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Sample records for spinal growth modulation

  1. Serotonergic modulation of spinal motor control

    DEFF Research Database (Denmark)

    Perrier, Jean-Francois Marie; Cotel, Florence

    2015-01-01

    Serotonin (5-HT) is a monoamine that powerfully modulates spinal motor control by acting on intrasynaptic and extrasynaptic receptors. Here we review the diversity of 5-HT actions on locomotor and motoneuronal activities. Two approaches have been used on in vitro spinal cord preparations: either...... and promotes the excitability of motoneurons, while stronger release inhibits rhythmic activity and motoneuron firing. This latter effect is responsible for central fatigue and secures rotation of motor units....

  2. Growth Modulation in Achondroplasia.

    Science.gov (United States)

    McClure, Philip K; Kilinc, Eray; Birch, John G

    2017-09-01

    Achondroplasia is the most common skeletal dysplasia with a rate of nearly 1/10,000. The development of lower extremity deformity is well documented, and various modes of correction have been reported. There are no reports on the use of growth modulation to correct angular deformity in achondroplasia. Medical Records from 1985 to 2015 were reviewed for the diagnosis of achondroplasia and growth modulation procedures. Patients who had been treated for angular deformity of the legs by growth modulation were identified. A detailed analysis of their medical record and preoperative and final lower extremity radiographs was completed. Four patients underwent growth modulation procedures, all to correct existing varus deformity of the legs. Three of the 4 patients underwent bilateral distal femoral and proximal tibial growth modulation. The remaining patient underwent tibial correction only. Two of the 4 patients had a combined proximal fibular epiphysiodesis. All limbs had some improvement of alignment; however, 1 patient went on to bilateral osteotomies. Only 1 limb corrected to a neutral axis with growth modulation alone at last follow-up, initial implantation was done before 5 years of age. Growth modulation is an effective means for deformity correction in the setting of achondroplasia. However implantation may need to be done earlier than would be typical for patients without achondroplasia. Osteotomy may still be required after growth modulation for incomplete correction.

  3. Spinal modulation of nociception by music.

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    Roy, M; Lebuis, A; Hugueville, L; Peretz, I; Rainville, P

    2012-07-01

    Numerous studies have demonstrated the capacity of music to modulate pain. However, the neurophysiological mechanisms responsible for this phenomenon remain unknown. In order to assess the involvement of descending modulatory mechanisms in the modulation of pain by music, we evaluated the effects of musical excerpts conveying different emotions (pleasant-stimulating, pleasant-relaxing, unpleasant-stimulating) on the spinally mediated nociceptive flexion reflex (or RIII), as well as on pain ratings and skin conductance responses. The RIII reflex and pain ratings were increased during the listening of unpleasant music compared with pleasant music, suggesting the involvement of descending pain-modulatory mechanisms in the effects of musical emotions on pain. There were no significant differences between the pleasant-stimulating and pleasant-relaxing musical condition, indicating that the arousal of music had little influence on pain processing. © 2012 European Federation of International Association for the Study of Pain Chapters.

  4. Somatosensory imprinting in spinal reflex modules.

    Science.gov (United States)

    Schouenborg, Jens

    2003-05-01

    Understanding how sensory information is used by motor systems for motor commands requires detailed knowledge about how the body shape and biomechanics are represented in the motor circuits. We have used the withdrawal reflex system as a model for studies of sensorimotor transformation. This system has a modular organisation in the adult. Each module performs a detailed and functionally adapted sensorimotor transformation related to the withdrawal efficacy of its output muscle(s). The weight distribution of the cutaneous input to a module is determined by the pattern of withdrawal efficacy of the muscle. Recently, we found that the somatotopic organisation and weight of the cutaneous input to the dorsal horn of the lower lumbar cord is related to this modular organisation. The dorsal horn in the lower lumbar cord thus appears to be organised in a column-like fashion, where each column performs a basic sensorimotor transformation related to the movement caused by a single muscle and the body shape. Since the withdrawal reflex system encodes error signals to the cerebellum through some of the spino-olivo cerebellar pathways, the modular concept is, in fact, a key to understanding sensory processing in higher order motor systems as well. Developmental studies indicate that each module is a self-organising circuitry that uses sensory feedback on muscle contractions to adjust its synaptic organisation. Furthermore, these studies suggest that the spontaneous movements during development, by providing structured sensory information related to movement pattern of single muscles and body shape, are instrumental in shaping the sensorimotor transformation in the spinal cord. These findings and their implications for the understanding of higher motor functions and their clinical aspects will be discussed.

  5. Priming Neural Circuits to Modulate Spinal Reflex Excitability

    OpenAIRE

    Estes, Stephen P.; Iddings, Jennifer A.; Field-Fote, Edelle C.

    2017-01-01

    While priming is most often thought of as a strategy for modulating neural excitability to facilitate voluntary motor control, priming stimulation can also be utilized to target spinal reflex excitability. In this application, priming can be used to modulate the involuntary motor output that often follows central nervous system injury. Individuals with spinal cord injury (SCI) often experience spasticity, for which antispasmodic medications are the most common treatment. Physical therapeutic/...

  6. Emotional modulation of pain and spinal nociception in fibromyalgia

    Science.gov (United States)

    Rhudy, Jamie L.; DelVentura, Jennifer L.; Terry, Ellen L.; Bartley, Emily J.; Olech, Ewa; Palit, Shreela; Kerr, Kara L.

    2013-01-01

    Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (e.g., depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in four blocks; two blocks assessed only physiological-emotional reactions (i.e., pleasure/arousal ratings, corrugator EMG, startle modulation, skin conductance) in the absence of pain and two blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (e.g., reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all three groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes. PMID:23622762

  7. Spinal cellular and network properties modulate pain perception

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    Darbon Pascal

    2016-01-01

    Previously, it has been shown that high levels of plasma glucocorticoids give rise to analgesia. However to our knowledge nothing has been reported regarding a direct non genomic modulation of neuronal spinal activity by peripheral CORT. In the present study, we used combined in vivo and in vitro electrophysiology approaches, associated with the measure of nociceptive mechanical sensitivity and plasma corticosterone level measurement to assess the impact of circulating CORT on rat nociception. We showed that CORT plasma level elevation produced analgesia via the reduction of nociceptive fiber mediated spinal responses. CORT is spinally reduced in the neuroactive metabolite THDOC that specifically enhances lamina II GABAergic synaptic transmission. The main consequence is a reduction of lamina II network excitability reflecting a selective decrease in processing of nociceptive inputs. The depressed neuronal activity at the spinal level then in turn leads to a weaker nociceptive message transmission to supraspinal structures and hence to an alleviation of pain.

  8. Modulation of spinal reflexes by sexual films of increasing intensity

    NARCIS (Netherlands)

    Both, Stephanie; Boxtel, Geert; Stekelenburg, Jeroen; Everaerd, Walter; Laan, Ellen

    2005-01-01

    Sexual arousal can be viewed as an emotional state generating sex-specific autonomic and general somatic motor system responses that prepare for sexual action. In the present study modulation of spinal tendious (T) reflexes by sexual films of varying intensity was investigated. T reflexes were

  9. Modulation of spinal reflexes by aversive and sexually appetitive stimuli

    NARCIS (Netherlands)

    Both, Stephanie; Everaerd, Walter; Laan, Ellen

    2003-01-01

    In this study, modulation of spinal tendinous (T) reflexes by sexual stimulation was investigated. T reflexes are augmented in states of appetitive and defensive action and modified by differences in arousal intensity. Reflexes were expected to be facilitated by both pleasant (sexual) and unpleasant

  10. Spinal cord direct current stimulation differentially modulates neuronal activity in the dorsal and ventral spinal cord.

    Science.gov (United States)

    Song, Weiguo; Martin, John H

    2017-03-01

    Spinal cord direct current stimulation (sDCS) has the potential for promoting motor function after injury through its modulatory actions on sensory processing, reflex functions, the motor cortex (M1) motor map, and motor output. Here we addressed systems-level mechanisms underlying sDCS neuromodulation of spinal circuits activated by M1 and peripheral forelimb electrical stimulation in anesthetized healthy rats. We determined the effects of cathodal and anodal sDCS (c- and a-sDCS) on local field potentials (LFP) and single-unit activity recorded at 32 sites simultaneously within the sixth cervical segment using a silicon multielectrode array. M1 stimulation produced distinctive dorsomedial and ventral LFP responses that showed polarity-dependent sDCS modulation. c-sDCS enhanced and a-sDCS depressed significantly ventral M1 responses; neither modulated dorsal responses significantly. Using evoked changes in β- and γ-oscillations to assay network function, c-sDCS enhanced and a-sDCS reduced oscillation power ventrally. c-sDCS increased and a-sDCS decreased background firing and firing synchrony of recorded pairs of single units. Peripheral stimulation produced a region-dependent response that showed polarity-dependent sDCS modulation. The dorsomedial LFP was unaffected by c-sDCS and weakly suppressed with a-sDCS. Peripheral-evoked unit responses showed limited polarity dependence. Our findings stress that ventral motor network behavior is enhanced by the neuromodulatory actions of c-sDCS. The combined actions of c-sDCS on M1-evoked neural responses and network behavior in the cervical spinal cord help explain the reported enhanced motor effects of this neuromodulation approach and inform the mechanisms of sDCS for promoting motor rehabilitation after spinal cord or brain injury. NEW & NOTEWORTHY Spinal cord direct current stimulation (sDCS) modulates spinal functions and shows potential for neural rehabilitation after motor systems injury. Using a multichannel

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

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    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

  12. (-)-Epigallocatechin-3-Gallate Modulates Spinal Cord Neuronal Degeneration by Enhancing Growth-Associated Protein 43, B-Cell Lymphoma 2, and Decreasing B-Cell Lymphoma 2-Associated X Protein Expression after Sciatic Nerve Crush Injury

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    Al-Maghrebi, May; Rao, Muddanna S.; Khraishah, Haitham

    2015-01-01

    Abstract Our previous studies have established that (-)-epigallocatechin-3-gallate (EGCG) has both neuroprotective and -regenerative capacity after sciatic nerve injury. Moreover, this improvement was evident on the behavioral level. The aim of this study was to investigate the central effects of ECGC on spinal cord motor neurons after sciatic nerve injury. Our study showed that administering 50 mg/kg intraperitoneally i.p. of EGCG to sciatic nerve-injured rats improved their performance on different motor functions and mechanical hyperesthesia neurobehavioral tests. Histological analysis of spinal cords of EGCG-treated sciatic nerve-injured (CRUSH+ECGC) animals showed an increase in the number of neurons in the anterior horn, when compared to the naïve, sham, and saline-treated sciatic nerve-injured (CRUSH) control groups. Additionally, immunohistochemical study of spinal cord sections revealed that EGCG reduced the expression of glial fibrillary acidic protein and increased the expression of growth-associated protein 43, a marker of regenerating axons. Finally, EGCG reduced the ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein/Bcl-2 and increased the expression of survivin gene. This study may shed some light on the future clinical use of EGCG and its constituents in the treatment of peripheral nerve injury. PMID:25025489

  13. Pain modulation by nitric oxide in the spinal cord.

    Directory of Open Access Journals (Sweden)

    Marco Aurelio M Freire

    2009-09-01

    Full Text Available Nitric oxide (NO is a versatile messenger molecule first associated with endothelial relaxing effects. In the central nervous system (CNS, NO synthesis is primarily triggered by activation of N-methyl-D-aspartate (NMDA receptors and has a Janus face, with both beneficial and harmful properties, depending on concentration and the identity of its synthetic enzyme isoform. There are three isoforms of the NO synthesizing enzyme nitric oxide synthase (NOS: neuronal (nNOS, endothelial (eNOS, and inducible nitric oxide synthase (iNOS, each one involved with specific events in the brain. In CNS, nNOS is involved with modulation of synaptic transmission through long-term potentiation in several regions, including nociceptive circuits in the spinal cord. Here, we review the role played by NO on central pain sensitization.

  14. Priming Neural Circuits to Modulate Spinal Reflex Excitability

    Science.gov (United States)

    Estes, Stephen P.; Iddings, Jennifer A.; Field-Fote, Edelle C.

    2017-01-01

    While priming is most often thought of as a strategy for modulating neural excitability to facilitate voluntary motor control, priming stimulation can also be utilized to target spinal reflex excitability. In this application, priming can be used to modulate the involuntary motor output that often follows central nervous system injury. Individuals with spinal cord injury (SCI) often experience spasticity, for which antispasmodic medications are the most common treatment. Physical therapeutic/electroceutic interventions offer an alternative treatment for spasticity, without the deleterious side effects that can accompany pharmacological interventions. While studies of physical therapeutic/electroceutic interventions have been published, a systematic comparison of these approaches has not been performed. The purpose of this study was to compare four non-pharmacological interventions to a sham-control intervention to assess their efficacy for spasticity reduction. Participants were individuals (n = 10) with chronic SCI (≥1 year) who exhibited stretch-induced quadriceps spasticity. Spasticity was quantified using the pendulum test before and at two time points after (immediate, 45 min delayed) each of four different physical therapeutic/electroceutic interventions, plus a sham-control intervention. Interventions included stretching, cyclic passive movement (CPM), transcutaneous spinal cord stimulation (tcSCS), and transcranial direct current stimulation (tDCS). The sham-control intervention consisted of a brief ramp-up and ramp-down of knee and ankle stimulation while reclined with legs extended. The order of interventions was randomized, and each was tested on a separate day with at least 48 h between sessions. Compared to the sham-control intervention, stretching, CPM, and tcSCS were associated with a significantly greater reduction in spasticity immediately after treatment. While the immediate effect was largest for stretching, the reduction persisted

  15. Emittance growth from electron beam modulation

    Energy Technology Data Exchange (ETDEWEB)

    Blaskiewicz, M.

    2009-12-01

    In linac ring colliders like MeRHIC and eRHIC a modulation of the electron bunch can lead to a modulation of the beam beam tune shift and steering errors. These modulations can lead to emittance growth. This note presents simple formulas to estimate these effects which generalize some previous results.

  16. Age-dependent modulation of cortical transcriptomes in spinal cord injury and repair.

    Directory of Open Access Journals (Sweden)

    Anne Jaerve

    Full Text Available Both injury and aging of the central nervous system reportedly produce profound changes in gene expression. Therefore, aging may interfere with the success of therapeutic interventions which were tailored for young patients. Using genome-scale transcriptional profiling, we identified distinct age-dependent expression profiles in rat sensorimotor cortex during acute, subacute and chronic phases of spinal cord injury (SCI. Aging affects the cortical transcriptomes triggered by transection of the corticospinal tract as there was only a small overlap between the significantly lesion-regulated genes in both age groups. Over-representation analysis of the lesion-regulated genes revealed that, in addition to biological processes in common, such as lipid metabolism, others, such as activation of complement cascade, were specific for aged animals. When a recently developed treatment to suppress fibrotic scarring (anti-scarring treatment AST was applied to the injured spinal cord of aged (22 months and young (2 months rats, we found that the cortical gene expression in old rats was modulated to resemble regeneration-associated profiles of young animals including the up-regulation of known repair promoting growth and transcription factors at 35 dpo. In combination with recent immunohistochemical findings demonstrating regenerative axon growth upon AST in aged animals, the present investigation on the level of gene expression strongly supports the feasibility of a successful AST therapy in elderly patients.

  17. Emotional modulation of pain and spinal nociception in persons with major depressive disorder (MDD)

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    Terry, Ellen L.; DelVentura, Jennifer L.; Bartley, Emily J.; Vincent, Ashley; Rhudy, Jamie L.

    2013-01-01

    Major depressive disorder (MDD) is associated with risk for chronic pain, but the mechanisms contributing to the MDD and pain relationship are unclear. To examine whether disrupted emotional modulation of pain might contribute, this study assessed emotional processing and emotional modulation of pain in healthy controls and unmedicated persons with MDD (14 MDD, 14 controls). Emotionally-charged pictures (erotica, neutral, mutilation) were presented in four blocks. Two blocks assessed physiological-emotional reactions (pleasure/arousal ratings, corrugator EMG, startle modulation, skin conductance) in the absence of pain and two blocks assessed emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations. Results indicated pictures generally evoked the intended emotional responses; erotic pictures elicited pleasure, subjective arousal, and smaller startle magnitudes, whereas mutilation pictures elicited displeasure, corrugator EMG activation, and subjective/physiological arousal. However, emotional processing was partially disrupted in MDD as evidenced by a blunted pleasure response to erotica and a failure to modulate startle according to a valence linear trend. Furthermore, emotional modulation of pain was observed in controls, but not MDD, even though there were no group differences in NFR threshold or emotional modulation of NFR. Together, these results suggest supraspinal processes associated with emotion processing and emotional modulation of pain may be disrupted in MDD, but brain-to-spinal cord processes that modulate spinal nociception are intact. Thus, emotional modulation of pain deficits may be a phenotypic marker for future pain risk in MDD. PMID:23954763

  18. Emotional modulation of pain and spinal nociception in persons with severe insomnia symptoms

    Science.gov (United States)

    DelVentura, Jennifer L.; Terry, Ellen L.; Bartley, Emily J.; Rhudy, Jamie L.

    2013-01-01

    Background Impaired sleep enhances pain, perhaps by disrupting pain modulation. Purpose Given that emotion modulates pain, the present study examined whether emotional modulation of pain and nociception is impaired in persons with severe insomnia symptoms relative to controls. Methods Insomnia group (n=12) met ICD-10 symptoms for primary insomnia and controls (n=13) reported no sleep impairment. Participants were shown emotionally-evocative pictures (mutilation, neutral, erotica) during which suprathreshold pain stimuli were delivered to evoke pain and the nociceptive flexion reflex (NFR; physiological correlate of spinal nociception). Results Emotional responses to pictures were similar in both groups, except that subjective valence/pleasure ratings were blunted in insomnia. Emotional modulation of pain and NFR was observed in controls, but only emotional modulation of NFR was observed in insomnia. Conclusions Consistent with previous findings, pain modulation is disrupted in insomnia which might promote pain. This may stem from disrupted supraspinal circuits not disrupted brain-to-spinal cord circuits. PMID:24101292

  19. Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury.

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    Soheila Karimi-Abdolrezaee

    Full Text Available The adult spinal cord harbours a population of multipotent neural precursor cells (NPCs with the ability to replace oligodendrocytes. However, despite this capacity, proliferation and endogenous remyelination is severely limited after spinal cord injury (SCI. In the post-traumatic microenvironment following SCI, endogenous spinal NPCs mainly differentiate into astrocytes which could contribute to astrogliosis that exacerbate the outcomes of SCI. These findings emphasize a key role for the post-SCI niche in modulating the behaviour of spinal NPCs after SCI. We recently reported that chondroitin sulphate proteoglycans (CSPGs in the glial scar restrict the outcomes of NPC transplantation in SCI by reducing the survival, migration and integration of engrafted NPCs within the injured spinal cord. These inhibitory effects were attenuated by administration of chondroitinase (ChABC prior to NPC transplantation. Here, in a rat model of compressive SCI, we show that perturbing CSPGs by ChABC in combination with sustained infusion of growth factors (EGF, bFGF and PDGF-AA optimize the activation and oligodendroglial differentiation of spinal NPCs after injury. Four days following SCI, we intrathecally delivered ChABC and/or GFs for seven days. We performed BrdU incorporation to label proliferating cells during the treatment period after SCI. This strategy increased the proliferation of spinal NPCs, reduced the generation of new astrocytes and promoted their differentiation along an oligodendroglial lineage, a prerequisite for remyelination. Furthermore, ChABC and GF treatments enhanced the response of non-neural cells by increasing the generation of new vascular endothelial cells and decreasing the number of proliferating macrophages/microglia after SCI. In conclusions, our data strongly suggest that optimization of the behaviour of endogenous spinal NPCs after SCI is critical not only to promote endogenous oligodendrocyte replacement, but also to reverse

  20. Hindlimb movement in the cat induced by amplitude-modulated stimulation using extra-spinal electrodes

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    Tai, Changfeng; Wang, Jicheng; Shen, Bing; Wang, Xianchun; Roppolo, James R.; de Groat, William C.

    2008-06-01

    Hindlimb movement in the cat induced by electrical stimulation with an amplitude-modulated waveform of the dorsal surface of the L5-S1 spinal cord or the L5-S1 dorsal/ventral roots was investigated before and after acute spinal cord transection at the T13-L1 level. Stimulation of the spinal cord or dorsal/ventral root at the same spinal segment induced similar movements including coordinated multi-joint flexion or extension. The induced movements changed from flexion to extension when the stimulation was moved from rostral (L5) to caudal (S1) spinal segments. Stimulation of a dorsal or ventral root on one side induced only ipsilateral hindlimb movement. However, stimulation on the dorsal surface of the spinal cord along the midline or across the spinal cord induced bilateral movements. The extension induced by stimulation of L7 dorsal root produced the largest ground reaction force that was strong enough to support body weight. Dorsal root stimulation induced a larger ground reaction force than ventral root stimulation and produced a more graded recruitment curve. Stepping at different speeds could be generated by combined stimulation of the rostral (L5) and the caudal (L6/L7) spinal segments with an appropriate timing between the different stimulation channels. Acute transection of the spinal cord did not change the responses indicating that the induced movements did not require the involvement of the supraspinal locomotor centers. The methods and the stimulation strategy developed in this study might be utilized to restore locomotor function after spinal cord injury.

  1. Continuous Descending Modulation of the Spinal Cord Revealed by Functional MRI.

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    Patrick W Stroman

    Full Text Available Spontaneous variations in spinal cord activity may arise from regulation of any of a number of functions including sensory, motor, and autonomic control. Here, we use functional MRI (fMRI of healthy participants to identify properties of blood oxygenation-level dependent (BOLD variations in the spinal cord in response to knowledge that either a noxious stimulus is impending, or that no stimulus is to be expected. Expectation of a noxious stimulus, or no stimulus, is shown to have a significant effect on wide-spread BOLD signal variations in the spinal cord over the entire time period of the fMRI acquisition. Coordination of BOLD responses between/within spinal cord and brainstem regions are also influenced by this knowledge. We provide evidence that such signal variations are the result of continuous descending modulation of spinal cord function. BOLD signal variations in response to noxious stimulation of the hand are also shown, as in previous studies. The observation of both continuous and reactive BOLD responses to emotional/cognitive factors and noxious peripheral stimulation may have important implications, not only for our understanding of endogenous pain modulation, but also in showing that spinal cord activity is under continuous regulatory control.

