juvenile neurons along with the neuron-specific nuclear protein (NeuN) typically expressed in mature neurons. They were therefore suggested to remain in a rather incomplete maturation state. The aim of this study was to assess whether such juvenile state is stable in postnatal animals or whether CSF-cNs may reach maturity at older stages than neurons in the parenchyma. We show, in the cervical SC. and the brainstem that, in relation to age, CSF-cN density declines and that their cell bodies become more distant from the cc, except in its ventral part. Moreover, in adults (from 1month) by comparison with neonatal mice, we show that CSF-cNs have evolved to a more mature state, as indicated by the increase in the percentage of cells positive for NeuN and of its level of expression. In parallel, CSF-cNs exhibit, in adult, lower DCX immunoreactivity and do not express PSA-NCAM and TUC4, two neurogenic markers. Nevertheless, CSF-cNs still share in adult characteristics of juvenile neurons such as the presence of phospho-CREB and DCX while NeuN expression remained low. This phenotype persists in 12-month-old animals. Thus, despite a pursuit of neuronal maturation during the postnatal period, CSF-cNs retain a durable low differentiated state. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

A brain-specific gene cluster isolated from the region of the mouse obesity locus is expressed in the adult hypothalamus and during mouse development

DOE Office of Scientific and Technical Information (OSTI.GOV)

Laig-Webster, M.; Lim, M.E.; Chehab, F.F.

1994-09-01

The molecular defect underlying an autosomal recessive form of genetic obesity in a classical mouse model C57 BL/6J-ob/ob has not yet been elucidated. Whereas metabolic and physiological disturbances such as diabetes and hypertension are associated with obesity, the site of expression and the nature of the primary lesion responsible for this cascade of events remains elusive. Our efforts aimed at the positional cloning of the ob gene by YAC contig mapping and gene identification have resulted in the cloning of a brain-specific gene cluster from the ob critical region. The expression of this gene cluster is remarkably complex owing tomore » the multitude of brain-specific mRNA transcripts detected on Northern blots. cDNA cloning of these transcripts suggests that they are expressed from different genes as well as by alternate splicing mechanisms. Furthermore, the genomic organization of the cluster appears to consist of at least two identical promoters displaying CpG islands characteristic of housekeeping genes, yet clearly involving tissue-specific expression. Sense and anti-sense synthetic RNA probes were derived from a common DNA sequence on 3 cDNA clones and hybridized to 8-16 days mouse embryonic stages and mouse adult brain sections. Expression in development was noticeable as of the 11th day of gestation and confined to the central nervous system mainly in the telencephalon and spinal cord. Coronal and sagittal sections of the adult mouse brain showed expression only in 3 different regions of the brain stem. In situ hybridization to mouse hypothalamus sections revealed the presence of a localized and specialized group of cells expressing high levels of mRNA, suggesting that this gene cluster may also be involved in the regulation of hypothalamic activities. The hypothalamus has long been hypothesized as a primary candidate tissue for the expression of the obesity gene mainly because of its well-established role in the regulation of energy metabolism and

BAMOS: A recording application for BAsso MOuse scale of locomotion in experimental models of spinal cord injury.

PubMed

Gómez, Alberto; Nieto-Díaz, Manuel; Del Águila, Ángela; Arias, Enrique

2018-05-01

Transparency in science is increasingly a hot topic. Scientists are required to show not only results but also evidence of how they have achieved these results. In experimental studies of spinal cord injury, there are a number of standardized tests, such as the Basso-Beattie-Bresnahan locomotor rating scale for rats and Basso Mouse Scale for mice, which researchers use to study the pathophysiology of spinal cord injury and to evaluate the effects of experimental therapies. Although the standardized data from the Basso-Beattie-Bresnahan locomotor rating scale and the Basso Mouse Scale are particularly suited for storage and sharing in databases, systems of data acquisition and repositories are still lacking. To the best of our knowledge, both tests are usually conducted manually, with the data being recorded on a paper form, which may be documented with video recordings, before the data is transferred to a spreadsheet for analysis. The data thus obtained is used to compute global scores, which is the information that usually appears in publications, with a wealth of information being omitted. This information may be relevant to understand locomotion deficits or recovery, or even important aspects of the treatment effects. Therefore, this paper presents a mobile application to record and share Basso Mouse Scale tests, meeting the following criteria: i) user-friendly; ii) few hardware requirements (only a smartphone or tablet with a camera running under Android Operating System); and iii) based on open source software such as SQLite, XML, Java, Android Studio and Android SDK. The BAMOS app can be downloaded and installed from the Google Market repository and the app code is available at the GitHub repository. The BAMOS app demonstrates that mobile technology constitutes an opportunity to develop tools for aiding spinal cord injury scientists in recording and sharing experimental data. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparison of alpha-synuclein immunoreactivity in the spinal cord between the adult and aged beagle dog

PubMed Central

Ahn, Ji-Hyeon; Choi, Jung-Hoon; Park, Joon-Ha; Yan, Bing-Chun; Kim, In-Hye; Lee, Jae-Chul; Lee, Dae-Hwan; Kim, Jin-Sang

2012-01-01

Alpha-synuclein (α-syn) is a presynaptic protein that is richly expressed in the central and peripheral nervous systems of mammals, and it is related to the pathogenesis of Parkinson's disease and other neurodegenerative disorders. In the present study, we compared the distribution of the immunoreactivity of α-syn and its related gliosis in the spinal cord of young adult (2-3 years) and aged (10-12 years) beagle dogs. We discovered that α-syn immunoreactivity was present in many neurons in the thoracic level of the aged spinal cord, however, its protein level was not distinct inform that of the adult spinal cord. In addition, ionized calcium-binding adapter molecule-1 (a marker for microglia) immunoreactivity, and not glial fibrillary acidic protein (a marker for astrocytes) immunoreactivity, was somewhat increased in the aged group compared to the adult group. These results indicate that α-syn immunoreactivity was not dramatically changed in the dog spinal cord during aging. PMID:23091516

Spinal Interneurons and Forelimb Plasticity after Incomplete Cervical Spinal Cord Injury in Adult Rats

PubMed Central

Rombola, Angela M.; Rousseau, Celeste A.; Mercier, Lynne M.; Fitzpatrick, Garrett M.; Reier, Paul J.; Fuller, David D.; Lane, Michael A.

2015-01-01

Abstract Cervical spinal cord injury (cSCI) disrupts bulbospinal projections to motoneurons controlling the upper limbs, resulting in significant functional impairments. Ongoing clinical and experimental research has revealed several lines of evidence for functional neuroplasticity and recovery of upper extremity function after SCI. The underlying neural substrates, however, have not been thoroughly characterized. The goals of the present study were to map the intraspinal motor circuitry associated with a defined upper extremity muscle, and evaluate chronic changes in the distribution of this circuit following incomplete cSCI. Injured animals received a high cervical (C2) lateral hemisection (Hx), which compromises supraspinal input to ipsilateral spinal motoneurons controlling the upper extremities (forelimb) in the adult rat. A battery of behavioral tests was used to characterize the time course and extent of forelimb motor recovery over a 16 week period post-injury. A retrograde transneuronal tracer – pseudorabies virus – was used to define the motor and pre-motor circuitry controlling the extensor carpi radialis longus (ECRL) muscle in spinal intact and injured animals. In the spinal intact rat, labeling was observed unilaterally within the ECRL motoneuron pool and within spinal interneurons bilaterally distributed within the dorsal horn and intermediate gray matter. No changes in labeling were observed 16 weeks post-injury, despite a moderate degree of recovery of forelimb motor function. These results suggest that recovery of the forelimb function assessed following C2Hx injury does not involve recruitment of new interneurons into the ipsilateral ECRL motor pathway. However, the functional significance of these existing interneurons to motor recovery requires further exploration. PMID:25625912

Regulation of Survival Motor Neuron Protein by the Nuclear Factor-Kappa B Pathway in Mouse Spinal Cord Motoneurons.

PubMed

Arumugam, Saravanan; Mincheva-Tasheva, Stefka; Periyakaruppiah, Ambika; de la Fuente, Sandra; Soler, Rosa M; Garcera, Ana

2018-06-01

Survival motor neuron (SMN) protein deficiency causes the genetic neuromuscular disorder spinal muscular atrophy (SMA), characterized by spinal cord motoneuron degeneration. Since SMN protein level is critical to disease onset and severity, analysis of the mechanisms involved in SMN stability is one of the central goals of SMA research. Here, we describe the role of several members of the NF-κB pathway in regulating SMN in motoneurons. NF-κB is one of the main regulators of motoneuron survival and pharmacological inhibition of NF-κB pathway activity also induces mouse survival motor neuron (Smn) protein decrease. Using a lentiviral-based shRNA approach to reduce the expression of several members of NF-κB pathway, we observed that IKK and RelA knockdown caused Smn reduction in mouse-cultured motoneurons whereas IKK or RelB knockdown did not. Moreover, isolated motoneurons obtained from the severe SMA mouse model showed reduced protein levels of several NF-κB members and RelA phosphorylation. We describe the alteration of NF-κB pathway in SMA cells. In the context of recent studies suggesting regulation of altered intracellular pathways as a future pharmacological treatment of SMA, we propose the NF-κB pathway as a candidate in this new therapeutic approach.

Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation.

PubMed

Farooq, Faraz; Abadía-Molina, Francisco; MacKenzie, Duncan; Hadwen, Jeremiah; Shamim, Fahad; O'Reilly, Sean; Holcik, Martin; MacKenzie, Alex

2013-09-01

The loss of functional Survival Motor Neuron (SMN) protein due to mutations or deletion in the SMN1 gene causes autosomal recessive neurodegenerative spinal muscle atrophy (SMA). A potential treatment strategy for SMA is to upregulate the amount of SMN protein originating from the highly homologous SMN2 gene, compensating in part for the absence of the functional SMN1 gene. We have previously shown that in vitro activation of the p38 pathway stabilizes and increases SMN mRNA levels leading to increased SMN protein levels. In this report, we explore the impact of the p38 activating, FDA-approved, blood brain barrier permeating compound celecoxib on SMN levels in vitro and in a mouse model of SMA. We demonstrate a significant induction of SMN protein levels in human and mouse neuronal cells upon treatment with celecoxib. We show that activation of the p38 pathway by low doses celecoxib increases SMN protein in a HuR protein-dependent manner. Furthermore, celecoxib treatment induces SMN expression in brain and spinal cord samples of wild-type mice in vivo. Critically, celecoxib treatment increased SMN levels, improved motor function and enhanced survival in a severe SMA mouse model. Our results identify low dose celecoxib as a potential new member of the SMA therapeutic armamentarium.

Adult-onset intradural spinal teratoma: report of 18 consecutive cases and outcomes in a single center.

PubMed

Wan, Wei; Yang, Cheng; Yan, Wangjun; Liu, Tielong; Yang, Xinghai; Song, Dianwen; Xiao, Jianru

2017-07-01

Eighteen consecutive patients with adult-onset intradural spinal teratoma underwent surgical treatment in our center from 1998 to 2013. Teratoma is defined as a neoplasm composed of elements derived from three germ cell layers (ectoderm, endoderm and mesoderm). Intraspinal teratoma is extremely rare and accounts for 0.2-0.5% of all spinal cord tumors. Moreover, teratoma occurs primarily in neonates and young children. Adult-onset intradural spinal teratoma is even rare. The aim of this study was to discuss the clinical characteristics, diagnosis and therapeutic strategies of adult-onset intradural spinal teratoma. This retrospective study included 18 consecutive adult patients with intradural teratoma who were surgically treated in our center between 1998 and 2013. The clinical features, pathogenesis, diagnostic strategies and surgical outcomes were discussed. Neurological function outcomes were evaluated by the JOA scoring system. Of the 18 included patients, 4 patients received subtotal resection and the other 14 patients received total resection. All the 18 cases were diagnosed with mature teratoma. The mean follow-up period was 79.7 (median 60.5; range 27-208) months. Local recurrence occurred in two of the four patients who underwent subtotal resection and in no patient who underwent total resection. The neurologic status improved in 16 cases and remained unchanged in the other two patients. Adult-onset intradural spinal teratoma is extremely rare. To the best of our knowledge, this is the largest series of patients with this disease. Despite the slow-growth and indolent nature, radical resection remains the recommended treatment to reduce tumor recurrence.

Analysis of the fibroblast growth factor system reveals alterations in a mouse model of spinal muscular atrophy.

PubMed

Hensel, Niko; Ratzka, Andreas; Brinkmann, Hella; Klimaschewski, Lars; Grothe, Claudia; Claus, Peter

2012-01-01

The monogenetic disease Spinal Muscular Atrophy (SMA) is characterized by a progressive loss of motoneurons leading to muscle weakness and atrophy due to severe reduction of the Survival of Motoneuron (SMN) protein. Several models of SMA show deficits in neurite outgrowth and maintenance of neuromuscular junction (NMJ) structure. Survival of motoneurons, axonal outgrowth and formation of NMJ is controlled by neurotrophic factors such as the Fibroblast Growth Factor (FGF) system. Besides their classical role as extracellular ligands, some FGFs exert also intracellular functions controlling neuronal differentiation. We have previously shown that intracellular FGF-2 binds to SMN and regulates the number of a subtype of nuclear bodies which are reduced in SMA patients. In the light of these findings, we systematically analyzed the FGF-system comprising five canonical receptors and 22 ligands in a severe mouse model of SMA. In this study, we demonstrate widespread alterations of the FGF-system in both muscle and spinal cord. Importantly, FGF-receptor 1 is upregulated in spinal cord at a pre-symptomatic stage as well as in a mouse motoneuron-like cell-line NSC34 based model of SMA. Consistent with that, phosphorylations of FGFR-downstream targets Akt and ERK are increased. Moreover, ERK hyper-phosphorylation is functionally linked to FGFR-1 as revealed by receptor inhibition experiments. Our study shows that the FGF system is dysregulated at an early stage in SMA and may contribute to the SMA pathogenesis.

Griffonia simplicifolia Isolectin B4 Identifies a Specific Subpopulation of Angiogenic Blood Vessels Following Contusive Spinal Cord Injury in the Adult Mouse

PubMed Central

BENTON, RICHARD L.; MADDIE, MELISSA A.; MINNILLO, DANIELLE R.; HAGG, THEO; WHITTEMORE, SCOTT R.

2009-01-01

After traumatic spinal cord injury (SCI), disruption and plasticity of the microvasculature within injured spinal tissue contribute to the pathological cascades associated with the evolution of both primary and secondary injury. Conversely, preserved vascular function most likely results in tissue sparing and subsequent functional recovery. It has been difficult to identify subclasses of damaged or regenerating blood vessels at the cellular level. Here, adult mice received a single intravenous injection of the Griffonia simplicifolia isolectin B4 (IB4) at 1–28 days following a moderate thoracic (T9) contusion. Vascular binding of IB4 was maximally observed 7 days following injury, a time associated with multiple pathologic aspects of the intrinsic adaptive angiogenesis, with numbers of IB4 vascular profiles decreasing by 21 days postinjury. Quantitative assessment of IB4 binding shows that it occurs within the evolving lesion epicenter, with affected vessels expressing a temporally specific dysfunctional tight junctional phenotype as assessed by occludin, claudin-5, and ZO-1 immunoreactivities. Taken together, these results demonstrate that intravascular lectin delivery following SCI is a useful approach not only for observing the functional status of neovascular formation but also for definitively identifying specific subpopulations of reactive spinal microvascular elements. PMID:18092342

Resilience and the rehabilitation of adult spinal cord injury survivors: A qualitative systematic review.

PubMed

Kornhaber, Rachel; Mclean, Loyola; Betihavas, Vasiliki; Cleary, Michelle

2018-01-01

To synthesize the qualitative research evidence that explored how survivors of adult spinal cord injury experience and make sense of resilience. Spinal cord injury is often a sudden and unexpected life-changing event requiring complex and long-term rehabilitation. The development of resilience is essential in determining how spinal cord injury survivors negotiate this injury and rehabilitation. A qualitative systematic review and thematic synthesis of the research evidence. CINAHL, PubMed, Embase, Scopus and PsycINFO were searched, no restriction dates were used. Methodological quality was assessed using the Critical Appraisal Skills Programme checklist. Thematic synthesis focused on how survivors of adult spinal cord injury experience and make sense of resilience. Six qualitative research articles reported the experiences of 84 spinal cord injury survivors. Themes identified were: uncertainty and regaining independence; prior experiences of resilience; adopting resilient thinking; and strengthening resilience through supports. Recovery and rehabilitation following spinal cord survivors is influenced by the individual's capacity for resilience. Resilience may be influenced by previous life experiences and enhanced by supportive nursing staff encouraging self-efficacy. Survivors identified the need for active involvement in decision-making about their care to enable a sense of regaining control of their lives. This has the potential to have a significant impact on their self-efficacy and in turn health outcomes. © 2017 John Wiley & Sons Ltd.

Nestin- and Doublecortin-Positive Cells Reside in Adult Spinal Cord Meninges and Participate in Injury-Induced Parenchymal Reaction

PubMed Central

Decimo, Ilaria; Bifari, Francesco; Rodriguez, Francisco Javier; Malpeli, Giorgio; Dolci, Sissi; Lavarini, Valentina; Pretto, Silvia; Vasquez, Sandra; Sciancalepore, Marina; Montalbano, Alberto; Berton, Valeria; Krampera, Mauro; Fumagalli, Guido

2011-01-01

Adult spinal cord has little regenerative potential, thus limiting patient recovery following injury. In this study, we describe a new population of cells resident in the adult rat spinal cord meninges that express the neural stem/precursor markers nestin and doublecortin. Furthermore, from dissociated meningeal tissue a neural stem cell population was cultured in vitro and subsequently shown to differentiate into functional neurons or mature oligodendrocytes. Proliferation rate and number of nestin- and doublecortin-positive cells increased in vivo in meninges following spinal cord injury. By using a lentivirus-labeling approach, we show that meningeal cells, including nestin- and doublecortin-positive cells, migrate in the spinal cord parenchyma and contribute to the glial scar formation. Our data emphasize the multiple roles of meninges in the reaction of the parenchyma to trauma and indicate for the first time that spinal cord meninges are potential niches harboring stem/precursor cells that can be activated by injury. Meninges may be considered as a new source of adult stem/precursor cells to be further tested for use in regenerative medicine applied to neurological disorders, including repair from spinal cord injury. Stem Cells 2011;29:2062–2076. PMID:22038821

Nestin- and doublecortin-positive cells reside in adult spinal cord meninges and participate in injury-induced parenchymal reaction.

PubMed

Decimo, Ilaria; Bifari, Francesco; Rodriguez, Francisco Javier; Malpeli, Giorgio; Dolci, Sissi; Lavarini, Valentina; Pretto, Silvia; Vasquez, Sandra; Sciancalepore, Marina; Montalbano, Alberto; Berton, Valeria; Krampera, Mauro; Fumagalli, Guido

2011-12-01

Adult spinal cord has little regenerative potential, thus limiting patient recovery following injury. In this study, we describe a new population of cells resident in the adult rat spinal cord meninges that express the neural stem/precursor markers nestin and doublecortin. Furthermore, from dissociated meningeal tissue a neural stem cell population was cultured in vitro and subsequently shown to differentiate into functional neurons or mature oligodendrocytes. Proliferation rate and number of nestin- and doublecortin-positive cells increased in vivo in meninges following spinal cord injury. By using a lentivirus-labeling approach, we show that meningeal cells, including nestin- and doublecortin-positive cells, migrate in the spinal cord parenchyma and contribute to the glial scar formation. Our data emphasize the multiple roles of meninges in the reaction of the parenchyma to trauma and indicate for the first time that spinal cord meninges are potential niches harboring stem/precursor cells that can be activated by injury. Meninges may be considered as a new source of adult stem/precursor cells to be further tested for use in regenerative medicine applied to neurological disorders, including repair from spinal cord injury. Copyright © 2011 AlphaMed Press.

Lifestyle and health conditions of adults with spinal cord injury.

PubMed

Xavier de França, Inacia Sátiro; Cruz Enders, Bertha; Silva Coura, Alexsandro; Pereira Cruz, Giovanna Karinny; da Silva Aragão, Jamilly; Carvalho de Oliveira, Déborah Raquel

2014-01-01

. To describe the lifestyle of adults with spinal cord injury and explore its relation with some health conditions. Cross sectional study, in which a questionnaire containing sociodemographic, habits and health conditions variables was used. Forty-seven people with spinal cord injury participated and answered the self-report questionnaire. The group under study was predominantly male (92%), under 40 years of age (47%), and had low educational level (76%). The most frequent risk factors related to the lifestyle were: smoking (28%), alcohol consumption (36%), coffee consumption (92%) and being physically inactive (64%). Association was found between having four or more risk factors related to lifestyle and the loss of appetite, as well as constipation. . The actual inadequate lifestyle is associated with the health conditions of patients, and the nursing team should pay special attention to the education and promotion of health related to people with spinal cord injury.

Analysis of National Rates, Cost, and Sources of Cost Variation in Adult Spinal Deformity.

PubMed

Zygourakis, Corinna C; Liu, Caterina Y; Keefe, Malla; Moriates, Christopher; Ratliff, John; Dudley, R Adams; Gonzales, Ralph; Mummaneni, Praveen V; Ames, Christopher P

2018-03-01

Several studies suggest significant variation in cost for spine surgery, but there has been little research in this area for spinal deformity. To determine the utilization, cost, and factors contributing to cost for spinal deformity surgery. The cohort comprised 55 599 adults who underwent spinal deformity fusion in the 2001 to 2013 National Inpatient Sample database. Patient variables included age, gender, insurance, median income of zip code, county population, severity of illness, mortality risk, number of comorbidities, length of stay, elective vs nonelective case. Hospital variables included bed size, wage index, hospital type (rural, urban nonteaching, urban teaching), and geographical region. The outcome was total hospital cost for deformity surgery. Statistics included univariate and multivariate regression analyses. The number of spinal deformity cases increased from 1803 in 2001 (rate: 4.16 per 100 000 adults) to 6728 in 2013 (rate: 13.9 per 100 000). Utilization of interbody fusion devices increased steadily during this time period, while bone morphogenic protein usage peaked in 2010 and declined thereafter. The mean inflation-adjusted case cost rose from $32 671 to $43 433 over the same time period. Multivariate analyses showed the following patient factors were associated with cost: age, race, insurance, severity of illness, length of stay, and elective admission (P < .01). Hospitals in the western United States and those with higher wage indices or smaller bed sizes were significantly more expensive (P < .05). The rate of adult spinal deformity surgery and the mean case cost increased from 2001 to 2013, exceeding the rate of inflation. Both patient and hospital factors are important contributors to cost variation for spinal deformity surgery. Copyright © 2017 by the Congress of Neurological Surgeons

Neuronal activity in the isolated mouse spinal cord during spontaneous deletions in fictive locomotion: insights into locomotor central pattern generator organization

PubMed Central

Zhong, Guisheng; Shevtsova, Natalia A; Rybak, Ilya A; Harris-Warrick, Ronald M

2012-01-01

We explored the organization of the spinal central pattern generator (CPG) for locomotion by analysing the activity of spinal interneurons and motoneurons during spontaneous deletions occurring during fictive locomotion in the isolated neonatal mouse spinal cord, following earlier work on locomotor deletions in the cat. In the isolated mouse spinal cord, most spontaneous deletions were non-resetting, with rhythmic activity resuming after an integer number of cycles. Flexor and extensor deletions showed marked asymmetry: flexor deletions were accompanied by sustained ipsilateral extensor activity, whereas rhythmic flexor bursting was not perturbed during extensor deletions. Rhythmic activity on one side of the cord was not perturbed during non-resetting spontaneous deletions on the other side, and these deletions could occur with no input from the other side of the cord. These results suggest that the locomotor CPG has a two-level organization with rhythm-generating (RG) and pattern-forming (PF) networks, in which only the flexor RG network is intrinsically rhythmic. To further explore the neuronal organization of the CPG, we monitored activity of motoneurons and selected identified interneurons during spontaneous non-resetting deletions. Motoneurons lost rhythmic synaptic drive during ipsilateral deletions. Flexor-related commissural interneurons continued to fire rhythmically during non-resetting ipsilateral flexor deletions. Deletion analysis revealed two classes of rhythmic V2a interneurons. Type I V2a interneurons retained rhythmic synaptic drive and firing during ipsilateral motor deletions, while type II V2a interneurons lost rhythmic synaptic input and fell silent during deletions. This suggests that the type I neurons are components of the RG, whereas the type II neurons are components of the PF network. We propose a computational model of the spinal locomotor CPG that reproduces our experimental results. The results may provide novel insights into the

eGFP expression under the Uchl1 promoter labels corticospinal motor neurons and a subpopulation of degeneration resistant spinal motor neurons in ALS mouse models

NASA Astrophysics Data System (ADS)

Yasvoina, Marina V.

Current understanding of basic cellular and molecular mechanisms for motor neuron vulnerability during motor neuron disease initiation and progression is incomplete. The complex cytoarchitecture and cellular heterogeneity of the cortex and spinal cord greatly impedes our ability to visualize, isolate, and study specific neuron populations in both healthy and diseased states. We generated a novel reporter line, the Uchl1-eGFP mouse, in which cortical and spinal components of motor neuron circuitry are genetically labeled with eGFP under the Uchl1 promoter. A series of cellular and anatomical analyses combined with retrograde labeling, molecular marker expression, and electrophysiology were employed to determine identity of eGFP expressing cells in the motor cortex and the spinal cord of novel Uchl1-eGFP reporter mice. We conclude that eGFP is expressed in corticospinal motor neurons (CSMN) in the motor cortex and a subset of S-type alpha and gamma spinal motor neurons (SMN) in the spinal cord. hSOD1G93A and Alsin-/- mice, mouse models for amyotrophic lateral sclerosis (ALS), were bred to Uchl1-eGFP reporter mouse line to investigate the pathophysiology and underlying mechanisms of CSMN degeneration in vivo. Evidence suggests early and progressive degeneration of CSMN and SMN in the hSOD1G93A transgenic mice. We show an early increase of autophagosome formation in the apical dendrites of vulnerable CSMN in hSOD1G93A-UeGFP mice, which is localized to the apical dendrites. In addition, labeling S-type alpha and gamma SMN in the hSOD1G93A-UeGFP mice provide a unique opportunity to study basis of their resistance to degeneration. Mice lacking alsin show moderate clinical phenotype and mild CSMN axon degeneration in the spinal cord, which suggests vulnerability of CSMN. Therefore, we investigated the CSMN cellular and axon defects in aged Alsin-/- mice bred to Uchl1-eGFP reporter mouse line. We show that while CSMN are preserved and lack signs of degeneration, CSMN axons

New Insights on the Morphology of Adult Mouse Penis1

PubMed Central

Rodriguez, Esequiel; Weiss, Dana A.; Yang, Jennifer H.; Menshenina, Julia; Ferretti, Max; Cunha, Tristan J.; Barcellos, Dale; Chan, Lok Yun; Risbridger, Gail; Cunha, Gerald R.; Baskin, Laurence S.

2011-01-01

ABSTRACT The adult mouse penis represents the end point of masculine sex differentiation of the embryonic genital tubercle and contains bone, cartilage, the urethra, erectile bodies, several types of epithelium, and many individual cell types arrayed into specific anatomical structures. Using contemporary high-resolution imaging techniques, we sought to provide new insights to the current description of adult mouse penile morphology to enable understanding of penile abnormalities, including hypospadias. Examination of serial transverse and longitudinal sections, scanning electron microscopy, and three-dimensional (3D) reconstruction provided a new appreciation of the individual structures in the adult mouse penis and their 3D interrelationships. In so doing, we discovered novel paired erectile bodies, the male urogenital mating protuberance (MUMP), and more accurately described the urethral meatus. These morphological observations were quantified by morphometric analysis and now provide accurate morphological end points of sex differentiation of mouse penis that will be the foundation of future studies to identify normal and abnormal penile development. PMID:21918128

A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury.

PubMed

Liu, Zhuo-Hao; Yip, Ping K; Adams, Louise; Davies, Meirion; Lee, Jae Won; Michael, Gregory J; Priestley, John V; Michael-Titus, Adina T

2015-09-16

Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity. In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat

Protective effects of butyrate-based compounds on a mouse model for spinal muscular atrophy.

PubMed

Butchbach, Matthew E R; Lumpkin, Casey J; Harris, Ashlee W; Saieva, Luciano; Edwards, Jonathan D; Workman, Eileen; Simard, Louise R; Pellizzoni, Livio; Burghes, Arthur H M

2016-05-01

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analog (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs-glyceryl tributyrate (BA3G) and VX563-on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favorable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. Copyright © 2016 Elsevier Inc. All rights reserved.

Protective Effects of Butyrate-based Compounds on a Mouse Model for Spinal Muscular Atrophy

PubMed Central

Butchbach, Matthew E. R.; Lumpkin, Casey J.; Harris, Ashlee W.; Saieva, Luciano; Edwards, Jonathan D.; Workman, Eileen; Simard, Louise R.; Pellizzoni, Livio; Burghes, Arthur H. M.

2016-01-01

Proximal spinal muscular atrophy (SMA) is a childhood-onset degenerative disease resulting from the selective loss of motor neurons in the spinal cord. SMA is caused by the loss of SMN1 (survival motor neuron 1) but retention of SMN2. The number of copies of SMN2 modifies disease severity in SMA patients as well as in mouse models, making SMN2 a target for therapeutics development. Sodium butyrate (BA) and its analogue (4PBA) have been shown to increase SMN2 expression in SMA cultured cells. In this study, we examined the effects of BA, 4PBA as well as two BA prodrugs—glyceryl tributyrate (BA3G) and VX563—on the phenotype of SMNΔ7 SMA mice. Treatment with 4PBA, BA3G and VX563 but not BA beginning at PND04 significantly improved the lifespan and delayed disease end stage, with administration of VX563 also improving the growth rate of these mice. 4PBA and VX563 improved the motor phenotype of SMNΔ7 SMA mice and prevented spinal motor neuron loss. Interestingly, neither 4PBA nor VX563 had an effect on SMN expression in the spinal cords of treated SMNΔ7 SMA mice; however, they inhibited histone deacetylase (HDAC) activity and restored the normal phosphorylation states of Akt and glycogen synthase kinase 3β, both of which are altered by SMN deficiency in vivo. These observations show that BA-based compounds with favourable pharmacokinetics ameliorate SMA pathology possibly by modulating HDAC and Akt signaling. PMID:26892876

A Comprehensive Atlas of the Adult Mouse Penis

PubMed Central

Phillips, Tiffany R.; Wright, David K.; Gradie, Paul E.; Johnston, Leigh A.; Pask, Andrew J.

2016-01-01

Mice are routinely used to study the development of the external genitalia and, in particular, the process of male urethral closure. This is because misplacement of the male penile urethra, or hypospadias, is amongst the most common birth defects reported in humans. While mice present a tractable model to study penile development, several structures differ between mice and humans, and there is a lack of consensus in the literature on their annotation and developmental origins. Defining the ontology of the mouse prepuce is especially important for the relevance and interpretation of mouse models of hypospadias to human conditions. We have developed a detailed annotation of the adult mouse penis that addresses these differences and enables an accurate comparison of murine and human hypospadias phenotypes. Through MRI data, gross morphology and section histology, we define the origin of the mouse external and internal prepuces, their relationship to the single human foreskin as well as provide a comprehensive view of the various structures of the mouse penis and their associated muscle attachments within the body. These data are combined to annotate structures in a novel 3D adult penis atlas that can be downloaded, viewed at any angle, and manipulated to examine the relationship of various structures. PMID:26112156

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord

PubMed Central

Petracca, Yanina L.; Sartoretti, Maria Micaela; Di Bella, Daniela J.; Marin-Burgin, Antonia; Carcagno, Abel L.; Schinder, Alejandro F.; Lanuza, Guillermo M.

2016-01-01

Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the developing spinal cord is still a pending question. In this study, we show that cerebrospinal fluid-contacting neurons (CSF-cNs), an anatomically discrete cell type of the ependymal area, originate from surprisingly late neurogenic events in the ventral spinal cord. CSF-cNs are identified by the expression of the transcription factors Gata2 and Gata3, and the ionic channels Pkd2l1 and Pkd1l2. Contrasting with Gata2/3+ V2b interneurons, differentiation of CSF-cNs is independent of Foxn4 and takes place during advanced developmental stages previously assumed to be exclusively gliogenic. CSF-cNs are produced from two distinct dorsoventral regions of the mouse spinal cord. Most CSF-cNs derive from progenitors circumscribed to the late-p2 and the oligodendrogenic (pOL) domains, whereas a second subset of CSF-cNs arises from cells bordering the floor plate. The development of these two subgroups of CSF-cNs is differentially controlled by Pax6, they adopt separate locations around the postnatal central canal and they display electrophysiological differences. Our results highlight that spatiotemporal mechanisms are instrumental in creating neural cell diversity in the ventral spinal cord to produce distinct classes of interneurons, motoneurons, CSF-cNs, glial cells and ependymal cells. PMID:26839365

Neurotrophic factors and receptors in the immature and adult spinal cord after mechanical injury or kainic acid.

PubMed

Widenfalk, J; Lundströmer, K; Jubran, M; Brene, S; Olson, L

2001-05-15

Delivery of neurotrophic factors to the injured spinal cord has been shown to stimulate neuronal survival and regeneration. This indicates that a lack of sufficient trophic support is one factor contributing to the absence of spontaneous regeneration in the mammalian spinal cord. Regulation of the expression of neurotrophic factors and receptors after spinal cord injury has not been studied in detail. We investigated levels of mRNA-encoding neurotrophins, glial cell line-derived neurotrophic factor (GDNF) family members and related receptors, ciliary neurotrophic factor (CNTF), and c-fos in normal and injured spinal cord. Injuries in adult rats included weight-drop, transection, and excitotoxic kainic acid delivery; in newborn rats, partial transection was performed. The regulation of expression patterns in the adult spinal cord was compared with that in the PNS and the neonate spinal cord. After mechanical injury of the adult rat spinal cord, upregulations of NGF and GDNF mRNA occurred in meningeal cells adjacent to the lesion. BDNF and p75 mRNA increased in neurons, GDNF mRNA increased in astrocytes close to the lesion, and GFRalpha-1 and truncated TrkB mRNA increased in astrocytes of degenerating white matter. The relatively limited upregulation of neurotrophic factors in the spinal cord contrasted with the response of affected nerve roots, in which marked increases of NGF and GDNF mRNA levels were observed in Schwann cells. The difference between the ability of the PNS and CNS to provide trophic support correlates with their different abilities to regenerate. Kainic acid delivery led to only weak upregulations of BDNF and CNTF mRNA. Compared with several brain regions, the overall response of the spinal cord tissue to kainic acid was weak. The relative sparseness of upregulations of endogenous neurotrophic factors after injury strengthens the hypothesis that lack of regeneration in the spinal cord is attributable at least partly to lack of trophic support.

Early development of the circumferential axonal pathway in mouse and chick spinal cord.

PubMed

Holley, J A

1982-03-10

The early development of the circumferential axonal pathway in the brachial and lumbar spinal cord of mouse and chick embryos was studied by scanning and transmission electron microscopy. The cellular processes which comprise this pathway grow in the transverse plane and along the lateral margin of the marginal zone (i.e., circumferentially oriented), as typified by the early embryonic commissural axons. The first formative event observed was in the ventrolateral margin of the primitive spinal cord ventricular zone. Cellular processes were found near the external limiting membrane that appeared to grow a variable distance either dorsally or ventrally. Later in development, presumptive motor column neurons migrated into the ventrolateral region, distal to these early circumferentially oriented processes. Concurrently, other circumferentially oriented perikarya and processes appeared along the dorsolateral margin. Due to their aligned sites of origin and parallel growth, the circumferential processes formed a more or less continuous line or pathway, which in about 10% of the scanned specimens could be followed along the entire lateral margin of the embryonic spinal cord. Several specimens later in development had two sets of aligned circumferential processes in the ventral region. Large numbers of circumferential axons were then found to follow the preformed pathway by fasciculation, after the primitive motor column had become established. Since the earliest circumferential processes appeared to differentiate into axons and were found nearly 24 hours prior to growth of most circumferential axons, their role in guidance as pioneering axons was suggested.

The Effects of Ionizing Radiation and Hyperthermia on Mouse Spinal Cord.

NASA Astrophysics Data System (ADS)

Lo, Yeh-Chi

Assays were developed to quantify spinal cord damage in the mouse following radiation (X), hyperthermia (H) and their combination. The spinal cord (T_9-L _5) of C3Hf/Sed//Kam mice was irradiated with single (12-75 Gy) or fractionated doses (2 Gy to 23 Gy per fraction). Four arbitrary scales of neurological change were used. Findings for X were: (1) Radiation induces progressive damage, from mild to severe. (2) The latency to damage depended on the dose and the level of damage. Following doses around the ED50 (20-27 Gy), the onset of paralysis occurred between 6 and 8 months. (3) For the NSD equation, the exponent for N was 0.36-0.33 for mild to severe paralysis (score 1-3). Comparison of ED_{rm 50s} for 2 fractions separated by various intervals showed no time effect until 30-60 days. (4) If the data for higher doses per fraction were excluded (>10 Gy), the alpha/beta ratios were 3.5-5.6 for score 1-3. (5) Histological evidence of demyelination was evident at the time of paralysis. Using a water bath, the spinal cord was heated at 42.0 to 43.0^circC for 10-100 min. The results were: (1) Hyperthermia produces an acute reversible damage in the surviving mice. (2) No detectable late effects were seen up to 1.5 years. (3) A value of 0.48 for R in the thermal dose equation was found. (4) Heat lesions included neuronal and vascular damage, but this was seen only at high thermal dose. Mild thermal doses (42.5^circ C for 20-50 min.) were combined with single radiation doses ranging from 12 to 35 Gy in various sequences and time intervals. Findings were: (1) An acute and reversible potentiated damage (score 1) was found when H was given 5 min. before or 5 min., 7, 30, 60 and 150 days after X, but not in 7 days before or 1 day or 90 days after X. (2) An enhanced late effect was found when H was given 5 min. or 150 days after X. (3) Late effects were reduced when heat was given 5 min. or 1 day before or 1 day after X. (4) It seems that target cells (or targets within cells

Identification of neuroanatomic circuits from spinal cord to stomach in mouse: retrograde transneuronal viral tracing study.

PubMed

Ye, Da-Wei; Liu, Cheng; Tian, Xue-Bi; Xiang, Hong-Bing

2014-01-01

To determine the spinal innervation and neuronal connections is important for studying gastric carbohydrate metabolism and motor responses. Neurons involved in the efferent control of the stomach were identified following visualization of pseudorabies virus (PRV)-614 retrograde tracing. PRV-614 was injected into the ventral stomach wall in 13 adult C57BL/6J strain male mice. On the fifth day postinjection, animals were humanely sacrificed, and spinal cords were removed and sectioned, and processed for PRV visualization. The virus injected into the ventral stomach wall was specifically transported to the thoracic spinal cord. At 5 d after injection of the PRV-614, stomach enlargement and tissue edema were found, and PRV-614 positive cells were found in the intermediolateral cell column, the intercalates nucleus or the central autonomic nucleus of spinal cord segments T3 to L1, and major PRV-614 labeled cells were focused in the T6-10 segment. Our results revealed neuroanatomical circuits between stomach and the spinal intermediolateral cell column neurons.

Body and Corporality in adolescents and young adults with spinal cord injury.

PubMed

Duarte Torres, Diana Milena; Torres Bolaños, Yuri Marcela; Moreno Fergusson, María Elisa

2016-04-01

To describe the meaning given by adolescents and young adults to the changes in their bodies and corporality after a spinal cord injury. Qualitative study based on symbolic interactionism in which 12 adolescents and young adults, who had suffered spinal cord injury 6 months or more before, participated. The information was recollected through a series of in-depth interviews and field journals. The guidelines proposed by Corbin and Strauss were followed for the process of codification and categorization of the data. Four categories were identified that describe the meanings given by participants to the changes in their bodies and corporality: Transformation of self-image, living with contradictions in the relationships with others, withstanding the burden of a disability and adapting to the new conditions. The results allow for the comprehension of the meanings that are given by the people who have suffered a spinal cord lesion to their situation. This will in turn open the possibility of offering these people a better individual nursing care that focuses more on the particular needs, so that both they and their families can be helped on their way to adaptation to the new situation.

Current Status of Adult Spinal Deformity

PubMed Central

Youssef, J. A.; Orndorff, D. O.; Patty, C. A.; Scott, M. A.; Price, H. L.; Hamlin, L. F.; Williams, T. L.; Uribe, J. S.; Deviren, V.

2012-01-01

Purpose To review the current literature for the nonoperative and operative treatment for adult spinal deformity. Recent Findings With more than 11 million baby boomers joining the population of over 60 years of age in the United States, the incidence of lumbar deformity is greatly increasing. Recent literature suggests that a lack of evidence exists to support the effectiveness of nonoperative treatment for adult scoliosis. In regards to operative treatment, current literature reports a varying range of improved clinical outcomes, curve correction, and complication rates. The extension of fusion to S1 compared with L5 and lower thoracic levels compared with L1 remains a highly controversial topic among literature. Summary Most adult deformity patients never seek nonoperative or operative treatment. Of the few that seek treatment, many can benefit from nonoperative treatment. However, in selected patients who have failed nonoperative treatment and who are candidates for surgical intervention, the literature reflects positive outcomes related to surgical intervention as compared with nonoperative treatment despite varying associated ranges in morbidity and mortality rates. If nonoperative therapy fails in addressing a patient's complaints, then an appropriate surgical procedure that relieves neural compression, corrects excessive sagittal or coronal imbalance, and results in a solidly fused, pain-free spine is warranted. PMID:24436852

Current status of adult spinal deformity.

PubMed

Youssef, J A; Orndorff, D O; Patty, C A; Scott, M A; Price, H L; Hamlin, L F; Williams, T L; Uribe, J S; Deviren, V

2013-03-01

Purpose To review the current literature for the nonoperative and operative treatment for adult spinal deformity. Recent Findings With more than 11 million baby boomers joining the population of over 60 years of age in the United States, the incidence of lumbar deformity is greatly increasing. Recent literature suggests that a lack of evidence exists to support the effectiveness of nonoperative treatment for adult scoliosis. In regards to operative treatment, current literature reports a varying range of improved clinical outcomes, curve correction, and complication rates. The extension of fusion to S1 compared with L5 and lower thoracic levels compared with L1 remains a highly controversial topic among literature. Summary Most adult deformity patients never seek nonoperative or operative treatment. Of the few that seek treatment, many can benefit from nonoperative treatment. However, in selected patients who have failed nonoperative treatment and who are candidates for surgical intervention, the literature reflects positive outcomes related to surgical intervention as compared with nonoperative treatment despite varying associated ranges in morbidity and mortality rates. If nonoperative therapy fails in addressing a patient's complaints, then an appropriate surgical procedure that relieves neural compression, corrects excessive sagittal or coronal imbalance, and results in a solidly fused, pain-free spine is warranted.

Induction of parkinsonism-related proteins in the spinal motor neurons of transgenic mouse carrying a mutant SOD1 gene.

PubMed

Morimoto, Nobutoshi; Nagai, Makiko; Miyazaki, Kazunori; Ohta, Yasuyuki; Kurata, Tomoko; Takehisa, Yasushi; Ikeda, Yoshio; Matsuura, Tohru; Asanuma, Masato; Abe, Koji

2010-06-01

Amyotrophic lateral sclerosis is a progressive and fatal disease caused by selective death of motor neurons, and a number of these patients carry mutations in the superoxide dismutase 1 (SOD1) gene involved in ameliorating oxidative stress. Recent studies indicate that oxidative stress and disruption of mitochondrial homeostasis is a common mechanism for motor neuron degeneration in amyotrophic lateral sclerosis and the loss of midbrain dopamine neurons in Parkinson's disease. Therefore, the present study investigated the presence and alterations of familial Parkinson's disease-related proteins, PINK1 and DJ-1, in spinal motor neurons of G93ASOD1 transgenic mouse model of amyotrophic lateral sclerosis. Following onset of disease, PINK1 and DJ-1 protein expression increased in the spinal motor neurons. The activated form of p53 also increased and translocated to the nuclei of spinal motor neurons, followed by increased expression of p53-activated gene 608 (PAG608). This is the first report demonstrating that increased expression of PAG608 correlates with activation of phosphorylated p53 in spinal motor neurons of an amyotrophic lateral sclerosis model. These results provide further evidence of the profound correlations between spinal motor neurons of amyotrophic lateral sclerosis and parkinsonism-related proteins.

Endogenous stem cell proliferation induced by intravenous hedgehog agonist administration after contusion in the adult rat spinal cord.

PubMed

Bambakidis, Nicholas C; Horn, Eric M; Nakaji, Peter; Theodore, Nicholas; Bless, Elizabeth; Dellovade, Tammy; Ma, Chiyuan; Wang, Xukui; Preul, Mark C; Coons, Stephen W; Spetzler, Robert F; Sonntag, Volker K H

2009-02-01

Sonic hedgehog (Shh) is a glycoprotein molecule that upregulates the transcription factor Gli1. The Shh protein plays a critical role in the proliferation of endogenous neural precursor cells when directly injected into the spinal cord after a spinal cord injury in adult rodents. Small-molecule agonists of the hedgehog (Hh) pathway were used in an attempt to reproduce these findings through intravenous administration. The expression of Gli1 was measured in rat spinal cord after the intravenous administration of an Hh agonist. Ten adult rats received a moderate contusion and were treated with either an Hh agonist (10 mg/kg, intravenously) or vehicle (5 rodents per group) 1 hour and 4 days after injury. The rats were killed 5 days postinjury. Tissue samples were immediately placed in fixative. Samples were immunohistochemically stained for neural precursor cells, and these cells were counted. Systemic dosing with an Hh agonist significantly upregulated Gli1 expression in the spinal cord (p < 0.005). After spinal contusion, animals treated with the Hh agonist had significantly more nestin-positive neural precursor cells around the rim of the lesion cavity than in vehicle-treated controls (means +/- SDs, 46.9 +/- 12.9 vs 20.9 +/- 8.3 cells/hpf, respectively, p < 0.005). There was no significant difference in the area of white matter injury between the groups. An intravenous Hh agonist at doses that upregulate spinal cord Gli1 transcription also increases the population of neural precursor cells after spinal cord injury in adult rats. These data support previous findings based on injections of Shh protein directly into the spinal cord.

The late and dual origin of cerebrospinal fluid-contacting neurons in the mouse spinal cord.

PubMed

Petracca, Yanina L; Sartoretti, Maria Micaela; Di Bella, Daniela J; Marin-Burgin, Antonia; Carcagno, Abel L; Schinder, Alejandro F; Lanuza, Guillermo M

2016-03-01

Considerable progress has been made in understanding the mechanisms that control the production of specialized neuronal types. However, how the timing of differentiation contributes to neuronal diversity in the developing spinal cord is still a pending question. In this study, we show that cerebrospinal fluid-contacting neurons (CSF-cNs), an anatomically discrete cell type of the ependymal area, originate from surprisingly late neurogenic events in the ventral spinal cord. CSF-cNs are identified by the expression of the transcription factors Gata2 and Gata3, and the ionic channels Pkd2l1 and Pkd1l2. Contrasting with Gata2/3(+) V2b interneurons, differentiation of CSF-cNs is independent of Foxn4 and takes place during advanced developmental stages previously assumed to be exclusively gliogenic. CSF-cNs are produced from two distinct dorsoventral regions of the mouse spinal cord. Most CSF-cNs derive from progenitors circumscribed to the late-p2 and the oligodendrogenic (pOL) domains, whereas a second subset of CSF-cNs arises from cells bordering the floor plate. The development of these two subgroups of CSF-cNs is differentially controlled by Pax6, they adopt separate locations around the postnatal central canal and they display electrophysiological differences. Our results highlight that spatiotemporal mechanisms are instrumental in creating neural cell diversity in the ventral spinal cord to produce distinct classes of interneurons, motoneurons, CSF-cNs, glial cells and ependymal cells. © 2016. Published by The Company of Biologists Ltd.

TEMPORAL NEUROTRANSMITTER CONDITIONING RESTORES THE FUNCTIONAL ACTIVITY OF ADULT SPINAL-CORD NEURONS IN LONG-TERM CULTURE

PubMed Central

Das, Mainak; Bhargava, Neelima; Bhalkikar, Abhijeet; Kang, Jung Fong; Hickman, James J

2008-01-01

The ability to culture functional adult mammalian spinal-cord neurons represents an important step in the understanding and treatment of a spectrum of neurological disorders including spinal cord injury. Previously, the limited functional recovery of these cells, as characterized by a diminished ability to initiate action potentials and to exhibit repetitive firing patterns, has arisen as a major impediment to their physiological relevance. In this report we demonstrate that single temporal doses of the neurotransmitters serotonin, glutamate (N-acetyl-DL-glutamic acid) and acetylcholine-chloride leads to the full electrophysiological functional recovery of adult mammalian spinal-cord neurons, when they are cultured under defined serum-free conditions. Approximately 60% of the neurons treated regained their electrophysiological signature, often firing single, double and, most importantly, multiple action potentials. PMID:18005959

Simultaneous submicrometric 3D imaging of the micro-vascular network and the neuronal system in a mouse spinal cord

PubMed Central

Fratini, Michela; Bukreeva, Inna; Campi, Gaetano; Brun, Francesco; Tromba, Giuliana; Modregger, Peter; Bucci, Domenico; Battaglia, Giuseppe; Spanò, Raffaele; Mastrogiacomo, Maddalena; Requardt, Herwig; Giove, Federico; Bravin, Alberto; Cedola, Alessia

2015-01-01

Faults in vascular (VN) and neuronal networks of spinal cord are responsible for serious neurodegenerative pathologies. Because of inadequate investigation tools, the lacking knowledge of the complete fine structure of VN and neuronal system represents a crucial problem. Conventional 2D imaging yields incomplete spatial coverage leading to possible data misinterpretation, whereas standard 3D computed tomography imaging achieves insufficient resolution and contrast. We show that X-ray high-resolution phase-contrast tomography allows the simultaneous visualization of three-dimensional VN and neuronal systems of ex-vivo mouse spinal cord at scales spanning from millimeters to hundreds of nanometers, with nor contrast agent nor sectioning and neither destructive sample-preparation. We image both the 3D distribution of micro-capillary network and the micrometric nerve fibers, axon-bundles and neuron soma. Our approach is very suitable for pre-clinical investigation of neurodegenerative pathologies and spinal-cord-injuries, in particular to resolve the entangled relationship between VN and neuronal system. PMID:25686728

Adult spinal deformity treated with minimally invasive surgery. Description of surgical technique, radiological results and literature review.

PubMed

Domínguez, I; Luque, R; Noriega, M; Rey, J; Alía, J; Urda, A; Marco, F

The prevalence of adult spinal deformity has been increasing exponentially over time. Surgery has been credited with good radiological and clinical results. The incidence of complications is high. MIS techniques provide good results with fewer complications. This is a retrospective study of 25 patients with an adult spinal deformity treated by MIS surgery, with a minimum follow-up of 6 months. Radiological improvement was SVA from 5 to 2cm, coronal Cobb angle from 31° to 6°, and lumbar lordosis from 18° to 38°. All of these parameters remained stable over time. We also present the complications that appeared in 4 patients (16%). Only one patient needed reoperation. We describe the technique used and review the references on the subject. We conclude that the MIS technique for treating adult spinal deformity has comparable results to those of the conventional techniques but with fewer complications. Copyright © 2017 SECOT. Publicado por Elsevier España, S.L.U. All rights reserved.

18F-FDG PET/CT evaluation of children and young adults with suspected spinal fusion hardware infection.

PubMed

Bagrosky, Brian M; Hayes, Kari L; Koo, Phillip J; Fenton, Laura Z

2013-08-01

Evaluation of the child with spinal fusion hardware and concern for infection is challenging because of hardware artifact with standard imaging (CT and MRI) and difficult physical examination. Studies using (18)F-FDG PET/CT combine the benefit of functional imaging with anatomical localization. To discuss a case series of children and young adults with spinal fusion hardware and clinical concern for hardware infection. These people underwent FDG PET/CT imaging to determine the site of infection. We performed a retrospective review of whole-body FDG PET/CT scans at a tertiary children's hospital from December 2009 to January 2012 in children and young adults with spinal hardware and suspected hardware infection. The PET/CT scan findings were correlated with pertinent clinical information including laboratory values of inflammatory markers, postoperative notes and pathology results to evaluate the diagnostic accuracy of FDG PET/CT. An exempt status for this retrospective review was approved by the Institution Review Board. Twenty-five FDG PET/CT scans were performed in 20 patients. Spinal fusion hardware infection was confirmed surgically and pathologically in six patients. The most common FDG PET/CT finding in patients with hardware infection was increased FDG uptake in the soft tissue and bone immediately adjacent to the posterior spinal fusion rods at multiple contiguous vertebral levels. Noninfectious hardware complications were diagnosed in ten patients and proved surgically in four. Alternative sources of infection were diagnosed by FDG PET/CT in seven patients (five with pneumonia, one with pyonephrosis and one with superficial wound infections). FDG PET/CT is helpful in evaluation of children and young adults with concern for spinal hardware infection. Noninfectious hardware complications and alternative sources of infection, including pneumonia and pyonephrosis, can be diagnosed. FDG PET/CT should be the first-line cross-sectional imaging study in patients

Identification of Newly Committed Pancreatic Cells in the Adult Mouse Pancreas.

PubMed

Socorro, Mairobys; Criscimanna, Angela; Riva, Patricia; Tandon, Manuj; Prasadan, Krishna; Guo, Ping; Humar, Abhinav; Husain, Sohail Z; Leach, Steven D; Gittes, George K; Esni, Farzad

2017-12-13

Multipotent epithelial cells with high Aldehyde dehydrogenase activity have been previously reported to exist in the adult pancreas. However, whether they represent true progenitor cells remains controversial. In this study, we isolated and characterized cells with ALDH activity in the adult mouse or human pancreas during physiological conditions or injury. We found that cells with ALDH activity are abundant in the mouse pancreas during early postnatal growth, pregnancy, and in mouse models of pancreatitis and type 1 diabetes (T1D). Importantly, a similar population of cells is found abundantly in healthy children, or in patients with pancreatitis or T1D. We further demonstrate that cells with ALDH activity can commit to either endocrine or acinar lineages, and can be divided into four sub-populations based on CD90 and Ecadherin expression. Finally, our in vitro and in vivo studies show that the progeny of ALDH1 + /CD90 - /Ecad - cells residing in the adult mouse pancreas have the ability to initiate Pancreatic and duodenal homeobox (Pdx1) expression for the first time. In summary, we provide evidence for the existence of a sortable population of multipotent non-epithelial cells in the adult pancreas that can commit to the pancreatic lineage following proliferation and mesenchymal to epithelial transition (MET).

Localization of PPAR isotypes in the adult mouse and human brain

PubMed Central

Warden, Anna; Truitt, Jay; Merriman, Morgan; Ponomareva, Olga; Jameson, Kelly; Ferguson, Laura B.; Mayfield, R. Dayne; Harris, R. Adron

2016-01-01

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. PPAR agonists have well-documented anti-inflammatory and neuroprotective roles in the central nervous system. Recent evidence suggests that PPAR agonists are attractive therapeutic agents for treating neurodegenerative diseases as well as addiction. However, the distribution of PPAR mRNA and protein in brain regions associated with these conditions (i.e. prefrontal cortex, nucleus accumbens, amygdala, ventral tegmental area) is not well defined. Moreover, the cell type specificity of PPARs in mouse and human brain tissue has yet to be investigated. We utilized quantitative PCR and double immunofluorescence microscopy to determine that both PPAR mRNA and protein are expressed ubiquitously throughout the adult mouse brain. We found that PPARs have unique cell type specificities that are consistent between species. PPARα was the only isotype to colocalize with all cell types in both adult mouse and adult human brain tissue. Overall, we observed a strong neuronal signature, which raises the possibility that PPAR agonists may be targeting neurons rather than glia to produce neuroprotection. Our results fill critical gaps in PPAR distribution and define novel cell type specificity profiles in the adult mouse and human brain. PMID:27283430

Localization of PPAR isotypes in the adult mouse and human brain.

PubMed

Warden, Anna; Truitt, Jay; Merriman, Morgan; Ponomareva, Olga; Jameson, Kelly; Ferguson, Laura B; Mayfield, R Dayne; Harris, R Adron

2016-06-10

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as ligand-activated transcription factors. PPAR agonists have well-documented anti-inflammatory and neuroprotective roles in the central nervous system. Recent evidence suggests that PPAR agonists are attractive therapeutic agents for treating neurodegenerative diseases as well as addiction. However, the distribution of PPAR mRNA and protein in brain regions associated with these conditions (i.e. prefrontal cortex, nucleus accumbens, amygdala, ventral tegmental area) is not well defined. Moreover, the cell type specificity of PPARs in mouse and human brain tissue has yet to be investigated. We utilized quantitative PCR and double immunofluorescence microscopy to determine that both PPAR mRNA and protein are expressed ubiquitously throughout the adult mouse brain. We found that PPARs have unique cell type specificities that are consistent between species. PPARα was the only isotype to colocalize with all cell types in both adult mouse and adult human brain tissue. Overall, we observed a strong neuronal signature, which raises the possibility that PPAR agonists may be targeting neurons rather than glia to produce neuroprotection. Our results fill critical gaps in PPAR distribution and define novel cell type specificity profiles in the adult mouse and human brain.

Cerebellar stem cells do not produce neurons and astrocytes in adult mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Xin; Guan, Wuqiang; Yu, Yong-Chun

Highlights: • No new neurons and astrocytes are generated in adult mouse cerebellum. • Very few mash1{sup +} or nestin{sup +} stem cells exist, and most of them are quiescent. • Cell proliferation rate is diversified among cerebellar regions and decreases over time. - Abstract: Although previous studies implied that cerebellar stem cells exist in some adult mammals, little is known about whether these stem cells can produce new neurons and astrocytes. In this study by bromodeoxyuridine (BrdU) intraperitoneal (i.p.) injection, we found that there are abundant BrdU{sup +} cells in adult mouse cerebellum, and their quantity and density decreasesmore » significantly over time. We also found cell proliferation rate is diversified in different cerebellar regions. Among these BrdU{sup +} cells, very few are mash1{sup +} or nestin{sup +} stem cells, and the vast majority of cerebellar stem cells are quiescent. Data obtained by in vivo retrovirus injection indicate that stem cells do not produce neurons and astrocytes in adult mouse cerebellum. Instead, some cells labeled by retrovirus are Iba1{sup +} microglia. These results indicate that very few stem cells exist in adult mouse cerebellum, and none of these stem cells contribute to neurogenesis and astrogenesis under physiological condition.« less

Adult-type myogenesis of the frog Xenopus laevis specifically suppressed by notochord cells but promoted by spinal cord cells in vitro.

PubMed

Yamane, Hitomi; Ihara, Setsunosuke; Kuroda, Masaaki; Nishikawa, Akio

2011-08-01

Larval-to-adult myogenic conversion occurs in the dorsal muscle but not in the tail muscle during Xenopus laevis metamorphosis. To know the mechanism for tail-specific suppression of adult myogenesis, response character was compared between adult myogenic cells (Ad-cells) and larval tail myogenic cells (La-cells) to a Sonic hedgehog (Shh) inhibitor, notochord (Nc) cells, and spinal cord (SC) cells in vitro. Cyclopamine, an Shh inhibitor, suppressed the differentiation of cultured Ad (but not La) cells, suggesting the significance of Shh signaling in promoting adult myogenesis. To test the possibility that Shh-producing axial elements (notochord and spinal cord) regulate adult myogenesis, Ad-cells or La-cells were co-cultured with Nc or SC cells. The results showed that differentiation of Ad-cells were strongly inhibited by Nc cells but promoted by SC cells. If Ad-cells were "separately" co-cultured with Nc cells without direct cell-cell interactions, adult differentiation was not inhibited but rather promoted, suggesting that Nc cells have two roles, one is a short-range suppression and another is a long-range promotion for adult myogenesis. Immunohistochemical analysis showed both notochord and spinal cord express the N-terminal Shh fragment throughout metamorphosis. The "spinal cord-promotion" and long-range effect by Nc cells on adult myogenesis is thus involved in Shh signaling, while the signaling concerning the short-range "Nc suppression" will be determined by future studies. Interestingly, these effects, "Nc suppression" and "SC promotion" were not observed for La-cells. Situation where the spinal cord/notochord cross-sectional ratio is quite larger in tadpole trunk than in the tail seems to contribute to trunk-specific promotion and tail-specific suppression of adult myogenesis during Xenopus metamorphosis.

Combined spinal epidural anesthesia for laparoscopic appendectomy in adults: A case series

PubMed Central

Mane, Rajesh S.; Patil, Manjunath C.; Kedareshvara, K. S.; Sanikop, C. S.

2012-01-01

Background: Laparoscopy is one of the most common surgical procedures and is the procedure of choice for most of the elective abdominal surgeries performed preferably under endotracheal general anesthesia. Technical advances in the field of laparoscopy have helped to reduce surgical trauma and discomfort, reduce anesthetic requirement resulting in shortened hospital stay. Recently, regional anaesthetic techniques have been found beneficial, especially in patients at a high risk to receive general anesthesia. Herewith we present a case series of laparoscopic appendectomy in eight American Society of Anaesthesiologists (ASA) I and II patients performed under spinal-epidural anaesthesia. Methods: Eight ASA Grade I and II adult patients undergoing elective Laparoscopic appendectomy received Combined Spinal Epidural Anaesthesia. Spinal Anaesthesia was performed at L2-L3 interspace using 2 ml of 0.5% (10 mg) hyperbaric Bupivacaine mixed with 0.5ml (25 micrograms) of Fentanyl. Epidural catheter was inserted at T10-T11 interspace for inadequate spinal anaesthesia and postoperative pain relief. Perioperative events and operative difficulty were studied. Systemic drugs were administered if patients complained of shoulder pain, abdominal discomfort, nausea or hypotension. Results: Spinal anaesthesia was adequate for surgery with no operative difficulty in all the patients. Intraoperatively, two patients experienced right shoulder pain and received Fentanyl, one patient was given Midazolam for anxiety and two were given Ephedrine for hypotension. The postoperative period was uneventful. Conclusion: Spinal anaesthesia with Hyperbaric Bupivacaine and Fentanyl is adequate and safe for elective laparoscopic appendectomy in healthy patients but careful evaluation of the method is needed particularly in compromised cardio respiratory conditions. PMID:22412773

Left–right coordination from simple to extreme conditions during split‐belt locomotion in the chronic spinal adult cat

PubMed Central

Desrochers, Étienne; Thibaudier, Yann; Hurteau, Marie‐France; Dambreville, Charline

2016-01-01

Key points Coordination between the left and right sides is essential for dynamic stability during locomotion.The immature or neonatal mammalian spinal cord can adjust to differences in speed between the left and right sides during split‐belt locomotion by taking more steps on the fast side.We show that the adult mammalian spinal cord can also adjust its output so that the fast side can take more steps.During split‐belt locomotion, only certain parts of the cycle are modified to adjust left–right coordination, primarily those associated with swing onset.When the fast limb takes more steps than the slow limb, strong left–right interactions persist.Therefore, the adult mammalian spinal cord has a remarkable adaptive capacity for left–right coordination, from simple to extreme conditions. Abstract Although left–right coordination is essential for locomotion, its control is poorly understood, particularly in adult mammals. To investigate the spinal control of left–right coordination, a spinal transection was performed in six adult cats that were then trained to recover hindlimb locomotion. Spinal cats performed tied‐belt locomotion from 0.1 to 1.0 m s−1 and split‐belt locomotion with low to high (1:1.25–10) slow/fast speed ratios. With the left hindlimb stepping at 0.1 m s−1 and the right hindlimb stepping from 0.2 to 1.0 m s−1, 1:1, 1:2, 1:3, 1:4 and 1:5 left–right step relationships could appear. The appearance of 1:2+ relationships was not linearly dependent on the difference in speed between the slow and fast belts. The last step taken by the fast hindlimb displayed longer cycle, stance and swing durations and increased extensor activity, as the slow limb transitioned to swing. During split‐belt locomotion with 1:1, 1:2 and 1:3 relationships, the timing of stance onset of the fast limb relative to the slow limb and placement of both limbs at contact were invariant with increasing slow/fast speed ratios. In contrast, the timing of

Standardization of a spinal cord lesion model and neurologic evaluation using mice

PubMed Central

Borges, Paulo Alvim; Cristante, Alexandre Fogaça; de Barros-Filho, Tarcísio Eloy Pessoa; Natalino, Renato Jose Mendonça; dos Santos, Gustavo Bispo; Marcon, Raphael Marcus

2018-01-01

OBJECTIVE: To standardize a spinal cord lesion mouse model. METHODS: Thirty BALB/c mice were divided into five groups: four experimental groups and one control group (sham). The experimental groups were subjected to spinal cord lesion by a weight drop from different heights after laminectomy whereas the sham group only underwent laminectomy. Mice were observed for six weeks, and functional behavior scales were applied. The mice were then euthanized, and histological investigations were performed to confirm and score spinal cord lesion. The findings were evaluated to prove whether the method of administering spinal cord lesion was effective and different among the groups. Additionally, we correlated the results of the functional scales with the results from the histology evaluations to identify which scale is more reliable. RESULTS: One mouse presented autophagia, and six mice died during the experiment. Because four of the mice that died were in Group 5, Group 5 was excluded from the study. All the functional scales assessed proved to be significantly different from each other, and mice presented functional evolution during the experiment. Spinal cord lesion was confirmed by histology, and the results showed a high correlation between the Basso, Beattie, Bresnahan Locomotor Rating Scale and the Basso Mouse Scale. The mouse function scale showed a moderate to high correlation with the histological findings, and the horizontal ladder test had a high correlation with neurologic degeneration but no correlation with the other histological parameters evaluated. CONCLUSION: This spinal cord lesion mouse model proved to be effective and reliable with exception of lesions caused by a 10-g drop from 50 mm, which resulted in unacceptable mortality. The Basso, Beattie, Bresnahan Locomotor Rating Scale and Basso Mouse Scale are the most reliable functional assessments, and but the horizontal ladder test is not recommended. PMID:29561931

Cervical Spinal Cord Atrophy Profile in Adult SMN1-Linked SMA

PubMed Central

El Mendili, Mohamed-Mounir; Lenglet, Timothée; Stojkovic, Tanya; Behin, Anthony; Guimarães-Costa, Raquel; Salachas, François; Meininger, Vincent; Bruneteau, Gaelle; Le Forestier, Nadine; Laforêt, Pascal; Lehéricy, Stéphane; Benali, Habib; Pradat, Pierre-François

2016-01-01

Purpose The mechanisms underlying the topography of motor deficits in spinal muscular atrophy (SMA) remain unknown. We investigated the profile of spinal cord atrophy (SCA) in SMN1-linked SMA, and its correlation with the topography of muscle weakness. Materials and Methods Eighteen SMN1-linked SMA patients type III/V and 18 age/gender-matched healthy volunteers were included. Patients were scored on manual muscle testing and functional scales. Spinal cord was imaged using 3T MRI system. Radial distance (RD) and cord cross-sectional area (CSA) measurements in SMA patients were compared to those in controls and correlated with strength and disability scores. Results CSA measurements revealed a significant cord atrophy gradient mainly located between C3 and C6 vertebral levels with a SCA rate ranging from 5.4% to 23% in SMA patients compared to controls. RD was significantly lower in SMA patients compared to controls in the anterior-posterior direction with a maximum along C4 and C5 vertebral levels (p-values < 10−5). There were no correlations between atrophy measurements, strength and disability scores. Conclusions Spinal cord atrophy in adult SMN1-linked SMA predominates in the segments innervating the proximal muscles. Additional factors such as neuromuscular junction or intrinsic skeletal muscle defects may play a role in more complex mechanisms underlying weakness in these patients. PMID:27089520

National Administrative Databases in Adult Spinal Deformity Surgery: A Cautionary Tale.

PubMed

Buckland, Aaron J; Poorman, Gregory; Freitag, Robert; Jalai, Cyrus; Klineberg, Eric O; Kelly, Michael; Passias, Peter G

2017-08-15

Comparison between national administrative databases and a prospective multicenter physician managed database. This study aims to assess the applicability of National Administrative Databases (NADs) in adult spinal deformity (ASD). Our hypothesis is that NADs do not include comparable patients as in a physician-managed database (PMD) for surgical outcomes in adult spinal deformity. NADs such as National Inpatient Sample (NIS) and National Surgical Quality Improvement Program (NSQIP) provide large numbers of publications owing to ease of data access and lack of IRB approval requirement. These databases utilize billing codes, not clinical inclusion criteria, and have not been validated against PMDs in ASD surgery. The NIS was searched for years 2002 to 2012 and NSQIP for years 2006 to 2013 using validated spinal deformity diagnostic codes. Procedural codes (ICD-9 and CPT) were then applied to each database. A multicenter PMD including years 2008 to 2015 was used for comparison. Databases were assessed for levels fused, osteotomies, decompressed levels, and invasiveness. Database comparisons for surgical details were made in all patients, and also for patients with ≥ 5 level spinal fusions. Approximately, 37,368 NIS, 1291 NSQIP, and 737 PMD patients were identified. NADs showed an increased use of deformity billing codes over the study period (NIS doubled, 68x NSQIP, P < 0.001), but ASD remained stable in the PMD.Surgical invasiveness, levels fused and use of 3-column osteotomy (3-CO) were significantly lower for all patients in the NIS (11.4-13.7) and NSQIP databases (6.4-12.7) compared with PMD (27.5-32.3). When limited to patients with ≥5 levels, invasiveness, levels fused, and use of 3-CO remained significantly higher in the PMD compared with NADs (P < 0.001). National databases NIS and NSQIP do not capture the same patient population as is captured in PMDs in ASD. Physicians should remain cautious in interpreting conclusions drawn from these databases

Combining Adult Learning Theory with Occupational Therapy Intervention for Bladder and Bowel Management after Spinal Cord Injury: A Case Report.

PubMed

Gallagher, Gina; Bell, Alison

2016-01-01

Bladder and bowel management is an important goal of rehabilitation for clients with spinal cord injury. Dependence is these areas have been linked to a variety of secondary complications, including decreased quality of life, urinary tract infections and pressure ulcers (Hammell, 2010; Hicken et al, 2001). Occupational therapists have been identified as important members of the health care team in spinal cord injury rehabilitation; however, specific roles and interventions have not been clearly described. This case report will describe occupational therapy interventions embedded with principles of adult learning theory to address bladder and bowel management with an adult client who sustained an incomplete thoracic level spinal cord injury.

Steadiness of Spinal Regions during Single-Leg Standing in Older Adults with and without Chronic Low Back Pain

PubMed Central

Kuo, Yi-Liang; Huang, Kuo-Yuan; Chiang, Pei-Tzu; Lee, Pei-Yun; Tsai, Yi-Ju

2015-01-01

The aims of this study were to compare the steadiness index of spinal regions during single-leg standing in older adults with and without chronic low back pain (LBP) and to correlate measurements of steadiness index with the performance of clinical balance tests. Thirteen community-dwelling older adults (aged 55 years or above) with chronic LBP and 13 age- and gender-matched asymptomatic volunteers participated in this study. Data collection was conducted in a university research laboratory. Measurements were steadiness index of spinal regions (trunk, thoracic spine, lumbar spine, and pelvis) during single-leg standing including relative holding time (RHT) and relative standstill time (RST), and clinical balance tests (timed up and go test and 5-repetition sit to stand test). The LBP group had a statistically significantly smaller RHT than the control group, regardless of one leg stance on the painful or non-painful sides. The RSTs on the painful side leg in the LBP group were not statistically significantly different from the average RSTs of both legs in the control group; however, the RSTs on the non-painful side leg in the LBP group were statistically significantly smaller than those in the control group for the trunk, thoracic spine, and lumbar spine. No statistically significant intra-group differences were found in the RHTs and RSTs between the painful and non-painful side legs in the LBP group. Measurements of clinical balance tests also showed insignificant weak to moderate correlations with steadiness index. In conclusion, older adults with chronic LBP demonstrated decreased spinal steadiness not only in the symptomatic lumbar spine but also in the other spinal regions within the kinetic chain of the spine. When treating older adults with chronic LBP, clinicians may also need to examine their balance performance and spinal steadiness during balance challenging tests. PMID:26024534

A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1

PubMed Central

Liu, Yi Bessie; Tewari, Ambika; Salameh, Johnny; Arystarkhova, Elena; Hampton, Thomas G; Brashear, Allison; Ozelius, Laurie J; Khodakhah, Kamran; Sweadner, Kathleen J

2015-01-01

A new mutant mouse (lamb1t) exhibits intermittent dystonic hindlimb movements and postures when awake, and hyperextension when asleep. Experiments showed co-contraction of opposing muscle groups, and indicated that symptoms depended on the interaction of brain and spinal cord. SNP mapping and exome sequencing identified the dominant causative mutation in the Lamb1 gene. Laminins are extracellular matrix proteins, widely expressed but also known to be important in synapse structure and plasticity. In accordance, awake recording in the cerebellum detected abnormal output from a circuit of two Lamb1-expressing neurons, Purkinje cells and their deep cerebellar nucleus targets, during abnormal postures. We propose that dystonia-like symptoms result from lapses in descending inhibition, exposing excess activity in intrinsic spinal circuits that coordinate muscles. The mouse is a new model for testing how dysfunction in the CNS causes specific abnormal movements and postures. DOI: http://dx.doi.org/10.7554/eLife.11102.001 PMID:26705335

Abundance of gap junctions at glutamatergic mixed synapses in adult Mosquitofish spinal cord neurons

PubMed Central

Serrano-Velez, Jose L.; Rodriguez-Alvarado, Melanie; Torres-Vazquez, Irma I.; Fraser, Scott E.; Yasumura, Thomas; Vanderpool, Kimberly G.; Rash, John E.; Rosa-Molinar, Eduardo

2014-01-01

“Dye-coupling”, whole-mount immunohistochemistry for gap junction channel protein connexin 35 (Cx35), and freeze-fracture replica immunogold labeling (FRIL) reveal an abundance of electrical synapses/gap junctions at glutamatergic mixed synapses in the 14th spinal segment that innervates the adult male gonopodium of Western Mosquitofish, Gambusia affinis (Mosquitofish). To study gap junctions’ role in fast motor behavior, we used a minimally-invasive neural-tract-tracing technique to introduce gap junction-permeant or -impermeant dyes into deep muscles controlling the gonopodium of the adult male Mosquitofish, a teleost fish that rapidly transfers (complete in <20 mS) spermatozeugmata into the female reproductive tract. Dye-coupling in the 14th spinal segment controlling the gonopodium reveals coupling between motor neurons and a commissural primary ascending interneuron (CoPA IN) and shows that the 14th segment has an extensive and elaborate dendritic arbor and more gap junctions than do other segments. Whole-mount immunohistochemistry for Cx35 results confirm dye-coupling and show it occurs via gap junctions. Finally, FRIL shows that gap junctions are at mixed synapses and reveals that >50 of the 62 gap junctions at mixed synapses are in the 14th spinal segment. Our results support and extend studies showing gap junctions at mixed synapses in spinal cord segments involved in control of genital reflexes in rodents, and they suggest a link between mixed synapses and fast motor behavior. The findings provide a basis for studies of specific roles of spinal neurons in the generation/regulation of sex-specific behavior and for studies of gap junctions’ role in regulating fast motor behavior. Finally, the CoPA IN provides a novel candidate neuron for future studies of gap junctions and neural control of fast motor behaviors. PMID:25018700

Elimination of Left-Right Reciprocal Coupling in the Adult Lamprey Spinal Cord Abolishes the Generation of Locomotor Activity

PubMed Central

Messina, J. A.; St. Paul, Alison; Hargis, Sarah; Thompson, Wengora E.; McClellan, Andrew D.

2017-01-01

The contribution of left-right reciprocal coupling between spinal locomotor networks to the generation of locomotor activity was tested in adult lampreys. Muscle recordings were made from normal animals as well as from experimental animals with rostral midline (ML) spinal lesions (~13%→35% body length, BL), before and after spinal transections (T) at 35% BL. Importantly, in the present study actual locomotor movements and muscle burst activity, as well as other motor activity, were initiated in whole animals by descending brain-spinal pathways in response to sensory stimulation of the anterior head. For experimental animals with ML spinal lesions, sensory stimulation could elicit well-coordinated locomotor muscle burst activity, but with some significant differences in the parameters of locomotor activity compared to those for normal animals. Computer models representing normal animals or experimental animals with ML spinal lesions could mimic many of the differences in locomotor activity. For experimental animals with ML and T spinal lesions, right and left rostral hemi-spinal cords, disconnected from intact caudal cord, usually produced tonic or unpatterned muscle activity. Hemi-spinal cords sometimes generated spontaneous or sensory-evoked relatively high frequency “burstlet” activity that probably is analogous to the previously described in vitro “fast rhythm”, which is thought to represent lamprey locomotor activity. However, “burstlet” activity in the present study had parameters and features that were very different than those for lamprey locomotor activity: average frequencies were ~25 Hz, but individual frequencies could be >50 Hz; burst proportions (BPs) often varied with cycled time; “burstlet” activity usually was not accompanied by a rostrocaudal phase lag; and following ML spinal lesions alone, “burstlet” activity could occur in the presence or absence of swimming burst activity, suggesting the two were generated by different

Participation in organized sports is positively associated with employment in adults with spinal cord injury.

PubMed

Blauwet, Cheri; Sudhakar, Supreetha; Doherty, Ashley L; Garshick, Eric; Zafonte, Ross; Morse, Leslie R

2013-05-01

The aim of this study was to determine the association between participation in organized sports programs and employment in adults with chronic spinal cord injury. This is a cross-sectional study of 149 adults with chronic spinal cord injury. Motor level and completeness of injury were confirmed by physical examination. Information related to demographics, employment, level of education, body mass index, duration of injury, participation in individually planned exercise, and participation in organized sports was obtained using a standardized questionnaire. Multivariable logistic regression analyses were used to assess factors associated with employment. In univariate analyses, employment was associated with younger age (P = 0.001) and a higher level of education (P = 0.01), whereas obesity decreased the likelihood of employment (P = 0.04). Participation in organized sports approached significance (P = 0.06). In the multivariable analysis and after adjusting for age, education, and body mass index, participation in organized sports was significantly associated with employment (odds ratio, 2.4; P = 0.04). Sex, duration of injury, wheelchair use, and participation in individually planned exercise were not significantly associated with employment (P = 0.16-0.94). In the adults with chronic spinal cord injury, participation in organized sports was positively associated with employment. Further studies are necessary to determine the causative nature of this association and how various factors related to sports participation may contribute.

Spontaneous recovery of locomotion induced by remaining fibers after spinal cord transection in adult rats.

PubMed

You, Si-Wei; Chen, Bing-Yao; Liu, Hui-Ling; Lang, Bing; Xia, Jie-Lai; Jiao, Xi-Ying; Ju, Gong

2003-01-01

A major issue in analysis of experimental results after spinal cord injury is spontaneous functional recovery induced by remaining nerve fibers. The authors investigated the relationship between the degree of locomotor recovery and the percentage and location of the fibers that spared spinal cord transection. The spinal cords of 12 adult rats were transected at T9 with a razor blade, which often resulted in sparing of nerve fibers in the ventral spinal cord. The incompletely-transected animals were used to study the degree of spontaneous recovery of hindlimb locomotion, evaluated with the BBB rating scale, in correlation to the extent and location of the remaining fibers. Incomplete transection was found in the ventral spinal cord in 42% of the animals. The degree of locomotor recovery was highly correlated with the percentage of the remaining fibers in the ventral and ventrolateral funiculi. In one of the rats, 4.82% of remaining fibers in unilateral ventrolateral funiculus were able to sustain a certain recovery of locomotion. Less than 5% of remaining ventrolateral white matter is sufficient for an unequivocal motor recovery after incomplete spinal cord injury. Therefore, for studies with spinal cord transection, the completeness of sectioning should be carefully checked before any conclusion can be reached. The fact that the degree of locomotor recovery is correlated with the percentage of remaining fibers in the ventrolateral spinal cord, exclusive of most of the descending motor tracts, may imply an essential role of propriospinal connections in the initiation of spontaneous locomotor recovery.

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

PubMed Central

Liu, Ying Hsiu; Sahashi, Kentaro; Rigo, Frank; Bennett, C. Frank

2015-01-01

Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice. PMID:25583329

Effect of lycopene on the blood-spinal cord barrier after spinal cord injury in mice.

PubMed

Zhang, Qian; Wang, Jianbo; Gu, Zhengsong; Zhang, Qing; Zheng, Hong

2016-09-05

The current study aimed to investigate the effect of lycopene on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a mouse model. Lycopene inhibited lipid peroxidation and oxidative DNA damage as a highly efficient antioxidant and free radical scavenger. Lycopene (4 mg/kg/d) was administrated immediately following SCI. The permeability of the BSCB and water content in the spinal cord tissue were evaluated. Additionally, levels of expression of tight junction proteins and heme oxygenase-1 (HO-1) were determined with Western blotting. An enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 48 h after SCI to evaluate the expression of inflammation-related cytokines. In addition, recovery of motor function was assessed 1 d, 2 d, 5 d, 10 d, and 15 d after SCI using the Basso Mouse Scale to score locomotion. Compared to the group with an untreated SCI, mice with an SCI treated with lycopene had significantly reduced spinal cord tissue water content and BSCB permeability. Furthermore, motor function of mice with an SCI was also greatly improved by lycopene administration. The expression of the proinflammatory factors TNF-α and NF-kB increased markedly 48 h after SCI, and their upregulation was significantly attenuated by lycopene treatment. The expression of molecules that protect tight junctions, zonula occluden-1 and claudin-5, was upregulated by lycopene treatment after SCI. Taken together, these results clearly indicate that lycopene attenuated SCI by promoting repair of the damaged BSCB, so lycopene is a novel and promising treatment for SCI in humans.

The lumbar lordosis index: a new ratio to detect spinal malalignment with a therapeutic impact for sagittal balance correction decisions in adult scoliosis surgery.

PubMed

Boissière, Louis; Bourghli, Anouar; Vital, Jean-Marc; Gille, Olivier; Obeid, Ibrahim

2013-06-01

Sagittal malalignment is frequently observed in adult scoliosis. C7 plumb line, lumbar lordosis and pelvic tilt are the main factors to evaluate sagittal balance and the need of a vertebral osteotomy to correct it. We described a ratio: the lumbar lordosis index (ratio lumbar lordosis/pelvic incidence) (LLI) and analyzed its relationships with spinal malalignment and vertebral osteotomies. 53 consecutive patients with a surgical adult scoliosis had preoperative and postoperative full spine EOS radiographies to measure spino-pelvic parameters and LLI. The lack of lordosis was calculated after prediction of theoretical lumbar lordosis. Correlation analysis between the different parameters was performed. All parameters were correlated with spinal malalignment but LLI is the most correlated parameter (r = -0.978). It is also the best parameter in this study to predict the need of a spinal osteotomy (r = 1 if LLI <0.5). LLI is a statistically validated parameter for sagittal malalignment analysis. It can be used as a mathematical tool to detect spinal malalignment in adult scoliosis and guides the surgeon decision of realizing a vertebral osteotomy for adult scoliosis sagittal correction. It can be used as well for the interpretation of clinical series in adult scoliosis.

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model.

PubMed

Gu, Xiaoping; Zheng, Yaguo; Ren, Bingxu; Zhang, Rui; Mei, Fengmei; Zhang, Juan; Ma, Zhengliang

2010-10-05

Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain.

Heterogeneity in Spinal Bone Mineral Density Among Young Adults From Three Eastern Provincial Capital Cities in Mainland China.

PubMed

Cheng, Xiao-Guang; Li, Kai; Ou, Shan-Xing; Tang, Guang-Yu; Wang, Qian-Qian; Wang, Chao; Wang, Ling; Tian, Wei

This study compares spinal volumetric bone mineral density (vBMD) with spinal areal bone mineral density (aBMD) among young adults from 3 eastern provincial capital cities in Mainland China. A total of 416 young adults (age range: 20-40 yr) from 3 eastern provincial capital cities (Beijing, Shanghai, and Guangzhou) in Mainland China were recruited in this study. From each subject, the vBMD of the lumbar spine was measured by the Mindways quantitative computed tomography system. Moreover, the aBMD of the lumbar spine, measured by the dual-energy X-ray absorptiometry, was extracted from a previous multicenter large-scale study, and the 420 participants were matched by age, gender, height, weight, as well as geographic territory. The vBMD and the aBMD values were further compared and analyzed. Generally, the bone mineral density (BMD) results were significantly different among participants from the 3 cities (p <0.05). Specifically, both vBMD and aBMD values of participants from Beijing were significantly different from those from Guangzhou (p <0.05). Additionally, a statistically significant difference in aBMD values was also found between participants from Beijing and Shanghai (p <0.05). However, no significant differences were found between participants from Shanghai and Guangzhou in terms of the aBMD and vBMD values (p 1  > 0.05 and p 2  > 0.05). Interestingly, the overall mean vBMD value was 5.9% greater in women than those in men for all the 3 cities (p <0.001). This study demonstrated an overall heterogeneity in spinal BMD among young adults from 3 eastern provincial capital cities in Mainland China. Specifically, the taller and heavier young adults from the northern part of China have smaller spinal vBMD but higher spinal aBMD values than those who were shorter and lighter from the southern part of China. Copyright © 2016 International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

Subretinal delivery and electroporation in pigmented and nonpigmented adult mouse eyes

PubMed Central

Nickerson, John M.; Goodman, Penny; Chrenek, Micah A.; Johnson, Christiana J.; Berglin, Lennart; Redmond, T. Michael.; Boatright, Jeffrey H.

2013-01-01

Subretinal injection offers one of the best ways to deliver many classes of drugs, reagents, cells and treatments to the photoreceptor, Müller, and retinal pigment epithelium (RPE) cells of the retina. Agents delivered to this space are placed within microns of the intended target cell, accumulating to high concentrations because there is no dilution due to transport processes or diffusion. Dilution in the interphotoreceptor space (IPS) is minimal because the IPS volume is only 10-20 microliters in the human eye and less than 1 microliter in the mouse eye. For gene delivery purposes, we wished to transfect the cells adjacent to the IPS in adult mouse eyes. Others transfect these cells in neonatal rats to study the development of the retina. In both neonates and adults, electroporation is found to be effective Here we describe the optimization of electroporation conditions for RPE cells in the adult mouse eye with naked plasmids. However, both techniques, subretinal injection and electroporation, present some technical challenges that require skill on the part of the surgeon to prevent untoward damage to the eye. Here we describe methods that we have used for the past ten years (1). PMID:22688698

A developmentally plastic adult mouse kidney cell line spontaneously generates multiple adult kidney structures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Webb, Carol F., E-mail: carol-webb@omrf.org; Immunobiology and Cancer Research, Oklahoma Medical Research Foundation, Oklahoma City, OK; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

Despite exciting new possibilities for regenerative therapy posed by the ability to induce pluripotent stem cells, recapitulation of three-dimensional kidneys for repair or replacement has not been possible. ARID3a-deficient mouse tissues generated multipotent, developmentally plastic cells. Therefore, we assessed the adult mouse ARID3a−/− kidney cell line, KKPS5, which expresses renal progenitor surface markers as an alternative cell source for modeling kidney development. Remarkably, these cells spontaneously developed into multicellular nephron-like structures in vitro, and engrafted into immunocompromised medaka mesonephros, where they formed mouse nephron structures. These data implicate KKPS5 cells as a new model system for studying kidney development. - Highlights:more » • An ARID3a-deficient mouse kidney cell line expresses multiple progenitor markers. • This cell line spontaneously forms multiple nephron-like structures in vitro. • This cell line formed mouse kidney structures in immunocompromised medaka fish kidneys. • Our data identify a novel model system for studying kidney development.« less

Effect of stretching program in an industrial workplace on hamstring flexibility and sagittal spinal posture of adult women workers: a randomized controlled trial.

PubMed

Muyor, José M; López-Miñarro, Pedro A; Casimiro, Antonio J

2012-01-01

To determine the effect of a stretching program performed in the workplace on the hamstring muscle extensibility and sagittal spinal posture of adult women. Fifty-eight adult women volunteers (mean age of 44.23 ± 8.87 years) from a private fruit and vegetable company were randomly assigned to experimental (n=27) or control (n=31) groups. The experimental group performed three exercises of hamstrings stretching of 20 seconds per exercise, three sessions a week for a period of 12 weeks. The control group did not participate in any hamstring stretching program. Hamstring flexibility was evaluated through the passive straight leg raise test and toe-touch test, performed both before and after the stretching program. Thoracic and lumbar curvatures and pelvic inclination were measured in relaxed standing and toe-touch test with a Spinal Mouse. Significant increases (p < 0.01) in toe-touch score and straight leg raise angle (in both legs) were found in the experimental group during post-test, while the control group showed a non-significant decrease for both toe-touch score and straight leg raise test. A significant decrease in thoracic curve and significant increase in pelvic inclination were found in the toe-touch test for the experimental group (p <0.05). However, no significant changes were found in standing posture for any group. Hamstring stretching exercises performed in the working place are effective for increasing hamstring muscle extensibility. This increase generates a more aligned thoracic curve and more anterior pelvic inclination when maximal trunk flexion is performed.

The Adult Mouse Anatomical Dictionary: a tool for annotating and integrating data

PubMed Central

Hayamizu, Terry F; Mangan, Mary; Corradi, John P; Kadin, James A; Ringwald, Martin

2005-01-01

We have developed an ontology to provide standardized nomenclature for anatomical terms in the postnatal mouse. The Adult Mouse Anatomical Dictionary is structured as a directed acyclic graph, and is organized hierarchically both spatially and functionally. The ontology will be used to annotate and integrate different types of data pertinent to anatomy, such as gene expression patterns and phenotype information, which will contribute to an integrated description of biological phenomena in the mouse. PMID:15774030

Subpial Adeno-associated Virus 9 (AAV9) Vector Delivery in Adult Mice.

PubMed

Tadokoro, Takahiro; Miyanohara, Atsushi; Navarro, Michael; Kamizato, Kota; Juhas, Stefan; Juhasova, Jana; Marsala, Silvia; Platoshyn, Oleksandr; Curtis, Erik; Gabel, Brandon; Ciacci, Joseph; Lukacova, Nada; Bimbova, Katarina; Marsala, Martin

2017-07-13

The successful development of a subpial adeno-associated virus 9 (AAV9) vector delivery technique in adult rats and pigs has been reported on previously. Using subpially-placed polyethylene catheters (PE-10 or PE-5) for AAV9 delivery, potent transgene expression through the spinal parenchyma (white and gray matter) in subpially-injected spinal segments has been demonstrated. Because of the wide range of transgenic mouse models of neurodegenerative diseases, there is a strong desire for the development of a potent central nervous system (CNS)-targeted vector delivery technique in adult mice. Accordingly, the present study describes the development of a spinal subpial vector delivery device and technique to permit safe and effective spinal AAV9 delivery in adult C57BL/6J mice. In spinally immobilized and anesthetized mice, the pia mater (cervical 1 and lumbar 1-2 spinal segmental level) was incised with a sharp 34 G needle using an XYZ manipulator. A second XYZ manipulator was then used to advance a blunt 36G needle into the lumbar and/or cervical subpial space. The AAV9 vector (3-5 µL; 1.2 x 10 13 genome copies (gc)) encoding green fluorescent protein (GFP) was then injected subpially. After injections, neurological function (motor and sensory) was assessed periodically, and animals were perfusion-fixed 14 days after AAV9 delivery with 4% paraformaldehyde. Analysis of horizontal or transverse spinal cord sections showed transgene expression throughout the entire spinal cord, in both gray and white matter. In addition, intense retrogradely-mediated GFP expression was seen in the descending motor axons and neurons in the motor cortex, nucleus ruber, and formatio reticularis. No neurological dysfunction was noted in any animals. These data show that the subpial vector delivery technique can successfully be used in adult mice, without causing procedure-related spinal cord injury, and is associated with highly potent transgene expression throughout the spinal neuraxis.

Utility of Survival Motor Neuron ELISA for Spinal Muscular Atrophy Clinical and Preclinical Analyses

PubMed Central

Kobayashi, Dione T.; Olson, Rory J.; Sly, Laurel; Swanson, Chad J.; Chung, Brett; Naryshkin, Nikolai; Narasimhan, Jana; Bhattacharyya, Anuradha; Mullenix, Michael; Chen, Karen S.

2011-01-01

Objectives Genetic defects leading to the reduction of the survival motor neuron protein (SMN) are a causal factor for Spinal Muscular Atrophy (SMA). While there are a number of therapies under evaluation as potential treatments for SMA, there is a critical lack of a biomarker method for assessing efficacy of therapeutic interventions, particularly those targeting upregulation of SMN protein levels. Towards this end we have engaged in developing an immunoassay capable of accurately measuring SMN protein levels in blood, specifically in peripheral blood mononuclear cells (PBMCs), as a tool for validating SMN protein as a biomarker in SMA. Methods A sandwich enzyme-linked immunosorbent assay (ELISA) was developed and validated for measuring SMN protein in human PBMCs and other cell lysates. Protocols for detection and extraction of SMN from transgenic SMA mouse tissues were also developed. Results The assay sensitivity for human SMN is 50 pg/mL. Initial analysis reveals that PBMCs yield enough SMN to analyze from blood volumes of less than 1 mL, and SMA Type I patients' PBMCs show ∼90% reduction of SMN protein compared to normal adults. The ELISA can reliably quantify SMN protein in human and mouse PBMCs and muscle, as well as brain, and spinal cord from a mouse model of severe SMA. Conclusions This SMN ELISA assay enables the reliable, quantitative and rapid measurement of SMN in healthy human and SMA patient PBMCs, muscle and fibroblasts. SMN was also detected in several tissues in a mouse model of SMA, as well as in wildtype mouse tissues. This SMN ELISA has general translational applicability to both preclinical and clinical research efforts. PMID:21904622

Increased excitability of spinal pain reflexes and altered frequency-dependent modulation in the dopamine D3-receptor knockout mouse.

PubMed

Keeler, Benjamin E; Baran, Christine A; Brewer, Kori L; Clemens, Stefan

2012-12-01

Frequency-dependent modulation and dopamine (DA) receptors strongly modulate neural circuits in the spinal cord. Of the five known DA receptor subtypes, the D3 receptor has the highest affinity to DA, and D3-mediated actions are mainly inhibitory. Using an animal model of spinal sensorimotor dysfunction, the D3 receptor knockout mouse (D3KO), we investigated the physiological consequences of D3 receptor dysfunction on pain-associated signaling pathways in the spinal cord, the initial integration site for the processing of pain signaling. In the D3KO spinal cord, inhibitory actions of DA on the proprioceptive monosynaptic stretch reflex are converted from depression to facilitation, but its effects on longer-latency and pain-associated reflex responses and the effects of FM have not been studied. Using behavioral approaches in vivo, we found that D3KO animals exhibit reduced paw withdrawal latencies to thermal pain stimulation (Hargreaves' test) over wild type (WT) controls. Electrophysiological and pharmacological approaches in the isolated spinal cord in vitro showed that constant current stimulation of dorsal roots at a pain-associated frequency was associated with a significant reduction in the frequency-dependent modulation of longer-latency reflex (LLRs) responses but not monosynaptic stretch reflexes (MSRs) in D3KO. Application of the D1 and D2 receptor agonists and the voltage-gated calcium-channel ligand, pregabalin, but not DA, was able to restore the frequency-dependent modulation of the LLR in D3KO to WT levels. Thus we demonstrate that nociception-associated LLRs and proprioceptive MSRs are differentially modulated by frequency, dopaminergics and the Ca(2+) channel ligand, pregabalin. Our data suggest a role for the DA D3 receptor in pain modulation and identify the D3KO as a possible model for increased nociception. Copyright © 2012 Elsevier Inc. All rights reserved.

Intratumoral hemorrhage because of primary spinal mixed germ cell tumor presenting with atypical radiological features in an adult.

PubMed

Yamamoto, Junkoh; Takahashi, Mayu; Nakano, Yoshiteru; Saito, Takeshi; Kitagawa, Takehiro; Ueta, Kunihiro; Miyaoka, Ryo; Nakamura, Eiichiro; Nishizawa, Shigeru

2013-10-01

Germ cell tumors are known to arise in the central nervous system, usually in the intracranial regions. However, primary spinal mixed germ cell tumors are extremely rare. This is the first reported case of intratumoral hemorrhage because of a primary spinal mixed germ cell tumor consisting of germinoma and immature teratoma in the conus medullaris of an adult patient that presented with rapid changes on magnetic resonance image (MRI). We report this rare case and discuss the clinical manifestations of an intramedullary spinal mixed germ cell tumor in adult. A case report. A 42-year-old woman experienced buttock numbness, and a spinal cord tumor was observed on the conus medullaris on MRI. The patient was scheduled for an operation in 1 month, but she developed sudden-onset neurologic deterioration. Rapid progression of the tumor was observed on follow-up MRI. The tumor was removed by emergency surgery and was identified as a primary mixed germinoma and immature teratoma. The patient received adjuvant chemotherapy and radiotherapy after gross total resection. The neurologic deficit of the patient was relieved, and recurrence of the tumor was not observed 26 months after the surgery. We present this rare case and emphasize the necessity of precise diagnosis and early treatment of primary spinal germ cell tumor. Close observation on MRI is required after surgery, and adjuvant chemotherapy and radiotherapy should be considered according to the pathologic features. Copyright © 2013 Elsevier Inc. All rights reserved.

Skin test sensitivity to mouse predicts allergic symptoms to nasal challenge in urban adults.

PubMed

Chong, Laura K; Ong, Mary Jane; Curtin-Brosnan, Jean; Matsui, Elizabeth C

2010-01-01

Epidemiologic studies have shown an association between mouse allergen exposure and asthma morbidity among urban populations, but confirmatory challenge studies in community populations have not been performed. This study was designed to examine the clinical relevance of mouse sensitization using a nasal challenge model. Forty-nine urban adults with asthma underwent skin-prick testing (SPT) and intradermal testing (IDT) with mouse epithelia extract. A positive SPT was defined as a net wheal size ≥3 mm and a positive IDT was defined as a net wheal size ≥6 mm using a 1:100 dilution of extract (1:10 w/v was obtained from Greer Laboratories (Lenoir, NC) as a single lot [Mus m 1 concentration = 2130 ng/mL]). Mouse-specific IgE (m-IgE) was measured by ImmunoCAP (Phadia, Uppsala, Sweden). Nasal challenge was performed with increasing concentrations of mouse epithelia extract and symptoms were assessed by visual analog scale. A positive challenge was defined as a 20-mm increase in the scale. The age range of the 49 participants was 18-50 years; 41% were men and 86% were black. Fourteen participants were SPT(+) to mouse, 15 participants were SPT(-) but (IDT(+)), and 20 participants were negative on both SPT(-) and IDT(-) (SPT(-)/IDT(-)). Sixty-four percent of the SPT(+) group, 40% of the IDT(+) group, and 20% of the SPT(-)/IDT(-) group had a positive nasal challenge. Sixty-seven percent (10/15) of those who were either SPT(+) or m-IgE(+) had a positive nasal challenge. SPT or the combination of SPT plus m-IgE performed best in diagnosing mouse allergy. The great majority of mouse-sensitized urban adults with asthma appear to have clinically relevant sensitization. Urban adults with asthma should be evaluated for mouse sensitization using SPT or SPT plus m-IgE testing.

Prolactin Stimulates Precursor Cells in the Adult Mouse Hippocampus

PubMed Central

Walker, Tara L.; Vukovic, Jana; Koudijs, Margaretha M.; Blackmore, Daniel G.; Mackay, Eirinn W.; Sykes, Alex M.; Overall, Rupert W.; Hamlin, Adam S.; Bartlett, Perry F.

2012-01-01

In the search for ways to combat degenerative neurological disorders, neurogenesis-stimulating factors are proving to be a promising area of research. In this study, we show that the hormonal factor prolactin (PRL) can activate a pool of latent precursor cells in the adult mouse hippocampus. Using an in vitro neurosphere assay, we found that the addition of exogenous PRL to primary adult hippocampal cells resulted in an approximate 50% increase in neurosphere number. In addition, direct infusion of PRL into the adult dentate gyrus also resulted in a significant increase in neurosphere number. Together these data indicate that exogenous PRL can increase hippocampal precursor numbers both in vitro and in vivo. Conversely, PRL null mice showed a significant reduction (approximately 80%) in the number of hippocampal-derived neurospheres. Interestingly, no deficit in precursor proliferation was observed in vivo, indicating that in this situation other niche factors can compensate for a loss in PRL. The PRL loss resulted in learning and memory deficits in the PRL null mice, as indicated by significant deficits in the standard behavioral tests requiring input from the hippocampus. This behavioral deficit was rescued by direct infusion of recombinant PRL into the hippocampus, indicating that a lack of PRL in the adult mouse hippocampus can be correlated with impaired learning and memory. PMID:22973440

Intraperitoneal injection of thalidomide attenuates bone cancer pain and decreases spinal tumor necrosis factor-α expression in a mouse model

PubMed Central

2010-01-01

Background Tumor necrosis factor α (TNF-α) may have a pivotal role in the genesis of mechanical allodynia and thermal hyperalgesia during inflammatory and neuropathic pain. Thalidomide has been shown to selectively inhibit TNF-α production. Previous studies have suggested that thalidomide exerts anti-nociceptive effects in various pain models, but its effects on bone cancer pain have not previously been studied. Therefore, in the present study, we investigated the effect of thalidomide on bone cancer-induced hyperalgesia and up-regulated expression of spinal TNF-α in a mouse model. Results Osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce ongoing bone cancer related pain behaviors. At day 5, 7, 10 and 14 after operation, the expression of TNF-α in the spinal cord was higher in tumor-bearing mice compared to the sham mice. Intraperitoneal injection of thalidomide (50 mg/kg), started at day 1 after surgery and once daily thereafter until day 7, attenuated bone cancer-evoked mechanical allodynia and thermal hyperalgesia as well as the up-regulation of TNF-α in the spinal cord. Conclusions These results suggest that thalidomide can efficiently alleviate bone cancer pain and it may be a useful alternative or adjunct therapy for bone cancer pain. Our data also suggest a role of spinal TNF-α in the development of bone cancer pain. PMID:20923560

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats.

PubMed

Chu, Weihua; Yuan, Jichao; Huang, Lei; Xiang, Xin; Zhu, Haitao; Chen, Fei; Chen, Yanyan; Lin, Jiangkai; Feng, Hua

2015-07-01

Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.

Amino terminus of substance P potentiates kainic acid-induced activity in the mouse spinal cord.

PubMed

Larson, A A; Sun, X

1992-12-01

Sensitization to the behavioral effects produced by repeated injections of kainic acid (KA) into the mouse spinal cord area has been previously shown to be abolished by pretreatment with capsaicin, a neurotoxin of substance P (SP)-containing primary afferent C-fibers. While SP has a variety of well characterized biological actions that are mediated by interactions of its COOH terminus with neurokinin receptors, more recently we have characterized an amino-terminally directed SP binding site. The present studies were initiated to determine whether behavioral sensitization to repeated injections of intrathecally administered KA is mediated by the COOH or NH2 terminal of SP. In the present studies, pretreatment with SP(1-7), an NH2-terminal fragment of SP, but not SP(5-11), a COOH-terminal fragment, potentiated KA-induced behavioral activity in mice. Pretreatment with [D-Pro2,D-Phe7]SP(1-7), an inhibitor of SP NH2-terminal binding, blocked the potentiative effect of SP(1-7) as well as the sensitization to repeated injections of KA. In contrast, [D-Pro2,D-Trp7,9]SP, a neurokinin antagonist, had little effect on behavioral sensitization to KA. The present study suggests that SP has an important modulatory role on excitatory amino acid activity in the spinal cord that is mediated by an action of the NH2 terminal of SP at a non-neurokinin receptor.

The human natural killer-1 (HNK-1) glycan mimetic ursolic acid promotes functional recovery after spinal cord injury in mouse.

PubMed

Sahu, Sudhanshu; Li, Rong; Kadeyala, Praveen Kumar; Liu, Shisong; Schachner, Melitta

2018-05-01

Human natural killer-1 (HNK-1) cell antigen is a glycan epitope involved in several neural events, such as neuritogenesis, myelination, synaptic plasticity and regeneration of the nervous system after injury. We have recently identified the small organic compound ursolic acid (UA) as a HNK-1 mimetic with the aim to test its therapeutic potential in the central nervous system. UA, a plant-derived pentacyclic triterpenoid, is well known for its multiple biological functions, including neuroprotective, antioxidant and anti-inflammatory activities. In the present study, we evaluated its functions in a mouse model of spinal cord injury (SCI) and explored the molecular mechanisms underlying its positive effects. Oral administration of UA to mice 1 h after SCI and thereafter once daily for 6 weeks enhanced the regaining of motor functions and axonal regrowth, and decreased astrogliosis. UA administration decreased levels of proinflammatory markers, including interleukin-6 and tumor necrosis factor-α, in the injured spinal cord at the acute phase of inflammation and activated the mitogen-activated protein kinase and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways in the injured spinal cord. Taken together, these results suggest that UA may be a candidate for treatment of nervous system injuries. Copyright © 2017. Published by Elsevier Inc.

Cervical Spinal Cord Dimensions and Clinical Outcomes in Adults with Klippel-Feil Syndrome: A Comparison with Matched Controls

PubMed Central

Cho, Woojin; Lee, Dong-Ho; Auerbach, Joshua D.; Sehn, Jennifer K.; Nabb, Colin E.; Riew, K. Daniel

2014-01-01

Study Design Retrospective case–control study. Objectives To confirm the fact that spinal cord dimensions are smaller in adults with Klippel-Feil syndrome (KFS) than in pediatric patients with KFS and to compare the clinical characteristics and outcomes of neurologic complications in patients with KFS with matched controls. Methods We performed an independent 1:2 case–control retrospective radiographic and chart review of a consecutive series of adults with KFS who underwent surgical intervention. The control group consisted of consecutive non-KFS surgical patients. Patients were matched in 1:2 case–control manner. Their charts were reviewed and the clinical characteristics were compared. Axial T2-weighted magnetic resonance imaging (MRI) was used to measure the anteroposterior and mediolateral axial spinal cord and spinal canal at the operative levels and measurements were compared. Results A total of 22 patients with KFS and 44 controls were identified. The KFS group had a tendency of more myeloradiculopathy, and the control group had a tendency toward more radiculopathy. Both tendencies, however, were not significantly different. MRIs of 10 patients from the KFS group and 22 controls were available. There was no difference in the area of both spinal cord and canal at the operative levels. Conclusion Contrary to the finding in previous reports on pediatric patients, there were no differences between KFS and well-matched control groups in terms of age of onset, presentation, revision rate, complication rate, surgical outcome, and cross-sectional spinal cord and canal dimensions at the operative level. PMID:25396101

Leisure time physical activity among older adults with long-term spinal cord injury.

PubMed

Jörgensen, S; Martin Ginis, K A; Lexell, J

2017-09-01

Cross-sectional. To describe participation in leisure time physical activity (LTPA) (amount, intensity and type) among older adults with long-term spinal cord injury (SCI), and to investigate the associations with sociodemographics, injury characteristics and secondary health conditions (SHCs). Home settings in southern Sweden. Data from the Swedish Aging with Spinal Cord Injury Study (SASCIS). The physical activity recall assessment for people with SCI was used to assess LTPA among 84 men and 35 women (mean age 63.5 years, mean time since injury 24 years, injury levels C1-L5, American Spinal Injury Association Impairment Scale A-D). Associations were analyzed statistically using hierarchical multivariable regression. Twenty-nine percent reported no LTPA, whereas 53% performed moderate-to-heavy intensity LTPA. The mean minutes per day of total LTPA was 34.7 (±41.5, median 15, range 0-171.7) and of moderate-to-heavy LTPA 22.5 (±35.1, median 5.0, range 0-140.0). The most frequently performed activities were walking and wheeling. Sociodemographics, injury characteristics and SHCs (bowel-related and bladder-related problems, spasticity and pain) explained 10.6% and 13.4%, respectively, of the variance in total and moderate-to-heavy LTPA. Age and wheelchair use were significantly, negatively associated with total LTPA. Women, wheelchair users and employed participants performed significantly less moderate-to-heavy LTPA than men, those using walking devices/no mobility device and unemployed participants. Many older adults with long-term SCI do not reach the amount or intensity of LTPA needed to achieve fitness benefits. Research is needed on how to increase LTPA and to identify modifiable factors that could enhance their participation.

Dopaminergic modulation of locomotor network activity in the neonatal mouse spinal cord

PubMed Central

Sharples, Simon A.; Humphreys, Jennifer M.; Jensen, A. Marley; Dhoopar, Sunny; Delaloye, Nicole; Clemens, Stefan

2015-01-01

Dopamine is now well established as a modulator of locomotor rhythms in a variety of developing and adult vertebrates. However, in mice, while all five dopamine receptor subtypes are present in the spinal cord, it is unclear which receptor subtypes modulate the rhythm. Dopamine receptors can be grouped into two families—the D1/5 receptor group and the D2/3/4 group, which have excitatory and inhibitory effects, respectively. Our data suggest that dopamine exerts contrasting dose-dependent modulatory effects via the two receptor families. Our data show that administration of dopamine at concentrations >35 μM slowed and increased the regularity of a locomotor rhythm evoked by bath application of 5-hydroxytryptamine (5-HT) and N-methyl-d(l)-aspartic acid (NMA). This effect was independent of the baseline frequency of the rhythm that was manipulated by altering the NMA concentration. We next examined the contribution of the D1- and D2-like receptor families on the rhythm. Our data suggest that the D1-like receptor contributes to enhancement of the stability of the rhythm. Overall, the D2-like family had a pronounced slowing effect on the rhythm; however, quinpirole, the D2-like agonist, also enhanced rhythm stability. These data indicate a receptor-dependent delegation of the modulatory effects of dopamine on the spinal locomotor pattern generator. PMID:25652925

POSTNATAL PHENOTYPE AND LOCALIZATION OF SPINAL CORD V1 DERIVED INTERNEURONS

PubMed Central

Alvarez, Francisco J.; Jonas, Philip C.; Sapir, Tamar; Hartley, Robert; Berrocal, Maria C.; Geiman, Eric J.; Todd, Andrew J.; Goulding, Martyn

2010-01-01

Developmental studies identified four classes (V0, V1, V2, V3) of embryonic interneurons in the ventral spinal cord. Very little however is known about their adult phenotypes. In order to further characterize interneuron cell types in the adult, the location, neurotransmitter phenotype, calcium-buffering protein expression and axon distributions of V1-derived neurons in the mouse spinal cord was determined. In the mature (P20 and older) spinal cord, most V1-derived neurons are located in lateral LVII and in LIX, few in medial LVII and none in LVIII. Approximately 40% express calbindin and/or parvalbumin, while few express calretinin. Of seven groups of ventral interneurons identified according to calcium-buffering protein expression, two groups (1 and 4) correspond with V1-derived neurons. Group 1 are Renshaw cells and intensely express calbindin and coexpress parvalbumin and calretinin. They represent 9% of the V1 population. Group 4 express only parvalbumin and represent 27% of V1-derived neurons. V1-derived group 4 neurons receive contacts from primary sensory afferents and are therefore proprioceptive interneurons and the most ventral neurons in this group receive convergent calbindin-IR Renshaw cell inputs. This subgroup resembles Ia inhibitory interneurons (IaINs) and represents 13% of V1-derived neurons. Adult V1-interneuron axons target LIX and LVII and some enter the deep dorsal horn. V1-axons do not cross the midline. V1 derived axonal varicosities were mostly (>80%) glycinergic and a third were GABAergic. None were glutamatergic or cholinergic. In summary, V1 interneurons develop into ipsilaterally projecting, inhibitory interneurons that include Renshaw cells, Ia inhibitory interneurons and other unidentified proprioceptive interneurons. PMID:16255029

Histology and ultrastructure of transitional changes in skin morphology in the juvenile and adult four-striped mouse (Rhabdomys pumilio).

PubMed

Stewart, Eranée; Ajao, Moyosore Salihu; Ihunwo, Amadi Ogonda

2013-01-01

The four-striped mouse has a grey to brown coloured coat with four characteristic dark stripes interspersed with three lighter stripes running along its back. The histological differences in the skin of the juvenile and adult mouse were investigated by Haematoxylin and Eosin and Masson Trichrome staining, while melanocytes in the skin were studied through melanin-specific Ferro-ferricyanide staining. The ultrastructure of the juvenile skin, hair follicles, and melanocytes was also explored. In both the juvenile and adult four-striped mouse, pigment-containing cells were observed in the dermis and were homogeneously dispersed throughout this layer. Apart from these cells, the histology of the skin of the adult four-striped mouse was similar to normal mammalian skin. In the juvenile four-striped mouse, abundant hair follicles of varying sizes were observed in the dermis and hypodermis, while hair follicles of similar size were only present in the dermis of adult four-striped mouse. Ultrastructural analysis of juvenile hair follicles revealed that the arrangement and differentiation of cellular layers were typical of a mammal. This study therefore provides unique transition pattern in the four-striped mouse skin morphology different from the textbook description of the normal mammalian skin.

Dissection of complex adult traits in a mouse synthetic population.

PubMed

Burke, David T; Kozloff, Kenneth M; Chen, Shu; West, Joshua L; Wilkowski, Jodi M; Goldstein, Steven A; Miller, Richard A; Galecki, Andrzej T

2012-08-01

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modest-sized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Human Glial-Restricted Progenitor Transplantation into Cervical Spinal Cord of the SOD1G93A Mouse Model of ALS

PubMed Central

Lepore, Angelo C.; O'Donnell, John; Kim, Andrew S.; Williams, Timothy; Tuteja, Alicia; Rao, Mahendra S.; Kelley, Linda L.; Campanelli, James T.; Maragakis, Nicholas J.

2011-01-01

Cellular abnormalities are not limited to motor neurons in amyotrophic lateral sclerosis (ALS). There are numerous observations of astrocyte dysfunction in both humans with ALS and in SOD1G93A rodents, a widely studied ALS model. The present study therapeutically targeted astrocyte replacement in this model via transplantation of human Glial-Restricted Progenitors (hGRPs), lineage-restricted progenitors derived from human fetal neural tissue. Our previous findings demonstrated that transplantation of rodent-derived GRPs into cervical spinal cord ventral gray matter (in order to target therapy to diaphragmatic function) resulted in therapeutic efficacy in the SOD1G93A rat. Those findings demonstrated the feasibility and efficacy of transplantation-based astrocyte replacement for ALS, and also show that targeted multi-segmental cell delivery to cervical spinal cord is a promising therapeutic strategy, particularly because of its relevance to addressing respiratory compromise associated with ALS. The present study investigated the safety and in vivo survival, distribution, differentiation, and potential efficacy of hGRPs in the SOD1G93A mouse. hGRP transplants robustly survived and migrated in both gray and white matter and differentiated into astrocytes in SOD1G93A mice spinal cord, despite ongoing disease progression. However, cervical spinal cord transplants did not result in motor neuron protection or any therapeutic benefits on functional outcome measures. This study provides an in vivo characterization of this glial progenitor cell and provides a foundation for understanding their capacity for survival, integration within host tissues, differentiation into glial subtypes, migration, and lack of toxicity or tumor formation. PMID:21998733

Sox2 and Jagged1 Expression in Normal and Drug-Damaged Adult Mouse Inner Ear

PubMed Central

Campbell, Sean; Taylor, Ruth R.; Forge, Andrew; Hume, Clifford R.

2007-01-01

Inner ear hair cells detect environmental signals associated with hearing, balance, and body orientation. In humans and other mammals, significant hair cell loss leads to irreversible hearing and balance deficits, whereas hair cell loss in nonmammalian vertebrates is repaired by the spontaneous generation of replacement hair cells. Research in mammalian hair cell regeneration is hampered by the lack of in vivo damage models for the adult mouse inner ear and the paucity of cell-type-specific markers for non-sensory cells within the sensory receptor epithelia. The present study delineates a protocol to drug damage the adult mouse auditory epithelium (organ of Corti) in situ and uses this protocol to investigate Sox2 and Jagged1 expression in damaged inner ear sensory epithelia. In other tissues, the transcription factor Sox2 and a ligand member of the Notch signaling pathway, Jagged1, are involved in regenerative processes. Both are involved in early inner ear development and are expressed in developing support cells, but little is known about their expressions in the adult. We describe a nonsurgical technique for inducing hair cell damage in adult mouse organ of Corti by a single high-dose injection of the aminoglycoside kanamycin followed by a single injection of the loop diuretic furosemide. This drug combination causes the rapid death of outer hair cells throughout the cochlea. Using immunocytochemical techniques, Sox2 is shown to be expressed specifically in support cells in normal adult mouse inner ear and is not affected by drug damage. Sox2 is absent from auditory hair cells, but is expressed in a subset of vestibular hair cells. Double-labeling experiments with Sox2 and calbindin suggest Sox2-positive hair cells are Type II. Jagged1 is also expressed in support cells in the adult ear and is not affected by drug damage. Sox2 and Jagged1 may be involved in the maintenance of support cells in adult mouse inner ear. PMID:18157569

Notch Signaling Pathway Is Activated in Motoneurons of Spinal Muscular Atrophy

PubMed Central

Caraballo-Miralles, Víctor; Cardona-Rossinyol, Andrea; Garcera, Ana; Torres-Benito, Laura; Soler, Rosa M.; Tabares, Lucía; Lladó, Jerònia; Olmos, Gabriel

2013-01-01

Spinal muscular atrophy (SMA) is a neurodegenerative disease produced by low levels of Survival Motor Neuron (SMN) protein that affects alpha motoneurons in the spinal cord. Notch signaling is a cell-cell communication system well known as a master regulator of neural development, but also with important roles in the adult central nervous system. Aberrant Notch function is associated with several developmental neurological disorders; however, the potential implication of the Notch pathway in SMA pathogenesis has not been studied yet. We report here that SMN deficiency, induced in the astroglioma cell line U87MG after lentiviral transduction with a shSMN construct, was associated with an increase in the expression of the main components of Notch signaling pathway, namely its ligands, Jagged1 and Delta1, the Notch receptor and its active intracellular form (NICD). In the SMNΔ7 mouse model of SMA we also found increased astrocyte processes positive for Jagged1 and Delta1 in intimate contact with lumbar spinal cord motoneurons. In these motoneurons an increased Notch signaling was found, as denoted by increased NICD levels and reduced expression of the proneural gene neurogenin 3, whose transcription is negatively regulated by Notch. Together, these findings may be relevant to understand some pathologic attributes of SMA motoneurons. PMID:23759991

Development of a multi-electrode array for spinal cord epidural stimulation to facilitate stepping and standing after a complete spinal cord injury in adult rats.

PubMed

Gad, Parag; Choe, Jaehoon; Nandra, Mandheerej Singh; Zhong, Hui; Roy, Roland R; Tai, Yu-Chong; Edgerton, V Reggie

2013-01-21

stimulation parameters, i.e., stimulation frequency and intensity, and cathode/anode orientation. The array also was used to assess functional connectivity between the cord dorsum to interneuronal circuits and specific motor pools via evoked potentials induced at 1 Hz stimulation in the absence of any anesthesia. Therefore the high density electrode array allows high spatial resolution and the ability to selectively activate different neural pathways within the lumbosacral region of the spinal cord to facilitate standing and stepping in adult spinal rats and provides the capability to evoke motor potentials and thus a means for assessing connectivity between sensory circuits and specific motor pools and muscles.

Regulation by commensal bacteria of neurogenesis in the subventricular zone of adult mouse brain.

PubMed

Sawada, Naoki; Kotani, Takenori; Konno, Tasuku; Setiawan, Jajar; Nishigaito, Yuka; Saito, Yasuyuki; Murata, Yoji; Nibu, Ken-Ichi; Matozaki, Takashi

2018-04-15

In the mouse olfactory bulb (OB), interneurons such as granule cells and periglomerular cells are continuously replaced by adult-born neurons, which are generated in the subventricular zone (SVZ) of the brain. We have now investigated the role of commensal bacteria in regulation of such neuronal cell turnover in the adult mouse brain. Administration of mixture of antibiotics to specific pathogen-free (SPF) mice markedly attenuated the incorporation of bromodeoxyuridine (BrdU) into the SVZ cells. The treatment with antibiotics also reduced newly generated BrdU-positive neurons in the mouse OB. In addition, the incorporation of BrdU into the SVZ cells of germ-free (GF) mice was markedly reduced compared to that apparent for SPF mice. In contrast, the reduced incorporation of BrdU into the SVZ cells of GF mice was recovered by their co-housing with SPF mice, suggesting that commensal bacteria promote the incorporation of BrdU into the SVZ cells. Finally, we found that administration of ampicillin markedly attenuated the incorporation of BrdU into the SVZ cells of SPF mice. Our results thus suggest that ampicillin-sensitive commensal bacteria regulate the neurogenesis in the SVZ of adult mouse brain. Copyright © 2018 Elsevier Inc. All rights reserved.

Spinal microcircuits comprising dI3 interneurons are necessary for motor functional recovery following spinal cord transection

PubMed Central

Bui, Tuan V; Stifani, Nicolas; Akay, Turgay; Brownstone, Robert M

2016-01-01

The spinal cord has the capacity to coordinate motor activities such as locomotion. Following spinal transection, functional activity can be regained, to a degree, following motor training. To identify microcircuits involved in this recovery, we studied a population of mouse spinal interneurons known to receive direct afferent inputs and project to intermediate and ventral regions of the spinal cord. We demonstrate that while dI3 interneurons are not necessary for normal locomotor activity, locomotor circuits rhythmically inhibit them and dI3 interneurons can activate these circuits. Removing dI3 interneurons from spinal microcircuits by eliminating their synaptic transmission left locomotion more or less unchanged, but abolished functional recovery, indicating that dI3 interneurons are a necessary cellular substrate for motor system plasticity following transection. We suggest that dI3 interneurons compare inputs from locomotor circuits with sensory afferent inputs to compute sensory prediction errors that then modify locomotor circuits to effect motor recovery. DOI: http://dx.doi.org/10.7554/eLife.21715.001 PMID:27977000

Teaching Adult Rats Spinalized as Neonates to Walk Using Trunk Robotic Rehabilitation: Elements of Success, Failure, and Dependence

PubMed Central

Udoekwere, Ubong I.; Oza, Chintan S.

2016-01-01

Robot therapy promotes functional recovery after spinal cord injury (SCI) in animal and clinical studies. Trunk actions are important in adult rats spinalized as neonates (NTX rats) that walk autonomously. Quadrupedal robot rehabilitation was tested using an implanted orthosis at the pelvis. Trunk cortical reorganization follows such rehabilitation. Here, we test the functional outcomes of such training. Robot impedance control at the pelvis allowed hindlimb, trunk, and forelimb mechanical interactions. Rats gradually increased weight support. Rats showed significant improvement in hindlimb stepping ability, quadrupedal weight support, and all measures examined. Function in NTX rats both before and after training showed bimodal distributions, with “poor” and “high weight support” groupings. A total of 35% of rats initially classified as “poor” were able to increase their weight-supported step measures to a level considered “high weight support” after robot training, thus moving between weight support groups. Recovered function in these rats persisted on treadmill with the robot both actuated and nonactuated, but returned to pretraining levels if they were completely disconnected from the robot. Locomotor recovery in robot rehabilitation of NTX rats thus likely included context dependence and/or incorporation of models of robot mechanics that became essential parts of their learned strategy. Such learned dependence is likely a hurdle to autonomy to be overcome for many robot locomotor therapies. Notwithstanding these limitations, trunk-based quadrupedal robot rehabilitation helped the rats to visit mechanical states they would never have achieved alone, to learn novel coordinations, and to achieve major improvements in locomotor function. SIGNIFICANCE STATEMENT Neonatal spinal transected rats without any weight support can be taught weight support as adults by using robot rehabilitation at trunk. No adult control rats with neonatal spinal

Teaching Adult Rats Spinalized as Neonates to Walk Using Trunk Robotic Rehabilitation: Elements of Success, Failure, and Dependence.

PubMed

Udoekwere, Ubong I; Oza, Chintan S; Giszter, Simon F

2016-08-10

Robot therapy promotes functional recovery after spinal cord injury (SCI) in animal and clinical studies. Trunk actions are important in adult rats spinalized as neonates (NTX rats) that walk autonomously. Quadrupedal robot rehabilitation was tested using an implanted orthosis at the pelvis. Trunk cortical reorganization follows such rehabilitation. Here, we test the functional outcomes of such training. Robot impedance control at the pelvis allowed hindlimb, trunk, and forelimb mechanical interactions. Rats gradually increased weight support. Rats showed significant improvement in hindlimb stepping ability, quadrupedal weight support, and all measures examined. Function in NTX rats both before and after training showed bimodal distributions, with "poor" and "high weight support" groupings. A total of 35% of rats initially classified as "poor" were able to increase their weight-supported step measures to a level considered "high weight support" after robot training, thus moving between weight support groups. Recovered function in these rats persisted on treadmill with the robot both actuated and nonactuated, but returned to pretraining levels if they were completely disconnected from the robot. Locomotor recovery in robot rehabilitation of NTX rats thus likely included context dependence and/or incorporation of models of robot mechanics that became essential parts of their learned strategy. Such learned dependence is likely a hurdle to autonomy to be overcome for many robot locomotor therapies. Notwithstanding these limitations, trunk-based quadrupedal robot rehabilitation helped the rats to visit mechanical states they would never have achieved alone, to learn novel coordinations, and to achieve major improvements in locomotor function. Neonatal spinal transected rats without any weight support can be taught weight support as adults by using robot rehabilitation at trunk. No adult control rats with neonatal spinal transections spontaneously achieve similar changes

Acute Effects of Hamstring Stretching on Sagittal Spinal Curvatures and Pelvic Tilt

PubMed Central

López-Miñarro, Pedro A.; Muyor, José M.; Belmonte, Felipe; Alacid, Fernando

2012-01-01

The aim of this study was to determine acute effects of hamstring stretching in thoracic and lumbar spinal curvatures and pelvic tilt. Fifty-five adults (29.24 ± 7.41 years) were recruited for this study. Subjects performed a hamstring stretching protocol consisting of four exercises. The session consisted of 3 sets of each exercise and subjects held the position for 20 seconds with a 30-second rest period between sets and exercises. Thoracic and lumbar spinal angles and pelvic tilt were measured with a SpinalMouse in relaxed standing, sit-and-reach test and Macrae & Wright position. Hamstring extensibility was determined by active straight leg raise test and sit-and-reach score. All measures were performed before and immediately after the hamstring stretching protocol. Active straight leg raise angle and sitand-reach score significantly improved immediately after the stretching protocol (p<0.001). Greater anterior pelvic tilt (p<0.001) and lumbar flexion (p<0.05) and a smaller thoracic kyphosis in the sit-and-reach (p<0.001) were found after the stretching protocol. However, stretching produced no significant change on spinal curvatures or pelvic tilt in standing and maximal trunk flexion with knees flexed. In conclusion, static stretching of the hamstring is associated to an immediate change in the sagittal spinal curvatures and pelvic position when performing trunk flexion with knees extended, so that allowing for greater lumbar flexion and anterior pelvic tilt and lower thoracic kyphosis. Hamstring stretching is recommended prior to sport activities involving trunk flexion with the knees straight. PMID:23486214

A prospective evaluation of a pressure ulcer prevention and management E-Learning Program for adults with spinal cord injury.

PubMed

Brace, Jacalyn A; Schubart, Jane R

2010-08-01

Pressure ulcers are a common complication of spinal cord injury (SCI). Pressure ulcer education programs for spinal cord injured individuals have been found to have a positive effect on care protocol adherence. A prospective study was conducted among hospitalized spinal cord-injured men and women to determine if viewing the Pressure Ulcer Prevention and Management Education for Adults with Spinal Cord Injury: E-Learning Program affects their knowledge scores. A 20-question multiple-choice pre-/post learning test was developed and validated by 12 rehabilitation nurses. Twenty (20) patients (13 men, seven women; mean age 49 years, [SD: 18.26] with injuries to the cervical [seven], thoracic [six], and lumbar [six] regions) volunteered. Most (42%) had completed high school and time since SCI ranged from 2 weeks to 27 years. Eighteen (18) participants completed both the pre- and post test. Of those, 16 showed improvement in pressure ulcer knowledge scores. The median scores improved from 65 (range 25 to 100) pre-program to 92.5 (range 75 to 100) post-program. Descriptive statistics, Student's t-test, and analysis of variance (ANOVA) were used to analyze the data. The results suggest that a single viewing of this e-learning program could improve pressure ulcer knowledge of hospitalized adults with SCI. Research to ascertain the effects of this and other educational programs on pressure ulcer rates is needed.

Impact of Gender on 30-Day Complications After Adult Spinal Deformity Surgery.

PubMed

Kothari, Parth; Lee, Nathan J; Leven, Dante M; Lakomkin, Nikita; Shin, John I; Skovrlj, Branko; Steinberger, Jeremy; Guzman, Javier Z; Cho, Samuel K

2016-07-15

Retrospective study of prospectively collected data. To determine if postoperative morbidity for patients undergoing spinal deformity surgery varies by sex. Influence of sex has been investigated in other surgical procedures but has not yet been studied in adult spinal deformity surgery. The American College of Surgeons National Surgical Quality Improvement Program is a large multicenter clinical registry that prospectively collects preoperative risk factors, intraoperative variables, and 30-day postoperative morbidity and mortality outcomes from about 400 hospitals nationwide. Current Procedural Terminology codes were used to query the database for adults who underwent fusion for spinal deformity. Patients were separated into groups of male and female sex. Univariate analysis and multivariate logistic regression were used to analyze the effect of sex on the incidence of postoperative morbidity and mortality. Female sex was found to be a predictor of any complication[odds ratio (OR): 1.4, 95% confidence interval (CI) 1.2-1.7, P < 0.0001], intra- or postoperative RBC transfusion (OR: 1.6, 95% CI 1.4-1.9, P < .0001), urinary tract infection (OR: 2.0, 95% CI 1.2-3.3, P = 0.0046), and length of stay >5 days (OR: 1.3, 95% CI 1.1-1.5, P = 0.0015). Male sex was associated with higher rate of pulmonary (2.9% vs. 2.0%, P = 0.0344) and cardiac complications (0.9% vs. 0.5%, P = 0.0497). However, male sex as an independent risk factor for pulmonary (OR: 1.4, 95% CI 1.0-2.1, P = 0.0715) and cardiac complications (OR: 1.9, 95% CI 0.9-4.0, P = 0.1076) did not reach significance. Female sex was found to increase overall morbidity, particularly for urinary tract infection, transfusion, and length of stay >5 days. Male sex was associated with greater incidence of pulmonary and cardiac complications. Thus, sex and other patient characteristics highlighted must be considered as part of surgical risk planning and patient counseling. 3.

Cell Saver for Adult Spinal Deformity Surgery Reduces Cost.

PubMed

Gum, Jeffrey L; Carreon, Leah Yacat; Kelly, Michael P; Hostin, Richard; Robinson, Chessie; Burton, Douglas C; Polly, David W; Shaffrey, Christopher I; LaFage, Virginie; Schwab, Frank J; Ames, Christopher P; Kim, Han Jo; Smith, Justin S; Bess, R Shay

2017-07-01

Retrospective cohort. To determine if the use of cell saver reduces overall blood costs in adult spinal deformity (ASD) surgery. Recent studies have questioned the clinical value of cell saver during spine procedures. ASD patients enrolled in a prospective, multicenter surgical database who had complete preoperative and surgical data were identified. Patients were stratified into (1) cell saver available during surgery, but no intraoperative autologous infusion (No Infusion group), or (2) cell saver available and received autologous infusion (Infusion group). There were 427 patients in the Infusion group and 153 in the No infusion group. Patients in both groups had similar demographics. Mean autologous infusion volume was 698 mL. The Infusion group had a higher percentage of EBL relative to the estimated blood volume (42.2%) than the No Infusion group (19.6%, p < .000). Allogeneic transfusion was more common in the Infusion group (255/427, 60%) than the No Infusion group (67/153, 44%, p = .001). The number of allogeneic blood units transfused was also higher in the Infusion group (2.4) than the No Infusion group (1.7, p = .009). Total blood costs ranged from $396 to $2,146 in the No Infusion group and from $1,262 to $5,088 in the Infusion group. If the cost of cell saver blood was transformed into costs of allogeneic blood, total blood costs for the Infusion group would range from $840 to $5,418. Thus, cell saver use yielded a mean cost savings ranging from $330 to $422 (allogeneic blood averted). Linear regression showed that after an EBL of 614 mL, cell saver becomes cost-efficient. Compared to transfusing allogeneic blood, cell saver autologous infusion did not reduce the proportion or the volume of allogeneic transfusion for patients undergoing surgery for adult spinal deformity. The use of cell saver becomes cost-efficient above an EBL of 614 mL, producing a cost savings of $330 to $422. Level III. Copyright © 2017 Scoliosis Research Society. Published by

The spatiotemporal relationships between chondroitin sulfate proteoglycans and terminations of calcitonin gene related peptide and parvalbumin immunoreactive afferents in the spinal cord of mouse embryos.

PubMed

Wang, Liqing; Yu, Chao; Wang, Jun; Zhao, Hui; Chan, Sun-On

2017-08-10

Chondroitin sulfate (CS) proteoglycans (PGs) are a family of complex molecules in the extracellular matrix and cell surface that regulate axon growth and guidance during development of the central nervous system. In this study, the expression of CSPGs was investigated in the mouse spinal cord at late embryonic and neonatal stages using CS-56 antibody. CS immunoreactivity was observed abundantly in ventral regions of spinal cord of embryonic day (E) 15 embryos. At E16 to E18, CS expression spread dorsally, but never reached the superficial layers of the dorsal horn. This pattern was maintained until postnatal day 4, the latest stage examined. Antibodies against calcitonin gene related peptide (CGRP) and parvalbumin (PV) were employed to label primary afferents from nociceptors and proprioceptors, respectively. CGRP-immunoreactive fibers terminated in the superficial regions of the dorsal horn where CSPGs were weakly expressed, whereas PV-immunoreactive fibers were found in CSPG-rich regions in the ventral horn. Therefore, we conclude that CS expression is spatiotemporally regulated in the spinal cord, which correlates to the termination of sensory afferents. This pattern suggests a role of CSPGs on patterning afferents in the spinal cord, probably through a differential response of axons to these growth inhibitory molecules. Copyright © 2017 Elsevier B.V. All rights reserved.