  2. Spinal cord stimulation and modulation of neuropathic pain

    NARCIS (Netherlands)

    de Vos, Cecilia Cecilia Clementine

    2013-01-01

    This thesis reports on the opportunities of several new applications of spinal cord stimulation (SCS) for the treatment of neuropathic pain. Our pilot study and consecutively performed international randomised controlled trial on effects of SCS in patients with painful diabetic neuropathy showed

  3. Modeling trans-spinal direct current stimulation for the modulation of the lumbar spinal motor pathways

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    Kuck, A.; Stegeman, D. F.; van Asseldonk, E. H. F.

    2017-10-01

    Objective. Trans-spinal direct current stimulation (tsDCS) is a potential new technique for the treatment of spinal cord injury (SCI). TsDCS aims to facilitate plastic changes in the neural pathways of the spinal cord with a positive effect on SCI recovery. To establish tsDCS as a possible treatment option for SCI, it is essential to gain a better understanding of its cause and effects. We seek to understand the acute effect of tsDCS, including the generated electric field (EF) and its polarization effect on the spinal circuits, to determine a cellular target. We further ask how these findings can be interpreted to explain published experimental results. Approach. We use a realistic full body finite element volume conductor model to calculate the EF of a 2.5 mA direct current for three different electrode configurations. We apply the calculated electric field to realistic motoneuron models to investigate static changes in membrane resting potential. The results are combined with existing knowledge about the theoretical effect on a neuronal level and implemented into an existing lumbar spinal network model to simulate the resulting changes on a network level. Main results. Across electrode configurations, the maximum EF inside the spinal cord ranged from 0.47 V m-1 to 0.82 V m-1. Axon terminal polarization was identified to be the dominant cellular target. Also, differences in electrode placement have a large influence on axon terminal polarization. Comparison between the simulated acute effects and the electrophysiological long-term changes observed in human tsDCS studies suggest an inverse relationship between the two. Significance. We provide methods and knowledge for better understanding the effects of tsDCS and serve as a basis for a more targeted and optimized application of tsDCS.

  4. Mandibular appliance modulates condylar growth through integrins.

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    Marques, M Rubia; Hajjar, D; Franchini, K Gomes; Moriscot, A Sigari; Santos, M Fagundes

    2008-02-01

    Functional orthopedic therapy corrects growth discrepancies between the maxilla and mandible, possibly through postural changes in the musculature and modulation of the mandibular condylar cartilage growth. Using Wistar rats, we tested the hypothesis that chondrocytes respond to forces generated by a mandibular propulsor appliance by changes in gene expression, and that integrins are important mediators in this response. Immunohistochemical analyses demonstrated that the use of the appliance for different periods of time modulated the expression of fibronectin, alpha5 and alphav integrin subunits, as well as cell proliferation in the cartilage. In vitro, cyclic distension of condylar cartilage-derived cells increased fibronectin mRNA, as well as Insulin-like Growth Factor-I and II mRNA and cell proliferation. A peptide containing the Arginine-Glycine-Asparagine sequence (RGD), the main cell-binding sequence in fibronectin, blocked almost all these effects, confirming that force itself modulates the growth of the rat condylar cartilage, and that RGD-binding integrins participate in mechanotransduction.

  5. Spinal muscular atrophy: Factors that modulate motor neurone vulnerability.

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    Tu, Wen-Yo; Simpson, Julie E; Highley, J Robin; Heath, Paul R

    2017-06-01

    Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the selective loss of particular groups of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. To date, no effective treatment is available, however, there are ongoing clinical trials are in place which promise much for the future. However, there remains an ongoing problem in trying to link a single gene loss to motor neurone degeneration. Fortunately, given successful disease models that have been established and intensive studies on SMN functions in the past ten years, we are fast approaching the stage of identifying the underlying mechanisms of SMA pathogenesis Here we discuss potential disease modifying factors on motor neurone vulnerability, in the belief that these factors give insight into the pathological mechanisms of SMA and therefore possible therapeutic targets. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Noradrenergic modulation of intrinsic and synaptic properties of lumbar motoneurons in the neonatal rat spinal cord

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    Maylis Tartas

    2010-03-01

    Full Text Available Although it is known that noradrenaline powerfully controls spinal motor networks, few data are available regarding the noradrenergic modulation of intrinsic and synaptic properties of neurons in motor networks. Our work explores the cellular basis of noradrenergic modulation in the rat motor spinal cord. We first show that lumbar motoneurons express the three classes of adrenergic receptors at birth. Using patch-clamp recordings in the newborn rat spinal cord preparation, we characterized the effects of noradrenaline and of specific agonists of the three classes of adrenoreceptors on motoneuron membrane properties. Noradrenaline increases the motoneuron excitability partly via the inhibition of a KIR like current. Methoxamine (α1, clonidine (α2 and isoproterenol (β differentially modulate the motoneuron membrane potential but also increase motoneuron excitability, these effects being respectively inhibited by the antagonists prazosin (α1, yohimbine (α2 and propranolol (β. We show that the glutamatergic synaptic drive arising from the T13-L2 network is enhanced in motoneurons by noradrenaline, methoxamine and isoproterenol. On the other hand, noradrenaline, isoproterenol and clonidine inhibit both the frequency and amplitude of miniature glutamatergic EPSCs while methoxamine increases their frequency. The T13-L2 synaptic drive is thereby differentially modulated from the other glutamatergic synapses converging onto motoneurons and enhanced by presynaptic α1 and β receptor activation. Our data thus show that the noradrenergic system exerts a powerful and complex neuromodulation of lumbar motor networks in the neonatal rat spinal cord.

  7. Agmatine Modulates the Phenotype of Macrophage Acute Phase after Spinal Cord Injury in Rats.

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    Kim, Jae Hwan; Kim, Jae Young; Mun, Chin Hee; Suh, Minah; Lee, Jong Eun

    2017-10-01

    Agmatine is a decarboxylated arginine by arginine decarboxylase. Agmatine is known to be a neuroprotective agent. It has been reported that agmatine works as a NMDA receptor blocker or a competitive nitric oxide synthase inhibitor in CNS injuries. In spinal cord injury, agmatine showed reduction of neuropathic pain, improvement of locomotor function, and neuroprotection. Macrophage is a key cellular component in neuroinflammation, a major cause of impairment after spinal cord injury. Macrophage has subtypes, M1 and M2 macrophages. M1 macrophage induces a pro-inflammatory response, but M2 inspires an anti-inflammatory response. In this study, it was clarified whether the neuroprotective effect of agmatine is related with the modulation of macrophage subdivision after spinal cord injury. Spinal cord injury was induced in rats with contusion using MASCIS. Animals received agmatine (100 mg/kg, IP) daily for 6 days beginning the day after spinal cord injury. The proportion of M1 and M2 macrophages are confirmed with immunohistochemistry and FACS. CD206+ & ED1+ cells were counted as M2 macrophages. The systemic treatment of agmatine increased M2 macrophages caudal side to epicenter 1 week after spinal cord injury in immunohistochemistry. M2 macrophage related markers, Arginase-1 and CD206 mRNA, were increased in the agmatine treatment group and M2 macrophage expressing and stimulated cytokine, IL-10 mRNA, also was significantly overexpressed by agmatine injection. Among BMPs, BMP2/4/7, agmatine significantly increased only the expression of BMP2 known to reduce M1 macrophage under inflammatory status. These results suggest that agmatine reduces impairment after spinal cord injury through modulating the macrophage phenotype.

  8. What's New in Pediatric Spine Growth Modulation and Implant Technology for Early-Onset Scoliosis?

    Science.gov (United States)

    Wessell, Nolan M; Martus, Jeffrey E; Halanski, Matthew A; Snyder, Brian; Truong, Walter

    2018-01-01

    Early-onset scoliosis (EOS) affects roughly 1 to 2 out of 10,000 live births per year. Because this subset of patients has a yet to achieve a majority of their skeletal growth, a number of treatment challenges need to be addressed before surgical intervention. If left untreated, EOS can cause a number of problems throughout the patient's lifespan, particularly in regards to the growth of the thorax and pulmonary development. A wide variety of surgical systems and techniques are available to the treating surgeon. A review of the orthopaedic literature from 2010 to 2015 relating to pediatric spine growth modulation was performed. Ninety-eight papers were identified and, following exclusion criteria, a total of 31 papers were selected for further review. This paper summarizes the recently published literature regarding growth-friendly spinal implants, the status of their Food and Drug Administration approval labeling as well as the indications, applications, and complications associated with their implementation. There are a growing number of options at the surgeon's disposal when treating patients with EOS. As surgeons, we must continue to be vigilant in our demand for sound clinical evidence as we strive to provide optimal care for our patients. The rapidly advancing field of spinal growth modulation is exciting. More work must be done to further enhance our ability to predictably modulate growth in the pediatric spine.

  9. Aldynoglia cells and modulation of RhoGTPase activity as useful tools for spinal cord injury repair

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    Doncel-Pérez, Ernesto; Nieto-Sampedro, Manuel

    2016-01-01

    A combined approach in spinal cord injury (SCI) therapy is the modulation of the cellular and molecular processes involved in glial scarring. Aldaynoglial cells are neural cell precursors with a high capacity to differentiate into neurons, promote axonal growth, wrapping and myelination of resident neurons. These important characteristics of aldaynoglia can be combined with specific inhibition of the RhoGTPase activity in astroglia and microglia that cause reduction of glial proliferation, retraction of glial cell processes and myelin production by oligodendrocytes. Previously we used experimental central nervous system (CNS) injury models, like spinal cord contusion and striatal lacunar infarction and observed that administration of RhoGTPase glycolipid inhibitor or aldaynoglial cells, respectively, produced a significant gain of functional recovery in treated animals. The combined therapy with neuro-regenerative properties strategy is highly desirable to treat SCI for functional potentiation of neurons and oligodendrocytes, resulting in better locomotor recovery. Here we suggest that treatment of spinal lesions with aldaynoglia from neurospheres plus local administration of a RhoGTPase inhibitor could have an additive effect and promote recovery from SCI. PMID:27630672

  10. The effect of three-dimensional geometrical changes during adolescent growth on the biomechanics of a spinal motion segment

    NARCIS (Netherlands)

    Homminga, J.; Hekman, E. E. G.; Veldhuizen, A. G.; Verkerke, G. J.; Meijer, G.

    2010-01-01

    During adolescent growth, vertebrae and intervertebral discs undergo various geometrical changes. Although such changes in geometry are well known, their effects on spinal stiffness remains poorly understood. However, this understanding is essential in the treatment of spinal abnormalities during

  11. Human platelet-rich plasma promotes axon growth in brain-spinal cord coculture.

    Science.gov (United States)

    Takeuchi, Michiko; Kamei, Naosuke; Shinomiya, Rikuo; Sunagawa, Toru; Suzuki, Osami; Kamoda, Hiroto; Ohtori, Seiji; Ochi, Mitsuo

    2012-08-22

    Platelet-rich plasma (PRP) contains several growth factors, including platelet-derived growth factor (PDGF), transforming growth factor-β1 (TGF-β1), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF), that are associated with repair processes after central nervous system injury. Although PRP have been applied to some regenerative therapies, the regeneration effects of PRP on spinal cord injury have not been reported. This study applied a rat organ coculture system to examine the ability of PRP to enhance axonal growth in spinal cord tissues and to identify the growth factors in PRP that contribute to the regulation of axon growth. PRP from human peripheral blood was added to organ cocultures. Furthermore, neutralizing antibodies against PDGF-AB, TGF-β1, IGF-1, or VEGF were added to the cocultures with PRP. Axon growth from the brain cortex into the spinal cord was assessed quantitatively using anterograde axon tracing with DiI. Addition of PRP to the cocultures promoted axon growth, and the axon growth was significantly suppressed by the addition of neutralizing antibodies against IGF-1 and VEGF, but not PDGF-AB. In contrast, axon growth was promoted significantly by the addition of neutralizing antibodies against TGF-β1. These findings indicate that PRP promotes axon growth in spinal cord tissues through mechanisms associated with IGF-1 and VEGF, and that TGF-β1 in PRP exerts negative effects on axon growth.

  12. Periodic modulation of repetitively elicited monosynaptic reflexes of the human lumbosacral spinal cord

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    Danner, Simon M.; Freundl, Brigitta; Binder, Heinrich; Mayr, Winfried; Rattay, Frank; Minassian, Karen

    2015-01-01

    In individuals with motor-complete spinal cord injury, epidural stimulation of the lumbosacral spinal cord at 2 Hz evokes unmodulated reflexes in the lower limbs, while stimulation at 22–60 Hz can generate rhythmic burstlike activity. Here we elaborated on an output pattern emerging at transitional stimulation frequencies with consecutively elicited reflexes alternating between large and small. We analyzed responses concomitantly elicited in thigh and leg muscle groups bilaterally by epidural stimulation in eight motor-complete spinal cord-injured individuals. Periodic amplitude modulation of at least 20 successive responses occurred in 31.4% of all available data sets with stimulation frequency set at 5–26 Hz, with highest prevalence at 16 Hz. It could be evoked in a single muscle group only but was more strongly expressed and consistent when occurring in pairs of antagonists or in the same muscle group bilaterally. Latencies and waveforms of the modulated reflexes corresponded to those of the unmodulated, monosynaptic responses to 2-Hz stimulation. We suggest that the cyclical changes of reflex excitability resulted from the interaction of facilitatory and inhibitory mechanisms emerging after specific delays and with distinct durations, including postactivation depression, recurrent inhibition and facilitation, as well as reafferent feedback activation. The emergence of large responses within the patterns at a rate of 5.5/s or 8/s may further suggest the entrainment of spinal mechanisms as involved in clonus. The study demonstrates that the human lumbosacral spinal cord can organize a simple form of rhythmicity through the repetitive activation of spinal reflex circuits. PMID:25904708

  13. Human Mesenchymal Stem Cells Modulate Inflammatory Cytokines after Spinal Cord Injury in Rat

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    Lucia Machová Urdzíková

    2014-06-01

    Full Text Available Transplantation of mesenchymal stem cells (MSC improves functional recovery in experimental models of spinal cord injury (SCI; however, the mechanisms underlying this effect are not completely understood. We investigated the effect of intrathecal implantation of human MSC on functional recovery, astrogliosis and levels of inflammatory cytokines in rats using balloon-induced spinal cord compression lesions. Transplanted cells did not survive at the lesion site of the spinal cord; however, functional recovery was enhanced in the MSC-treated group as was confirmed by the Basso, Beattie, and Bresnahan (BBB and the flat beam test. Morphometric analysis showed a significantly higher amount of remaining white matter in the cranial part of the lesioned spinal cords. Immunohistochemical analysis of the lesions indicated the rearrangement of the glial scar in MSC-treated animals. Real-time PCR analysis revealed an increased expression of Irf5, Mrc1, Fgf2, Gap43 and Gfap. Transplantation of MSCs into a lesioned spinal cord reduced TNFα, IL-4, IL-1β, IL-2, IL-6 and IL-12 and increased the levels of MIP-1α and RANTES when compared to saline-treated controls. Intrathecal implantation of MSCs reduces the inflammatory reaction and apoptosis, improves functional recovery and modulates glial scar formation after SCI, regardless of cell survival. Therefore, repeated applications may prolong the beneficial effects induced by MSC application.

  14. Nerve-Specific Input Modulation to Spinal Neurons during a Motor Task in the Monkey.

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    Confais, Joachim; Kim, Geehee; Tomatsu, Saeka; Takei, Tomohiko; Seki, Kazuhiko

    2017-03-08

    If not properly regulated, the large amount of reafferent sensory signals generated by our own movement could destabilize the CNS. We investigated how input from peripheral nerves to spinal cord is modulated during behavior. We chronically stimulated the deep radial nerve (DR; proprioceptive, wrist extensors), the median nerve (M; mixed, wrist flexors and palmar skin) and the superficial radial nerve (SR; cutaneous, hand dorsum) while four monkeys performed a delayed wrist flexion-extension task. Spinal neurons putatively receiving direct sensory input were defined based on their evoked response latency following nerve stimulation. We compared the influence of behavior on the evoked response (responsiveness to a specific peripheral input) and firing rate of 128 neuron-nerve pairs based on their source nerve. Firing rate increased during movement regardless of source nerve, whereas evoked response modulation was strikingly nerve-dependent. In SR ( n = 47) and M ( n = 27) neurons (cutaneous or mixed input), the evoked response was suppressed during wrist flexion and extension. In contrast, in DR neurons ( n = 54, pure proprioceptive input), the evoked response was facilitated exclusively during movements corresponding to the contraction of DR spindle-bearing muscles (i.e., wrist extension). Furthermore, modulations of firing rate and evoked response were uncorrelated in SR and M neurons, whereas they tended to be positively comodulated in DR neurons. Our results suggest that proprioceptive and cutaneous inputs to the spinal cord are modulated differently during voluntary movements, suggesting a refined gating mechanism of sensory signals according to behavior. SIGNIFICANCE STATEMENT Voluntary movements produce copious sensory signals, which may overwhelm the CNS if not properly regulated. This regulation is called "gating" and occurs at several levels of the CNS. To evaluate the specificity of sensory gating, we investigated how different sources of somatosensory

  15. Adenosine-mediated modulation of ventral horn interneurons and spinal motoneurons in neonatal mice

    Science.gov (United States)

    Witts, Emily C.; Nascimento, Filipe

    2015-01-01

    Neuromodulation allows neural networks to adapt to varying environmental and biomechanical demands. Purinergic signaling is known to be an important modulatory system in many parts of the CNS, including motor control circuitry. We have recently shown that adenosine modulates the output of mammalian spinal locomotor control circuitry (Witts EC, Panetta KM, Miles GB. J Neurophysiol 107: 1925–1934, 2012). Here we investigated the cellular mechanisms underlying this adenosine-mediated modulation. Whole cell patch-clamp recordings were performed on ventral horn interneurons and motoneurons within in vitro mouse spinal cord slice preparations. We found that adenosine hyperpolarized interneurons and reduced the frequency and amplitude of synaptic inputs to interneurons. Both effects were blocked by the A1-type adenosine receptor antagonist DPCPX. Analysis of miniature postsynaptic currents recorded from interneurons revealed that adenosine reduced their frequency but not amplitude, suggesting that adenosine acts on presynaptic receptors to modulate synaptic transmission. In contrast to interneurons, recordings from motoneurons revealed an adenosine-mediated depolarization. The frequency and amplitude of synaptic inputs to motoneurons were again reduced by adenosine, but we saw no effect on miniature postsynaptic currents. Again these effects on motoneurons were blocked by DPCPX. Taken together, these results demonstrate differential effects of adenosine, acting via A1 receptors, in the mouse spinal cord. Adenosine has a general inhibitory action on ventral horn interneurons while potentially maintaining motoneuron excitability. This may allow for adaptation of the locomotor pattern generated by interneuronal networks while helping to ensure the maintenance of overall motor output. PMID:26311185

  16. Observing object lifting errors modulates cortico-spinal excitability and improves object lifting performance.

    Science.gov (United States)

    Buckingham, Gavin; Wong, Jeremy D; Tang, Minnie; Gribble, Paul L; Goodale, Melvyn A

    2014-01-01

    Observing the actions of others has been shown to modulate cortico-spinal excitability and affect behaviour. However, the sensorimotor consequences of observing errors are not well understood. Here, participants watched actors lift identically weighted large and small cubes which typically elicit expectation-based fingertip force errors. One group of participants observed the standard overestimation and underestimation-style errors that characterise early lifts with these cubes (Error video--EV). Another group watched the same actors performing the well-adapted error-free lifts that characterise later, well-practiced lifts with these cubes (No error video--NEV). We then examined actual object lifting performance in the subjects who watched the EV and NEV. Despite having similar cognitive expectations and perceptions of heaviness, the group that watched novice lifters making errors themselves made fewer overestimation-style errors than those who watched the expert lifts. To determine how the observation of errors alters cortico-spinal excitability, we measured motor evoked potentials in separate group of participants while they passively observed these EV and NEV. Here, we noted a novel size-based modulation of cortico-spinal excitability when observing the expert lifts, which was eradicated when watching errors. Together, these findings suggest that individuals' sensorimotor systems are sensitive to the subtle visual differences between observing novice and expert performance. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Changes in functional properties and 5-HT modulation above and below a spinal transection in lamprey

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    Matthew eBecker

    2015-01-01

    Full Text Available In addition to the disruption of neural function below spinal cord injuries (SCI, there also can be changes in neuronal properties above and below the lesion site. The relevance of these changes is generally unclear, but they must be understood if we are to provide rational interventions. Pharmacological approaches to improving locomotor function have been studied extensively, but it is still unclear what constitutes an optimal approach. Here, we have used the lamprey to compare the modulatory effects of 5-HT and lesion-induced changes in cellular and synaptic properties in unlesioned and lesioned animals. While analyses typically focus on the sub-lesion spinal cord, we have also examined effects above the lesion to see if there are changes here that could potentially contribute to the functional recovery.Cellular and synaptic properties differed in unlesioned and lesioned spinal cords and above and below the lesion site. The cellular and synaptic modulatory effects of 5-HT also differed in lesioned and unlesioned animals, again in region-specific ways above and below the lesion site. A role for 5-HT in promoting recovery was suggested by the potential for improvement in locomotor activity when 5-HT was applied to poorly recovered animals, and by the consistent failure of animals to recover when they were incubated in PCPA to deplete 5-HT. However, PCPA did not affect swimming in animals that had already recovered, suggesting a difference in 5-HT effects after lesioning. These results show changes in 5-HT modulation and cellular and synaptic properties after recovery from a spinal cord transection. Importantly, effects are not confined to the sub-lesion spinal cord but also occur above the lesion site. This suggests that the changes may not simply reflect compensatory responses to the loss of descending inputs, but reflect the need for co-ordinated changes above and below the lesion site. The changes in modulatory effects should be considered in

  18. [Growth modulation in operative treatment of juvenile scoliosis by USS paediatric].

    Science.gov (United States)

    Pfandlsteiner, Thomas; Wallnoefer, Peter; Wimmer, Cornelius

    2010-05-01

    Growth modulation in operative treatment of juvenile scoliosis can be done by USS paediatric instrumentation to control spinal growth in patients of small stature with juvenile scoliosis. The double-rod system has to be distracted every 4-6 months. The system is used in young patients too tall for VEPTR (vertical expandable prosthetic titanium rib) instrumentation. The system with a very low profile allows reduced soft-tissue pressure saving soft tissue from atrophy or the development of pseudocysts above the screws. With this procedure controlled growth with growth modulation of the spine is possible and final spondylodesis can be done later. Congenital, idiopathic and neuromuscular scolioses. Children, who are too tall and big for a VEPTR instrumentation. Cobb angle > 40 degrees or progression > 10 degrees during brace therapy. Adults. Dysplastic pedicles with vertebral anomalies. Arthrogryposis. The patient should be positioned prone, lying flat on the table. Median skin incision with subperiosteal preparation of the paraspinal muscles is done to expose the vertebrae. Next, the pedicle is prepared with a tap, and the USS paediatric pedicle screw system with its very low profile is inserted under fluoroscopic control in anterior-posterior and lateral view. In the upper thoracic spine the authors use screws 4.2 mm in diameter, in the lower thoracic spine 5-mm screws, and in the lumbar spine 6-mm screws. Measurement of the rod length and insertion of the rod are performed. When spinal growth for > 4 years is expected, distraction of the double-rod system by the use of two dominos is done on the concave and convex side of the curve to modulate spinal growth. When spinal growth for 2-4 years is expected, distraction is done just at the concave side of the curve. For correction of the curve, either segmental correction or classic derotation by the Cotrel-Dubousset technique can be performed. Postoperative on block rotation. Mobilization of the patient on day 2 after

  19. Sustaining intrinsic growth capacity of adult neurons promotes spinal cord regeneration

    Science.gov (United States)

    Neumann, Simona; Skinner, Kate; Basbaum, Allan I.

    2005-11-01

    The peripheral axonal branch of primary sensory neurons readily regenerates after peripheral nerve injury, but the central branch, which courses in the dorsal columns of the spinal cord, does not. However, if a peripheral nerve is transected before a spinal cord injury, sensory neurons that course in the dorsal columns will regenerate, presumably because their intrinsic growth capacity is enhanced by the priming peripheral nerve lesion. As the effective priming lesion is made before the spinal cord injury it would clearly have no clinical utility, and unfortunately, a priming lesion made after a spinal cord injury results in an abortive regenerative response. Here, we show that two priming lesions, one made at the time of a spinal cord injury and a second 1 week after a spinal cord injury, in fact, promote dramatic regeneration, within and beyond the lesion. The first lesion, we hypothesize, enhances intrinsic growth capacity, and the second one sustains it, providing a paradigm for promoting CNS regeneration after injury. primary afferents | dorsal columns | neurite outgrowth | sprouting | priming

  20. Motor cortex-periaqueductal gray-spinal cord neuronal circuitry may involve in modulation of nociception: a virally mediated transsynaptic tracing study in spinally transected transgenic mouse model.

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    Da-Wei Ye

    Full Text Available Several studies have shown that motor cortex stimulation provided pain relief by motor cortex plasticity and activating descending inhibitory pain control systems. Recent evidence indicated that the melanocortin-4 receptor (MC4R in the periaqueductal gray played an important role in neuropathic pain. This study was designed to assess whether MC4R signaling existed in motor cortex-periaqueductal gray-spinal cord neuronal circuitry modulated the activity of sympathetic pathway by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV-614 was injected into the left gastrocnemius muscle in adult male MC4R-green fluorescent protein (GFP transgenic mice (n = 15. After a survival time of 4-6 days, the mice (n = 5 were randomly assigned to humanely sacrifice, and spinal cords and brains were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the left gastrocnemius muscle were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML, periaqueductal gray and motor cortex. Our findings support the hypothesis that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may participate in the modulation of the melanocortin-sympathetic signaling and contribute to the descending modulation of nociceptive transmission, suggesting that MC4R signaling in motor cortex-periaqueductal gray-spinal cord neural pathway may modulate the activity of sympathetic outflow sensitive to nociceptive signals.

  1. Structural and Functional Substitution of Deleted Primary Sensory Neurons by New Growth from Intrinsic Spinal Cord Nerve Cells: An Alternative Concept in Reconstruction of Spinal Cord Circuits.

    Science.gov (United States)

    James, Nicholas D; Angéria, Maria; Bradbury, Elizabeth J; Damberg, Peter; McMahon, Stephen B; Risling, Mårten; Carlstedt, Thomas

    2017-01-01

    In a recent clinical report, return of the tendon stretch reflex was demonstrated after spinal cord surgery in a case of total traumatic brachial plexus avulsion injury. Peripheral nerve grafts had been implanted into the spinal cord to reconnect to the peripheral nerves for motor and sensory function. The dorsal root ganglia (DRG) containing the primary sensory nerve cells had been surgically removed in order for secondary or spinal cord sensory neurons to extend into the periphery and replace the deleted DRG neurons. The present experimental study uses a rat injury model first to corroborate the clinical finding of a re-established spinal reflex arch, and second, to elucidate some of the potential mechanisms underlying these findings by means of morphological, immunohistochemical, and electrophysiological assessments. Our findings indicate that, after spinal cord surgery, the central nervous system sensory system could replace the traumatically detached original peripheral sensory connections through new neurite growth from dendrites.

  2. Structural and Functional Substitution of Deleted Primary Sensory Neurons by New Growth from Intrinsic Spinal Cord Nerve Cells: An Alternative Concept in Reconstruction of Spinal Cord Circuits

    Directory of Open Access Journals (Sweden)

    Nicholas D. James

    2017-07-01

    Full Text Available In a recent clinical report, return of the tendon stretch reflex was demonstrated after spinal cord surgery in a case of total traumatic brachial plexus avulsion injury. Peripheral nerve grafts had been implanted into the spinal cord to reconnect to the peripheral nerves for motor and sensory function. The dorsal root ganglia (DRG containing the primary sensory nerve cells had been surgically removed in order for secondary or spinal cord sensory neurons to extend into the periphery and replace the deleted DRG neurons. The present experimental study uses a rat injury model first to corroborate the clinical finding of a re-established spinal reflex arch, and second, to elucidate some of the potential mechanisms underlying these findings by means of morphological, immunohistochemical, and electrophysiological assessments. Our findings indicate that, after spinal cord surgery, the central nervous system sensory system could replace the traumatically detached original peripheral sensory connections through new neurite growth from dendrites.

  3. Experimental reduction of pain catastrophizing modulates pain report but not spinal nociception as verified by mediation analyses.

    Science.gov (United States)

    Terry, Ellen L; Thompson, Kathryn A; Rhudy, Jamie L

    2015-08-01

    Pain catastrophizing is associated with enhanced pain; however, the mechanisms by which it modulates pain are poorly understood. Evidence suggests that catastrophizing modulates supraspinal processing of pain but does not modulate spinal nociception (as assessed by nociceptive flexion reflex [NFR]). Unfortunately, most NFR studies have been correlational. To address this, this study experimentally reduced catastrophizing to determine whether it modulates spinal nociception (NFR). Healthy pain-free participants (N = 113) were randomly assigned to a brief 30-minute catastrophizing reduction manipulation or a control group that received pain education. Before and after manipulations, 2 types of painful stimuli were delivered to elicit (1) NFR (single trains of stimuli) and (2) temporal summation of NFR (3 stimulations at 2 Hz). After each set of stimuli, participants were asked to report their pain intensity and unpleasantness, as well as their situation-specific catastrophizing. Manipulation checks verified that catastrophizing was effectively reduced. Furthermore, pain intensity and unpleasantness to both stimulation types were reduced by the catastrophizing manipulation, effects that were mediated by catastrophizing. Although NFRs were not affected by the catastrophizing manipulation, temporal summation of NFR was reduced. However, this effect was not mediated by catastrophizing. These results indicate that reductions in catastrophizing lead to reductions in pain perception but do not modulate spinal nociception and provides further evidence that catastrophizing modulates pain at the supraspinal, not the spinal, level.

  4. Growth factors and cytokines in patients with long bone fractures and associated spinal cord injury.

    Science.gov (United States)

    Khallaf, Fathy G; Kehinde, Elijah O; Mostafa, Ahmed

    2016-06-01

    The aim of the study was to test the effect of acute traumatic spinal cord injury of quadriplegia or paraplegia on bone healing in patients with associated long bone fractures and to investigate the molecular and cellular events of the underlying mechanism for a possible acceleration. Healing indicators of long bone fractures and growth factors, IGF-II, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), Activin-A, and cytokine I-L-1, in the patients' blood were calculated and measured for 21 patients with spinal cord injuries and associated long bone fractures in prospective controlled study and compared to 20 patients with only spinal cord injuries, 30 patients with only long bone fractures, and 30 healthy volunteers. The study results showed that long bone fractures in patients with associated acute traumatic spinal cord injury of quadriplegia or paraplegia heal more expectedly, faster, and with exuberant florid union callus (P > 0.001) and show statistically significant higher levels of growth factors like PDGF, VEGF, Activin-A, and cytokine I-L-1, along the 3 weeks of follow-up (P > 0.005). I-IGF-II showed statistically significant subnormal level along the whole follow-up period in the same patients (P > 0.005). We concluded that long bone fractures in spinal cord injury patients heal more expectedly, faster, and with exuberant and florid callus formation; growth factors like IGF-II, PDGF, VEGF, Activin-A, and cytokine I-L-I have roles as mediators, in molecular events and as byproducts of the subtle mechanism of accelerated osteogenesis in these patients and may represent therapeutic potentials to serve as agents to enhance bone repair.

  5. OCAM regulates embryonic spinal cord stem cell proliferation by modulating ErbB2 receptor.

    Science.gov (United States)

    Deleyrolle, Loïc; Sabourin, Jean-Charles; Rothhut, Bernard; Fujita, Hiroko; Guichet, Pierre-Olivier; Teigell, Marisa; Ripoll, Chantal; Chauvet, Norbert; Perrin, Florence; Mamaeva, Daria; Noda, Tetsuo; Mori, Kensaku; Yoshihara, Yoshihiro; Hugnot, Jean-Philippe

    2015-01-01

    The proliferation and differentiation of neural stem cells are tightly controlled by intrinsic and extrinsic cues. Cell adhesion molecules are increasingly recognized as regulators of these processes. Here we report the expression of the olfactory cell adhesion molecule (OCAM/NCAM2/RNCAM) during mouse spinal cord development and in neural stem cells cultured as neurospheres. OCAM is also weakly expressed in the dormant adult stem cell niche around the central canal and is overexpressed after spinal cord injury. Both transmembrane (TM) and glycosylphosphatidylinositol (GPI)-linked isoforms are present in neurospheres. Electron microscopy and internalisation experiments revealed a dynamic trafficking of OCAM between the membrane and intracellular compartments. After differentiation, OCAM remains in neurons and oligodendrocytes whereas no expression is detected in astrocytes. Using OCAM knockout (KO) mice, we found that mutant spinal cord stem cells showed an increased proliferation and self-renewal rates although no effect on differentiation was observed. This effect was reversed by lentivirus-mediated re-introduction of OCAM. Mechanistically, we identified the ErbB2/Neu/HER2 protein as being implicated in the enhanced proliferation of mutant cells. ErbB2 protein expression and phosphorylation level were significantly increased in KO cells whereas no difference was observed at the mRNA level. Overexpression of ErbB2 in wild-type and mutant cells also increased their growth while reintroduction of OCAM in mutant cells reduced the level of phosphorylated ErbB2. These results indicate that OCAM exerts a posttranscriptional control on the ErbB2 signalling in spinal cord stem cells. This study adds further support for considering cell adhesion molecules as regulators of the ErbB signalling.

  6. OCAM regulates embryonic spinal cord stem cell proliferation by modulating ErbB2 receptor.

    Directory of Open Access Journals (Sweden)

    Loïc Deleyrolle

    Full Text Available The proliferation and differentiation of neural stem cells are tightly controlled by intrinsic and extrinsic cues. Cell adhesion molecules are increasingly recognized as regulators of these processes. Here we report the expression of the olfactory cell adhesion molecule (OCAM/NCAM2/RNCAM during mouse spinal cord development and in neural stem cells cultured as neurospheres. OCAM is also weakly expressed in the dormant adult stem cell niche around the central canal and is overexpressed after spinal cord injury. Both transmembrane (TM and glycosylphosphatidylinositol (GPI-linked isoforms are present in neurospheres. Electron microscopy and internalisation experiments revealed a dynamic trafficking of OCAM between the membrane and intracellular compartments. After differentiation, OCAM remains in neurons and oligodendrocytes whereas no expression is detected in astrocytes. Using OCAM knockout (KO mice, we found that mutant spinal cord stem cells showed an increased proliferation and self-renewal rates although no effect on differentiation was observed. This effect was reversed by lentivirus-mediated re-introduction of OCAM. Mechanistically, we identified the ErbB2/Neu/HER2 protein as being implicated in the enhanced proliferation of mutant cells. ErbB2 protein expression and phosphorylation level were significantly increased in KO cells whereas no difference was observed at the mRNA level. Overexpression of ErbB2 in wild-type and mutant cells also increased their growth while reintroduction of OCAM in mutant cells reduced the level of phosphorylated ErbB2. These results indicate that OCAM exerts a posttranscriptional control on the ErbB2 signalling in spinal cord stem cells. This study adds further support for considering cell adhesion molecules as regulators of the ErbB signalling.

  7. RELATIONSHIP OF LIGAMENTUM FLAVUM HYPERTROPHY IN LUMBAR SPINAL STENOSIS WITH TRANSFORMING GROWTH FACTOR β-1

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    Deniz Gokpinar

    2017-03-01

    Full Text Available Aim: Lumbar spinal stenosis is the most common cause of low back pain in the elderly. Lumbar spinal canal stenosis develops as a result of degenerative changes in the posterior canal including bone proliferation of the facet joints and ligamentum flavum hypertrophy. With this study, We aimed to contribute to the literature by demonstrating that ligamentum flavum hypertrophy in lumbar spinal stenosis may be directed by increased concentrations of TGF-β1, at the stenosis site. Materials and Methods: In our study, TGF-βl concentrations in the ligamentum flavum samples taken from patients with lumbar disk hernia and lumbar spinal stenosis during surgical intervention. In addition, thickness of ligamentum flavum in these patients was calculated by averaging the lumbar MRI-tissue thickness, and all these results were statistically compared among the patients. Results: Ligamentum flavum thickness values in two groups were 3.46±1 mm in lumbar disk hernia and 5.63±1.35 mm in lumbar spinal stenosis and the differences were statistically significant (p=0.000. Group averages of Transforming Growth Factor β -1 with standard deviations were 1676.47±642 pg/g in lumbar disk hernia and 6816.68±5147.57 pg/g in lumbar spinal stenosis. The average difference in these results was considered statistically significant (p=0.000. Conclusion: In conclusion, we demonstrated in our study that TGF-β1 has an effect on ligamentum flavum hypertrophy in lumbar spinal stenosis. [J Contemp Med 2017; 7(1.000: 13-16

  8. Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis.

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    Hernstadt, Hayley; Wang, Shuxing; Lim, Grewo; Mao, Jianren

    2009-08-25

    Translocator protein 18 kDa (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), is predominantly located in the mitochondrial outer membrane and plays an important role in steroidogenesis, immunomodulation, cell survival and proliferation. Previous studies have shown an increased expression of TSPO centrally in neuropathology, as well as in injured nerves. TSPO has also been implicated in modulation of nociception. In the present study, we examined the hypothesis that TSPO is involved in the initiation and maintenance of inflammatory pain using a rat model of Complete Freund's Adjuvant (CFA)-induced monoarthritis of the tibio-tarsal joint. Immunohistochemistry was performed using Iba-1 (microglia), NeuN (neurons), anti-Glial Fibrillary Acidic Protein, GFAP (astrocytes) and anti-PBR (TSPO) on Days 1, 7 and 14 after CFA-induced arthritis. Rats with CFA-induced monoarthritis showed mechanical allodynia and thermal hyperalgesia on the ipsilateral hindpaw, which correlated with the increased TSPO expression in ipsilateral laminae I-II on all experimental days. Iba-1 expression in the ipsilateral dorsal horn was also increased on Days 7 and 14. Moreover, TSPO was colocalized with Iba-1, GFAP and NeuN within the spinal cord dorsal horn. The TSPO agonist Ro5-4864, given intrathecally, dose-dependently retarded or prevented the development of mechanical allodynia and thermal hyperalgesia in rats with CFA-induced monoarthritis. These findings provide evidence that spinal TSPO is involved in the development and maintenance of inflammatory pain behaviors in rats. Thus, spinal TSPO may present a central target as a complementary therapy to reduce inflammatory pain.

  9. Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats.

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    Wang, Han-Jun; Wang, Wei; Patel, Kaushik P; Rozanski, George J; Zucker, Irving H

    2013-07-01

    Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 μg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR.

  10. Modulation of thermal somatosensory thresholds within local and remote spinal dermatomes following cervical repetitive magnetic stimulation.

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    Albu, Sergiu; Gómez-Soriano, Julio; Bravo-Esteban, Elisabeth; Palazon, Ramiro; Kumru, Hatice; Avila-Martin, Gerardo; Galán-Arriero, Iriana; Taylor, Julian

    2013-10-25

    Repetitive magnetic stimulation (rMS) modulates thermal somatosensory function at both low (0.2-1.0Hz) and high (5.0-20.0Hz) frequencies within the conditioned dermatome. However the effects of 1Hz and 20Hz cervical (C6-C7) rMS on thermosensory thresholds and contact heat evoked potentials (CHEPs) tested within local and remote spinal dermatomes are not known. Thirty healthy subjects participated in the study. Warm and cold detection threshold, heat and cold pain thresholds, and Cz/Fz CHEPs were evaluated within the C6, T10 and extrasegmental V3 control dermatome, before and after random assignment of subjects to sham, 1 or 20Hz C6-C7 rMS. Following both 1 and 20Hz cervical rMS, warm detection threshold increased within the local C6 dermatome. Furthermore 1Hz cervical rMS increased warm detection threshold within the remote T10 dermatome, but not within the V3-trigeminal control area. Cervical rMS failed to modulate cold detection threshold, heat and cold pain threshold or Cz/Fz CHEP amplitude from the dermatomal test sites. Both 1 and 20Hz cervical rMS modulated warm detection threshold within the locally conditioned C6 dermatome. The concomitant increase in warm detection threshold within the T10 dermatome following 1Hz rMS provides evidence for remote neuromodulation of thermosensory function via intraspinal control mechanisms. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  11. Task-related modulation of crossed spinal inhibition between human lower limbs.

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    Hanna-Boutros, Berthe; Sangari, Sina; Karasu, Aliye; Giboin, Louis-Solal; Marchand-Pauvert, Véronique

    2014-05-01

    Crossed reflex action mediated by muscle spindle afferent inputs has recently been revealed in humans. This raised the question of whether a complex spinal network involving commissural interneurons receiving inputs from proprioceptors and suprasegmental structures, as described in cats, persists in humans and contributes to the interlimb coordination during movement. First, we investigated the neurophysiological mechanisms underlying crossed reflex action between ankle plantar flexors and its corticospinal control from primary motor cortex. Second, we studied its modulation during motor tasks. We observed crossed inhibition in contralateral soleus motoneurons occurring with about 3 ms central latency, which is consistent with spinal transmission through oligosynaptic pathway. The early phase of inhibition was evoked with lower stimulus intensity than the late phase, suggesting mediation by group I and group II afferents, respectively. The postsynaptic origin of crossed inhibition is confirmed by the finding that both H-reflex and motor-evoked potential were reduced upon conditioning stimulation. Transcranial magnetic stimulation over ipsilateral and contralateral primary motor cortex reduced crossed inhibition, especially its late group II part. Last, late group II crossed inhibition was particularly depressed during motor tasks, especially when soleus was activated during the walking stance phase. Our results suggest that both group I and group II commissural interneurons participate in crossed reflex actions between ankle plantar flexors. Neural transmission at this level is depressed by descending inputs activated by transcranial magnetic stimulation over the primary motor cortex or during movement. The specific modulation of group II crossed inhibition suggests control from monoaminergic midbrain structures and its role for interlimb coordination during locomotion.

  12. Multiple monoaminergic modulation of posturo-locomotor network activity in the newborn rat spinal cord

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    Lauriane eBeliez

    2014-08-01

    Full Text Available Studies devoted to understanding locomotor control have mainly addressed the functioning of the neural circuits controlling leg movements and relatively little is known of the operation of networks that activate trunk muscles in coordination with limb movements. The aim of the present work was (1 to identify the exogenous neurotransmitter cocktail that most strongly activates postural thoracic circuitry; (2 to investigate how the biogenic amines serotonin (5-HT, dopamine (DA and noradrenaline (NA modulate the coordination between limb and axial motor networks. Experiments were carried out on in vitro isolated spinal cord preparations from newborn rats. We recorded from ventral roots to monitor hindlimb locomotor and axial postural network activity. Each combination of the three amines with excitatory amino acids (EAAs elicited coordinated rhythmic motor activity at all segmental levels with specific characteristics. The variability in cycle period was similar with 5-HT and DA while it was significantly higher with NA. DA elicited motor bursts of smaller amplitude in thoracic segments compared to 5-HT and NA, while both DA and NA elicited motor bursts of higher amplitude than 5-HT in the lumbar and sacral segments. The amines modulated the phase relationships of bursts in various segments with respect to the reference lumbar segment. At the thoracic level there was a phase lag between all recorded segments in the presence of 5-HT, while DA and NA elicited synchronous bursting. At the sacral level, 5-HT and DA induced an intersegmental phase shift while relationships became phase-locked with NA. Various combinations of EAAs with two or even all three amines elicited rhythmic motor output that was more variable than with one amine alone. Our results provide new data on the coordinating processes between spinal cord networks, demonstrating that each amine has a characteristic signature regarding its specific effect on intersegmental phase

  13. Affective disturbance associated with premenstrual dysphoric disorder does not disrupt emotional modulation of pain and spinal nociception.

    Science.gov (United States)

    Rhudy, Jamie L; Bartley, Emily J; Palit, Shreela; Kuhn, Bethany L; Kerr, Kara L; Martin, Satin L; DelVentura, Jennifer L; Terry, Ellen L

    2014-10-01

    In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late-luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture-viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD-related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  14. Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord.

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    Muresanu, Dafin F; Sharma, Aruna; Lafuente, José V; Patnaik, Ranjana; Tian, Z Ryan; Nyberg, Fred; Sharma, Hari S

    2015-10-01

    Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.