Physical Activity and Quality of Life in Adults With Spinal Cord Injury

PubMed Central

Stevens, Sandy L; Caputo, Jennifer L; Fuller, Dana K; Morgan, Don W

2008-01-01

Background/Objective: To document the relationship between level of physical activity and quality of life in persons with spinal cord injury. Design: Cross-sectional investigation. Participants/Methods: Men (n = 32) and women (n = 30) with complete and incomplete spinal cord lesions below C6 volunteered to participate in this study. The average length of time since the onset of disability was 9 years (range, 1.5–40 years). Using an interview-formatted survey (Quality of Well-Being Scale), a measure of quality of life was obtained for each participant. Physical activity levels were determined using the Physical Activity Scale for Individuals with Physical Disabilities. Results: A strong positive association (r = 0.75; P < 0.05) was observed between level of physical activity and quality of life. Multiple regression analysis also showed that when level of physical activity, anatomical location of the injury, completeness of injury, and time since injury were used as explanatory variables, level of physical activity was the only significant predictor of quality of life, accounting for 56% of the total variation in quality of life. Conclusions: Results from this study show that a significant and moderately strong positive relationship exists between level of physical activity and quality of life in adults with spinal cord injury. From a clinical perspective, these findings suggest that interventions aimed at promoting physical activity may be effective in improving quality of life in this population. PMID:18959354

Motor neuron mitochondrial dysfunction in spinal muscular atrophy

PubMed Central

Miller, Nimrod; Shi, Han; Zelikovich, Aaron S.; Ma, Yong-Chao

2016-01-01

Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease. PMID:27488123

Complete reorganization of the motor cortex of adult rats following long-term spinal cord injuries.

PubMed

Tandon, Shashank; Kambi, Niranjan; Mohammed, Hisham; Jain, Neeraj

2013-07-01

Understanding brain reorganization following long-term spinal cord injuries is important for optimizing recoveries based on residual function as well as developing brain-controlled assistive devices. Although it has been shown that the motor cortex undergoes partial reorganization within a few weeks after peripheral and spinal cord injuries, it is not known if the motor cortex of rats is capable of large-scale reorganization after longer recovery periods. Here we determined the organization of the rat (Rattus norvegicus) motor cortex at 5 or more months after chronic lesions of the spinal cord at cervical levels using intracortical microstimulation. The results show that, in the rats with the lesions, stimulation of neurons in the de-efferented forelimb motor cortex no longer evokes movements of the forelimb. Instead, movements of the body parts in the adjacent representations, namely the whiskers and neck were evoked. In addition, at many sites, movements of the ipsilateral forelimb were observed at threshold currents. The extent of representations of the eye, jaw and tongue movements was unaltered by the lesion. Thus, large-scale reorganization of the motor cortex leads to complete filling-in of the de-efferented cortex by neighboring representations following long-term partial spinal cord injuries at cervical levels in adult rats. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Spinal sagittal balance substantially influences locomotive syndrome and physical performance in community-living middle-aged and elderly women.

PubMed

Muramoto, Akio; Imagama, Shiro; Ito, Zenya; Hirano, Kenichi; Ishiguro, Naoki; Hasegawa, Yukiharu

2016-03-01

Spinal sagittal imbalance has been well known risk factor of decreased quality of life in the field of adult spinal deformity. However, the impact of spinal sagittal balance on locomotive syndrome and physical performance in community-living elderly has not yet been clarified. The present study investigated the influence of spinal sagittal alignment on locomotive syndrome (LS) and physical performance in community-living middle-aged and elderly women. A total of 125 women between the age of 40-88 years (mean 66.2 ± 9.7 years) who completed the questionnaires, spinal mouse test, physical examination and physical performance tests in Yakumo study were enrolled in this study. Participants answered the 25-Question Geriatric Locomotive Function Scale (GLFS-25), the visual analog scale (VAS) for low back pain (LBP), knee pain. LS was defined as having a score of >16 points on the GLFS-25. Using spinal mouse, spinal inclination angle (SIA), thoracic kyphosis angle (TKA), lumbar lordosis angle (LLA), sacral slope angle (SSA), thoracic spinal range of motion (TSROM), lumbar spinal range of motion (LSROM) were measured. Timed-up-and-go test (TUG), one-leg standing time with eyes open (OLS), and maximum stride, back muscle strength were also measured. The relationship between spinal sagittal parameters and GLFS-25, VAS and physical performance tests were analyzed. 26 people were diagnosed as LS and 99 were diagnosed as non-LS. LBP and knee pain were greater, physical performance tests were poorer, SIA were greater, LLA were smaller in LS group compared to non-LS group even after adjustment by age. SIA significantly correlated with GLFS-25, TUG, OLS and maximum stride even after adjustment by age. The cutoff value of SIA for locomotive syndrome was 6°. People with a SIA of 6° or greater were grouped as "Inclined" and people with a SIA of less than 6° were grouped as "Non-inclined". 21 people were "Inclined" and 104 were "Non-inclined". Odds ratio to fall in LS of

TRANSCRIPT EXPRESSION OF VESICULAR GLUTAMATE TRANSPORTERS IN LUMBAR DORSAL ROOT GANGLIA AND THE SPINAL CORD OF MICE – EFFECTS OF PERIPHERAL AXOTOMY OR HINDPAW INFLAMMATION

PubMed Central

MALET, M.; VIEYTES, C. A.; LUNDGREN, K. H.; SEAL, R. P.; TOMASELLA, E.; SEROOGY, K. B.; HÖKFELT, T.; GEBHART, G.F.; BRUMOVSKY, P. R.

2013-01-01

Using specific riboprobes, we characterized the expression of VGLUT1-VGLUT3 transcripts in lumbar 4-5 (L4-5) DRGs and the thoracolumbar to lumbosacral spinal cord in male BALB/C mice after a 1- or 3-day hindpaw inflammation, or a 7-day sciatic nerve axotomy. Sham animals were also included. In sham and contralateral L4-5 DRGs of injured mice, VGLUT1-, VGLUT2- and VGLUT3 mRNAs were expressed in ~45%, ~69% or ~17% of neuron profiles (NPs), respectively. VGLUT1 was expressed in large and medium-sized NPs, VGLUT2 in NPs of all sizes, and VGLUT3 in small and medium-sized NPs. In the spinal cord, VGLUT1 was restricted to a number of NPs at thoracolumbar and lumbar segments, in what appears to be the dorsal nucleus of Clarke, and in mid laminae III-IV. In contrast, VGLUT2 was present in numerous NPs at all analyzed spinal segments, except the lateral aspects of the ventral horns, especially at the lumbar enlargement, where it was virtually absent. VGLUT3 was detected in a discrete number of NPs in laminae III-IV of the dorsal horn. Axotomy resulted in a moderate decrease in the number of DRG NPs expressing VGLUT3, whereas VGLUT1 and VGLUT2 were unaffected. Likewise, the percentage of NPs expressing VGLUT transcripts remained unaltered after hindpaw inflammation, both in DRGs and the spinal cord. Altogether, these results confirm previous descriptions on VGLUTs expression in adult mice DRGs, with the exception of VGLUT1, whose protein expression was detected in a lower percentage of mouse DRG NPs. A detailed account on the location of neurons expressing VGLUTs transcripts in the adult mouse spinal cord is also presented. Finally, the lack of change in the number of neurons expressing VGLUT1 and VGLUT2 transcripts after axotomy, as compared to data on protein expression, suggests translational rather than transcriptional regulation of VGLUTs after injury. PMID:23727452

Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse.

PubMed

Jean-Xavier, Céline; Perreault, Marie-Claude

2018-01-01

The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs) during drug-induced fictive locomotor-like activity (LLA) in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC) and hindlimb MNs in lateral motor column (LMC). The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor.

Influence of Brain Stem on Axial and Hindlimb Spinal Locomotor Rhythm Generating Circuits of the Neonatal Mouse

PubMed Central

Jean-Xavier, Céline; Perreault, Marie-Claude

2018-01-01

The trunk plays a pivotal role in limbed locomotion. Yet, little is known about how the brain stem controls trunk activity during walking. In this study, we assessed the spatiotemporal activity patterns of axial and hindlimb motoneurons (MNs) during drug-induced fictive locomotor-like activity (LLA) in an isolated brain stem-spinal cord preparation of the neonatal mouse. We also evaluated the extent to which these activity patterns are affected by removal of brain stem. Recordings were made in the segments T7, L2, and L5 using calcium imaging from individual axial MNs in the medial motor column (MMC) and hindlimb MNs in lateral motor column (LMC). The MN activities were analyzed during both the rhythmic and the tonic components of LLA, the tonic component being used as a readout of generalized increase in excitability in spinal locomotor networks. The most salient effect of brain stem removal was an increase in locomotor rhythm frequency and a concomitant reduction in burst durations in both MMC and LMC MNs. The lack of effect on the tonic component of LLA indicated specificity of action during the rhythmic component. Cooling-induced silencing of the brain stem reproduced the increase in rhythm frequency and accompanying decrease in burst durations in L2 MMC and LMC, suggesting a dependency on brain stem neuron activity. The work supports the idea that the brain stem locomotor circuits are operational already at birth and further suggests an important role in modulating trunk activity. The brain stem may influence the axial and hindlimb spinal locomotor rhythm generating circuits by extending their range of operation. This may represent a critical step of locomotor development when learning how to walk in different conditions and environments is a major endeavor. PMID:29479302

Effect of locomotor training in completely spinalized cats previously submitted to a spinal hemisection.

PubMed

Martinez, Marina; Delivet-Mongrain, Hugo; Leblond, Hugues; Rossignol, Serge

2012-08-08

After a spinal hemisection in cats, locomotor plasticity occurring at the spinal level can be revealed by performing, several weeks later, a complete spinalization below the first hemisection. Using this paradigm, we recently demonstrated that the hemisection induces durable changes in the symmetry of locomotor kinematics that persist after spinalization. Can this asymmetry be changed again in the spinal state by interventions such as treadmill locomotor training started within a few days after the spinalization? We performed, in 9 adult cats, a spinal hemisection at thoracic level 10 and then a complete spinalization at T13, 3 weeks later. Cats were not treadmill trained during the hemispinal period. After spinalization, 5 of 9 cats were not trained and served as control while 4 of 9 cats were trained on the treadmill for 20 min, 5 d a week for 3 weeks. Using detailed kinematic analyses, we showed that, without training, the asymmetrical state of locomotion induced by the hemisection was retained durably after the subsequent spinalization. By contrast, training cats after spinalization induced a reversal of the left/right asymmetries, suggesting that new plastic changes occurred within the spinal cord through locomotor training. Moreover, training was shown to improve the kinematic parameters and the performance of the hindlimb on the previously hemisected side. These results indicate that spinal locomotor circuits, previously modified by past experience such as required for adaptation to the hemisection, can remarkably respond to subsequent locomotor training and improve bilateral locomotor kinematics, clearly showing the benefits of locomotor training in the spinal state.

Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease.

PubMed

Gonzalez Deniselle, María Claudia; López-Costa, Juan José; Saavedra, Jorge Pecci; Pietranera, Luciana; Gonzalez, Susana L; Garay, Laura; Guennoun, Rachida; Schumacher, Michael; De Nicola, Alejandro F

2002-12-01

Motor neuron degeneration characterizes the spinal cord of patients with amyotrophic lateral sclerosis and the Wobbler mouse mutant. Considering that progesterone (PROG) provides neuroprotection in experimental ischemia and injury, its potential role in neurodegeneration was studied in the murine model. Two-month-old symptomatic Wobbler mice were left untreated or received sc a 20-mg PROG implant for 15 days. Both light and electron microscopy of Wobbler mice spinal cord showed severely affected motor neurons with profuse cytoplasmic vacuolation of the endoplasmic reticulum and/or Golgi apparatus and ruptured mitochondria with damaged cristae, a profile indicative of a type II cytoplasmic form of cell death. In contrast to untreated mice, neuropathology was less severe in Wobbler mice receiving PROG; including a reduction of vacuolation and of the number of vacuolated cells and better conservation of the mitochondrial ultrastructure. In biochemical studies, we determined the mRNA for the alpha3 subunit of Na,K-ATPase, a neuronal enzyme controlling ion fluxes, neurotransmission, membrane potential, and nutrient uptake. In untreated Wobbler mice, mRNA levels in motor neurons were reduced by half compared to controls, whereas PROG treatment of Wobbler mice restored the expression of alpha3 subunit Na,K-ATPase mRNA. Therefore, PROG was able to rescue motor neurons from degeneration, based on recovery of histopathological abnormalities and of mRNA levels of the sodium pump. However, because the gene mutation in Wobbler mice is still unknown, further studies are needed to unveil the action of PROG and the mechanism of neuronal death in this genetic model of neurodegeneration.

Primary Spinal OPC Culture System from Adult Zebrafish to Study Oligodendrocyte Differentiation In Vitro.

PubMed

Kroehne, Volker; Tsata, Vasiliki; Marrone, Lara; Froeb, Claudia; Reinhardt, Susanne; Gompf, Anne; Dahl, Andreas; Sterneckert, Jared; Reimer, Michell M

2017-01-01

Endogenous oligodendrocyte progenitor cells (OPCs) are a promising target to improve functional recovery after spinal cord injury (SCI) by remyelinating denuded, and therefore vulnerable, axons. Demyelination is the result of a primary insult and secondary injury, leading to conduction blocks and long-term degeneration of the axons, which subsequently can lead to the loss of their neurons. In response to SCI, dormant OPCs can be activated and subsequently start to proliferate and differentiate into mature myelinating oligodendrocytes (OLs). Therefore, researchers strive to control OPC responses, and utilize small molecule screening approaches in order to identify mechanisms of OPC activation, proliferation, migration and differentiation. In zebrafish, OPCs remyelinate axons of the optic tract after lysophosphatidylcholine (LPC)-induced demyelination back to full thickness myelin sheaths. In contrast to zebrafish, mammalian OPCs are highly vulnerable to excitotoxic stress, a cause of secondary injury, and remyelination remains insufficient. Generally, injury induced remyelination leads to shorter internodes and thinner myelin sheaths in mammals. In this study, we show that myelin sheaths are lost early after a complete spinal transection injury, but are re-established within 14 days after lesion. We introduce a novel, easy-to-use, inexpensive and highly reproducible OPC culture system based on dormant spinal OPCs from adult zebrafish that enables in vitro analysis. Zebrafish OPCs are robust, can easily be purified with high viability and taken into cell culture. This method enables to examine why zebrafish OPCs remyelinate better than their mammalian counterparts, identify cell intrinsic responses, which could lead to pro-proliferating or pro-differentiating strategies, and to test small molecule approaches. In this methodology paper, we show efficient isolation of OPCs from adult zebrafish spinal cord and describe culture conditions that enable analysis up to 10

Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord.

PubMed

Keirstead, H S; Levine, J M; Blakemore, W F

1998-02-01

Elucidation of the response of oligodendrocyte progenitor cell populations to demyelination in the adult central nervous system (CNS) is critical to understanding why remyelination fails in multiple sclerosis. Using the anti-NG2 monoclonal antibody to identify oligodendrocyte progenitor cells, we have documented their response to antibody-induced demyelination in the dorsal column of the adult rat spinal cord. The number of NG2+ cells in the vicinity of demyelinated lesions increased by 72% over the course of 3 days following the onset of demyelination. This increase in NG2+ cell numbers did not reflect a nonspecific staining of reactive cells, as GFAP, OX-42, and Rip antibodies did not co-localise with NG2 + cells in double immunostained tissue sections. NG2 + cells incorporated BrdU 48-72 h following the onset of demyelination. After the onset of remyelination (10-14 days), the number of NG2+ cells decreased to 46% of control levels and remained consistently low for 2 months. When spinal cords were exposed to 40 Grays of x-irradiation prior to demyelination, the number of NG2+ cells decreased to 48% of control levels by 3 days following the onset of demyelination and remained unchanged at 3 weeks. Since 40 Grays of x-irradiation kills dividing cells, these studies illustrate a responsive and nonresponsive NG2+ cell population following demyelination in the adult spinal cord and suggest that the responsive NG2+ cell population does not renew itself.

Reduce, reuse, recycle - Developmental signals in spinal cord regeneration.

PubMed

Cardozo, Marcos Julian; Mysiak, Karolina S; Becker, Thomas; Becker, Catherina G

2017-12-01

Anamniotes, fishes and amphibians, have the capacity to regenerate spinal cord tissue after injury, generating new neurons that mature and integrate into the spinal circuitry. Elucidating the molecular signals that promote this regeneration is a fundamental question in regeneration research. Model systems, such as salamanders and larval and adult zebrafish are used to analyse successful regeneration. This shows that many developmental signals, such as Notch, Hedgehog (Hh), Bone Morphogenetic Protein (BMP), Wnt, Fibroblast Growth Factor (FGF), Retinoic Acid (RA) and neurotransmitters are redeployed during regeneration and activate resident spinal progenitor cells. Here we compare the roles of these signals in spinal cord development and regeneration of the much larger and fully patterned adult spinal cord. Understanding how developmental signalling systems are reactivated in successfully regenerating species may ultimately lead to ways to reactivate similar systems in mammalian progenitor cells, which do not show neurogenesis after spinal injury. Copyright © 2017. Published by Elsevier Inc.

Potential of adult mammalian lumbosacral spinal cord to execute and acquire improved locomotion in the absence of supraspinal input

NASA Technical Reports Server (NTRS)

Edgerton, V. R.; Roy, R. R.; Hodgson, J. A.; Prober, R. J.; de Guzman, C. P.; de Leon, R.

1992-01-01

The neural circuitry of the lumbar spinal cord can generate alternating extension and flexion of the hindlimbs. The hindlimbs of adult cats with complete transection of the spinal cord at a low thoracic level (T12-T13) can perform full weight-supporting locomotion on a treadmill belt moving at a range of speeds. Some limitations in the locomotor capacity can be associated with a deficit in the recruitment level of the fast extensors during the stance phase and the flexors during the swing phase of a step cycle. The level of locomotor performance, however, can be enhanced by daily training on a treadmill while emphasizing full weight-support stepping and by providing appropriately timed sensory stimulation, loading, and/or pharmacologic stimulation of the hindlimb neuromuscular apparatus. Furthermore, there appears to be an interactive effect of these interventions. For example, the maximum treadmill speed that a spinal adult cat can attain and maintain is significantly improved with daily full weight-supporting treadmill training, but progressive recruitment of fast extensors becomes apparent only when the hindlimbs are loaded by gently pulling down on the tail during the stepping. Stimulation of the sural nerve at the initiation of the flexion phase of the step cycle can likewise markedly improve the locomotor capability. Administration of clonidine, in particular in combination with an elevated load, resulted in the most distinct and consistent alternating bursts of electromyographic activity during spinal stepping. These data indicate that the spinal cord has the ability to execute alternating activation of the extensor and flexor musculature of the hindlimbs (stepping) and that this ability can be improved by several interventions such as training, sensory stimulation, and use of some pharmacologic agents. Thus, it appears that the spinal cord, without supraspinal input, is highly plastic and has the potential to "learn," that is, to acquire and improve its

Lessons for spinal cord injury rehabilitation taken from adult developmental psychology: 2011 Essie Morgan Lecture

PubMed Central

Rose, Jon

2012-01-01

Background/objective Developmental phases affect how individuals cope with and challenge threats to self-concept, health and functioning. Understanding prominent models of adult psychological development can help spinal cord injury/disease (SCI/D) rehabilitation professionals facilitate positive change and growth. Design Author's theoretical model informed by literature review and personal experience. Setting Veterans administration (VA) medical center interdisciplinary outpatient clinic providing primary and specialty care to veterans with spinal cord injuries and disorders. Conclusion Threats to life expectations, health, well-being, identity, and other aspects of self create crises that can result in psychopathology or psychological growth. SCI/D can present multiple threats across the lifespan. For example, self-image, ability to perform various activities, ability to feel attractive, and even life itself may be challenged by SCI/D or its complications. Threats may be perceived at the time of injury or onset of symptoms. Also, as the injured body declines further over time, complications can cause significant temporary or permanent functional decline. Individuals interpret each of these threats in the context of current developmental needs. How people cope is influenced by developmental factors and personality traits. An integrated model of adult psychological development based on the works of Erikson, Gutmann, and Baltes is related to the literature on coping with SCI/D. This model provides insights that interdisciplinary rehabilitation teams may use to facilitate personal growth, optimal functioning, and physical health as adults with SCI negotiate normal developmental challenges throughout their lifetimes. PMID:22507022

Systematic reviews of physical and rehabilitation medicine Cochrane contents. Part 1. Disabilities due to spinal disorders and pain syndromes in adults.

PubMed

Negrini, S; Imperio, G; Villafañe, J H; Negrini, F; Zaina, F

2013-08-01

This article is the first in a series presenting the strongest published evidence for physical and rehabilitation medicine (PRM) to date coming from the Cochrane Collaboration. The intent of the series is to stimulate ideas for reviews and research in neglected areas of PRM. To systematically review the rehabilitation contents of the Cochrane Collaboration on disabilities due to spinal disorders or pain syndromes in adults. The Cochrane Database of Systematic Reviews was searched at the end of June 2013 for articles relevant for PRM about disabilities resulting from spinal disorders or pain syndromes in adults. Retrieved papers were classified according to the PRM approach: active therapies, which require active participation by patients to achieve treatment goals, and passive treatments, which rely on the application of external forces. The quality of the reviews was checked against the AMSTAR checklist. Reviews on spinal disorders or pain syndromes were found in the Cochrane Back Group (CBG) and in the Pain, Palliative and Supportive Care Group (CPPSCG). Thirty-eight (42.8%) of 89 Cochrane reviews in the CBG and 7 (2.4%) of 293 Cochrane reviews in the CPPSCG were included. All were of high quality (range, 8-11 points out of 11 on the AMSTAR checklist). The contents of the reviews are given in detail. This review presents an overview of the current evidence for PRM in the treatment of disabilities due to spinal disorders or pain syndromes in adults. Within PRM there is ample space for research in the Cochrane Collaboration and for producing original studies (randomized controlled trials [RCTs]). To apply evidence-based clinical practice, clinicians must be familiar with the current best evidence.

Spinal inhibition and motor function in adults with spastic cerebral palsy

PubMed Central

Condliffe, E. G.; Jeffery, D. T.; Emery, D. J.

2016-01-01

Key points Abnormal activation of motoneurons in the spinal cord by sensory pathways is thought to contribute to impaired movement control and spasticity in individuals with cerebral palsy.Here we use single motor unit recordings to show how individual motoneurons in the spinal cord respond to sensory inputs in a group of participants with cerebral palsy having different degrees of motor dysfunction.In participants who had problems walking independently and required assistive devices such as wheelchairs, sensory pathways only excited motoneurons in the spinal cord.In contrast, in participants with cerebral palsy who walked independently for long distances, sensory inputs both inhibited and excited motoneurons in the spinal cord, similar to what we found in uninjured control participants.These findings demonstrate that in individuals with severe cerebral palsy, inhibitory control of motoneurons from sensory pathways is reduced and may contribute to motor dysfunction and spasticity. Abstract Reduced inhibition of spinal motoneurons by sensory pathways may contribute to heightened reflex activity, spasticity and impaired motor function in individuals with cerebral palsy (CP). To measure if the activation of inhibitory post‐synaptic potentials (IPSPs) by sensory inputs is reduced in CP, the tonic discharge rate of single motor units from the soleus muscle was plotted time‐locked to the occurrence of a sensory stimulation to produce peri‐stimulus frequencygrams (PSFs). Stimulation to the medial arch of the foot was used to activate cutaneomuscular afferents in 17 adults with bilateral spastic CP and 15 neurologically intact (NI) peers. Evidence of IPSP activation from the PSF profiles, namely a marked pause or reduction in motor unit firing rates at the onset of the cutaneomuscular reflex, was found in all NI participants but in only half of participants with CP. In the other half of the participants with CP, stimulation of cutaneomuscular afferents produced a PSF

Teriparatide versus low-dose bisphosphonates before and after surgery for adult spinal deformity in female Japanese patients with osteoporosis.

PubMed

Seki, Shoji; Hirano, Norikazu; Kawaguchi, Yoshiharu; Nakano, Masato; Yasuda, Taketoshi; Suzuki, Kayo; Watanabe, Kenta; Makino, Hiroto; Kanamori, Masahiko; Kimura, Tomoatsu

2017-08-01

Complications of adult spinal deformity surgery are problematic in osteoporotic individuals. We compared outcomes between Japanese patients treated perioperatively with teriparatide vs. low-dose bisphosphonates. Fifty-eight osteoporotic adult Japanese female patients were enrolled and assigned to perioperative teriparatide (33 patients) and bisphosphonate (25 patients) groups in non-blinded fashion. Pre- and post-operative X-ray and computed tomography imaging were used to assess outcome, and rates were compared between the groups and according to age. Pain scores and Oswestry Disability Indices (ODI) were calculated before and 2 years after surgery. Adjacent vertebral fractures and implant failure, fusion failure, and poor pain and ODI outcomes were significantly more common in the bisphosphonates group than the teriparatide group. Perioperative administration of teriparatide is more effective than that of low-dose bisphosphonates in preventing complications and maintaining fusion rates in osteoporotic Japanese females with spinal deformities undergoing surgery.

A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA)

PubMed Central

Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

2015-01-01

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA. PMID:26258776

A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA).

PubMed

Luchetti, Andrea; Ciafrè, Silvia Anna; Murdocca, Michela; Malgieri, Arianna; Masotti, Andrea; Sanchez, Massimo; Farace, Maria Giulia; Novelli, Giuseppe; Sangiuolo, Federica

2015-08-06

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.

Fluoxetine increases plasticity and modulates the proteomic profile in the adult mouse visual cortex

PubMed Central

Ruiz-Perera, L.; Muniz, M.; Vierci, G.; Bornia, N.; Baroncelli, L.; Sale, A.; Rossi, F.M.

2015-01-01

The scarce functional recovery of the adult CNS following injuries or diseases is largely due to its reduced potential for plasticity, the ability to reorganize neural connections as a function of experience. Recently, some new strategies restoring high levels of plasticity in the adult brain have been identified, especially in the paradigmatic model of the visual system. A chronic treatment with the anti-depressant fluoxetine reinstates plasticity in the adult rat primary visual cortex, inducing recovery of vision in amblyopic animals. The molecular mechanisms underlying this effect remain largely unknown. Here, we explored fluoxetine effects on mouse visual cortical plasticity, and exploited a proteomic approach to identify possible candidates mediating the outcome of the antidepressant treatment on adult cortical plasticity. We showed that fluoxetine restores ocular dominance plasticity in the adult mouse visual cortex, and identified 31 differentially expressed protein spots in fluoxetine-treated animals vs. controls. MALDITOF/TOF mass spectrometry identification followed by bioinformatics analysis revealed that these proteins are involved in the control of cytoskeleton organization, endocytosis, molecular transport, intracellular signaling, redox cellular state, metabolism and protein degradation. Altogether, these results indicate a complex effect of fluoxetine on neuronal signaling mechanisms potentially involved in restoring plasticity in the adult brain. PMID:26205348

An N-terminal fragment of substance P, substance P(1-7), down-regulates neurokinin-1 binding in the mouse spinal cord.

PubMed

Yukhananov RYu; Larson, A A

1994-08-29

Injected intrathecally, substance P (SP) down-regulates neurokinin-1 (NK-1) binding in the spinal cord and desensitizes rats to the behavioral effect of SP. N-terminal fragments of SP, such as SP(1-7), induce antinociception and play a role in desensitization to SP in mice. The goal of this study was to assess the abilities of N- and C-terminal fragments of SP to down-regulate NK-1 binding. Binding of [3H]SP to mouse spinal cord membranes was inhibited by SP, CP-96,345, and to a lesser extent by SP(5-11), but not SP(1-7), consistent with these binding sites being NK-1 receptors. Injection of SP(5-11) intrathecally did not affect the affinity (Kd) or concentration (Bmax) of [3H]SP binding. However, injection of 1 nmol of SP(1-7) decreased the Bmax of [3H]SP binding in the spinal cord at 6 h after its injection just as this dose of SP decreased the Bmax at 24 h. These data suggest that the N-terminus of SP is responsible for down-regulation of NK-1 binding. As SP(5-11) did not down-regulate NK-1 binding, activation of NK-1 sites does not appear necessary or sufficient for down-regulation of SP binding. In contrast, SP(1-7), in spite of its inability to interact with NK-1 sites, did down-regulate SP binding, suggesting an indirect mechanism dissociated from NK-1 receptors.

External validation of the adult spinal deformity (ASD) frailty index (ASD-FI).

PubMed

Miller, Emily K; Vila-Casademunt, Alba; Neuman, Brian J; Sciubba, Daniel M; Kebaish, Khaled M; Smith, Justin S; Alanay, Ahmet; Acaroglu, Emre R; Kleinstück, Frank; Obeid, Ibrahim; Sánchez Pérez-Grueso, Francisco Javier; Carreon, Leah Y; Schwab, Frank J; Bess, Shay; Scheer, Justin K; Lafage, Virginie; Shaffrey, Christopher I; Pellisé, Ferran; Ames, Christopher P

2018-03-30

To assess the ability of the recently developed adult spinal deformity frailty index (ASD-FI) to predict odds of perioperative complications, odds of reoperation, and length of hospital stay after adult spinal deformity (ASD) surgery using a database other than the one used to create the index. We used the ASD-FI to calculate frailty scores for 266 ASD patients who had minimum postoperative follow-up of 2 years in the European Spine Study Group (ESSG) database. Patients were enrolled from 2012 through 2013. Using ASD-FI scores, we categorized patients as not frail (NF) (< 0.3 points), frail (0.3-0.5 points), or severely frail (SF) (> 0.5 points). Multivariable logistic regression, adjusted for preoperative and surgical factors such as operative time and blood loss, was performed to determine the relationship between ASD-FI category and odds of major complications, odds of reoperation, and length of hospital stay. We categorized 135 patients (51%) as NF, 90 patients (34%) as frail, and 41 patients (15%) as SF. Overall mean ASD-FI score was 0.29 (range 0-0.8). The adjusted odds of experiencing a major intraoperative or postoperative complication (OR 4.5, 95% CI 2.0-10) or having a reoperation (OR 3.9, 95% CI 1.7-8.9) were higher for SF patients compared with NF patients. Mean hospital stay was 2.1 times longer (95% CI 1.8-2.4) for SF patients compared with NF patients. Greater patient frailty, as measured by the ASD-FI, is associated with longer hospital stays and greater odds of major complications and reoperation. These slides can be retrieved under Electronic Supplementary Material.

A potential inhibitory function of draxin in regulating mouse trunk neural crest migration.

PubMed

Zhang, Sanbing; Su, Yuhong; Gao, Jinbao; Zhang, Chenbing; Tanaka, Hideaki

2017-01-01

Draxin is a repulsive axon guidance protein that plays important roles in the formation of three commissures in the central nervous system and dorsal interneuron 3 (dI3) in the chick spinal cord. In the present study, we report the expression pattern of mouse draxin in the embryonic mouse trunk spinal cord. In the presence of draxin, the longest net migration length of a migrating mouse trunk neural crest cell was significantly reduced. In addition, the relative number of apolar neural crest cells increased as the draxin treatment time increased. Draxin caused actin cytoskeleton rearrangement in the migrating trunk neural crest cells. Our data suggest that draxin may regulate mouse trunk neural crest cell migration by the rearrangement of cell actin cytoskeleton and by reducing the polarization activity of these cells subsequently.

The NH2-terminus of substance P modulates NMDA-induced activity in the mouse spinal cord.

PubMed

Hornfeldt, C S; Sun, X; Larson, A A

1994-05-01

Excitatory amino acids (EAAs) and substance P are believed to transmit nociceptive information in the spinal cord. As substance P NH2-terminal fragments can modulate non-NMDA EAA-mediated activity, we examined the effects of substance P fragments to ascertain whether the COOH- or NH2-terminus of substance P modulates the actions of NMDA in the spinal cord. NMDA activity was measured by the intensity of behaviors produced by NMDA (0.2 nmol) administered intrathecally in the mouse. The NMDA response was attenuated after pretreatment with either substance P (22.5 pmol, 30 min) or the NH2-terminal fragment of substance P, SP-(1-7). Pretreatment with the COOH-terminal fragment SP-(5-11) (22.5 pmol, 30 min), a neurokinin ligand, had no effect on NMDA-induced behaviors, suggesting that the inhibitory effect of substance P is caused by the NH2-terminus. Pretreatment with D-Pro2,D-Phe7 substance P-(1-7), a SP-(1-7) antagonist, potentiated NMDA activity, suggesting a tonic inhibitory effect of the substance P NH2-terminus. Desensitization to NMDA typically develops when NMDA is injected at 2 min intervals. While pretreatment with SP-(1-7) inhibited NMDA, coadministration of SP-(1-7) (22.5 pmol), with the first of four injections of NMDA, first inhibited but then potentiated responses to each challenge with NMDA. Coadministration of the same dose of SP-(1-7) with the fourth injection of NMDA immediately potentiated the response to NMDA.(ABSTRACT TRUNCATED AT 250 WORDS)

The RNA-binding protein Musashi-1 is produced in the developing and adult mouse eye.

PubMed

Raji, B; Dansault, A; Leemput, J; de la Houssaye, G; Vieira, V; Kobetz, A; Arbogast, L; Masson, C; Menasche, M; Abitbol, M

2007-08-10

Musashi-1 (Msi1) is an RNA-binding protein produced in various types of stem cells including neural stem/progenitor cells and astroglial progenitor cells in the vertebrate central nervous system. Other RNA-binding proteins such as Pumilio-1, Pumilio-2, Staufen-1, and Staufen-2 have been characterized as potential markers of several types of stem or progenitor cells. We investigated the involvement of Msi1 in mouse eye development and adult mouse eye functions by analyzing the profile of Msi1 production in all ocular structures during development and adulthood. We studied Msi1 production by in situ hybridization and immunohistochemistry of ocular tissue sections and by semi-quantitative RT-PCR and western blot analysis from the embryonic stage of 12.5 days post coitum (E12.5 dpc) when the first retinal ganglion cells (RGCs) begin to appear to the adult stage when all retinal cell types are present. Msi1 mRNA was present at all studied stages of eye development. Msi1 protein was detected in the primitive neuroblastic layer (NbL), the ganglion cell layer (GCL), and in all major differentiated neurons of postnatal developing and adult retinae. During postnatal developing stages, faint diffuse Msi1 protein staining is converted to a more specific distribution once mouse retina is fully differentiated. The most striking result of our study concerns the large amounts of Msi1 protein and mRNA in several unexpected sites of adult mouse eyes including the corneal epithelium and endothelium, stromal keratocytes, progenitor cells of the limbus, equatorial lens stem cells, differentiated lens epithelial cells, and differentiating lens fibers. Msi1 was also found in the pigmented and nonpigmented cells of the ciliary processes, the melanocytes of the ciliary body, the retinal pigment epithelium, differentiated retinal neurons, and most probably in the retinal glial cells such as Müller glial cells, astrocytes, and the oligodendocytes surrounding the axons of the optic nerve

Tissue distribution and developmental expression of type XVI collagen in the mouse.

PubMed

Lai, C H; Chu, M L

1996-04-01

The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse tissue and developing mouse embryo was examined by immunohistochemistry and in situ hybridization. A polyclonal antiserum was raised against a recombinant fusion protein, which contained a segment of 161 amino acids in the N-terminal noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of metabolically labelled human or mouse fibroblast cell lysates with this antibody revealed a major, bacterial collagenase sensitive polypeptide of approximately 210 kDa. The size agrees with the prediction from the full-length cDNA. Immunofluorescence examination of adult mouse tissues using the affinity purified antibody revealed a rather broad distribution of the protein. The heart, kidney, intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited significant levels of expression, while the skeletal muscle, lung and brain showed very restricted and low signals. During development, no significant expression of the mRNA or protein was observed in embryo of day 8 of gestation, but strong signals was detected in placental trophoblasts. Expression in embryos was detectable first after day 11 of gestation with weak positive signals appearing in the heart. In later stages of development, stronger RNA hybridizations were observed in a variety of tissues, particularly in atrial and ventricular walls of the developing heart, spinal root neural fibers and skin. These data demonstrate that type XVI collagen represents another collagenous component widely distributed in the extracellular matrix and may contribute to the structural integrity of various tissues.

Lumbar Muscle Cross-Sectional Areas Do Not Predict Clinical Outcomes in Adults With Spinal Stenosis: A Longitudinal Study.

PubMed

Gellhorn, Alfred C; Suri, Pradeep; Rundell, Sean D; Olafsen, Nathan; Carlson, M Jake; Johnson, Steve; Fry, Adrielle; Annaswamy, Thiru M; Gilligan, Christopher; Comstock, Bryan; Heagerty, Patrick; Friedly, Janna; Jarvik, Jeffrey G

2017-06-01

Minimal longitudinal data exist regarding the role of lumbar musculature in predicting back pain and function. In cross-sectional study designs, there is often atrophy of the segmental multifidus muscle in subjects with low back pain compared with matched controls. However, the cross-sectional design of these studies prevents drawing conclusions regarding whether lumbar muscle characteristics predict or modify future back pain or function. The primary objective of this study is to determine whether the cross-sectional area (CSA) of lumbar muscles predict functional status or back pain at 6- or 12-month follow-up in older adults with spinal degeneration. The secondary objective is to evaluate whether these muscle characteristics improve outcome prediction above and beyond the prognostic information conferred by demographic and psychosocial variables. Secondary analysis of a randomized controlled trial. A total of 209 adults aged 50 years and older with clinical and radiographic spinal stenosis from the Lumbar Epidural steroid injection for Spinal Stenosis (LESS) trial. Using baseline magnetic resonance images, we calculated CSAs of the lumbar multifidus, psoas, and quadratus lumborum muscles using a standardized protocol by manually tracing the borders of each of the muscles. The relationship between lumbar muscle CSAs and baseline measures was assessed with Pearson or Spearman correlation coefficients. The relationship between lumbar muscle characteristics and 6- and 12-month Roland Morris Disability Questionnaire (RDQ) and back pain Numeric Rating Scale (NRS) responses was further evaluated with multivariate linear regression. A hierarchical approach to the regression was performed: a basic model with factors of conceptual importance including age, gender, BMI, and baseline RDQ score formed the first step. The second and third steps evaluated whether psychosocial variables or muscle measures conferred additional prognostic information to the basic model. Function

Nogo-receptor gene activity: cellular localization and developmental regulation of mRNA in mice and humans.

PubMed

Josephson, Anna; Trifunovski, Alexandra; Widmer, Hans Ruedi; Widenfalk, Johan; Olson, Lars; Spenger, Christian

2002-11-18

Nogo (reticulon-4) is a myelin-associated protein that is expressed in three different splice variants, Nogo-A, Nogo-B, and Nogo-C. Nogo-A inhibits neurite regeneration in the central nervous system. Messenger RNA encoding Nogo is expressed in oligodendrocytes and central and peripheral neurons, but not in astrocytes or Schwann cells. Nogo is a transmembraneous protein; the extracellular domain is termed Nogo-66, and a Nogo-66-receptor (Nogo-R) has been identified. We performed in situ hybridization in human and mouse nervous tissues to map the cellular distribution of Nogo-R gene activity patterns in fetal and adult human spinal cord and sensory ganglia, adult human brain, and the nervous systems of developing and adult mice. In the human fetus Nogo-R was transcribed in the ventral horn of the spinal cord and in dorsal root ganglia. In adult human tissues Nogo-R gene activity was found in neocortex, hippocampus, amygdala, and a subset of large and medium-sized neurons of the dorsal root ganglia. Nogo-R mRNA was not expressed in the adult human spinal cord at detectable levels. In the fetal mouse, Nogo-R was diffusely expressed in brain, brainstem, trigeminal ganglion, spinal cord, and dorsal root ganglia at all stages. In the adult mouse strong Nogo-R mRNA expression was found in neurons in neocortex, hippocampus, amygdala, habenula, thalamic nuclei, brainstem, the granular cell layer of cerebellum, and the mitral cell layer of the olfactory bulb. Neurons in the adult mouse striatum, the medial septal nucleus, and spinal cord did not express Nogo-R mRNA at detectable levels. In summary, Nogo-66-R mRNA expression in humans and mice was observed in neurons of the developing nervous system Expression was downregulated in the adult spinal cord of both species, and specific expression patterns were seen in the adult brain. Copyright 2002 Wiley-Liss, Inc.

Floor plate-derived sonic hedgehog regulates glial and ependymal cell fates in the developing spinal cord.

PubMed

Yu, Kwanha; McGlynn, Sean; Matise, Michael P

2013-04-01

Cell fate specification in the CNS is controlled by the secreted morphogen sonic hedgehog (Shh). At spinal cord levels, Shh produced by both the notochord and floor plate (FP) diffuses dorsally to organize patterned gene expression in dividing neural and glial progenitors. Despite the fact that two discrete sources of Shh are involved in this process, the individual contribution of the FP, the only intrinsic source of Shh throughout both neurogenesis and gliogenesis, has not been clearly defined. Here, we have used conditional mutagenesis approaches in mice to selectively inactivate Shh in the FP (Shh(FP)) while allowing expression to persist in the notochord, which underlies the neural tube during neurogenesis but not gliogenesis. We also inactivated Smo, the common Hh receptor, in neural tube progenitors. Our findings confirm and extend prior studies suggesting an important requirement for Shh(FP) in specifying oligodendrocyte cell fates via repression of Gli3 in progenitors. Our studies also uncover a connection between embryonic Shh signaling and astrocyte-mediated reactive gliosis in adults, raising the possibility that this pathway is involved in the development of the most common cell type in the CNS. Finally, we find that intrinsic spinal cord Shh signaling is required for the proper formation of the ependymal zone, the epithelial cell lining of the central canal that is also an adult stem cell niche. Together, our studies identify a crucial late embryonic role for Shh(FP) in regulating the specification and differentiation of glial and epithelial cells in the mouse spinal cord.

Development of putative inhibitory neurons in the embryonic and postnatal mouse superficial spinal dorsal horn.

PubMed

Balázs, Anita; Mészár, Zoltán; Hegedűs, Krisztina; Kenyeres, Annamária; Hegyi, Zoltán; Dócs, Klaudia; Antal, Miklós

2017-07-01

The superficial spinal dorsal horn is the first relay station of pain processing. It is also widely accepted that spinal synaptic processing to control the modality and intensity of pain signals transmitted to higher brain centers is primarily defined by inhibitory neurons in the superficial spinal dorsal horn. Earlier studies suggest that the construction of pain processing spinal neural circuits including the GABAergic components should be completed by birth, although major chemical refinements may occur postnatally. Because of their utmost importance in pain processing, we intended to provide a detailed knowledge concerning the development of GABAergic neurons in the superficial spinal dorsal horn, which is now missing from the literature. Thus, we studied the developmental changes in the distribution of neurons expressing GABAergic markers like Pax2, GAD65 and GAD67 in the superficial spinal dorsal horn of wild type as well as GAD65-GFP and GAD67-GFP transgenic mice from embryonic day 11.5 (E11.5) till postnatal day 14 (P14). We found that GABAergic neurons populate the superficial spinal dorsal horn from the beginning of its delineation at E14.5. We also showed that the numbers of GABAergic neurons in the superficial spinal dorsal horn continuously increase till E17.5, but there is a prominent decline in their numbers during the first two postnatal weeks. Our results indicate that the developmental process leading to the delineation of the inhibitory and excitatory cellular assemblies of pain processing neural circuits in the superficial spinal dorsal horn of mice is not completed by birth, but it continues postnatally.

Spinal injury in car crashes: crash factors and the effects of occupant age.

PubMed

Bilston, Lynne E; Clarke, Elizabeth C; Brown, Julie

2011-08-01

Motor vehicle crashes are the leading cause of serious spinal injury in most developed nations. However, since these injuries are rare, systematic analyses of the crash factors that are predictive of spinal injury have rarely been performed. This study aimed to use a population-reference crash sample to identify crash factors associated with moderate to severe spinal injury, and how these vary with occupant age. The US National Automotive Sampling System Crashworthiness Data System (NASS) data for 1993-2007 were analysed using logistic regression to identify crash factors associated with Abbreviated Injury Scale (AIS)2+ spinal injury among restrained vehicle passengers. Risk of moderate or severe spinal injury (AIS2+) was associated with higher severity crashes (OR=3.5 (95% CI 2.6 to 4.6)), intrusion into an occupant's seating position (OR=2.7 (95% CI 1.9 to 3.7)), striking a fixed object rather than another car (OR=1.7 (95% CI 1.3 to 2.1)), and use of a shoulder-only belt (OR=2.7 (95% CI 1.5 to 4.8)). Older occupants (65 years or older) were at higher risk of spinal injury than younger adults in frontal, side and rollover crashes. Children under 16 were at a lower risk of spinal injury than adults in all crash types except frontal crashes. While the risk of serious spinal injury in motor vehicle crashes is low, these injuries are more common in crashes of higher severity or into fixed objects, and in the presence of intrusion. There are elevated risks of spinal injury for older occupants compared with younger adults, which may reflect changes in biomechanical tolerances with age. Children appear to be at lower risk of serious spinal injury than adults except in frontal crashes.

A comparison of serotonin neuromodulation of mouse spinal V2a interneurons using perforated patch and whole cell recording techniques

PubMed Central

Dietz, Shelby; Husch, Andreas; Harris-Warrick, Ronald M.

2012-01-01

Whole cell recordings (WCRs) are frequently used to study neuronal properties, but may be problematic when studying neuromodulatory responses, due to dialysis of the cell's cytoplasm. Perforated patch recordings (PPR) avoid cellular dialysis and might reveal additional modulatory effects that are lost during WCR. We have previously used WCR to characterize the responses of the V2a class of Chx10-expressing neurons to serotonin (5-HT) in the neonatal mouse spinal cord (Zhong et al., 2010). Here we directly compare multiple aspects of the responses to 5-HT using WCR and PPR in Chx10-eCFP neurons in spinal cord slices from 2 to 4 day old mice. Cellular properties recorded in PPR and WCR were similar, but high-quality PP recordings could be maintained for significantly longer. Both WCR and PPR cells could respond to 5-HT, and although neurons recorded by PPR showed a significantly greater response to 5-HT in some parameters, the absolute differences between PPR and WCR were small. We conclude that WCR is an acceptable recording method for short-term recordings of neuromodulatory effects, but the less invasive PPR is preferable for detailed analyses and is necessary for stable recordings lasting an hour or more. PMID:23060747

Cellular basis of neuroepithelial bending during mouse spinal neural tube closure

PubMed Central

McShane, Suzanne G.; Molè, Matteo A.; Savery, Dawn; Greene, Nicholas D. E; Tam, Patrick P.L.; Copp, Andrew J.

2015-01-01

Summary Bending of the neural plate at paired dorsolateral hinge points (DLHPs) is required for neural tube closure in the spinal region of the mouse embryo. As a step towards understanding the morphogenetic mechanism of DLHP development, we examined variations in neural plate cellular architecture and proliferation during closure. Neuroepithelial cells within the median hinge point (MHP) contain nuclei that are mainly basally located and undergo relatively slow proliferation, with a 7 h cell cycle length. In contrast, cells in the dorsolateral neuroepithelium, including the DLHP, exhibit nuclei distributed throughout the apico-basal axis and undergo rapid proliferation, with a 4 h cell cycle length. As the neural folds elevate, cell numbers increase to a greater extent in the dorsolateral neural plate that contacts the surface ectoderm, compared with the more ventromedial neural plate where cells contact paraxial mesoderm and notochord. This marked increase in dorsolateral cell number cannot be accounted for solely on the basis of enhanced cell proliferation in this region. We hypothesised that neuroepithelial cells may translocate in a ventral-to-dorsal direction as DLHP formation occurs, and this was confirmed by vital cell labelling in cultured embryos. The translocation of cells into the neural fold, together with its more rapid cell proliferation, leads to an increase in cell density dorsolaterally compared with the more ventromedial neural plate. These findings suggest a model in which DLHP formation may proceed through ‘buckling’ of the neuroepithelium at a dorso-ventral boundary marked by a change in cell-packing density. PMID:26079577

Occupational characteristics of adults with pediatric-onset spinal cord injury.

PubMed

Hwang, Miriam; Zebracki, Kathy; Vogel, Lawrence C

2015-01-01

Employment rates among individuals with spinal cord injury (SCI) are lower than in the general population and little is known about the specific occupations in which they are employed. To describe specific occupations of adults with pediatric-onset SCI using the 2010 Standard Occupational Classification (SOC) system and to determine associations between SOC occupations and demographic factors. Cross-sectional data specific to education and employment were collected from the last interviews of a larger longitudinal study. Occupations were categorized according to the 2010 SOC system. SOC groups were compared within gender level of injury and final education. Of the 461 total participants 219 (47.5%) were employed and specific occupations were available for 179. Among the SOC groups Education Law Community Service Arts and Media Occupations were most prevalent (30.2%) followed by Management Business and Finance Occupations (21.1%) Computer Engineering and Science Occupations (10.6%) Administrative and Office Support Occupations (10.0%) Service Occupations (7.3%) Healthcare Practitioners and Technical Occupations (3.9%) and Production Occupations (3.4%). Differences were found in the distribution of SOC groups between gender levels of injury and final education groups. A wide variety of occupations were reported in adults with pediatric-onset SCI generally in concordance with final education and functional ability levels.

Compensatory axon sprouting for very slow axonal die-back in a transgenic model of spinal muscular atrophy type III.

PubMed

Udina, Esther; Putman, Charles T; Harris, Luke R; Tyreman, Neil; Cook, Victoria E; Gordon, Tessa

2017-03-01

Smn +/- transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back. Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn +/- transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn +/- transgenic mouse increases their susceptibility to cell death demonstrated

Deconstructing Chronic Low Back Pain in the Older Adult-Step by Step Evidence and Expert-Based Recommendations for Evaluation and Treatment. Part VI: Lumbar Spinal Stenosis.

PubMed

Fritz, Julie M; Rundell, Sean D; Dougherty, Paul; Gentili, Angela; Kochersberger, Gary; Morone, Natalia E; Naga Raja, Srinivasa; Rodriguez, Eric; Rossi, Michelle I; Shega, Joseph; Sowa, Gwendolyn; Weiner, Debra K

2016-03-01

. To present the sixth in a series of articles designed to deconstruct chronic low back pain (CLBP) in older adults. This article focuses on the evaluation and management of lumbar spinal stenosis (LSS), the most common condition for which older adults undergo spinal surgery. . The evaluation and treatment algorithm, a table articulating the rationale for the individual algorithm components, and stepped-care drug recommendations were developed using a modified Delphi approach. The Principal Investigator, a five-member content expert panel and a nine-member primary care panel were involved in the iterative development of these materials. The illustrative clinical case was taken from the clinical practice of a contributor's colleague (SR). . We present an algorithm and supportive materials to help guide the care of older adults with LSS, a condition that occurs not uncommonly in those with CLBP. The case illustrates the importance of function-focused management and a rational approach to conservative care. . Lumbar spinal stenosis exists not uncommonly in older adults with CLBP and management often can be accomplished without surgery. Treatment should address all conditions in addition to LSS contributing to pain and disability. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Interleukin-33 treatment reduces secondary injury and improves functional recovery after contusion spinal cord injury.

PubMed

Pomeshchik, Yuriy; Kidin, Iurii; Korhonen, Paula; Savchenko, Ekaterina; Jaronen, Merja; Lehtonen, Sarka; Wojciechowski, Sara; Kanninen, Katja; Koistinaho, Jari; Malm, Tarja

2015-02-01

Interleukin-33 (IL-33) is a member of the interleukin-1 cytokine family and highly expressed in the naïve mouse brain and spinal cord. Despite the fact that IL-33 is known to be inducible by various inflammatory stimuli, its cellular localization in the central nervous system and role in pathological conditions is controversial. Administration of recombinant IL-33 has been shown to attenuate experimental autoimmune encephalomyelitis progression in one study, yet contradictory reports also exist. Here we investigated for the first time the pattern of IL-33 expression in the contused mouse spinal cord and demonstrated that after spinal cord injury (SCI) IL-33 was up-regulated and exhibited a nuclear localization predominantly in astrocytes. Importantly, we found that treatment with recombinant IL-33 alleviated secondary damage by significantly decreasing tissue loss, demyelination and astrogliosis in the contused mouse spinal cord, resulting in dramatically improved functional recovery. We identified both central and peripheral mechanisms of IL-33 action. In spinal cord, IL-33 treatment reduced the expression of pro-inflammatory tumor necrosis factor-alpha and promoted the activation of anti-inflammatory arginase-1 positive M2 microglia/macrophages, which chronically persisted in the injured spinal cord for up to at least 42 days after the treatment. In addition, IL-33 treatment showed a tendency towards reduced T-cell infiltration into the spinal cord. In the periphery, IL-33 treatment induced a shift towards the Th2 type cytokine profile and reduced the percentage and absolute number of cytotoxic, tumor necrosis factor-alpha expressing CD4+ cells in the spleen. Additionally, IL-33 treatment increased expression of T-regulatory cell marker FoxP3 and reduced expression of M1 marker iNOS in the spleen. Taken together, these results provide the first evidence that IL-33 administration is beneficial after CNS trauma. Treatment with IL33 may offer a novel therapeutic

Microsurgical resection of intramedullary spinal cord ependymoma.

PubMed

McCormick, Paul C

2014-09-01

Ependymomas are the most commonly occurring intramedullary spinal cord tumor in adults. With few exceptions these tumors are histologically benign, although they exhibit some biologic variability with respect to growth rate. While unencapsulated, spinal ependymomas are non-infiltrative and present a clear margin of demarcation from the surrounding spinal cord that serves as an effective dissection plane. This video demonstrates the technique of microsurgical resection of an intramedullary ependymoma through a posterior midline myelotomy. The video can be found here: http://youtu.be/lcHhymSvSqU.

Adult mouse brain gene expression patterns bear an embryologic imprint

PubMed Central

Zapala, Matthew A.; Hovatta, Iiris; Ellison, Julie A.; Wodicka, Lisa; Del Rio, Jo A.; Tennant, Richard; Tynan, Wendy; Broide, Ron S.; Helton, Rob; Stoveken, Barbara S.; Winrow, Christopher; Lockhart, Daniel J.; Reilly, John F.; Young, Warren G.; Bloom, Floyd E.; Lockhart, David J.; Barlow, Carrolee

2005-01-01

The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional “imprint” consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anterior–posterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene expression patterns in adult structures. We also observed a significant number of embryonic patterning and homeobox genes with region-specific expression in the adult nervous system. The relationships between global expression patterns for different anatomical regions and the nature of the observed region-specific genes suggest that the adult brain retains a degree of overall gene expression established during embryogenesis that is important for regional specificity and the functional relationships between regions in the adult. The complete collection of extensively annotated gene expression data along with data mining and visualization tools have been made available on a publicly accessible web site (www.barlow-lockhart-brainmapnimhgrant.org). PMID:16002470

46-year-old man with a spinal cord mass.

PubMed

Sanders, Mary Ann; Vitaz, Todd; Rosenblum, Marc; Plaga, Alexis R; Parker, Joseph C; Parker, John R

2011-01-01

Medulloblastoma accounts for only 1% of all adult CNS tumors. Likewise, recurrence of adult medulloblastoma greater than 20 years after initial diagnosis is extremely rare.We describe a case of adult medulloblastoma with late relapse of disease. The patient was 24 years old when first diagnosed and was treated with total tumor resection and craniospinal radiation. At the age of 45, an enhancing 1.3 cm intradural extramedullary spinal cord lesion at T5 was discovered on MRI. This was presumed to be recurrent medulloblastoma in the form of drop metastasis and the patient was treated with spinal radiation. Several months following treatment, at the age of 46, a follow-up MRI demonstrated an enhancing 1.4 cm intradural extramedullary spinal cord lesion at T7. The lesion was resected and histopathologic examination was most consistent with medulloblastoma, late drop metastasis. Although rare, adult medulloblastoma recurring 20 years after initial diagnosis should always be considered in the main differential diagnosis when working up CNS lesions at or outside the primary tumor site.

Aetioepidemiological profile of spinal injury patients in Eastern Nepal.

PubMed

Lakhey, S; Jha, N; Shrestha, B P; Niraula, S

2005-10-01

This is a retrospective case series of 233 spinal injury patients admitted to the orthopaedic ward of BPKIHS from May 1997 to April 2001. The inpatient records were analysed. In all, 40.3% of spinal injuries resulted from falls from trees while cutting leaves for fodder, and 27.9% resulted from falls from first/second floors. More than 75% of total spinal injuries are largely preventable. Overall, 46.8% of our spinal injury patients had complete cord transection at the level of injury. All adolescents and adults, irrespective of age or sex, should be the target groups for community education and intervention programmes for prevention of spinal injury.

The triple monoamine re-uptake inhibitor DOV 216,303 promotes functional recovery after spinal cord contusion injury in mice.

PubMed

Chu, Tak-Ho; Cummins, Karen; Stys, Peter K

2018-05-14

Serotonin, noradrenaline and dopamine are important neuromodulators for locomotion in the spinal cord. Disruption of descending axons after spinal cord injury resulted in reduction of excitatory and neuromodulatory inputs to spinal neurons for locomotion. Receptor agonists or reuptake inhibitors for these neuromodulators have been shown to be beneficial in incomplete spinal cord injury. In this study, we tested a triple re-uptake inhibitor, DOV 216,303, for its ability to affect motor function recovery after spinal cord injury in mice. We impacted C57 mouse spinal cord at the T11 vertebral level and administered vehicle or DOV 216,303 at 10 mg/kg, b.i.d via intraperitoneal injections for 7 days. We monitored motor function with the Basso Mouse Scale for locomotion for 4 weeks. Spinal cords were harvested and histological examinations were performed to assess tissue sparing and lesion severity. Results showed that DOV 216,303-treated mice recovered significantly better than vehicle treated mice starting at 14 days post injury until the end of the survival period. Lesion size of the DOV 216,303 treated mice was also smaller compared to that of vehicle treated mice. This study suggests DOV 216,303 as a potential therapeutic after spinal cord injury warrants further investigation. Copyright © 2018 Elsevier B.V. All rights reserved.

Congenital Bone Fractures in Spinal Muscular Atrophy: Functional Role for SMN Protein in Bone Remodeling

PubMed Central

Shanmugarajan, Srinivasan; Swoboda, Kathryn J.; Iannaccone, Susan T.; Ries, William L.; Maria, Bernard L.; Reddy, Sakamuri V.

2009-01-01

Spinal muscular atrophy is the second most common fatal childhood disorder. Core clinical features include muscle weakness caused by degenerating lower motor neurons and a high incidence of bone fractures and hypercalcemia. Fractures further compromise quality of life by progression of joint contractures or additional loss of motor function. Recent observations suggest that bone disease in spinal muscular atrophy may not be attributed entirely to lower motor neuron degeneration. The presence of the spinal muscular atrophy disease-determining survival motor neuron gene (SMN), SMN expression, and differential splicing in bone-resorbing osteoclasts was recently discovered. Its ubiquitous expression and the differential expression of splice variants suggest that SMN has specific roles in bone cell function. SMN protein also interacts with osteoclast stimulatory factor. Mouse models of human spinal muscular atrophy disease suggest a potential role of SMN protein in skeletal development. Dual energy x-ray absorptiometry analysis demonstrated a substantial decrease in total bone area and poorly developed caudal vertebra in the mouse model. These mice also had pelvic bone fractures. Studies delineating SMN signaling mechanisms and gene transcription in a cell-specific manner will provide important molecular insights into the pathogenesis of bone disease in children with spinal muscular atrophy. Moreover, understanding bone remodeling in spinal muscular atrophy may lead to novel therapeutic approaches to enhance skeletal health and quality of life. This article reviews the skeletal complications associated with spinal muscular atrophy and describes a functional role for SMN protein in osteoclast development and bone resorption activity. PMID:17761651

Initiating or blocking locomotion in spinal cats by applying noradrenergic drugs to restricted lumbar spinal segments.

PubMed

Marcoux, J; Rossignol, S

2000-11-15

After an acute low thoracic spinal transection (T13), cats can be made to walk with the hindlimbs on a treadmill with clonidine, an alpha2-noradrenergic agonist. Because previous studies of neonatal rat spinal cord in vitro suggest that the most important lumbar segments for rhythmogenesis are L1-L2, we investigated the role of various lumbar segments in the initiation of walking movements on a treadmill of adult cats spinalized (T13), 5-6 d earlier. The locomotor activities were evaluated from electromyographic and video recordings. The results show that: (1) localized topical application of clonidine in restricted baths over either the L3-L4 or the L5-L7 segments was sufficient to induce walking movements. Yohimbine, an alpha2-noradrenergic antagonist, could block this locomotion when applied over L3-L4 or L5-L7; (2) microinjections of clonidine in one or two lumbar segments from L3 to L5 could also induce locomotion; (3) after an intravenous injection of clonidine, locomotion was blocked by microinjections of yohimbine in segments L3, L4, or L5 but not if the injection was in L6; (4) locomotion was also blocked in all cases by additional spinal transections at L3 or L4. These results show that it is possible to initiate walking in the adult spinal cat with a pharmacological stimulation of a restricted number of lumbar segments and also that the integrity of the L3-L4 segments is necessary to sustain the locomotor activity.

An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris.

PubMed

Schulze, Katja; Galichet, Arnaud; Sayar, Beyza S; Scothern, Anthea; Howald, Denise; Zymann, Hillard; Siffert, Myriam; Zenhäusern, Denise; Bolli, Reinhard; Koch, Peter J; Garrod, David; Suter, Maja M; Müller, Eliane J

2012-02-01

Evidence has accumulated that changes in intracellular signaling downstream of desmoglein 3 (Dsg3) may have a significant role in epithelial blistering in the autoimmune disease pemphigus vulgaris (PV). Currently, most studies on PV involve passive transfer of pathogenic antibodies into neonatal mice that have not finalized epidermal morphogenesis, and do not permit analysis of mature hair follicles (HFs) and stem cell niches. To investigate Dsg3 antibody-induced signaling in the adult epidermis at defined stages of the HF cycle, we developed a model with passive transfer of AK23 (a mouse monoclonal pathogenic anti-Dsg3 antibody) into adult 8-week-old C57Bl/6J mice. Validated using histopathological and molecular methods, we found that this model faithfully recapitulates major features described in PV patients and PV models. Two hours after AK23 transfer, we observed widening of intercellular spaces between desmosomes and EGFR activation, followed by increased Myc expression and epidermal hyperproliferation, desmosomal Dsg3 depletion, and predominant blistering in HFs and oral mucosa. These data confirm that the adult passive transfer mouse model is ideally suited for detailed studies of Dsg3 antibody-mediated signaling in adult skin, providing the basis for investigations on novel keratinocyte-specific therapeutic strategies.

Functional characterization of dI6 interneurons in the neonatal mouse spinal cord.

PubMed

Dyck, Jason; Lanuza, Guillermo M; Gosgnach, Simon

2012-06-01

Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior.

Functional characterization of dI6 interneurons in the neonatal mouse spinal cord

PubMed Central

Dyck, Jason; Lanuza, Guillermo M.

2012-01-01

Our understanding of the neural control of locomotion has been greatly enhanced by the ability to identify and manipulate genetically defined populations of interneurons that comprise the locomotor central pattern generator (CPG). To date, the dI6 interneurons are one of the few populations that settle in the ventral region of the postnatal spinal cord that have not been investigated. In the present study, we utilized a novel transgenic mouse line to electrophysiologically characterize dI6 interneurons located close to the central canal and study their function during fictive locomotion. The majority of dI6 cells investigated were found to be rhythmically active during fictive locomotion and could be divided into two electrophysiologically distinct populations of interneurons. The first population fired rhythmic trains of action potentials that were loosely coupled to ventral root output and contained several intrinsic membrane properties of rhythm-generating neurons, raising the possibility that these cells may be involved in the generation of rhythmic activity in the locomotor CPG. The second population fired rhythmic trains of action potentials that were tightly coupled to ventral root output and lacked intrinsic oscillatory mechanisms, indicating that these neurons may be driven by a rhythm-generating network. Together these results indicate that dI6 neurons comprise an important component of the locomotor CPG that participate in multiple facets of motor behavior. PMID:22442567

PAX6 MiniPromoters drive restricted expression from rAAV in the adult mouse retina

PubMed Central

Hickmott, Jack W; Chen, Chih-yu; Arenillas, David J; Korecki, Andrea J; Lam, Siu Ling; Molday, Laurie L; Bonaguro, Russell J; Zhou, Michelle; Chou, Alice Y; Mathelier, Anthony; Boye, Sanford L; Hauswirth, William W; Molday, Robert S; Wasserman, Wyeth W; Simpson, Elizabeth M

2016-01-01

Current gene therapies predominantly use small, strong, and readily available ubiquitous promoters. However, as the field matures, the availability of small, cell-specific promoters would be greatly beneficial. Here we design seven small promoters from the human paired box 6 (PAX6) gene and test them in the adult mouse retina using recombinant adeno-associated virus. We chose the retina due to previous successes in gene therapy for blindness, and the PAX6 gene since it is: well studied; known to be driven by discrete regulatory regions; expressed in therapeutically interesting retinal cell types; and mutated in the vision-loss disorder aniridia, which is in need of improved therapy. At the PAX6 locus, 31 regulatory regions were bioinformatically predicted, and nine regulatory regions were constructed into seven MiniPromoters. Driving Emerald GFP, these MiniPromoters were packaged into recombinant adeno-associated virus, and injected intravitreally into postnatal day 14 mice. Four MiniPromoters drove consistent retinal expression in the adult mouse, driving expression in combinations of cell-types that endogenously express Pax6: ganglion, amacrine, horizontal, and Müller glia. Two PAX6-MiniPromoters drive expression in three of the four cell types that express PAX6 in the adult mouse retina. Combined, they capture all four cell types, making them potential tools for research, and PAX6-gene therapy for aniridia. PMID:27556059

PAX6 MiniPromoters drive restricted expression from rAAV in the adult mouse retina.

PubMed

Hickmott, Jack W; Chen, Chih-Yu; Arenillas, David J; Korecki, Andrea J; Lam, Siu Ling; Molday, Laurie L; Bonaguro, Russell J; Zhou, Michelle; Chou, Alice Y; Mathelier, Anthony; Boye, Sanford L; Hauswirth, William W; Molday, Robert S; Wasserman, Wyeth W; Simpson, Elizabeth M

2016-01-01

Current gene therapies predominantly use small, strong, and readily available ubiquitous promoters. However, as the field matures, the availability of small, cell-specific promoters would be greatly beneficial. Here we design seven small promoters from the human paired box 6 (PAX6) gene and test them in the adult mouse retina using recombinant adeno-associated virus. We chose the retina due to previous successes in gene therapy for blindness, and the PAX6 gene since it is: well studied; known to be driven by discrete regulatory regions; expressed in therapeutically interesting retinal cell types; and mutated in the vision-loss disorder aniridia, which is in need of improved therapy. At the PAX6 locus, 31 regulatory regions were bioinformatically predicted, and nine regulatory regions were constructed into seven MiniPromoters. Driving Emerald GFP, these MiniPromoters were packaged into recombinant adeno-associated virus, and injected intravitreally into postnatal day 14 mice. Four MiniPromoters drove consistent retinal expression in the adult mouse, driving expression in combinations of cell-types that endogenously express Pax6: ganglion, amacrine, horizontal, and Müller glia. Two PAX6-MiniPromoters drive expression in three of the four cell types that express PAX6 in the adult mouse retina. Combined, they capture all four cell types, making them potential tools for research, and PAX6-gene therapy for aniridia.

Modulation of [3H]DAGO binding by substance P (SP) and SP fragments in the mouse brain and spinal cord via MU1 interactions.

PubMed

Krumins, S A; Kim, D C; Seybold, V S; Larson, A A

1989-01-01

Binding of [3H]DAGO to fresh, frozen or beta-funaltrexamine (beta-FNA) pretreated membranes of mouse brain and spinal cord was extensively studied using substance P (SP) or SP fragments as potential competitors and/or modulators. The objective was to determine whether SP exerts its analgesic effect by interacting with mu opioid receptors. The affinity of DAGO was reduced and binding capacity was increased in the presence of SP or the N-terminal SP fragments SP(1-9) and SP(1-4) but not the C-terminal SP fragment SP(5-11). Because sub-nanomolar concentrations of SP or N-terminal SP fragments displaced [3H] DAGO binding to a minor but detectable degree, it is suggested that SP interacts with mu 1 sites through its N-terminus portion. The effect of SP on DAGO binding was less in the spinal cord compared to the rest of the brain. Modulation of DAGO binding by SP was enhanced in the brain after pretreatment of membranes with the narcotic antagonist beta-FNA. These results suggest a novel mechanism for the analgesic action of SP.

In vitro and in vivo analysis and characterization of engineered spinal neural implants (Conference Presentation)

NASA Astrophysics Data System (ADS)

Shor, Erez; Shoham, Shy; Levenberg, Shulamit

2016-03-01

Spinal cord injury is a devastating medical condition. Recent developments in pre-clinical and clinical research have started to yield neural implants inducing functional recovery after spinal cord transection injury. However, the functional performance of the transplants was assessed using histology and behavioral experiments which are unable to study cell dynamics and the therapeutic response. Here, we use neurophotonic tools and optogenetic probes to investigate cellular level morphology and activity characteristics of neural implants over time at the cellular level. These methods were used in-vitro and in-vivo, in a mouse spinal cord injury implant model. Following previous attempts to induce recovery after spinal cord injury, we engineered a pre-vascularized implant to obtain better functional performance. To image network activity of a construct implanted in a mouse spinal cord, we transfected the implant to express GCaMP6 calcium activity indicators and implanted these constructs under a spinal cord chamber enabling 2-photon chronic in vivo neural activity imaging. Activity and morphology analysis image processing software was developed to automatically quantify the behavior of the neural and vascular networks. Our experimental results and analyses demonstrate that vascularized and non-vascularized constructs exhibit very different morphologic and activity patterns at the cellular level. This work enables further optimization of neural implants and also provides valuable tools for continuous cellular level monitoring and evaluation of transplants designed for various neurodegenerative disease models.

Distinct spatiotemporal expression of ISM1 during mouse and chick development.

PubMed

Osório, Liliana; Wu, Xuewei; Zhou, Zhongjun

2014-01-01

Isthmin 1 (ISM1) constitutes the founder of a new family of secreted proteins characterized by the presence of 2 functional domains: thrombospondin type 1 repeat (TSR1) and adhesion-associated domain in MUC4 and other proteins (AMOP). ISM1 was identified in the frog embryo as a member of the FGF8 synexpression group due to its expression in the brain midbrain-hindbrain boundary (MHB) or isthmus. In zebrafish, ISM1 was described as a WNT- and NODAL-regulated gene. The function of ISM1 remains largely elusive. So far, ISM1 has been described as an angiogenesis inhibitor that has a dual function in endothelial cell survival and cell death. For a better understanding of ISM1 function, we examined its spatiotemporal distribution in mouse and chick using RT-PCR, ISH, and IHC analyses. In the mouse, ISM1 transcripts are found in tissues such as the anterior mesendoderm, paraxial and lateral plate mesoderm, MHB and trunk neural tube, as well as in the somites and dermomyotome. In the newborn and adult, ISM1 is prominently expressed in the lung and brain. In addition to its putative role during embryonic and postnatal development, ISM1 may also be important for organ homeostasis in the adult. In the chick embryo, ISM1 transcripts are strongly detected in the ear, eye, and spinal cord primordia. Remarkable differences in ISM1 spatiotemporal expression were found during mouse and chick development, despite the high homology of ISM1 orthologs in these species.

Distinct spatiotemporal expression of ISM1 during mouse and chick development

PubMed Central

Osório, Liliana; Wu, Xuewei; Zhou, Zhongjun

2014-01-01

Isthmin 1 (ISM1) constitutes the founder of a new family of secreted proteins characterized by the presence of 2 functional domains: thrombospondin type 1 repeat (TSR1) and adhesion-associated domain in MUC4 and other proteins (AMOP). ISM1 was identified in the frog embryo as a member of the FGF8 synexpression group due to its expression in the brain midbrain–hindbrain boundary (MHB) or isthmus. In zebrafish, ISM1 was described as a WNT- and NODAL-regulated gene. The function of ISM1 remains largely elusive. So far, ISM1 has been described as an angiogenesis inhibitor that has a dual function in endothelial cell survival and cell death. For a better understanding of ISM1 function, we examined its spatiotemporal distribution in mouse and chick using RT-PCR, ISH, and IHC analyses. In the mouse, ISM1 transcripts are found in tissues such as the anterior mesendoderm, paraxial and lateral plate mesoderm, MHB and trunk neural tube, as well as in the somites and dermomyotome. In the newborn and adult, ISM1 is prominently expressed in the lung and brain. In addition to its putative role during embryonic and postnatal development, ISM1 may also be important for organ homeostasis in the adult. In the chick embryo, ISM1 transcripts are strongly detected in the ear, eye, and spinal cord primordia. Remarkable differences in ISM1 spatiotemporal expression were found during mouse and chick development, despite the high homology of ISM1 orthologs in these species. PMID:24675886

What Are the Key Statistics about Brain and Spinal Cord Cancers?

MedlinePlus

... Brain and Spinal Cord Tumors in Adults Key Statistics for Brain and Spinal Cord Tumors The American ... Cord Tumors . Visit the American Cancer Society’s Cancer Statistics Center for more key statistics. Written by References ...

Action-based sensory encoding in spinal sensorimotor circuits.

PubMed

Schouenborg, Jens

2008-01-01

The concept of a modular organisation of the spinal withdrawal reflex circuits has proven to be fundamental for the understanding of how the spinal cord is organised and how the sensorimotor circuits translate sensory information into adequate movement corrections. Recent studies indicate that a task-related body representation is engraved at the network level through learning-dependent mechanisms involving an active probing procedure termed 'somatosensory imprinting' during development. It was found that somatosensory imprinting depends on the tactile input that is associated with spontaneous movements that occur during sleep and results in elimination of erroneous connections and establishment of correct connections. In parallel studies it was found that the strength of the first order tactile synapses in rostrocaudally elongated zones in the adult dorsal horn in the lower lumbar cord is related to the modular organisation of the withdrawal reflexes. Hence, the topographical organisation of the tactile input to this spinal area seems to be action-based rather than a simple body map as previously thought. Far from being innate and adult like at birth, the adult organisation seems to emerge from an initial 'floating' and diffuse body representation with many inappropriate connections through profound activity-dependent rearrangements of afferent synaptic connections. It is suggested that somatosensory imprinting plays a key role in the self-organisation of the spinal cord during development.

Occupational Characteristics of Adults with Pediatric-Onset Spinal Cord Injury

PubMed Central

Zebracki, Kathy; Vogel, Lawrence C.

2015-01-01

Background: Employment rates among individuals with spinal cord injury (SCI) are lower than in the general population and little is known about the specific occupations in which they are employed. Objectives: To describe specific occupations of adults with pediatric-onset SCI using the 2010 Standard Occupational Classification (SOC) system and to determine associations between SOC occupations and demographic factors. Methods: Cross-sectional data specific to education and employment were collected from the last interviews of a larger longitudinal study. Occupations were categorized according to the 2010 SOC system. SOC groups were compared within gender level of injury and final education. Results: Of the 461 total participants 219 (47.5%) were employed and specific occupations were available for 179. Among the SOC groups Education Law Community Service Arts and Media Occupations were most prevalent (30.2%) followed by Management Business and Finance Occupations (21.1%) Computer Engineering and Science Occupations (10.6%) Administrative and Office Support Occupations (10.0%) Service Occupations (7.3%) Healthcare Practitioners and Technical Occupations (3.9%) and Production Occupations (3.4%). Differences were found in the distribution of SOC groups between gender levels of injury and final education groups. Conclusion: A wide variety of occupations were reported in adults with pediatric-onset SCI generally in concordance with final education and functional ability levels. PMID:25762856

Neuron-Enriched Gene Expression Patterns are Regionally Anti-Correlated with Oligodendrocyte-Enriched Patterns in the Adult Mouse and Human Brain

PubMed Central

Tan, Powell Patrick Cheng; French, Leon; Pavlidis, Paul

2013-01-01

An important goal in neuroscience is to understand gene expression patterns in the brain. The recent availability of comprehensive and detailed expression atlases for mouse and human creates opportunities to discover global patterns and perform cross-species comparisons. Recently we reported that the major source of variation in gene transcript expression in the adult normal mouse brain can be parsimoniously explained as reflecting regional variation in glia to neuron ratios, and is correlated with degree of connectivity and location in the brain along the anterior-posterior axis. Here we extend this investigation to two gene expression assays of adult normal human brains that consisted of over 300 brain region samples, and perform comparative analyses of brain-wide expression patterns to the mouse. We performed principal components analysis (PCA) on the regional gene expression of the adult human brain to identify the expression pattern that has the largest variance. As in the mouse, we observed that the first principal component is composed of two anti-correlated patterns enriched in oligodendrocyte and neuron markers respectively. However, we also observed interesting discordant patterns between the two species. For example, a few mouse neuron markers show expression patterns that are more correlated with the human oligodendrocyte-enriched pattern and vice-versa. In conclusion, our work provides insights into human brain function and evolution by probing global relationships between regional cell type marker expression patterns in the human and mouse brain. PMID:23440889

Neuron-Enriched Gene Expression Patterns are Regionally Anti-Correlated with Oligodendrocyte-Enriched Patterns in the Adult Mouse and Human Brain.

PubMed

Tan, Powell Patrick Cheng; French, Leon; Pavlidis, Paul

2013-01-01

An important goal in neuroscience is to understand gene expression patterns in the brain. The recent availability of comprehensive and detailed expression atlases for mouse and human creates opportunities to discover global patterns and perform cross-species comparisons. Recently we reported that the major source of variation in gene transcript expression in the adult normal mouse brain can be parsimoniously explained as reflecting regional variation in glia to neuron ratios, and is correlated with degree of connectivity and location in the brain along the anterior-posterior axis. Here we extend this investigation to two gene expression assays of adult normal human brains that consisted of over 300 brain region samples, and perform comparative analyses of brain-wide expression patterns to the mouse. We performed principal components analysis (PCA) on the regional gene expression of the adult human brain to identify the expression pattern that has the largest variance. As in the mouse, we observed that the first principal component is composed of two anti-correlated patterns enriched in oligodendrocyte and neuron markers respectively. However, we also observed interesting discordant patterns between the two species. For example, a few mouse neuron markers show expression patterns that are more correlated with the human oligodendrocyte-enriched pattern and vice-versa. In conclusion, our work provides insights into human brain function and evolution by probing global relationships between regional cell type marker expression patterns in the human and mouse brain.

Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury.

PubMed

Nakamura, Yuka; Fujita, Yuki; Ueno, Masaki; Takai, Toshiyuki; Yamashita, Toshihide

2011-01-21

Myelin components that inhibit axonal regeneration are believed to contribute significantly to the lack of axonal regeneration noted in the adult central nervous system. Three proteins found in myelin, Nogo, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein, inhibit neurite outgrowth in vitro. All of these proteins interact with the same receptors, namely, the Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PIR-B). As per previous reports, corticospinal tract (CST) regeneration is not enhanced in NgR-knock-out mice after spinal cord injury. Therefore, we assessed CST regeneration in PIR-B-knock-out mice. We found that hindlimb motor function, as assessed using the Basso mouse scale, footprint test, inclined plane test, and beam walking test, did not differ between the PIR-B-knock-out and wild-type mice after dorsal hemisection of the spinal cord. Further, tracing of the CST fibers after injury did not reveal enhanced axonal regeneration or sprouting in the CST of the PIR-B-knock-out mice. Systemic administration of NEP1-40, a NgR antagonist, to PIR-B knock-out mice did not enhance the regenerative response. These results indicate that PIR-B knock-out is not sufficient to induce extensive axonal regeneration after spinal cord injury.

A robust method for RNA extraction and purification from a single adult mouse tendon.

PubMed

Grinstein, Mor; Dingwall, Heather L; Shah, Rishita R; Capellini, Terence D; Galloway, Jenna L

2018-01-01

Mechanistic understanding of tendon molecular and cellular biology is crucial toward furthering our abilities to design new therapies for tendon and ligament injuries and disease. Recent transcriptomic and epigenomic studies in the field have harnessed the power of mouse genetics to reveal new insights into tendon biology. However, many mouse studies pool tendon tissues or use amplification methods to perform RNA analysis, which can significantly increase the experimental costs and limit the ability to detect changes in expression of low copy transcripts. Single Achilles tendons were harvested from uninjured, contralateral injured, and wild type mice between three and five months of age, and RNA was extracted. RNA Integrity Number (RIN) and concentration were determined, and RT-qPCR gene expression analysis was performed. After testing several RNA extraction approaches on single adult mouse Achilles tendons, we developed a protocol that was successful at obtaining high RIN and sufficient concentrations suitable for RNA analysis. We found that the RNA quality was sensitive to the time between tendon harvest and homogenization, and the RNA quality and concentration was dependent on the duration of homogenization. Using this method, we demonstrate that analysis of Scx gene expression in single mouse tendons reduces the biological variation caused by pooling tendons from multiple mice. We also show successful use of this approach to analyze Sox9 and Col1a2 gene expression changes in injured compared with uninjured control tendons. Our work presents a robust, cost-effective, and straightforward method to extract high quality RNA from a single adult mouse Achilles tendon at sufficient amounts for RT-qPCR as well as RNA-seq. We show this can reduce variation and decrease the overall costs associated with experiments. This approach can also be applied to other skeletal tissues, as well as precious human samples.

Normal spinal bone marrow in adults: dynamic gadolinium-enhanced MR imaging.

PubMed

Montazel, Jean-Luc; Divine, Marine; Lepage, Eric; Kobeiter, Hicham; Breil, Stephane; Rahmouni, Alain

2003-12-01

To determine the patterns of dynamic enhancement of normal spinal bone marrow in adults at gadolinium-enhanced magnetic resonance (MR) imaging and the changes that occur with aging. Dynamic contrast material-enhanced MR imaging of the thoracolumbar spine was performed in 71 patients. The maximum percentage of enhancement (Emax), enhancement slope, and enhancement washout were determined from bone marrow enhancement time curves (ETCs). The bone marrow signal intensity on T1-weighted spin-echo MR images was qualitatively classified into three grade categories. Quantitative ETC values were correlated with patient age and bone marrow fat content grade. Statistical analysis included mean t test comparison, analysis of variance, and regression analysis of the correlations between age and quantitative MR parameters. Emax, slope, and washout varied widely among the patients. Emax values were obtained within 1 minute after contrast material injection and ranged from 0% to 430%. Emax values were significantly higher in patients younger than 40 years than in those aged 40 years or older (P <.001). These values decreased with increasing age in a logarithmic relationship (r = 0.71). Emax values decreased as fat content increased, but some overlap among the fat content grades was noted. Analysis of variance revealed that Emax was significantly related to age (younger than 40 years vs 40 years or older) (P <.001) and fat content grade (P <.001) but not significantly related to sex. Dynamic contrast-enhanced MR imaging patterns of normal spinal bone marrow are dependent mainly on patient age and fat content.

Pharmacodynamic and pharmacokinetic studies of agmatine after spinal administration in the mouse.

PubMed

Roberts, John C; Grocholski, Brent M; Kitto, Kelley F; Fairbanks, Carolyn A

2005-09-01

Agmatine is an endogenous decarboxylation product of arginine that has been previously shown to antagonize the N-methyl-d-aspartate (NMDA) receptor and inhibit nitric-oxide synthase. Many neuropharmacological studies have shown that exogenous administration of agmatine prevents or reverses biological phenomena dependent on central nervous system glutamatergic systems, including opioid-induced tolerance, opioid self-administration, and chronic pain. However, the central nervous system (CNS) pharmacokinetic profile of agmatine remains minimally defined. The present study determined the spinal cord pharmacokinetics and acute pharmacodynamics of intrathecally administered agmatine in mice. After a single bolus intrathecal injection, agmatine concentrations in spinal cord (cervical, thoracic, and lumbosacral) tissue and serum were quantified by an isocratic high-performance liquid chromatography fluorescence detection system. Agmatine persisted at near maximum concentrations in all levels of the spinal cord for several hours with a half-life of approximately 12 h. Initial agmatine concentrations in serum were 10% those in CNS. However, the serum half-life was less than 10 min after intrathecal injection of agmatine, consistent with previous preliminary pharmacokinetic reports of systemically administered agmatine. The pharmacodynamic response to agmatine in the NMDA-nociceptive behavior and thermal hyperalgesia tests was assessed. Whereas MK-801 (dizocilpine maleate) inhibits these two responses with equal potency, agmatine inhibits the thermal hyperalgesia with significantly increased potency compared with the nociceptive behavior, suggesting two sites of action. In contrast to the pharmacokinetic results, the agmatine inhibition of both behaviors had a duration of only 10 to 30 min. Collectively, these results suggest the existence of a currently undefined agmatinergic extracellular clearance process in spinal cord.

Association between seeking oral health information online and knowledge in adults with spinal cord injury: A pilot study

PubMed Central

Yuen, Hon K.; Azuero, Andres; London, Steven

2011-01-01

Objective To characterize adults with spinal cord injury (SCI) who seek oral health information online, and investigate whether seeking oral health information online is associated with oral health knowledge and behaviors. Methods An online oral health survey was posted on the South Carolina Spinal Cord Injury Association website. Respondents were 192 adult residents of the US ages 19–83 years who identified themselves as having SCI occurring at least 1 year before the survey date. Results About 12% (n = 23) of the respondents searched oral health information online in the past 12 months. Significant associations between the proportion of respondents who searched for oral health information online and socio-demographic and the proportion of respondents who engaged in various oral health behaviors were not detected. However, multivariable logistic regression indicated that respondents who searched oral health information online in the past 12 months have 3.4 times the odds of possessing adequate oral health knowledge compared to respondents who did not search oral health information online (adjusted odds ratio = 3.41, 95% confidence interval = 1.35, 8.62, P = 0.01). Conclusions Given the significant association between seeking oral health information online and adequate oral health knowledge, this study suggests that online oral health information may be a potential avenue for dental health professionals to supplement oral health education in adults with SCI. PMID:21903017

Ileus Following Adult Spinal Deformity Surgery.

PubMed

Durand, Wesley M; Ruddell, Jack H; Eltorai, Adam E M; DePasse, J Mason; Daniels, Alan H

2018-05-23

Postoperative ileus (POI) is a common complication after spine surgery, with particularly high rates after adult spinal deformity surgery (ASD). Few investigations have been conducted, however, on predictors of POI following ASD. The objective of this investigation was to determine risk factors for POI in patients undergoing ASD. We also sought to determine the association between POI and in-hospital mortality, length of stay, and total charges. Data were obtained from the National/Nationwide Inpatient Sample, years 2010 - 2014. ASD patients aged ≥26 years-old were selected using ICD-9-CM codes. Multiple logistic and linear regression were utilized. In total, 59,410 patients were included in the analysis. 7.4% of patients experienced POI. On adjusted analysis, the following variables were associated with increased risk of POI: male sex (OR 1.43, CI 1.10 - 1.85), anterior surgical approach (OR 1.78, CI 1.22 - 2.60), 9+ levels fused (OR 1.84, CI 1.24 - 2.73), electrolyte disorders (OR 2.70, CI 2.15 - 3.39), and pathologic weight loss (OR 1.94, CI 1.08 - 3.46). POI was associated with significantly longer length of stay (+39%, CI 29% - 51%) and higher total charges (+23%, CI 14% - 31%). Risk factors for POI were identified. Patients suffering from ileus exhibited 2.9 days longer length of stay and ∼$80,000 higher total charges. These results may be applied clinically to identify patients at risk of POI and to consider addressing modifiable risk factors preoperatively. Future studies should be conducted with additional data to develop models capable of accurately predicting and preventing POI. Copyright © 2018 Elsevier Inc. All rights reserved.

Hindlimb Immobilization in a Wheelchair Alters Functional Recovery Following Contusive Spinal Cord Injury in the Adult Rat

PubMed Central

Caudle, Krista L.; Brown, Edward H.; Shum-Siu, Alice; Burke, Darlene A.; Magnuson, Trystan S. G.; Voor, Michael J.; Magnuson, David S. K.

2015-01-01

Background Locomotor training of rats with thoracic contusion spinal cord injuries can induce task-specific changes in stepping but rarely results in improved overground locomotion, possibly due to a ceiling effect. Thus, the authors hypothesize that incompletely injured rats maximally retrain themselves while moving about in their cages over the first few weeks postinjury. Objective To test the hypothesis using hindlimb immobilization after mild thoracic contusion spinal cord injury in adult female rats. A passive stretch protocol was included as an independent treatment. Methods Wheelchairs were used to hold the hindlimbs stationary in an extended position leaving the forelimbs free. The wheelchairs were used for 15 to 18 hours per day, 5 days per week for 8 weeks, beginning at 4 days postinjury. A 20-minute passive hindlimb stretch therapy was applied to half of the animals. Results Hindlimb locomotor function of the wheelchair group was not different from controls at 1 week postinjury but declined significantly over the next 4 weeks. Passive stretch had no influence on wheelchair animals but limited functional recovery of normally housed animals, preventing them from regaining forelimb–hindlimb coordination. Following 8 weeks of wheelchair immobilization and stretch therapy, only the wheelchair group displayed an improvement in function when returned to normal housing but retained significant deficits in stepping and coordination out to 16 weeks. Conclusion Hindlimb immobilization and passive stretch may hinder or conceal the normal course of functional recovery of spinal cord injured rats. These observations have implications for the management of acute clinical spinal cord injuries. PMID:21697451

Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

PubMed Central

Cherry, Jonathan J; Osman, Erkan Y; Evans, Matthew C; Choi, Sungwoon; Xing, Xuechao; Cuny, Gregory D; Glicksman, Marcie A; Lorson, Christian L; Androphy, Elliot J

2013-01-01

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA. PMID:23740718

The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord

PubMed Central

Tröster, Philip; Haseleu, Julia; Petersen, Jonas; Drees, Oliver; Schmidtko, Achim; Schwaller, Frederick; Lewin, Gary R.; Ter-Avetisyan, Gohar; Winter, York; Peters, Stefanie; Feil, Susanne; Feil, Robert; Rathjen, Fritz G.; Schmidt, Hannes

2018-01-01

A cGMP signaling cascade composed of C-type natriuretic peptide, the guanylyl cyclase receptor Npr2 and cGMP-dependent protein kinase I (cGKI) controls the bifurcation of sensory axons upon entering the spinal cord during embryonic development. However, the impact of axon bifurcation on sensory processing in adulthood remains poorly understood. To investigate the functional consequences of impaired axon bifurcation during adult stages we generated conditional mouse mutants of Npr2 and cGKI (Npr2fl/fl;Wnt1Cre and cGKIKO/fl;Wnt1Cre) that lack sensory axon bifurcation in the absence of additional phenotypes observed in the global knockout mice. Cholera toxin labeling in digits of the hind paw demonstrated an altered shape of sensory neuron termination fields in the spinal cord of conditional Npr2 mouse mutants. Behavioral testing of both sexes indicated that noxious heat sensation and nociception induced by chemical irritants are impaired in the mutants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are not affected. Recordings from C-fiber nociceptors in the hind limb skin showed that Npr2 function was not required to maintain normal heat sensitivity of peripheral nociceptors. Thus, the altered behavioral responses to noxious heat found in Npr2fl/fl;Wnt1Cre mice is not due to an impaired C-fiber function. Overall, these data point to a critical role of axonal bifurcation for the processing of pain induced by heat or chemical stimuli. PMID:29472841

Peer mentoring of adults with spinal cord injury: a transformational leadership perspective.

PubMed

Beauchamp, Mark R; Scarlett, Louisa J; Ruissen, Geralyn R; Connelly, Catherine E; McBride, Christopher B; Casemore, Sheila; Martin Ginis, Kathleen A

2016-09-01

Drawing from the tenets of transformational leadership theory, the purpose of this study was to examine the nature of effective peer mentoring of adults with a spinal cord injury (SCI) from the perspective of mentees. The study utilised a qualitative methodology (informed by a social constructionist approach), involving 15 adult mentees with a SCI (mean age = 47.2; mean time since injury = 14.5 years), in which data were obtained via semi-structured interviews. The results revealed that effective mentoring, as used by mentors with SCIs, closely aligns with the core components of transformational leadership. Specifically, all four dimensions of transformational leadership (idealised influence, inspirational motivation, individualised consideration and intellectual stimulation) as displayed by mentors with a SCI were evident in their interactions with mentees. Participants who perceived their mentors to use transformational leadership behaviours reported increases in motivation, self-confidence, hope and overall well-being, relatedness with their mentor, greater comfort/acceptance of their situation, a redefined sense of their limitations, as well as greater engagement in various life pursuits. Displays of transformational leadership by peer mentors (i.e. transformational mentoring) were reported by mentees to be associated with a range of adaptive psychological and behavioural outcomes. The results have the potential to inform the development and dissemination of peer mentor-based interventions and initiatives. Implications for Rehabilitation Within the context of spinal cord injury (SCI) rehabilitation, positive peer mentorship is reflected in mentors' use of transformational leadership behaviours (idealised influence, inspirational motivation, individualised consideration and intellectual stimulation). When SCI peer mentors use transformational leadership behaviours, mentees report a redefined sense of their limitations, and increased self-confidence, hope

A ‘tool box’ for deciphering neuronal circuits in the developing chick spinal cord

PubMed Central

Hadas, Yoav; Etlin, Alex; Falk, Haya; Avraham, Oshri; Kobiler, Oren; Panet, Amos; Lev-Tov, Aharon; Klar, Avihu

2014-01-01

The genetic dissection of spinal circuits is an essential new means for understanding the neural basis of mammalian behavior. Molecular targeting of specific neuronal populations, a key instrument in the genetic dissection of neuronal circuits in the mouse model, is a complex and time-demanding process. Here we present a circuit-deciphering ‘tool box’ for fast, reliable and cheap genetic targeting of neuronal circuits in the developing spinal cord of the chick. We demonstrate targeting of motoneurons and spinal interneurons, mapping of axonal trajectories and synaptic targeting in both single and populations of spinal interneurons, and viral vector-mediated labeling of pre-motoneurons. We also demonstrate fluorescent imaging of the activity pattern of defined spinal neurons during rhythmic motor behavior, and assess the role of channel rhodopsin-targeted population of interneurons in rhythmic behavior using specific photoactivation. PMID:25147209

Functional role of connexin43 gap junction channels in adult mouse heart assessed by inducible gene deletion.

PubMed

Eckardt, D; Theis, M; Degen, J; Ott, T; van Rijen, H V M; Kirchhoff, S; Kim, J-S; de Bakker, J M T; Willecke, K

2004-01-01

The gap junction protein Connexin43 (Cx43) is expressed in various cell types during embryonic development and in adult mice. Cx43 null mice (Cx43-/-) die perinatally due to cardiac malformation. In order to define the major functional role of Cx43 gap junction channels in adult mice and to circumvent perinatal death as well as direct or indirect compensation of Cx43 deficiency during development, we established a novel conditional Cx43 mouse mutant. To ablate Cx43 in adult mice in all cells that express Cx43 at a certain time, we targeted the 4-hydroxytamoxifen inducible Cre recombinase, Cre-ER(T), into the endogenous Cx43 locus. This approach left only one Cx43 coding region to be deleted upon induction of Cre-ER(T) activity. Highly efficient inducible ablation of Cx43 was shown in an embryonic stem cell test system and in adult mice. Although Cx43 protein was decreased in different tissues after induction of Cre-ER(T)-mediated recombination, cardiac abnormalities most likely account for death of those mice. Surface and telemetric ECG recordings revealed significant delay of ventricular activation and death during periods of bradyarrhythmia preceded by tachycardias. This novel approach of inducible ablation of Cx43 highlights the functional importance of normal activation of ventricular cardiomyocytes mediated by Cx43 gap junction channels in adult mouse heart to prevent initiation of fatal arrhythmias. The new mouse model should be useful for further analyses of molecular changes initiated by acute loss of Cx43 expression in various cell types.

The familial dysautonomia disease gene IKBKAP is required in the developing and adult mouse central nervous system

PubMed Central

Chaverra, Marta; George, Lynn; Thorne, Julian; Grindeland, Andrea; Ueki, Yumi; Eiger, Steven; Cusick, Cassie; Babcock, A. Michael; Carlson, George A.

2017-01-01

ABSTRACT Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN type III, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that, in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap

A Comprehensive Analysis of the SRS-Schwab Adult Spinal Deformity Classification and Confounding Variables: A Prospective, Non-US Cross-sectional Study in 292 Patients.

PubMed

Hallager, Dennis Winge; Hansen, Lars Valentin; Dragsted, Casper Rokkjær; Peytz, Nina; Gehrchen, Martin; Dahl, Benny

2016-05-01

Cross-sectional analyses on a consecutive, prospective cohort. To evaluate the ability of the Scoliosis Research Society (SRS)-Schwab Adult Spinal Deformity Classification to group patients by widely used health-related quality-of-life (HRQOL) scores and examine possible confounding variables. The SRS-Schwab Adult Spinal Deformity Classification includes sagittal modifiers considered important for HRQOL and the clinical impact of the classification has been validated in patients from the International Spine Study Group database; however, equivocal results were reported for the Pelvic Tilt modifier and potential confounding variables were not evaluated. Between March 2013 and May 2014, all adult spinal deformity patients from our outpatient clinic with sufficient radiographs were prospectively enrolled. Analyses of HRQOL variance and post hoc analyses were performed for each SRS-Schwab modifier. Age, history of spine surgery, and aetiology of spinal deformity were considered potential confounders and their influence on the association between SRS-Schwab modifiers and aggregated Oswestry Disability Index (ODI) scores was evaluated with multivariate proportional odds regressions. P values were adjusted for multiple testing. Two hundred ninety-two of 460 eligible patients were included for analyses. The SRS-Schwab Classification significantly discriminated HRQOL scores between normal and abnormal sagittal modifier classifications. Individual grade comparisons showed equivocal results; however, Pelvic Tilt grade + versus +  + did not discriminate patients according to any HRQOL score. All modifiers showed significant proportional odds for worse aggregated ODI scores with increasing grade levels and the effects were robust to confounding. However, age group and aetiology had individual significant effects. The SRS-Schwab sagittal modifiers reliably grouped patients graded 0 versus + / +  + according to the most widely used HRQOL scores and the

The Overexpression of TDP-43 Protein in the Neuron and Oligodendrocyte Cells Causes the Progressive Motor Neuron Degeneration in the SOD1 G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.

PubMed

Lu, Yi; Tang, Chunyan; Zhu, Lei; Li, Jiao; Liang, Huiting; Zhang, Jie; Xu, Renshi

2016-01-01

The recent investigation suggested that the TDP-43 protein was closely related to the motor neuron degeneration in amyotrophic lateral sclerosis (ALS), but the pathogenesis contributed to motor neuron degeneration largely remained unknown. Therefore, we detected the alteration of TDP-43 expression and distribution in the adult spinal cord of the SOD1 G93A transgenic mouse model for searching the possible pathogenesis of ALS. We examined the TDP-43 expression and distribution in the different anatomic regions, segments and neural cells in the adult spinal cord at the different stages of the SOD1 wild-type and G93A transgenic model by the fluorescent immunohistochemical technology. We revealed that the amount of TDP-43 positive cell was cervical>lumbar>thoracic segment, that in the ventral horn was more than that in the dorsal horn, a few of TDP-43 protein sparsely expressed and distributed in the other regions, the TDP-43 protein weren't detected in the white matter and the central canal. The TDP-43 protein was mostly expressed and distributed in the nuclear of neuron cells and the cytoplasm of oligodendrocyte cells of the gray matter surrounding the central canal of spinal cord by the granular shape in the SOD1 wild-type and G93A transgenic mice. The amount of TDP-43 positive cell significantly increased at the onset and progression stages of ALS following with the increase of neuron death in spinal cord, particularly in the ventral horn of cervical segment at the progression stage. Our results suggested that the overexpression of TDP-43 protein in the neuron and oligodendrocyte cell causes the progressive motor neuron degeneration in the ALS-like mouse model.

Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

PubMed

Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

2016-07-29

Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

Ligament augmentation for prevention of proximal junctional kyphosis and proximal junctional failure in adult spinal deformity.

PubMed

Safaee, Michael M; Deviren, Vedat; Dalle Ore, Cecilia; Scheer, Justin K; Lau, Darryl; Osorio, Joseph A; Nicholls, Fred; Ames, Christopher P

2018-05-01

OBJECTIVE Proximal junctional kyphosis (PJK) is a well-recognized, yet incompletely defined, complication of adult spinal deformity surgery. There is no standardized definition for PJK, but most studies describe PJK as an increase in the proximal junctional angle (PJA) of greater than 10°-20°. Ligament augmentation is a novel strategy for PJK reduction that provides strength to the upper instrumented vertebra (UIV) and adjacent segments while also reducing junctional stress at those levels. METHODS In this study, ligament augmentation was used in a consecutive series of adult spinal deformity patients at a single institution. Patient demographics, including age; sex; indication for surgery; revision surgery; surgical approach; and use of 3-column osteotomies, vertebroplasty, or hook fixation at the UIV, were collected. The PJA was measured preoperatively and at last follow-up using 36-inch radiographs. Data on change in PJA and need for revision surgery were collected. Univariate and multivariate analyses were performed to identify factors associated with change in PJA and proximal junctional failure (PJF), defined as PJK requiring surgical correction. RESULTS A total of 200 consecutive patients were included: 100 patients before implementation of ligament augmentation and 100 patients after implementation of this technique. The mean age of the ligament augmentation cohort was 66 years, and 67% of patients were women. Over half of these cases (51%) were revision surgeries, with 38% involving a combined anterior or lateral and posterior approach. The mean change in PJA was 6° in the ligament augmentation group compared with 14° in the control group (p < 0.001). Eighty-four patients had a change in PJA of less than 10°. In a multivariate linear regression model, age (p = 0.016), use of hook fixation at the UIV (p = 0.045), and use of ligament augmentation (p < 0.001) were associated with a change in PJA. In a separate model, only ligament augmentation (OR 0

Apoptosis and proliferation of oligodendrocyte progenitor cells in the irradiated rodent spinal cord

DOE Office of Scientific and Technical Information (OSTI.GOV)

Atkinson, Shelley L.; Li Yuqing; Wong, C. Shun

2005-06-01

Purpose: Oligodendrocytes undergo early apoptosis after irradiation. The aim of this study was to determine the relationship between oligodendroglial apoptosis and proliferation of oligodendrocyte progenitor cells (OPC) in the irradiated central nervous system. Methods and Materials: Adult rats and p53 transgenic mice were given single doses of 2 Gy, 8 Gy, or 22 Gy to the cervical spinal cord. Apoptosis was assessed using TUNEL (Tdt-mediated dUTP terminal nick-end labeling) staining or by examining nuclear morphology. Oligodendrocyte progenitor cells were identified with an NG2 antibody or by in situ hybridization for platelet-derived growth factor receptor {alpha}. Proliferation of OPC was assessedmore » by in vivo bromodeoxyuridine (BrdU) labeling and subsequent immunohistochemistry. Because radiation-induced apoptosis of oligodendroglial cells is p53 dependent, p53 transgenic mice were used to study the relationship between apoptosis and cell proliferation. Results: Oligodendrocyte progenitor cells underwent apoptosis within 24 h of irradiation in the rat. That did not result in a change in OPC density at 24 h. Oligodendrocyte progenitor cell density was significantly reduced by 2-4 weeks, but showed recovery by 6 weeks after irradiation. An increase in BrdU-labeled cells was observed at 2 weeks after 8 Gy or 22 Gy, and proliferating cells in the rat spinal cord were immunoreactive for NG2. The mouse spinal cord showed a similar early cell proliferation after irradiation. No difference was observed in the proliferation response in the spinal cord of p53 -/- mice compared with wild type animals. Conclusions: Oligodendroglial cells undergo early apoptosis and OPC undergo early proliferation after ionizing radiation. However, apoptosis is not likely to be the trigger for early proliferation of OPC in the irradiated central nervous system.« less

Localization of cholinergic innervation and neurturin receptors in adult mouse heart and expression of the neurturin gene.

PubMed

Mabe, Abigail M; Hoard, Jennifer L; Duffourc, Michelle M; Hoover, Donald B

2006-10-01

Neurturin (NRTN) is a neurotrophic factor required during development for normal cholinergic innervation of the heart, but whether NRTN continues to function in the adult heart is unknown. We have therefore evaluated NRTN expression in adult mouse heart and the association of NRTN receptors with intracardiac cholinergic neurons and nerve fibers. Mapping the regional distribution and density of cholinergic nerves in mouse heart was an integral part of this goal. Analysis of RNA from adult C57BL/6 mouse hearts demonstrated NRTN expression in atrial and ventricular tissue. Virtually all neurons in the cardiac parasympathetic ganglia exhibited the cholinergic phenotype, and over 90% of these cells contained both components of the NRTN receptor, Ret tyrosine kinase and GDNF family receptor alpha2 (GFRalpha2). Cholinergic nerve fibers, identified by labeling for the high affinity choline transporter, were abundant in the sinus and atrioventricular nodes, ventricular conducting system, interatrial septum, and much of the right atrium, but less abundant in the left atrium. The right ventricular myocardium contained a low density of cholinergic nerves, which were sparse in other regions of the working ventricular myocardium. Some cholinergic nerves were also associated with coronary vessels. GFRalpha2 was present in most cholinergic nerve fibers and in Schwann cells and their processes throughout the heart. Some cholinergic nerve fibers, such as those in the sinus node, also exhibited Ret immunoreactivity. These findings provide the first detailed mapping of cholinergic nerves in mouse heart and suggest that the neurotrophic influence of NRTN on cardiac cholinergic innervation continues in mature animals.

Transcranial cerebellar direct current stimulation and transcutaneous spinal cord direct current stimulation as innovative tools for neuroscientists

PubMed Central

Priori, Alberto; Ciocca, Matteo; Parazzini, Marta; Vergari, Maurizio; Ferrucci, Roberta

2014-01-01

Two neuromodulatory techniques based on applying direct current (DC) non-invasively through the skin, transcranial cerebellar direct current stimulation (tDCS) and transcutaneous spinal DCS, can induce prolonged functional changes consistent with a direct influence on the human cerebellum and spinal cord. In this article we review the major experimental works on cerebellar tDCS and on spinal tDCS, and their preliminary clinical applications. Cerebellar tDCS modulates cerebellar motor cortical inhibition, gait adaptation, motor behaviour, and cognition (learning, language, memory, attention). Spinal tDCS influences the ascending and descending spinal pathways, and spinal reflex excitability. In the anaesthetised mouse, DC stimulation applied under the skin along the entire spinal cord may affect GABAergic and glutamatergic systems. Preliminary clinical studies in patients with cerebellar disorders, and in animals and patients with spinal cord injuries, have reported beneficial effects. Overall the available data show that cerebellar tDCS and spinal tDCS are two novel approaches for inducing prolonged functional changes and neuroplasticity in the human cerebellum and spinal cord, and both are new tools for experimental and clinical neuroscientists. PMID:24907311

Are there endogenous stem cells in the spinal cord?

PubMed

Ferrucci, Michela; Ryskalin, Larisa; Busceti, Carla L; Gaglione, Anderson; Biagioni, Francesca; Fornai, Francesco

2017-12-01

Neural progenitor cells (NPC) represent the stem-like niche of the central nervous system that maintains a regenerative potential also in the adult life. Despite NPC in the brain are well documented, the presence of NPC in the spinal cord has been controversial for a long time. This is due to a scarce activity of NPC within spinal cord, which also makes difficult their identification. The present review recapitulates the main experimental studies, which provided evidence for the occurrence of NPC within spinal cord, with a special emphasis on spinal cord injury and amyotrophic lateral sclerosis. By using experimental models, here we analyse the site-specificity, the phenotype and the main triggers of spinal cord NPC. Moreover, data are reported on the effect of specific neurogenic stimuli on these spinal cord NPC in an effort to comprehend the endogenous neurogenic potential of this stem cell niche.

Clitoral Sexual Arousal: Neuronal Tracing Study From the Clitoris Through the Spinal Tracts

PubMed Central

Martin-Alguacil, Nieves; Schober, Justine M.; Sengelaub, Dale R.; Pfaff, Donald W.; Shelley, Deborah N.

2009-01-01

Purpose Although genital tactile stimulation is regarded as a precursor to sexual arousal and a recognized initiator of central nervous system arousal, specific afferent neural pathways transmit sensory stimuli of arousal, beginning at the epithelial level on the clitoris and following the course of arousal stimuli through the central nervous system. Limited knowledge exists of the pathway from the cutaneous receptors of nerves originating in the epithelial tissue of the clitoris and continuing to spinal cord afferents. Such information may contribute to an understanding of sexual arousal, particularly in female vertebrates. We further defined the neural pathways and mechanisms responsible for arousal originating in the epithelium of the clitoris as well as related neural pathways to the spinal cord in a murine model. Materials and Methods We performed a comprehensive review of the published relevant clinical and histological material from human and nonhuman vertebrate studies. In 29 adult female C57B1/6 mice the distribution of pelvic nerves and vessels was mapped. Gross dissection of 4 female mice was facilitated by resin injection of the vascular system in 2. Neuronal tracing was performed in 25 mice that received clitoral injection of wheat germ agglutinin-horseradish peroxidase into the clitoris and were sacrificed after 72 to 96 hours. The spinal cord and periclitoral tissue were removed and fixed. Immunohistochemistry was performed. Results Gross anatomy of the mouse clitoris showed that pudendal and hypogastric nerves have a major role in the innervation of the external genitalia. Neuronal tracing revealed that the greatest nerve density was noted in the L5/6 spinal cord. The distribution extended from S1 to L2 with no labeling seen in the L3 spinal cord. Wheat germ agglutinin-horseradish peroxidase labeling was seen caudal in levels S1 through L4 and rostral in L2. Conclusions Understanding the neuroanatomy of the clitoris using a murine model may provide

Rapid and efficient gene delivery into the adult mouse brain via focal electroporation

PubMed Central

Nomura, Tadashi; Nishimura, Yusuke; Gotoh, Hitoshi; Ono, Katsuhiko

2016-01-01

In vivo gene delivery is required for studying the cellular and molecular mechanisms of various biological events. Virus-mediated gene transfer or generation of transgenic animals is widely used; however, these methods are time-consuming and expensive. Here we show an improved electroporation technique for acute gene delivery into the adult mouse brain. Using a syringe-based microelectrode, local DNA injection and the application of electric current can be performed simultaneously; this allows rapid and efficient gene transduction of adult non-neuronal cells. Combining this technique with various expression vectors that carry specific promoters resulted in targeted gene expression in astrocytic cells. Our results constitute a powerful strategy for the genetic manipulation of adult brains in a spatio-temporally controlled manner. PMID:27430903

Epigenetic transgenerational inheritance of vinclozolin induced mouse adult onset disease and associated sperm epigenome biomarkers.

PubMed

Guerrero-Bosagna, Carlos; Covert, Trevor R; Haque, Md M; Settles, Matthew; Nilsson, Eric E; Anway, Matthew D; Skinner, Michael K

2012-12-01

The endocrine disruptor vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease. Copyright © 2012 Elsevier Inc. All rights reserved.

Epigenetic Transgenerational Inheritance of Vinclozolin Induced Mouse Adult Onset Disease and Associated Sperm Epigenome Biomarkers

PubMed Central

Guerrero-Bosagna, Carlos; Covert, Trevor R.; Haque, Md. M.; Settles, Matthew; Nilsson, Eric E.; Anway, Matthew D.; Skinner, Michael K.

2012-01-01

The endocrine disruptor vinclozolin has previously been shown to promote epigenetic transgenerational inheritance of adult onset disease in the rat. The current study was designed to investigate the transgenerational actions of vinclozolin on the mouse. Transient exposure of the F0 generation gestating female during gonadal sex determination promoted transgenerational adult onset disease in F3 generation male and female mice, including spermatogenic cell defects, testicular abnormalities, prostate abnormalities, kidney abnormalities and polycystic ovarian disease. Pathology analysis demonstrated 75% of the vinclozolin lineage animals developed disease with 34% having two or more different disease states. Interestingly, the vinclozolin induced transgenerational disease was observed in the outbred CD-1 strain, but not the inbred 129 mouse strain. Analysis of the F3 generation sperm epigenome identified differential DNA methylation regions that can potentially be utilized as epigenetic biomarkers for transgenerational exposure and disease. PMID:23041264

Growth of adult spinal cord in knifefish: Development and parametrization of a distributed model.

PubMed

Ilieş, Iulian; Sipahi, Rifat; Zupanc, Günther K H

2018-01-21

The study of indeterminate-growing organisms such as teleost fish presents a unique opportunity for improving our understanding of central nervous tissue growth during adulthood. Integrating the existing experimental data associated with this process into a theoretical framework through mathematical or computational modeling provides further research avenues through sensitivity analysis and optimization. While this type of approach has been used extensively in investigations of tumor growth, wound healing, and bone regeneration, the development of nervous tissue has been rarely studied within a modeling framework. To address this gap, the present work introduces a distributed model of spinal cord growth in the knifefish Apteronotus leptorhynchus, an established teleostean model of adult growth in the central nervous system. The proposed model incorporates two mechanisms, cell proliferation by active stem/progenitor cells and cell drift due to population pressure, both of which are subject to global constraints. A coupled reaction-diffusion equation approach was adopted to represent the densities of actively-proliferating and non-proliferating cells along the longitudinal axis of the spinal cord. Computer simulations using this model yielded biologically-feasible growth trajectories. Subsequent comparisons with whole-organism growth curves allowed the estimation of previously-unknown parameters, such as relative growth rates. Copyright © 2017 Elsevier Ltd. All rights reserved.

Morphological Characteristics of Motor Neurons Do Not Determine Their Relative Susceptibility to Degeneration in a Mouse Model of Severe Spinal Muscular Atrophy

PubMed Central

Mutsaers, Chantal A.; Thomson, Derek; Hamilton, Gillian; Parson, Simon H.; Gillingwater, Thomas H.

2012-01-01

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice – including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA. PMID:23285108

A Simplified, Langendorff-Free Method for Concomitant Isolation of Viable Cardiac Myocytes and Nonmyocytes From the Adult Mouse Heart

PubMed Central

Ackers-Johnson, Matthew; Li, Peter Yiqing; Holmes, Andrew P.; O’Brien, Sian-Marie; Pavlovic, Davor; Foo, Roger S.

2018-01-01

Rationale Cardiovascular disease represents a global pandemic. The advent of and recent advances in mouse genomics, epigenomics, and transgenics offer ever-greater potential for powerful avenues of research. However, progress is often constrained by unique complexities associated with the isolation of viable myocytes from the adult mouse heart. Current protocols rely on retrograde aortic perfusion using specialized Langendorff apparatus, which poses considerable logistical and technical barriers to researchers and demands extensive training investment. Objective To identify and optimize a convenient, alternative approach, allowing the robust isolation and culture of adult mouse cardiac myocytes using only common surgical and laboratory equipment. Methods and Results Cardiac myocytes were isolated with yields comparable to those in published Langendorff-based methods, using direct needle perfusion of the LV ex vivo and without requirement for heparin injection. Isolated myocytes can be cultured antibiotic free, with retained organized contractile and mitochondrial morphology, transcriptional signatures, calcium handling, responses to hypoxia, neurohormonal stimulation, and electric pacing, and are amenable to patch clamp and adenoviral gene transfer techniques. Furthermore, the methodology permits concurrent isolation, separation, and coculture of myocyte and nonmyocyte cardiac populations. Conclusions We present a novel, simplified method, demonstrating concomitant isolation of viable cardiac myocytes and nonmyocytes from the same adult mouse heart. We anticipate that this new approach will expand and accelerate innovative research in the field of cardiac biology. PMID:27502479

A comparison of hydrostatic weighing and air displacement plethysmography in adults with spinal cord injury.

PubMed

Clasey, Jody L; Gater, David R

2005-11-01

To compare (1) total body volume (V(b)) and density (D(b)) measurements obtained by hydrostatic weighing (HW) and air displacement plethysmography (ADP) in adults with spinal cord injury (SCI); (2) measured and predicted thoracic gas volume (V(TG)); and (3) differences in percentage of fat measurements using ADP-obtained D(b) and HW-obtained D(b) measures that were interchanged in a 4-compartment body composition model (4-comp %fat). Twenty adults with SCI underwent ADP and V(TG), and HW testing. In a subgroup (n=13) of subjects, 4-comp %fat procedures were computed. Research laboratories in a university setting. Twenty adults with SCI below the T3 vertebrae and motor complete paraplegia. Not applicable. Statistical analyses, including determination of group mean differences, shared variance, total error, and 95% confidence intervals. The 2 methods yielded small yet significantly different V(b) and D(b). The groups' mean V(TG) did not differ significantly, but the large relative differences indicated an unacceptable amount of individual error. When the 4-comp %fat measurements were compared, there was a trend toward significant differences (P=.08). ADP is a valid alternative method of determining the V(b) and D(b) in adults with SCI; however, the predicted V(TG) should be used with caution.

The association of socio-economic factors with physical fitness and activity behaviours, spinal posture and retinal vessel parameters in first graders in urban Switzerland.

PubMed

Imhof, Katharina; Faude, Oliver; Donath, Lars; Bean-Eisenhut, Salome; Hanssen, Henner; Zahner, Lukas

2016-01-01

Socio-economic status during childhood has been shown to be a strong predictor of adult health outcome. Therefore, we examined associations of parental educational level, household income and migrant background with physical fitness, spinal flexibility, spinal posture as well as retinal vessel diameters in children of an urban Swiss region. A total of 358 first graders of the Swiss canton Basel-Stadt (age: 7.3, SD: 0.4) were examined. Physical fitness (20 m shuttle run test, 20 m sprint, jumping sidewards and balancing backwards), spinal flexibility and spinal posture (MediMouse®, Idiag, Fehraltdorf, Switzerland) and retinal microcirculation (Static Retinal Vessel Analyzer, Imedos Systems UG, Jena, Germany) were assessed. Parental education, household income, migrant background and activity behaviour were evaluated with a questionnaire. Parental education was associated with child aerobic fitness (P = 0.03) and screen time (P < 0.001). Household income was associated with jumping sidewards (P = 0.009), balancing backwards (P = 0.03) and sports club participation (P = 0.02). Migrant background was associated with BMI (P = 0.001), body fat (P = 0.03), aerobic fitness (P = 0.007), time spent playing outdoors (P < 0.001) and screen time (P < 0.001). For spinal flexibility and retinal vessel diameter, no associations were found (0.06 < P < 0.8). Low parental education, low household income and a migrant background are associated with poor physical fitness, higher BMI and body fat percentage and low-activity behaviour.

Comparison of Diffusion MRI Acquisition Protocols for the In Vivo Characterization of the Mouse Spinal Cord: Variability Analysis and Application to an Amyotrophic Lateral Sclerosis Model

PubMed Central

Marcuzzo, Stefania; Bonanno, Silvia; Padelli, Francesco; Moreno-Manzano, Victoria; García-Verdugo, José Manuel; Bernasconi, Pia; Mantegazza, Renato; Bruzzone, Maria Grazia; Zucca, Ileana

2016-01-01

Diffusion-weighted Magnetic Resonance Imaging (dMRI) has relevant applications in the microstructural characterization of the spinal cord, especially in neurodegenerative diseases. Animal models have a pivotal role in the study of such diseases; however, in vivo spinal dMRI of small animals entails additional challenges that require a systematical investigation of acquisition parameters. The purpose of this study is to compare three acquisition protocols and identify the scanning parameters allowing a robust estimation of the main diffusion quantities and a good sensitivity to neurodegeneration in the mouse spinal cord. For all the protocols, the signal-to-noise and contrast-to noise ratios and the mean value and variability of Diffusion Tensor metrics were evaluated in healthy controls. For the estimation of fractional anisotropy less variability was provided by protocols with more diffusion directions, for the estimation of mean, axial and radial diffusivity by protocols with fewer diffusion directions and higher diffusion weighting. Intermediate features (12 directions, b = 1200 s/mm2) provided the overall minimum inter- and intra-subject variability in most cases. In order to test the diagnostic sensitivity of the protocols, 7 G93A-SOD1 mice (model of amyotrophic lateral sclerosis) at 10 and 17 weeks of age were scanned and the derived diffusion parameters compared with those estimated in age-matched healthy animals. The protocols with an intermediate or high number of diffusion directions provided the best differentiation between the two groups at week 17, whereas only few local significant differences were highlighted at week 10. According to our results, a dMRI protocol with an intermediate number of diffusion gradient directions and a relatively high diffusion weighting is optimal for spinal cord imaging. Further work is needed to confirm these results and for a finer tuning of acquisition parameters. Nevertheless, our findings could be important for the

Predicting critical care unit-level complications after long-segment fusion procedures for adult spinal deformity.

PubMed

De la Garza-Ramos, Rafael; Nakhla, Jonathan; Gelfand, Yaroslav; Echt, Murray; Scoco, Aleka N; Kinon, Merritt D; Yassari, Reza

2018-03-01

To identify predictive factors for critical care unit-level complications (CCU complication) after long-segment fusion procedures for adult spinal deformity (ASD). The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database [2010-2014] was reviewed. Only adult patients who underwent fusion of 7 or more spinal levels for ASD were included. CCU complications included intraoperative arrest/infarction, ventilation >48 hours, pulmonary embolism, renal failure requiring dialysis, cardiac arrest, myocardial infarction, unplanned intubation, septic shock, stroke, coma, or new neurological deficit. A stepwise multivariate regression was used to identify independent predictors of CCU complications. Among 826 patients, the rate of CCU complications was 6.4%. On multivariate regression analysis, dependent functional status (P=0.004), combined approach (P=0.023), age (P=0.044), diabetes (P=0.048), and surgery for over 8 hours (P=0.080) were significantly associated with complication development. A simple scoring system was developed to predict complications with 0 points for patients aged <50, 1 point for patients between 50-70, 2 points for patients 70 or over, 1 point for diabetes, 2 points dependent functional status, 1 point for combined approach, and 1 point for surgery over 8 hours. The rate of CCU complications was 0.7%, 3.2%, 9.0%, and 12.6% for patients with 0, 1, 2, and 3+ points, respectively (P<0.001). The findings in this study suggest that older patients, patients with diabetes, patients who depend on others for activities of daily living, and patients who undergo combined approaches or surgery for over 8 hours may be at a significantly increased risk of developing a CCU-level complication after ASD surgery.

Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury

PubMed Central

Ferguson, Adam R.; Huie, J. Russell; Crown, Eric D.; Baumbauer, Kyle M.; Hook, Michelle A.; Garraway, Sandra M.; Lee, Kuan H.; Hoy, Kevin C.; Grau, James W.

2012-01-01

Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity-dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI. PMID

Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology

PubMed Central

Dey, Aditi; Castleton, Anna Z.; Schwab, Claire; Samuel, Edward; Sivakumaran, Janani; Beaton, Brendan; Zareian, Nahid; Zhang, Christie Yu; Rai, Lena; Enver, Tariq; Moorman, Anthony V.; Fielding, Adele K.

2014-01-01

The distinct nature of acute lymphoblastic leukemia (ALL) in adults, evidenced by inferior treatment outcome and different genetic landscape, mandates specific studies of disease-initiating mechanisms. In this study, we used NOD/LtSz-scid IL2Rγ nullc (NSG) mouse xenotransplantation approaches to elucidate leukemia-initiating cell (LIC) biology in primary adult precursor B (pre-B) ALL to optimize disease modeling. In contrast with xenografting studies of pediatric ALL, we found that modification of the NSG host environment using preconditioning total body irradiation (TBI) was indispensable for efficient engraftment of adult non-t(4;11) pre-B ALL, whereas t(4;11) pre-B ALL was successfully reconstituted without this adaptation. Furthermore, TBI-based xenotransplantation of non-t(4;11) pre-B ALL enabled detection of a high frequency of LICs (<1:6900) and permitted frank leukemic engraftment from a remission sample containing drug-resistant minimal residual disease. Investigation of TBI-sensitive stromal-derived factor-1/chemokine receptor type 4 signaling revealed greater functional dependence of non-t(4;11) pre-B ALL on this niche-based interaction, providing a possible basis for the differential engraftment behavior. Thus, our studies establish the optimal conditions for experimental modeling of human adult pre-B ALL and demonstrate the critical protumorogenic role of microenvironment-derived SDF-1 in regulating adult pre-B LIC activity that may present a therapeutic opportunity. PMID:24825861

A head movement image (HMI)-controlled computer mouse for people with disabilities.

PubMed

Chen, Yu-Luen; Chen, Weoi-Luen; Kuo, Te-Son; Lai, Jin-Shin

2003-02-04

This study proposes image processing and microprocessor technology for use in developing a head movement image (HMI)-controlled computer mouse system for the spinal cord injured (SCI). The system controls the movement and direction of the mouse cursor by capturing head movement images using a marker installed on the user's headset. In the clinical trial, this new mouse system was compared with an infrared-controlled mouse system on various tasks with nine subjects with SCI. The results were favourable to the new mouse system. The differences between the new mouse system and the infrared-controlled mouse were reaching statistical significance in each of the test situations (p<0.05). The HMI-controlled computer mouse improves the input speed. People with disabilities need only wear the headset and move their heads to freely control the movement of the mouse cursor.

Two-photon laser scanning microscopy imaging of intact spinal cord and cerebral cortex reveals requirement for CXCR6 and neuroinflammation in immune cell infiltration of cortical injury sites.

PubMed

Kim, Jiyun V; Jiang, Ning; Tadokoro, Carlos E; Liu, Liping; Ransohoff, Richard M; Lafaille, Juan J; Dustin, Michael L

2010-01-31

The mouse spinal cord is an important site for autoimmune and injury models. Skull thinning surgery provides a minimally invasive window for microscopy of the mouse cerebral cortex, but there are no parallel methods for the spinal cord. We introduce a novel, facile and inexpensive method for two-photon laser scanning microscopy of the intact spinal cord in the mouse by taking advantage of the naturally accessible intervertebral space. These are powerful methods when combined with gene-targeted mice in which endogenous immune cells are labeled with green fluorescent protein (GFP). We first demonstrate that generation of the intervertebral window does not elicit a reaction of GFP(+) microglial cells in CX3CR1(gfp/+) mice. We next demonstrate a distinct rostrocaudal migration of GFP(+) immune cells in the spinal cord of CXCR6(gfp/+) mice during active experimental autoimmune encephalomyelitis (EAE). Interestingly, infiltration of the cerebral cortex by GFP(+) cells in these mice required three conditions: EAE induction, cortical injury and expression of CXCR6 on immune cells. Copyright 2009 Elsevier B.V. All rights reserved.

Behaviour change intervention increases physical activity, spinal mobility and quality of life in adults with ankylosing spondylitis: a randomised trial.

PubMed

O'Dwyer, Tom; Monaghan, Ann; Moran, Jonathan; O'Shea, Finbar; Wilson, Fiona

2017-01-01

Does a 3-month behaviour change intervention targeting physical activity (PA) increase habitual physical activity in adults with ankylosing spondylitis (AS)? Does the intervention improve health-related physical fitness, AS-related features, and attitude to exercise? Are any gains maintained over a 3-month follow-up? Parallel-group, randomised, controlled trial with concealed allocation, assessor blinding and intention-to-treat analysis. Forty adults with a diagnosis of AS, on stable medication, and without PA-limiting comorbidities. Over a 3-month period, the experimental group engaged in individually-tailored, semi-structured consultations aiming to motivate and support individuals in participating in PA. The control group continued with usual care. The primary outcome was PA measured by accelerometry over 1 week. Secondary outcomes included clinical questionnaires and measures of health-related physical fitness. Measures were taken at baseline, post-intervention, and after a 3-month follow-up period. Baseline characteristics were similar across groups, except age and body composition. There were statistically significant, moderate-to-large time-by-group effects in health-enhancing PA (mixed-design ANOVA for overall effect F(2, 76)=14.826, p<0.001), spinal mobility (F(2, 76)=5.691, p<0.005) and quality of life (χ 2 (2)=8.400, p<0.015) favouring the intervention group; post-intervention improvements were sustained 3 months later. No significant effects were seen in other physical fitness outcomes or on clinical questionnaires. No adverse effects were reported during the study. Health-enhancing PA, spinal mobility and quality of life were significantly improved after the intervention, and improvements were maintained at 3-month follow-up. NCT02374502. [O'Dwyer T, Monaghan A, Moran J, O'Shea F, Wilson F (2016) Behaviour change intervention increases physical activity, spinal mobility and quality of life in adults with ankylosing spondylitis: a randomised trial

Changes in spinal alignment.

PubMed

Veintemillas Aráiz, M T; Beltrán Salazar, V P; Rivera Valladares, L; Marín Aznar, A; Melloni Ribas, P; Valls Pascual, R

2016-04-01

Spinal misalignments are a common reason for consultation at primary care centers and specialized departments. Misalignment has diverse causes and is influenced by multiple factors: in adolescence, the most frequent misalignment is scoliosis, which is idiopathic in 80% of cases and normally asymptomatic. In adults, the most common cause is degenerative. It is important to know the natural history and to detect factors that might predict progression. The correct diagnosis of spinal deformities requires specific imaging studies. The degree of deformity determines the type of treatment. The aim is to prevent progression of the deformity and to recover the flexibility and balance of the body. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

Life satisfaction in adults with pediatric-onset spinal cord injuries.

PubMed

Anderson, Caroline J; Krajci, Katherine A; Vogel, Lawrence C

2002-01-01

To determine the level of life satisfaction of adults with pediatric-onset spinal cord injuries (SCI) and the factors associated with life satisfaction. A structured interview including standardized measures. Participants were individuals who sustained SCI at age 18 years or younger, were 24 years of age or olderat interview, did not have significant brain injury, and were living in the United States or Canada. A structured interview, the Functional Independence Measure (FIM), the Craig Handicap Assessment and Reporting Technique (CHART), the Short-Form 12 (SF-12), and the Satisfaction with Life Scale (SWLS). Two hundred sixteen individuals were interviewed. Mean age at injury was 1 4 years, mean age at interview was 29 years, and mean duration of injury was 14 years. The mean SWLS score was 23.6, and the median score was 25. There was not a significant difference between men and women, but those with tetraplegia were significantly less satisfied than were those with paraplegia. A regression model identified age at injury, community mobility (CHART), marital status, use of street drugs, perceived mental health (SF-12), and medical complications as predictors of life satisfaction. Other factors strongly associated with SWLS were employment, income, independent living, FIM total plus physical and sociocognitive domain scores, perceived physical health (SF-12), and CHART total plus the subscales of physical independence, cognitive independence, and occupation. Life satisfaction in adults with pediatric-onset SCI is associated with demographic, injury-related, and functional limitation factors, as well as with health status and community integration outcomes.

The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice.

PubMed

Uchida, Kenzo; Nakajima, Hideaki; Hirai, Takayuki; Yayama, Takafumi; Chen, Kebing; Guerrero, Alexander Rodriguez; Johnson, William Eustace; Baba, Hisatoshi

2012-12-15

The twy/twy mouse undergoes spontaneous chronic mechanical compression of the spinal cord; this in vivo model system was used to examine the effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived neurotrophic factor (BDNF) gene delivery to spinal neural cells. To investigate the targeting and potential neuroprotective effect of retrograde AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. Several studies have investigated the neuroprotective effects of neurotrophins, including BDNF, in spinal cord injury. However, no report has described the effects of retrograde neurotrophic factor gene delivery in compressed spinal cords, including gene targeting and the potential to prevent neural cell apoptosis. AdV-BDNF or AdV-LacZ (as a control gene) was injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for retrograde gene delivery via the spinal accessory motor neurons. Heterozygous Institute of Cancer Research mice (+/twy), which do not undergo spontaneous spinal compression, were used as a control for the effects of such compression on gene delivery. The localization and cell specificity of β-galactosidase expression (produced by LacZ gene transfection) and BDNF expression in the spinal cord were examined by coimmunofluorescence staining for neural cell markers (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus AdV-LacZ-transfected control mice was assessed by scoring the prevalence of apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor marker, NG2. RESULTS

Noradrenergic innervation of the rat spinal cord caudal to a complete spinal cord transection: effects of olfactory ensheathing glia.

PubMed

Takeoka, Aya; Kubasak, Marc D; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R; Phelps, Patricia E

2010-03-01

Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG- than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now we report that NA axons are present throughout the caudal stump of both media- and OEG-injected spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This effect could be mediated through direct association with SMNs and/or indirectly via cholinergic interneurons. Copyright 2009 Elsevier Inc. All rights reserved.

NORADRENERGIC INNERVATION OF THE RAT SPINAL CORD CAUDAL TO A COMPLETE SPINAL CORD TRANSECTION: EFFECTS OF OLFACTORY ENSHEATHING GLIA

PubMed Central

Takeoka, Aya; Kubasak, Marc D.; Zhong, Hui; Kaplan, Jennifer; Roy, Roland R.; Phelps, Patricia E.

2010-01-01

Transplantation of olfactory bulb-derived olfactory ensheathing glia (OEG) combined with step training improves hindlimb locomotion in adult rats with a complete spinal cord transection. Spinal cord injury studies use the presence of noradrenergic (NA) axons caudal to the injury site as evidence of axonal regeneration and we previously found more NA axons just caudal to the transection in OEG- than media-injected spinal rats. We therefore hypothesized that OEG transplantation promotes descending coeruleospinal regeneration that contributes to the recovery of hindlimb locomotion. Now we report that NA axons are present throughout the caudal stump of both media- and OEG-injected spinal rats and they enter the spinal cord from the periphery via dorsal and ventral roots and along large penetrating blood vessels. These results indicate that the presence of NA fibers in the caudal spinal cord is not a reliable indicator of coeruleospinal regeneration. We then asked if NA axons appose cholinergic neurons associated with motor functions, i.e., central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more NA varicosities adjacent to central canal cluster cells, partition cells, and SMNs in the lumbar enlargement of OEG- than media-injected rats. As non-synaptic release of NA is common in the spinal cord, more associations between NA varicosities and motor-associated cholinergic neurons in the lumbar spinal cord may contribute to the improved treadmill stepping observed in OEG-injected spinal rats. This effect could be mediated through direct association with SMNs and/or indirectly via cholinergic interneurons. PMID:20025875

Targeted retrograde transfection of adenovirus vector carrying brain-derived neurotrophic factor gene prevents loss of mouse (twy/twy) anterior horn neurons in vivo sustaining mechanical compression.

PubMed

Xu, Kan; Uchida, Kenzo; Nakajima, Hideaki; Kobayashi, Shigeru; Baba, Hisatoshi

2006-08-01

Immunohistochemical analysis after adenovirus (AdV)-mediated BDNF gene transfer in and around the area of mechanical compression in the cervical spinal cord of the hyperostotic mouse (twy/twy). To investigate the neuroprotective effect of targeted AdV-BDNF gene transfection in the twy mouse with spontaneous chronic compression of the spinal cord motoneurons. Several studies reported the neuroprotective effects of neurotrophins on injured spinal cord. However, no report has described the effect of targeted retrograde neurotrophic gene delivery on motoneuron survival in chronic compression lesions of the cervical spinal cord resembling lesions of myelopathy. LacZ marker gene using adenoviral vector (AdV-LacZ) was used to evaluate retrograde delivery from the sternomastoid muscle in adult twy mice (16-week-old) and (control). Four weeks after the AdV-LacZ or AdV-BDNF injection, the compressed cervical spinal cord was removed en bloc for immunohistologic investigation of b-galactosidase activity and immunoreactivity and immunoblot analyses of BDNF. The number of anterior horn neurons was counted using Nissl, ChAT and AChE staining. Spinal accessory motoneurons between C1 and C3 segments were successfully transfected by AdV-LacZ in both twy and ICR mice after targeted intramuscular injection. Immunoreactivity to BDNF was significantly stronger in AdV-BDNF-gene transfected twy mice than in AdV-LacZ-gene transfected mice. At the cord level showing the maximum compression in AdV-BDNF-transfected twy mice, the number of anterior horn neurons was sinificantly higher in the topographic neuronal cell counting of Nissl-, ChAT-, and AChE-stained samples than in AdV-LacZ-injected twy mice. Targeted AdV-BDNF-gene delivery significantly increased Nissl-stained anterior horn neurons and enhanced cholinergic enzyme activities in the twy. Our results suggest that targeted retrograde AdV-BDNF-gene in vivo delivery may enhance neuronal survival even under chronic mechanical compression.