  15. Spinal cord stimulation modulates cerebral function: an fMRI study

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    Moens, M. [Universitair Ziekenhuis Brussel, Department of Neurosurgery and Center for Neuroscience, Brussels (Belgium); Sunaert, S.; Peeters, R. [UZ Leuven, Katholieke Universiteit Leuven, Department of Radiology, Leuven (Belgium); Marien, P. [ZNA Middelheim General Hospital, Department of Neurology, Antwerp (Belgium); Vrije Universiteit Brussel, Department of Clinical and Experimental Neurolinguistics, Brussels (Belgium); Brouns, R.; Smedt, A. de [Universitair Ziekenhuis Brussel, Department of Neurology and Center for Neuroscience, Brussels (Belgium); Droogmans, S. [Universitair Ziekenhuis Brussel, Department of Cardiology, Brussels (Belgium); Schuerbeek, P. van [Universitair Ziekenhuis Brussel, Department of Radiology, Brussels (Belgium); Poelaert, J. [Universitair Ziekenhuis Brussel, Department of Anesthesiology, Brussels (Belgium); Nuttin, B. [UZ Leuven, Katholieke Universiteit Leuven, Department of Neurosurgery, Leuven (Belgium)

    2012-12-15

    Although spinal cord stimulation (SCS) is widely used for chronic neuropathic pain after failed spinal surgery, little is known about the underlying physiological mechanisms. This study aims to investigate the neural substrate underlying short-term (30 s) SCS by means of functional magnetic resonance imaging in 20 patients with failed back surgery syndrome (FBSS). Twenty patients with FBSS, treated with externalized SCS, participated in a blocked functional magnetic resonance imaging design with stimulation and rest phases of 30 s each, repeated eight times in a row. During scanning, patients rated pain intensity over time using an 11-point numerical rating scale with verbal anchors (0 = no pain at all to 10 = worst pain imaginable) by pushing buttons (left hand, lesser pain; right hand, more pain). This scale was back projected to the patients on a flat screen allowing them to manually direct the pain indicator. To increase the signal-to-noise ratio, the 8-min block measurements were repeated three times. Marked deactivation of the bilateral medial thalamus and its connections to the rostral and caudal cingulate cortex and the insula was found; the study also showed immediate pain relief obtained by short-term SCS correlated negatively with activity in the inferior olivary nucleus, the cerebellum, and the rostral anterior cingulate cortex. Results indicate the key role of the medial thalamus as a mediator and the involvement of a corticocerebellar network implicating the modulation and regulation of averse and negative affect related to pain. The observation of a deactivation of the ipsilateral antero-medial thalamus might be used as a region of interest for further response SCS studies. (orig.)

  16. Long-Term Extensive Ectopic Hair Growth on the Spinal Cord of Mice from Transplanted Whisker Follicles.

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    Wenluo Cao

    Full Text Available We have previously demonstrated that hair follicles contain nestin-expressing pluripotent stem cells that can effect nerve and spinal cord repair upon transplantation. In the present study, isolated whisker follicles from nestin-driven green fluorescent protein (ND-GFP mice were histocultured on Gelfoam for 3 weeks for the purpose of transplantation to the spinal cord to heal an induced injury. The hair shaft was cut off from Gelfoam-histocultured whisker follicles, and the remaining part of the whisker follicles containing GFP-nestin expressing pluripotent stem cells were transplanted into the injured spinal cord of nude mice, along with the Gelfoam. After 90 days, the mice were sacrificed and the spinal cord lesion was observed to have healed. ND-GFP expression was intense at the healed area of the spinal cord, as observed by fluorescence microscopy, demonstrating that the hair follicle stem cells were involved in healing the spinal cord. Unexpectedly, the transplanted whisker follicles sprouted out remarkably long hair shafts in the spinal cord during the 90 days after transplantation of Gelfoam whisker histocultures to the injured spine. The pigmented hair fibers, grown from the transplanted whisker histocultures, curved and enclosed the spinal cord. The unanticipated results demonstrate the great potential of hair growth after transplantation of Gelfoam hair follicle histocultures, even at an ectopic site.

  17. Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy.

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    Penelope J Boyd

    2017-04-01

    Full Text Available Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA, resulting from low levels of ubiquitously-expressed survival motor neuron (SMN protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant, gastrocnemius (intermediate vulnerability, and tibialis anterior (vulnerable muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1, was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1, rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo.

  18. Metamorphosis of human lumbar vertebrae induced by VEPTR growth modulation and stress shielding.

    Science.gov (United States)

    Hasler, Carol C; Studer, Daniel; Büchler, Philippe

    2015-08-01

    Distraction-based spinal growth modulation by growing rods or vertical expandable prosthetic titanium ribs (VEPTRs) is the mainstay of instrumented operative strategies to correct early onset spinal deformities. In order to objectify the benefits, it has become common sense to measure the gain in spine height by assessing T1-S1 distance on anteroposterior (AP) radiographs. However, by ignoring growth changes on vertebral levels and by limiting measurement to one plane, valuable data is missed regarding the three-dimensional (3D) effects of growth modulation. This information might be interesting when it comes to final fusion or, even more so, when the protective growing implants are removed and the spine re-exposed to physiologic forces at the end of growth. The goal of this retrospective radiographic study was to assess the growth modulating impact of year-long, distraction-based VEPTR treatment on the morphology of single vertebral bodies. We digitally measured lumbar vertebral body height (VBH) and upper endplate depth (VBD) at the time of the index procedure and at follow-up in nine patients with rib-to-ileum constructs (G1) spanning an anatomically normal lumbar spine. Nine patients with congenital thoracic scoliosis and VEPTR rib-to-rib constructs, but uninstrumented lumbar spines, served as controls (G2). All had undergone more than eight half-yearly VEPTR expansions. A Wilcoxon signed-rank test was used for statistical comparison of initial and follow-up VBH, VBD and height/depth (H/D) ratio (significance level 0.05). The average age was 7.1 years (G1) and 5.2 year (G2, p > 0.05) at initial surgery; the average overall follow-up time was 5.5 years (p = 1). In both groups, VBH increased significantly without a significant intergroup difference. Group 1 did not show significant growth in depth, whereas VBD increased significantly in the control group. As a consequence, the H/D ratio increased significantly in group 1 whereas it remained unchanged in

  19. An engineering analysis of a closed cycle plant growth module

    Science.gov (United States)

    Stickford, G. H., Jr.; Jakob, F. E.; Landstrom, D. K.

    1986-01-01

    The SOLGEM model is a numerical engineering model which solves the flow and energy balance equations for the air flowing through a growing environment, assuming quasi-steady state conditions within the system. SOLGEM provides a dynamic simulation of the controlled environment system in that the temperature and flow conditions of the growing environment are estimated on an hourly basis in response to the weather data and the plant growth parameters. The flow energy balance considers the incident solar flux; incoming air temperature, humidity, and flow rate; heat exchange with the roof and floor; and heat and moisture exchange with the plants. A plant transpiration subroutine was developed based plant growth research facility, intended for the study of bioregenerative life support theories. The results of a performance analysis of the plant growth module are given. The estimated energy requirements of the module components and the total energy are given.

  20. Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content

    Directory of Open Access Journals (Sweden)

    Almeida Armando

    2009-07-01

    Full Text Available Abstract Background While acute effects of stress on pain are well described, those produced by chronic stress are still a matter of dispute. Previously we demonstrated that chronic unpredictable stress results in antinociception in the tail-flick test, an effect that is mediated by increased levels of corticosteroids. In the present study, we evaluated nociception in rats after chronic treatment with corticosterone (CORT and dexamethasone (DEX in order to discriminate the role of each type of corticosteroid receptors in antinociception. Results Both experimental groups exhibited a pronounced antinociceptive effect after three weeks of treatment when compared to controls (CONT; however, at four weeks the pain threshold in CORT-treated animals returned to basal levels whereas in DEX-treated rats antinociception was maintained. In order to assess if these differences are associated with altered expression of neuropeptides involved in nociceptive transmission we evaluated the density of substance P (SP, calcitonin gene-related peptide (CGRP, somatostatin (SS and B2-γ-aminobutiric acid receptors (GABAB2 expression in the spinal dorsal horn using light density measurements and stereological techniques. After three weeks of treatment the expression of CGRP in the superficial dorsal horn was significantly decreased in both CORT and DEX groups, while GABAB2 was significantly increased; the levels of SP for both experimental groups remained unchanged at this point. At 4 weeks, CGRP and SP are reduced in DEX-treated animals and GABAB2 unchanged, but all changes were restored to CONT levels in CORT-treated animals. The expression of SS remained unaltered throughout the experimental period. Conclusion These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the

  1. Preclinical evidence supporting the clinical development of central pattern generator-modulating therapies for chronic spinal cord-injured patients

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    Pierre eGuertin

    2014-05-01

    Full Text Available Ambulation or walking is one of the main gaits of locomotion. In terrestrial animals, it may be defined as a series of rhythmic and bilaterally coordinated movement of the limbs which creates a forward movement of the body. This applies regardless of the number of limbs - from arthropods with six or more limbs to bipedal primates. These fundamental similarities among species may explain why comparable neural systems and cellular properties have been found, thus far, to control in similar ways locomotor rhythm generation in most animal models. The aim of this article is to provide a comprehensive review of the known structural and functional features associated with central nervous system (CNS networks that are involved in the control of ambulation and other stereotyped motor patterns - specifically Central Pattern Generators (CPGs that produce basic rhythmic patterned outputs for locomotion, micturition, ejaculation, and defecation. Although there is compelling evidence of their existence in humans, CPGs have been most studied in reduced models including in vitro isolated preparations, genetically-engineered mice and spinal cord-transected animals. Compared with other structures of the CNS, the spinal cord is generally considered as being well-preserved phylogenetically. As such, most animal models of SCI should be considered as valuable tools for the development of novel pharmacological strategies aimed at modulating spinal activity and restoring corresponding functions in chronic spinal cord-injured patients.

  2. EXPRESS: Histone hyperacetylation modulates spinal type II metabotropic glutamate receptor alleviating stress-induced visceral hypersensitivity in female rats.

    Science.gov (United States)

    Cao, Dong-Yuan; Bai, Guang; Ji, Yaping; Karpowicz, Jane M; Traub, Richard J

    2016-01-01

    Stress is often a trigger to exacerbate chronic pain including visceral hypersensitivity associated with irritable bowel syndrome, a female predominant functional bowel disorder. Epigenetic mechanisms that mediate stress responses are a potential target to interfere with visceral pain. The purpose of this study was to examine the effect of a histone deacetylase inhibitor, suberoylanilide hydroxamic acid, on visceral hypersensitivity induced by a subchronic stressor in female rats and to investigate the involvement of spinal glutamate receptors. Three daily sessions of forced swim induced visceral hypersensitivity. Intrathecal suberoylanilide hydroxamic acid prevented or reversed the stress-induced visceral hypersensitivity, increased spinal histone 3 acetylation and increased mGluR2 and mGluR3 expression. Chromatin immunoprecipitation (ChIP) analysis revealed enrichment of H3K9Ac and H3K18Ac at several promoter Grm2 and Grm3 regions. The mGluR2/3 antagonist LY341495 reversed the inhibitory effect of suberoylanilide hydroxamic acid on the stress-induced visceral hypersensitivity. In surprising contrast, stress and/or suberoylanilide hydroxamic acid had no effect on spinal NMDA receptor expression or function. These data reveal histone modification modulates mGluR2/3 expression in the spinal cord to attenuate stressinduced visceral hypersensitivity. HDAC inhibitors may provide a potential approach to relieve visceral hypersensitivity associated with irritable bowel syndrome.

  3. Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury.

    Science.gov (United States)

    Zhu, Y; Soderblom, C; Krishnan, V; Ashbaugh, J; Bethea, J R; Lee, J K

    2015-02-01

    Spinal cord injury (SCI) leads to formation of a fibrotic scar that is inhibitory to axon regeneration. Recent evidence indicates that the fibrotic scar is formed by perivascular fibroblasts, but the mechanism by which they are recruited to the injury site is unknown. Using bone marrow transplantation in mouse model of spinal cord injury, we show that fibroblasts in the fibrotic scar are associated with hematogenous macrophages rather than microglia, which are limited to the surrounding astroglial scar. Depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation that is associated with increased axonal growth in the fibrotic scar. Cytokine gene expression analysis after macrophage depletion indicates that decreased Tnfsf8, Tnfsf13 (tumor necrosis factor superfamily members) and increased BMP1-7 (bone morphogenetic proteins) expression may serve as anti-fibrotic mechanisms. Our study demonstrates that hematogenous macrophages are necessary for fibrotic scar formation and macrophage depletion results in changes in multiple cytokines that make the injury site less fibrotic and more conducive to axonal growth. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Blockade of spinal nerves inhibits expression of neural growth factor in the myocardium at an early stage of acute myocardial infarction in rats.

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    Yue, W; Guo, Z

    2012-09-01

    Neural growth factor (NGF) is required for healing and sprouting of cardiac sympathetic and sensory nerves and plays important roles in cardiac protection, sustaining cardiac function and regeneration in ischaemic heart disease. The overexpression or lack of the NGF could be harmful to the heart. In this study, we examined the role of spinal nerves in the modulation of expression of the NGF in the myocardium at risk of ischaemia soon after acute myocardial infarction in rats. Coronary artery occlusion (CAO) was carried out in anaesthetized rats with and without preconditioning of blockade of the spinal nerves. The expression of the NGF protein and mRNA in the myocardium at risk of ischaemia was examined using immunohistochemical assay, enzyme-linked immunosorbent assay, and real-time quantitative reverse transcription polymerase chain reaction assay. In the left ventricle, immunoreactive cells and fibre-like structures were mainly located in the myocardium and in the epicardium. The NGF protein expression was increased by two-fold in the myocardium at risk of ischaemia during the 60 min of CAO, while the NGF mRNA was up-regulated three-fold, at 360 min after acute myocardial infarction. The blockade of the spinal nerves completely abolished the up-regulation of the NGF in the myocardium (Pacute myocardial infarction, an effect which can be inhibited by the blockade of these nerves.

  5. Esmolol modulates inhibitory neurotransmission in the substantia gelatinosa of the spinal trigeminal nucleus of the rat

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    Kato Fusao

    2011-09-01

    Full Text Available Abstract Background β1-adrenaline receptor antagonists are often used to avoid circulatory complications during anesthesia in patients with cardiovascular diseases. Of these drugs, esmolol, a short-acting β antagonist, is also reported to exert antinociceptive and anesthetic sparing effects. This study was designed to identify the central mechanism underlying the antinociceptive effect of esmolol. Methods Wistar rats (7-21 d, 17-50 g were anesthetized with ketamine (100-150 mg/kg or isoflurane (5% and decapitated. Horizontal slices (400-μm thick of the lower brainstem containing the substantia gelatinosa (SG of the caudal part of the spinal trigeminal nucleus (Sp5c, in which the nociceptive primary afferents form the first intracranial synapses, were made with a vibrating slicer. The miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSCs, respectively were simultaneously recorded from visually identified SG neurons of the Sp5c in the presence of tetrodotoxin (1 μM. Additionally, mIPSCs were recorded during pharmacological isolation of GABA- and glycine-mediated mIPSCs with kynurenic acid (1 mM. Results Esmolol (500 μM significantly and selectively increased the mIPSC frequency (to 214.2% ± 34.2% of the control, mean ± SEM, n = 35; P 2+. Conclusions These data suggest that esmolol modulates inhibitory transmitter release in the Sp5c through a mechanism involving Ca2+-entry but in a β1-adrenoceptor-independent manner. The present results suggest that the facilitation of inhibitory transmitter release in the central nociceptive network underlies, at least in part, the antinociceptive effect of esmolol.

  6. Neutralizing Endogenous VEGF Following Traumatic Spinal Cord Injury Modulates Microvascular Plasticity but not Tissue Sparing or Functional Recovery

    Science.gov (United States)

    Benton, Richard L.; Maddie, Melissa A.; Gruenthal, Mark J.; Hagg, Theo; Whittemore, Scott R.

    2010-01-01

    Acute loss of spinal cord vascularity followed by an endogenous adaptive angiogenic response with concomitant microvascular dysfunction is a hallmark of traumatic spinal cord injury (SCI). Recently, the potent vasoactive factor vascular endothelial growth factor (VEGF) has received much attention as a putative therapeutic for the treatment of various neurodegenerative disorders, including SCI. Exogenous VEGF exerts both protective and destabilizing effects on microvascular elements and tissue following SCI but the role of endogenous VEGF is unclear. In the present study, we systemically applied a potent and well characterized soluble VEGF antagonist to adult C57Bl/6 mice post-SCI to elucidate the relative contribution of VEGF on the acute evolving microvascular response and its impact on functional recovery. While the VEGF Trap did not alter vascular density in the injury epicenter or penumbra, an overall increase in the number of Griffonia simplicifolia isolectin-B4 bound microvessels was observed, suggesting a VEGF-dependency to more subtle aspects of endothelial plasticity post-SCI. Neutralizing endogenous VEGF neither attenuated nor exacerbated chronic histopathology or functional recovery. These results support the idea that overall, endogenous VEGF is not neuroprotective or detrimental following traumatic SCI. Furthermore, they suggest that angiogenesis in traumatically injured spinal tissue is regulated by multiple effectors and is not limited by endogenous VEGF activation of affected spinal microvessels. PMID:19442162

  7. 1995 Volvo Award in basic sciences. The use of an osteoinductive growth factor for lumbar spinal fusion. Part I: Biology of spinal fusion.

    Science.gov (United States)

    Boden, S D; Schimandle, J H; Hutton, W C; Chen, M I

    1995-12-15

    The histology of lumbar intertransverse process spinal fusion was studied in an experimental model in rabbits. To qualitatively and quantitatively analyze the sequential histology of spinal fusion using a previously validated animal model. Few previous studies have described the sequential histology during the posterolateral spinal fusion healing process using autogenous bone, and a basic understanding of the biology of this repair process is lacking. Fourteen adult New Zealand white rabbits underwent single-level posterolateral lumbar intertransverse process arthrodesis with autogenous iliac bone graft. Animals were killed 1-10 weeks after surgery, and the fusion masses were analyzed histologically and quantitated using a semiautomated image analysis system. Three distinct phases of healing were identified (inflammatory, reparative, and remodeling) and occurred in sequence but in a delayed fashion in the central zone of the fusion mass compared with the outer transverse process zones. Membraneous bone formation, evident first at the ends of the fusion eminating from the decorticated transverse processes, was the predominant mechanism of healing. The central zone was somewhat different in that there was a period of endochondral bone formation during weeks 3 and 4 in this zone where cartilage formed and was converted to bone. Remodeling in the central zone had equilibrated with the transverse process zones by 10 weeks. Lumbar intertransverse process spinal fusion is a complex process from a spatial and temporal standpoint. When autogenous bone is used as the graft material, this process critically depends on a variety of factors from the decorticated host bone and exposed marrow. The persistence of a central cartilage zone may be related to some types of nonunions and deserves future investigation. This enhanced understanding of the biology of spinal fusion with autogenous bone graft will provide a foundation for optimizing the use of osteoinductive bone growth

  8. Positional uncertainties on sterotactic radiosurgery for spinal metastases using volumetric modulated arc therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jeon, Seung Hyuck; Park, So Yeon; Kim, Jin Ho; Kim, Jung In; Park, Jong Min [Dept. of Nuclear Engineering, Seoul National University Hospital, Seoul (Korea, Republic of)

    2016-04-15

    For spinal metastatic cancers, stereotactic radiosurgery (SRS) plays a key role in tumor control and pain relief by delivering high doses to the lesions. Dose limiting factor to this treatment is spinal cord tolerance. Radiation-induced spinal cord injury, although uncommon, can result in paralysis, sensory deficits, or Brown-Sequard syndrome. Hence, various efforts are necessary to eliminate the risk of radiation myelitis, while keeping adequate dose delivery to target volumes. The Body-FIX system is employed to immobilize the patients. Despite these efforts, residual setup errors and intrafraction motions can cause dosimetric uncertainties. In this context, this study aimed to investigate residual setup errors and intrafraction motions in SRS of spinal metastasis. With appropriate immobilization and 4 DoF corrections, an 1-mm PTV margin is adequate for CTV coverage, accounting for both residual errors. Even with an perfect 6 DoF correction, at least 1-mm PTV margin is still necessary to address intrafraction motions. Given the fixed relative position between the spinal cord and vertebrae, it is assumed that the spinal cord is subject to a same degree of positional uncertainty.

  9. Modulation of growth cone filopodial length by carbon monoxide.

    Science.gov (United States)

    Estes, Stephen; Artinian, Liana; Rehder, Vincent

    2017-06-01

    Carbon monoxide (CO) is physiologically produced via heme degradation by heme oxygenase enzymes. Whereas CO has been identified as an important physiological signaling molecule, the roles it plays in neuronal development and regeneration are poorly understood. During these events, growth cones guide axons through a rich cellular environment to locate target cells and establish synaptic connections. Previously, we have shown that another gaseous signaling molecule, nitric oxide (NO), has potent effects on growth cone motility. With NO and CO sharing similar cellular targets, we wanted to determine whether CO affected growth cone motility as well. We assessed how CO affected growth cone filopodial length and determined the signaling pathway by which this effect was mediated. Using two well-characterized neurons from the freshwater snail, Helisoma trivolvis, it was found that the CO donor, carbon monoxide releasing molecule-2 (CORM-2), increased filopodial length. CO utilized a signaling pathway that involved the activation of soluble guanylyl cyclase, protein kinase G, and ryanodine receptors. While increases in filopodial length often occur from robust increases in intracellular calcium levels, the timing in which CO increased filopodial length corresponded with low basal calcium levels in growth cones. Taken together with findings of a heme oxygenase-like protein in the Helisoma nervous system, these results provide evidence for CO as a modulator of growth cone motility and implicate CO as a neuromodulatory signal during neuronal development and/or regeneration. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 677-690, 2017. © 2016 Wiley Periodicals, Inc.

  10. Plant Growth Research for Food Production: Development and Testing of Expandable Tuber Growth Module

    Science.gov (United States)

    Cordova, Brennan A.