Activation of the Wnt/{beta}-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Yanchun; Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong; Guan, Yingjun, E-mail: guanyj@wfmc.edu.cn

Highlights: Black-Right-Pointing-Pointer Wnt3a and Cyclin D1 were upregulated in the spinal cord of the ALS mice. Black-Right-Pointing-Pointer {beta}-catenin translocated from the cell membrane to the nucleus in the ALS mice. Black-Right-Pointing-Pointer Wnt3a, {beta}-catenin and Cyclin D1 co-localized for astrocytes were all increased. Black-Right-Pointing-Pointer BrdU/Cyclin D1 double-positive cells were increased in the spinal cord of ALS mice. Black-Right-Pointing-Pointer BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. -- Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however,more » the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, {beta}-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/{beta}-catenin signaling pathway. We determined the expression of Wnt3a, {beta}-catenin, and Cyclin D1 in the adult spinal cord of SOD1{sup G93A} ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, {beta}-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, {beta}-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, {beta}-catenin or Cyclin D1 in mature GFAP{sup +} astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest

Arc restores juvenile plasticity in adult mouse visual cortex

PubMed Central

Jenks, Kyle R.; Kim, Taekeun; Pastuzyn, Elissa D.; Okuno, Hiroyuki; Taibi, Andrew V.; Bear, Mark F.

2017-01-01

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here, we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild-type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation. PMID:28790183

Inducing hindlimb locomotor recovery in adult rat after complete thoracic spinal cord section using repeated treadmill training with perineal stimulation only

PubMed Central

Alluin, Olivier; Delivet-Mongrain, Hugo

2015-01-01

Although a complete thoracic spinal cord section in various mammals induces paralysis of voluntary movements, the spinal lumbosacral circuitry below the lesion retains its ability to generate hindlimb locomotion. This important capacity may contribute to the overall locomotor recovery after partial spinal cord injury (SCI). In rats, it is usually triggered by pharmacological and/or electrical stimulation of the cord while a robot sustains the animals in an upright posture. In the present study we daily trained a group of adult spinal (T7) rats to walk with the hindlimbs for 10 wk (10 min/day for 5 days/wk), using only perineal stimulation. Kinematic analysis and terminal electromyographic recordings revealed a strong effect of training on the reexpression of hindlimb locomotion. Indeed, trained animals gradually improved their locomotion while untrained animals worsened throughout the post-SCI period. Kinematic parameters such as averaged and instant swing phase velocity, step cycle variability, foot drag duration, off period duration, and relationship between the swing features returned to normal values only in trained animals. The present results clearly demonstrate that treadmill training alone, in a normal horizontal posture, elicited by noninvasive perineal stimulation is sufficient to induce a persistent hindlimb locomotor recovery without the need for more complex strategies. This provides a baseline level that should be clearly surpassed if additional locomotor-enabling procedures are added. Moreover, it has a clinical value since intrinsic spinal reorganization induced by training should contribute to improve locomotor recovery together with afferent feedback and supraspinal modifications in patients with incomplete SCI. PMID:26203108

Impact of Glycemic Control on Morbidity and Mortality in Adult Idiopathic Scoliosis Patients Undergoing Spinal Fusion.

PubMed

Shin, John I; Phan, Kevin; Kothari, Parth; Kim, Jun S; Guzman, Javier Z; Cho, Samuel K

2017-08-01

This is a retrospective analysis of administrative database. To elucidate the effect of glycemic control on surgical outcomes of middle-aged and elderly idiopathic scoliosis patients undergoing spinal fusion surgery. Diabetes mellitus (DM) is a condition thought to adversely affect outcomes of spine surgery. However, no study has stratified glycemic control levels and their impact on outcome for idiopathic scoliosis patients receiving a spinal fusion surgery. Previous studies may have reported higher than true rates of complications for controlled diabetic patients, who are the majority of diabetic patients. The Nationwide Inpatient Sample was queried from years 2002 to 2011. We extracted idiopathic scoliosis patients older than 45 years of age that received spinal fusion and analyzed complications and outcomes variables among 3 cohorts: nondiabetic patients, controlled diabetics, and uncontrolled diabetics. Multivariate analyses were used to assess whether glycemic control was a risk factor for adverse postoperative outcomes. Controlled diabetics had significantly increased rates of acute renal failure (ARF), while uncontrolled diabetics had significantly increased rates of acute postoperative hemorrhage. In multivariate analyses controlling for patient factors and comorbidities, controlled DM was found to be an independent predictor of ARF [odds ratio (OR), 1.863; 95% confidence interval (CI), 1.346-2.579; P=0.0002), and uncontrolled DM was found to be a significant risk factor for acute postoperative hemorrhage (OR, 2.182; 95% CI, 1.192-3.997; P=0.0115), ARF (OR, 4.839; 95% CI, 1.748-13.392; P=0.0024), deep vein thrombosis (OR, 5.825; 95% CI, 1.329-25.522, P=0.0194) and in-patient mortality (OR, 8.889; 95% CI, 1.001-78.945; P=0.0499). Controlled DM was found to be a risk factor for ARF in adult idiopathic scoliosis patients undergoing spinal fusion surgery, while uncontrolled DM was shown to be a risk factor for postoperative hemorrhage, ARF, deep vein

Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy

PubMed Central

Zhao, Xin; Feng, Zhihua; Ling, Karen K. Y.; Mollin, Anna; Sheedy, Josephine; Yeh, Shirley; Petruska, Janet; Narasimhan, Jana; Dakka, Amal; Welch, Ellen M.; Karp, Gary; Chen, Karen S.; Metzger, Friedrich; Ratni, Hasane; Lotti, Francesco; Tisdale, Sarah; Naryshkin, Nikolai A.; Pellizzoni, Livio; Paushkin, Sergey; Ko, Chien-Ping; Weetall, Marla

2016-01-01

Spinal muscular atrophy (SMA) is caused by the loss or mutation of both copies of the survival motor neuron 1 (SMN1) gene. The related SMN2 gene is retained, but due to alternative splicing of exon 7, produces insufficient levels of the SMN protein. Here, we systematically characterize the pharmacokinetic and pharmacodynamics properties of the SMN splicing modifier SMN-C1. SMN-C1 is a low-molecular weight compound that promotes the inclusion of exon 7 and increases production of SMN protein in human cells and in two transgenic mouse models of SMA. Furthermore, increases in SMN protein levels in peripheral blood mononuclear cells and skin correlate with those in the central nervous system (CNS), indicating that a change of these levels in blood or skin can be used as a non-invasive surrogate to monitor increases of SMN protein levels in the CNS. Consistent with restored SMN function, SMN-C1 treatment increases the levels of spliceosomal and U7 small-nuclear RNAs and corrects RNA processing defects induced by SMN deficiency in the spinal cord of SMNΔ7 SMA mice. A 100% or greater increase in SMN protein in the CNS of SMNΔ7 SMA mice robustly improves the phenotype. Importantly, a ∼50% increase in SMN leads to long-term survival, but the SMA phenotype is only partially corrected, indicating that certain SMA disease manifestations may respond to treatment at lower doses. Overall, we provide important insights for the translation of pre-clinical data to the clinic and further therapeutic development of this series of molecules for SMA treatment. PMID:26931466

Adenosine A1-Dopamine D1 Receptor Heteromers Control the Excitability of the Spinal Motoneuron.

PubMed

Rivera-Oliver, Marla; Moreno, Estefanía; Álvarez-Bagnarol, Yocasta; Ayala-Santiago, Christian; Cruz-Reyes, Nicole; Molina-Castro, Gian Carlo; Clemens, Stefan; Canela, Enric I; Ferré, Sergi; Casadó, Vicent; Díaz-Ríos, Manuel

2018-05-24

While the role of the ascending dopaminergic system in brain function and dysfunction has been a subject of extensive research, the role of the descending dopaminergic system in spinal cord function and dysfunction is just beginning to be understood. Adenosine plays a key role in the inhibitory control of the ascending dopaminergic system, largely dependent on functional complexes of specific subtypes of adenosine and dopamine receptors. Combining a selective destabilizing peptide strategy with a proximity ligation assay and patch-clamp electrophysiology in slices from male mouse lumbar spinal cord, the present study demonstrates the existence of adenosine A 1 -dopamine D 1 receptor heteromers in the spinal motoneuron by which adenosine tonically inhibits D 1 receptor-mediated signaling. A 1 -D 1 receptor heteromers play a significant control of the motoneuron excitability, represent main targets for the excitatory effects of caffeine in the spinal cord and can constitute new targets for the pharmacological therapy after spinal cord injury, motor aging-associated disorders and restless legs syndrome.

Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy

PubMed Central

Ling, Karen K. Y.; Gibbs, Rebecca M.; Feng, Zhihua; Ko, Chien-Ping

2012-01-01

Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy. PMID:21968514

Huntingtin Acts Non Cell-Autonomously on Hippocampal Neurogenesis and Controls Anxiety-Related Behaviors in Adult Mouse

PubMed Central

Pla, Patrick; Orvoen, Sophie; Benstaali, Caroline; Dodier, Sophie; Gardier, Alain M.; David, Denis J.; Humbert, Sandrine; Saudou, Frédéric

2013-01-01

Huntington’s disease (HD) is a fatal neurodegenerative disease, characterized by motor defects and psychiatric symptoms, including mood disorders such as anxiety and depression. HD is caused by an abnormal polyglutamine (polyQ) expansion in the huntingtin (HTT) protein. The development and analysis of various mouse models that express pathogenic polyQ-HTT revealed a link between mutant HTT and the development of anxio-depressive behaviors and various hippocampal neurogenesis defects. However, it is unclear whether such phenotype is linked to alteration of HTT wild-type function in adults. Here, we report the analysis of a new mouse model in which HTT is inducibly deleted from adult mature cortical and hippocampal neurons using the CreERT2/Lox system. These mice present defects in both the survival and the dendritic arborization of hippocampal newborn neurons. Our data suggest that these non-cell autonomous effects are linked to defects in both BDNF transport and release upon HTT silencing in hippocampal neurons, and in BDNF/TrkB signaling. The controlled deletion of HTT also had anxiogenic-like effects. Our results implicate endogenous wild-type HTT in adult hippocampal neurogenesis and in the control of mood disorders. PMID:24019939

Longitudinal employment outcomes in adults with pediatric-onset spinal cord injury.

PubMed

Hwang, M; Zebracki, K; Chlan, K M; Vogel, L C

2014-06-01

Longitudinal survey. To determine in adults with pediatric-onset spinal cord injury (SCI) employment outcomes, longitudinal changes in employment over time and changes in psychosocial outcomes associated with employment status. Community setting. Adults who had sustained a SCI before 19 years of age and had completed at least three consecutive annual interviews were included in the study. Generalized estimating equation models were formulated to obtain odds ratio (OR) of change in employment status and outcomes over time. Total 1691 interviews were conducted in 283 participants, 182 men and 101 women (88% Caucasian; age at baseline, 27.3±3.7 years; duration at baseline, 12.7±5.0 years). At the last interview (age, 34.4±5.2 years; duration, 19.9±6.1 years), 49.5% were employed and 47.0% had a baccalaureate or post-baccalaureate degree. There was no significant change in employment status over time (OR 1.01, confidence interval (CI) 0.98-1.04). Odds of employment increased over time in participants who were women (1.04, CI 1.00-1.08), married (1.05, CI 1.02-1.08) and attained baccalaureate (1.03, CI 1.00-1.07) or post-baccalaureate (1.05, CI 1.02-1.08) degree. Employment odds decreased with occurrence of autonomic dysreflexia (0.80, CI 0.65-0.99), spasticity (0.80, CI 0.59-0.99) or chronic medical condition (0.83, CI 0.71-0.98). Life satisfaction scores increased over time in those who remained employed (1.11, CI 1.01-1.22); odds of depression increased over time in those who remained unemployed (1.13, CI 1.04-1.23). Employment status remained relatively stable in adults with pediatric-onset SCI; however, changes in employment were associated with education, secondary health conditions and psychosocial well-being.

Experimental Mouse Model of Lumbar Ligamentum Flavum Hypertrophy.

PubMed

Saito, Takeyuki; Yokota, Kazuya; Kobayakawa, Kazu; Hara, Masamitsu; Kubota, Kensuke; Harimaya, Katsumi; Kawaguchi, Kenichi; Hayashida, Mitsumasa; Matsumoto, Yoshihiro; Doi, Toshio; Shiba, Keiichiro; Nakashima, Yasuharu; Okada, Seiji

2017-01-01

Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.

Volume and fat infiltration of spino-pelvic musculature in adults with spinal deformity

PubMed Central

Moal, Bertrand; Bronsard, Nicolas; Raya, José G; Vital, Jean Marc; Schwab, Frank; Skalli, Wafa; Lafage, Virginie

2015-01-01

AIM: To investigate fat infiltration and volume of spino-pelvic muscles in adults spinal deformity (ASD) with magnetic resonance imaging (MRI) and 3D reconstructions. METHODS: Nineteen female ASD patients (mean age 60 ± 13) were included prospectively and consecutively and had T1-weighted Turbo Spin Echo sequence MRIs with Dixon method from the proximal tibia up to T12 vertebra. The Dixon method permitted to evaluate the proportion of fat inside each muscle (fat-water ratio). In order to investigate the accuracy of the Dixon method for estimating fat vs water, the same MRI acquisition was performed on phantoms of four vials composed of different proportion of fat vs water. With Muscl’X software, 3D reconstructions of 17 muscles or group of muscles were obtained identifying the muscle’s contour on a limited number of axial images [Deformation of parametric specific objects (DPSO) Method]. Musclar volume (Vmuscle), infiltrated fat volume (Vfat) and percentage of fat infiltration [Pfat, calculated as follow: Pfat = 100 × (Vfat/Vmuscle)] were characterized by extensor or flexor function respectively for the spine, hip and knee and theirs relationship with demographic data were investigated. RESULTS: Phantom acquisition demonstrated a non linear relation between Dixon fat-water ratio and the real fat-water ratio. In order to correct the Dixon fat-water ratio, the non linear relation was approximated with a polynomial function of degree three using the phantom acquisition. On average, Pfat was 13.3% ± 5.3%. Muscles from the spinal extensor group had a Pfat significantly greater than the other muscles groups, and the largest variability (Pfat = 31.9% ± 13.8%, P < 0.001). Muscles from the hip extensor group ranked 2nd in terms of Pfat (14% ± 8%), and were significantly greater than those of the knee extensor (P = 0.030). Muscles from the knee extensor group demonstrated the least Pfat (12% ± 8%). They were also the only group with a significant correlation

The role of cerebral spinal fluid in light propagation through the mouse head: improving fluorescence tomography with Monte Carlo modeling

NASA Astrophysics Data System (ADS)

Ancora, Daniele; Zacharopoulos, Athanasios; Ripoll, Jorge; Zacharakis, Giannis

2016-03-01

Optical Neuroimaging is a highly dynamical field of research owing to the combination of many advanced imaging techniques and computational tools that uncovered unexplored paths through the functioning of the brain. Light propagation modelling through such complicated structures has always played a crucial role as the basis for a high resolution and quantitative imaging where even the slightest improvement could lead to significant results. Fluorescence Diffuse Optical Tomography (fDOT), a widely used technique for three dimensional imaging of small animals and tissues, has been proved to be inaccurate for neuroimaging the mouse head without the knowledge of a-priori anatomical information of the subject. Commonly a normalized Born approximation model is used in fDOT reconstruction based on forward photon propagation using Diffusive Equation (DE) which has strong limitations in the optically clear regime. The presence of the Cerebral Spinal Fluid (CSF) instead, a thin optically clear layer surrounding the brain, can be more accurately taken into account using Monte Carlo approaches which nowadays is becoming more usable thanks to parallelized GPU algorithms. In this work we discuss the results of a synthetic experimental comparison, resulting to the increase of the accuracy for the Born approximation by introducing the CSF layer in a realistic mouse head structure with respect to the current model. We point out the importance of such clear layer for complex geometrical models, while for simple slab phantoms neglecting it does not introduce a significant error.

Primary osseous tumors of the pediatric spinal column: review of pathology and surgical decision making.

PubMed

Ravindra, Vijay M; Eli, Ilyas M; Schmidt, Meic H; Brockmeyer, Douglas L

2016-08-01

Spinal column tumors are rare in children and young adults, accounting for only 1% of all spine and spinal cord tumors combined. They often present diagnostic and therapeutic challenges. In this article, the authors review the current management of primary osseous tumors of the pediatric spinal column and highlight diagnosis, management, and surgical decision making.

Enrichment and isolation of neurons from adult mouse brain for ex vivo analysis.

PubMed

Berl, Sabina; Karram, Khalad; Scheller, Anja; Jungblut, Melanie; Kirchhoff, Frank; Waisman, Ari

2017-05-01

Isolation of neurons from the adult mouse CNS is important in order to study their gene expression during development or the course of different diseases. Here we present two different methods for the enrichment or isolation of neurons from adult mouse CNS. These methods: are either based on flow cytometry sorting of eYFP expressing neurons, or by depletion of non-neuronal cells by sorting with magnetic-beads. Enrichment by FACS sorting of eYFP positive neurons results in a population of 62.4% NeuN positive living neurons. qPCR data shows a 3-5fold upregulation of neuronal markers. The isolation of neurons based on depletion of non-neuronal cells using the Miltenyi Neuron Isolation Kit, reaches a purity of up to 86.5%. qPCR data of these isolated neurons shows an increase in neuronal markers and an absence of glial markers, proving pure neuronal RNA isolation. Former data related to neuronal gene expression are mainly based on histology, which does not allow for high-throughput transcriptome analysis to examine differential gene expression. These protocols can be used to study cell type specific gene expression of neurons to unravel their function in the process of damage to the CNS. Copyright © 2017 Elsevier B.V. All rights reserved.

Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli.

PubMed

Akiyama, Tasuku; Iodi Carstens, Mirela; Carstens, Earl

2011-01-01

Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABA(A) and GABA(B) antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished) by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli.

[Isolation, purification and primary culture of adult mouse cardiac fibroblasts].

PubMed

Li, Rujun; Gong, Kaizheng; Zhang, Zhengang

2017-01-01

Objective To establish a method for primary culture of adult mouse cardiac fibroblasts. Methods Myocardial tissues from adult mice were digested with 1 g/L trypsin and 0.8 g/L collagenase IV by oscillating water bath for a short time repeatedly. Cardiac fibroblasts and myocardial cells were isolated with differential adhesion method. Immunofluorescence staining was used to assess the purity of cardiac fibroblasts. The cell morphology was observed under an inverted phase contrast microscope. The proliferation of cardiac fibroblasts was analyzed by growth curve and CCK-8 assay. The Smad2/3 phosphorylation induced by TGF-β1 was detected by Western blotting. Results After 90 minutes of differential adhesion, adherent fibroblasts formed spherical cell mass and after 3 days, cells were spindle-shaped and proliferated rapidly. Cells were confluent after 5 days and the growth curve presented nearly "S" shape. The positive expression rate of vimentin was 95%. CCK-8 assay showed that the optimal cell proliferating activity was found from day 3 to day 5. The level of phosphorylated Smad2/3 obviously increased at the second passage induced by TGF-β1. Conclusion This method is economical and stable to isolate cardiac fibroblasts with high activity and high purity from adult mice.

Extended magnetic resonance imaging studies on the effect of classically activated microglia transplantation on white matter regeneration following spinal cord focal injury in adult rats

PubMed Central

Marcol, Wiesław; Ślusarczyk, Wojciech; Larysz-Brysz, Magdalena; Łabuzek, Krzysztof; Kapustka, Bartosz; Staszkiewicz, Rafał; Rosicka, Paulina; Kalita, Katarzyna; Węglarz, Władysław; Lewin-Kowalik, Joanna

2017-01-01

Spinal cord injuries are still a serious problem for regenerative medicine. Previous research has demonstrated that activated microglia accumulate in spinal lesions, influencing the injured tissues in various ways. Therefore, transplantation of activated microglia may have a beneficial role in the regeneration of the nervous system. The present study examined the influence of transplanted activated microglial cells in adult rats with injured spinal cords. Rats were randomly divided into an experimental (M) and control (C) group, and were subjected to non-laminectomy focal injury of spinal cord white matter by means of a high-pressured air stream. In group M, activated cultured microglial cells were injected twice into the site of injury. Functional outcome and morphological features of regeneration were analyzed during a 12-week follow-up. The lesions were characterized by means of magnetic resonance imaging (MRI). Neurons in the brain stem and motor cortex were labeled with FluoroGold (FG). A total of 12 weeks after surgery, spinal cords and brains were collected and subjected to histopathological and immunohistochemical examinations. Lesion sizes in the spinal cord were measured and the number of FG-positive neurons was counted. Rats in group M demonstrated significant improvement of locomotor performance when compared with group C (P<0.05). MRI analysis demonstrated moderate improvement in water diffusion along the spinal cord in the group M following microglia treatment, as compared with group C. The water diffusion perpendicular to the spinal cord in group M was closer to the reference values for a healthy spinal cord than it was in group C. The sizes of lesions were also significantly smaller in group M than in the group C (P<0.05). The number of brain stem and motor cortex FG-positive neurons in group M was significantly higher than in group C. The present study demonstrated that delivery of activated microglia directly into the injured spinal cord gives

Use of quadrupedal step training to re-engage spinal interneuronal networks and improve locomotor function after spinal cord injury.

PubMed

Shah, Prithvi K; Garcia-Alias, Guillermo; Choe, Jaehoon; Gad, Parag; Gerasimenko, Yury; Tillakaratne, Niranjala; Zhong, Hui; Roy, Roland R; Edgerton, V Reggie

2013-11-01

Can lower limb motor function be improved after a spinal cord lesion by re-engaging functional activity of the upper limbs? We addressed this issue by training the forelimbs in conjunction with the hindlimbs after a thoracic spinal cord hemisection in adult rats. The spinal circuitries were more excitable, and behavioural and electrophysiological analyses showed improved hindlimb function when the forelimbs were engaged simultaneously with the hindlimbs during treadmill step-training as opposed to training only the hindlimbs. Neuronal retrograde labelling demonstrated a greater number of propriospinal labelled neurons above and below the thoracic lesion site in quadrupedally versus bipedally trained rats. The results provide strong evidence that actively engaging the forelimbs improves hindlimb function and that one likely mechanism underlying these effects is the reorganization and re-engagement of rostrocaudal spinal interneuronal networks. For the first time, we provide evidence that the spinal interneuronal networks linking the forelimbs and hindlimbs are amenable to a rehabilitation training paradigm. Identification of this phenomenon provides a strong rationale for proceeding toward preclinical studies for determining whether training paradigms involving upper arm training in concert with lower extremity training can enhance locomotor recovery after neurological damage.

[The metabolic profilings study of serum and spinal cord from acute spinal cord injury rats ¹H NMR spectroscopy].

PubMed

Hu, Hua-Hui; Huang, Xiao-Long; Quan, Ren-Fu; Yang, Zong-Bao; Xu, Jing-Jing

2017-02-25

To establish the rat model of acute spinal cord injury, followed by aprimary study on this model with ¹H NMR based on metabonomics and to explore the metabonomics and biomarkers of spinal cord injury rat. Twenty eight-week-old adult male SD rats of clean grade, with body weight of (200±10) g, were divided into sham operation group and model group in accordance with the law of random numbers, and every group had 10 rats. The rats of sham operation group were operated without damaging the spinal cord, and rats of model group were made an animal model of spinal cord incomplete injury according to the modified Allen's method. According to BBB score to observate the motor function of rats on the 1th, 5th, and 7th days after surgery. Postoperative spinal cord tissue was collected in order to pathologic observation at the 7th day, and the metabolic profilings of serum and spinal cord from spinal cord injury rats were studied by ¹H NMR spectroscopy. The hindlimb motion of rats did not obviously change in sham operation group, there was no significant difference at each time point;and rats of model group occurred flaccid paralysis of both lower extremities, there was a significant difference at each time; there was significant differences between two groups at each time. Pathological results showed the spinal cord structure was normal with uniform innervation in shame group, while in model group, the spinal cord structure was mussy, and the neurons were decreased, with inflammatory cells and necrotic tissue. Analysis of metabonomics showed that concentration of very low density fat protein (VLDL), low density fat protein (LDL), glutamine, citric acid, dimethylglycine (DMG) in the serum and glutathione, 3-OH-butyrate, N-Acetyl-L-aspartic acid (NAA), glycerophosphocholine (GPC), glutamic acid, and ascorbate in spinal cord had significant changes( P <0.05). There are significant differences in metabolic profile from serum and spinal cord sample between model group and sham

Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

PubMed Central

2014-01-01

Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

Nonreciprocal mechanisms in up- and downregulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels

PubMed Central

Lombardo, Joseph

2016-01-01

KCNQ/Kv7 channels form a slow noninactivating K+ current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/Kv7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K+ current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/Kv7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/Kv7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/Kv7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/Kv7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/Kv7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/Kv7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/Kv7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners. PMID:27512022

Adult Spinal Deformity Patients Recall Fewer Than 50% of the Risks Discussed in the Informed Consent Process Preoperatively and the Recall Rate Worsens Significantly in the Postoperative Period.

PubMed

Saigal, Rajiv; Clark, Aaron J; Scheer, Justin K; Smith, Justin S; Bess, Shay; Mummaneni, Praveen V; McCarthy, Ian M; Hart, Robert A; Kebaish, Khaled M; Klineberg, Eric O; Deviren, Vedat; Schwab, Frank; Shaffrey, Christopher I; Ames, Christopher P

2015-07-15

Recall of the informed consent process in patients undergoing adult spinal deformity surgery and their family members was investigated prospectively. To quantify the percentage recall of the most common complications discussed during the informed consent process in adult spinal deformity surgery, assess for differences between patients and family members, and correlate with mental status. Given high rates of complications in adult spinal deformity surgery, it is critical to shared decision making that patients are adequately informed about risks and are able to recall preoperative discussion of possible complications to mitigate medical legal risk. Patients undergoing adult spinal deformity surgery underwent an augmented informed consent process involving both verbal and video explanations. Recall of the 11 most common complications was scored. Mental status was assessed with the mini-mental status examination-brief version. Patients subjectively scored the informed consent process and video. After surgery, the recall test and mini-mental status examination-brief version were readministered at 5 additional time points: hospital discharge, 6 to 8 weeks, 3 months, 6 months, and 1 year postoperatively. Family members were assessed at the first 3 time points for comparison. Fifty-six patients enrolled. Despite ranking the consent process as important (median overall score: 10/10; video score: 9/10), median patient recall was only 45% immediately after discussion and video re-enforcement and subsequently declined to 18% at 6 to 8 weeks and 1 year postoperatively. Median family recall trended higher at 55% immediately and 36% at 6 to 8 weeks postoperatively. The perception of the severity of complications significantly differs between patient and surgeon. Mental status scores showed a transient, significant decrease from preoperation to discharge but were significantly higher at 1 year. Despite being well-informed in an optimized informed consent process, patients cannot

Effect of fluoxetine on disease progression in a mouse model of ALS

PubMed Central

Koschnitzky, J. E.; Quinlan, K. A.; Lukas, T. J.; Kajtaz, E.; Kocevar, E. J.; Mayers, W. F.; Siddique, T.

2014-01-01

Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are often prescribed to amyotrophic lateral sclerosis (ALS) patients; however, the impact of these prescriptions on ALS disease progression has not been systematically tested. To determine whether SSRIs impact disease progression, fluoxetine (Prozac, 5 or 10 mg/kg) was administered to mutant superoxide dismutase 1 (SOD1) mice during one of three age ranges: neonatal [postnatal day (P)5–11], adult presymptomatic (P30 to end stage), and adult symptomatic (P70 to end stage). Long-term adult fluoxetine treatment (started at either P30 or P70 and continuing until end stage) had no significant effect on disease progression. In contrast, neonatal fluoxetine treatment (P5-11) had two effects. First, all animals (mutant SOD1G93A and control: nontransgenic and SOD1WT) receiving the highest dose (10 mg/kg) had a sustained decrease in weight from P30 onward. Second, the high-dose SOD1G93A mice reached end stage ∼8 days (∼6% decrease in life span) sooner than vehicle and low-dose animals because of an increased rate of motor impairment. Fluoxetine increases synaptic serotonin (5-HT) levels, which is known to increase spinal motoneuron excitability. We confirmed that 5-HT increases spinal motoneuron excitability during this neonatal time period and therefore hypothesized that antagonizing 5-HT receptors during the same time period would improve disease outcome. However, cyproheptadine (1 or 5 mg/kg), a 5-HT receptor antagonist, had no effect on disease progression. These results show that a brief period of antidepressant treatment during a critical time window (the transition from neonatal to juvenile states) can be detrimental in ALS mouse models. PMID:24598527

miR-155 Deletion in Mice Overcomes Neuron-Intrinsic and Neuron-Extrinsic Barriers to Spinal Cord Repair.

PubMed

Gaudet, Andrew D; Mandrekar-Colucci, Shweta; Hall, Jodie C E; Sweet, David R; Schmitt, Philipp J; Xu, Xinyang; Guan, Zhen; Mo, Xiaokui; Guerau-de-Arellano, Mireia; Popovich, Phillip G

2016-08-10

Axon regeneration after spinal cord injury (SCI) fails due to neuron-intrinsic mechanisms and extracellular barriers including inflammation. microRNA (miR)-155-5p is a small, noncoding RNA that negatively regulates mRNA translation. In macrophages, miR-155-5p is induced by inflammatory stimuli and elicits a response that could be toxic after SCI. miR-155 may also independently alter expression of genes that regulate axon growth in neurons. Here, we hypothesized that miR-155 deletion would simultaneously improve axon growth and reduce neuroinflammation after SCI by acting on both neurons and macrophages. New data show that miR-155 deletion attenuates inflammatory signaling in macrophages, reduces macrophage-mediated neuron toxicity, and increases macrophage-elicited axon growth by ∼40% relative to control conditions. In addition, miR-155 deletion increases spontaneous axon growth from neurons; adult miR-155 KO dorsal root ganglion (DRG) neurons extend 44% longer neurites than WT neurons. In vivo, miR-155 deletion augments conditioning lesion-induced intraneuronal expression of SPRR1A, a regeneration-associated gene; ∼50% more injured KO DRG neurons expressed SPRR1A versus WT neurons. After dorsal column SCI, miR-155 KO mouse spinal cord has reduced neuroinflammation and increased peripheral conditioning-lesion-enhanced axon regeneration beyond the epicenter. Finally, in a model of spinal contusion injury, miR-155 deletion improves locomotor function at postinjury times corresponding with the arrival and maximal appearance of activated intraspinal macrophages. In miR-155 KO mice, improved locomotor function is associated with smaller contusion lesions and decreased accumulation of inflammatory macrophages. Collectively, these data indicate that miR-155 is a novel therapeutic target capable of simultaneously overcoming neuron-intrinsic and neuron-extrinsic barriers to repair after SCI. Axon regeneration after spinal cord injury (SCI) fails due to neuron

Adult thoracolumbar and lumbar scoliosis treated with long vertebral fusion to the sacropelvis: a comparison between new hybrid selective spinal fusion versus anterior-posterior spinal instrumentation.

PubMed

Yagi, Mitsuru; Patel, Ravi; Lawhorne, Thomas W; Cunningham, Matthew E; Boachie-Adjei, Oheneba

2014-04-01

Combined anteroposterior spinal fusion with instrumentation has been used for many years to treat adult thoracolumbar/lumbar scoliosis. This surgery remains a technical challenge to spine surgeons, and current literature reports high complication rates. The purpose of this study is to validate a new hybrid technique (a combination of single-rod anterior instrumentation and a shorter posterior instrumentation to the sacrum) to treat adult thoracolumbar/lumbar scoliosis. This study is a retrospective consecutive case series of surgically treated patients with adult lumbar or thoracolumbar scoliosis. This is a retrospective study of 33 matched pairs of patients with adult scoliosis who underwent two different surgical procedures: a new hybrid technique versus a third-generation anteroposterior spinal fusion. Preoperative and postoperative outcome measures include self-report measures, physiological measures, and functional measures. In a retrospective case-control study, 33 patients treated with the hybrid technique were matched with 33 patients treated with traditional anteroposterior fusion based on preoperative radiographic parameters. Mean follow-up in the hybrid group was 5.3 years (range, 2-11 years), compared with 4.6 years (range, 2-10 years) in the control group. Operating room (OR) time, estimated blood loss, and levels fused were collected as surrogates for surgical morbidity. Radiographic parameters were collected preoperatively, postoperatively, and at final follow-up. The Scoliosis Research Society Patient Questionnaire (SRS-22r) and Oswestry Disability Index (ODI) scores were collected for clinical outcomes. Operating room time, EBL, and levels fused were significantly less in the hybrid group compared with the control group (p<.0001). The postoperative thoracic Cobb angle was similar between the hybrid and control techniques (p=.24); however, the hybrid technique showed significant improvement in the thoracolumbar/lumbar curves (p=.004) and the

MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma.

PubMed

Wang, Wenzhao; Tang, Shi; Li, Hongfei; Liu, Ronghan; Su, Yanlin; Shen, Lin; Sun, Mingjie; Ning, Bin

2018-06-05

Traumatic spinal cord injury (SCI) causes permanent disability to at least 180,000 people per year worldwide. Early regulation of spinal fibroblast proliferation may inhibit fibrotic scar formation, allowing the creation of a favorable environment for neuronal regeneration and thereby enhancing recovery from traumatic SCIs. In this study, we aimed to identify the role of microRNA-21a-5p (miR-21a-5p) in regulating spinal fibroblasts after mechanical trauma and to investigate the dysregulation of miR-21a-5p in the pathological process of spinal SCI. We investigated the differential expression of microRNAs in primary spinal fibroblasts after mechanical trauma and found that the expression of miR-21a-5p was higher in spinal fibroblasts after scratch damage (SD). In addition, mouse spinal fibroblasts were transfected with miR-21a-5p mimics/inhibitor, and the role of miR-21a-5p in spinal fibrogenic activation was analyzed. These experiments demonstrated that miR-21a-5p overexpression promoted fibrogenic activity in spinal fibroblasts after mechanical trauma, as well as enhancing proliferation and attenuating apoptosis in spinal fibroblasts. Finally, the potential role of miR-21a-5p in regulating the Smad signaling pathway was examined. MiR-21a-5p activated the Smad signaling pathway by enhancing Smad2/3 phosphorylation. These results suggest that miR-21a-5p promotes spinal fibrosis after mechanical trauma. Based on these findings, we propose a close relationship between miR-21a-5p and spinal fibrosis, providing a new potential therapeutic target for SCI. Copyright © 2018. Published by Elsevier Inc.

An immunohistochemical identification key for cell types in adult mouse prostatic and urethral tissue sections

PubMed Central

Turco, Anne E.; Gottschalk, Adam; Halberg, Richard B.; Guo, Jinjin; McMahon, Jill A.; McMahon, Andrew P.

2017-01-01

Though many methods can be used to identify cell types contained in complex tissues, most require cell disaggregation and destroy information about where cells reside in relation to their microenvironment. Here, we describe a polytomous key for cell type identification in intact sections of adult mouse prostate and prostatic urethra. The key is organized as a decision tree and initiates with one round of immunostaining for nerve, epithelial, fibromuscular/hematolymphoid, or vascular associated cells. Cell identities are recursively eliminated by subsequent staining events until the remaining pool of potential cell types can be distinguished by direct comparison to other cells. We validated our identification key using wild type adult mouse prostate and urethra tissue sections and it currently resolves sixteen distinct cell populations which include three nerve fiber types as well as four epithelial, five fibromuscular/hematolymphoid, one nerve-associated, and three vascular-associated cell types. We demonstrate two uses of this novel identification methodology. We first used the identification key to characterize prostate stromal cell type changes in response to constitutive phosphatidylinositide-3-kinase activation in prostate epithelium. We then used the key to map cell lineages in a new reporter mouse strain driven by Wnt10aem1(cre/ERT2)Amc. The identification key facilitates rigorous and reproducible cell identification in prostate tissue sections and can be expanded to resolve additional cell types as new antibodies and other resources become available. PMID:29145476

Ablation of Mouse Adult Neurogenesis Alters Olfactory Bulb Structure and Olfactory Fear Conditioning

PubMed Central

Valley, Matthew T.; Mullen, Tanner R.; Schultz, Lucy C.; Sagdullaev, Botir T.; Firestein, Stuart

2009-01-01

Adult neurogenesis replenishes olfactory bulb (OB) interneurons throughout the life of most mammals, yet during this constant flux it remains unclear how the OB maintains a constant structure and function. In the mouse OB, we investigated the dynamics of turnover and its impact on olfactory function by ablating adult neurogenesis with an x-ray lesion to the sub-ventricular zone (SVZ). Regardless of the magnitude of the lesion to the SVZ, we found no change in the survival of young adult born granule cells (GCs) born after the lesion, and a gradual decrease in the population of GCs born before the lesion. After a lesion producing a 96% reduction of incoming adult born GCs to the OB, we found a diminished behavioral fear response to conditioned odor cues but not to audio cues. Interestingly, despite this behavioral deficit and gradual anatomical changes, we found no electrophysiological changes in the GC population assayed in vivo through dendro-dendritic synaptic plasticity and odor-evoked local field potential oscillations. These data indicate that turnover in the granule cell layer is generally decoupled from the rate of adult neurogenesis, and that OB adult neurogenesis plays a role in a wide behavioral system extending beyond the OB. PMID:20582278

CD24-Positive Cells from Normal Adult Mouse Liver Are Hepatocyte Progenitor Cells

PubMed Central

Qiu, Qiong; Hernandez, Julio Cesar; Dean, Adam M.; Rao, Pulivarthi H.

2011-01-01

The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45−, Ter119−) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes. PMID:21361791

CD24-positive cells from normal adult mouse liver are hepatocyte progenitor cells.

PubMed

Qiu, Qiong; Hernandez, Julio Cesar; Dean, Adam M; Rao, Pulivarthi H; Darlington, Gretchen J

2011-12-01

The identification of specific cell surface markers that can be used to isolate liver progenitor cells will greatly facilitate experimentation to determine the role of these cells in liver regeneration and their potential for therapeutic transplantation. Previously, the cell surface marker, CD24, was observed to be expressed on undifferentiated bipotential mouse embryonic liver stem cells and 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced oval cells. Here, we describe the isolation and characterization of a rare, primary, nonhematopoietic, CD24+ progenitor cell population from normal, untreated mouse liver. By immunohistochemistry, CD24-expressing cells in normal adult mouse liver were colocalized with CK19-positive cholangiocytes. This nonhematopoietic (CD45-, Ter119-) CD24+ cell population isolated by flow cytometry represented 0.04% of liver cells and expressed several markers of liver progenitor/oval cells. The immunophenotype of nonhematopoietic CD24+ cells was CD133, Dlk, and Sca-1 high, but c-Kit, Thy-1, and CD34 low. The CD24+ cells had increased expression of CK19, epithelial cell adhesion molecule, Sox 9, and FN14 compared with the unsorted cells. Upon transplantation of nonhematopoietic CD24+ cells under the sub-capsule of the livers of Fah knockout mice, cells differentiated into mature functional hepatocytes. Analysis of X and Y chromosome complements were used to determine whether or not fusion of the engrafted cells with the recipient hepatocytes occurred. No cells were found that contained XXXY or any other combination of donor and host sex chromosomes as would be expected if cell fusion had occurred. These results suggested that CD24 can be used as a cell surface marker for isolation of hepatocyte progenitor cells from normal adult liver that are able to differentiate into hepatocytes.

Spinal Nerve Root Haemangioblastoma Associated with Reactive Polycythemia

PubMed Central

Law, Eric K. C.; Lee, Ryan K. L.; Griffith, James F.; Siu, Deyond Y. W.; Ng, Ho Keung

2014-01-01

Haemangioblastomas are uncommon tumours that usually occur in the cerebellum and, less commonly, in the intramedullary spinal cord. The extramedullary spinal canal is an uncommon location for these tumours. Also haemangioblastoma at this site is not known to be associated with polycythemia. We present the clinical, imaging, and histological findings of an adult patient with extramedullary spinal haemangioblastoma and reactive polycythemia. Radiography and computed tomography (CT) revealed a medium-sized tumour that most likely arose from an extramedullary spinal nerve root. This tumour appeared to be slow growing as evidenced by the accompanying well-defined bony resorption with a sclerotic rim and mild neural foraminal widening. Magnetic resonance imaging revealed prominent flow voids consistent with tumoural hypervascularity. CT-guided biopsy was performed. Although preoperative angiographic embolisation was technically successful, excessive intraoperative tumour bleeding necessitated tumour debulking rather than complete tumour resection. Histology of the resected specimen revealed haemangioblastoma. Seven months postoperatively, the patients back pain and polycythemia have resolved. PMID:25431722

Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin.

PubMed

Pivetta, Chiara; Esposito, Maria Soledad; Sigrist, Markus; Arber, Silvia

2014-01-30

Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement. Copyright © 2014 Elsevier Inc. All rights reserved.

Long-Distance Axonal Growth from Human Induced Pluripotent Stem Cells After Spinal Cord Injury

PubMed Central

Lu, Paul; Woodruff, Grace; Wang, Yaozhi; Graham, Lori; Hunt, Matt; Wu, Di; Boehle, Eileen; Ahmad, Ruhel; Poplawski, Gunnar; Brock, John; Goldstein, Lawrence S. B.; Tuszynski, Mark H.

2014-01-01

Human induced pluripotent stem cells (iPSCs) from a healthy 86 year-old male were differentiated into neural stem cells and grafted into adult immunodeficient rats after spinal cord injury. Three months after C5 lateral hemisections, iPSCs survived and differentiated into neurons and glia, and extended tens of thousands of axons from the lesion site over virtually the entire length of the rat central nervous system. These iPSC-derived axons extended through adult white matter of the injured spinal cord, frequently penetrating gray matter and forming synapses with rat neurons. In turn, host supraspinal motor axons penetrated human iPSC grafts and formed synapses. These findings indicate that intrinsic neuronal mechanisms readily overcome the inhibitory milieu of the adult injured spinal cord to extend many axons over very long distances; these capabilities persist even in neurons reprogrammed from very aged human cells. PMID:25123310

Antisense reduction of tau in adult mice protects against seizures.

PubMed

DeVos, Sarah L; Goncharoff, Dustin K; Chen, Guo; Kebodeaux, Carey S; Yamada, Kaoru; Stewart, Floy R; Schuler, Dorothy R; Maloney, Susan E; Wozniak, David F; Rigo, Frank; Bennett, C Frank; Cirrito, John R; Holtzman, David M; Miller, Timothy M

2013-07-31

Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS--brain and spinal cord tissue, interstitial fluid, and CSF--while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.

Management of lumbar spinal stenosis.

PubMed

Lurie, Jon; Tomkins-Lane, Christy

2016-01-04

Lumbar spinal stenosis (LSS) affects more than 200,000 adults in the United States, resulting in substantial pain and disability. It is the most common reason for spinal surgery in patients over 65 years. Lumbar spinal stenosis is a clinical syndrome of pain in the buttocks or lower extremities, with or without back pain. It is associated with reduced space available for the neural and vascular elements of the lumbar spine. The condition is often exacerbated by standing, walking, or lumbar extension and relieved by forward flexion, sitting, or recumbency. Clinical care and research into lumbar spinal stenosis is complicated by the heterogeneity of the condition, the lack of standard criteria for diagnosis and inclusion in studies, and high rates of anatomic stenosis on imaging studies in older people who are completely asymptomatic. The options for non-surgical management include drugs, physiotherapy, spinal injections, lifestyle modification, and multidisciplinary rehabilitation. However, few high quality randomized trials have looked at conservative management. A systematic review concluded that there is insufficient evidence to recommend any specific type of non-surgical treatment. Several different surgical procedures are used to treat patients who do not improve with non-operative therapies. Given that rapid deterioration is rare and that symptoms often wax and wane or gradually improve, surgery is almost always elective and considered only if sufficiently bothersome symptoms persist despite trials of less invasive interventions. Outcomes (leg pain and disability) seem to be better for surgery than for non-operative treatment, but the evidence is heterogeneous and often of limited quality. © BMJ Publishing Group Ltd 2015.

VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models.

PubMed

Hadwen, Jeremiah; MacKenzie, Duncan; Shamim, Fahad; Mongeon, Kevin; Holcik, Martin; MacKenzie, Alex; Farooq, Faraz

2014-01-09

Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA. Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models. Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target.

Early functional impairment of sensory-motor connectivity in a mouse model of spinal muscular atrophy

PubMed Central

Mentis, George Z.; Blivis, Dvir; Liu, Wenfang; Drobac, Estelle; Crowder, Melissa E.; Kong, Lingling; Alvarez, Francisco J.; Sumner, Charlotte J.; O'Donovan, Michael J.

2011-01-01

SUMMARY To define alterations of neuronal connectivity that occur during motor neuron degeneration, we characterized the function and structure of spinal circuitry in spinal muscular atrophy (SMA) model mice. SMA motor neurons show reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites. These abnormalities occur at an early stage of disease in motor neurons innervating proximal hindlimb muscles and medial motor neurons innervating axial muscles, but only at end-stage disease in motor neurons innervating distal hindlimb muscles. Motor neuron loss follows afferent synapse loss with the same temporal and topographical pattern. Trichostatin A, which improves motor behavior and survival of SMA mice, partially restores spinal reflexes illustrating the reversibility of these synaptic defects. De-afferentation of motor neurons is an early event in SMA and may be a primary cause of motor dysfunction that is amenable to therapeutic intervention. PMID:21315257

Function of GATA Factors in the Adult Mouse Liver

PubMed Central

Zheng, Rena; Rebolledo-Jaramillo, Boris; Zong, Yiwei; Wang, Liqing; Russo, Pierre; Hancock, Wayne; Stanger, Ben Z.; Hardison, Ross C.; Blobel, Gerd A.

2013-01-01

GATA transcription factors and their Friend of Gata (FOG) cofactors control the development of diverse tissues. GATA4 and GATA6 are essential for the expansion of the embryonic liver bud, but their expression patterns and functions in the adult liver are unclear. We characterized the expression of GATA and FOG factors in whole mouse liver and purified hepatocytes. GATA4, GATA6, and FOG1 are the most prominently expressed family members in whole liver and hepatocytes. GATA4 chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq) identified 4409 occupied sites, associated with genes enriched in ontologies related to liver function, including lipid and glucose metabolism. However, hepatocyte-specific excision of Gata4 had little impact on gross liver architecture and function, even under conditions of regenerative stress, and, despite the large number of GATA4 occupied genes, resulted in relatively few changes in gene expression. To address possible redundancy between GATA4 and GATA6, both factors were conditionally excised. Surprisingly, combined Gata4,6 loss did not exacerbate the phenotype resulting from Gata4 loss alone. This points to the presence of an unusually robust transcriptional network in adult hepatocytes that ensures the maintenance of liver function. PMID:24367609

Nonreciprocal mechanisms in up- and downregulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels.

PubMed

Lombardo, Joseph; Harrington, Melissa A

2016-11-01

KCNQ/K v 7 channels form a slow noninactivating K + current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/K v 7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K + current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/K v 7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/K v 7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/K v 7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/K v 7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/K v 7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/K v 7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/K v 7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners. Copyright © 2016 the American Physiological Society.

Adeno-associated virus-mediated gene delivery into the scala media of the normal and deafened adult mouse ear.

PubMed

Kilpatrick, L A; Li, Q; Yang, J; Goddard, J C; Fekete, D M; Lang, H

2011-06-01

Murine models are ideal for studying cochlear gene transfer, as many hearing loss-related mutations have been discovered and mapped within the mouse genome. However, because of the small size and delicate nature, the membranous labyrinth of the mouse is a challenging target for the delivery of viral vectors. To minimize injection trauma, we developed a procedure for the controlled release of adeno-associated viruses (AAVs) into the scala media of adult mice. This procedure poses minimal risk of injury to structures of the cochlea and middle ear, and allows for near-complete preservation of low and middle frequency hearing. In this study, transduction efficiency and cellular specificity of AAV vectors (serotypes 1, 2, 5, 6 and 8) were investigated in normal and drug-deafened ears. Using the cytomegalovirus promoter to drive gene expression, a variety of cell types were transduced successfully, including sensory hair cells and supporting cells, as well as cells in the auditory nerve and spiral ligament. Among all five serotypes, inner hair cells were the most effectively transduced cochlear cell type. All five serotypes of AAV vectors transduced cells of the auditory nerve, though serotype 8 was the most efficient vector for transduction. Our findings indicate that efficient AAV inoculation (via the scala media) can be performed in adult mouse ears, with hearing preservation a realistic goal. The procedure we describe may also have applications for intra-endolymphatic drug delivery in many mouse models of human deafness.

Adeno-associated virus-mediated gene delivery into the scala media of the normal and deafened adult mouse ear

PubMed Central

Kilpatrick, Lauren A.; Li, Qian; Yang, John; Goddard, John C; Fekete, Donna M.; Lang, Hainan

2010-01-01

Murine models are ideal for studying cochlear gene transfer as many hearing loss-related mutations have been discovered and mapped within the mouse genome. However, due to its small size and delicate nature, the membranous labyrinth of the mouse is a challenging target for delivery of viral vectors. To minimize injection trauma, we developed a procedure for the controlled release of adeno-associated viruses (AAV) into the scala media of adult mice. This procedure poses minimal risk of injury to structures of the cochlea and middle ear and allows for near-complete preservation of low and middle frequency hearing. In the present study, transduction efficiency and cellular specificity of AAV vectors (serotypes 1, 2, 5, 6, and 8) were investigated in normal and drug-deafened ears. Using the cytomegalovirus (CMV) promoter to drive gene expression, a variety of cell types were transduced successfully, including sensory hair cells and supporting cells, as well as cells in the auditory nerve and spiral ligament. Among all five serotypes, inner hair cells (IHCs) were the most effectively transduced cochlear cell type. All five serotypes of AAV vectors transduced cells of the auditory nerve, though serotype 8 was the most efficient vector for transduction. Our findings indicate that efficient AAV inoculation (via the scala media) can be performed in adult mouse ears, with hearing preservation a realistic goal. The procedure we describe may also have applications for intra-endolymphatic drug delivery in many mouse models of human deafness. PMID:21209625

Delayed grafting of fetal CNS tissue into chronic compression lesions of the adult cat spinal cord.

PubMed

Anderson, D K; Reier, P J; Wirth Iii, E D; Theele, D P; Mareci, T; Brown, S A

1991-01-01

This review summarizes a series of experiments involving transplants of embryonic feline CNS tissue into chronic compression lesions of the adult cat spinal cord. Fetal spinal cord (FSC), caudal brainstem (BSt), neocortex (NCx) or a combination of either FSC/NCx or FSC/BSt was transplanted as solid pieces or as a suspension of dissociated cells into the developed cystic cavities produced by static-load compression trauma 2-10 weeks prior to grafting. All cats were immunosuppressed with cyclosporin A and their locomotor function was assessed for 6-30 weeks. Following the period of evaluation, all recipients were perfused with fixative and tissue specimens, taken at the transplantation site, were processed for general histological and/or immunocytochemical analysis. Viable graft tissue was found in all animals with the exception of two cats which showed active rejection of their transplants. All of the viable intraspinal grafts were extensively vascularized and did not show any signs of imminent or on-going tissue rejection. Fetal cat CNS grafts showed an extended maturational phase in that features of immature neural tissue (e.g. a paucity of myelination) were still seen even 6-9 weeks after transplantation. By 20-30 weeks, FSC and BSt grafts had attained a more advanced stage of maturation. Transplants in these chronic lesions were extensively blended with both the gray and white matter of the host spinal cord and could be visualized by magnetic resonance imaging (MRI). MRI could also detect regions of cavitation at the graft-host interface, as well as within some transplants. While preliminary evidence from behavioral studies suggest that the FSC and BSt grafts may improve or spare locomotor function in some recipients, a more rigorous analysis of post-grafting locomotor function is required to determine conclusively the functionality of these transplants.

Regenerative Potential of Ependymal Cells for Spinal Cord Injuries Over Time.

PubMed

Li, Xiaofei; Floriddia, Elisa M; Toskas, Konstantinos; Fernandes, Karl J L; Guérout, Nicolas; Barnabé-Heider, Fanie

2016-11-01

Stem cells have a high therapeutic potential for the treatment of spinal cord injury (SCI). We have shown previously that endogenous stem cell potential is confined to ependymal cells in the adult spinal cord which could be targeted for non-invasive SCI therapy. However, ependymal cells are an understudied cell population. Taking advantage of transgenic lines, we characterize the appearance and potential of ependymal cells during development. We show that spinal cord stem cell potential in vitro is contained within these cells by birth. Moreover, juvenile cultures generate more neurospheres and more oligodendrocytes than adult ones. Interestingly, juvenile ependymal cells in vivo contribute to glial scar formation after severe but not mild SCI, due to a more effective sealing of the lesion by other glial cells. This study highlights the importance of the age-dependent potential of stem cells and post-SCI environment in order to utilize ependymal cell's regenerative potential. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Intradetrusor injections of botulinum toxin A in adult patients with spinal dysraphism.

PubMed

Peyronnet, Benoit; Even, Alexia; Capon, Grégoire; de Seze, Marianne; Hascoet, Juliette; Biardeau, Xavier; Baron, Maximilien; Perrouin-Verbe, Marie-Aimée; Boutin, Jean-Michel; Saussine, Christian; Phé, Véronique; Lenormand, Loic; Chartier-Kastler, Emmanuel; Cornu, Jean-Nicolas; Karsenty, Gilles; Manunta, Andrea; Schurch, Brigitte; Denys, Pierre; Amarenco, Gérard; Game, Xavier

2018-05-07

The aim of the present study was to report the outcomes of botulinum toxin A (BTX-A) intradetrusor injections in adult patients with spina bifida. All patients with spinal dysraphism who had undergone intradetrusor injections of BTX-A from 2002 to 2016 in 14 centers were included retrospectively. The primary endpoint was the global success of injections, defined subjectively as the combination of urgency, urinary incontinence and detrusor overactivity/low bladder compliance resolution. Univariate and multivariate analysis were performed to seek for predictors of global success. 125 patients were included with a global success rate of the first injection was 62.3% with resolution of urinary incontinence in 73.5% of patients. All urodynamic parameters improved significantly at 6-8 weeks compared to baseline including maximum detrusor pressure (-12 cmH2O; p<0.001), maximum cystometric capacity (+86.6 ml ; p<0.001) and compliance (+8.9 ml/cmH2O ; p=0.002). Out of 561 intradetrusor BTX-A injections, 20 complications were recorded (3.6%) with three muscular weaknesses. Global success rate of the first injection was significantly lower in case of poor compliance (34.4% vs. 86.9%; OR=0.08; p<0.001). In multivariate analysis, poor compliance was associated with lower global success rate (OR=0.13; p<0.001) and female gender (OR=3.53; p=0.01) and age (OR=39.9; p<0.001) were predictors of global success. Intradetrusor BTX-A injections were effective in adult spina bifida patients exhibiting detrusor overactivity. In contrast, the effectiveness was much lower in adult spina bifida patients with poor bladder compliance. The other predictors of global success were female gender and older age. Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Whole-Mount Adult Ear Skin Imaging Reveals Defective Neuro-Vascular Branching Morphogenesis in Obese and Type 2 Diabetic Mouse Models.

PubMed

Yamazaki, Tomoko; Li, Wenling; Yang, Ling; Li, Ping; Cao, Haiming; Motegi, Sei-Ichiro; Udey, Mark C; Bernhard, Elise; Nakamura, Takahisa; Mukouyama, Yoh-Suke

2018-01-11

Obesity and type 2 diabetes are frequently associated with peripheral neuropathy. Though there are multiple methods for diagnosis and analysis of morphological changes of peripheral nerves and blood vessels, three-dimensional high-resolution imaging is necessary to appreciate the pathogenesis with an anatomically recognizable branching morphogenesis and patterning. Here we established a novel technique for whole-mount imaging of adult mouse ear skin to visualize branching morphogenesis and patterning of peripheral nerves and blood vessels. Whole-mount immunostaining of adult mouse ear skin showed that peripheral sensory and sympathetic nerves align with large-diameter blood vessels. Diet-induced obesity (DIO) mice exhibit defective vascular smooth muscle cells (VSMCs) coverage, while there is no significant change in the amount of peripheral nerves. The leptin receptor-deficient db/db mice, a severe obese and type 2 diabetic mouse model, exhibit defective VSMC coverage and a large increase in the amount of smaller-diameter nerve bundles with myelin sheath and unmyelinated nerve fibers. Interestingly, an increase in the amount of myeloid immune cells was observed in the DIO but not db/db mouse skin. These data suggest that our whole-mount imaging method enables us to investigate the neuro-vascular and neuro-immune phenotypes in the animal models of obesity and diabetes.

Vestibular lesion-induced developmental plasticity in spinal locomotor networks during Xenopus laevis metamorphosis.

PubMed

Beyeler, Anna; Rao, Guillaume; Ladepeche, Laurent; Jacques, André; Simmers, John; Le Ray, Didier

2013-01-01

During frog metamorphosis, the vestibular sensory system remains unchanged, while spinal motor networks undergo a massive restructuring associated with the transition from the larval to adult biomechanical system. We investigated in Xenopus laevis the impact of a pre- (tadpole stage) or post-metamorphosis (juvenile stage) unilateral labyrinthectomy (UL) on young adult swimming performance and underlying spinal locomotor circuitry. The acute disruptive effects on locomotion were similar in both tadpoles and juvenile frogs. However, animals that had metamorphosed with a preceding UL expressed restored swimming behavior at the juvenile stage, whereas animals lesioned after metamorphosis never recovered. Whilst kinematic and electrophysiological analyses of the propulsive system showed no significant differences in either juvenile group, a 3D biomechanical simulation suggested that an asymmetry in the dynamic control of posture during swimming could account for the behavioral restoration observed in animals that had been labyrinthectomized before metamorphosis. This hypothesis was subsequently supported by in vivo electromyography during free swimming and in vitro recordings from isolated brainstem/spinal cord preparations. Specifically, animals lesioned prior to metamorphosis at the larval stage exhibited an asymmetrical propulsion/posture coupling as a post-metamorphic young adult. This developmental alteration was accompanied by an ipsilesional decrease in propriospinal coordination that is normally established in strict left-right symmetry during metamorphosis in order to synchronize dorsal trunk muscle contractions with bilateral hindlimb extensions in the swimming adult. Our data thus suggest that a disequilibrium in descending vestibulospinal information during Xenopus metamorphosis leads to an altered assembly of adult spinal locomotor circuitry. This in turn enables an adaptive compensation for the dynamic postural asymmetry induced by the vestibular imbalance

Spinal Cord Lesions in Congenital Toxoplasmosis Demonstrated with Neuroimaging, Including Their Successful Treatment in an Adult.

PubMed

Burrowes, Delilah; Boyer, Kenneth; Swisher, Charles N; Noble, A Gwendolyn; Sautter, Mari; Heydemann, Peter; Rabiah, Peter; Lee, Daniel; McLeod, Rima

2012-03-01

Neuroimaging studies for persons in the National Collaborative Chicago-Based Congenital Toxoplasmosis Study (NCCCTS) with symptoms and signs referable to the spinal cord were reviewed. Three infants had symptomatic spinal cord lesions, another infant a Chiari malformation, and another infant a symptomatic peri-spinal cord lipoma. One patient had an unusual history of prolonged spinal cord symptoms presenting in middle age. Neuroimaging was used to establish her diagnosis and response to treatment. This 43 year-old woman with congenital toxoplasmosis developed progressive leg spasticity, weakness, numbness, difficulty walking, and decreased visual acuity and color vision without documented re-activation of her chorioretinal disease. At 52 years of age, spinal cord lesions in locations correlating with her symptoms and optic atrophy were diagnosed with 3 Tesla MRI scan. Treatment with pyrimethamine and sulfadiazine decreased her neurologic symptoms, improved her neurologic examination, and resolved her enhancing spinal cord lesions seen on MRI.

Provider Adherence to Implementation of Clinical Practice Guidelines for Neurogenic Bowel in Adults With Spinal Cord Injury

PubMed Central

Goetz, Lance L; Nelson, Audrey L; Guihan, Marylou; Bosshart, Helen T; Harrow, Jeffrey J; Gerhart, Kevin D; Krasnicka, Barbara; Burns, Stephen P

2005-01-01

Background/Objectives: Clinical Practice Guidelines (CPGs) have been published on a number of topics in spinal cord injury (SCI) medicine. Research in the general medical literature shows that the distribution of CPGs has a minimal effect on physician practice without targeted implementation strategies. The purpose of this study was to determine (a) whether dissemination of an SCI CPG improved the likelihood that patients would receive CPG recommended care and (b) whether adherence to CPG recommendations could be improved through a targeted implementation strategy. Specifically, this study addressed the “Neurogenic Bowel Management in Adults with Spinal Cord Injury” Clinical Practice Guideline published in March 1998 by the Consortium for Spinal Cord Medicine Methods: CPG adherence was determined from medical record review at 6 Veterans Affairs SCI centers for 3 time periods: before guideline publication (T1), after guideline publication but before CPG implementation (T2), and after targeted CPG implementation (T3). Specific implementation strategies to enhance guideline adherence were chosen to address the barriers identified by SCI providers in focus groups before the intervention. Results: Overall adherence to recommendations related to neurogenic bowel did not change between T1 and T2 (P = not significant) but increased significantly between T2 and T3 (P < 0.001) for 3 of 6 guideline recommendations. For the other 3 guideline recommendations, adherence rates were noted to be high at T1. Conclusions: While publication of the CPG alone did not alter rates of provider adherence, the use of a targeted implementation plan resulted in increases in adherence rates with some (3 of 6) CPG recommendations for neurogenic bowel management. PMID:16869086

Developmental regulation of N-methyl-D-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord

NASA Technical Reports Server (NTRS)

Stegenga, S. L.; Kalb, R. G.

2001-01-01

Spinal motor neurons undergo experience-dependent development during a critical period in early postnatal life. It has been suggested that the repertoire of glutamate receptor subunits differs between young and mature motor neurons and contributes to this activity-dependent development. In the present study we examined the expression patterns of N-methyl-D-aspartate- and kainate-type glutamate receptor subunits during the postnatal maturation of the spinal cord. Young motor neurons express much higher levels of the N-methyl-D-aspartate receptor subunit NR1 than do adult motor neurons. Although there are eight potential splice variants of NR1, only a subgroup is expressed by motor neurons. With respect to NR2 receptor subunits, young motor neurons express NR2A and C, while adult motor neurons express only NR2A. Young motor neurons express kainate receptor subunits GluR5, 6 and KA2 but we are unable to detect these or any other kainate receptor subunits in the adult spinal cord. Other spinal cord regions display a distinct pattern of developmental regulation of N-methyl-D-aspartate and kainate receptor subunit expression in comparison to motor neurons. Our findings indicate a precise spatio-temporal regulation of individual subunit expression in the developing spinal cord. Specific combinations of subunits in developing neurons influence their excitable properties and could participate in the emergence of adult neuronal form and function.

Bimanual reach to grasp movements after cervical spinal cord injury.

PubMed

Britten, Laura; Coats, Rachel; Ichiyama, Ronaldo; Raza, Wajid; Jamil, Firas; Astill, Sarah

2017-01-01

Injury to the cervical spinal cord results in bilateral deficits in arm/hand function reducing functional independence and quality of life. To date little research has been undertaken to investigate control strategies of arm/hand movements following cervical spinal cord injury (cSCI). This study aimed to investigate unimanual and bimanual coordination in patients with acute cSCI using 3D kinematic analysis as they performed naturalistic reach to grasp actions with one hand, or with both hands together (symmetrical task), and compare this to the movement patterns of uninjured younger and older adults. Eighteen adults with a cSCI (mean 61.61 years) with lesions at C4-C8, with an American Spinal Injury Association (ASIA) grade B to D and 16 uninjured younger adults (mean 23.68 years) and sixteen uninjured older adults (mean 70.92 years) were recruited. Participants with a cSCI produced reach-to-grasp actions which took longer, were slower, and had longer deceleration phases than uninjured participants. These differences were exacerbated during bimanual reach-to-grasp tasks. Maximal grasp aperture was no different between groups, but reached earlier by people with cSCI. Participants with a cSCI were less synchronous than younger and older adults but all groups used the deceleration phase for error correction to end the movement in a synchronous fashion. Overall, this study suggests that after cSCI a level of bimanual coordination is retained. While there seems to be a greater reliance on feedback to produce both the reach to grasp, we observed minimal disruption of the more impaired limb on the less impaired limb. This suggests that bimanual movements should be integrated into therapy.

Astrocytes influence the severity of spinal muscular atrophy

PubMed Central

Rindt, Hansjörg; Feng, Zhihua; Mazzasette, Chiara; Glascock, Jacqueline J.; Valdivia, David; Pyles, Noah; Crawford, Thomas O.; Swoboda, Kathryn J.; Patitucci, Teresa N.; Ebert, Allison D.; Sumner, Charlotte J.; Ko, Chien-Ping; Lorson, Christian L.

2015-01-01

Systemically low levels of survival motor neuron-1 (SMN1) protein cause spinal muscular atrophy (SMA). α-Motor neurons of the spinal cord are considered particularly vulnerable in this genetic disorder and their dysfunction and loss cause progressive muscle weakness, paralysis and eventually premature death of afflicted individuals. Historically, SMA was therefore considered a motor neuron-autonomous disease. However, depletion of SMN in motor neurons of normal mice elicited only a very mild phenotype. Conversely, restoration of SMN to motor neurons in an SMA mouse model had only modest effects on the SMA phenotype and survival. Collectively, these results suggested that additional cell types contribute to the pathogenesis of SMA, and understanding the non-autonomous requirements is crucial for developing effective therapies. Astrocytes are critical for regulating synapse formation and function as well as metabolic support for neurons. We hypothesized that astrocyte functions are disrupted in SMA, exacerbating disease progression. Using viral-based restoration of SMN specifically to astrocytes, survival in severe and intermediate SMA mice was observed. In addition, neuromuscular circuitry was improved. Astrogliosis was prominent in end-stage SMA mice and in post-mortem patient spinal cords. Increased expression of proinflammatory cytokines was partially normalized in treated mice, suggesting that astrocytes contribute to the pathogenesis of SMA. PMID:25911676

Oligodendrocyte- and Neuron-Specific Nogo-A Restrict Dendritic Branching and Spine Density in the Adult Mouse Motor Cortex.