    2017-01-01

    Controlled and reliable growth of a variety of vegetable crops is an important capability for manned deep space exploration systems for providing nutritional supplementation and psychological benefits to crew members. Because current systems have been limited to leafy vegetables that require minimal root space, a major goal for these systems is to increase their ability to grow new types of crops, including tuber plants and root vegetables that require a large root space. An expandable root zone module and housing was developed to integrate this capability into the Vegetable Production System (Veggie). The expandable module uses a waterproof, gas-permeable bag with a structure that allows for root space to increase vertically throughout the growth cycle to accommodate for expanding tuber growth, while minimizing the required media mass. Daikon radishes were chosen as an ideal tuber crop for their subterraneous tuber size and rapid growth cycle, and investigations were done to study expanding superabsorbent hydrogels as a potential growth media. These studies showed improved water retention, but restricted oxygen availability to roots with pure gel media. It was determined that these hydrogels could be integrated in lower proportions into standard soil to achieve media expansion and water retention desired. Using the constructed module prototype and ideal gel and soil media mixture, daikon radishes are being grown in the system to test the capability and success of the system through a full growth cycle.

  11. Spinal Cord Dysfunction (SCD)

    Data.gov (United States)

    Department of Veterans Affairs — The Spinal Cord Dysfunction (SCD) module supports the maintenance of local and national registries for the tracking of patients with spinal cord injury and disease...

  12. Convection-enhanced delivery of a hydrophilic nitrosourea ameliorates deficits and suppresses tumor growth in experimental spinal cord glioma models.

    Science.gov (United States)

    Ogita, Shogo; Endo, Toshiki; Sugiyama, Shinichiro; Saito, Ryuta; Inoue, Tomoo; Sumiyoshi, Akira; Nonaka, Hiroi; Kawashima, Ryuta; Sonoda, Yukihiko; Tominaga, Teiji

    2017-05-01

    Convection-enhanced delivery (CED) is a technique allowing local infusion of therapeutic agents into the central nervous system, circumventing the blood-brain or spinal cord barrier. To evaluate the utility of nimustine hydrochloride (ACNU) CED in controlling tumor progression in an experimental spinal cord glioma model. Toxicity studies were performed in 42 rats following the administration of 4 μl of ACNU CED into the mid-thoracic spinal cord at concentrations ranging from 0.1 to 10 mg/ml. Behavioral analyses and histological evaluations were performed to assess ACNU toxicity in the spinal cord. A survival study was performed in 32 rats following the implantation of 9 L cells into the T8 spinal cord. Seven days after the implantation, rats were assigned to four groups: ACNU CED (0.25 mg/ml; n = 8); ACNU intravenous (i.v.) (0.4 mg; n = 8); saline CED (n = 8); saline i.v. (n = 8). Hind limb movements were evaluated daily in all rats for 21 days. Tumor sizes were measured histologically. The maximum tolerated ACNU concentration was 0.25 mg/ml. Preservation of hind limb motor function and tumor growth suppression was observed in the ACNU CED (0.25 mg/ml) and ACNU i.v. groups. Antitumor effects were more prominent in the ACNU CED group especially in behavioral analyses (P < 0.05; log-rank test). ACNU CED had efficacy in controlling tumor growth and preserving neurological function in an experimental spinal cord tumor model. ACNU CED can be a viable treatment option for spinal cord high-grade glioma.

  13. Growth Factor Dependent Cholinergic Function and Survival in Primary Mouse Spinal Cord Cultures

    National Research Council Canada - National Science Library

    Sheridan, Robert E; Adler, Michael

    2006-01-01

    .... However, while the mature spinal cord contains an appreciable number of cholinergic% motoneurons, cultures of embryonic spinal cord have a paucity of these neurons and release little or no acetylcholine upon stimulation...

  14. Relative shortening and functional tethering of spinal cord in adolescent scoliosis – Result of asynchronous neuro-osseous growth, summary of an electronic focus group debate of the IBSE

    Directory of Open Access Journals (Sweden)

    Burwell R Geoffrey

    2008-06-01

    concept is regarded as one component of a larger concept. The other component relates to the brain and cranium of AIS subjects because abnormalities have been found in brain (infratentorial and supratentorial and skull (vault and base. The possible relevance of systemic melatonin-signaling pathway dysfunction, platelet calmodulin levels and putative vertebral vascular biology to the asynchronous neuro-osseous growth concept is discussed. A biomechanical model to test the spinal component of the concept is in hand. There is no published research on the biomechanical properties of the spinal cord for scoliosis specimens. Such research on normal spinal cords includes movements (kinematics, stress-strain responses to uniaxial loading, and anterior forces created by the stretched cord in forward flexion that may alter sagittal spinal shape during adolescent growth. The asynchronous neuro-osseous growth concept for the spine evokes controversy. Dr Chu and colleagues respond to five other concepts of pathogenesis for AIS and suggest that relative anterior spinal overgrowth and biomechanical growth modulation may also contribute to AIS pathogenesis.

  15. Systems biology investigation of cAMP modulation to increase SMN levels for the treatment of spinal muscular atrophy.

    Directory of Open Access Journals (Sweden)

    Sean G Mack

    Full Text Available Spinal muscular atrophy (SMA, a leading genetic cause of infant death worldwide, is an autosomal recessive disorder caused by the loss of SMN1 (survival motor neuron 1, which encodes the protein SMN. The loss of SMN1 causes a deficiency in SMN protein levels leading to motor neuron cell death in the anterior horn of the spinal cord. SMN2, however, can also produce some functional SMN to partially compensate for loss of SMN1 in SMA suggesting increasing transcription of SMN2 as a potential therapy to treat patients with SMA. A cAMP response element was identified on the SMN2 promoter, implicating cAMP activation as a step in the transcription of SMN2. Therefore, we investigated the effects of modulating the cAMP signaling cascade on SMN production in vitro and in silico. SMA patient fibroblasts were treated with the cAMP signaling modulators rolipram, salbutamol, dbcAMP, epinephrine and forskolin. All of the modulators tested were able to increase gem formation, a marker for SMN protein in the nucleus, in a dose-dependent manner. We then derived two possible mathematical models simulating the regulation of SMN2 expression by cAMP signaling. Both models fit well with our experimental data. In silico treatment of SMA fibroblasts simultaneously with two different cAMP modulators resulted in an additive increase in gem formation. This study shows how a systems biology approach can be used to develop potential therapeutic targets for treating SMA.

  16. Spinal dual-energy computed tomography: improved visualisation of spinal tumorous growth with a noise-optimised advanced monoenergetic post-processing algorithm

    Energy Technology Data Exchange (ETDEWEB)

    Kraus, Mareen; Weiss, Jakob; Selo, Nadja; Notohamiprodjo, Mike; Bamberg, Fabian; Nikolaou, Konstantin; Othman, Ahmed E. [Eberhard Karls University Tuebingen, Department of Diagnostic and Interventional Radiology, Tuebingen (Germany); Flohr, Thomas [Siemens Healthcare GmbH, Erlangen (Germany)

    2016-11-15

    The aim of this study was to evaluate the effect of advanced monoenergetic post-processing (MEI+) on the visualisation of spinal growth in contrast-enhanced dual-energy CT (DE-CT). Twenty-six oncologic patients (age, 61 ± 17 years) with spinal tumorous growth were included. Patients underwent contrast-enhanced dual-energy CT on a third-generation dual-source CT scanner. Image acquisition was in dual-energy mode (100/Sn150kV), and scans were initiated 90 s after contrast agent administration. Virtual monoenergetic images (MEI+) were reconstructed at four different kiloelectron volts (keV) levels (40, 60, 80, 100) and compared to the standard blended portal venous computed tomography (CT{sub pv}). Image quality was assessed qualitatively (conspicuity, delineation, sharpness, noise, confidence; two independent readers; 5-point Likert scale; 5 = excellent) and quantitatively by calculating signal-to-noise (SNR) and contrast-to-noise-ratios (CNR). For a subgroup of 10 patients with MR imaging within 4 months of the DE-CT, we compared the monoenergetic images to the MRIs qualitatively. Highest contrast of spinal growth was observed in MEI+ at 40 keV, with significant differences to CT{sub pv} and all other keV reconstructions (60, 80, 100; p < 0.01). Highest conspicuity, delineation and sharpness were observed in MEI+ at 40 keV, with significant differences to CT{sub pv} (p < 0.001). Similarly, MEI+ at 40 keV yielded highest diagnostic confidence (4.6 ± 0.6), also with significant differences to CT{sub pv} (3.45 ± 0.9, p < 0.001) and to high keV reconstructions (80, 100; p ≤ 0.001). Similarly, CNR calculations revealed highest scores for MEI+ at 40 keV followed by 60 keV and CT{sub pv}, with significant differences to high keV MEI+ reconstructions. Qualitative analysis scores peaked for MR images followed by the MEI+ 40-keV reconstructions. MEI+ at low keV levels can significantly improve image quality and delineation of spinal growth in patients with portal

  17. Spinal dual-energy computed tomography: improved visualisation of spinal tumorous growth with a noise-optimised advanced monoenergetic post-processing algorithm.

    Science.gov (United States)

    Kraus, Mareen; Weiss, Jakob; Selo, Nadja; Flohr, Thomas; Notohamiprodjo, Mike; Bamberg, Fabian; Nikolaou, Konstantin; Othman, Ahmed E

    2016-11-01

    The aim of this study was to evaluate the effect of advanced monoenergetic post-processing (MEI+) on the visualisation of spinal growth in contrast-enhanced dual-energy CT (DE-CT). Twenty-six oncologic patients (age, 61 ± 17 years) with spinal tumorous growth were included. Patients underwent contrast-enhanced dual-energy CT on a third-generation dual-source CT scanner. Image acquisition was in dual-energy mode (100/Sn150kV), and scans were initiated 90 s after contrast agent administration. Virtual monoenergertic images (MEI+) were reconstructed at four different kiloelectron volts (keV) levels (40, 60, 80, 100) and compared to the standard blended portal venous computed tomography (CTpv). Image quality was assessed qualitatively (conspicuity, delineation, sharpness, noise, confidence; two independent readers; 5-point Likert scale; 5 = excellent) and quantitatively by calculating signal-to-noise (SNR) and contrast-to-noise-ratios (CNR). For a subgroup of 10 patients with MR imaging within 4 months of the DE-CT, we compared the monoenergetic images to the MRIs qualitatively. Highest contrast of spinal growth was observed in MEI+ at 40 keV, with significant differences to CTpv and all other keV reconstructions (60, 80, 100; p < 0.01). Highest conspicuity, delineation and sharpness were observed in MEI+ at 40 keV, with significant differences to CTpv (p < 0.001). Similarly, MEI+ at 40 keV yielded highest diagnostic confidence (4.6 ± 0.6), also with significant differences to CTpv (3.45 ± 0.9, p < 0.001) and to high keV reconstructions (80, 100; p ≤ 0.001). Similarly, CNR calculations revealed highest scores for MEI+ at 40 keV followed by 60 keV and CTpv, with significant differences to high keV MEI+ reconstructions. Qualitative analysis scores peaked for MR images followed by the MEI+ 40-keV reconstructions. MEI+ at low keV levels can significantly improve image quality and delineation of spinal growth in patients with

  18. Epigenetic influences that modulate infant growth, development, and disease.

    Science.gov (United States)

    Hussain, Naveed

    2012-07-15

    Epigenetic modifications are key processes in understanding normal human development and are largely responsible for the myriad cell and tissue types that originate from a single-celled fertilized ovum. The three most common processes involved in bringing about epigenetic changes are DNA methylation, histone modification, and miRNA effects. There are critical periods in the development of the zygote, the embryo, and the fetus where in the organism is most susceptible to epigenetic influences because of normal demethylation and de novo methylation processes that occur in the womb. A number of epigenetic modifications of normal growth patterns have been recognized, leading to altered development and disease states in the mammalian fetus and infant. 'Fetal programming' due to these epigenetic changes has been implicated in pathogenesis of adult-onset disease such as hypertension, diabetes, and cardiovascular disease. There may also be transgenerational effects of such epigenetic modifications. The impact of environmental agents and endogenous factors such as stress at critical periods of infant development has immediate, life-long and even multi-generational effects. Both the timing and the degree of insult may be important. Understanding these influences may help prevent onset of disease and promote normal growth. Use of one-carbon metabolism modifying agents such as folic acid during critical periods of epigenetic modulation may have significant clinical impact. Their use as therapeutic agents in targeted epigenetic modulation of genes may be the new frontier for clinical therapeutics.

  19. FLIM FRET Visualization of Cdc42 Activation by Netrin-1 in Embryonic Spinal Commissural Neuron Growth Cones.

    Directory of Open Access Journals (Sweden)

    Benjamin Rappaz

    Full Text Available Netrin-1 is an essential extracellular chemoattractant that signals through its receptor DCC to guide commissural axon extension in the embryonic spinal cord. DCC directs the organization of F-actin in growth cones by activating an intracellular protein complex that includes the Rho GTPase Cdc42, a critical regulator of cell polarity and directional migration. To address the spatial distribution of signaling events downstream of netrin-1, we expressed the FRET biosensor Raichu-Cdc42 in cultured embryonic rat spinal commissural neurons. Using FLIM-FRET imaging we detected rapid activation of Cdc42 in neuronal growth cones following application of netrin-1. Investigating the signaling mechanisms that control Cdc42 activation by netrin-1, we demonstrate that netrin-1 rapidly enriches DCC at the leading edge of commissural neuron growth cones and that netrin-1 induced activation of Cdc42 in the growth cone is blocked by inhibiting src family kinase signaling. These findings reveal the activation of Cdc42 in embryonic spinal commissural axon growth cones and support the conclusion that src family kinase activation downstream of DCC is required for Cdc42 activation by netrin-1.

  20. FLIM FRET Visualization of Cdc42 Activation by Netrin-1 in Embryonic Spinal Commissural Neuron Growth Cones.

    Science.gov (United States)

    Rappaz, Benjamin; Lai Wing Sun, Karen; Correia, James P; Wiseman, Paul W; Kennedy, Timothy E

    2016-01-01

    Netrin-1 is an essential extracellular chemoattractant that signals through its receptor DCC to guide commissural axon extension in the embryonic spinal cord. DCC directs the organization of F-actin in growth cones by activating an intracellular protein complex that includes the Rho GTPase Cdc42, a critical regulator of cell polarity and directional migration. To address the spatial distribution of signaling events downstream of netrin-1, we expressed the FRET biosensor Raichu-Cdc42 in cultured embryonic rat spinal commissural neurons. Using FLIM-FRET imaging we detected rapid activation of Cdc42 in neuronal growth cones following application of netrin-1. Investigating the signaling mechanisms that control Cdc42 activation by netrin-1, we demonstrate that netrin-1 rapidly enriches DCC at the leading edge of commissural neuron growth cones and that netrin-1 induced activation of Cdc42 in the growth cone is blocked by inhibiting src family kinase signaling. These findings reveal the activation of Cdc42 in embryonic spinal commissural axon growth cones and support the conclusion that src family kinase activation downstream of DCC is required for Cdc42 activation by netrin-1.

  1. Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats.

    Science.gov (United States)

    Tripathi, Richa B; McTigue, Dana M

    2008-09-10

    Demyelination and oligodendrocyte loss following spinal cord injury (SCI) are well documented. Recently, we showed oligodendrocyte progenitor cell (OPC) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders. We have since begun investigating potential mechanisms for this endogenous repair response. Here, we examined ciliary neurotrophic factor (CNTF) and fibroblast growth factor-2 (FGF-2) expression, because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders. We hypothesized that CNTF and FGF-2 would increase after SCI, especially in regions of enhanced oligogenesis. First, CNTF protein was quantified using Western blots, which revealed that CNTF protein continually rose through 28 days post injury (dpi). Next, by using immunohistochemistry, we examined the spatiotemporal expression of CNTF in cross-sections spanning the injury site. CNTF immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords. Significantly increased CNTF was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls. By 28 dpi, CNTF expression was significantly higher along lesion borders compared with outlying spared tissue; a similar distribution of phosphorylated STAT3, a transcription factor up-regulated by CNTF and to a lesser extent FGF-2, was also detected. Because CNTF can potentiate FGF-2 expression, we examined the distribution of FGF-2+ cells. Significantly more FGF-2+ cells were noted along lesion borders at 7 and 28 dpi. Thus, both CNTF and FGF-2 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury-induced gliogenesis. (c) 2008 Wiley-Liss, Inc.

  2. Ischemic postconditioning protects the spinal cord from ischemia-reperfusion injury via modulation of redox signaling.

    Science.gov (United States)

    Song, Wenying; Sun, Jing; Su, Binxiao; Yang, Rui; Dong, Hailong; Xiong, Lize

    2013-09-01

    It is well known that ischemic postconditioning reduces ischemic-reperfusion injury, but the underlying mechanism is not fully understood. The current study investigated the role of reactive oxygen species-mediated upregulation of endogenous antioxidant enzymes in the generation of a protective effect induced by ischemic postconditioning against spinal cord reperfusion injury in the rabbit. New Zealand White rabbits were randomly allocated to sham, ischemia-reperfusion, and postconditioning groups (3 cycles of 30 seconds of reperfusion and 30 seconds of occlusion during the onset of reperfusion). Spinal cord ischemia was induced by clamping the infrarenal abdominal aorta for 20 minutes in the ischemia-reperfusion and postconditioning groups. Forty-eight hours after reperfusion, the neurologic status of the lower limbs was assessed. Blood samples were collected for analysis of serum neuron-specific enolase levels, and the lumbar spinal cord segments (L5-7) were harvested for histopathologic and antioxidant enzyme activities and mRNA analysis with or without administration of N-2-mercaptopropionylglycine (an effective oxygen free radical scavenger) given at different reperfusion times. Continuous administration of N-2-mercaptopropionylglycine for 13 minutes, starting at 10 minutes before (but not 10 minutes after) the beginning of reperfusion, attenuated the neuroprotective effect of postconditioning against spinal cord ischemia and reversed the increase in activity of the antioxidant enzymes superoxide dismutase and catalase in spinal cord tissue subjected to ischemic postconditioning. The results indicate that reactive oxygen species-triggered upregulation of endogenous antioxidant enzyme activities may be involved in the mechanism of neuroprotection of ischemic postconditioning. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

  3. CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats.

    Directory of Open Access Journals (Sweden)

    Zhen Li

    Full Text Available Each of the lateral capsular division of central nucleus of amygdala(CeLC, periaqueductal gray (PAG, rostral ventromedial medulla(RVM and spinal cord has been proved to contribute to the development of opioid-induced hyperalgesia(OIH. Especially, Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα in CeLC and spinal cord seems to play a key role in OIH modulation. However, the pain pathway through which CaMKIIα modulates OIH is not clear. The pathway from CeLC to spinal cord for this modulation was explored in the present study. Mechanical and thermal hyperalgesia were tested by von Frey test or Hargreaves test, respectively. CaMKIIα activity (phospho-CaMKIIα, p-CaMKIIα was evaluated by western blot analysis. CaMKIIα antagonist (KN93 was micro-infused into CeLC, spinal cord or PAG, respectively, to evaluate its effect on behavioral hyperalgesia and p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord. Then the underlying synaptic mechanism was explored by recording miniature excitatory postsynaptic currents (mEPSCs on PAG slices using whole-cell voltage-clamp methods. Results showed that inhibition of CeLC, PAG or spinal CaMKIIα activity respectively by KN93, reversed both mechanical and thermal hyperalgesia. Microinjection of KN93 into CeLC decreased p-CaMKIIα expression in CeLC, PAG, RVM and spinal cord; while intrathecal KN93 can only block spinal but not CeLC CaMKIIα activity. KN93 injected into PAG just decreased p-CaMKIIα expression in PAG, RVM and spinal cord, but not in the CeLC. Similarly, whole-cell voltage-clamp recording found the frequency and amplitude of mEPSCs in PAG cells were decreased by KN93 added in PAG slice or micro-infused into CeLC in vivo. These results together with previous findings suggest that CaMKIIα may modulate OIH via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway.

  4. Vitamin B(12) dependent changes in mouse spinal cord expression of vitamin B(12) related proteins and the epidermal growth factor system

    DEFF Research Database (Denmark)

    Mutti, Elena; Lildballe, Dorte L; Kristensen, Lise

    2013-01-01

    Chronic vitamin B(12) (cobalamin) deficiency in the mammalian central nervous system causes degenerative damage, especially in the spinal cord. Previous studies have shown that cobalamin status alters spinal cord expression of epidermal growth factor (EGF) and its receptor in rats. Employing...

  5. A Novel Growth-Promoting Pathway Formed by GDNF-Overexpressing Schwann Cells Promotes Propriospinal Axonal Regeneration, Synapse formation, and Partial Recovery of Function after Spinal Cord Injury

    Science.gov (United States)

    Deng, Lingxiao; Deng, Ping; Ruan, Yiwen; Xu, Zao Cheng; Liu, Naikui; Wen, Xuejun; Smith, George M.; Xu, Xiao-Ming

    2013-01-01

    Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells (SCs) overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function. PMID:23536080

  6. A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury.

    Science.gov (United States)

    Deng, Ling-Xiao; Deng, Ping; Ruan, Yiwen; Xu, Zao Cheng; Liu, Nai-Kui; Wen, Xuejun; Smith, George M; Xu, Xiao-Ming

    2013-03-27

    Descending propriospinal neurons (DPSN) are known to establish functional relays for supraspinal signals, and they display a greater growth response after injury than do the long projecting axons. However, their regenerative response is still deficient due to their failure to depart from growth supportive cellular transplants back into the host spinal cord, which contains numerous impediments to axon growth. Here we report the construction of a continuous growth-promoting pathway in adult rats, formed by grafted Schwann cells overexpressing glial cell line-derived neurotrophic factor (GDNF). We demonstrate that such a growth-promoting pathway, extending from the axonal cut ends to the site of innervation in the distal spinal cord, promoted regeneration of DPSN axons through and beyond the lesion gap of a spinal cord hemisection. Within the distal host spinal cord, regenerated DPSN axons formed synapses with host neurons leading to the restoration of action potentials and partial recovery of function.

  7. Elevated Serum Insulin-Like Growth Factor 1 Levels in Patients with Neurological Remission after Traumatic Spinal Cord Injury.

    Directory of Open Access Journals (Sweden)

    Arash Moghaddam

    Full Text Available After traumatic spinal cord injury, an acute phase triggered by trauma is followed by a subacute phase involving inflammatory processes. We previously demonstrated that peripheral serum cytokine expression changes depend on neurological outcome after spinal cord injury. In a subsequent intermediate phase, repair and remodeling takes place under the mediation of growth factors such as Insulin-like Growth Factor 1 (IGF-1. IGF-1 is a promising growth factor which is thought to act as a neuroprotective agent. Since previous findings were taken from animal studies, our aim was to investigate this hypothesis in humans based on peripheral blood serum. Forty-five patients after traumatic spinal cord injury were investigated over a period of three months after trauma. Blood samples were taken according to a fixed schema and IGF-1 levels were determined. Clinical data including AIS scores at admission to the hospital and at discharge were collected and compared with IGF-1 levels. In our study, we could observe distinct patterns in the expression of IGF-1 in peripheral blood serum after traumatic spinal cord injury regardless of the degree of plegia. All patients showed a marked increase of levels seven days after injury. IGF-1 serum levels were significantly different from initial measurements at four and nine hours and seven and 14 days after injury, as well as one, two and three months after injury. We did not detect a significant correlation between fracture and the IGF-1 serum level nor between the quantity of operations performed after trauma and the IGF-1 serum level. Patients with clinically documented neurological remission showed consistently higher IGF-1 levels than patients without neurological remission. This data could be the base for the establishment of animal models for further and much needed research in the field of spinal cord injury.

  8. EphrinBs/EphBs signaling is involved in modulation of spinal nociceptive processing through a mitogen-activated protein kinases-dependent mechanism.

    Science.gov (United States)

    Ruan, Jia-Ping; Zhang, Hong-Xing; Lu, Xian-Fu; Liu, Yue-Peng; Cao, Jun-Li

    2010-05-01

    Our previous studies have demonstrated that EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. The aim of this study was to further investigate whether mitogen-activated protein kinases (MAPKs), as the downstream effectors, participate in modulation of spinal nociceptive information related to ephrinBs/EphBs. Thermal hyperalgesia and mechanical allodynia were measured using radiant heat and von Frey filaments test. Immunofluorescence staining was used to detect the expression of p-MAPKs and of p-MAPKs/neuronal nuclei, or p-MAPKs/glial fibrillary acidic protein double label. C-Fos expression was determined by immunohistochemistry. The expression of p-MAPKs was also determined by Western blot assay. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal p-MAPKs and c-Fos expression. Immunofluorescence staining revealed that p-MAPKs colocalized with the neuronal marker (neuronal nuclei) and the astrocyte marker (glial fibrillary acidic protein). Inhibition of MAPKs prevented and reversed pain behaviors and the increase of spinal c-Fos expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal p-MAPKs and c-Fos protein. Furthermore, pretreatment with MK-801, an N-methyl-d-aspartate receptor antagonist, prevented behavioral hyperalgesia and activation of spinal MAPKs induced by intrathecal injection of ephrinB1-Fc. These results demonstrated that activation of MAPKs contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs.

  9. Exercise-Dependent Modulation of Neurourological Health Following Spinal Cord Injury

    Science.gov (United States)

    2014-11-01

    Dekaban, V. Omana, L. C. Weaver, CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury. Experimental...to weight support and control their trunk on their own. While studies aimed at limiting movements (hindlimb immobilization ) have a negative impact on... syndrome : thalamic hy- perexcitability after spinothalamic tract lesions. J. Neurosci. 28, 11959–11969. 92. Zhao, P., Waxman, S.G., and Hains, B.C. (2007

  10. Growth hormone STAT5-mediated signaling and its modulation in mice liver during the growth period.

    Science.gov (United States)

    Martinez, Carolina S; Piazza, Verónica G; Ratner, Laura D; Matos, Marina N; González, Lorena; Rulli, Susana B; Miquet, Johanna G; Sotelo, Ana I

    2013-01-01

    Postnatal growth exhibits two instances of rapid growth in mice: the first is perinatal and independent of growth hormone (GH), the second is peripuberal and GH-dependent. Signal transducer and activator of transcription 5b (STAT5b) is the main GH-signaling mediator and it is related to IGF1 synthesis and somatic growth. The aim of this work was to assess differential STAT5 sensitivity to GH during the growth period in mouse liver of both sexes. Three representative ages were selected: 1-week-old animals, in the GH-independent phase of growth; 2.5-week-old mice, at the onset of the GH-dependent phase of growth; and 9-week-old young adults. GH-signaling mediators were assessed by immunoblotting, quantitative RT-PCR and immunohistochemistry. GH-induced STAT5 phosphorylation is low at one-week and maximal at 2.5-weeks of age when compared to young adults, accompanied by higher protein content at the onset of growth. Suppressor CIS and phosphatase PTP1B exhibit high levels in one-week animals, which gradually decline, while SOCS2 and SOCS3 display higher levels at adulthood. Nuclear phosphorylated STAT5 is low in one-week animals while in 2.5-week animals it is similar to 9-week control; expression of SOCS3, an early response GH-target gene, mimics this pattern. STAT5 coactivators glucocorticoid receptor (GR) and hepatic nuclear factor 1 (HNF1) abundance is higher in adulthood. Therefore, GH-induced STAT5 signaling presents age-dependent activity in liver, with its maximum coinciding with the onset of GH-dependent phase of growth, accompanied by an age-dependent variation of modulating factors. This work contributes to elucidate the molecular mechanisms implicated in GH responsiveness during growth. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Ganglioside with nerve growth factor for the recovery of extremity function following spinal cord injury and somatosensory evoked potential.

    Science.gov (United States)

    Zhai, H-W; Gong, Z-K; Sun, J; Chen, W; Zhang, M; Zhou, J-J; Zheng, B

    2015-06-01

    To investigate the effect ganglioside with nerve growth factor on the recovery of extremity functionality following spinal cord injury and somatosensory evoked potential. A total of 62 patients with spinal cord injury admitted to our hospital from February 2012 to October 2013 were selected and randomized to treatment (N = 31) and control groups (N = 31). The combination of systematic rehabilitation training and GM-1 intervention were prescribed to patients in the control group, while an additional intervention of mNGF (mouse nerve growth factor) was prescribed to patients in the treatment group. All patients were subject to Functional Independence Measure (FIM), Modified Barthel Index (MBI) and P- and N- wave latency of bilateral lower extremities by SEP method evaluations at 3 months before and after the intervention. Three months after the intervention, the FIM and MBI scores improved significantly in both groups, with significant recovery in the P- and N-wave latencies. (p efficacy and accurately reflect changes in neurological function.

  12. Role of Cranial and Spinal Virtual and Augmented Reality Simulation Using Immersive Touch Modules in Neurosurgical Training

    Science.gov (United States)

    Alaraj, Ali; Charbel, Fady T.; Birk, Daniel; Tobin, Mathew; Luciano, Cristian; Banerjee, Pat P.; Rizzi, Silvio; Sorenson, Jeff; Foley, Kevin; Slavin, Konstantin; Roitberg, Ben

    2013-01-01

    Recent studies have shown that mental script-based rehearsal and simulation-based training improves the transfer of surgical skills in various medical disciplines. Despite significant advances in technology and intraoperative techniques over the last several decades, surgical skills training on neurosurgical operations still carries significant risk of serious morbidity or mortality. Potentially avoidable technical errors are well recognized as contributing to poor surgical outcome. Surgical education is undergoing overwhelming change, with reduction of working hours and current trends to focus on patient’s safety and linking reimbursement with clinical outcomes, and there is a need for adjunctive means for neurosurgical training;this has been recent advancement in simulation technology. ImmersiveTouch (IT) is an augmented reality (AR) system that integrates a haptic device and a high-resolution stereoscopic display. This simulation platform utilizes multiple sensory modalities, recreating many of the environmental cues experienced during an actual procedure. Modules available include ventriculostomy, bone drilling, percutaneous trigeminal rhizotomy, in addition to simulated spinal modules such as pedicle screw placement, vertebroplasty, and lumbar puncture. We present our experience with development of such AR neurosurgical modules and the feedback from neurosurgical residents. PMID:23254799

  13. Role of cranial and spinal virtual and augmented reality simulation using immersive touch modules in neurosurgical training.

    Science.gov (United States)

    Alaraj, Ali; Charbel, Fady T; Birk, Daniel; Tobin, Matthew; Tobin, Mathew; Luciano, Cristian; Banerjee, Pat P; Rizzi, Silvio; Sorenson, Jeff; Foley, Kevin; Slavin, Konstantin; Roitberg, Ben

    2013-01-01

    Recent studies have shown that mental script-based rehearsal and simulation-based training improve the transfer of surgical skills in various medical disciplines. Despite significant advances in technology and intraoperative techniques over the last several decades, surgical skills training on neurosurgical operations still carries significant risk of serious morbidity or mortality. Potentially avoidable technical errors are well recognized as contributing to poor surgical outcome. Surgical education is undergoing overwhelming change, as a result of the reduction of work hours and current trends focusing on patient safety and linking reimbursement with clinical outcomes. Thus, there is a need for adjunctive means for neurosurgical training, which is a recent advancement in simulation technology. ImmersiveTouch is an augmented reality system that integrates a haptic device and a high-resolution stereoscopic display. This simulation platform uses multiple sensory modalities, re-creating many of the environmental cues experienced during an actual procedure. Modules available include ventriculostomy, bone drilling, percutaneous trigeminal rhizotomy, and simulated spinal modules such as pedicle screw placement, vertebroplasty, and lumbar puncture. We present our experience with the development of such augmented reality neurosurgical modules and the feedback from neurosurgical residents.

  14. Serotonin, dopamine and noradrenaline adjust actions of myelinated afferents via modulation of presynaptic inhibition in the mouse spinal cord.

    Directory of Open Access Journals (Sweden)

    David L García-Ramírez

    Full Text Available Gain control of primary afferent neurotransmission at their intraspinal terminals occurs by several mechanisms including primary afferent depolarization (PAD. PAD produces presynaptic inhibition via a reduction in transmitter release. While it is known that descending monoaminergic pathways complexly regulate sensory processing, the extent these actions include modulation of afferent-evoked PAD remains uncertain. We investigated the effects of serotonin (5HT, dopamine (DA and noradrenaline (NA on afferent transmission and PAD. Responses were evoked by stimulation of myelinated hindlimb cutaneous and muscle afferents in the isolated neonatal mouse spinal cord. Monosynaptic responses were examined in the deep dorsal horn either as population excitatory synaptic responses (recorded as extracellular field potentials; EFPs or intracellular excitatory postsynaptic currents (EPSCs. The magnitude of PAD generated intraspinally was estimated from electrotonically back-propagating dorsal root potentials (DRPs recorded on lumbar dorsal roots. 5HT depressed the DRP by 76%. Monosynaptic actions were similarly depressed by 5HT (EFPs 54%; EPSCs 75% but with a slower time course. This suggests that depression of monosynaptic EFPs and DRPs occurs by independent mechanisms. DA and NA had similar depressant actions on DRPs but weaker effects on EFPs. IC50 values for DRP depression were 0.6, 0.8 and 1.0 µM for 5HT, DA and NA, respectively. Depression of DRPs by monoamines was nearly-identical in both muscle and cutaneous afferent-evoked responses, supporting a global modulation of the multimodal afferents stimulated. 5HT, DA and NA produced no change in the compound antidromic potentials evoked by intraspinal microstimulation indicating that depression of the DRP is unrelated to direct changes in the excitability of intraspinal afferent fibers, but due to metabotropic receptor activation. In summary, both myelinated afferent-evoked DRPs and monosynaptic

  15. The Potential for Cellular Therapy Combined with Growth Factors in Spinal Cord Injury

    Directory of Open Access Journals (Sweden)

    Jack Rosner

    2012-01-01

    Full Text Available Any traumatic spinal cord injury (SCI may cause symptoms ranging from pain to complete loss of motor and sensory functions below the level of the injury. Currently, there are over 2 million SCI patients worldwide. The cost of their necessary continuing care creates a burden for the patient, their families, and society. Presently, few SCI treatments are available and none have facilitated neural regeneration and/or significant functional improvement. Research is being conducted in the following areas: pathophysiology, cellular therapies (Schwann cells, embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, olfactory ensheathing cells, growth factors (BDNF, inhibitory molecules (NG2, myelin protein, and combination therapies (cell grafts and neurotrophins, cotransplantation. Results are often limited because of the inhibitory environment created following the injury and the limited regenerative potential of the central nervous system. Therapies that show promise in small animal models may not transfer to nonhuman primates and humans. None of the research has resulted in remarkable improvement, but many areas show promise. Studies have suggested that a combination of therapies may enhance results and may be more effective than a single therapy. This paper reviews and discusses the most promising new SCI research including combination therapies.

  16. Posttraumatic growth and adjustment to spinal cord injury: Moderated by posttraumatic depreciation?

    Science.gov (United States)

    Kunz, Simon; Joseph, Stephen; Geyh, Szilvia; Peter, Claudio

    2017-07-01

    Findings on the relationship of posttraumatic growth (PTG) with adjustment to potentially traumatic events are inconsistent, whereupon posttraumatic depreciation (PTD) has been suggested as a possible moderator. The objective of this study is to investigate the associations between PTG and PTD on one side and life satisfaction and indicators of mental and physical health on the other side in individuals with spinal cord injury (SCI). The primary study aim is to test whether PTD moderates the relationships of PTG and different adjustment indicators. A total of 141 patients administered to one of the four Swiss SCI rehabilitation centers completed questionnaires assessing PTG and PTD and different indicators of mental and physical health as well as life satisfaction at discharge from first rehabilitation. Correlational and regression methods were used to examine the research question. PTG and PTD were significantly positively correlated (rs = .47). PTD was significantly associated with lower mental and physical health and lower life satisfaction, with small to large effect sizes. PTD moderated the associations of PTG with symptoms of depression and life satisfaction (β of interaction term = -.18 and .24, respectively). PTG was significantly related to lower levels of symptoms of depression and higher life satisfaction in individuals experiencing moderate to high levels of PTD. In contrast, PTG was not significantly related to these outcomes in individuals with low PTD levels. The neglect of PTD in research partially explains mixed findings on the relationship of PTG and adjustment to potentially traumatic events. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  17. Vascular endothelial growth factor and basic fibroblast growth factor differentially modulate early postnatal coronary angiogenesis.

    Science.gov (United States)

    Tomanek, R J; Sandra, A; Zheng, W; Brock, T; Bjercke, R J; Holifield, J S

    2001-06-08

    The roles of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF [FGF-2]) in early postnatal regulation of coronary angiogenesis were investigated by administering neutralizing antibodies to these growth factors between postnatal days 5 and 12. Immunohistochemistry and Western blotting both revealed decreases in VEGF protein in the hearts of rats treated with either antibody. In contrast, bFGF mRNA increased in both treated groups, whereas VEGF mRNA was unchanged. Using stereological assessment of perfusion-fixed hearts, we found that both anti-VEGF and anti-bFGF inhibited the rapid and marked capillary growth that occurs during this time period and that the effects of the two neutralizing antibodies are not additive. Arteriolar growth, as indicated by a lower length density, was inhibited by anti-bFGF, but not anti-VEGF. When both anti-VEGF and anti-bFGF were administered, arteriolar length density was not significantly lower, but the population of small arterioles (<15 microm) was markedly reduced, whereas the percentage of large arterioles (26 to 50 microm) more than doubled. Thus, inhibition of both growth factors negated or limited the formation of small arterioles and facilitated an expansion of the largest arterioles. These in vivo data are the first to document that during the early neonatal period, (1) both VEGF and bFGF modulate capillary growth, (2) bFGF facilitates arteriolar growth, and (3) the two growth factors interact to establish the normal hierarchy of the arteriolar tree.

  18. Hepatocyte growth factor (HGF) modulates Leydig cell extracellular matrix components.

    Science.gov (United States)

    Catizone, A; Ricci, G; Tufano, M A; Perfetto, B; Canipari, R; Galdieri, M

    2010-01-01

    Hepatocyte growth factor (HGF) is a pleiotropic factor that plays multiple roles during mammalian development. We previously demonstrated that in the postnatal testes, the HGF receptor, c-met, is expressed by Leydig cells and HGF increases the steroidogenetic activity of the cells. In the present article, we report that HGF modifies the composition of the extracellular matrix of cultured Leydig cells. We show that HGF increases the metabolic activity of isolated Leydig cells; in particular, the factor increases urokinase plasminogen activator and matrix metalloproteinase 2 secretion. We have also shown that the levels of active transforming growth factor beta are increased by HGF. On the contrary, using the Western blotting technique, a strong reduction in the amount of fibronectin present in the culture medium of cells cultured in the presence of HGF has been detected. The presented data demonstrate that HGF modulates several functional activities of Leydig cells, further supporting the hypothesis that this factor has a relevant role in the regulation of mammalian spermatogenesis.

  19. Hepatocyte growth factor-modulated rat Leydig cell functions.

    Science.gov (United States)

    Del Bravo, Jessica; Catizone, Angela; Ricci, Giulia; Galdieri, Michela

    2007-01-01

    Hepatocyte growth factor (HGF) regulates many cellular functions acting through c-Met, its specific tyrosine kinase receptor. We previously reported that in prepuberal rats HGF is secreted by the peritubular myoid cells during the entire postnatal testicular development and by the Sertoli cells only at puberty. We have also demonstrated that germ cells at different stages of development express c-Met and that HGF modulates germ cell proliferation and apoptosis. In the present article, we extend our study to the interstitial compartment of the testis and demonstrate that the c-Met protein is present on Leydig cells. The receptor is functionally active as demonstrated by the detected effects of HGF. We report in this article that HGF significantly increases the amount of testosterone secreted by the Leydig cells and decreases the number of Leydig cells undergoing apoptosis. The antiapoptotic effect of HGF is mediated by caspase-3 activity because the amount of the active fragment of the enzyme is decreased in Leydig cells cultured in the presence of HGF. However, treatment with the growth factor does not modify the expression levels of caspase-3 mRNA. These data indicate that HGF regulates the functional activities of Leydig cells. Interestingly, the steroidogenetic activity of the cells is increased by HGF in cultured explants of testicular tissues as well as the antiapoptotic effect of HGF. Therefore, our data indicate that HGF has a crucial role in the regulation of male fertility.

  20. Tris buffer modulates polydopamine growth, aggregation, and paramagnetic properties.

    Science.gov (United States)

    Della Vecchia, Nicola Fyodor; Luchini, Alessandra; Napolitano, Alessandra; D'Errico, Gerardino; Vitiello, Giuseppe; Szekely, Noemi; d'Ischia, Marco; Paduano, Luigi

    2014-08-19

    Despite the growing technological interest of polydopamine (dopamine melanin)-based coatings for a broad variety of applications, the factors governing particle size, shape, and electronic properties of this bioinspired multifunctional material have remained little understood. Herein, we report a detailed characterization of polydopamine growth, particle morphology, and paramagnetic properties as a function of dopamine concentration and nature of the buffer (pH 8.5). Dynamic Light Scattering data revealed an increase in the hydrodynamic radii (Rh) of melanin particles with increasing dopamine concentration in all buffers examined, especially in phosphate buffer. Conversely, a marked inhibition of particle growth was apparent in Tris buffer, with Rh remaining as low as polydopamine samples prepared in Tris buffer, denoting more homogeneous paramagnetic centers with respect to similar samples obtained in phosphate and bicarbonate buffers. Overall, these results disclose Tris buffer as an efficient modulator of polydopamine buildup and properties for the rational control and fine-tuning of melanin aggregate size, morphology, and free radical behavior.

  1. Comparison of the immature sheep spine and the growing human spine: a spondylometric database for growth modulating research.

    Science.gov (United States)

    Hasler, Carol; Sprecher, Christoph Martin; Milz, Stefan

    2010-11-01

    A comparative study on growth of the sheep and human spine. To validate the immature sheep spine as model for the growing human spine and to yield a database for planning and interpretation of future animal experiments. With the current change of paradigm to nonfusion strategies for pediatric spine deformities, experimental surgery on spines of growing goats, sheep, and pigs has gained importance as preclinical proof-of-concept test. However, despite the proceeding use of animals, there is a lack of knowledge regarding the growth of the sheep spine and the relation to the human spine. Thoracic and lumbar cadaver spines were harvested from 50 Swiss alpine sheep. Specimens were obtained from newborn, 1, 3, 6, 9 and 12, 15 and 18 months old female sheep. Direct spondylometry yielded vertebral body heights, widths, and depths and spinal canal size, which were compared to pooled data on human spine growth retrieved from the literature. Sheep spine growth ceases at age 15 to 18 months, which corresponds to a time-lapse model of human growth. Main growth occurs within the first 3 to 6 months of life, as opposed to human spines with maximal growth during the first 4 years and puberty. The relation between sheep and human vertebral shape is continuously changing with growth: at birth, sheep vertebrae are twice as tall, but equally wide and deep. At skeletal maturity, height is 15% to 25% bigger in sheep, but width 15% to 30% and depth 30% to 50% are smaller. The immature sheep spine offers fast effects if growth-modulating interventions are performed within the first 3 to 6 months of age. The differences in vertebral shapes and further distinctions between human and sheep spines such as biomechanics, facet anatomy, and rib cage morphology have to be considered when interpreting results after experimental surgery.

  2. Spinal cord stimulation modulates cerebral neurobiology: a proton magnetic resonance spectroscopy study

    Energy Technology Data Exchange (ETDEWEB)

    Moens, Maarten [Universitair Ziekenhuis Brussel, Department of Neurosurgery and Center for Neuroscience, Brussels (Belgium); Marien, Peter [ZNA Middelheim General Hospital, Department of Neurology, Antwerp (Belgium); Vrije Universiteit Brussel, Department of Clinical and Experimental Neurolinguistics, Brussels (Belgium); Brouns, Raf; Smedt, Ann de [Universitair Ziekenhuis Brussel, Neurology and Center for Neuroscience, Brussels (Belgium); Poelaert, Jan [Universitair Ziekenhuis Brussel, Anesthesiology, Brussels (Belgium); Buyl, Ronald [Vrije Universiteit Brussel, Department of Biostatistics and Medical Informatics, Brussels (Belgium); Droogmans, Steven [Universitair Ziekenhuis Brussel, Cardiology, Brussels (Belgium); Schuerbeek, Peter van [Universitair Ziekenhuis Brussel, Radiology, Brussels (Belgium); Sunaert, Stefan [Katholieke Universiteit Leuven, Department of Radiology, UZ Leuven, Leuven (Belgium); Nuttin, Bart [Katholieke Universiteit Leuven, Neurosurgery, UZ Leuven, Leuven (Belgium)

    2013-08-15

    Although spinal cord stimulation (SCS) is a widely used treatment for chronic neuropathic pain secondary to spinal surgery, little is known about the underlying physiological mechanisms. The primary aim of this study is to investigate the neural substrate underlying short-term SCS by means of {sup 1}H MR spectroscopy with short echo time, in 20 patients with failed back surgery syndrome. Marked increase of {gamma}-aminobutyric acid (GABA) and decrease in glucose in the ipsilateral thalamus were found between baseline situation without SCS and after 9' of SCS, indicating the key role of the ipsilateral thalamus as a mediator of chronic neuropathic pain. In addition, this study also showed a progressive decrease in glucose in the ipsilateral thalamus over time, which is in line with the findings of previous studies reporting deactivation in the ipsilateral thalamic region. The observation of GABA increase and glucose decrease over time in the ipsilateral thalamus may be the causal mechanism of the pain relief due to SCS or an epiphenomenon. (orig.)