PubMed

Zemmar, Ajmal; Chen, Chia-Chien; Weinmann, Oliver; Kast, Brigitt; Vajda, Flora; Bozeman, James; Isaad, Noel; Zuo, Yi; Schwab, Martin E

2018-06-01

Nogo-A has been well described as a myelin-associated inhibitor of neurite outgrowth and functional neuroregeneration after central nervous system (CNS) injury. Recently, a new role of Nogo-A has been identified as a negative regulator of synaptic plasticity in the uninjured adult CNS. Nogo-A is present in neurons and oligodendrocytes. However, it is yet unclear which of these two pools regulate synaptic plasticity. To address this question we used newly generated mouse lines in which Nogo-A is specifically knocked out in (1) oligodendrocytes (oligoNogo-A KO) or (2) neurons (neuroNogo-A KO). We show that both oligodendrocyte- and neuron-specific Nogo-A KO mice have enhanced dendritic branching and spine densities in layer 2/3 cortical pyramidal neurons. These effects are compartmentalized: neuronal Nogo-A affects proximal dendrites whereas oligodendrocytic Nogo-A affects distal regions. Finally, we used two-photon laser scanning microscopy to measure the spine turnover rate of adult mouse motor cortex layer 5 cells and find that both Nogo-A KO mouse lines show enhanced spine remodeling after 4 days. Our results suggest relevant control functions of glial as well as neuronal Nogo-A for synaptic plasticity and open new possibilities for more selective and targeted plasticity enhancing strategies.

Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice

PubMed Central

Deguise, Marc-Olivier; De Repentigny, Yves; McFall, Emily; Auclair, Nicole; Sad, Subash

2017-01-01

Abstract Spinal muscular atrophy (SMA) has long been solely considered a neurodegenerative disorder. However, recent work has highlighted defects in many other cell types that could contribute to disease aetiology. Interestingly, the immune system has never been extensively studied in SMA. Defects in lymphoid organs could exacerbate disease progression by neuroinflammation or immunodeficiency. Smn depletion led to severe alterations in the thymus and spleen of two different mouse models of SMA. The spleen from Smn depleted mice was dramatically smaller at a very young age and its histological architecture was marked by mislocalization of immune cells in the Smn2B/- model mice. In comparison, the thymus was relatively spared in gross morphology but showed many histological alterations including cortex thinning in both mouse models at symptomatic ages. Thymocyte development was also impaired as evidenced by abnormal population frequencies in the Smn2B/- thymus. Cytokine profiling revealed major changes in different tissues of both mouse models. Consistent with our observations, we found that survival motor neuron (Smn) protein levels were relatively high in lymphoid organs compared to skeletal muscle and spinal cord during postnatal development in wild type mice. Genetic introduction of one copy of the human SMN2 transgene was enough to rescue splenic and thymic defects in Smn2B/- mice. Thus, Smn is required for the normal development of lymphoid organs, and altered immune function may contribute to SMA disease pathogenesis. PMID:28108555

Biciliated ependymal cell proliferation contributes to spinal cord growth

PubMed Central

Alfaro-Cervello, Clara; Soriano-Navarro, Mario; Mirzadeh, Zaman; Alvarez-Buylla, Arturo; Garcia-Verdugo, Jose Manuel

2013-01-01

Two neurogenic regions have been described in the adult brain, the lateral ventricle subventricular zone and the dentate gyrus subgranular zone. It has been suggested that neural stem cells also line the central canal of the adult spinal cord. Using transmission and scanning electron microscopy and immunostaining, we describe here the organization and cell types of the central canal epithelium in adult mice. The identity of dividing cells was determined by three-dimensional ultrastructural reconstructions of [3H]thymidine-labeled cells and confocal analysis of bromodeoxyuridine labeling. The most common cell type lining the central canal had two long motile (9+2) cilia and was vimentin+, CD24+, FoxJ1+, Sox2+ and CD133+, but nestin- and glial fibrillary acidic protein (GFAP)-. These biciliated ependymal cells of the central canal (Ecc) resembled E2 cells of the lateral ventricles, but their basal bodies were different from that of E2 or E1 cells. Interestingly, we frequently found Ecc cells with two nuclei and four cilia, suggesting they are formed by incomplete cytokinesis or cell fusion. GFAP+ astrocytes with a single cilium and an orthogonally oriented centriole were also observed. The majority of dividing cells corresponded to biciliated Ecc cells. Central canal proliferation was most common during the active period of spinal cord growth. Pairs of labeled Ecc cells were observed within the central canal in adult mice 2.5 weeks post-labeling. Our work suggests that the vast majority of postnatal dividing cells in the central canal are Ecc cells and their proliferation is associated with the growth of the spinal cord. PMID:22434575

Spinal Implant Density and Postoperative Lumbar Lordosis as Predictors for the Development of Proximal Junctional Kyphosis in Adult Spinal Deformity.

PubMed

McClendon, Jamal; Smith, Timothy R; Sugrue, Patrick A; Thompson, Sara E; O'Shaughnessy, Brian A; Koski, Tyler R

2016-11-01

To evaluate spinal implant density and proximal junctional kyphosis (PJK) in adult spinal deformity (ASD). Consecutive patients with ASD receiving ≥5 level fusions were retrospectively analyzed between 2007 and 2010. ASD, elective fusions, minimum 2-year follow-up. age <18 years, neuromuscular or congenital scoliosis, cervical or cervicothoracic fusions, nonelective conditions (infection, tumor, trauma). Instrumented fusions were classified by the Scoliosis Research Society-Schwab ASD classification. Statistical analysis consisted of descriptives (measures of central tendency, dispersion, frequencies), independent Student t tests, χ 2 , analysis of variance, and logistic regression to determine association of implant density [(number of screws + number of hooks)/surgical levels of fusion] and PJK. Mean and median follow-up was 2.8 and 2.7 years, respectively. Eighty-three patients (17 male, 66 female) with a mean age of 59.7 years (standard deviation, 10.3) were analyzed. Mean body mass index (BMI) was 29.5 kg/m 2 (range, 18-56 kg/m 2 ) with mean preoperative Oswestry Disability Index of 48.67 (range, 6-86) and mean preoperative sagittal vertical axis of 8.42. The mean levels fused were 9.95 where 54 surgeries had interbody fusion. PJK prevalence was 21.7%, and pseudoarthrosis was 19.3%. Mean postoperative Oswestry Disability Index was 27.4 (range, 0-74). Independent Student t tests showed that PJK was not significant for age, gender, BMI, rod type, mean postoperative sagittal vertical axis, or Scoliosis Research Society-Schwab ASD classification; but iliac fixation approached significance (P = 0.077). Implant density and postoperative lumbar lordosis (LL) were predictors for PJK (P = 0.018 and 0.045, respectively). Controlling for age, BMI, and gender, postoperative LL (not implant density) continued to show significance in multivariate logistic regression model. PJK, although influenced by a multitude of factors, may be statistically related to implant

Squalenoyl adenosine nanoparticles provide neuroprotection after stroke and spinal cord injury

NASA Astrophysics Data System (ADS)

Gaudin, Alice; Yemisci, Müge; Eroglu, Hakan; Lepetre-Mouelhi, Sinda; Turkoglu, Omer Faruk; Dönmez-Demir, Buket; Caban, Seçil; Sargon, Mustafa Fevzi; Garcia-Argote, Sébastien; Pieters, Grégory; Loreau, Olivier; Rousseau, Bernard; Tagit, Oya; Hildebrandt, Niko; Le Dantec, Yannick; Mougin, Julie; Valetti, Sabrina; Chacun, Hélène; Nicolas, Valérie; Desmaële, Didier; Andrieux, Karine; Capan, Yilmaz; Dalkara, Turgay; Couvreur, Patrick

2014-12-01

There is an urgent need to develop new therapeutic approaches for the treatment of severe neurological trauma, such as stroke and spinal cord injuries. However, many drugs with potential neuropharmacological activity, such as adenosine, are inefficient upon systemic administration because of their fast metabolization and rapid clearance from the bloodstream. Here, we show that conjugation of adenosine to the lipid squalene and the subsequent formation of nanoassemblies allows prolonged circulation of this nucleoside, providing neuroprotection in mouse stroke and rat spinal cord injury models. The animals receiving systemic administration of squalenoyl adenosine nanoassemblies showed a significant improvement of their neurologic deficit score in the case of cerebral ischaemia, and an early motor recovery of the hindlimbs in the case of spinal cord injury. Moreover, in vitro and in vivo studies demonstrated that the nanoassemblies were able to extend adenosine circulation and its interaction with the neurovascular unit. This Article shows, for the first time, that a hydrophilic and rapidly metabolized molecule such as adenosine may become pharmacologically efficient owing to a single conjugation with the lipid squalene.

Axonal regeneration in zebrafish spinal cord

PubMed Central

Hui, Subhra Prakash

2018-01-01

Abstract In the present review we discuss two interrelated events—axonal damage and repair—known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals. PMID:29721326

Axonal regeneration in zebrafish spinal cord.

PubMed

Ghosh, Sukla; Hui, Subhra Prakash

2018-03-01

In the present review we discuss two interrelated events-axonal damage and repair-known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals.

[Spinal subarachnoid haematoma after spinal anaesthesia: case report].

PubMed

Vidal, Marion; Strzelecki, Antoine; Houadec, Mireille; Krikken, Isabelle Ranz; Danielli, Antoine; Souza Neto, Edmundo Pereira de

2016-01-01

Subarachnoid haematoma after spinal anaesthesia is known to be very rare. In the majority of these cases, spinal anaesthesia was difficult to perform and/or unsuccessful; other risk factors included antiplatelet or anticoagulation therapy, and direct spinal cord trauma. We report a case of subarachnoid haematoma after spinal anaesthesia in a young patient without risk factors. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Spinal subarachnoid haematoma after spinal anaesthesia: case report.

PubMed

Vidal, Marion; Strzelecki, Antoine; Houadec, Mireille; Krikken, Isabelle Ranz; Danielli, Antoine; Souza Neto, Edmundo Pereira de

2016-01-01

Subarachnoid haematoma after spinal anaesthesia is known to be very rare. In the majority of these cases, spinal anaesthesia was difficult to perform and/or unsuccessful; other risk factors included antiplatelet or anticoagulation therapy, and direct spinal cord trauma. We report a case of subarachnoid haematoma after spinal anaesthesia in a young patient without risk factors. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Neural stem/progenitor cell properties of glial cells in the adult mouse auditory nerve

PubMed Central

Lang, Hainan; Xing, Yazhi; Brown, LaShardai N.; Samuvel, Devadoss J.; Panganiban, Clarisse H.; Havens, Luke T.; Balasubramanian, Sundaravadivel; Wegner, Michael; Krug, Edward L.; Barth, Jeremy L.

2015-01-01

The auditory nerve is the primary conveyor of hearing information from sensory hair cells to the brain. It has been believed that loss of the auditory nerve is irreversible in the adult mammalian ear, resulting in sensorineural hearing loss. We examined the regenerative potential of the auditory nerve in a mouse model of auditory neuropathy. Following neuronal degeneration, quiescent glial cells converted to an activated state showing a decrease in nuclear chromatin condensation, altered histone deacetylase expression and up-regulation of numerous genes associated with neurogenesis or development. Neurosphere formation assays showed that adult auditory nerves contain neural stem/progenitor cells (NSPs) that were within a Sox2-positive glial population. Production of neurospheres from auditory nerve cells was stimulated by acute neuronal injury and hypoxic conditioning. These results demonstrate that a subset of glial cells in the adult auditory nerve exhibit several characteristics of NSPs and are therefore potential targets for promoting auditory nerve regeneration. PMID:26307538

Localized CT-Guided Irradiation Inhibits Neurogenesis in Specific Regions of the Adult Mouse Brain

PubMed Central

Ford, E. C.; Achanta, P.; Purger, D.; Armour, M.; Reyes, J.; Fong, J.; Kleinberg, L.; Redmond, K.; Wong, J.; Jang, M. H.; Jun, H.; Song, H-J.; Quinones-Hinojosa, A.

2011-01-01

Radiation is used in the study of neurogenesis in the adult mouse both as a model for patients undergoing radiation therapy for CNS malignancies and as a tool to interrupt neurogenesis. We describe the use of a dedicated CT-guided precision device to irradiate specific sub-regions of the adult mouse brain. Improved CT visualization was accomplished with intrathecal injection of iodinated contrast agent, which enhances the lateral ventricles. T2-weighted MRI images were also used for target localization. Visualization of delivered beams (10 Gy) in tissue was accomplished with immunohistochemical staining for the protein γ-H2AX, a marker of DNA double-strand breaks. γ-H2AX stains showed that the lateral ventricle wall could be targeted with an accuracy of 0.19 mm (n = 10). In the hippocampus, γ-H2AX staining showed that the dentate gyrus can be irradiated unilaterally with a localized arc treatment. This resulted in a significant decrease of proliferative neural progenitor cells as measured by Ki-67 staining (P < 0.001) while leaving the contralateral side intact. Two months after localized irradiation, neurogenesis was significantly inhibited in the irradiated region as seen with EdU/NeuN double labeling (P < 0.001). Localized radiation in the rodent brain is a promising new tool for the study of neurogenesis. PMID:21449714

The changing balance of brainstem–spinal cord modulation of pain processing over the first weeks of rat postnatal life

PubMed Central

Hathway, G J; Koch, S; Low, L; Fitzgerald, M

2009-01-01

Brainstem–spinal cord connections play an essential role in adult pain processing, and the modulation of spinal pain network excitability by brainstem nuclei is known to contribute to hyperalgesia and chronic pain. Less well understood is the role of descending brainstem pathways in young animals when pain networks are more excitable and exposure to injury and stress can lead to permanent modulation of pain processing. Here we show that up to postnatal day 21 (P21) in the rat, the rostroventral medulla of the brainstem (RVM) exclusively facilitates spinal pain transmission but that after this age (P28 to adult), the influence of the RVM shifts to biphasic facilitation and inhibition. Graded electrical microstimulation of the RVM at different postnatal ages revealed a robust shift in the balance of descending control of both spinal nociceptive flexion reflex EMG activity and individual dorsal horn neuron firing properties, from excitation to inhibition, beginning after P21. The shift in polarity of descending control was also observed following excitotoxic lesions of the RVM in adult and P21 rats. In adults, RVM lesions decreased behavioural mechanical sensory reflex thresholds, whereas the same lesion in P21 rats increased thresholds. These data demonstrate, for the first time, the changing postnatal influence of the RVM in spinal nociception and highlight the central role of descending brainstem control in the maturation of pain processing. PMID:19403624

Peripheral denervation participates in heterotopic ossification in a spinal cord injury model

PubMed Central

Salga, Marjorie; Begot, Laurent; Holy, Xavier; Chedik, Malha; de l’Escalopier, Nicolas; Torossian, Fréderic; Levesque, Jean-Pierre; Lataillade, Jean-Jacques; Le Bousse-Kerdilès, Marie-Caroline; Genêt, François

2017-01-01

We previously reported the development of a new acquired neurogenic HO (NHO) mouse model, combining spinal cord transection (SCI) and chemical muscle injury. Pathological mechanisms responsible for ectopic osteogenesis after central neurological damage are still to be elucidated. In this study, we first hypothesized that peripheral nervous system (PNS) might convey pathological signals from injured spinal cord to muscles in NHO mouse model. Secondly, we sought to determine whether SCI could lead to intramuscular modifications of BMP2 signaling pathways. Twenty one C57Bl6 mice were included in this protocol. Bilateral cardiotoxin (CTX) injection in hamstring muscles was associated with a two-stage surgical procedure, combining thoracic SCI with unilateral peripheral denervation. Volumes of HO (Bone Volume, BV) were measured 28 days after surgery using micro-computed tomography imaging techniques and histological analyses were made to confirm intramuscular osteogenesis. Volume comparisons were conducted between right and left hind limb of each animal, using a Wilcoxon signed rank test. Quantitative polymerase chain reaction (qPCR) was performed to explore intra muscular expression of BMP2, Alk3 and Id1. Nineteen mice survive the complete SCI and peripheral denervation procedure. When CTX injections were done right after surgery (n = 7), bilateral HO were detected in all animals after 28 days. Micro-CT measurements showed significantly increased BV in denervated paws (1.47 mm3 +/- 0.5) compared to contralateral sides (0.56 mm3 +/-0.4), p = 0.03. When peripheral denervation and CTX injections were performed after sham SCI surgery (n = 6), bilateral HO were present in three mice at day 28. Quantitative PCR analyses showed no changes in intra muscular BMP2 expression after SCI as compared to control mice (shamSCI). Peripheral denervation can be reliably added to spinal cord transection in NHO mouse model. This new experimental design confirms that neuro inflammatory

Fully implantable, battery-free wireless optoelectronic devices for spinal optogenetics.

PubMed

Samineni, Vijay K; Yoon, Jangyeol; Crawford, Kaitlyn E; Jeong, Yu Ra; McKenzie, Kajanna C; Shin, Gunchul; Xie, Zhaoqian; Sundaram, Saranya S; Li, Yuhang; Yang, Min Young; Kim, Jeonghyun; Wu, Di; Xue, Yeguang; Feng, Xue; Huang, Yonggang; Mickle, Aaron D; Banks, Anthony; Ha, Jeong Sook; Golden, Judith P; Rogers, John A; Gereau, Robert W

2017-11-01

The advent of optogenetic tools has allowed unprecedented insights into the organization of neuronal networks. Although recently developed technologies have enabled implementation of optogenetics for studies of brain function in freely moving, untethered animals, wireless powering and device durability pose challenges in studies of spinal cord circuits where dynamic, multidimensional motions against hard and soft surrounding tissues can lead to device degradation. We demonstrate here a fully implantable optoelectronic device powered by near-field wireless communication technology, with a thin and flexible open architecture that provides excellent mechanical durability, robust sealing against biofluid penetration and fidelity in wireless activation, thereby allowing for long-term optical stimulation of the spinal cord without constraint on the natural behaviors of the animals. The system consists of a double-layer, rectangular-shaped magnetic coil antenna connected to a microscale inorganic light-emitting diode (μ-ILED) on a thin, flexible probe that can be implanted just above the dura of the mouse spinal cord for effective stimulation of light-sensitive proteins expressed in neurons in the dorsal horn. Wireless optogenetic activation of TRPV1-ChR2 afferents with spinal μ-ILEDs causes nocifensive behaviors and robust real-time place aversion with sustained operation in animals over periods of several weeks to months. The relatively low-cost electronics required for control of the systems, together with the biocompatibility and robust operation of these devices will allow broad application of optogenetics in future studies of spinal circuits, as well as various peripheral targets, in awake, freely moving and untethered animals, where existing approaches have limited utility.

Short term treatment versus long term management of neck and back disability in older adults utilizing spinal manipulative therapy and supervised exercise: a parallel-group randomized clinical trial evaluating relative effectiveness and harms.

PubMed

Vihstadt, Corrie; Maiers, Michele; Westrom, Kristine; Bronfort, Gert; Evans, Roni; Hartvigsen, Jan; Schulz, Craig

2014-01-01

Back and neck disability are frequent in older adults resulting in loss of function and independence. Exercise therapy and manual therapy, like spinal manipulative therapy (SMT), have evidence of short and intermediate term effectiveness for spinal disability in the general population and growing evidence in older adults. For older populations experiencing chronic spinal conditions, long term management may be more appropriate to maintain improvement and minimize the impact of future exacerbations. Research is limited comparing short courses of treatment to long term management of spinal disability. The primary aim is to compare the relative effectiveness of 12 weeks versus 36 weeks of SMT and supervised rehabilitative exercise (SRE) in older adults with back and neck disability. Randomized, mixed-methods, comparative effectiveness trial conducted at a university-affiliated research clinic in the Minneapolis/St. Paul, Minnesota metropolitan area. Independently ambulatory community dwelling adults ≥ 65 years of age with back and neck disability of minimum 12 weeks duration (n = 200). 12 weeks SMT + SRE or 36 weeks SMT + SRE. Blocked 1:1 allocation; computer generated scheme, concealed in sequentially numbered, opaque, sealed envelopes. Functional outcome examiners are blinded to treatment allocation; physical nature of the treatments prevents blinding of participants and providers to treatment assignment. 36 weeks post-randomization. Self-report questionnaires administered at 2 baseline visits and 4, 12, 24, 36, 52, and 78 weeks post-randomization. Primary outcomes include back and neck disability, measured by the Oswestry Disability Index and Neck Disability Index. Secondary outcomes include pain, general health status, improvement, self-efficacy, kinesiophobia, satisfaction, and medication use. Functional outcome assessment occurs at baseline and week 37 for hand grip strength, short physical performance battery, and accelerometry

Survival of glucose phosphate isomerase null somatic cells and germ cells in adult mouse chimaeras

PubMed Central

Keighren, Margaret A.; Flockhart, Jean H.

2016-01-01

ABSTRACT The mouse Gpi1 gene encodes the glycolytic enzyme glucose phosphate isomerase. Homozygous Gpi1−/− null mouse embryos die but a previous study showed that some homozygous Gpi1−/− null cells survived when combined with wild-type cells in fetal chimaeras. One adult female Gpi1−/−↔Gpi1c/c chimaera with functional Gpi1−/− null oocytes was also identified in a preliminary study. The aims were to characterise the survival of Gpi1−/− null cells in adult Gpi1−/−↔Gpi1c/c chimaeras and determine if Gpi1−/− null germ cells are functional. Analysis of adult Gpi1−/−↔Gpi1c/c chimaeras with pigment and a reiterated transgenic lineage marker showed that low numbers of homozygous Gpi1−/− null cells could survive in many tissues of adult chimaeras, including oocytes. Breeding experiments confirmed that Gpi1−/− null oocytes in one female Gpi1−/−↔Gpi1c/c chimaera were functional and provided preliminary evidence that one male putative Gpi1−/−↔Gpi1c/c chimaera produced functional spermatozoa from homozygous Gpi1−/− null germ cells. Although the male chimaera was almost certainly Gpi1−/−↔Gpi1c/c, this part of the study is considered preliminary because only blood was typed for GPI. Gpi1−/− null germ cells should survive in a chimaeric testis if they are supported by wild-type Sertoli cells. It is also feasible that spermatozoa could bypass a block at GPI, but not blocks at some later steps in glycolysis, by using fructose, rather than glucose, as the substrate for glycolysis. Although chimaera analysis proved inefficient for studying the fate of Gpi1−/− null germ cells, it successfully identified functional Gpi1−/− null oocytes and revealed that some Gpi1−/− null cells could survive in many adult tissues. PMID:27103217

The minimally invasive spinal deformity surgery algorithm: a reproducible rational framework for decision making in minimally invasive spinal deformity surgery.

PubMed

Mummaneni, Praveen V; Shaffrey, Christopher I; Lenke, Lawrence G; Park, Paul; Wang, Michael Y; La Marca, Frank; Smith, Justin S; Mundis, Gregory M; Okonkwo, David O; Moal, Bertrand; Fessler, Richard G; Anand, Neel; Uribe, Juan S; Kanter, Adam S; Akbarnia, Behrooz; Fu, Kai-Ming G

2014-05-01

Minimally invasive surgery (MIS) is an alternative to open deformity surgery for the treatment of patients with adult spinal deformity. However, at this time MIS techniques are not as versatile as open deformity techniques, and MIS techniques have been reported to result in suboptimal sagittal plane correction or pseudarthrosis when used for severe deformities. The minimally invasive spinal deformity surgery (MISDEF) algorithm was created to provide a framework for rational decision making for surgeons who are considering MIS versus open spine surgery. A team of experienced spinal deformity surgeons developed the MISDEF algorithm that incorporates a patient's preoperative radiographic parameters and leads to one of 3 general plans ranging from MIS direct or indirect decompression to open deformity surgery with osteotomies. The authors surveyed fellowship-trained spine surgeons experienced with spinal deformity surgery to validate the algorithm using a set of 20 cases to establish interobserver reliability. They then resurveyed the same surgeons 2 months later with the same cases presented in a different sequence to establish intraobserver reliability. Responses were collected and tabulated. Fleiss' analysis was performed using MATLAB software. Over a 3-month period, 11 surgeons completed the surveys. Responses for MISDEF algorithm case review demonstrated an interobserver kappa of 0.58 for the first round of surveys and an interobserver kappa of 0.69 for the second round of surveys, consistent with substantial agreement. In at least 10 cases there was perfect agreement between the reviewing surgeons. The mean intraobserver kappa for the 2 surveys was 0.86 ± 0.15 (± SD) and ranged from 0.62 to 1. The use of the MISDEF algorithm provides consistent and straightforward guidance for surgeons who are considering either an MIS or an open approach for the treatment of patients with adult spinal deformity. The MISDEF algorithm was found to have substantial inter- and

Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult

PubMed Central

Carreira, Vinicius S.; Fan, Yunxia; Kurita, Hisaka; Wang, Qin; Ko, Chia-I; Naticchioni, Mindi; Jiang, Min; Koch, Sheryl; Zhang, Xiang; Biesiada, Jacek; Medvedovic, Mario; Xia, Ying; Rubinstein, Jack; Puga, Alvaro

2015-01-01

The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr -/- and in utero TCDD-exposed Ahr +/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr -/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. PMID:26555816

C/EBPα and C/EBPβ Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin

PubMed Central

House, John S.; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C.

2010-01-01

C/EBPα and C/EBPβ are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPα and C/EBPβ in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPα or C/EBPβ alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPα and C/EBPβ in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPα and C/EBPβ in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPα and C/EBPβ are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal. PMID:20352127

C/EBPalpha and C/EBPbeta are required for Sebocyte differentiation and stratified squamous differentiation in adult mouse skin.

PubMed

House, John S; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C

2010-03-23

C/EBPalpha and C/EBPbeta are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPalpha and C/EBPbeta in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPalpha or C/EBPbeta alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPalpha and C/EBPbeta in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPalpha and C/EBPbeta in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPalpha and C/EBPbeta are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.

Bimanual reach to grasp movements after cervical spinal cord injury

PubMed Central

Raza, Wajid; Jamil, Firas

2017-01-01

Injury to the cervical spinal cord results in bilateral deficits in arm/hand function reducing functional independence and quality of life. To date little research has been undertaken to investigate control strategies of arm/hand movements following cervical spinal cord injury (cSCI). This study aimed to investigate unimanual and bimanual coordination in patients with acute cSCI using 3D kinematic analysis as they performed naturalistic reach to grasp actions with one hand, or with both hands together (symmetrical task), and compare this to the movement patterns of uninjured younger and older adults. Eighteen adults with a cSCI (mean 61.61 years) with lesions at C4-C8, with an American Spinal Injury Association (ASIA) grade B to D and 16 uninjured younger adults (mean 23.68 years) and sixteen uninjured older adults (mean 70.92 years) were recruited. Participants with a cSCI produced reach-to-grasp actions which took longer, were slower, and had longer deceleration phases than uninjured participants. These differences were exacerbated during bimanual reach-to-grasp tasks. Maximal grasp aperture was no different between groups, but reached earlier by people with cSCI. Participants with a cSCI were less synchronous than younger and older adults but all groups used the deceleration phase for error correction to end the movement in a synchronous fashion. Overall, this study suggests that after cSCI a level of bimanual coordination is retained. While there seems to be a greater reliance on feedback to produce both the reach to grasp, we observed minimal disruption of the more impaired limb on the less impaired limb. This suggests that bimanual movements should be integrated into therapy. PMID:28384247

Subdural Thoracolumbar Spine Hematoma after Spinal Anesthesia: A Rare Occurrence and Literature Review of Spinal Hematomas after Spinal Anesthesia

PubMed Central

Maddali, Prasanthi; Walker, Blake; Fisahn, Christian; Page, Jeni; Diaz, Vicki; Zwillman, Michael E; Oskouian, Rod J; Tubbs, R. Shane

2017-01-01

Spinal hematomas are a rare but serious complication of spinal epidural anesthesia and are typically seen in the epidural space; however, they have been documented in the subdural space. Spinal subdural hematomas likely exist within a traumatically induced space within the dural border cell layer, rather than an anatomical subdural space. Spinal subdural hematomas present a dangerous clinical situation as they have the potential to cause significant compression of neural elements and can be easily mistaken for spinal epidural hematomas. Ultrasound can be an effective modality to diagnose subdural hematoma when no epidural blood is visualized. We have reviewed the literature and present a full literature review and a case presentation of an 82-year-old male who developed a thoracolumbar spinal subdural hematoma after spinal epidural anesthesia. Anticoagulant therapy is an important predisposing risk factor for spinal epidural hematomas and likely also predispose to spinal subdural hematomas. It is important to consider spinal subdural hematomas in addition to spinal epidural hematomas in patients who develop weakness after spinal epidural anesthesia, especially in patients who have received anticoagulation. PMID:28357164

Subdural Thoracolumbar Spine Hematoma after Spinal Anesthesia: A Rare Occurrence and Literature Review of Spinal Hematomas after Spinal Anesthesia.

PubMed

Maddali, Prasanthi; Walker, Blake; Fisahn, Christian; Page, Jeni; Diaz, Vicki; Zwillman, Michael E; Oskouian, Rod J; Tubbs, R Shane; Moisi, Marc

2017-02-16

Spinal hematomas are a rare but serious complication of spinal epidural anesthesia and are typically seen in the epidural space; however, they have been documented in the subdural space. Spinal subdural hematomas likely exist within a traumatically induced space within the dural border cell layer, rather than an anatomical subdural space. Spinal subdural hematomas present a dangerous clinical situation as they have the potential to cause significant compression of neural elements and can be easily mistaken for spinal epidural hematomas. Ultrasound can be an effective modality to diagnose subdural hematoma when no epidural blood is visualized. We have reviewed the literature and present a full literature review and a case presentation of an 82-year-old male who developed a thoracolumbar spinal subdural hematoma after spinal epidural anesthesia. Anticoagulant therapy is an important predisposing risk factor for spinal epidural hematomas and likely also predispose to spinal subdural hematomas. It is important to consider spinal subdural hematomas in addition to spinal epidural hematomas in patients who develop weakness after spinal epidural anesthesia, especially in patients who have received anticoagulation.

Can the mammalian lumbar spinal cord learn a motor task?

PubMed

Hodgson, J A; Roy, R R; de Leon, R; Dobkin, B; Edgerton, V R

1994-12-01

Progress toward restoring locomotor function in low thoracic spinal transected cats and the application of similar techniques to patients with spinal cord injury is reviewed. Complete spinal cord transection (T12-T13) in adult cats results in an immediate loss of locomotor function in the hindlimbs. Limited locomotor function returns after several months in cats that have not received specific therapies designed to restore hindlimb stepping. Training transected cats to step on a treadmill for 30 min.d-1 and 5 d.wk-1 greatly improves their stepping ability. The most successful outcome was in cats where training began early, i.e., 1 wk after spinal transection. Cats trained to stand instead of stepping had great difficulty using the hindlimbs for locomotion. These effects were reversible over a 20-month period such that cats unable to step as a result of standing training could be trained to step and, conversely, locomotion in stepping-trained cats could be abolished by standing training. These results indicate that the spinal cord is capable of learning specific motor tasks. It has not been possible to elicit locomotion in patients with clinically complete spinal injuries, but appropriately coordinated EMG activity has been demonstrated in musculature of the legs during assisted locomotion on a treadmill.

Management of Spinal Deformities and Evidence of Treatment Effectiveness

PubMed Central

Bettany-Saltikov, Josette; Turnbull, Deborah; Ng, Shu Yan; Webb, Richard

2017-01-01

Introduction: The review evaluates the up-to-date evidence for the treatment of spinal deformities, including scoliosis and hyperkyphosis in adolescents and adults. Material and Methods: The PubMed database was searched for review articles, prospective controlled trials and randomized controlled trials related to the treatment of spinal deformities. Articles on syndromic scoliosis were excluded and so were the articles on hyperkyphosis of the spine with causes other than Scheuermann’s disease and osteoporosis. Articles on conservative and surgical treatments of idiopathic scoliosis, adult scoliosis and hyperkyphosis were also included. For retrospective papers, only studies with a follow up period exceeding 10 years were included. Results: The review showed that early-onset idiopathic scoliosis has a worse outcome than late-onset idiopathic scoliosis, which is rather benign. Patients with AIS function well as adults; they have no more health problems when compared to patients without scoliosis, other than a slight increase in back pain and aesthetic concern. Conservative treatment of adolescent idiopathic scoliosis (AIS) using physiotherapeutic scoliosis-specific exercises (PSSE), specifically PSSR and rigid bracing was supported by level I evidence. Yet to date, there is no high quality evidence (RCT`s) demonstrating that surgical treatment is superior to conservative treatment for the management of AIS. For adult scoliosis, there are only a few studies on the effectiveness of PSSEs and a conclusion cannot as yet be drawn. For hyperkyphosis, there is no high-quality evidence for physiotherapy, bracing or surgery for the treatment of adolescents and adults. However, bracing has been found to reduce thoracic hyperkyphosis, ranging from 55 to 80° in adolescents. In patients over the age of 60, bracing improves the balance score, and reduces spinal deformity and pain. Surgery is indicated in adolescents and adults in the presence of progression of kyphosis

Ecto-domain phosphorylation promotes functional recovery from spinal cord injury

PubMed Central

Suehiro, Kenji; Nakamura, Yuka; Xu, Shuai; Uda, Youichi; Matsumura, Takafumi; Yamaguchi, Yoshiaki; Okamura, Hitoshi; Yamashita, Toshihide; Takei, Yoshinori

2014-01-01

Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP. PMID:24826969

Interaction of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and opioid receptors in spinal cord nociceptive reflexes.

PubMed

Ramos-Zepeda, Guillermo; Herrero, Juan F

2013-08-14

We previously observed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) is a very effective antinociceptive agent on intact but not on spinalized adult rats with inflammation. Since a close connection between opioid and adenosine A1 receptors has been described, we studied a possible relationship between these systems in the spinal cord. CPA-mediated antinociception was challenged by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1, 3-dimethylxanthine (CPT) and by the opioid receptor antagonist naloxone on male adult Wistar rats with carrageenan-induced inflammation. Withdrawal reflexes activated by noxious mechanical and electrical stimulation were recorded using the single motor technique in intact and sham-spinalized animals. CPA was very effective in intact and sham spinalized rats but not in spinalized animals. Full reversal of CPA antinociception was observed with i.v. 1mg/kg of naloxone but not with 20mg/kg of CPT i.v. in responses to noxious mechanical and electrical stimulation. CPT fully prevented CPA from any antinociceptive action whereas naloxone did not modify CPA activity. These results suggest a centrally-mediated action, since CPA depressed the wind-up phenomenon which is derived of the activity of spinal cord neurons. The present study provides strong in vivo evidence of an antinociceptive activity mediated by the adenosine A1 receptor system in the spinal cord, linked to an activation of opioid receptors in adult animals with inflammation. © 2013.

Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Li; Wu, Zhou; Baba, Masashi

Research highlights: {yields} Cathepsin B (CB), a lysosomal cysteine protease, is expressed in neuron and glia. {yields} CB increased in hypogrossal nucleus neurons after nerve injury in adult mice. {yields} CB-deficiency significantly increased the mean survival ratio of injured neurons. {yields} Thus, CB plays a critical role in axotomy-induced neuronal death in adult mice. -- Abstract: There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, themore » understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in

Recording temperature affects the excitability of mouse superficial dorsal horn neurons, in vitro.

PubMed

Graham, B A; Brichta, A M; Callister, R J

2008-05-01

Superficial dorsal horn (SDH) neurons in laminae I-II of the spinal cord play an important role in processing noxious stimuli. These neurons represent a heterogeneous population and are divided into various categories according to their action potential (AP) discharge during depolarizing current injection. We recently developed an in vivo mouse preparation to examine functional aspects of nociceptive processing and AP discharge in SDH neurons and to extend investigation of pain mechanisms to the genetic level of analysis. Not surprisingly, some in vivo data obtained at body temperature (37 degrees C) differed from those generated at room temperature (22 degrees C) in spinal cord slices. In the current study we examine how temperature influences SDH neuron properties by making recordings at 22 and 32 degrees C in transverse spinal cord slices prepared from L3-L5 segments of adult mice (C57Bl/6). Patch-clamp recordings (KCH(3)SO(4) internal) were made from visualized SDH neurons. At elevated temperature all SDH neurons had reduced input resistance and smaller, briefer APs. Resting membrane potential and AP afterhyperpolarization amplitude were temperature sensitive only in subsets of the SDH population. Notably, elevated temperature increased the prevalence of neurons that did not discharge APs during current injection. These reluctant firing neurons expressed a rapid A-type potassium current, which is enhanced at higher temperatures and thus restrains AP discharge. When compared with previously published whole cell recordings obtained in vivo (37 degrees C) our results suggest that, on balance, in vitro data collected at elevated temperature more closely resemble data collected under in vivo conditions.

Spinal cord injury-induced immune deficiency syndrome enhances infection susceptibility dependent on lesion level

PubMed Central

Brommer, Benedikt; Engel, Odilo; Kopp, Marcel A.; Watzlawick, Ralf; Müller, Susanne; Prüss, Harald; Chen, Yuying; DeVivo, Michael J.; Finkenstaedt, Felix W.; Dirnagl, Ulrich; Liebscher, Thomas; Meisel, Andreas

2016-01-01

Pneumonia is the leading cause of death after acute spinal cord injury and is associated with poor neurological outcome. In contrast to the current understanding, attributing enhanced infection susceptibility solely to the patient’s environment and motor dysfunction, we investigate whether a secondary functional neurogenic immune deficiency (spinal cord injury-induced immune deficiency syndrome, SCI-IDS) may account for the enhanced infection susceptibility. We applied a clinically relevant model of experimental induced pneumonia to investigate whether the systemic SCI-IDS is functional sufficient to cause pneumonia dependent on spinal cord injury lesion level and investigated whether findings are mirrored in a large prospective cohort study after human spinal cord injury. In a mouse model of inducible pneumonia, high thoracic lesions that interrupt sympathetic innervation to major immune organs, but not low thoracic lesions, significantly increased bacterial load in lungs. The ability to clear the bacterial load from the lung remained preserved in sham animals. Propagated immune susceptibility depended on injury of central pre-ganglionic but not peripheral postganglionic sympathetic innervation to the spleen. Thoracic spinal cord injury level was confirmed as an independent increased risk factor of pneumonia in patients after motor complete spinal cord injury (odds ratio = 1.35, P < 0.001) independently from mechanical ventilation and preserved sensory function by multiple regression analysis. We present evidence that spinal cord injury directly causes increased risk for bacterial infection in mice as well as in patients. Besides obvious motor and sensory paralysis, spinal cord injury also induces a functional SCI-IDS (‘immune paralysis’), sufficient to propagate clinically relevant infection in an injury level dependent manner. PMID:26754788

Cycling exercise and fetal spinal cord transplantation act synergistically on atrophied muscle following chronic spinal cord injury in rats.

PubMed

Peterson, C A; Murphy, R J; Dupont-Versteegden, E E; Houlé, J D

2000-01-01

The potential of two interventions, alone or in combination, to restore chronic spinal cord transection-induced changes in skeletal muscles of adult Sprague-Dawley rats was studied. Hind limb skeletal muscles were examined in the following groups of animals: rats with a complete spinal cord transection (Tx) for 8 weeks; Tx with a 4-week delay before initiation of a 4-week motor-assisted cycling exercise (Ex) program; Tx with a 4-week delay before transplantation (Tp) of fetal spinal cord tissue into the lesion cavity; Tx with a 4-week delay before Tp and Ex; and uninjured control animals. Muscle mass, muscle to body mass ratios, and mean myofiber cross-sectional areas were significantly reduced 8 weeks after transection. Whereas transplantation of fetal spinal cord tissue did not reverse this atrophy and exercise alone had only a modest effect in restoring lost muscle mass, the combination of exercise and transplantation significantly increased muscle mass, muscle to body mass ratios, and mean myofiber cross-sectional areas in both soleus and plantaris muscles. Spinal cord injury (SCI) also caused changes in myosin heavy chain (MyHC) expression toward faster isoforms in both soleus and plantaris and increased soleus myofiber succinate dehydrogenase (SDH) activity. Combined exercise and transplantation led to a change in the expression of the fastest MyHC isoform in soleus but had no effect in the plantaris. Exercise alone and in combination with transplantation reduced SDH activity to control levels in the soleus. These results suggest a synergistic action of exercise and transplantation of fetal spinal cord tissue on skeletal muscle properties following SCI, even after an extended post-injury period before intervention.

Effects of Adult Romantic Attachment and Social Support on Resilience and Depression in Individuals with Spinal Cord Injuries

PubMed Central

Dodd, Zane; Warren, Ann Marie; Riggs, Shelley; Clark, Mike

2015-01-01

Background: Spinal cord injury (SCI) can cause psychological consequences that negatively affect quality of life. It is increasingly recognized that factors such as resilience and social support may produce a buffering effect and are associated with improved health outcomes. However the influence of adult attachment style on an individual’s ability to utilize social support after SCI has not been examined. Objective: The purpose of this study was to examine relationships between adult romantic attachment perceived social support depression and resilience in individuals with SCI. In addition we evaluated potential mediating effects of social support and adult attachment on resilience and depression. Methods: Participants included 106 adults with SCI undergoing inpatient rehabilitation. Individuals completed measures of adult attachment (avoidance and anxiety) social support resilience and depression. Path analysis was performed to assess for presence of mediation effects. Results: When accounting for the smaller sample size support was found for the model (comparative fit index = .927 chi square = 7.86 P = .01 β = -0.25 standard error [SE] = -2.93 P < .05). The mediating effect of social support on the association between attachment avoidance and resilience was the only hypothesized mediating effect found to be significant (β = -0.25 SE = -2.93 P < .05). Conclusion: Results suggest that individuals with SCI with higher levels of attachment avoidance have lower perceived social support which relates to lower perceived resilience. Assessing attachment patterns during inpatient rehabilitation may allow therapists to intervene to provide greater support. PMID:26364285

C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation.

PubMed

Matsui, Toshiyasu; Hongo, Yu; Haizuka, Yoshinori; Kaida, Kenichi; Matsumura, George; Martin, Donna M; Kobayashi, Yasushi

2013-08-26

Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C-terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation

PubMed Central

Matsui, Toshiyasu; Hongo, Yu; Haizuka, Yoshinori; Kaida, Kenichi; Matsumura, George; Martin, Donna M.; Kobayashi, Yasushi

2013-01-01

Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C-terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons. PMID:23756176

Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse

PubMed Central

Caldeira, Vanessa; Dougherty, Kimberly J.; Borgius, Lotta; Kiehn, Ole

2017-01-01

Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype and progenitor domain, but does not overlap with the Shox2 non-V2a population. We also show that Hb9::Cre-derived INs include the comparatively small medial population of INs which continues to express Hb9 postnatally. When excitatory neurotransmission is selectively blocked by deleting Vglut2 from Hb9::Cre-derived INs, there is no difference in left-right and/or flexor-extensor phasing between these cords and controls, suggesting that excitatory Hb9::Cre-derived INs do not affect pattern generation. In contrast, the frequencies of locomotor activity are significantly lower in cords from Hb9::Cre-Vglut2Δ/Δ mice than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion. PMID:28128321

Development of an evidence-informed leisure time physical activity resource for adults with spinal cord injury: the SCI Get Fit Toolkit.

PubMed

Arbour-Nicitopoulos, K P; Martin Ginis, K A; Latimer-Cheung, A E; Bourne, C; Campbell, D; Cappe, S; Ginis, S; Hicks, A L; Pomerleau, P; Smith, K

2013-06-01

To systematically develop an evidence-informed leisure time physical activity (LTPA) resource for adults with spinal cord injury (SCI). Canada. The Appraisal of Guidelines, Research and Evaluation (AGREE) II protocol was used to develop a toolkit to teach and encourage adults with SCI how to make smart and informed choices about being physically active. A multidisciplinary expert panel appraised the evidence and generated specific recommendations for the content of the toolkit. Pilot testing was conducted to refine the toolkit's presentation. Recommendations emanating from the consultation process were that the toolkit be a brief, evidence-based resource that contains images of adults with tetraplegia and paraplegia, and links to more detailed online information. The content of the toolkit should include the physical activity guidelines (PAGs) for adults with SCI, activities tailored to manual and power chair users, the benefits of LTPA, and strategies to overcome common LTPA barriers for adults with SCI. The inclusion of action plans and safety tips was also recommended. These recommendations have resulted in the development of an evidence-informed LTPA resource to assist adults with SCI in meeting the PAGs. This toolkit will have important implications for consumers, health care professionals and policy makers for encouraging LTPA in the SCI community.

Spinal stenosis

MedlinePlus

... stenosis; LBP - stenosis Patient Instructions Spine surgery - discharge Images Sciatic nerve Spinal stenosis Spinal stenosis References Försth P, Ólafsson G, Carlsson T, et al. A randomized, controlled trial of fusion surgery for lumbar spinal stenosis. N Engl J ...

Light distribution properties in spinal cord for optogenetic stimulation (Conference Presentation)

NASA Astrophysics Data System (ADS)

GÄ secka, Alicja; Bahdine, Mohamed; Lapointe, Nicolas; Rioux, Veronique; Perez-Sanchez, Jimena; Bonin, Robert P.; De Koninck, Yves; Côté, Daniel

2016-03-01

Optogenetics is currently one of the most popular technique in neuroscience. It enables cell-selective and temporally-precise control of neuronal activity. Good spatial control of the stimulated area and minimized tissue damage requires a specific knowledge about light scattering properties. Light propagation in cell cultures and brain tissue is relatively well documented and allows for a precise and reliable delivery of light to the neurons. In spinal cord, light must pass through highly organized white matter before reaching cell bodies present in grey matter, this heterogenous structure makes it difficult to predict the propagation pattern. In this work we investigate the light distribution properties through mouse and monkey spinal cord. The light propagation depends on a fibers orientation, leading to less deep penetration profile in the direction perpendicular to the fibers and lower attenuation in the direction parallel to the fibers. Additionally, the use of different illumination wavelengths results in variations of the attenuation coefficient. Next, we use Monte-Carlo simulation to study light transport. The model gives a full 3-D simulation of light distribution in spinal cord and takes into account different scattering properties related to the fibers orientation. These studies are important to estimate the minimum optical irradiance required at the fiber tip to effectively excite the optogenetic proteins in a desired region of spinal cord.

Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis.

PubMed

Liu, Kevin X; Edwards, Benjamin; Lee, Sheena; Finelli, Mattéa J; Davies, Ben; Davies, Kay E; Oliver, Peter L

2015-05-01

Amyotrophic lateral sclerosis is a devastating neurodegenerative disorder characterized by the progressive loss of spinal motor neurons. While the aetiological mechanisms underlying the disease remain poorly understood, oxidative stress is a central component of amyotrophic lateral sclerosis and contributes to motor neuron injury. Recently, oxidation resistance 1 (OXR1) has emerged as a critical regulator of neuronal survival in response to oxidative stress, and is upregulated in the spinal cord of patients with amyotrophic lateral sclerosis. Here, we tested the hypothesis that OXR1 is a key neuroprotective factor during amyotrophic lateral sclerosis pathogenesis by crossing a new transgenic mouse line that overexpresses OXR1 in neurons with the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Interestingly, we report that overexpression of OXR1 significantly extends survival, improves motor deficits, and delays pathology in the spinal cord and in muscles of SOD1(G93A) mice. Furthermore, we find that overexpression of OXR1 in neurons significantly delays non-cell-autonomous neuroinflammatory response, classic complement system activation, and STAT3 activation through transcriptomic analysis of spinal cords of SOD1(G93A) mice. Taken together, these data identify OXR1 as the first neuron-specific antioxidant modulator of pathogenesis and disease progression in SOD1-mediated amyotrophic lateral sclerosis, and suggest that OXR1 may serve as a novel target for future therapeutic strategies. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.

Phosphorylated neurofilament heavy: A potential blood biomarker to evaluate the severity of acute spinal cord injuries in adults

PubMed Central

Singh, Ajai; Kumar, Vineet; Ali, Sabir; Mahdi, Abbas Ali; Srivastava, Rajeshwer Nath

2017-01-01

Aims: The aim of this study is to analyze the serial estimation of phosphorylated neurofilament heavy (pNF-H) in blood plasma that would act as a potential biomarker for early prediction of the neurological severity of acute spinal cord injuries (SCI) in adults. Settings and Design: Pilot study/observational study. Subjects and Methods: A total of 40 patients (28 cases and 12 controls) of spine injury were included in this study. In the enrolled cases, plasma level of pNF-H was evaluated in blood samples and neurological evaluation was performed by the American Spinal Injury Association Injury Scale at specified period. Serial plasma neurofilament heavy values were then correlated with the neurological status of these patients during follow-up visits and were analyzed statistically. Statistical Analysis Used: Statistical analysis was performed using GraphPad InStat software (version 3.05 for Windows, San Diego, CA, USA). The correlation analysis between the clinical progression and pNF-H expression was done using Spearman's correlation. Results: The mean baseline level of pNF-H in cases was 6.40 ± 2.49 ng/ml, whereas in controls it was 0.54 ± 0.27 ng/ml. On analyzing the association between the two by Mann–Whitney U–test, the difference in levels was found to be statistically significant. The association between the neurological progression and pNF-H expression was determined using correlation analysis (Spearman's correlation). At 95% confidence interval, the correlation coefficient was found to be 0.64, and the correlation was statistically significant. Conclusions: Plasma pNF-H levels were elevated in accordance with the severity of SCI. Therefore, pNF-H may be considered as a potential biomarker to determine early the severity of SCI in adult patients. PMID:29291173

Musashi and Plasticity of Xenopus and Axolotl Spinal Cord Ependymal Cells

PubMed Central

Chernoff, Ellen A. G.; Sato, Kazuna; Salfity, Hai V. N.; Sarria, Deborah A.; Belecky-Adams, Teri

2018-01-01

The differentiated state of spinal cord ependymal cells in regeneration-competent amphibians varies between a constitutively active state in what is essentially a developing organism, the tadpole of the frog Xenopus laevis, and a quiescent, activatable state in a slowly growing adult salamander Ambystoma mexicanum, the Axolotl. Ependymal cells are epithelial in intact spinal cord of all vertebrates. After transection, body region ependymal epithelium in both Xenopus and the Axolotl disorganizes for regenerative outgrowth (gap replacement). Injury-reactive ependymal cells serve as a stem/progenitor cell population in regeneration and reconstruct the central canal. Expression patterns of mRNA and protein for the stem/progenitor cell-maintenance Notch signaling pathway mRNA-binding protein Musashi (msi) change with life stage and regeneration competence. Msi-1 is missing (immunohistochemistry), or at very low levels (polymerase chain reaction, PCR), in both intact regeneration-competent adult Axolotl cord and intact non-regeneration-competent Xenopus tadpole (Nieuwkoop and Faber stage 62+, NF 62+). The critical correlation for successful regeneration is msi-1 expression/upregulation after injury in the ependymal outgrowth and stump-region ependymal cells. msi-1 and msi-2 isoforms were cloned for the Axolotl as well as previously unknown isoforms of Xenopus msi-2. Intact Xenopus spinal cord ependymal cells show a loss of msi-1 expression between regeneration-competent (NF 50–53) and non-regenerating stages (NF 62+) and in post-metamorphosis froglets, while msi-2 displays a lower molecular weight isoform in non-regenerating cord. In the Axolotl, embryos and juveniles maintain Msi-1 expression in the intact cord. In the adult Axolotl, Msi-1 is absent, but upregulates after injury. Msi-2 levels are more variable among Axolotl life stages: rising between late tailbud embryos and juveniles and decreasing in adult cord. Cultures of regeneration-competent Xenopus tadpole

Retinal lesions induce fast intrinsic cortical plasticity in adult mouse visual system.

PubMed

Smolders, Katrien; Vreysen, Samme; Laramée, Marie-Eve; Cuyvers, Annemie; Hu, Tjing-Tjing; Van Brussel, Leen; Eysel, Ulf T; Nys, Julie; Arckens, Lutgarde

2016-09-01

Neuronal activity plays an important role in the development and structural-functional maintenance of the brain as well as in its life-long plastic response to changes in sensory stimulation. We characterized the impact of unilateral 15° laser lesions in the temporal lower visual field of the retina, on visually driven neuronal activity in the afferent visual pathway of adult mice using in situ hybridization for the activity reporter gene zif268. In the first days post-lesion, we detected a discrete zone of reduced zif268 expression in the contralateral hemisphere, spanning the border between the monocular segment of the primary visual cortex (V1) with extrastriate visual area V2M. We could not detect a clear lesion projection zone (LPZ) in areas lateral to V1 whereas medial to V2M, agranular and granular retrosplenial cortex showed decreased zif268 levels over their full extent. All affected areas displayed a return to normal zif268 levels, and this was faster in higher order visual areas than in V1. The lesion did, however, induce a permanent LPZ in the retinorecipient layers of the superior colliculus. We identified a retinotopy-based intrinsic capacity of adult mouse visual cortex to recover from restricted vision loss, with recovery speed reflecting the areal cortical magnification factor. Our observations predict incomplete visual field representations for areas lateral to V1 vs. lack of retinotopic organization for areas medial to V2M. The validation of this mouse model paves the way for future interrogations of cortical region- and cell-type-specific contributions to functional recovery, up to microcircuit level. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients.

PubMed

Delic, Vedad; Kurien, Crupa; Cruz, Josean; Zivkovic, Sandra; Barretta, Jennifer; Thomson, Avery; Hennessey, Daniel; Joseph, Jaheem; Ehrhart, Jared; Willing, Alison E; Bradshaw, Patrick; Garbuzova-Davis, Svitlana

2018-08-01

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease. © 2018 Wiley Periodicals, Inc.

Validity of a smartphone protractor to measure sagittal parameters in adult spinal deformity.

PubMed

Kunkle, William Aaron; Madden, Michael; Potts, Shannon; Fogelson, Jeremy; Hershman, Stuart

2017-10-01

Smartphones have become an integral tool in the daily life of health-care professionals (Franko 2011). Their ease of use and wide availability often make smartphones the first tool surgeons use to perform measurements. This technique has been validated for certain orthopedic pathologies (Shaw 2012; Quek 2014; Milanese 2014; Milani 2014), but never to assess sagittal parameters in adult spinal deformity (ASD). This study was designed to assess the validity, reproducibility, precision, and efficiency of using a smartphone protractor application to measure sagittal parameters commonly measured in ASD assessment and surgical planning. This study aimed to (1) determine the validity of smartphone protractor applications, (2) determine the intra- and interobserver reliability of smartphone protractor applications when used to measure sagittal parameters in ASD, (3) determine the efficiency of using a smartphone protractor application to measure sagittal parameters, and (4) elucidate whether a physician's level of experience impacts the reliability or validity of using a smartphone protractor application to measure sagittal parameters in ASD. An experimental validation study was carried out. Thirty standard 36″ standing lateral radiographs were examined. Three separate measurements were performed using a marker and protractor; then at a separate time point, three separate measurements were performed using a smartphone protractor application for all 30 radiographs. The first 10 radiographs were then re-measured two more times, for a total of three measurements from both the smartphone protractor and marker and protractor. The parameters included lumbar lordosis, pelvic incidence, and pelvic tilt. Three raters performed all measurements-a junior level orthopedic resident, a senior level orthopedic resident, and a fellowship-trained spinal deformity surgeon. All data, including the time to perform the measurements, were recorded, and statistical analysis was performed to

Significance of fixation of the vertebral column for spinal cord injury experiments.

PubMed

Liu, Fei; Luo, Zhuo-Jin; You, Si-Wei; Jiao, Xi-Ying; Meng, Xiao-Mei; Shi, Ming; Wang, Chun-Ting; Ju, Gong

2003-08-01

Thoracic spinal cord transections were performed in adult rats. The animals were divided into two groups, with or without internal fixation of the involved vertebral column. Histologic and immunohistochemical studies were performed to compare the effect of internal fixation of the vertebral column. To find out the aspects and extent of beneficial effects of vertebral column fixation for spinal cord repair. Vertebral column fixation is a routine procedure in clinical spinal cord surgery. Paradoxically, most, if not all, animal spinal cord experiments seem to have ignored the importance of vertebral column fixation. During trunk movements, the vertebral column flexes to different directions, accompanied by bending of the spinal cord. Following spinal cord lesions, with frequent bending of the cord there will be repeated bleeding, inflammation, and other pathologic processes at the lesion site. Thus, the healing process will be hampered. The severity of the damages that will be brought about by bending of the cord is, to a certain degree, unpredictable. There will be rather big individual variations in injury and repair among the same type of experiments, rendering quantification and conclusion difficult. Adult Sprague-Dawley rats were used. The thoracic spinal cord was transected. Strong stainless steel wires were used for internal fixation of the vertebral column. The histology of the horizontal sections of the spinal cord segment, which included the lesion site, was examined at the 14th postoperative day. The volumes of the secondary degeneration and meningeal scar, the gap between the borders of the proximal and distal stumps of the transected spinal cord, the thickness of the meningeal scar, the astrocytic reaction, and the abundance of regenerating nerve fibers at the lesion site were compared between the vertebral column fixed and nonfixed groups. Whenever possible, the results were evaluated quantitatively. In all these aspects, the internally fixed group was

Cervical spinal stenosis and sports-related cervical cord neurapraxia in children.

PubMed

Boockvar, J A; Durham, S R; Sun, P P

2001-12-15

Congenital spinal stenosis has been demonstrated to contribute to cervical cord neurapraxia after cervical spinal cord injury in adult athletes. A sagittal canal diameter <14 mm and/or a Torg ratio (sagittal diameter of the spinal canal: midcervical sagittal vertebral body diameter) of <0.8 are indicative of significant cervical spinal stenosis. Although sports-related cervical spine injuries are common in children, the role of congenital cervical stenosis in the etiology of these injuries remains unclear. The authors measured the sagittal canal diameter and the Torg ratio in children presenting with cervical cord neurapraxia resulting from sports-related cervical spinal cord injuries to determine the presence of congenital spinal stenosis. A total of 13 children (9 male, 4 female) presented with cervical cord neurapraxia after a sports-related cervical spinal cord injury. Age ranged from 7 to 15 years (mean +/- SD, 11.5 +/- 2.7 years). The sports involved were football (n = 4), wrestling (n = 2), hockey (n = 2), and soccer, gymnastics, baseball, kickball, and pogosticking (n = 1 each). Lateral cervical spine radiographs were used to determine the sagittal canal diameter and the Torg ratio at C4. The sagittal canal diameter (mean +/- SD, 17.58 +/- 1.63 mm) and the Torg ratio (mean +/- SD, 1.20 +/- 0.24) were normal in all of these children. Using the sagittal canal diameter and the Torg ratio as a measurement of congenital spinal stenosis, the authors did not find evidence of congenital cervical spinal stenosis in a group of children with sports-related cervical spinal cord neurapraxia. The occurrence of cervical cord neurapraxia in pediatric patients can be attributed to the mobility of the pediatric spine rather than to congenital cervical spinal stenosis.

Localization and regulation of PML bodies in the adult mouse brain.

PubMed

Hall, Małgorzata H; Magalska, Adriana; Malinowska, Monika; Ruszczycki, Błażej; Czaban, Iwona; Patel, Satyam; Ambrożek-Latecka, Magdalena; Zołocińska, Ewa; Broszkiewicz, Hanna; Parobczak, Kamil; Nair, Rajeevkumar R; Rylski, Marcin; Pawlak, Robert; Bramham, Clive R; Wilczyński, Grzegorz M

2016-06-01

PML is a tumor suppressor protein involved in the pathogenesis of promyelocytic leukemia. In non-neuronal cells, PML is a principal component of characteristic nuclear bodies. In the brain, PML has been implicated in the control of embryonic neurogenesis, and in certain physiological and pathological phenomena in the adult brain. Yet, the cellular and subcellular localization of the PML protein in the brain, including its presence in the nuclear bodies, has not been investigated comprehensively. Because the formation of PML bodies appears to be a key aspect in the function of the PML protein, we investigated the presence of these structures and their anatomical distribution, throughout the adult mouse brain. We found that PML is broadly expressed across the gray matter, with the highest levels in the cerebral and cerebellar cortices. In the cerebral cortex PML is present exclusively in neurons, in which it forms well-defined nuclear inclusions containing SUMO-1, SUMO 2/3, but not Daxx. At the ultrastructural level, the appearance of neuronal PML bodies differs from the classic one, i.e., the solitary structure with more or less distinctive capsule. Rather, neuronal PML bodies have the form of small PML protein aggregates located in the close vicinity of chromatin threads. The number, size, and signal intensity of neuronal PML bodies are dynamically influenced by immobilization stress and seizures. Our study indicates that PML bodies are broadly involved in activity-dependent nuclear phenomena in adult neurons.

Purinergic Modulation of Spinal Neuroglial Maladaptive Plasticity Following Peripheral Nerve Injury.

PubMed

Cirillo, Giovanni; Colangelo, Anna Maria; Berbenni, Miluscia; Ippolito, Vita Maria; De Luca, Ciro; Verdesca, Francesco; Savarese, Leonilde; Alberghina, Lilia; Maggio, Nicola; Papa, Michele

2015-12-01

Modulation of spinal reactive gliosis following peripheral nerve injury (PNI) is a promising strategy to restore synaptic homeostasis. Oxidized ATP (OxATP), a nonselective antagonist of purinergic P2X receptors, was found to recover a neuropathic behavior following PNI. We investigated the role of intraperitoneal (i.p.) OxATP treatment in restoring the expression of neuronal and glial markers in the mouse spinal cord after sciatic spared nerve injury (SNI). Using in vivo two-photon microscopy, we imaged Ca(2+) transients in neurons and astrocytes of the dorsal horn of spinal cord at rest and upon right hind paw electrical stimulation in sham, SNI, and OxATP-treated mice. Neuropathic behavior was investigated by von Frey and thermal plantar test. Glial [glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1)] and GABAergic [vesicular GABA transporter (vGAT) and glutamic acid decarboxylase 65/76 (GAD65/67)] markers and glial [glutamate transporter (GLT1) and GLAST] and neuronal amino acid [EAAC1, vesicular glutamate transporter 1 (vGLUT1)] transporters have been evaluated. In SNI mice, we found (i) increased glial response, (ii) decreased glial amino acid transporters, and (iii) increased levels of neuronal amino acid transporters, and (iv) in vivo analysis of spinal neurons and astrocytes showed a persistent increase of Ca(2+) levels. OxATP administration reduced glial activation, modulated the expression of glial and neuronal glutamate/GABA transporters, restored neuronal and astrocytic Ca(2+) levels, and prevented neuropathic behavior. In vitro studies validated that OxATP (i) reduced levels of reactive oxygen species (ROS), (ii) reduced astrocytic proliferation, (iii) increase vGLUT expression. All together, these data support the correlation between reactive gliosis and perturbation of the spinal synaptic homeostasis and the role played by the purinergic system in modulating spinal plasticity following PNI.

Postural dynamism during computer mouse and keyboard use: A pilot study.

PubMed

Van Niekerk, S M; Fourie, S M; Louw, Q A

2015-09-01

Prolonged sedentary computer use is a risk factor for musculoskeletal pain. The aim of this study was to explore postural dynamism during two common computer tasks, namely mouse use and keyboard typing. Postural dynamism was described as the total number of postural changes that occurred during the data capture period. Twelve participants were recruited to perform a mouse and a typing task. The data of only eight participants could be analysed. A 3D motion analysis system measured the number of cervical and thoracic postural changes as well as, the range in which the postural changes occurred. The study findings illustrate that there is less postural dynamism of the cervical and thoracic spinal regions during computer mouse use, when compared to keyboard typing. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Wnt3 and Gata4 regulate axon regeneration in adult mouse DRG neurons.

PubMed

Duan, Run-Shan; Liu, Pei-Pei; Xi, Feng; Wang, Wei-Hua; Tang, Gang-Bin; Wang, Rui-Ying; Saijilafu; Liu, Chang-Mei

2018-05-05

Neurons in the adult central nervous system (CNS) have a poor intrinsic axon growth potential after injury, but the underlying mechanisms are largely unknown. Wingless-related mouse mammary tumor virus integration site (WNT) family members regulate neural stem cell proliferation, axon tract and forebrain development in the nervous system. Here we report that Wnt3 is an important modulator of axon regeneration. Downregulation or overexpression of Wnt3 in adult dorsal root ganglion (DRG) neurons enhances or inhibits their axon regeneration ability respectively in vitro and in vivo. Especially, we show that Wnt3 modulates axon regeneration by repressing mRNA translation of the important transcription factor Gata4 via binding to the three prime untranslated region (3'UTR). Downregulation of Gata4 could restore the phenotype exhibited by Wnt3 downregulation in DRG neurons. Taken together, these data indicate that Wnt3 is a key intrinsic regulator of axon growth ability of the nervous system. Copyright © 2018 Elsevier Inc. All rights reserved.

Short-scan-time multi-slice diffusion MRI of the mouse cervical spinal cord using echo planar imaging.

PubMed

Callot, Virginie; Duhamel, Guillaume; Cozzone, Patrick J; Kober, Frank

2008-10-01

Mouse spinal cord (SC) diffusion-weighted imaging (DWI) provides important information on tissue morphology and structural changes that may occur during pathologies such as multiple sclerosis or SC injury. The acquisition scheme of the commonly used DWI techniques is based on conventional spin-echo encoding, which is time-consuming. The purpose of this work was to investigate whether the use of echo planar imaging (EPI) would provide good-quality diffusion MR images of mouse SC, as well as accurate measurements of diffusion-derived metrics, and thus enable diffusion tensor imaging (DTI) and highly resolved DWI within reasonable scan times. A four-shot diffusion-weighted spin-echo EPI (SE-EPI) sequence was evaluated at 11.75 T on a group of healthy mice (n = 10). SE-EPI-derived apparent diffusion coefficients of gray and white matter were compared with those obtained using a conventional spin-echo sequence (c-SE) to validate the accuracy of the method. To take advantage of the reduction in acquisition time offered by the EPI sequence, multi-slice DTI acquisitions were performed covering the cervical segments (six slices, six diffusion-encoding directions, three b values) within 30 min (vs 2 h for c-SE). From these measurements, fractional anisotropy and mean diffusivities were calculated, and fiber tracking along the C1 to C6 cervical segments was performed. In addition, high-resolution images (74 x 94 microm(2)) were acquired within 5 min per direction. Clear delineation of gray and white matter and identical apparent diffusion coefficient values were obtained, with a threefold reduction in acquisition time compared with c-SE. While overcoming the difficulties associated with high spatially and temporally resolved DTI measurements, the present SE-EPI approach permitted identification of reliable quantitative parameters with a reproducibility compatible with the detection of pathologies. The SE-EPI method may be particularly valuable when multiple sets of images

A Progressive Translational Mouse Model of Human VCP Disease: The VCP R155H/+ Mouse

PubMed Central

Nalbandian, Angèle; Llewellyn, Katrina J.; Badadani, Mallikarjun; Yin, Hong Z.; Nguyen, Christopher; Katheria, Veeral; Watts, Giles; Mukherjee, Jogeshwar; Vesa, Jouni; Caiozzo, Vincent; Mozaffar, Tahseen; Weiss, John H.; Kimonis, Virginia E.

2012-01-01

Introduction Mutations in the valosin containing protein (VCP) gene cause hereditary Inclusion Body Myopathy (hIBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently they have been linked to 2% of familial ALS cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis. Methods The VCPR155H/+ knock-in mouse model was assessed for muscle strength, immunohistochemical, Western, apoptosis, autophagy and MicroPET/CT imaging analyses. Results VCPR155H/+ mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons. Discussion VCPR155H/+ knock-in mice represent an excellent pre-clinical model for understanding VCP-associated disease mechanisms and future treatments. PMID:23169451

Tracking functional status across the spinal cord injury lifespan: linking pediatric and adult patient-reported outcome scores.