  3. Neuronal RARβ Signaling Modulates PTEN Activity Directly in Neurons and via Exosome Transfer in Astrocytes to Prevent Glial Scar Formation and Induce Spinal Cord Regeneration.

    Science.gov (United States)

    Goncalves, Maria B; Malmqvist, Tony; Clarke, Earl; Hubens, Chantal J; Grist, John; Hobbs, Carl; Trigo, Diogo; Risling, Mårten; Angeria, Maria; Damberg, Peter; Carlstedt, Thomas P; Corcoran, Jonathan P T

    2015-11-25

    Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin

  4. 1995 Volvo Award in basic sciences. The use of an osteoinductive growth factor for lumbar spinal fusion. Part II: Study of dose, carrier, and species.

    Science.gov (United States)

    Boden, S D; Schimandle, J H; Hutton, W C

    1995-12-15

    Efficacy of a bovine-derived osteoinductive growth factor was studied in a rabbit model and in a nonhuman primate model of posterolateral lumbar spinal fusion. To determine the minimum effective dose of growth factor and the influence of different carrier material on the outcome of intertransverse process lumbar fusion. Bone morphogenetic proteins and related growth factors are becoming increasingly available in purified extract or genetically engineered forms and are capable of inducing new bone formation in vivo. Osteoinductive growth factors to enhance lumbar spinal infusion have not been well studied in models of posterolateral intertransverse process fusion. Because of the diminished potential of bone regeneration in primates (including humans) compared with phylogenetically lower animals, extrapolations regarding dose and efficacy cannot be made directly from results obtained in experiments performed on phylogenetically lower animals. Experiments on non-human primates are a critical step before attempting to use these growth factors on humans. METHODS. One hundred fifteen adult New Zealand white rabbits and 10 adult rhesus macaques underwent single level posterolateral intertransverse process lumbar spinal arthrodesis to evaluate different doses and carrier materials for a bovine-derived osteoinductive bone protein extract. Rabbit fusion masses were evaluated 5 weeks after arthrodesis by manual palpation, radiography, biomechanical testing, and light microscopy. Monkey fusion masses were evaluated 12 weeks after arthrodesis by radiography and light microscopy. Successful posterolateral intertransverse process spinal fusions were achieved in the rabbit models using an osteoinductive growth factor with three different carriers (autogenous iliac bone, demineralized allogeneic bone matrix, and natural coral). There was a dose-dependent response to the osteoinductive growth factor in the rabbit model, indicating that a threshold must be overcome before bone

  5. Sexual hormones modulate compensatory renal growth and function

    Directory of Open Access Journals (Sweden)

    Pablo J. Azurmendi

    2013-12-01

    Full Text Available The role played by sexual hormones and vasoactive substances in the compensatory renal growth (CRG that follows uninephrectomy (uNx is still controversial. Intact and gonadectomized adult Wistar rats of both sexes, with and without uNx, performed at 90 days age, were studied at age 150 days. Daily urine volume, electrolyte excretion and kallikrein activity (UKa were determined. Afterwards, glomerular filtration rate and blood pressure were measured, the kidneys weighed and DNA, protein and RNA studied to determine nuclei content and cell size. When the remnant kidney weight at age 150 days was compared with the weight of the kidney removed at the time of uNx, male uNx rats showed the greatest CRG (50% while growth in the other uNx groups was 25%, 15% and 19% in orchidectomized, female and ovariectomized rats, respectively. The small CRG observed in the uNx female rats was accompanied by the lowest glomerular filtration value, 0.56 ± 0.02 ml/min/g kwt compared, with the other uNx groups, p < 0.05. Cell size (protein or RNA/DNA was similar for all the groups except for uNx orchidectomized rats. In this group the cytoplasmatic protein or RNA content was lower than in the other groups while DNA (nuclei content was similar. Some degree of hyperplasia was determined by DNA content in the uNx groups. Male sexual hormones positively influenced CRG and its absence modulated cell size. Female sexual hormones, instead, did not appear to stimulate CRG. The kallikrein kinin system may not be involved in CRG.

  6. Sexual hormones modulate compensatory renal growth and function.

    Science.gov (United States)

    Azurmendi, Pablo J; Oddo, Elisabet M; Toledo, Jorge E; Martin, Rodolfo S; Ibarra, Fernando R; Arrizurieta, Elvira E

    2013-01-01

    The role played by sexual hormones and vasoactive substances in the compensatory renal growth (CRG) that follows uninephrectomy (uNx) is still controversial. Intact and gonadectomized adult Wistar rats of both sexes, with and without uNx, performed at 90 days age, were studied at age 150 days. Daily urine volume, electrolyte excretion and kallikrein activity (UKa) were determined. Afterwards, glomerular filtration rate and blood pressure were measured, the kidneys weighed and DNA, protein and RNA studied to determine nuclei content and cell size. When the remnant kidney weight at age 150 days was compared with the weight of the kidney removed at the time of uNx, male uNx rats showed the greatest CRG (50%) while growth in the other uNx groups was 25%, 15% and 19% in orchidectomized, female and ovariectomized rats, respectively. The small CRG observed in the uNx female rats was accompanied by the lowest glomerular filtration value, 0.56 ± 0.02 ml/ min/g kwt compared, with the other uNx groups, p protein or RNA/DNA) was similar for all the groups except for uNx orchidectomized rats. In this group the cytoplasmatic protein or RNA content was lower than in the other groups while DNA (nuclei content) was similar. Some degree of hyperplasia was determined by DNA content in the uNx groups. Male sexual hormones positively influenced CRG and its absence modulated cell size. Female sexual hormones, instead, did not appear to stimulate CRG. The kallikrein kinin system may not be involved in CRG.

  7. Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice

    Science.gov (United States)

    Li, Jun; Sung, Cecilia Ying Ju; Lee, Nikki; Ni, Yueqiong; Pihlajamäki, Jussi; Panagiotou, Gianni; El-Nezami, Hani

    2016-01-01

    The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotic-treated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment. PMID:26884164

  8. Delayed cell cycle pathway modulation facilitates recovery after spinal cord injury

    Science.gov (United States)

    Wu, Junfang; Stoica, Bogdan A.; Dinizo, Michael; Pajoohesh-Ganji, Ahdeah; Piao, Chunshu; Faden, Alan I.

    2012-01-01

    Traumatic spinal cord injury (SCI) causes tissue loss and associated neurological dysfunction through mechanical damage and secondary biochemical and physiological responses. We have previously described the pathobiological role of cell cycle pathways following rat contusion SCI by examining the effects of early intrathecal cell cycle inhibitor treatment initiation or gene knockout on secondary injury. Here, we delineate changes in cell cycle pathway activation following SCI and examine the effects of delayed (24 h) systemic administration of flavopiridol, an inhibitor of major cyclin-dependent kinases (CDKs), on functional recovery and histopathology in a rat SCI contusion model. Immunoblot analysis demonstrated a marked upregulation of cell cycle-related proteins, including pRb, cyclin D1, CDK4, E2F1 and PCNA, at various time points following SCI, along with downregulation of the endogenous CDK inhibitor p27. Treatment with flavopiridol reduced induction of cell cycle proteins and increased p27 expression in the injured spinal cord. Functional recovery was significantly improved after SCI from day 7 through day 28. Treatment significantly reduced lesion volume and the number of Iba-1+ microglia in the preserved tissue and increased the myelinated area of spared white matter as well as the number of CC1+ oligodendrocytes. Furthermore, flavopiridol attenuated expression of Iba-1 and glactin-3, associated with microglial activation and astrocytic reactivity by reduction of GFAP, NG2, and CHL1 expression. Our current study supports the role of cell cycle activation in the pathophysiology of SCI and by using a clinically relevant treatment model, provides further support for the therapeutic potential of cell cycle inhibitors in the treatment of human SCI. PMID:22510563

  9. Growth Culture Conditions and Nutrient Signaling Modulating Yeast Chronological Longevity

    Directory of Open Access Journals (Sweden)

    Júlia Santos

    2012-01-01

    Full Text Available The manipulation of nutrient-signaling pathways in yeast has uncovered the impact of environmental growth conditions in longevity. Studies using calorie restriction show that reducing glucose concentration of the culture media is sufficient to increase replicative and chronological lifespan (CLS. Other components of the culture media and factors such as the products of fermentation have also been implicated in the regulation of CLS. Acidification of the culture media mainly due to acetic acid and other organic acids production negatively impacts CLS. Ethanol is another fermentative metabolite capable of inducing CLS reduction in aged cells by yet unknown mechanisms. Recently, ammonium was reported to induce cell death associated with shortening of CLS. This effect is correlated to the concentration of NH4+ added to the culture medium and is particularly evident in cells starved for auxotrophy-complementing amino acids. Studies on the nutrient-signaling pathways regulating yeast aging had a significant impact on aging-related research, providing key insights into mechanisms that modulate aging and establishing the yeast as a powerful system to extend knowledge on longevity regulation in multicellular organisms.

  10. On Growth Rate of Wind Waves: Impact of Short-Scale Breaking Modulations

    OpenAIRE

    Kudryavtsev, Vladimir; Chapron, Bertrand

    2016-01-01

    The wave generation model based on the rapid distortion concept significantly underestimates empirical values of the wave growth rate. As suggested before, inclusion of the aerodynamic roughness modulations effect on the amplitude of the slope-correlated surface pressure could potentially reconcile this model approach with observations. This study explores the role of short-scale breaking modulations to amplify the growth rate of modulating longer waves. As developed, airflow separations from...

  11. LncRNA expression in the spinal cord modulated by minocycline in a mouse model of spared nerve injury

    Directory of Open Access Journals (Sweden)

    Liu ZH

    2017-10-01

    Full Text Available Zihao Liu, Ying Liang, Honghua Wang, Zhenhe Lu, Jinsheng Chen, Qiaodong Huang, Lei Sheng, Yinghong Ma, Huiying Du, Qingjuan GongDepartment of Pain Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China Abstract: Neuropathic pain is a common and refractory chronic pain that affects millions of people worldwide. Its underlying mechanisms are still unclear, but they may involve long noncoding RNAs (lncRNAs, which play crucial roles in a variety of biological functions, including nociception. We used microarrays to investigate the possible interactions between lncRNAs and neuropathic pain and identified 22,213 lncRNAs and 19,528 mRNAs in the spinal cord in a mouse model of spared nerve injury (SNI-induced neuropathic pain. The abundance levels of 183 lncRNAs and 102 mRNAs were significantly modulated by both SNI and administration of minocycline. A quantitative real-time polymerase chain reaction analysis validated expression changes in three lncRNAs (NR_015491, ENSMUST00000174263, and ENSMUST00000146263. Class distribution analysis of differentially expressed lncRNAs revealed intergenic lncRNAs as the largest category. Functional analysis indicated that SNI-induced gene regulations might be involved in the activities of cytokines (IL17A and IL17F and chemokines (CCL2, CCL5, and CCL7, whereas minocycline might exert a pain-alleviating effect on mice through actin binding, thereby regulating nociception by controlling the cytoskeleton. Thus, lncRNAs might be responsible for SNI-induced neuropathic pain and the attenuation caused by minocycline. Our study could implicate lncRNAs as potential targets for future treatment of neuropathic pain. Keywords: LncRNA, neuropathic pain, spinal cord, minocycline

  12. Nitric Oxide Orchestrates a Power-Law Modulation of Sympathetic Firing Behaviors in Neonatal Rat Spinal Cords

    Directory of Open Access Journals (Sweden)

    Chun-Kuei Su

    2018-03-01

    Full Text Available Nitric oxide (NO is a diffusible gas and has multifarious effects on both pre- and postsynaptic events. As a consequence of complex excitatory and inhibitory integrations, NO effects on neuronal activities are heterogeneous. Using in vitro preparations of neonatal rats that retain the splanchnic sympathetic nerves and the thoracic spinal cord as an experimental model, we report here that either enhancement or attenuation of NO production in the neonatal rat spinal cords could increase, decrease, or not change the spontaneous firing behaviors recorded from splanchnic sympathetic single fibers. To elucidate the mathematical features of NO-mediated heterogeneous responses, the ratios of changes in firing were plotted against their original firing rates. In log-log plots, a linear data distribution demonstrated that NO-mediated heterogeneity in sympathetic firing responses was well described by a power function. Selective antagonists were applied to test if glycinergic, GABAergic, glutamatergic, and cholinergic neurotransmission in the spinal cord are involved in NO-mediated power-law firing modulations (plFM. NO-mediated plFM diminished in the presence of mecamylamine (an open-channel blocker of nicotinic cholinergic receptors, indicating that endogenous nicotinic receptor activities were essential for plFM. Applications of strychnine (a glycine receptor blocker, gabazine (a GABAA receptor blocker, or kynurenate (a broad-spectrum ionotropic glutamate receptor blocker also caused plFM. However, strychnine- or kynurenate-induced plFM was diminished by L-NAME (an NO synthase inhibitor pretreatments, indicating that the involvements of glycine or ionotropic glutamate receptor activities in plFM were secondary to NO signaling. To recapitulate the arithmetic natures of the plFM, the plFM were simulated by firing changes in two components: a step increment and a fractional reduction of their basal firing activities. Ionotropic glutamate receptor

  13. Modulation of activity and conduction in single dorsal column axons by kilohertz-frequency spinal cord stimulation.

    Science.gov (United States)

    Crosby, Nathan D; Janik, John J; Grill, Warren M

    2017-01-01

    Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a potential paresthesia-free treatment for chronic pain. However, the effects of KHF-SCS on spinal dorsal column (DC) axons and its mechanisms of action remain unknown. The objectives of this study were to quantify activation and conduction block of DC axons by KHF-SCS across a range of frequencies (1, 5, 10, or 20 kHz) and waveforms (biphasic pulses or sinusoids). Custom platinum electrodes delivered SCS to the T10/T11 dorsal columns of anesthetized male Sprague-Dawley rats. Single DC axons and compound action potentials were recorded during KHF-SCS to evaluate SCS-evoked activity. Responses to KHF-SCS in DC axons included brief onset firing, slowly accommodating asynchronous firing, and conduction block. The effects of KHF-SCS mostly occurred well above motor thresholds, but isolated units were activated at amplitudes shown to reduce behavioral sensitivity in rats. Activity evoked by SCS was similar across a range of frequencies (5-20 kHz) and waveforms (biphasic and sinusoidal). Stimulation at 1-kHz SCS evoked more axonal firing that was also more phase-synchronized to the SCS waveform, but only at amplitudes above motor threshold. These data quantitatively characterize the central nervous system activity that may modulate pain perception and paresthesia, and thereby provide a foundation for continued investigation of the mechanisms of KHF-SCS and its optimization as a therapy for chronic pain. Given the asynchronous and transient nature of DC activity, it is unlikely that the same mechanisms underlying conventional SCS (i.e., persistent, periodic DC activation) apply to KHF-SCS. Kilohertz-frequency spinal cord stimulation (KHF-SCS) is a new mode of SCS that may offer better pain relief than conventional SCS. However, the mechanism of action is poorly characterized, especially the effects of stimulation on dorsal column (DC) axons, which are the primary target of stimulation. This study provides the first

  14. A selective α2 B adrenoceptor agonist (A-1262543) and duloxetine modulate nociceptive neurones in the medial prefrontal cortex, but not in the spinal cord of neuropathic rats.

    Science.gov (United States)

    Chu, K L; Xu, J; Frost, J; Li, L; Gomez, E; Dart, M J; Jarvis, M F; Meyer, M D; McGaraughty, S

    2015-05-01

    The noradrenergic system contributes to pain modulation, but the roles of its specific adrenoceptors are still being defined. We have identified a novel, potent (rat EC50  = 4.3 nM) and selective α2B receptor agonist, A-1262543, to further explore this adrenoceptor subtype's contribution to pathological nociception. Systemic administration of A-1262543 (1-10 mg/kg, intraperitoneal) dose-dependently attenuated mechanical allodynia in animals with a spinal nerve ligation injury. To further explore its mechanism of action, the activity of nociceptive neurones in the spinal cord and medial prefrontal cortex (mPFC) were examined after injection of 3 mg/kg of A-1262543 (intravenous, i.v.). These effects were compared with duloxetine (3 mg/kg, i.v.), a dual noradrenaline (NA) and serotonin (5-HT) reuptake inhibitor. Systemic administration of A-1262543 or duloxetine did not alter the spontaneous or evoked firing of spinal wide dynamic range and nociceptive-specific neurones in the neuropathic rats, indicating that neither compound engaged spinal, peripheral or descending pathways. In contrast to the lack of effect on spinal neurones, both A-1262543 and duloxetine reduced the evoked and spontaneous firing of 'pain-responsive' (PR) neurones in the mPFC. Duloxetine, but not A-1262543, also inhibited the firing of pain non-responsive (nPR) neurones in the mPFC probably reflecting duloxetine's contribution to modulating non-pain endpoints. These data highlight that activation of the α2B adrenoceptor as well as inhibiting NA and 5-HT reuptake can result in modulating the ascending nociceptive system, and in particular, dampening the firing of PR neurones in the mPFC. © 2014 European Pain Federation - EFIC®

  15. Music modulation of pain perception and pain-related activity in the brain, brain stem, and spinal cord: a functional magnetic resonance imaging study.

    Science.gov (United States)

    Dobek, Christine E; Beynon, Michaela E; Bosma, Rachael L; Stroman, Patrick W

    2014-10-01

    The oldest known method for relieving pain is music, and yet, to date, the underlying neural mechanisms have not been studied. Here, we investigate these neural mechanisms by applying a well-defined painful stimulus while participants listened to their favorite music or to no music. Neural responses in the brain, brain stem, and spinal cord were mapped with functional magnetic resonance imaging spanning the cortex, brain stem, and spinal cord. Subjective pain ratings were observed to be significantly lower when pain was administered with music than without music. The pain stimulus without music elicited neural activity in brain regions that are consistent with previous studies. Brain regions associated with pleasurable music listening included limbic, frontal, and auditory regions, when comparing music to non-music pain conditions. In addition, regions demonstrated activity indicative of descending pain modulation when contrasting the 2 conditions. These regions include the dorsolateral prefrontal cortex, periaqueductal gray matter, rostral ventromedial medulla, and dorsal gray matter of the spinal cord. This is the first imaging study to characterize the neural response of pain and how pain is mitigated by music, and it provides new insights into the neural mechanism of music-induced analgesia within the central nervous system. This article presents the first investigation of neural processes underlying music analgesia in human participants. Music modulates pain responses in the brain, brain stem, and spinal cord, and neural activity changes are consistent with engagement of the descending analgesia system. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

  16. Extrasynaptic α6 subunit-containing GABAA receptors modulate excitability in turtle spinal motoneurons.

    Directory of Open Access Journals (Sweden)

    Carmen Andres

    Full Text Available Motoneurons are furnished with a vast repertoire of ionotropic and metabotropic receptors as well as ion channels responsible for maintaining the resting membrane potential and involved in the regulation of the mechanisms underlying its membrane excitability and firing properties. Among them, the GABAA receptors, which respond to GABA binding by allowing the flow of Cl- ions across the membrane, mediate two distinct forms of inhibition in the mature nervous system, phasic and tonic, upon activation of synaptic or extrasynaptic receptors, respectively. In a previous work we showed that furosemide facilitates the monosynaptic reflex without affecting the dorsal root potential. Our data also revealed a tonic inhibition mediated by GABAA receptors activated in motoneurons by ambient GABA. These data suggested that the high affinity GABAA extrasynaptic receptors may have an important role in motor control, though the molecular nature of these receptors was not determined. By combining electrophysiological, immunofluorescence and molecular biology techniques with pharmacological tools here we show that GABAA receptors containing the α6 subunit are expressed in adult turtle spinal motoneurons and can function as extrasynaptic receptors responsible for tonic inhibition. These results expand our understanding of the role of GABAA receptors in motoneuron tonic inhibition.

  17. Hepatocyte growth factor modulates Sertoli-Sertoli tight junction dynamics.

    Science.gov (United States)

    Catizone, A; Ricci, G; Galdieri, M

    2008-07-01

    In mammalian testes Sertoli cells form tight junctions whose function is fundamental for the maintenance of a normal spermatogenesis. Hepatocyte growth factor (HGF) is a cytokine influencing the cellular tight junctions either in normal or in tumor cells. We have previously demonstrated that HGF is expressed in the rat testis and influences many functional activities of somatic and germ cells. We now report that HGF decreases the levels of testicular occludin and influences the position of the molecule in the tight junctions as demonstrated by confocal microscopy analysis. In fact in the presence of the factor occludin was mainly localized in the suprabasal region of the tubules whereas in its absence occludin was prevalently localized in the basal region. Occludin production is known to be regulated by different cytokines including TGFbeta. We have investigated the role of HGF in the regulation of the levels of TGFbeta and we report that HGF significantly increases the amount of the active fraction of the factor without affecting the amount of the total TGFbeta. Urokinase type plasminogen activator (uPA) is closely related with the tight junctions and is one of the molecules able to activate the inactive TGF-beta. We found that HGF significantly increases the amount of uPA present in the testis suggesting that HGF regulates the amount of active TGFbeta via uPA levels. In conclusion we report that in the testis HGF regulates Sertoli-Sertoli tight junctions inducing a reduction and redistribution of occludin possibly modulating the levels of uPA and active TGFbeta. (c) 2008 Wiley-Liss, Inc.

  18. Functional reorganization of soleus H-reflex modulation during stepping after robotic-assisted step training in people with complete and incomplete spinal cord injury.