PubMed

Tian, Feng; Ni, Pengsheng; Mulcahey, M J; Hambleton, Ronald K; Tulsky, David; Haley, Stephen M; Jette, Alan M

2014-11-01

To use item response theory (IRT) methods to link scores from 2 recently developed contemporary functional outcome measures, the adult Spinal Cord Injury-Functional Index (SCI-FI) and the Pedi SCI (both the parent version and the child version). Secondary data analysis of the physical functioning items of the adult SCI-FI and the Pedi SCI instruments. We used a nonequivalent group design with items common to both instruments and the Stocking-Lord method for the linking. Linking was conducted so that the adult SCI-FI and Pedi SCI scaled scores could be compared. Community. This study included a total sample of 1558 participants. Pedi SCI items were administered to a sample of children (n=381) with SCI aged 8 to 21 years, and of parents/caregivers (n=322) of children with SCI aged 4 to 21 years. Adult SCI-FI items were administered to a sample of adults (n=855) with SCI aged 18 to 92 years. Not applicable. Five scales common to both instruments were included in the analysis: Wheelchair, Daily Routine/Self-care, Daily Routine/Fine Motor, Ambulation, and General Mobility functioning. Confirmatory factor analysis and exploratory factor analysis results indicated that the 5 scales are unidimensional. A graded response model was used to calibrate the items. Misfitting items were identified and removed from the item banks. Items that function differently between the adult and child samples (ie, exhibit differential item functioning) were identified and removed from the common items used for linking. Domain scores from the Pedi SCI instruments were transformed onto the adult SCI-FI metric. This IRT linking allowed estimation of adult SCI-FI scale scores based on Pedi SCI scale scores and vice versa; therefore, it provides clinicians with a means of tracking long-term functional data for children with an SCI across their entire lifespan. Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Progressive Spinal Kyphosis in the Aging Population.

PubMed

Ailon, Tamir; Shaffrey, Christopher I; Lenke, Lawrence G; Harrop, James S; Smith, Justin S

2015-10-01

Thoracic kyphosis tends to increase with age. Hyperkyphosis is defined as excessive curvature of the thoracic spine and may be associated with adverse health effects. Hyperkyphosis in isolation or as a component of degenerative kyphoscoliosis has important implications for the surgical management of adult spinal deformity. Our objective was to review the literature on the epidemiology, etiology, natural history, management, and outcomes of thoracic hyperkyphosis. We performed a narrative review of literature on thoracic hyperkyphosis and its implications for adult spinal deformity surgery. Hyperkyphosis has a prevalence of 20% to 40% and is more common in the geriatric population. The cause is multifactorial and involves an interaction between degenerative changes, vertebral compression fractures, muscular weakness, and altered biomechanics. It may be associated with adverse health consequences including impaired physical function, pain and disability, impaired pulmonary function, and increased mortality. Nonoperative management may slow the progression of kyphosis and improve function. Surgery is rarely performed for isolated hyperkyphosis in the elderly due to the associated risk, but is an option when kyphosis occurs in the context of significant deformity. In this scenario, increased thoracic kyphosis influences selection of fusion levels and overall surgical planning. Kyphosis is common in older individuals and is associated with adverse health effects and increased mortality. Current evidence suggests a role for nonoperative therapies in reducing kyphosis and delaying its progression. Isolated hyperkyphosis in the elderly is rarely treated surgically; however, increased thoracic kyphosis as a component of global spinal deformity has important implications for patient selection and operative planning.

Characterization of N-methyl-D-aspartate-evoked taurine release in the developing and adult mouse hippocampus.

PubMed

Saransaari, P; Oja, S S

2003-01-01

Taurine is an inhibitory amino acid acting as an osmoregulator and neuroromodulator in the brain, with neuroprotective properties. The ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) greatly potentiates taurine release from brain preparations in both normal and ischemic conditions, the effect being particularly marked in the developing hippocampus. We now characterized the regulation of NMDA-stimulated taurine release from hippocampal slices from adult (3-month-old) and developing (7-day-old) mouse using a superfusion system. The NMDA-stimulated taurine release was receptor-mediated in both adult and developing mouse hippocampus. In adults, only NO-generating compounds, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and hydroxylamine reduced the release, as did also NO synthase inhibitors, 7-nitroindazole and nitroarginine, indicating that the release is mediated by the NO/cGMP pathway. On the other hand, the regulation of the NMDA-evoked taurine release proved to be somewhat complex in the immature hippocampus. It was not affected by the NOergic compounds, but enhanced by the protein kinase C activator 4 beta-phorbol 12-myristate 13-acetate and adenosine receptor A(1) agonists, N(6)-cyclohexyladenosine and R(-)N(6)-(2-phenylisopropyl)adenosine in a receptor-mediated manner. The activation of both ionotropic 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors and metabotropic glutamate group I receptors also enhanced the evoked release. The NMDA-receptor-stimulated taurine release could be a part of the neuroprotective properties of taurine, being important particularly under cell-damaging conditions in the developing hippocampus and hence preventing excitotoxicity.

Short term treatment versus long term management of neck and back disability in older adults utilizing spinal manipulative therapy and supervised exercise: a parallel-group randomized clinical trial evaluating relative effectiveness and harms

PubMed Central

2014-01-01

Background Back and neck disability are frequent in older adults resulting in loss of function and independence. Exercise therapy and manual therapy, like spinal manipulative therapy (SMT), have evidence of short and intermediate term effectiveness for spinal disability in the general population and growing evidence in older adults. For older populations experiencing chronic spinal conditions, long term management may be more appropriate to maintain improvement and minimize the impact of future exacerbations. Research is limited comparing short courses of treatment to long term management of spinal disability. The primary aim is to compare the relative effectiveness of 12 weeks versus 36 weeks of SMT and supervised rehabilitative exercise (SRE) in older adults with back and neck disability. Methods/Design Randomized, mixed-methods, comparative effectiveness trial conducted at a university-affiliated research clinic in the Minneapolis/St. Paul, Minnesota metropolitan area. Participants Independently ambulatory community dwelling adults ≥ 65 years of age with back and neck disability of minimum 12 weeks duration (n = 200). Interventions 12 weeks SMT + SRE or 36 weeks SMT + SRE. Randomization Blocked 1:1 allocation; computer generated scheme, concealed in sequentially numbered, opaque, sealed envelopes. Blinding Functional outcome examiners are blinded to treatment allocation; physical nature of the treatments prevents blinding of participants and providers to treatment assignment. Primary endpoint 36 weeks post-randomization. Data collection Self-report questionnaires administered at 2 baseline visits and 4, 12, 24, 36, 52, and 78 weeks post-randomization. Primary outcomes include back and neck disability, measured by the Oswestry Disability Index and Neck Disability Index. Secondary outcomes include pain, general health status, improvement, self-efficacy, kinesiophobia, satisfaction, and medication use. Functional outcome assessment occurs

The circulation of the cerebrospinal fluid (CSF) in the spinal canal

NASA Astrophysics Data System (ADS)

Sanchez, Antonio L.; Martinez-Bazan, Carlos; Lasheras, Juan C.

2016-11-01

Cerebrospinal Fluid (CSF) is secreted in the choroid plexus in the lateral sinuses of the brain and fills the subarachnoid space bathing the external surfaces of the brain and the spinal canal. Absence of CSF circulation has been shown to impede its physiological function that includes, among others, supplying nutrients to neuronal and glial cells and removing the waste products of cellular metabolism. Radionuclide scanning images published by Di Chiro in 1964 showed upward migration of particle tracers from the lumbar region of the spinal canal, thereby suggesting the presence of an active bulk circulation responsible for bringing fresh CSF into the spinal canal and returning a portion of it to the cranial vault. However, the existence of this slow moving bulk circulation in the spinal canal has been a subject of dispute for the last 50 years. To date, there has been no physical explanation for the mechanism responsible for the establishment of such a bulk motion. We present a perturbation analysis of the flow in an idealized model of the spinal canal and show how steady streaming could be responsible for the establishment of such a circulation. The results of this analysis are compared to flow measurements conducted on in-vitro models of the spinal canal of adult humans.

Phenotyping of nNOS neurons in the postnatal and adult female mouse hypothalamus.

PubMed

Chachlaki, Konstantina; Malone, Samuel A; Qualls-Creekmore, Emily; Hrabovszky, Erik; Münzberg, Heike; Giacobini, Paolo; Ango, Fabrice; Prevot, Vincent

2017-10-15

Neurons expressing nitric oxide (NO) synthase (nNOS) and thus capable of synthesizing NO play major roles in many aspects of brain function. While the heterogeneity of nNOS-expressing neurons has been studied in various brain regions, their phenotype in the hypothalamus remains largely unknown. Here we examined the distribution of cells expressing nNOS in the postnatal and adult female mouse hypothalamus using immunohistochemistry. In both adults and neonates, nNOS was largely restricted to regions of the hypothalamus involved in the control of bodily functions, such as energy balance and reproduction. Labeled cells were found in the paraventricular, ventromedial, and dorsomedial nuclei as well as in the lateral area of the hypothalamus. Intriguingly, nNOS was seen only after the second week of life in the arcuate nucleus of the hypothalamus (ARH). The most dense and heavily labeled population of cells was found in the organum vasculosum laminae terminalis (OV) and the median preoptic nucleus (MEPO), where most of the somata of the neuroendocrine neurons releasing GnRH and controlling reproduction are located. A great proportion of nNOS-immunoreactive neurons in the OV/MEPO and ARH were seen to express estrogen receptor (ER) α. Notably, almost all ERα-immunoreactive cells of the OV/MEPO also expressed nNOS. Moreover, the use of EYFP Vglut2 , EYFP Vgat , and GFP Gad67 transgenic mouse lines revealed that, like GnRH neurons, most hypothalamic nNOS neurons have a glutamatergic phenotype, except for nNOS neurons of the ARH, which are GABAergic. Altogether, these observations are consistent with the proposed role of nNOS neurons in physiological processes. © 2017 Wiley Periodicals, Inc.

Effects of exercise on fitness and health of adults with spinal cord injury: A systematic review.

PubMed

van der Scheer, Jan W; Martin Ginis, Kathleen A; Ditor, David S; Goosey-Tolfrey, Victoria L; Hicks, Audrey L; West, Christopher R; Wolfe, Dalton L

2017-08-15

To synthesize and appraise research testing the effects of exercise interventions on fitness, cardiometabolic health, and bone health among adults with spinal cord injury (SCI). Electronic databases were searched (1980-2016). Included studies employed exercise interventions for a period ≥2 weeks, involved adults with acute or chronic SCI, and measured fitness (cardiorespiratory fitness, power output, or muscle strength), cardiometabolic health (body composition or cardiovascular risk factors), or bone health outcomes. Evidence was synthesized and appraised using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 211 studies met the inclusion criteria (22 acute, 189 chronic). For chronic SCI, GRADE confidence ratings were moderate to high for evidence showing exercise can improve all of the reviewed outcomes except bone health. For acute SCI, GRADE ratings were very low for all outcomes. For chronic SCI, there was low to moderate confidence in the evidence showing that 2-3 sessions/week of upper body aerobic exercise at a moderate to vigorous intensity for 20-40 minutes, plus upper body strength exercise (3 sets of 10 repetitions at 50%-80% 1-repetition maximum for all large muscle groups), can improve cardiorespiratory fitness, power output, and muscle strength. For chronic SCI, there was low to moderate confidence in the evidence showing that 3-5 sessions per week of upper body aerobic exercise at a moderate to vigorous intensity for 20-44 minutes can improve cardiorespiratory fitness, muscle strength, body composition, and cardiovascular risk. Exercise improves fitness and cardiometabolic health of adults with chronic SCI. The evidence on effective exercise types, frequencies, intensities, and durations should be used to formulate exercise guidelines for adults with SCI. © 2017 American Academy of Neurology.

An adult passive transfer mouse model to study desmoglein 3 signaling in pemphigus vulgaris

PubMed Central

Schulze, Katja; Galichet, Arnaud; Sayar, Beyza S.; Scothern, Anthea; Howald, Denise; Zymann, Hillard; Siffert, Myriam; Zenhäusern, Denise; Bolli, Reinhard; Koch, Peter J.; Garrod, David; Suter, Maja M.; Müller, Eliane J.

2011-01-01

Evidence has accumulated that changes in intracellular signaling downstream of desmoglein 3 (Dsg3) may play a significant role in epithelial blistering in the autoimmune disease pemphigus vulgaris (PV). Currently, most studies on PV involve passive transfer of pathogenic antibodies into neonatal mice which have not finalized epidermal morphogenesis, and do not permit analysis of mature hair follicles (HFs) and stem cell niches. To investigate Dsg3 antibody-induced signaling in the adult epidermis at defined stages of the HF cycle, we here developed a model with passive transfer of the monospecific pathogenic Dsg3 antibody AK23 into adult 8-week-old C57Bl/6J mice. Validated using histopathological and molecular methods, we found that this model faithfully recapitulates major features described in PV patients and PV models. Two hours after AK23 transfer we observed widening of intercellular spaces between desmosomes and EGFR activation, followed by increased Myc expression and epidermal hyperproliferation, desmosomal Dsg3 depletion and predominant blistering in HFs and oral mucosa. These data confirm that the adult passive transfer mouse model is ideally suited for detailed studies of Dsg3 antibody-mediated signaling in adult skin, providing the basis for investigations on novel keratinocyte-specific therapeutic strategies. PMID:21956125

Spinal sagittal contour affecting falls: cut-off value of the lumbar spine for falls.

PubMed

Ishikawa, Yoshinori; Miyakoshi, Naohisa; Kasukawa, Yuji; Hongo, Michio; Shimada, Yoichi

2013-06-01

Spinal deformities reportedly affect postural instability or falls. To prevent falls in clinical settings, the determination of a cut-off angle of spinal sagittal contour associated with increase risk for falls would be useful for screening for high-risk fallers. The purpose of this study was to calculate the spinal sagittal contour angle associated with increased risk for falls during medical checkups in community dwelling elders. The subjects comprised 213 patients (57 men, 156 women) with a mean age of 70.1 years (range, 55-85 years). The upright and flexion/extension thoracic kyphosis and lumbar lordosis angles, and the spinal inclination were evaluated with SpinalMouse(®). Postural instability was evaluated by stabilometry, using the total track length (LNG), enveloped areas (ENV), and track lengths in the lateral and anteroposterior directions (X LNG and Y LNG, respectively). The back extensor strength (BES) was measured using a strain-gauge dynamometer. The relationships among the parameters were analyzed statistically. Age, lumbar lordosis, spinal inclination, LNG, X LNG, Y LNG, and BES were significantly associated with falls (P<0.05). Multivariate logistic regression analyses revealed that lumbar lordosis was the most significant factor (P<0.01). Univariate logistic regression analyses for falls about lumbar lordosis angles revealed that angles of 3° and less were significant for falls. The present findings suggest that increased age, spinal inclination, LNG, X LNG, Y LNG, and decreased BES and lumbar lordosis, are associated with falls. An angle of lumbar lordosis of 3° or less was associated with falls in these community-dwelling elders. Copyright © 2012 Elsevier B.V. All rights reserved.

Prostacyclin regulates spinal nociceptive processing through cyclic adenosine monophosphate-induced translocation of glutamate receptors.

PubMed

Schuh, Claus Dieter; Brenneis, Christian; Zhang, Dong Dong; Angioni, Carlo; Schreiber, Yannick; Ferreiros-Bouzas, Nerea; Pierre, Sandra; Henke, Marina; Linke, Bona; Nüsing, Rolf; Scholich, Klaus; Geisslinger, Gerd

2014-02-01

Prostacyclin (PGI2) is known to be an important mediator of peripheral pain sensation (nociception) whereas little is known about its role in central sensitization. The levels of the stable PGI2-metabolite 6-keto-prostaglandin F1α (6-keto-PGF1α) and of prostaglandin E2 (PGE2) were measured in the dorsal horn with the use of mass spectrometry after peripheral inflammation. Expression of the prostanoid receptors was determined by immunohistology. Effects of prostacyclin receptor (IP) activation on spinal neurons were investigated with biochemical assays (cyclic adenosine monophosphate-, glutamate release-measurement, Western blot analysis) in embryonic cultures and adult spinal cord. The specific IP antagonist Cay10441 was applied intrathecally after zymosan-induced mechanical hyperalgesia in vivo. Peripheral inflammation caused a significant increase of the stable PGI2 metabolite 6-keto-PGF1α in the dorsal horn of wild-type mice (n = 5). IP was located on spinal neurons and did not colocalize with the prostaglandin E2 receptors EP2 or EP4. The selective IP-agonist cicaprost increased cyclic adenosine monophosphate synthesis in spinal cultures from wild-type but not from IP-deficient mice (n = 5-10). The combination of fluorescence-resonance-energy transfer-based cyclic adenosine monophosphate imaging and calcium imaging showed a cicaprost-induced cyclic adenosine monophosphate synthesis in spinal cord neurons (n = 5-6). Fittingly, IP activation increased glutamate release from acute spinal cord sections of adult mice (n = 13-58). Cicaprost, but not agonists for EP2 and EP4, induced protein kinase A-dependent phosphorylation of the GluR1 subunit and its translocation to the membrane. Accordingly, intrathecal administration of the IP receptor antagonist Cay10441 had an antinociceptive effect (n = 8-11). Spinal prostacyclin synthesis during early inflammation causes the recruitment of GluR1 receptors to membrane fractions, thereby augmenting the onset of central

A pilot study on the use of cerebrospinal fluid cell-free DNA in intramedullary spinal ependymoma.

PubMed

Connolly, Ian David; Li, Yingmei; Pan, Wenying; Johnson, Eli; You, Linya; Vogel, Hannes; Ratliff, John; Hayden Gephart, Melanie

2017-10-01

Cerebrospinal fluid (CSF) represents a promising source of cell-free DNA (cfDNA) for tumors of the central nervous system. A CSF-based liquid biopsy may obviate the need for riskier tissue biopsies and serve as a means for monitoring tumor recurrence or response to therapy. Spinal ependymomas most commonly occur in adults, and aggressive resection must be delicately balanced with the risk of injury to adjacent normal tissue. In patients with subtotal resection, recurrence commonly occurs. A CSF-based liquid biopsy matched to the patient's spinal ependymoma mutation profile has potential to be more sensitive then surveillance MRI, but the utility has not been well characterized for tumors of the spinal cord. In this study, we collected matched blood, tumor, and CSF samples from three adult patients with WHO grade II intramedullary spinal ependymoma. We performed whole exome sequencing on matched tumor and normal DNA to design Droplet Digital™ PCR (ddPCR) probes for tumor and wild-type mutations. We then interrogated CSF samples for tumor-derived cfDNA by performing ddPCR on extracted cfDNA. Tumor cfDNA was not reliably detected in the CSF of our cohort. Anatomic sequestration and low grade of intramedullary spinal cord tumors likely limits the role of CSF liquid biopsy.

Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar

PubMed Central

Wu, Di; Klaw, Michelle C.; Connors, Theresa; Kholodilov, Nikolai; Burke, Robert E.

2015-01-01

After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to: (1) the presence of inhibitory molecules, e.g., chondroitin sulfate proteoglycans (CSPG), in the glial scar at the lesion; and (2) the diminished growth capacity of adult neurons. We sought to determine whether expressing a constitutively active form of the GTPase Rheb (caRheb) in adult neurons after a complete SCI in rats improves intrinsic growth potential to result in axon regeneration out of a growth-supportive peripheral nerve grafted (PNG) into the SCI cavity. We also hypothesized that treating the glial scar with chondroitinase ABC (ChABC), which digests CSPG, would further allow caRheb-transduced neurons to extend axons across the distal graft interface. We found that targeting this pathway at a clinically relevant post-SCI time point improves both sprouting and regeneration of axons. CaRheb increased the number of axons, but not the number of neurons, that projected into the PNG, indicative of augmented sprouting. We also saw that caRheb enhanced sprouting far rostral to the injury. CaRheb not only increased growth rostral and into the graft, it also resulted in significantly more regrowth of axons across a ChABC-treated scar into caudal spinal cord. CaRheb+ neurons had higher levels of growth-associated-43, suggestive of a newly identified mechanism for mTOR-mediated enhancement of regeneration. Thus, we demonstrate for the first time that simultaneously addressing intrinsic and scar-associated, extrinsic impediments to regeneration results in significant regrowth beyond an extremely challenging, complete SCI site. SIGNIFICANCE STATEMENT After spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to the diminished growth capacity of adult neurons and the presence of inhibitory molecules in the scar at the lesion. We sought to simultaneously counter both of these obstacles to achieve more robust

Expressing Constitutively Active Rheb in Adult Neurons after a Complete Spinal Cord Injury Enhances Axonal Regeneration beyond a Chondroitinase-Treated Glial Scar.

PubMed

Wu, Di; Klaw, Michelle C; Connors, Theresa; Kholodilov, Nikolai; Burke, Robert E; Tom, Veronica J

2015-08-05

After a spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to: (1) the presence of inhibitory molecules, e.g., chondroitin sulfate proteoglycans (CSPG), in the glial scar at the lesion; and (2) the diminished growth capacity of adult neurons. We sought to determine whether expressing a constitutively active form of the GTPase Rheb (caRheb) in adult neurons after a complete SCI in rats improves intrinsic growth potential to result in axon regeneration out of a growth-supportive peripheral nerve grafted (PNG) into the SCI cavity. We also hypothesized that treating the glial scar with chondroitinase ABC (ChABC), which digests CSPG, would further allow caRheb-transduced neurons to extend axons across the distal graft interface. We found that targeting this pathway at a clinically relevant post-SCI time point improves both sprouting and regeneration of axons. CaRheb increased the number of axons, but not the number of neurons, that projected into the PNG, indicative of augmented sprouting. We also saw that caRheb enhanced sprouting far rostral to the injury. CaRheb not only increased growth rostral and into the graft, it also resulted in significantly more regrowth of axons across a ChABC-treated scar into caudal spinal cord. CaRheb(+) neurons had higher levels of growth-associated-43, suggestive of a newly identified mechanism for mTOR-mediated enhancement of regeneration. Thus, we demonstrate for the first time that simultaneously addressing intrinsic and scar-associated, extrinsic impediments to regeneration results in significant regrowth beyond an extremely challenging, complete SCI site. After spinal cord injury (SCI), CNS axons fail to regenerate, resulting in permanent deficits. This is due to the diminished growth capacity of adult neurons and the presence of inhibitory molecules in the scar at the lesion. We sought to simultaneously counter both of these obstacles to achieve more robust regeneration after

Isolation, characterization and propagation of mitotically active germ cells from adult mouse and human ovaries

PubMed Central

Woods, Dori C; Tilly, Jonathan L

2017-01-01

Accruing evidence indicates that production of new oocytes (oogenesis) and their enclosure by somatic cells (folliculogenesis) are processes not limited to the perinatal period in mammals. Endpoints ranging from oocyte counts to genetic lineage tracing and transplantation experiments support a paradigm shift in reproductive biology involving active renewal of oocyte-containing follicles during postnatal life. The recent purification of mitotically active oocyte progenitor cells, termed female germline stem cells (fGSCs) or oogonial stem cells (OSCs), from mouse and human ovaries opens up new avenues for research into the biology and clinical utility of these cells. Here we detail methods for the isolation of mouse and human OSCs from adult ovarian tissue, cultivation of the cells after purification, and characterization of the cells before and after ex vivo expansion. The latter methods include analysis of germ cell–specific markers and in vitro oogenesis, as well as the use of intraovarian transplantation to test the oocyte-forming potential of OSCs in vivo. PMID:23598447

Activity-dependent plasticity in spinal cord injury

PubMed Central

Lynskey, James V.; Belanger, Adam; Jung, Ranu

2008-01-01

The adult mammalian central nervous system (CNS) is capable of considerable plasticity, both in health and disease. After spinal neurotrauma, the degrees and extent of neuroplasticity and recovery depend on multiple factors, including the level and extent of injury, postinjury medical and surgical care, and rehabilitative interventions. Rehabilitation strategies focus less on repairing lost connections and more on influencing CNS plasticity for regaining function. Current evidence indicates that strategies for rehabilitation, including passive exercise, active exercise with some voluntary control, and use of neuroprostheses, can enhance sensorimotor recovery after spinal cord injury (SCI) by promoting adaptive structural and functional plasticity while mitigating maladaptive changes at multiple levels of the neuraxis. In this review, we will discuss CNS plasticity that occurs both spontaneously after SCI and in response to rehabilitative therapies. PMID:18566941

Exploring factors facilitating adults with spinal cord injury rejoining the workforce: a pilot study.

PubMed

Wilbanks, Susan R; Ivankova, Nataliya V

2015-01-01

Return-to-work (RTW) rates after spinal cord injury (SCI) in the USA are very low and are continuing to decline. Previous research has attempted to identify factors facilitating RTW; however, the phenomenon of RTW involves many personal factors and predicting RTW success remains difficult. The purpose of this pilot study was to explore the factors facilitating adults with SCI rejoining the workforce in an urban area in order to identify items that may be emphasized in the rehabilitation process. The study was completed using qualitative methods. Four adults who had acquired a traumatic SCI in adulthood and were currently employed participated. Their experiences in RTW after injury were collected via semi-structured interviews and photography of assistive devices. The most common facilitating factor was motivation, with family and rehabilitation professionals serving as extrinsic motivators. Other facilitators were resources and perceived benefits. Motivation and resources were important facilitators, including rehabilitation professional's personal influence and therapies, and resource assistance from state agencies. The results indicate that practitioners can play an important role in influencing RTW, and resources from state agencies are helpful when individuals know how to access and utilize them. Assistive technology supports successful return to work after SCI. Motivation strongly influences return to work after SCI and can be influenced by rehabilitation professionals, family and community members. Patients should be well informed about how to access assistance programs such as vocational rehabilitation.

Case studies of spinal deformities in ornamental koi, Cyprinus carpio L.

PubMed

Chin, H N; Loh, R; Hong, Y C; Gibson-Kueh, S

2017-01-01

This is a study of vertebral deformities in ornamental koi based on computed radiography and skeletons cleaned by dermestid beetles (Dermestes maculatus). All koi developed gradual onset of swimming abnormalities as adults. Extensive intervertebral osteophyte formation correlated with age of fish and was associated with hindquarter paresis in one koi. Vertebral compression and fusion were the most common spinal deformities occurring at multiple sites, similar to findings in other farmed fish. Site-specific spinal deformities were thought to develop due to differences in swimming behaviour and rates of vertebral growth. One koi had offspring with spinal deformities. Spinal deformities are significant problems in both European and Australian food fish hatcheries. The heritability of vertebral deformities in farmed fish is reportedly low unless there is concurrent poor husbandry or nutritional deficiencies. The specific aetiologies for vertebral deformities in koi in this study could not be ascertained. Current knowledge on spinal deformities in the better studied European food fish species suggests multifactorial aetiologies. Future research should include prospective longitudinal studies of larger numbers of koi from hatch and consideration of all potential risk factors such as husbandry, nutrition, temperature, photoperiod and genetics. © 2016 John Wiley & Sons Ltd.

Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries

PubMed Central

Musienko, Pavel; van den Brand, Rubia; Märzendorfer, Olivia; Roy, Roland R.; Gerasimenko, Yury; Edgerton, V. Reggie; Courtine, Grégoire

2012-01-01

Descending monoaminergic inputs markedly influence spinal locomotor circuits, but the functional relationships between specific receptors and the control of walking behavior remain poorly understood. To identify these interactions, we manipulated serotonergic, dopaminergic, and noradrenergic neural pathways pharmacologically during locomotion enabled by electrical spinal cord stimulation in adult spinal rats in vivo. Using advanced neurobiomechanical recordings and multidimensional statistical procedures, we reveal that each monoaminergic receptor modulates a broad but distinct spectrum of kinematic, kinetic and EMG characteristics, which we expressed into receptor–specific functional maps. We then exploited this catalogue of monoaminergic tuning functions to devise optimal pharmacological combinations to encourage locomotion in paralyzed rats. We found that, in most cases, receptor-specific modulatory influences summed near algebraically when stimulating multiple pathways concurrently. Capitalizing on these predictive interactions, we elaborated a multidimensional monoaminergic intervention that restored coordinated hindlimb locomotion with normal levels of weight bearing and partial equilibrium maintenance in spinal rats. These findings provide new perspectives on the functions of and interactions between spinal monoaminergic receptor systems in producing stepping, and define a framework to tailor pharmacotherapies for improving neurological functions after CNS disorders. PMID:21697376

Vertebral column resection for the treatment of severe spinal deformity.

PubMed

Lenke, Lawrence G; Sides, Brenda A; Koester, Linda A; Hensley, Marsha; Blanke, Kathy M

2010-03-01

The ability to treat severe pediatric and adult spinal deformities through an all-posterior vertebral column resection (VCR) has obviated the need for a circumferential approach in primary and revision surgery, but there is limited literature evaluating this new approach. Our purpose was therefore to provide further support of this technique. We reviewed 43 patients who underwent a posterior-only VCR using pedicle screws, anteriorly positioned cages, and intraoperative spinal cord monitoring between 2002 and 2006. Diagnoses included severe scoliosis, global kyphosis, angular kyphosis, or kyphoscoliosis. Forty (93%) procedures were performed at L1 or cephalad in the spinal cord (SC) territory. Seven patients (18%) lost intraoperative neurogenic monitoring evoked potentials (NMEPs) data during correction with data returning to baseline after prompt surgical intervention. All patients after surgery were at their baseline or showed improved SC function, whereas no one worsened. Two patients had nerve root palsies postoperatively, which resolved spontaneously at 6 months and 2 weeks. Spinal cord monitoring (specifically NMEP) is mandatory to prevent neurologic complications. Although technically challenging, a single-stage approach offers dramatic correction in both primary and revision surgery of severe spinal deformities. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

S-acylation of SOD1, CCS, and a stable SOD1-CCS heterodimer in human spinal cords from ALS and non-ALS subjects.

PubMed

Antinone, Sarah E; Ghadge, Ghanashyam D; Ostrow, Lyle W; Roos, Raymond P; Green, William N

2017-01-25

Previously, we found that human Cu, Zn-superoxide dismutase (SOD1) is S-acylated (palmitoylated) in vitro and in amyotrophic lateral sclerosis (ALS) mouse models, and that S-acylation increased for ALS-causing SOD1 mutants relative to wild type. Here, we use the acyl resin-assisted capture (acyl-RAC) assay to demonstrate S-acylation of SOD1 in human post-mortem spinal cord homogenates from ALS and non-ALS subjects. Acyl-RAC further revealed that endogenous copper chaperone for SOD1 (CCS) is S-acylated in both human and mouse spinal cords, and in vitro in HEK293 cells. SOD1 and CCS formed a highly stable heterodimer in human spinal cord homogenates that was resistant to dissociation by boiling, denaturants, or reducing agents and was not observed in vitro unless both SOD1 and CCS were overexpressed. Cysteine mutations that attenuate SOD1 maturation prevented the SOD1-CCS heterodimer formation. The degree of S-acylation was highest for SOD1-CCS heterodimers, intermediate for CCS monomers, and lowest for SOD1 monomers. Given that S-acylation facilitates anchoring of soluble proteins to cell membranes, our findings suggest that S-acylation and membrane localization may play an important role in CCS-mediated SOD1 maturation. Furthermore, the highly stable S-acylated SOD1-CCS heterodimer may serve as a long-lived maturation intermediate in human spinal cord.

S-acylation of SOD1, CCS, and a stable SOD1-CCS heterodimer in human spinal cords from ALS and non-ALS subjects

PubMed Central

Antinone, Sarah E.; Ghadge, Ghanashyam D.; Ostrow, Lyle W.; Roos, Raymond P.; Green, William N.

2017-01-01

Previously, we found that human Cu, Zn-superoxide dismutase (SOD1) is S-acylated (palmitoylated) in vitro and in amyotrophic lateral sclerosis (ALS) mouse models, and that S-acylation increased for ALS-causing SOD1 mutants relative to wild type. Here, we use the acyl resin-assisted capture (acyl-RAC) assay to demonstrate S-acylation of SOD1 in human post-mortem spinal cord homogenates from ALS and non-ALS subjects. Acyl-RAC further revealed that endogenous copper chaperone for SOD1 (CCS) is S-acylated in both human and mouse spinal cords, and in vitro in HEK293 cells. SOD1 and CCS formed a highly stable heterodimer in human spinal cord homogenates that was resistant to dissociation by boiling, denaturants, or reducing agents and was not observed in vitro unless both SOD1 and CCS were overexpressed. Cysteine mutations that attenuate SOD1 maturation prevented the SOD1-CCS heterodimer formation. The degree of S-acylation was highest for SOD1-CCS heterodimers, intermediate for CCS monomers, and lowest for SOD1 monomers. Given that S-acylation facilitates anchoring of soluble proteins to cell membranes, our findings suggest that S-acylation and membrane localization may play an important role in CCS-mediated SOD1 maturation. Furthermore, the highly stable S-acylated SOD1-CCS heterodimer may serve as a long-lived maturation intermediate in human spinal cord. PMID:28120938

Dwarfism and age-associated spinal degeneration of heterozygote cmd mice defective in aggrecan

PubMed Central

Watanabe, Hideto; Nakata, Ken; Kimata, Koji; Nakanishi, Isao; Yamada, Yoshihiko

1997-01-01

Mouse cartilage matrix deficiency (cmd) is an autosomal recessive disorder caused by a genetic defect of aggrecan, a large chondroitin sulfate proteoglycan in cartilage. The homozygotes (−/−) are characterized by cleft palate and short limbs, tail, and snout. They die just after birth because of respiratory failure, and the heterozygotes (+/−) appear normal at birth. Here we report that the heterozygotes show dwarfism and develop spinal misalignment with age. Within 19 months of age, they exhibit spastic gait caused by misalignment of the cervical spine and die because of starvation. Histological examination revealed a high incidence of herniation and degeneration of vertebral discs. Electron microscopy showed a degeneration of disc chondrocytes in the heterozygotes. These findings may facilitate the identification of mutations in humans predisposed to spinal degeneration. PMID:9192671

Anthocyanins protect against LPS-induced oxidative stress-mediated neuroinflammation and neurodegeneration in the adult mouse cortex.

PubMed

Khan, Muhammad Sohail; Ali, Tahir; Kim, Min Woo; Jo, Myeung Hoon; Jo, Min Gi; Badshah, Haroon; Kim, Myeong Ok

2016-11-01

Several studies provide evidence that reactive oxygen species (ROS) are key mediators of various neurological disorders. Anthocyanins are polyphenolic compounds and are well known for their anti-oxidant and neuroprotective effects. In this study, we investigated the neuroprotective effects of anthocyanins (extracted from black soybean) against lipopolysaccharide (LPS)-induced ROS-mediated neuroinflammation and neurodegeneration in the adult mouse cortex. Intraperitoneal injection of LPS (250 μg/kg) for 7 days triggers elevated ROS and oxidative stress, which induces neuroinflammation and neurodegeneration in the adult mouse cortex. Treatment with 24 mg/kg/day of anthocyanins for 14 days in LPS-injected mice (7 days before and 7 days co-treated with LPS) attenuated elevated ROS and oxidative stress compared to mice that received LPS-injection alone. The immunoblotting results showed that anthocyanins reduced the level of the oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). The immunoblotting and morphological results showed that anthocyanins treatment significantly reduced LPS-induced-ROS-mediated neuroinflammation through inhibition of various inflammatory mediators, such as IL-1β, TNF-α and the transcription factor NF- k B. Anthocyanins treatment also reduced activated astrocytes and microglia in the cortex of LPS-injected mice, as indicated by reductions in GFAP and Iba-1, respectively. Anthocyanins also prevent overexpression of various apoptotic markers, i.e., Bax, cytosolic cytochrome C, cleaved caspase-3 and PARP-1. Immunohistochemical fluoro-jade B (FJB) and Nissl staining indicated that anthocyanins prevent LPS-induced neurodegeneration in the mouse cortex. Our results suggest that dietary flavonoids, such as anthocyanins, have antioxidant and neuroprotective activities that could be beneficial to various neurological disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Spinal injury - resources

MedlinePlus

Resources - spinal injury ... The following organizations are good resources for information on spinal injury : National Institute of Neurological Disorders and Stroke -- www.ninds.nih.gov/Disorders/All-Disorders/Spinal-Cord- ...

Spinal cord injuries in Australian footballers.

PubMed

2003-07-01

Acute spinal cord injury is a serious concern in football, particularly the rugby codes. This Australia-wide study covers the years 1986-1996 and data are compared with those from a previous identical study for 1960-1985. A retrospective review of 80 players with a documented acute spinal cord injury admitted to the six spinal cord injury units in Australia. Personal interview was carried out in 85% of the participants to determine the injury circumstances and the level of compensation. The severity of the neurological deficit and the functional recovery were determined (Frankel grade). The annual incidence of injuries for all codes combined did not change over the study period, but there was some decrease in rugby union and an increase in rugby league. In particular there was a significant decline in the incidence of adult rugby union injuries (P = 0.048). Scrum injuries in union have decreased subsequent to law changes in 1985, particularly in schoolboys, although ruck and maul injuries are increasing; 39% of scrum injuries occurred in players not in their regular position. Tackles were the most common cause of injury in league, with two-on-one tackles accounting for nearly half of these. Schoolboy injuries tended to mirror those in adults, but with a lower incidence. Over half of the players remain wheelchair-dependent, and 10% returned to near-normality. Six players (7.5%) died as a result of their injuries. The rugby codes must be made safer by appropriate preventative strategies and law changes. In particular, attention is necessary for tackle injuries in rugby league and players out of regular position in scrummage. Compensation for injured players is grossly inadequate. There is an urgent need to establish a national registry to analyse these injuries prospectively.

Effects of core instability strength training on trunk muscle strength, spinal mobility, dynamic balance and functional mobility in older adults.

PubMed

Granacher, Urs; Lacroix, Andre; Muehlbauer, Thomas; Roettger, Katrin; Gollhofer, Albert

2013-01-01

Age-related postural misalignment, balance deficits and strength/power losses are associated with impaired functional mobility and an increased risk of falling in seniors. Core instability strength training (CIT) involves exercises that are challenging for both trunk muscles and postural control and may thus have the potential to induce benefits in trunk muscle strength, spinal mobility and balance performance. The objective was to investigate the effects of CIT on measures of trunk muscle strength, spinal mobility, dynamic balance and functional mobility in seniors. Thirty-two older adults were randomly assigned to an intervention group (INT; n = 16, aged 70.8 ± 4.1 years) that conducted a 9-week progressive CIT or to a control group (n = 16, aged 70.2 ± 4.5 years). Maximal isometric strength of the trunk flexors/extensors/lateral flexors (right, left)/rotators (right, left) as well as of spinal mobility in the sagittal and the coronal plane was measured before and after the intervention program. Dynamic balance (i.e. walking 10 m on an optoelectric walkway, the Functional Reach test) and functional mobility (Timed Up and Go test) were additionally tested. Program compliance was excellent with participants of the INT group completing 92% of the training sessions. Significant group × test interactions were found for the maximal isometric strength of the trunk flexors (34%, p < 0.001), extensors (21%, p < 0.001), lateral flexors (right: 48%, p < 0.001; left: 53%, p < 0.001) and left rotators (42%, p < 0.001) in favor of the INT group. Further, training-related improvements were found for spinal mobility in the sagittal (11%, p < 0.001) and coronal plane (11%, p = 0.06) directions, for stride velocity (9%, p < 0.05), the coefficient of variation in stride velocity (31%, p < 0.05), the Functional Reach test (20%, p < 0.05) and the Timed Up and Go test (4%, p < 0.05) in favor of the INT group. CIT proved to be a feasible exercise program for seniors with a high

Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2-positive cells

PubMed Central

2012-01-01

Background In contrast to mammals, amphibians, such as adult urodeles (for example, newts) and anuran larvae (for example, Xenopus) can regenerate their spinal cord after injury. However, the cellular and molecular mechanisms involved in this process are still poorly understood. Results Here, we report that tail amputation results in a global increase of Sox2 levels and proliferation of Sox2+ cells. Overexpression of a dominant negative form of Sox2 diminished proliferation of spinal cord resident cells affecting tail regeneration after amputation, suggesting that spinal cord regeneration is crucial for the whole process. After spinal cord transection, Sox2+ cells are found in the ablation gap forming aggregates. Furthermore, Sox2 levels correlated with regenerative capabilities during metamorphosis, observing a decrease in Sox2 levels at non-regenerative stages. Conclusions Sox2+ cells contribute to the regeneration of spinal cord after tail amputation and transection. Sox2 levels decreases during metamorphosis concomitantly with the lost of regenerative capabilities. Our results lead to a working hypothesis in which spinal cord damage activates proliferation and/or migration of Sox2+ cells, thus allowing regeneration of the spinal cord after tail amputation or reconstitution of the ependymal epithelium after spinal cord transection. PMID:22537391

Anatomical study of blood supply to the cervical spinal cord in the guinea pig.

PubMed

Mazensky, David; Danko, Jan; Petrovova, Eva; Flesarova, Slavka; Supuka, Peter; Supukova, Anna; Luptakova, Lenka; Purzyc, Halina

2015-06-01

The aim of this study was to describe the arterial arrangement of the cervical spinal cord in the guinea pig. The study was carried out on 20 adult English self guinea pigs using corrosion and dissection technique. Batson's corrosion casting kit no. 17(©) was used as a casting medium. The origin of the ventral spinal artery from the left vertebral artery was found on average in 35% of the cases and from the right vertebral artery on average in 40% of the cases. The ventral spinal artery with origin from the anastomosis of two medial branches was found on average in 25% of the cases. The presence of ventral radicular branches of rami spinales entering the ventral spinal artery in the cervical region was observed in 42% of the cases on the right side and in 58% of the cases on the left side. The presence of dorsal radicular branches of rami spinales that reached the spinal cord was observed in 63% of the cases on the left side and in 37% of the cases on the right side. The number of radicular branches supplying the spinal cord is greater in guinea pig than in humans. © 2014 Japanese Society of Animal Science.

Comprehensive interactome of Otx2 in the adult mouse neural retina.

PubMed

Fant, Bruno; Samuel, Alexander; Audebert, Stéphane; Couzon, Agnès; El Nagar, Salsabiel; Billon, Nathalie; Lamonerie, Thomas

2015-11-01

The Otx2 homeodomain transcription factor exerts multiple functions in specific developmental contexts, probably through the regulation of different sets of genes. Protein partners of Otx2 have been shown to modulate its activity. Therefore, the Otx2 interactome may play a key role in selecting a precise target-gene repertoire, hence determining its function in a specific tissue. To address the nature of Otx2 interactome, we generated a new recombinant Otx2(CTAP-tag) mouse line, designed for protein complexes purification. We validated this mouse line by establishing the Otx2 interactome in the adult neural retina. In this tissue, Otx2 is thought to have overlapping function with its paralog Crx. Our analysis revealed that, in contrary to Crx, Otx2 did not develop interactions with proteins that are known to regulate phototransduction genes but showed specific partnership with factors associated with retinal development. The relationship between Otx2 and Crx in the neural retina should therefore be considered as complementarity rather than redundancy. Furthermore, study of the Otx2 interactome revealed strong associations with RNA processing and translation machineries, suggesting unexpected roles for Otx2 in the regulation of selected target genes all along the transcription/translation pathway. The Otx2(CTAP-tag) line, therefore, appears suitable for a systematic approach to Otx2 protein-protein interactions. genesis 53:685-694, 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Incidence of tissue coring with the 25-gauge Quincke and Whitacre spinal needles.

PubMed

Campbell, D C; Douglas, M J; Taylor, G

1996-01-01

Tissue cores, implanted into the subarachnoid space during subarachnoid injections, can develop into intraspinal lumbar epidermoid tumors. The availability of smaller needles has made spinal anesthesia more popular. Therefore, this prospective, randomized, blinded study was undertaken to determine whether tissue coring occurs with two of the currently used 25-gauge spinal needles. Fifteen 25-gauge Quincke and seventeen 25-gauge Whitacre spinal needles, in which cerebrospinal fluid (CSF) was not identified and the local anesthetic solution not injected, were obtained from adult male patients undergoing spinal anesthesia. The needles were then evaluated by a pathologist following randomization with similar sterile, unused spinal needles. Twenty additional needles, ten of each type, in which CSF was identified and through which local anesthetic was injected, were also randomized with similar sterile, unused spinal needles and examined. Tissue cores were identified in 12 of the 15 Quincke and 7 of the 17 Whitacre spinal needles in which CSF was not identified (P < .05). Of the 20 needles in which CSF was identified and local anesthetic injected, no tissue cores were identified in the 10 Whitacre needles and only one small tissue core was identified in the 10 Quincke needles. All the tissue cores were identified as fat tissue. The 25-gauge Quincke and 25-gauge Whitacre spinal needles currently used in anesthesia can produce tissue coring.

The spinal inhibition of N-type voltage-gated calcium channels selectively prevents scratching behavior in mice.

PubMed

Maciel, I S; Azevedo, V M; Pereira, T C; Bogo, M R; Souza, A H; Gomez, M V; Campos, M M

2014-09-26

The present study investigated the effects of pharmacological spinal inhibition of voltage-gated calcium channels (VGCC) in mouse pruritus. The epidural administration of P/Q-type MVIIC or PhTx3.3, L-type verapamil, T-type NNC 55-0396 or R-type SNX-482 VGCC blockers failed to alter the scratching behavior caused by the proteinase-activated receptor 2 (PAR-2) activator trypsin, injected into the mouse nape skin. Otherwise, trypsin-elicited pruritus was markedly reduced by the spinal administration of preferential N-type VGCC inhibitors MVIIA and Phα1β. Time-course experiments revealed that Conus magus-derived toxin MVIIA displayed significant effects when dosed from 1h to 4h before trypsin, while the anti-pruritic effects of Phα1β from Phoneutria nigriventer remained significant for up to 12h. In addition to reducing trypsin-evoked itching, MVIIA or Phα1β also prevented the itching elicited by intradermal (i.d.) injection of SLIGRL-NH2, compound 48/80 or chloroquine, although they did not affect H2O2-induced scratching behavior. Furthermore, the co-administration of MVIIA or Phα1β markedly inhibited the pruritus caused by the spinal injection of gastrin-releasing peptide (GRP), but not morphine. Notably, the epidural administration of MVIIA or Phα1β greatly prevented the chronic pruritus allied to dry skin model. However, either tested toxin failed to alter the edema formation or neutrophil influx caused by trypsin, whereas they significantly reduced the c-Fos activation in laminas I, II and III of the spinal cord. Our data bring novel evidence on itching transmission mechanisms, pointing out the therapeutic relevance of N-type VGCC inhibitors to control refractory pruritus. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

New products tissue-engineering in the treatment of spinal cord injury

NASA Astrophysics Data System (ADS)

Bolshakov, I. N.; Sergienko, V. I.; Kiselev, S. L.; Lagarkova, M. A.; Remigaylo, A. A.; Mihaylov, A. A.; Prokopenko, S. V.

2015-11-01

In the treatment of patients with complicated spinal cord injury the Russian Health spends about one million rubles for each patient in the acute and the interim period after the injury. The number of complicated spinal cord injury is different in geographical areas Russian Federation from 30 to 50 people per 1 million that is affected by the year 5600. Applied to the present surgical and pharmacological techniques provide unsatisfactory results or minimally effective treatment. Transplantation of 100 thousand neuronal mouse predecessors (24 rats) or human neuronal predecessors (18 rats) in the anatomical gap rat spinal cord, followed by analysis of neurological deficit. The neuro-matrix implantation in the rat spinal cord containing 100 thousand neuronal precursors hESC, repeatable control neuro-matrix transplantation, non-cell mass, eliminating neurological deficit for 14 weeks after transplantation about 5-9 points on the scale of the BBB. The cultivation under conditions in vitro human induced pluripotent stem cells on collagen-chitosan matrix (hIPSC) showed that neurons differentiated from induced pluripotent stem cells grown on scaffolds as compact groups and has no neurites. Cells do not penetrate into the matrix during long-term cultivation and formed near the surface of the spherical structures resembling neurospheres. At least 90% of the cells were positive for the neuronal marker tubulin b3. Further studies should be performed to examine the compatibility of neuronal cultures and matrices.

The modulatory role of alpha-melanocyte stimulating hormone administered spinally in the regulation of blood glucose level in d-glucose-fed and restraint stress mouse models.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-08-01

Alpha-melanocyte stimulating hormone (α-MSH) is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of α-MSH located in the spinal cord in the regulation of the blood glucose level were investigated in d-glucose-fed and immobilization stress (IMO) mouse models. We found in the present study that intrathecal (i.t.) injection with α-MSH alone did not affect the blood glucose level. However, i.t. administration with α-MSH reduced the blood glucose level in d-glucose-fed model. The plasma insulin level was increased in d-glucose-fed model and was further increased by α-MSH, whereas α-MSH did not affect plasma corticosterone level in d-glucose-fed model. In addition, i.t. administration with glucagon alone enhanced blood glucose level and, i.t. injection with glucagon also increased the blood glucose level in d-glucose-fed model. In contrasted to results observed in d-glucose-fed model, i.t. treatment with α-MSH caused enhancement of the blood glucose level in IMO model. The plasma insulin level was increased in IMO model. The increased plasma insulin level by IMO was reduced by i.t. treatment with α-MSH, whereas i.t. pretreatment with α-MSH did not affect plasma corticosterone level in IMO model. Taken together, although spinally located α-MSH itself does not alter the blood glucose level, our results suggest that the activation of α-MSH system located in the spinal cord play important modulatory roles for the reduction of the blood glucose level in d-glucose fed model whereas α-MSH is responsible for the up-regulation of the blood glucose level in IMO model. The enhancement of insulin release may be responsible for modulatory action of α-MSH in down-regulation of the blood glucose in d-glucose fed model whereas reduction of insulin release may be responsible for modulatory action of α-MSH in up-regulation of the blood glucose in IMO model. Copyright © 2014 Elsevier Ltd. All rights reserved.

A Cystine-Rich Whey Supplement (Immunocal®) Delays Disease Onset and Prevents Spinal Cord Glutathione Depletion in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

PubMed Central

Ross, Erika K.; Winter, Aimee N.; Wilkins, Heather M.; Sumner, Whitney A.; Duval, Nathan; Patterson, David; Linseman, Daniel A.

2014-01-01

Depletion of the endogenous antioxidant, glutathione (GSH), underlies progression of the devastating neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Thus, strategies aimed at elevating GSH may yield new therapeutics for ALS. Here, we investigated the effects of a unique non-denatured whey protein supplement, Immunocal®, in the transgenic Gly position 93 to Ala (G93A) mutant hSOD1 (hSOD1G93A) mouse model of ALS. Immunocal® is rich in the GSH precursor, cystine, and is therefore capable of bolstering GSH content. Transgenic hSOD1G93A mice receiving Immunocal® displayed a significant delay in disease onset compared to untreated hSOD1G93A controls. Additionally, Immunocal® treatment significantly decreased the rate of decline in grip strength and prevented disease-associated reductions in whole blood and spinal cord tissue GSH levels in end-stage hSOD1G93A mice. However, Immunocal® did not extend survival, likely due to its inability to preserve the mitochondrial GSH pool in spinal cord. Combination treatment with Immunocal® and the anti-glutamatergic compound, riluzole, delayed disease onset and extended survival in hSOD1G93A mice. These findings demonstrate that sustaining tissue GSH with Immunocal® only modestly delays disease onset and slows the loss of skeletal muscle strength in hSOD1G93A mice. Moreover, the inability of Immunocal® to rescue mitochondrial GSH in spinal cord provides a possible mechanism for its lack of effect on survival and is a limiting factor in the potential utility of this supplement as a therapeutic for ALS. PMID:26785244

Delayed Retroclival and Cervical Spinal Subdural Hematoma Complicated by Preexisting Chiari Malformation in Adult Trauma Patient.

PubMed

Nguyen, Ha Son; Choi, Hoon; Kurpad, Shekar; Soliman, Hesham

2017-09-01

Traumatic spinal subdural hematoma involving the retroclival region and upper cervical spine is a rare pathology. To our knowledge, there have only been 2 prior cases in an adult trauma patient. We describe a patient with preexisting Chiari 1 malformation, who recently sustained a unilateral type 1 occipital condyle fracture with associated disruption of the tectorial membrane and transverse ligament, which returned with a retroclival subdural hematoma extending down to C7, causing spinal cord compression and symptomatic obstructive hydrocephalus. A 30-year-old female sustained a motor vehicle collision. Computed tomography C spine revealed a type I occipital condyle fracture. Magnetic resonance imaging C spine demonstrated disruption of the tectorial membrane and avulsion of the transverse ligament at its attachment to the left C1 tubercle; moreover, there was a Chiari 1 malformation. The patient was neurologically intact. A halo was recommended, but the patient opted for an aspen collar with close management. She was discharged but returned 3 days later with apneic episodes, along with bradycardia and hypertension. She was promptly intubated. Computed tomography head showed interval ventricular enlargement. Magnetic resonance imaging C spine revealed a new ventral hematoma spanning the retroclival region to C7, most pronounced at C2-C3. On examination, she opened her eyes to pain, her pupils were equal and reactive, and she withdrew in all extremities. An external ventricular drain was emergently placed. She underwent a suboccipital craniectomy, C1-3 laminectomies, and occiput-C4 instrumented fusion. The dura was significantly tense, and no epidural hematoma was observed during lateral exploration. Postoperatively, she woke up well, exhibiting a nonfocal neurologic examination. A diagnostic angiogram was negative. She was extubated uneventfully, and the external ventricular drain was weaned off in 4 days. Traumatic spinal subdural hematoma involving both the

Idiopathic normal pressure hydrocephalus: theoretical concept of a spinal etiology.

PubMed

Hamlat, Abderrahmane; Abderrahmane, Hamlat; Sid-Ahmed, Seddik; Seddik, Sid-Ahmed; Adn, Mahmoudreza; Mahmoudreza, Adn; Askar, Brahim; Brahim, Askar; Pasqualini, Edouardo; Edouardo, Pasqualini

2006-01-01

Normal pressure hydrocephalus (NPH) is an adult syndrome characterised by a combination of gait disturbance, varying degrees of cognitive decline, urinary incontinence, ventricular enlargement and normal mean intracranial pressure. Since this syndrome was first described, its pathophysiology has been a matter of great debate, although it is now considered that NPH could be divided into two groups: cases with unknown etiology (idiopathic normal pressure hydrocephalus, or INPH) and those which develop from several known causes (such as trauma, meningitis or subarachnoid haemorrhage). The pathophysiology of INPH is still unclear and a matter of debate. In this manuscript, the current pathophysiological conditions of INPH are analysed and the authors put forward the theory that the disease is a dynamic syndrome which occurs in patients who have suffered a significant loss of spinal compliance over time. Consequently, intracranial pressure increases more during systole in INPH patients because it cannot be compensated for by the escape of CSF into the spinal canal as effectively, due to the reduced volume or lack of distension of the spinal canal. This leads to an increase in ventricular size and causes cumulative brain damage over a long period of time and accounts for the slow, progressive nature of NPH. The loss of spinal compliance with age is fundamental to the proposed theory which provides a theoretical justification for studying the spinal canal in INPH and investigating the relationship between the progressive narrowing of the spinal canal and the compensating ability of the craniospinal system.

Small mammal MRI imaging in spinal cord injury: a novel practical technique for using a 1.5 T MRI.

PubMed

Levene, Howard B; Mohamed, Feroze B; Faro, Scott H; Seshadri, Asha B; Loftus, Christopher M; Tuma, Ronald F; Jallo, Jack I

2008-07-30

The field of spinal cord injury research is an active one. The pathophysiology of SCI is not yet entirely revealed. As such, animal models are required for the exploration of new therapies and treatments. We present a novel technique using available hospital MRI machines to examine SCI in a mouse SCI model. The model is a 60 kdyne direct contusion injury in a mouse thoracic spine. No new electronic equipment is required. A 1.5T MRI machine with a human wrist coil is employed. A standard multisection 2D fast spin-echo (FSE) T2-weighted sequence is used for imaging the mouse. The contrast-to-noise ratio (CNR) between the injured and normal area of the spinal cord showed a three-fold increase in the contrast between these two regions. The MRI findings could be correlated with kinematic outcome scores of ambulation, such as BBB or BMS. The ability to follow a SCI in the same animal over time should improve the quality of data while reducing the quantity of animals required in SCI research. It is the aim of the authors to share this non-invasive technique and to make it available to the scientific research community.

Risk factors of non-specific spinal pain in childhood.

PubMed

Szita, Julia; Boja, Sara; Szilagyi, Agnes; Somhegyi, Annamaria; Varga, Peter Pal; Lazary, Aron

2018-05-01

Non-specific spinal pain can occur at all ages and current evidence suggests that pediatric non-specific spinal pain is predictive for adult spinal conditions. A 5-year long, prospective cohort study was conducted to identify the lifestyle and environmental factors leading to non-specific spinal pain in childhood. Data were collected from school children aged 7-16 years, who were randomly selected from three different geographic regions in Hungary. The risk factors were measured with a newly developed patient-reported questionnaire (PRQ). The quality of the instrument was assessed by the reliability with the test-retest method. Test (N = 952) and validity (N = 897) datasets were randomly formed. Risk factors were identified with uni- and multivariate logistic regression models and the predictive performance of the final model was evaluated using the receiver operating characteristic (ROC) method. The final model was built up by seven risk factors for spinal pain for days; age > 12 years, learning or watching TV for more than 2 h/day, uncomfortable school-desk, sleeping problems, general discomfort and positive familiar medical history (χ 2  = 101.07; df = 8; p < 0.001). The probabilistic performance was confirmed with ROC analysis on the test and validation cohorts (AUC = 0.76; 0.71). A simplified risk scoring system showed increasing possibility for non-specific spinal pain depending on the number of the identified risk factors (χ 2  = 65.0; df = 4; p < 0.001). Seven significant risk factors of non-specific spinal pain in childhood were identified using the new, easy to use and reliable PRQ which makes it possible to stratify the children according to their individual risk. These slides can be retrieved under Electronic Supplementary Material.

Tethered Spinal Cord Syndrome

MedlinePlus

... the spinal cord. These attachments cause an abnormal stretching of the spinal cord. The course of the ... the spinal cord. These attachments cause an abnormal stretching of the spinal cord. The course of the ...

(-)-Epigallocatechin-3-gallate (EGCG) modulates neurological function when intravenously infused in acute and, chronically injured spinal cord of adult rats.

PubMed

Renno, Waleed M; Al-Khaledi, Ghanim; Mousa, Alyaa; Karam, Shaima M; Abul, Habib; Asfar, Sami

2014-02-01

Spinal cord injury (SCI) causes severe and long lasting motor and sensory deficits, chronic pain, and autonomic dysreflexia. (-)-epigallocatechin-3-gallate (EGCG) has shown to produce neuroprotective effect in a broad range of neurodegenerative disease animal models. This study designed to test the efficacy of intravenous infusion of EGCG for 36 h, in acutely injured rats' spinal cord: within first 4 h post-injury and, in chronically SC injured rats: after one year of injury. Functional outcomes measured using standard BBB scale, The Louisville Swim Scale (LSS) and, pain behavior assessment tests. 72 Female adult rats subjected to moderate thoracic SCI using MASCIS Impactor, blindly randomized as the following: (I) Acute SCI + EGCG (II) Acute SCI + saline. (III) Chronic SCI + EGCG. (IV) Chronic SCI + saline and, sham SCI animals. EGCG i.v. treatment of acute and, chronic SCI animals resulted in significantly better recovery of motor and sensory functions, BBB and LSS (P < 0.005) and (P < 0.05) respectively. Tactile allodynia, mechanical nociception (P < 0.05) significantly improved. Paw withdrawal and, tail flick latencies increase significantly (P < 0.05). Moreover, in the EGCG treated acute SCI animals the percentage of lesion size area significantly reduced (P < 0.0001) and, the number of neurons in the spinal cord increased (P < 0.001). Percent areas of GAP-43 and GFAP immunohistochemistry showed significant (P < 0.05) increase. We conclude that the therapeutic window of opportunity for EGCG to depict neurological recovery in SCI animals, is viable up to one year post SCI when intravenously infused for 36 h. Copyright © 2013 Elsevier Ltd. All rights reserved.

Novel spinal instrumentation to enhance osteogenesis and fusion: a preliminary study.

PubMed

MacEwan, Matthew R; Talcott, Michael R; Moran, Daniel W; Leuthardt, Eric C

2016-09-01

OBJECTIVE Instrumented spinal fusion continues to exhibit high failure rates in patients undergoing multilevel lumbar fusion or pseudarthrosis revision; with Grade II or higher spondylolisthesis; or in those possessing risk factors such as obesity, tobacco use, or metabolic disorders. Direct current (DC) electrical stimulation of bone growth represents a unique surgical adjunct in vertebral fusion procedures, yet existing spinal fusion stimulators are not optimized to enhance interbody fusion. To develop an advanced method of applying DC electrical stimulation to promote interbody fusion, a novel osteogenic spinal system capable of routing DC through rigid instrumentation and into the vertebral bodies was fabricated. A pilot study was designed to assess the feasibility of osteogenic instrumentation and compare the ability of osteogenic instrumentation to promote successful interbody fusion in vivo to standard spinal instrumentation with autograft. METHODS Instrumented, single-level, posterior lumbar interbody fusion (PLIF) with autologous graft was performed at L4-5 in adult Toggenburg/Alpine goats, using both osteogenic spinal instrumentation (plus electrical stimulation) and standard spinal instrumentation (no electrical stimulation). At terminal time points (3 months, 6 months), animals were killed and lumbar spines were explanted for radiographic analysis using a SOMATOM Dual Source Definition CT Scanner and high-resolution Microcat II CT Scanner. Trabecular continuity, radiodensity within the fusion mass, and regional bone formation were examined to determine successful spinal fusion. RESULTS Quantitative analysis of average bone density in pedicle screw beds confirmed that electroactive pedicle screws used in the osteogenic spinal system focally enhanced bone density in instrumented vertebral bodies. Qualitative and quantitative analysis of high-resolution CT scans of explanted lumbar spines further demonstrated that the osteogenic spinal system induced solid

The Prevalence and Phenotype of Activated Microglia/Macrophages within the Spinal Cord of the Hyperostotic Mouse (twy/twy) Changes in Response to Chronic Progressive Spinal Cord Compression: Implications for Human Cervical Compressive Myelopathy

PubMed Central

Hirai, Takayuki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Takeura, Naoto; Watanabe, Shuji; Sugita, Daisuke; Yoshida, Ai; Johnson, William E. B.; Baba, Hisatoshi

2013-01-01

Background Cervical compressive myelopathy, e.g. due to spondylosis or ossification of the posterior longitudinal ligament is a common cause of spinal cord dysfunction. Although human pathological studies have reported neuronal loss and demyelination in the chronically compressed spinal cord, little is known about the mechanisms involved. In particular, the neuroinflammatory processes that are thought to underlie the condition are poorly understood. The present study assessed the localized prevalence of activated M1 and M2 microglia/macrophages in twy/twy mice that develop spontaneous cervical spinal cord compression, as a model of human disease. Methods Inflammatory cells and cytokines were assessed in compressed lesions of the spinal cords in 12-, 18- and 24-weeks old twy/twy mice by immunohistochemical, immunoblot and flow cytometric analysis. Computed tomography and standard histology confirmed a progressive spinal cord compression through the spontaneously development of an impinging calcified mass. Results The prevalence of CD11b-positive cells, in the compressed spinal cord increased over time with a concurrent decrease in neurons. The CD11b-positive cell population was initially formed of arginase-1- and CD206-positive M2 microglia/macrophages, which later shifted towards iNOS- and CD16/32-positive M1 microglia/macrophages. There was a transient increase in levels of T helper 2 (Th2) cytokines at 18 weeks, whereas levels of Th1 cytokines as well as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and macrophage antigen (Mac) −2 progressively increased. Conclusions Spinal cord compression was associated with a temporal M2 microglia/macrophage response, which may act as a possible repair or neuroprotective mechanism. However, the persistence of the neural insult also associated with persistent expression of Th1 cytokines and increased prevalence of activated M1 microglia/macrophages, which may lead to neuronal loss and demyelination

Compressive spinal epidural mass caused by Propionibacterium acnes.

PubMed

Ha, Austin Y; DePasse, J Mason; Piskorski, Anna; Treaba, Diana O; Kojic, Erna M; Daniels, Alan H

2016-05-01

Propionibacterium acnes is a gram-positive and facultative anaerobe bacillus that is found within sebaceous follicles of the human skin and recognized as a cause of infections after spinal surgery. To our knowledge, there has been no previously reported case of symptomatic compressive chronic inflammatory epidural mass caused by P. acnes in a patient with no prior spinal procedures. This study aimed to describe a case of primary spinal infection by P. acnes. This study is a case report of a condition not previously described in the literature. We present the history, physical examination, laboratory, radiographic, and histopathologic findings of a chronic inflammatory epidural mass caused by P. acnes in an immunocompetent adult male with no history of spinal surgery. A 51-year-old man presented to our clinic with sudden onset bilateral lower extremity weakness, inability to ambulate, and urinary retention. His past clinical history was remarkable only for hernia and left knee surgery but no spinal surgery. A year earlier, he had an infected draining abscess of the right axilla that was successfully managed medically. At presentation, his serum erythrocyte sedimentation rate and C-reactive protein were moderately elevated. Pan-spine magnetic resonance imaging was notable for a circumferential epidural mass from C5 to T6. He underwent emergent decompression; the mass was removed and sent for culture and pathologic evaluation. Cultures from all three specimens collected during surgery grew P. acnes, and the patient was successfully managed on intravenous ceftriaxone, while pathology revealed a chronic inflammatory reactive process. This is the first reported case of a primary spinal mass with chronic inflammatory features caused by P. acnes. In cases of epidural mass of unknown origin, both pathologic specimens and cultures should be obtained as slow-growing organisms may mimic oncologic processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Spinal deformities rehabilitation - state of the art review.

PubMed

Weiss, Hans-Rudolf

2010-12-24

Medical rehabilitation aims at an improvement in function, capacity and participation. For the rehabilitation of spinal deformities, the goal is to maintain function and prevent secondary symptoms in the short- and long-term. In patients with scoliosis, predictable signs and symptoms include pain and reduced pulmonary function. A Pub Med review was completed in order to reveal substantial evidence for inpatient rehabilitation as performed in Germany. No evidence has been found in general to support claims for actual inpatient rehabilitation programmes as used today. Nevertheless, as there is some evidence that inpatient rehabilitation may be beneficial to patients with spinal deformities complicated by certain additional conditions, the body of evidence there is for conservative treatment of spinal deformities has been reviewed in order to allow suggestions for outpatient conservative treatment and inpatient rehabilitation. Today, for both children and adolescents, we are able to offer intensive rehabilitation programmes lasting three to five days, which enable the patients to acquire the skills necessary to prevent postures fostering scoliosis in everyday life without missing too much of school teaching subjects at home. The secondary functional impairments adult scoliosis patients might have, as in the opinion of the author, still today require the time of 3-4 weeks in the clinical in-patient setting. Time to address psychosocial as well as somatic limitations, namely chronic pains and cardiorespiratory malfunction is needed to preserve the patients working capability in the long-term. Outpatient treatment/rehabilitation is sufficient for adolescents with spinal deformities.Inpatient rehabilitation is recommended for patients with spinal deformities and pain or severe restrictive ventilation disorder.

SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse

PubMed Central

Ou, Xuan; Chae, Hee-Don; Wang, Rui-Hong; Shelley, William C.; Cooper, Scott; Taylor, Tammi; Kim, Young-June; Deng, Chu-Xia; Yoder, Mervin C.

2011-01-01

SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1−/− mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1−/− mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1+/++/−, and −/− mice. SIRT1−/− ESCs formed fewer mature blast cell colonies. Replated SIRT1−/− blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1−/−-derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1−/− ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased β-H1 globin, β-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1−/− ESC differentiation deficiencies. SIRT1−/− yolk sacs manifested fewer primitive erythroid precursors. SIRT1−/− and SIRT1+/− adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. PMID:20966168

Ectopic cross-talk between thyroid and retinoic acid signaling: A possible etiology for spinal neural tube defects.

PubMed

Li, Huili; Bai, Baoling; Zhang, Qin; Bao, Yihua; Guo, Jin; Chen, Shuyuan; Miao, Chunyue; Liu, Xiaozhen; Zhang, Ting

2015-12-01

Previous studies have highlighted the connections between neural tube defects (NTDs) and both thyroid hormones (TH) and vitamin A. However, whether the two hormonal signaling pathways interact in NTDs has remained unclear. We measured the expression levels of TH signaling genes in human fetuses with spinal NTDs associated with maternal hyperthyroidism as well as levels of retinoic acid (RA) signaling genes in mouse fetuses exposed to an overdose of RA using NanoString or real-time PCR on spinal cord tissues. Interactions between the two signaling pathways were detected by ChIP assays. The data revealed attenuated DIO2/DIO3 switching in fetuses with NTDs born to hyperthyroid mothers. The promoters of the RA signaling genes CRABP1 and RARB were ectopically occupied by increased RXRG and RXRB but displayed decreased levels of inhibitory histone modifications, suggesting that elevated TH signaling abnormally stimulates RA signaling genes. Conversely, in the mouse model, the observed decrease in Dio3 expression could be explained by increased levels of inhibitory histone modifications in the Dio3 promoter region, suggesting that overactive RA signaling may ectopically derepress TH signaling. This study thus raises in vivo a possible abnormal cross-promotion between two different hormonal signals through their common RXRs and the subsequent recruitment of histone modifications, prompting further investigation into their involvement in the etiology of spinal NTDs. Copyright © 2015 Elsevier B.V. All rights reserved.

Return to work following spinal cord injury: a review.

PubMed

Lidal, Ingeborg Beate; Huynh, Tuan Khai; Biering-Sørensen, Fin

2007-09-15

To review literature on return to work (RTW) and employment in persons with spinal cord injury (SCI), and present employment rates, factors influencing employment, and interventions aimed at helping people with SCI to obtain and sustain productive work. A systematic review for 2000 - 2006 was carried out in PubMed/Medline, AMED, (ISI) Web of Science, EMBASE, CINAHL, PsycInfo and Sociological abstracts database. The keywords 'spinal cord injuries', 'spinal cord disorder', 'spinal cord lesion' or 'spinal cord disease' were cross-indexed with 'employment', 'return to work', 'occupation' or 'vocational'. Out of approximately 270 hits, 110 references were used, plus 13 more found elsewhere. Among individuals with SCI working at the time of injury 21 - 67% returned to work after injury. RTW was higher in persons injured at a younger age, had less severe injuries and higher functional independence. Employment rate improved with time after SCI. Persons with SCI employed ranged from 11.5% to 74%. Individuals who sustained SCI during childhood or adolescence had higher adult employment rates. Most common reported barriers to employment were problems with transportation, health and physical limitations, lack of work experience, education or training, physical or architectural barriers, discrimination by employers, and loss of benefits. Individuals with SCI discontinue working at younger age. This review confirmed low employment rates after SCI. Future research should explore interventions aimed at helping people with SCI to obtain and sustain productive work.

Nonlinear optical techniques for imaging and manipulating the mouse central nervous system

NASA Astrophysics Data System (ADS)

Farrar, Matthew John

The spinal cord of vertebrates serves as the conduit for somatosensory information and motor control, as well as being the locus of neural circuits that govern fast reflexes and patterned behaviors, such as walking in mammals or swimming in fish. Consequently, pathologies of the spinal cord -such as spinal cord injury (SCI)- lead to loss of motor control and sensory perception, with accompanying decline in life expectancy and quality of life. Despite the devastating effects of these diseases, few therapies exist to substantially ameliorate patient outcome. In part, studies of spinal cord pathology have been limited by the inability to perform in vivo imaging at the level of cellular processes. The focus of this thesis is to present the underlying theory for and demonstration of novel multi-photon microscopy (MPM) and optical manipulation techniques as they apply to studies the mouse central nervous system (CNS), with an emphasis on the spinal cord. The scientific findings which have resulted from the implementation of these techniques are also presented. In particular, we have demonstrated that third harmonic generation is a dye-free method of imaging CNS myelin, a fundamental constituent of the spinal cord that is difficult to label using exogenous dyes and/or transgenic constructs. Since gaining optical access to the spinal cord is a prerequisite for spinal cord imaging, we review our development of a novel spinal cord imaging chamber and surgical procedure which allowed us to image for multiple weeks following implantation without the need for repeated surgeries. We also have used MPM to characterize spinal venous blood flow before and after point occlusions. We review a novel nonlinear microscopy technique that may serve to show optical interfaces in three dimensions inside scattering tissue. Finally, we discuss a model and show results of optoporation, a means of transfecting cells with genetic constructs. Brief reviews of MPM and SCI are also presented.

Interfacing peripheral nerve with macro-sieve electrodes following spinal cord injury.

PubMed

Birenbaum, Nathan K; MacEwan, Matthew R; Ray, Wilson Z

2017-06-01

Macro-sieve electrodes were implanted in the sciatic nerve of five adult male Lewis rats following spinal cord injury to assess the ability of the macro-sieve electrode to interface regenerated peripheral nerve fibers post-spinal cord injury. Each spinal cord injury was performed via right lateral hemisection of the cord at the T 9-10 site. Five months post-implantation, the ability of the macro-sieve electrode to interface the regenerated nerve was assessed by stimulating through the macro-sieve electrode and recording both electromyography signals and evoked muscle force from distal musculature. Electromyography measurements were recorded from the tibialis anterior and gastrocnemius muscles, while evoked muscle force measurements were recorded from the tibialis anterior, extensor digitorum longus, and gastrocnemius muscles. The macro-sieve electrode and regenerated sciatic nerve were then explanted for histological evaluation. Successful sciatic nerve regeneration across the macro-sieve electrode interface following spinal cord injury was seen in all five animals. Recorded electromyography signals and muscle force recordings obtained through macro-sieve electrode stimulation confirm the ability of the macro-sieve electrode to successfully recruit distal musculature in this injury model. Taken together, these results demonstrate the macro-sieve electrode as a viable interface for peripheral nerve stimulation in the context of spinal cord injury.

Proximal Junctional Failure After Long-Segment Instrumentation for Degenerative Lumbar Kyphosis With Ankylosing Spinal Disorder.

PubMed

Ikegami, Daisuke; Matsuoka, Takashi; Miyoshi, Yuji; Murata, Yoichi; Aoki, Yasuaki

2015-06-15

Case report. We report a case of proximal junctional failure at the ankylosed, but not the mobile, junction after segmental instrumented fusion for degenerative lumbar kyphosis with ankylosing spinal disorder. Proximal junctional failure (PJF) and proximal junctional kyphosis (PJK) are important complications that occur subsequent to long-segment instrumentation for correction of adult spinal deformity. Thus far, most studies have focused on the mobile junction as a site at which PJK/PJF can occur, and little is known about the relationship between PJK/PJF and ankylosing spinal disorders such as diffuse idiopathic skeletal hyperostosis. The patient was an 82-year-old female with degenerative lumbar kyphosis. She had abnormal confluent hyperostosis in the anterior longitudinal ligaments from Th5 to Th10. The patient was treated operatively with spinal instrumented fusion from Th10 to the sacrum. Four weeks subsequent to initial surgery, the patient developed progressive lower extremity paresis caused by the uppermost instrumented vertebrae fracture (Th10) and adjacent subluxation (Th9). Extension of fusion to Th5 with decompression at Th9-Th10 was performed. However, the patient showed no improvement in neurological function. PJF can occur at the ankylosing site above the uppermost instrumented vertebrae after long-segment instrumentation for adult spinal deformity. PJF in the ankylosed spine may cause severe fracture instability and cord deficit. The ankylosed spine should be integrated into the objective determination of materials contributing to the appropriate selection of fusion levels. 3.

The Role of Core Self-Evaluations in the Relationship between Stress and Depression in Persons with Spinal Cord Injury

ERIC Educational Resources Information Center

DeAngelis, Jesse B.; Yaghmaian, Rana; Smedema, Susan Miller

2016-01-01

Purpose: To investigate the role of core self-evaluations (CSE) in the relationship between perceived stress and depression in persons with spinal cord injury. Method: Two hundred forty-seven adults with spinal cord injury completed an online survey measuring perceived stress, CSE, and depressive symptoms. Results: A multiple regression analysis…

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

PubMed Central

Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

Speed and segmentation control mechanisms characterized in rhythmically-active circuits created from spinal neurons produced from genetically-tagged embryonic stem cells

PubMed Central

Sternfeld, Matthew J; Hinckley, Christopher A; Moore, Niall J; Pankratz, Matthew T; Hilde, Kathryn L; Driscoll, Shawn P; Hayashi, Marito; Amin, Neal D; Bonanomi, Dario; Gifford, Wesley D; Sharma, Kamal; Goulding, Martyn; Pfaff, Samuel L

2017-01-01

Flexible neural networks, such as the interconnected spinal neurons that control distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate oscillatory bursts with properties similar to in vivo central pattern generators. Inhibitory V1 neurons provided dual layers of regulation within excitatory rhythmogenic networks - they increased the rhythmic burst frequency of excitatory V3 neurons, and segmented excitatory motor neuron activity into sub-networks. Accordingly, the speed and pattern of spinal circuits that underlie complex motor behaviors may be regulated by quantitatively gating the intra-network cellular activity ratio of E-to-I neurons. DOI: http://dx.doi.org/10.7554/eLife.21540.001 PMID:28195039

Normal variation in sagittal spinal alignment parameters in adult patients: an EOS study using serial imaging.

PubMed

Hey, Hwee Weng Dennis; Tan, Kian Loong Melvin; Moorthy, Vikaesh; Lau, Eugene Tze-Chun; Lau, Leok-Lim; Liu, Gabriel; Wong, Hee-Kit

2018-03-01

To describe normal variations in sagittal spinal radiographic parameters over an interval period and establish physiological norms and guidelines for which these images should be interpreted. Data were prospectively collected from a continuous series of adult patients with first-episode mild low back pain presenting to a single institution. The sagittal parameters of two serial radiographic images taken 6-months apart were obtained with the EOS ® slot scanner. Measured parameters include CL, TK, TL, LL, PI, PT, SS, and end and apical vertebrae. Chi-squared test and Wilcoxon Signed Rank test were used to compare categorical and continuous variables, respectively. Sixty patients with a total of 120 whole-body sagittal X-rays were analysed. Mean age was 52.1 years (SD 21.2). Mean interval between the first and second X-rays was 126.2 days (SD 47.2). Small variations (< 1°) occur for all except PT (1.2°), CL (1.2°), and SVA (2.9 cm). Pelvic tilt showed significant difference between two images (p = 0.035). Subgroup analysis based on the time interval between X-rays, and between the first and second X-rays, did not show significant differences. Consistent findings were found for end and apical vertebrae of the thoracic and lumbar spine between the first and second X-rays for sagittal curve shapes. Radiographic sagittal parameters vary between serial images and reflect dynamism in spinal balancing. SVA and PT are predisposed to the widest variation. SVA has the largest variation between individuals of low pelvic tilt. Therefore, interpretation of these parameters should be patient specific and relies on trends rather than a one-time assessment.

Computer mouse movement patterns: A potential marker of mild cognitive impairment.

PubMed

Seelye, Adriana; Hagler, Stuart; Mattek, Nora; Howieson, Diane B; Wild, Katherine; Dodge, Hiroko H; Kaye, Jeffrey A

2015-12-01

Subtle changes in cognitively demanding activities occur in MCI but are difficult to assess with conventional methods. In an exploratory study, we examined whether patterns of computer mouse movements obtained from routine home computer use discriminated between older adults with and without MCI. Participants were 42 cognitively intact and 20 older adults with MCI enrolled in a longitudinal study of in-home monitoring technologies. Mouse pointer movement variables were computed during one week of routine home computer use using algorithms that identified and characterized mouse movements within each computer use session. MCI was associated with making significantly fewer total mouse moves ( p <.01), and making mouse movements that were more variable, less efficient, and with longer pauses between movements ( p <.05). Mouse movement measures were significantly associated with several cognitive domains ( p 's<.01-.05). Remotely monitored computer mouse movement patterns are a potential early marker of real-world cognitive changes in MCI.

Investigation of spinal cerebrospinal fluid-contacting neurons expressing PKD2L1: evidence for a conserved system from fish to primates

PubMed Central

Djenoune, Lydia; Khabou, Hanen; Joubert, Fanny; Quan, Feng B.; Nunes Figueiredo, Sophie; Bodineau, Laurence; Del Bene, Filippo; Burcklé, Céline; Tostivint, Hervé; Wyart, Claire

2014-01-01

Over 90 years ago, Kolmer and Agduhr identified spinal cerebrospinal fluid-contacting neurons (CSF-cNs) based on their morphology and location within the spinal cord. In more than 200 vertebrate species, they observed ciliated neurons around the central canal that extended a brush of microvilli into the cerebrospinal fluid (CSF). Although their morphology is suggestive of a primitive sensory cell, their function within the vertebrate spinal cord remains unknown. The identification of specific molecular markers for these neurons in vertebrates would benefit the investigation of their physiological roles. PKD2L1, a transient receptor potential channel that could play a role as a sensory receptor, has been found in cells contacting the central canal in mouse. In this study, we demonstrate that PKD2L1 is a specific marker for CSF-cNs in the spinal cord of mouse (Mus musculus), macaque (Macaca fascicularis) and zebrafish (Danio rerio). In these species, the somata of spinal PKD2L1+ CSF-cNs were located below or within the ependymal layer and extended an apical bulbous extension into the central canal. We found GABAergic PKD2L1-expressing CSF-cNs in all three species. We took advantage of the zebrafish embryo for its transparency and rapid development to identify the progenitor domains from which pkd2l1+ CSF-cNs originate. pkd2l1+ CSF-cNs were all GABAergic and organized in two rows—one ventral and one dorsal to the central canal. Their location and marker expression is consistent with previously described Kolmer–Agduhr cells. Accordingly, pkd2l1+ CSF-cNs were derived from the progenitor domains p3 and pMN defined by the expression of nkx2.2a and olig2 transcription factors, respectively. Altogether our results suggest that a system of CSF-cNs expressing the PKD2L1 channel is conserved in the spinal cord across bony vertebrate species. PMID:24834029

Fractionated radiation facilitates repair and functional motor recovery after spinal cord transection in rat.

PubMed

Kalderon, N; Xu, S; Koutcher, J A; Fuks, Z

2001-06-22

Previous studies suggest that motor recovery does not occur after spinal cord injury because reactive glia abort the natural repair processes. A permanent wound gap is left in the cord and the brain-cord circuitry consequently remains broken. Single-dose x-irradiation destroys reactive glia at the damage site in transected adult rat spinal cord. The wound then heals naturally, and a partially functional brain-cord circuitry is reconstructed. Timing is crucial; cell ablation is beneficial only within the third week after injury. Data presented here point to the possibility of translating these observations into a clinical therapy for preventing the paralysis following spinal cord injury in the human. The lesion site (at low thoracic level) in severed adult rat spinal cord was treated daily, over the third week postinjury, with protocols of fractionated radiation similar to those for treating human spinal cord tumors. This resulted, as with the single-dose protocol, in wound healing and restoration of some hindquarter motor function; in addition, the beneficial outcome was augmented. Of the restored hindlimb motor functions, weight-support and posture in stance was the only obvious one. Recovery of this motor function was partial to substantial and its incidence was 100% instead of about 50% obtained with the single-dose treatment. None of the hindlimbs, however, regained frequent stepping or any weight-bearing locomotion. These data indicate that the therapeutic outcome may be further augmented by tuning the radiation parameters within the critical time-window after injury. These data also indicate that dose-fractionation is an effective strategy and better than the single-dose treatment for targeting of reactive cells that abort the natural repair, suggesting that radiation therapy could be developed into a therapeutic procedure for repairing injured spinal cord.

Cervical spinal epidural arteriovenous fistula with coexisting spinal anterior spinal artery aneurysm presenting as subarachnoid hemorrhage--case report.

PubMed

Nakagawa, Ichiro; Park, Hun-Soo; Hironaka, Yasuo; Wada, Takeshi; Kichikawa, Kimihiko; Nakase, Hiroyuki

2014-01-01

Hemorrhagic presentation of spinal epidural arteriovenous fistulas (AVFs) is rare in patients with cervical spinal vascular lesions. The present report describes a patient with cervical spine epidural AVFs associated with anterior spinal artery aneurysm at the same vertebral level presenting with subarachnoid hemorrhage. A 54-year-old man presented with sudden onset of headache. Computed tomography of the head showed subarachnoid hemorrhage. Diagnostic angiography revealed an epidural AVF located at the C1-2 level that was fed mainly by the dorsal somatic branches of the segmental arteries from the radicular artery and anterior spinal artery. This AVF drained only into the epidural veins without perimedullary venous reflux. Further, there was a 4-mm anterior spinal artery aneurysm in the vicinity of the fistula that was thought to be the cause of the hemorrhage. Endovascular transarterial fistulas embolization from the right radicular artery was performed to eliminate the AVF and to reduce hemodynamic stress on the aneurysm. No new symptoms developed after the treatment and discharged without neurological deficits. The aneurysm was noted to be reduced in size after the treatment and totally disappeared by 1 year later, according to follow-up angiography. Anterior spinal artery aneurysm from a separate vascular distribution may coexist with spinal epidural AVFs. In the setting of spinal subarachnoid hemorrhage, comprehensive imaging is indicated to rule out such lesions. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Area-Specific Regulation of Quiescent Neural Stem Cells by Notch3 in the Adult Mouse Subependymal Zone.

PubMed

Kawai, Hiroki; Kawaguchi, Daichi; Kuebrich, Benjamin D; Kitamoto, Takeo; Yamaguchi, Masahiro; Gotoh, Yukiko; Furutachi, Shohei

2017-12-06

In the adult mammalian brain, neural stem cells (NSCs) generate new neurons throughout the mammal's lifetime. The balance between quiescence and active cell division among NSCs is crucial in producing appropriate numbers of neurons while maintaining the stem cell pool for a long period. The Notch signaling pathway plays a central role in both maintaining quiescent NSCs (qNSCs) and promoting cell division of active NSCs (aNSCs), although no one knows how this pathway regulates these apparently opposite functions. Notch1 has been shown to promote proliferation of aNSCs without affecting qNSCs in the adult mouse subependymal zone (SEZ). In this study, we found that Notch3 is expressed to a higher extent in qNSCs than in aNSCs while Notch1 is preferentially expressed in aNSCs and transit-amplifying progenitors in the adult mouse SEZ. Furthermore, Notch3 is selectively expressed in the lateral and ventral walls of the SEZ. Knockdown of Notch3 in the lateral wall of the adult SEZ increased the division of NSCs. Moreover, deletion of the Notch3 gene resulted in significant reduction of qNSCs specifically in the lateral and ventral walls, compared with the medial and dorsal walls, of the lateral ventricles. Notch3 deletion also reduced the number of qNSCs activated after antimitotic cytosine β-D-arabinofuranoside (Ara-C) treatment. Importantly, Notch3 deletion preferentially reduced specific subtypes of newborn neurons in the olfactory bulb derived from the lateral walls of the SEZ. These results indicate that Notch isoforms differentially control the quiescent and proliferative steps of adult SEZ NSCs in a domain-specific manner. SIGNIFICANCE STATEMENT In the adult mammalian brain, the subependymal zone (SEZ) of the lateral ventricles is the largest neurogenic niche, where neural stem cells (NSCs) generate neurons. In this study, we found that Notch3 plays an important role in the maintenance of quiescent NSCs (qNSCs), while Notch1 has been reported to act as a regulator

Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

PubMed

Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B E; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P; Shields, Christopher B

2013-04-01

Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model

Reciprocal functional interactions between the brainstem and the lower spinal cord

PubMed Central

Yazawa, Itaru

2014-01-01

The interplay of the neuronal discharge patterns regarding respiration and locomotion was investigated using electrophysiological techniques in a decerebrate and arterially perfused in situ mouse preparation. The phrenic, tibial, and/or peroneal nerve discharge became clearly organized into discharge episodes of increasing frequency and duration, punctuated by periods of quiescence as the perfusion flow rate increased at room temperature. The modulated sympathetic tone induced by the hyperoxic/normocapnic state was found to activate the locomotor pattern generator (LPG) via descending pathways and generate a left and right alternating discharge during discharge episodes in the motor nerves. The rhythm coupling of respiration and locomotion occurred at a 1:1 frequency ratio. Although the phrenic discharge synchronized with the tibial discharge at all flow rates tested, the time lag between peaks of the two discharges during locomotion was ≈400 ms rather than ≈200 ms, suggesting spinal feedback via ascending pathways. The incidence of the phrenic and tibial discharge episodes decreased by ≈50% after spinalization at the twelfth thoracic cord and the respiratory rhythm was more regular. These results indicate that: (i) locomotion can be generated in a hyperoxic/normocapnic state induced by specific respiratory conditions, (ii) the central mechanism regarding entrainment of respiratory and locomotor rhythms relies on spinal feedback via ascending pathways, initiated by the activated LPG generating locomotion, and (iii) the increase in respiratory rate seen during locomotion is caused not only by afferent mechanical and nociceptive inputs but also by impulses from the activated spinal cord producing a locomotor-like discharge via ascending pathways. PMID:24910591

Purification of Oogonial Stem Cells From Adult Mouse and Human Ovaries: An Assessment of the Literature and a View Toward the Future

PubMed Central

Woods, Dori C.; White, Yvonne A. R.; Tilly, Jonathan L.

2013-01-01

Contemporary claims that mitotically active female germ line or oogonial stem cells (OSCs) exist and support oogenesis during postnatal life in mammals have been debated in the field of reproductive biology since March 2004, when a mouse study posed the first serious challenge to the dogma of a fixed pool of oocytes being endowed at birth in more than 50 years. Other studies have since been put forth that further question the validity of this dogma, including the isolation of OSCs from neonatal and adult mouse ovaries by 4 independent groups using multiple strategies. Two of these groups also reported that isolated mouse OSCs, once transplanted back into ovaries of adult female mice, differentiate into fully functional eggs that ovulate, fertilize, and produce healthy embryos and offspring. Arguably, one of the most significant advances in this emerging field was provided by a new research study published this year, which reported the successful isolation and functional characterization of OSCs from ovaries of reproductive age women. Two commentaries on this latest work, one cautiously supportive and one highly skeptical, were published soon afterward. This article evaluates the current literature regarding postnatal oogenesis in mammals and discusses important next steps for future work on OSC biology and function. PMID:23024060

Purification of oogonial stem cells from adult mouse and human ovaries: an assessment of the literature and a view toward the future.

PubMed

Woods, Dori C; White, Yvonne A R; Tilly, Jonathan L

2013-01-01

Contemporary claims that mitotically active female germ line or oogonial stem cells (OSCs) exist and support oogenesis during postnatal life in mammals have been debated in the field of reproductive biology since March 2004, when a mouse study posed the first serious challenge to the dogma of a fixed pool of oocytes being endowed at birth in more than 50 years. Other studies have since been put forth that further question the validity of this dogma, including the isolation of OSCs from neonatal and adult mouse ovaries by 4 independent groups using multiple strategies. Two of these groups also reported that isolated mouse OSCs, once transplanted back into ovaries of adult female mice, differentiate into fully functional eggs that ovulate, fertilize, and produce healthy embryos and offspring. Arguably, one of the most significant advances in this emerging field was provided by a new research study published this year, which reported the successful isolation and functional characterization of OSCs from ovaries of reproductive age women. Two commentaries on this latest work, one cautiously supportive and one highly skeptical, were published soon afterward. This article evaluates the current literature regarding postnatal oogenesis in mammals and discusses important next steps for future work on OSC biology and function.

Recovery of bimodal locomotion in the spinal-transected salamander, Pleurodeles waltlii.

PubMed

Chevallier, Stéphanie; Landry, Marc; Nagy, Frédéric; Cabelguen, Jean-Marie

2004-10-01

Electromyographic (EMG) analysis was used to provide an assessment of the recovery of locomotion in spinal-transected adult salamanders (Pleurodeles waltlii). EMG recordings were performed during swimming and overground stepping in the same animal before and at various times (up to 500 days) after a mid-trunk spinalization. Two-three weeks after spinalization, locomotor EMG activity was limited to the forelimbs and the body rostral to the transection. Thereafter, there was a return of the locomotor EMG activity at progressively more caudal levels below the transection. The animals reached stable locomotor patterns 3-4 months post-transection. Several locomotor parameters (cycle duration, burst duration, burst proportion, intersegmental phase lag, interlimb coupling) measured at various recovery times after spinalization were compared with those in intact animals. These comparisons revealed transient and long-term alterations in the locomotor parameters both above and below the transection site. These alterations were much more pronounced for swimming than for stepping and revealed differences in adaptive plasticity between the two locomotor networks. Recovered locomotor activity was immediately abolished by retransection at the site of the original spinalization, suggesting that the spinal cord caudal to the transection was reinnervated by descending brain and/or propriospinal axons, and that this regeneration contributed to the restoration of locomotor activity. Anatomical studies conducted in parallel further demonstrated that some of the regenerated axons came from glutamatergic and serotoninergic immunoreactive cells within the reticular formation.

Spinal Stenosis

MedlinePlus

... Overview Spinal stenosis is a narrowing of the spaces within your spine, which can put pressure on ... stenosis, doctors may recommend surgery to create additional space for the spinal cord or nerves. Types of ...

Generation and characterization of Atoh1-Cre knock-in mouse line

PubMed Central

Yang, Hua; Xie, Xiaoling; Deng, Min; Chen, Xiaowei; Gan, Lin

2010-01-01

Summary Atoh1 encodes a basic helix-loop-helix (bHLH) transcription factor required for the development of the inner ear sensory epithelia, the dorsal spinal cord, brainstem, cerebellum, and intestinal secretory cells. In this study to create a genetic tool for the research on gene function in the ear sensory organs, we generated an Atoh1-Cre knock-in mouse line by replacing the entire Atoh1 coding sequences with the Cre coding sequences. Atoh1Cre/+mice were viable, fertile, and displayed no visible defects whereas the Atoh1Cre/Cremice died perinatally. The spatiotemporal activities of Cre recombinase were examined by crossing Atoh1-Cre mice with the R26R-lacZ conditional reporter mice. Atoh1-Cre activities were detected in the developing inner ear, the hindbrain, the spinal cord, and the intestine. In the inner ear, Atoh1-Cre activities were confined to the sensory organs in which lacZ expression is detected in nearly all of the hair cells and in many supporting cells. Thus, Atoh1-Cre mouse line serves as a useful tool for the functional study of genes in the inner ear. In addition, our results demonstrate that Atoh1 is expressed in the common progenitors destined for both hair and supporting cells. PMID:20533400

Examining How the Perception of Health Can Impact Participation and Autonomy Among Adults with Spinal Cord Injury.

PubMed

Piatt, Jennifer A; Van Puymbroeck, Marieke; Zahl, Melissa; Rosenbluth, Jeffrey P; Wells, Mary Sara

2016-01-01

Background: Studies examining participation as defined by the International Classification of Functioning, Disability and Health (ICF) as well as autonomy among the spinal cord injury population (SCI) are only starting to emerge. Little research has looked at how this population perceives their health status and the role this plays in active participation within their lives. Objective: This exploratory study was developed to determine whether the perception of health has an impact on participation and autonomy among adults with SCI. Methods: A convenience sample of adults with SCI currently receiving outpatient services from a rehabilitation hospital completed the online questionnaire. Forty-two subjects responded and were categorized into 2 groups: Group 1, positive perceived health, and Group 2, negative perceived health. The sample completed the Impact on Autonomy and Participation (IPA) that has 5 subscales (autonomy indoors, family role, autonomy outdoors, social life, and work/education) and demographic questions. Results: Multivariate analysis of variance (MANOVA) revealed that perceived health had a significant impact on family roles, autonomy outdoors, social life, and work/education. Perceived health did not have a significant impact on autonomy indoors. Conclusion: The perception of health may have an impact on participation and autonomy within the areas of family role, outdoors, work/education, and social life. Implications for rehabilitation are included.

Willingness to Pay for a Newborn Screening Test for Spinal Muscular Atrophy.

PubMed

Lin, Pei-Jung; Yeh, Wei-Shi; Neumann, Peter J

2017-01-01

The current US mandatory newborn screening panel does not include spinal muscular atrophy, the most common fatal genetic disease among children. We assessed population preferences for newborn screening for spinal muscular atrophy, and how test preferences varied depending on immediate treatment implications. We conducted an online willingness-to-pay survey of US adults (n = 982). Respondents were asked to imagine being parents of a newborn. Each respondent was presented with two hypothetical scenarios following the spinal muscular atrophy screening test: current standard of care (no treatment available) and one of three randomly assigned scenarios (new treatment available to improve functioning, survival, or both). We used a bidding game to elicit willingness to pay for the spinal muscular atrophy test, and performed a two-part model to estimate median and mean willingness-to-pay values. Most respondents (79% to 87%) would prefer screening their newborns for spinal muscular atrophy. People expressed a willingness to pay for spinal muscular atrophy screening even without an available therapy (median: $142; mean: $253). Willingness to pay increased with treatment availability (median: $161 to $182; mean: $270 to $297) and respondent income. Most respondents considered test accuracy, treatment availability, and treatment effectiveness very important or important factors in deciding willingness to pay. Most people would prefer and would be willing to pay for testing their newborn for spinal muscular atrophy, even in the absence of direct treatment. People perceive the spinal muscular atrophy test more valuable if treatment were available to improve the newborn's functioning and survival. Despite preferences for the test information, adding spinal muscular atrophy to newborn screening programs remains controversial. Future studies are needed to determine how early detection may impact long-term patient outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Low levels of citrin (SLC25A13) expression in adult mouse brain restricted to neuronal clusters.

PubMed

Contreras, Laura; Urbieta, Almudena; Kobayashi, Keiko; Saheki, Takeyori; Satrústegui, Jorgina

2010-04-01

The mitochondrial aspartate-glutamate carriers (AGC) aralar (SLC25A12) and citrin (SLC25A13) are components of the malate aspartate shuttle (MAS), a major intracellular pathway to transfer reducing equivalents from NADH to the mitochondrial matrix. Aralar is the main AGC isoform present in the adult brain, and it is expressed mainly in neurons. To search for the other AGC isoform, citrin, in brain glial cells, we used a citrin knockout mouse in which the lacZ gene was inserted into the citrin locus as reporter gene. In agreement with the low citrin levels known to be present in the adult mouse brain, beta-galactosidase expression was very low. Surprisingly, unlike the case with astroglial cultures that express citrin, no beta-galactosidase was found in brain glial cells. It was confined to neuronal cells within discrete neuronal clusters. Double-immunolabelling experiments showed that beta-galactosidase colocalized not with glial cell markers but with the pan-neuronal marker NeuN. The deep cerebellar nuclei and a few midbrain nuclei (reticular tegmental pontine nuclei; magnocellular red nuclei) were the regions where beta-galactosidase expression was highest, and it was up-regulated in fasted mice, as was also the case for liver beta-galactosidase. The results support the notion that glial cells have much lower AGC levels and MAS activity than neurons. (c) 2009 Wiley-Liss, Inc.

Percutaneous Radiofrequency Ablation of Painful Spinal Tumors Adjacent to the Spinal Cord with Real-Time Monitoring of Spinal Canal Temperature: A Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakatsuka, Atsuhiro, E-mail: nakatuka@clin.medic.mie-u.ac.jp; Yamakado, Koichiro; Takaki, Haruyuki

2009-01-15

PurposeTo prospectively evaluate the feasibility, safety, and clinical utility of bone radiofrequency (RF) ablation with real-time monitoring of the spinal canal temperature for the treatment of spinal tumors adjacent to the spinal cord.Materials and MethodsOur Institutional Review Board approved this study. Patients gave informed consent. The inclusion criteria were (a) a painful spinal metastasis and (b) a distance of 1 cm or less between the metastasis and the spinal cord. The thermocouple was placed in the spinal canal under CT fluoroscopic guidance. When the spinal canal temperature reached 45{sup o}C, RF application was immediately stopped. RF ablation was considered technicallymore » successful when the procedure was performed without major complications. Clinical success was defined as a fall in the visual analogue scale score of at least 2 points.ResultsTen patients with spinal tumors measuring 3-8 cm (mean, 4.9 {+-} 1.5 cm) were enrolled. The distance between the tumor and the spinal cord was 1-6 mm (mean, 2.4 {+-} 1.6 mm). All procedures were judged technically successful (100%). The spinal canal temperature did not exceed 45{sup o}C in 9 of the 10 patients (90%). In the remaining patient, the temperature rose to 48{sup o}C, resulting in transient neural damage, although RF application was immediately stopped when the temperature reached 45{sup o}C. Clinical success was achieved within 1 week in all patients (100%).ConclusionBone RF ablation with real-time monitoring of the spinal canal temperature is feasible, safe, and clinically useful for the treatment of painful spinal metastases adjacent to the spinal cord.« less

The influence of secondary conditions on job acquisition and retention in adults with spinal cord injury.

PubMed

Meade, Michelle A; Forchheimer, Martin B; Krause, James S; Charlifue, Susan

2011-03-01

To examine the associations of job acquisition and job retention to secondary conditions, hospitalizations, and nursing home stays for adults with spinal cord injury (SCI). Retrospective analysis of longitudinal data from multicenter study. Community setting. Two samples of adults participating in the SCI Model Systems; the first sample consisted of persons who reported being unemployed at follow-up (n=9501); the second sample consisted of those who reported working at follow-up (n=5,150). Not applicable. Job acquisition (change from not working at 1 anniversary of injury to working at the following data collection) and job retention (maintenance of work between 2 assessment periods). Discrete time hazard modeling was used to assess how secondary conditions affect job acquisition. After controlling for the effects of demographic and injury characteristics, hospitalizations within the last 12 months were associated with decreased chance of having obtained employment. Hierarchic logistic regression analyses were used to examine job retention. Hospitalizations and the presence of PUs were associated with lower odds of job retention once demographic and injury characteristics were controlled. Secondary conditions from the previous assessment period were not significantly related to either job acquisition or job retention after the variance from demographic and injury characteristics and current secondary conditions were controlled. Hospitalization, as well as a limited number of secondary conditions, were associated with reduced odds of both job acquisition and job retention among adults with SCI. Interventions that can prevent secondary conditions and reduce the need for hospitalizations may be beneficial in improving employment for this population. Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Hyperbaric Versus Isobaric Bupivacaine for Spinal Anesthesia: Systematic Review and Meta-analysis for Adult Patients Undergoing Noncesarean Delivery Surgery.

PubMed

Uppal, Vishal; Retter, Susanne; Shanthanna, Harsha; Prabhakar, Christopher; McKeen, Dolores M

2017-11-01

It is widely believed that the choice between isobaric bupivacaine and hyperbaric bupivacaine formulations alters the block characteristics for the conduct of surgery under spinal anesthesia. The aim of this study was to systematically review the comparative evidence regarding the effectiveness and safety of the 2 formulations when used for spinal anesthesia for adult noncesarean delivery surgery. Key electronic databases were searched for randomized controlled trials, excluding cesarean delivery surgeries under spinal anesthesia, without any language or date restrictions. The primary outcome measure for this review was the failure of spinal anesthesia. Two independent reviewers selected the studies and extracted the data. Results were expressed as relative risk (RR) or mean differences (MDs) with 95% confidence intervals (CIs). Seven hundred fifty-one studies were identified between 1946 and 2016. After screening, there were 16 randomized controlled clinical trials, including 724 participants, that provided data for the meta-analysis. The methodological reporting of most studies was poor, and appropriate judgment of their individual risk of bias elements was not possible. There was no difference between the 2 drugs regarding the need for conversion to general anesthesia (RR, 0.60; 95% CI, 0.08-4.41; P = .62; I = 0%), incidence of hypotension (RR, 1.15; 95% CI, 0.69-1.92; P = .58; I = 0%), nausea/vomiting (RR, 0.29; 95% CI, 0.06-1.32; P = .11; I = 7%), or onset of sensory block (MD = 1.7 minutes; 95% CI, -3.5 to 0.1; P = .07; I = 0%). The onset of motor block (MD = 4.6 minutes; 95% CI, 7.5-1.7; P = .002; I = 78%) was significantly faster with hyperbaric bupivacaine. Conversely, the duration of motor (MD = 45.2 minutes; 95% CI, 66.3-24.2; P < .001; I = 87%) and sensory (MD = 29.4 minutes; 95% CI, 15.5-43.3; P < .001; I = 73%) block was longer with isobaric bupivacaine. Both hyperbaric bupivacaine and isobaric bupivacaine provided effective anesthesia with no

Transplantation of wild-type mouse hematopoietic stem and progenitor cells ameliorates deficits in a mouse model of Friedreich’s ataxia

PubMed Central

Rocca, Celine J.; Goodman, Spencer M.; Dulin, Jennifer N.; Haquang, Joseph H.; Gertsman, Ilya; Blondelle, Jordan; Smith, Janell L. M.; Heyser, Charles J.; Cherqui, Stephanie

2017-01-01

Friedreich’s ataxia (FRDA) is an incurable autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin due to an intronic GAA-repeat expansion in the FXN gene. We report the therapeutic efficacy of transplanting wild-type mouse hematopoietic stem and progenitor cells (HSPCs) into the YG8R mouse model of FRDA. In the HSPC-transplanted YG8R mice, development of muscle weakness and locomotor deficits was abrogated as was degeneration of large sensory neurons in the dorsal root ganglia (DRGs) and mitochondrial capacity was improved in brain, skeletal muscle, and heart. Transplanted HSPCs engrafted and then differentiated into microglia in the brain and spinal cord and into macrophages in the DRGs, heart, and muscle of YG8R FRDA mice. We observed the transfer of wild-type frataxin and Cox8 mitochondrial proteins from HSPC-derived microglia/macrophages to FRDA mouse neurons and muscle myocytes in vivo. Our results show the HSPC-mediated phenotypic rescue of FRDA in YG8R mice and suggest that this approach should be investigated further as a strategy for treating FRDA. PMID:29070698

A kinematic model to assess spinal motion during walking.

PubMed

Konz, Regina J; Fatone, Stefania; Stine, Rebecca L; Ganju, Aruna; Gard, Steven A; Ondra, Stephen L

2006-11-15

A 3-dimensional multi-segment kinematic spine model was developed for noninvasive analysis of spinal motion during walking. Preliminary data from able-bodied ambulators were collected and analyzed using the model. Neither the spine's role during walking nor the effect of surgical spinal stabilization on gait is fully understood. Typically, gait analysis models disregard the spine entirely or regard it as a single rigid structure. Data on regional spinal movements, in conjunction with lower limb data, associated with walking are scarce. KinTrak software (Motion Analysis Corp., Santa Rosa, CA) was used to create a biomechanical model for analysis of 3-dimensional regional spinal movements. Measuring known angles from a mechanical model and comparing them to the calculated angles validated the kinematic model. Spine motion data were collected from 10 able-bodied adults walking at 5 self-selected speeds. These results were compared to data reported in the literature. The uniaxial angles measured on the mechanical model were within 5 degrees of the calculated kinematic model angles, and the coupled angles were within 2 degrees. Regional spine kinematics from able-bodied subjects calculated with this model compared well to data reported by other authors. A multi-segment kinematic spine model has been developed and validated for analysis of spinal motion during walking. By understanding the spine's role during ambulation and the cause-and-effect relationship between spine motion and lower limb motion, preoperative planning may be augmented to restore normal alignment and balance with minimal negative effects on walking.

Spinal Anesthesia in Infant Rats: Development of a Model and Assessment of Neurological Outcomes

PubMed Central

Yahalom, Barak; Athiraman, Umeshkumar; Soriano, Sulpicio G.; Zurakowski, David; Carpino, Elizabeth; Corfas, Gabriel; Berde, Charles B.

2012-01-01

Background Previous studies in infant rats and case-control studies of human infants undergoing surgery have raised concerns about potential neurodevelopmental toxicities of general anesthesia. Spinal anesthesia is an alternative to general anesthesia for some infant surgeries. To test for potential toxicity, we developed a spinal anesthesia model in infant rats. Methods Rats of postnatal ages 7, 14, and 21 days were assigned to: no treatment; 1% isoflurane for either 1 h or 6 h, or lumbar spinal injection of saline or bupivacaine, at doses of 3.75 mg/kg (low dose) or 7.5 mg/kg (high dose). Subgroups of animals underwent neurobehavioral testing and blood gas analysis. Brain and lumbar spinal cord sections were examined for apoptosis using cleaved caspase-3 immunostaining. Lumbar spinal cord was examined histologically. Rats exposed to spinal or general anesthesia as infants underwent Rotarod testing of motor performance as adults. Data were analyzed using analysis of variance (ANOVA) using general linear models, Friedman Tests, and Mann–Whitney U tests, as appropriate. Results Bupivacaine 3.75 mg/kg was effective for spinal anesthesia in all age groups, and produced sensory and motor function recovered in 40 to 60 min. Blood gases were similar among groups. Brain and spinal cord apoptosis increased in rats receiving 6 h of 1% isoflurane, but not among the other treatments. All groups showed intact motor performance at adulthood. Conclusions Spinal anesthesia is technically feasible in infant rats, and appears benign in terms of neuroapoptotic and neuromotor sequelae. PMID:21555934

Transplanted Peripheral Blood Stem Cells Mobilized by Granulocyte Colony-Stimulating Factor Promoted Hindlimb Functional Recovery After Spinal Cord Injury in Mice.

PubMed

Takahashi, Hiroshi; Koda, Masao; Hashimoto, Masayuki; Furuya, Takeo; Sakuma, Tsuyoshi; Kato, Kei; Okawa, Akihiko; Inada, Taigo; Kamiya, Koshiro; Ota, Mitsutoshi; Maki, Satoshi; Takahashi, Kazuhisa; Yamazaki, Masashi; Mannoji, Chikato

2016-01-01

Granulocyte colony-stimulating factor (G-CSF) mobilizes peripheral blood stem cells (PBSCs) derived from bone marrow. We hypothesized that intraspinal transplantation of PBSCs mobilized by G-CSF could promote functional recovery after spinal cord injury. Spinal cords of adult nonobese diabetes/severe immunodeficiency mice were injured using an Infinite Horizon impactor (60 kdyn). One week after the injury, 3.0 µl of G-CSF-mobilized human mononuclear cells (MNCs; 0.5 × 10(5)/µl), G-CSF-mobilized human CD34-positive PBSCs (CD34; 0.5 × 10(5)/µl), or normal saline was injected to the lesion epicenter. We performed immunohistochemistry. Locomotor recovery was assessed by Basso Mouse Scale. The number of transplanted human cells decreased according to the time course. The CD31-positive area was significantly larger in the MNC and CD34 groups compared with the vehicle group. The number of serotonin-positive fibers was significantly larger in the MNC and CD34 groups than in the vehicle group. Immunohistochemistry revealed that the number of apoptotic oligodendrocytes was significantly smaller in cell-transplanted groups, and the areas of demyelination in the MNC- and CD34-transplanted mice were smaller than that in the vehicle group, indicating that cell transplantation suppressed oligodendrocyte apoptosis and demyelination. Both the MNC and CD34 groups showed significantly better hindlimb functional recovery compared with the vehicle group. There was no significant difference between the two types of transplanted cells. Intraspinal transplantation of G-CSF-mobilized MNCs or CD34-positive cells promoted angiogenesis, serotonergic fiber regeneration/sparing, and preservation of myelin, resulting in improved hindlimb function after spinal cord injury in comparison with vehicle-treated control mice. Transplantation of G-CSF-mobilized PBSCs has advantages for treatment of spinal cord injury in the ethical and immunological viewpoints, although further exploration

Assessment of the effects of different sample perfusion procedures on phase-contrast tomographic images of mouse spinal cord

NASA Astrophysics Data System (ADS)

Stefanutti, E.; Sierra, A.; Miocchi, P.; Massimi, L.; Brun, F.; Maugeri, L.; Bukreeva, I.; Nurmi, A.; Begani Provinciali, G.; Tromba, G.; Gröhn, O.; Giove, F.; Cedola, A.; Fratini, M.

2018-03-01

Synchrotron X-ray Phase Contrast micro-Tomography (SXrPCμT) is a powerful tool in the investigation of biological tissues, including the central nervous system (CNS), and it allows to simultaneously detect the vascular and neuronal network avoiding contrast agents or destructive sample preparations. However, specific sample preparation procedures aimed to optimize the achievable contrast- and signal-to-noise ratio (CNR and SNR, respectively) are required. Here we report and discuss the effects of perfusion with two different fixative agents (ethanol and paraformaldehyde) and with a widely used contrast medium (MICROFIL®) on mouse spinal cord. As a main result, we found that ethanol enhances contrast at the grey/white matter interface and increases the contrast in correspondence of vascular features and fibres, thus providing an adequate spatial resolution to visualise the vascular network at the microscale. On the other hand, ethanol is known to induce tissue dehydration, likely reducing cell dimensions below the spatial resolution limit imposed by the experimental technique. Nonetheless, neurons remain well visible using either perfused paraformaldehyde or MICROFIL® compound, as these latter media do not affect tissues with dehydration effects. Paraformaldehyde appears as the best compromise: it is not a contrast agent, like MICROFIL®, but it is less invasive than ethanol and permits to visualise well both cells and blood vessels. However, a quantitative estimation of the relative grey matter volume of each sample has led us to conclude that no significant alterations in the grey matter extension compared to the white matter occur as a consequence of the perfusion procedures tested in this study.

Generation and characterization of Lhx9 – GFPCreERT2 knock-in mouse line

PubMed Central

Xie, Xiaoling; Deng, Min; Gan, Lin

2014-01-01

Summary LHX9 is a LIM-homeodomain transcription factor essential for the development of gonads, spinal cord interneurons, and thalamic neurons to name a few. We recently reported the expression of LHX9 in retinal amacrine cells during development. In this study, we generated an Lhx9 - GFPCreERT2 (GCE) knock-in mouse line by knocking-in a GCE cassette at the Lhx9 locus, thus inactivating endogenous Lhx9. Lhx9GCE/+ mice were viable, fertile, and displayed no overt phenotypical characteristics. Lhx9GCE/GCE mice were all phenotypically female, smaller in size, viable, but infertile. The specificity and efficacy of the Lhx9-GCE mouse line was verified by crossing it to a Rosa26 - tdTomato reporter mouse line, which reveals the Cre recombinase activities in retinal amacrine cells, developing limbs, testis, hippocampal neurons, thalamic neurons, and cerebellar neurons. Taken together, the Lhx9-GCE mouse line could serve as a beneficial tool for lineage tracing and gene manipulation experiments. PMID:25112520

Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas

PubMed Central

Rovira, Meritxell; Scott, Sherri-Gae; Liss, Andrew S.; Jensen, Jan; Thayer, Sarah P.; Leach, Steven D.

2009-01-01

The question of whether dedicated progenitor cells exist in adult vertebrate pancreas remains controversial. Centroacinar cells and terminal duct (CA/TD) cells lie at the junction between peripheral acinar cells and the adjacent ductal epithelium, and are frequently included among cell types proposed as candidate pancreatic progenitors. However these cells have not previously been isolated in a manner that allows formal assessment of their progenitor capacities. We have found that a subset of adult CA/TD cells are characterized by high levels of ALDH1 enzymatic activity, related to high-level expression of both Aldh1a1 and Aldh1a7. This allows their isolation by FACS using a fluorogenic ALDH1 substrate. FACS-isolated CA/TD cells are relatively depleted of transcripts associated with differentiated pancreatic cell types. In contrast, they are markedly enriched for transcripts encoding Sca1, Sdf1, c-Met, Nestin, and Sox9, markers previously associated with progenitor populations in embryonic pancreas and other tissues. FACS-sorted CA/TD cells are uniquely able to form self-renewing “pancreatospheres” in suspension culture, even when plated at clonal density. These spheres display a capacity for spontaneous endocrine and exocrine differentiation, as well as glucose-responsive insulin secretion. In addition, when injected into cultured embryonic dorsal pancreatic buds, these adult cells display a unique capacity to contribute to both the embryonic endocrine and exocrine lineages. Finally, these cells demonstrate dramatic expansion in the setting of chronic epithelial injury. These findings suggest that CA/TD cells are indeed capable of progenitor function and may contribute to the maintenance of tissue homeostasis in adult mouse pancreas. PMID:20018761

Insect GDNF:TTC fusion protein improves delivery of GDNF to mouse CNS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jianhong; Chian, Ru-Ju; Ay, Ilknur

2009-12-18

With a view toward improving delivery of exogenous glial cell line-derived neurotrophic factor (GDNF) to CNS motor neurons in vivo, we evaluated the bioavailability and pharmacological activity of a recombinant GDNF:tetanus toxin C-fragment fusion protein in mouse CNS. Following intramuscular injection, GDNF:TTC but not recombinant GDNF (rGDNF) produced strong GDNF immunostaining within ventral horn cells of the spinal cord. Intrathecal infusion of GDNF:TTC resulted in tissue concentrations of GDNF in lumbar spinal cord that were at least 150-fold higher than those in mice treated with rGDNF. While levels of immunoreactive choline acetyltransferase and GFR{alpha}-1 in lumbar cord were not alteredmore » significantly by intrathecal infusion of rGNDF, GDNF:TTC, or TTC, only rGDNF and GDNF:TTC caused significant weight loss following intracerebroventricular infusion. These studies indicate that insect cell-derived GDNF:TTC retains its bi-functional activity in mammalian CNS in vivo and improves delivery of GDNF to spinal cord following intramuscular- or intrathecal administration.« less

Adult Plasticity in the Subcortical Auditory Pathway of the Maternal Mouse

PubMed Central

Miranda, Jason A.; Shepard, Kathryn N.; McClintock, Shannon K.; Liu, Robert C.

2014-01-01

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system – motherhood – is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered. PMID:24992362

Adult plasticity in the subcortical auditory pathway of the maternal mouse.

PubMed

Miranda, Jason A; Shepard, Kathryn N; McClintock, Shannon K; Liu, Robert C

2014-01-01

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

Serotonergic Innervation of the Caudal Spinal Stump in Rats After Complete Spinal Transection: Effect of Olfactory Ensheathing Glia

PubMed Central

Takeoka, Aya; Kubasak, Marc D.; Zhong, Hui; Roy, Roland R.; Phelps, Patricia E.

2010-01-01

Spinal cord injury studies use the presence of serotonin (5-HT)-immunoreactive axons caudal to the injury site as evidence of axonal regeneration. As olfactory ensheathing glia (OEG) transplantation improves hindlimb locomotion in adult rats with complete spinal cord transection, we hypothesized that more 5-HT-positive axons would be found in the caudal stump of OEG- than media-injected rats. Previously we found 5-HT-immunolabeled axons that spanned the transection site only in OEG-injected rats but detected labeled axons just caudal to the lesion in both media- and OEG-injected rats. Now we report that many 5-HT-labeled axons are present throughout the caudal stump of both media- and OEG-injected rats. We found occasional 5-HT-positive interneurons that are one likely source of 5-HT-labeled axons. These results imply that the presence of 5-HT-labeled fibers in the caudal stump is not a reliable indicator of regeneration. We then asked if 5-HT-positive axons appose cholinergic neurons associated with motor functions: central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more 5-HT-positive varicosities in lamina X adjacent to central canal cluster cells in lumbar and sacral segments of OEG- than media-injected rats. SMNs and partition cells are less frequently apposed. As nonsynaptic release of 5-HT is common in the spinal cord, an increase in 5-HT-positive varicosities along motor-associated cholinergic neurons may contribute to the locomotor improvement observed in OEG-injected spinal rats. Furthermore, serotonin located within the caudal stump may activate lumbosacral locomotor networks. J. Comp. Neurol. 515: 664–676, 2009. PMID:19496067

Serotonergic innervation of the caudal spinal stump in rats after complete spinal transection: effect of olfactory ensheathing glia.

PubMed

Takeoka, Aya; Kubasak, Marc D; Zhong, Hui; Roy, Roland R; Phelps, Patricia E

2009-08-20

Spinal cord injury studies use the presence of serotonin (5-HT)-immunoreactive axons caudal to the injury site as evidence of axonal regeneration. As olfactory ensheathing glia (OEG) transplantation improves hindlimb locomotion in adult rats with complete spinal cord transection, we hypothesized that more 5-HT-positive axons would be found in the caudal stump of OEG- than media-injected rats. Previously we found 5-HT-immunolabeled axons that spanned the transection site only in OEG-injected rats but detected labeled axons just caudal to the lesion in both media- and OEG-injected rats. Now we report that many 5-HT-labeled axons are present throughout the caudal stump of both media- and OEG-injected rats. We found occasional 5-HT-positive interneurons that are one likely source of 5-HT-labeled axons. These results imply that the presence of 5-HT-labeled fibers in the caudal stump is not a reliable indicator of regeneration. We then asked if 5-HT-positive axons appose cholinergic neurons associated with motor functions: central canal cluster and partition cells (active during fictive locomotion) and somatic motor neurons (SMNs). We found more 5-HT-positive varicosities in lamina X adjacent to central canal cluster cells in lumbar and sacral segments of OEG- than media-injected rats. SMNs and partition cells are less frequently apposed. As nonsynaptic release of 5-HT is common in the spinal cord, an increase in 5-HT-positive varicosities along motor-associated cholinergic neurons may contribute to the locomotor improvement observed in OEG-injected spinal rats. Furthermore, serotonin located within the caudal stump may activate lumbosacral locomotor networks. (c) 2009 Wiley-Liss, Inc.

Effect of Epsilon Aminocaproic Acid on Red-Cell Transfusion Requirements in Major Spinal Surgery

PubMed Central

Berenholtz, Sean M.; Pham, Julius Cuong; Garrett-Mayer, Elizabeth; Atchison, Christine W; Kostuik, John P.; Cohen, David B.; Nundy, Shantanu; Dorman, Todd; Ness, Paul M.; Klag, Michael J.; Pronovost, Peter J.; Kebaish, Khaled M.

2009-01-01

Study Design Randomized, placebo-controlled trial Objective To evaluate the efficacy of epsilon aminocaproic acid (EACA) to reduce the number of red-cell (RBC) transfusions in adult patients undergoing major spinal surgery. Summary of Background Data Reconstructive spinal surgery is associated with significant blood loss. The number of studies evaluating the efficacy of EACA in adult patients undergoing spinal surgery remains scarce and limited. Methods EACA (100 mg/kg) or placebo was administered to 182 adult patients after the induction of anesthesia followed by an infusion that was continued for 8 hours postoperatively. Primary end-points included total allogeneic RBC transfusions through postoperative day (POD) 8 and postoperative allogeneic plus autologus RBC transfusions through POD 8. Results Mean total allogeneic RBC transfusions were not statistically different between the groups (5.9 units EACA versus 6.9 units placebo; P=0.17). Mean postoperative RBC transfusions in the EACA group was less (2.0 units versus 2.8 units placebo; P=0.03). There was no significant difference in mean estimated intraoperative EBL (2938 cc EACA vs. 3273 cc placebo; P=0.32). Mean intensive care unit length of stay was decreased (EACA 1.8 days versus 2.8 days placebo; P=0.04). The incidence of thromboembolic complications was similar (2.2% EACA vs 6.6% placebo; P=0.15). Conclusions The difference in total allogeneic RBC transfusions between the groups was not statistically significant. EACA was associated with a 30% (0.8 units) reduction in postoperative RBC transfusions and a one-day reduction in ICU LOS, without an increased incidence of thromboembolic events. EACA may be considered for patients undergoing major spinal surgery. Larger studies are needed to evaluate the relationship between EACA and total RBC requirements. PMID:19730217

Effect of epsilon aminocaproic acid on red-cell transfusion requirements in major spinal surgery.

PubMed

Berenholtz, Sean M; Pham, Julius Cuong; Garrett-Mayer, Elizabeth; Atchison, Christine W; Kostuik, John P; Cohen, David B; Nundy, Shantanu; Dorman, Todd; Ness, Paul M; Klag, Michael J; Pronovost, Peter J; Kebaish, Khaled M

2009-09-01

: Randomized, placebo-controlled trial. : To evaluate the efficacy of epsilon aminocaproic acid (EACA) to reduce the number of red-cell (RBC) transfusions in adult patients undergoing major spinal surgery. : Reconstructive spinal surgery is associated with significant blood loss. The number of studies evaluating the efficacy of EACA in adult patients undergoing spinal surgery remains scarce and limited. : EACA (100 mg/kg) or placebo was administered to 182 adult patients after the induction of anesthesia followed by an infusion that was continued for 8 hours after surgery. Primary end points included total allogeneic RBC transfusions through postoperative day 8 and postoperative allogeneic plus autologus RBC transfusions through postoperative day 8. : Mean total allogeneic RBC transfusions were not statistically different between the groups (5.9 units EACA vs. 6.9 units placebo; P = 0.17). Mean postoperative RBC transfusions in the EACA group was less (2.0 units vs. 2.8 units placebo; P = 0.03). There was no significantdifference in mean estimated intraoperative estimated-blood loss (2938 cc EACA vs. 3273 cc placebo; P = 0.32). Mean intensive care unit length of stay was decreased (EACA: 1.8 days vs. 2.8 days placebo; P = 0.04). The incidence of thromboembolic complications was similar (2.2% EACA vs. 6.6% placebo; P = 0.15). : The difference in total allogeneic RBC transfusions between the groups was not statistically significant. EACA was associated with a 30% (0.8 units) reduction in postoperative RBC transfusions and a 1-day reduction in ICU LOS, without an increased incidence of thromboembolic events. EACA may be considered for patients undergoing major spinal surgery. Larger studies are needed to evaluate the relationship between EACA and total RBC requirements.

Changes in lumbosacral spinal nerve roots on diffusion tensor imaging in spinal stenosis.

PubMed

Hou, Zhong-Jun; Huang, Yong; Fan, Zi-Wen; Li, Xin-Chun; Cao, Bing-Yi

2015-11-01

Lumbosacral degenerative disc disease is a common cause of lower back and leg pain. Conventional T1-weighted imaging (T1WI) and T2-weighted imaging (T2WI) scans are commonly used to image spinal cord degeneration. However, these modalities are unable to image the entire lumbosacral spinal nerve roots. Thus, in the present study, we assessed the potential of diffusion tensor imaging (DTI) for quantitative assessment of compressed lumbosacral spinal nerve roots. Subjects were 20 young healthy volunteers and 31 patients with lumbosacral stenosis. T2WI showed that the residual dural sac area was less than two-thirds that of the corresponding normal area in patients from L3 to S1 stenosis. On T1WI and T2WI, 74 lumbosacral spinal nerve roots from 31 patients showed compression changes. DTI showed thinning and distortion in 36 lumbosacral spinal nerve roots (49%) and abruption in 17 lumbosacral spinal nerve roots (23%). Moreover, fractional anisotropy values were reduced in the lumbosacral spinal nerve roots of patients with lumbosacral stenosis. These findings suggest that DTI can objectively and quantitatively evaluate the severity of lumbosacral spinal nerve root compression.

Clinical Evidence for Spinal Cord Stimulation for Failed Back Surgery Syndrome (FBSS): Systematic Review.

PubMed

Kapural, Leonardo; Peterson, Erika; Provenzano, David A; Staats, Peter

2017-07-15

A systematic review. A systematic literature review of the clinical data from prospective studies was undertaken to assess the efficacy of spinal cord stimulation (SCS) in the treatment of failed back surgery syndrome (FBSS) in adults. For patients with unrelenting back pain due to mechanical instability of the spine, degenerative disc disease, spinal injury, or deformity, spinal surgery is a well-accepted treatment option; however, even after surgical intervention, many patients continue to experience chronic back pain that can be notoriously difficult to treat. Clinical evidence suggests that for patients with FBSS, repeated surgery will not likely offer relief. Additionally, evidence suggests long-term use of opioid pain medications is not effective in this population, likely presents additional complications, and requires strict management. A systematic literature review was performed using several bibliographic databases, prospective studies in adults using SCS for FBSS were included. SCS has been shown to be a safe and efficacious treatment for this patient population. Recent technological developments in SCS offer even greater pain relief to patients' refractory to other treatment options, allowing patients to regain functionality and improve their quality of life with significant reductions in pain. N/A.

Histopathologic correlation of magnetic resonance imaging signal patterns in a spinal cord injury model.

PubMed

Weirich, S D; Cotler, H B; Narayana, P A; Hazle, J D; Jackson, E F; Coupe, K J; McDonald, C L; Langford, L A; Harris, J H

1990-07-01

Magnetic resonance imaging (MRI) provides a noninvasive method of monitoring the pathologic response to spinal cord injury. Specific MR signal intensity patterns appear to correlate with degrees of improvement in the neurologic status in spinal cord injury patients. Histologic correlation of two types of MR signal intensity patterns are confirmed in the current study using a rat animal model. Adult male Sprague-Dawley rats underwent spinal cord trauma at the midthoracic level using a weight-dropping technique. After laminectomy, 5- and 10-gm brass weights were dropped from designated heights onto a 0.1-gm impounder placed on the exposed dura. Animals allowed to regain consciousness demonstrated variable recovery of hind limb paraplegia. Magnetic resonance images were obtained from 2 hours to 1 week after injury using a 2-tesla MRI/spectrometer. Sacrifice under anesthesia was performed by perfusive fixation; spinal columns were excised en bloc, embedded, sectioned, and observed with the compound light microscope. Magnetic resonance axial images obtained during the time sequence after injury demonstrate a distinct correlation between MR signal intensity patterns and the histologic appearance of the spinal cord. Magnetic resonance imaging delineates the pathologic processes resulting from acute spinal cord injury and can be used to differentiate the type of injury and prognosis.

Transplantation of oligodendrocyte precursors and sonic hedgehog results in improved function and white matter sparing in the spinal cords of adult rats after contusion.

PubMed

Bambakidis, Nicholas C; Miller, Robert H

2004-01-01

A substantial cause of neurological disability in spinal cord injury is oligodendrocyte death leading to demyelination and axonal degeneration. Rescuing oligodendrocytes and preserving myelin is expected to result in significant improvement in functional outcome after spinal cord injury. Although previous investigators have used cellular transplantation of xenografted pluripotent embryonic stem cells and observed improved functional outcome, these transplants have required steroid administration and only a minority of these cells develop into oligodendrocytes. The objective of the present study was to determine whether allografts of oligodendrocyte precursors transplanted into an area of incomplete spinal cord contusion would improve behavioral and electrophysiological measures of spinal cord function. Additional treatment incorporated the use of the glycoprotein molecule Sonic hedgehog (Shh), which has been shown to play a critical role in oligodendroglial development and induce proliferation of endogenous neural precursors after spinal cord injury. Laboratory study. Moderate spinal cord contusion injury was produced in 39 adult rats at T9-T10. Ten animals died during the course of the study. Nine rats served as contusion controls (Group 1). Six rats were treated with oligodendrocyte precursor transplantation 5 days after injury (Group 2). The transplanted cells were isolated from newborn rat pups using immunopanning techniques. Another eight rats received an injection of recombinant Shh along with the oligodendrocyte precursors (Group 3), while six more rats were treated with Shh alone (Group 4). Eight additional rats received only T9 laminectomies to serve as noninjured controls (Group 0). Animals were followed for 28 days. After an initial complete hindlimb paralysis, rats of all groups receiving a contusive injury recovered substantial function within 1 week. By 28 days, rats in Groups 2 and 3 scored 4.7 and 5.8 points better on the Basso, Beattie, Bresnahan

Eosinophilic granuloma of spine in adults: a report of 30 cases and outcome.

PubMed

Huang, Wending; Yang, Xinghai; Cao, Dong; Xiao, Jianru; Yang, Mosong; Feng, Dapeng; Huang, Quan; Wu, Zhipeng; Zheng, Wei; Jia, Lianshun; Wu, Shujia

2010-07-01

Eosinophilic granuloma (EG) of the spine is rare, especially in adults. There had been few large and long-term studies reported in the literature. The management goals of this disease in adults are preservation of neurologic function, relief of pain and reconstruction of spinal stability. However, there are still controversies over appropriate management modality of eosinophilic granuloma. Clinical manifestations, radiographic presentations, therapeutic outcomes and follow-up findings of 30 adults who were histiologically diagnosed with spinal eosinophilic granuloma, including 28 patients who received surgical treatment at our institutions from 1985 to 2008 were reviewed retrospectively. There were 25 males and five females with a mean age of 34.5 years (range, 18-71 years). The post-operative follow-up period ranged from 2 to 22.4 years (mean, 8.3 years). Neurologic deficits developed in 21 patients, apparent kyphosis developed in four cases. In contrast to the classic feature of vertebra plana in children, we found that more severe lesions often led to asymmetric collapse in adult patients and only three patients presented with vertebra plana. Thirty-three vertebral lesions distributed throughout the spine column. Twenty-one lesions were in cervical spine, seven in the thoracic spine and five in the lumbar spine. Twenty-eight adult patients underwent surgical resection with or without chemotherapy or radiotherapy, and four (13.3%) patients had recurrence after surgery. No patient in our series died. The onset of spinal EG is insidious and mainly presents as osteolytic destruction. There is a particular high prevalence of lesions in the cervical spine and more severe lesions often led to asymmetric collapse. As the skeleton of adults is well-developed and the epiphysis has stopped growing, individualized management including surgical intervention should be considered in adult patients with spinal EG who present with neurological damage and spinal instability.

The unreimbursed costs of preventing revision surgery in adult spinal deformity: analysis of cost-effectiveness of proximal junctional failure prevention with ligament augmentation.

PubMed

Safaee, Michael M; Dalle Ore, Cecilia L; Zygourakis, Corinna C; Deviren, Vedat; Ames, Christopher P

2018-05-01

OBJECTIVE Proximal junctional kyphosis (PJK) is a well-recognized complication of surgery for adult spinal deformity and is characterized by increased kyphosis at the upper instrumented vertebra (UIV). PJK prevention strategies have the potential to decrease morbidity and cost by reducing rates of proximal junctional failure (PJF), which the authors define as radiographic PJK plus clinical sequelae requiring revision surgery. METHODS The authors performed an analysis of 195 consecutive patients with adult spinal deformity. Age, sex, levels fused, upper instrumented vertebra (UIV), use of 3-column osteotomy, pelvic fixation, and mean time to follow-up were collected. The authors also reviewed operative reports to assess for the use of surgical adjuncts targeted toward PJK prevention, including ligament augmentation, hook fixation, and vertebroplasty. The cost of surgery, including direct and total costs, was also assessed at index surgery and revision surgery. Only revision surgery for PJF was included. RESULTS The mean age of the cohort was 64 years (range 25-84 years); 135 (69%) patients were female. The mean number of levels fused was 10 (range 2-18) with the UIV as follows: 2 cervical (1%), 73 upper thoracic (37%), 108 lower thoracic (55%), and 12 lumbar (6%). Ligament augmentation was used in 99 cases (51%), hook fixation in 60 cases (31%), and vertebroplasty in 71 cases (36%). PJF occurred in 18 cases (9%). Univariate analysis found that ligament augmentation and hook fixation were associated with decreased rates of PJF. However, in a multivariate model that also incorporated age, sex, and UIV, only ligament augmentation maintained a significant association with PJF reduction (OR 0.196, 95% CI 0.050-0.774; p = 0.020). Patients with ligament augmentation, compared with those without, had a higher cost of index surgery, but ligament augmentation was overall cost effective and produced significant cost savings. In sensitivity analyses in which we independently