    Science.gov (United States)

    Knikou, Maria

    2013-07-01

    Body weight-supported (BWS) robotic-assisted step training on a motorized treadmill is utilized with the aim to improve walking ability in people after damage to the spinal cord. However, the potential for reorganization of the injured human spinal neuronal circuitry with this intervention is not known. The objectives of this study were to determine changes in the soleus H-reflex modulation pattern and activation profiles of leg muscles during stepping after BWS robotic-assisted step training in people with chronic spinal cord injury (SCI). Fourteen people who had chronic clinically complete, motor complete, and motor incomplete SCI received an average of 45 training sessions, 5 days per week, 1 h per day. The soleus H-reflex was evoked and recorded via conventional methods at similar BWS levels and treadmill speeds before and after training. After BWS robotic-assisted step training, the soleus H-reflex was depressed at late stance, stance-to-swing transition, and swing phase initiation, allowing a smooth transition from stance to swing. The soleus H-reflex remained depressed at early and mid-swing phases of the step cycle promoting a reciprocal activation of ankle flexors and extensors. The spinal reflex circuitry reorganization was, however, more complex, with the soleus H-reflex from the right leg being modulated either in a similar or in an opposite manner to that observed in the left leg at a given phase of the step cycle after training. Last, BWS robotic-assisted step training changed the amplitude and onset of muscle activity during stepping, decreased the step duration, and improved the gait speed. BWS robotic-assisted step training reorganized spinal locomotor neuronal networks promoting a functional amplitude modulation of the soleus H-reflex and thus step progression. These findings support that spinal neuronal networks of persons with clinically complete, motor complete, or motor incomplete SCI have the potential to undergo an endogenous

  19. Hierarchically Ordered Porous and High-Volume Polycaprolactone Microchannel Scaffolds Enhanced Axon Growth in Transected Spinal Cords.

    Science.gov (United States)

    Shahriari, Dena; Koffler, Jacob Y; Tuszynski, Mark H; Campana, Wendy M; Sakamoto, Jeff S

    2017-05-01

    The goal of this work was to design nerve guidance scaffolds with a unique architecture to maximize the open volume available for nerve growth. Polycaprolactone (PCL) was selected as the scaffold material based on its biocompatibility and month-long degradation. Yet, dense PCL does not exhibit suitable properties such as porosity, stiffness, strength, and cell adhesion to function as an effective nerve guidance scaffold. To address these shortcomings, PCL was processed using a modified salt-leaching technique to create uniquely controlled interconnected porosity. By controlling porosity, we demonstrated that the elastic modulus could be controlled between 2.09 and 182.1 MPa. In addition, introducing porosity and/or coating with fibronectin enhanced the PCL cell attachment properties. To produce PCL scaffolds with maximized open volume, porous PCL microtubes were fabricated and translated into scaffolds with 60 volume percent open volume. The scaffolds were tested in transected rat spinal cords. Linear axon growth within both the microtubes as well as the interstitial space between the tubes was observed, demonstrating that the entire open volume of the scaffold was available for nerve growth. Overall, a novel scaffold architecture and fabrication technique are presented. The scaffolds exhibit significantly higher volume than state-of-the-art scaffolds for promising spinal cord nerve repair.

  20. Different role of spinal 5-HT(hydroxytryptamine)7 receptors and descending serotonergic modulation in inflammatory pain induced in formalin and carrageenan rat models.

    Science.gov (United States)

    Yang, J; Bae, H B; Ki, H G; Oh, J M; Kim, W M; Lee, H G; Yoon, M H; Choi, J I

    2014-07-01

    Spinal serotonin (5-HT) receptors 3 (5-HT3R) and 7 (5-HT7R) are differentially involved in facilitatory or inhibitory descending modulation, respectively. Electrophysiological studies of the spinal cord have demonstrated that 5-HT3R is involved in nociception induced by intraplantar injection of formalin, but not carrageenan. In addition, depletion of spinal serotonin has been shown to attenuate pain behaviour in the formalin test, but there have been no such reports regarding the carrageenan model. This study compared the role of 5-HT7R and the influence of descending serotonergic modulation between formalin- and carrageenan-induced inflammatory pain. Effects of intrathecal (i.t.) AS-19 (5-HT7R agonist) and SB-269970 (5-HT3R antagonist) on flinching response in the formalin test and mechanical allodynia in the carrageenan model were evaluated in male Sprague-Dawley rats. The effect of serotonin depletion by i.t. 5,7-dihydroxytryptamine was also examined in the two models. Intrathecal AS-19 significantly reduced the flinching responses in the formalin test (Ppain induced by formalin but not carrageenan. Descending serotonergic modulation is differentially involved in inflammatory pain induced by formalin and carrageenan, with facilitatory and inhibitory effects, respectively. © The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels.

    Science.gov (United States)

    Zhang, Ming-Dong; Barde, Swapnali; Yang, Ting; Lei, Beilei; Eriksson, Lars I; Mathew, Joseph P; Andreska, Thomas; Akassoglou, Katerina; Harkany, Tibor; Hökfelt, Tomas G M; Terrando, Niccolò

    2016-10-25

    Pain is a critical component hindering recovery and regaining of function after surgery, particularly in the elderly. Understanding the role of pain signaling after surgery may lead to novel interventions for common complications such as delirium and postoperative cognitive dysfunction. Using a model of tibial fracture with intramedullary pinning in male mice, associated with cognitive deficits, we characterized the effects on the primary somatosensory system. Here we show that tibial fracture with pinning triggers cold allodynia and up-regulates nerve injury and inflammatory markers in dorsal root ganglia (DRGs) and spinal cord up to 2 wk after intervention. At 72 h after surgery, there is an increase in activating transcription factor 3 (ATF3), the neuropeptides galanin and neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), as well as neuroinflammatory markers including ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the fractalkine receptor CX3CR1 in DRGs. Using an established model of complete transection of the sciatic nerve for comparison, we observed similar but more pronounced changes in these markers. However, protein levels of BDNF remained elevated for a longer period after fracture. In the hippocampus, BDNF protein levels were increased, yet there were no changes in Bdnf mRNA in the parent granule cell bodies. Further, c-Fos was down-regulated in the hippocampus, together with a reduction in neurogenesis in the subgranular zone. Taken together, our results suggest that attenuated BDNF release and signaling in the dentate gyrus may account for cognitive and mental deficits sometimes observed after surgery.

  2. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    Science.gov (United States)

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-08

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities. Copyright © 2014 the authors 0270-6474/14/3413819-15$15.00/0.

  3. Modulation of ankle EMG in spinally contused rats through application of neuromuscular electrical stimulation timed to robotic treadmill training.

    Science.gov (United States)

    Askari, Sina; Kamgar, Parisa; Chao, TeKang; Diaz, Eric; de Leon, Ray D; Won, Deborah S

    2012-01-01

    While neuromuscular electrical stimulation (NMES) has enabled patients of neuromotor dysfunction to effectively regain some functions, analysis of neuromuscular changes underlying these functional improvements is lacking. We have developed an NMES system for a rodent model of SCI with the long term goal of creating a therapy which restores control over stepping back to the spinal circuitry. NMES was applied to the tibialis anterior (TA) and timed to the afferent feedback generated during robotic treadmill training (RTT). The effect of NMES+RTT on modifications in EMG was compared with that of RTT alone. A longitudinal study with a crossover design was conducted in which group 1 (n=7) received 2 weeks of RTT only followed by 2 weeks of NMES+RTT; group 2 (n=7) received 2 weeks of NMES+RTT followed by RTT only. On average, both types of training helped to modulate TA EMG activity over a gait cycle, resulting in EMG profiles across steps with peaks occurring just before or at the beginning of the swing phase, when ankle flexion is most needed. However, NMES+RTT resulted in concentration of EMG activation during the initial swing phase more than RTT only. In conjunction with these improvements in EMG activation presented here, a more complete analyses comparing changes after NMES+RTT vs. RTT is expected to further support the notion that NMES timed appropriately to hindlimb stepping could help to reinforce the motor learning that is induced by afferent activity generated by treadmill training.

  4. Modulation of Invading and Resident Inflammatory Cell Activation as a Novel Way to Mitigate Spinal Cord Injury Associated Neuropathic Pain

    Science.gov (United States)

    2016-10-01

    the non-psychoactive cannabinoid cannabidiol (CBD) on spinal cord injury neuropathic pain (SCI-NP) and associated lnllammation. Changes in thermal and...saliva plant, cannabidiol (CBD), to attenuate neuropathic pain stemming from spinal cord injury (SCI-NP). Experiments are designed to use a mouse...thermal and mechanical sensitivity following spinal cord injury while also testing whether these positive effects are mediated In part through

  5. Chondroitinase ABC promotes recovery of adaptive limb movements and enhances axonal growth caudal to a spinal hemisection.

    Science.gov (United States)

    Jefferson, Stephanie C; Tester, Nicole J; Howland, Dena R

    2011-04-13

    A number of studies have shown that chondroitinase ABC (Ch'ase ABC) digestion of inhibitory chondroitin sulfate glycosaminoglycans significantly enhances axonal growth and recovery in rodents following spinal cord injury (SCI). Further, our group has shown improved recovery following SCI in the larger cat model. The purpose of the current study was to determine whether intraspinal delivery of Ch'ase ABC, following T10 hemisections in adult cats, enhances adaptive movement features during a skilled locomotor task and/or promotes plasticity of spinal and supraspinal circuitry. Here, we show that Ch'ase ABC enhanced crossing of a peg walkway post-SCI and significantly improved ipsilateral hindlimb trajectories and integration into a functional forelimb-hindlimb coordination pattern. Recovery of these complex movements was associated with significant increases in neurofilament immunoreactivity immediately below the SCI in the ipsilateral white (p = 0.033) and contralateral gray matter (p = 0.003). Further, the rubrospinal tract is critical in the normal cat during skilled movements that require accurate paw placements and trajectories like those seen during peg walkway crossing. Rubrospinal connections were assessed following Fluoro-Gold injections, caudal to the hemisection. Significantly more retrogradely labeled right (axotomized) red nucleus (RN) neurons were seen in Ch'ase ABC-treated (23%) compared with control-treated cats (8%; p = 0.032) indicating that a larger number of RN neurons in Ch'ase ABC-treated cats had axons below the lesion level. Thus, following SCI, Ch'ase ABC may facilitate axonal growth at the spinal level, enhance adaptive features of locomotion, and affect plasticity of rubrospinal circuitry known to support adaptive behaviors in the normal cat.

  6. Adult skin-derived precursor Schwann cell grafts form growths in the injured spinal cord of Fischer rats.

    Science.gov (United States)

    May, Zacnicte; Kumar, Ranjan; Führmann, Tobias; Tam, Roger; Vulic, Katarina; Forero, Juan; Lucas-Osma, Ana M; Fenrich, Keith; Assinck, Peggy; Lee, Michael J; Moulson, Aaron; Shoichet, Molly S; Tetzlaff, Wolfram; Biernaskie, Jeff; Fouad, Karim

    2017-10-25

    In this study, GFP+ skin-derived precursor Schwann cells (SKP-SCs) from adult rats were grafted into the injured spinal cord of immunosuppressed rats. Our goal was to improve grafted cell survival in the injured spinal cord, which is typically low. Cells were grafted in hyaluronan-methylcellulose hydrogel (HAMC) or hyaluronan-methylcellulose modified with laminin- and fibronectin-derived peptide sequences (eHAMC). The criteria for selection of hyaluronan was for its shear-thinning properties, making the hydrogel easy to inject, methylcellulose for its inverse thermal gelation, helping to keep grafted cells in situ, and fibronectin and laminin to improve cell attachment and, thus, prevent cell death due to dissociation from substrate molecules (i.e., anoikis). Post-mortem examination revealed large masses of GFP+ SKP-SCs in the spinal cords of rats that received cells in HAMC (5 out of n = 8) and eHAMC (6 out of n = 8). Cell transplantation in eHAMC caused significantly greater spinal lesions compared to lesion and eHAMC only control groups. A parallel study showed similar masses in the contused spinal cord of rats after transplantation of adult GFP+ SKP-SCs without a hydrogel or immunosuppression. These findings suggest that adult GFP+ SKP-SCs, cultured/transplanted under the conditions described here, have a capacity for uncontrolled proliferation. Growth-formation in pre-clinical research has also been documented after transplantation of: human induced pluripotent stem cell-derived neural stem cells (Itakura et al., 2015), embryonic stem cells and embryonic stem cell-derived neurons (Brederlau et al., 2006; Dressel et al., 2008), bone marrow derived mesenchymal stem cells (Jeong et al., 2011) and rat nerve-derived SCs following in vitro expansion for ˃11 passages (Funk et al., 2007; Langford et al., 1988; Morrissey et al., 1991). It is of upmost importance to define the precise culture/transplantation parameters for maintenance of normal cell function and safe

  7. Clinical efficacy of percutaneous vertebroplasty combined with intensity-modulated radiotherapy for spinal metastases in patients with NSCLC

    Directory of Open Access Journals (Sweden)

    Li Y

    2015-08-01

    Full Text Available Yi Li,1,2 Yi Qing,1 Zhimin Zhang,3 Mengxia Li,1 Jiaying Xie,1 Ge Wang,1 Dong Wang1 1Department of Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, 2Department of Oncology, Beibei Traditional Chinese Medical Hospital, Chongqing, 3Department of Oncology, Wuhan General Hospital of Guangzhou Command, People’s Liberation Army, Wuhan, Hubei, People’s Republic of China Objective: This study aimed to evaluate the safety and efficacy of percutaneous vertebroplasty (PVP combined with intensity-modulated radiotherapy (IMRT for metastatic lesions of patients with non-small-cell lung cancer (NSCLC at centrum vertebrae.Methods: A total of 39 patients with spinal metastatic NSCLC (stage IV were treated with PVP followed by IMRT (30 Gy/10F/2 W for metastatic lesion at centrum vertebrae under local anesthesia. Retrospective analysis was done with medical records and radiological data. The change of visual analog scale (VAS, activities of daily living, and kyphotic angle was measured preoperatively. The presence of complications was assessed preoperatively (baseline at 24 hours, 1 week, and 1, 3, 6, 12, and 24 months postoperatively, or until the patient died or was lost to follow-up. Survival was assessed in the group.Results: A total of 39 consecutive patients were successfully treated with PVP via a translateral approach and IMRT. Their mean VAS score decreased from 7.93±1.09 preoperatively to 4.14±1.15 by the 24-hour postoperative time point and was 3.92±1.23 at 1 week, 4.27±1.93 at 1 month, 3.24±1.35 at 3 months, 2.27±0.96 at 6 months, and 2.59±1.55 at 12 months after the procedure. The mean VAS score at all of the postoperative time points was decreased significantly from the preoperative baseline score (P<0.05. Activities of daily living evaluation showed that the patients had a significantly high life quality after the combined approach (50.9±11.7 vs 82.3±9.9, P<0.05. No severe complications

  8. Long-term modulation of the intrinsic cardiac nervous system by spinal cord neurons in normal and ischaemic hearts

    NARCIS (Netherlands)

    Armour, JA; Linderoth, B; Arora, RC; DeJongste, MJL; Ardell, JL; Kingma, JG; Hill, M; Foreman, RD

    2002-01-01

    Electrical excitation of the dorsal aspect of the rostral thoracic spinal cord imparts long-term therapeutic benefits to patients with angina pectoris. Such spinal cord stimulation also induces short-term suppressor effects on the intrinsic cardiac nervous system. The purpose of this study was to

  9. Growth modulation with a medial malleolar screw for ankle valgus deformity

    OpenAIRE

    Rupprecht, Martin; Spiro, Alexander S.; Breyer, Sandra; Vettorazzi, Eik; Ridderbusch, Karsten; Stücker, Ralf

    2015-01-01

    Background and purpose Growth modulation with a medial malleolar screw is used to correct ankle valgus deformity in children with a wide spectrum of underlying etiologies. It is unclear whether the etiology of the deformity affects the angular correction rate with this procedure. Patients and methods 79 children (20 girls) with ankle valgus deformity had growth modulation by a medial malleolar screw (125 ankles). To be included, patients had to have undergone screw removal at the time of skel...

  10. Bimodal Modulation of Ipsilateral Spinal-Coeruleo-Spinal Pathway in CRPS: A Novel Model for Explaining Different Clinical Features of the Syndrome.

    Science.gov (United States)

    Carcamo, Cesar R

    2015-08-01

    The objective is to present a hypothesis to explain the sensory, autonomic, and motor disturbances associated with complex regional pain syndrome (CRPS) syndrome. The author reviewed the available and relevant literature, which was supplemented with research on experimental animal models, with a focus on how they may translate into humans, particularly in areas about pathophysiologic mechanisms of CRPS. We propose that different CRPS subtypes may result from facilitative or inhibitory influences exerted by the spinal-coeruleo-spinal pathway in three sites at the spinal cord: the dorsal horn (DH), intermediolateral cell column (IML) and ventral horn (VH). A facilitatory influence over DH may have a pronociceptive effect that explains exacerbated pain, sensory disturbances, and spreading sensitization and neuroinflammation. Conversely, a facilitatory influence over preganglionic neurons located in IML cell column may increase sympathetic outflow with peripheral vasoconstriction, which leads to cold skin, ipsilateral limb ischaemia, and sympathetically maintained pain (SMP). For patients presenting with these symptoms, a descending inhibitory influence would be predicted to result in decreased sympathetic outflow and warm skin, as well as impairment of peripheral vasoconstrictor reflexes. Finally, a descending inhibitory influence over VH could explain muscle weakness and decreased active range of motion, while also facilitating motor reflexes, tremor and dystonia. The proposed model provides a mechanistically based diagnostic scheme for classifying and explaining the sensory, autonomic and motor disturbances associated with CRPS syndrome. Wiley Periodicals, Inc.

  11. Peroxisomal catalase deficiency modulates yeast lifespan depending on growth conditions

    NARCIS (Netherlands)

    Kawalek, Adam; Lefevre, Sophie D.; Veenhuis, Marten; van der Klei, Ida J.

    We studied the role of peroxisomal catalase in chronological aging of the yeast Hansenula polymorpha in relation to various growth substrates. Catalase-deficient (cat) cells showed a similar chronological life span (CLS) relative to the wild-type control upon growth on carbon and nitrogen sources

  12. Urotheliogenic modulation of intrinsic activity in spinal cord-transected rat bladders: role of mucosal muscarinic receptors

    Science.gov (United States)

    Ikeda, Y.; Kanai, A.

    2008-01-01

    We examined the modulation of intrinsic (i.e., spontaneous) detrusor contractions by the urothelium and the lamina propria through optical mapping approaches. Normal adult and spinal cord-transected (SCT) rat bladders were stained with Ca2+- and voltage-sensitive dyes, and optical activity generated from intrinsic contractions was mapped from the mucosal surface of whole bladder sheets. Both normal adult and SCT rat bladders displayed intrinsic contractions, where normal bladders showed low-amplitude, high-frequency contractions with disorganized patterns of activity. In contrast, in the SCT animals there were high-amplitude, low-frequency contractions that displayed an organized spread of membrane potential and intracellular Ca2+. The difference in contractile activity was mirrored in the Ca2+ and membrane potential maps of bladder sheets. Normal bladders showed multiple initiation sites across the mucosal surface, whereas SCT bladders showed only one or two fixed initiation sites localized to the dome. The magnitude of intrinsic contractions could be enhanced by stretch or low-dose arecaidine (50 nM), a muscarinic-specific agonist. Partial removal of the mucosa decreased the amplitude of the intrinsic contractions and decreased the response to stretch or arecaidine. Optical mapping of mucosa-denuded sheets, where enhanced spontaneous activity was abolished, or application of 1 μM nifedipine to remove smooth muscle signals, but not the mucosal signals, shows that intrinsic activity in pathological bladders is driven by the mucosal layer. In summary, we suggest an urotheliogenic origin for intrinsic activity, where structures within the mucosal layer organize and thereby enhance intrinsic detrusor contractions. PMID:18550643

  13. Regulation of the Escherichia coli rmf gene encoding the ribosome modulation factor: growth phase- and growth rate-dependent control.

    OpenAIRE

    Yamagishi, M.; Matsushima, H; Wada, A.; Sakagami, M.; Fujita, N.; Ishihama, A

    1993-01-01

    Ribosome modulation factor (RMF) is a protein specifically associated with 100S ribosome dimers which start to accumulate in Escherichia coli cells upon growth transition from exponential to stationary phase. The structural gene, rmf, encoding the 55 amino acid residues RMF protein has been cloned from the 21.8 min region of the E. coli genome and sequenced. While rmf was silent in rapidly growing exponential phase cells, a high level of transcription took place concomitantly with the growth ...

  14. Dihydropyridine Derivatives as Cell Growth Modulators In Vitro

    Science.gov (United States)

    Bruvere, Imanta; Bisenieks, Egils; Uldrikis, Janis; Plotniece, Aiva; Pajuste, Karlis; Rucins, Martins; Vigante, Brigita; Kalme, Zenta; Gosteva, Marina; Domracheva, Ilona; Vukovic, Tea; Milkovic, Lidija

    2017-01-01

    The effects of eleven 1,4-dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (3H-thymidine incorporation) were compared with their antiradical activities (DPPH assay), using well-known DHP antioxidant diludine as a reference. Thus, tested DHPs belong to three groups: (1) antioxidant diludine; (2) derivatives with pyridinium moieties at position 4 of the 1,4-DHP ring; (3) DHPs containing cationic methylene onium (pyridinium, trialkylammonium) moieties at positions 2 and 6 of the 1,4-DHP ring. Diludine and DHPs of group 3 exerted antiradical activities, unlike compounds of group 2. However, novel DHPs had cell type and concentration dependent effects on 3H-thymidine incorporation, while diludine did not. Hence, IB-32 (group 2) suppressed the growth of HOS and HeLa, enhancing growth of L929 cells, while K-2-11 (group 3) enhanced growth of every cell line tested, even in the presence of doxorubicin. Therefore, growth regulating and antiradical activity principles of novel DHPs should be further studied to find if DHPs of group 2 could selectively suppress cancer growth and if those of group 3 promote wound healing. PMID:28473879

  15. Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy

    Science.gov (United States)

    2011-01-01

    , genetic, epigenetic, biochemical, metabolic phenotypes and pharmacogenomic research to identify susceptible individuals at risk and modulate abnormal molecular pathways of AIS. The potential of epigenetic-based medical therapy for AIS cannot be assessed at present, and must await new research derived from the evaluation of epigenetic concepts of spinal growth in health and deformity. The tenets outlined here for AIS are applicable to other musculoskeletal growth disorders including infantile and juvenile idiopathic scoliosis. PMID:22136338

  16. A re-assessment of long distance growth and connectivity of neural stem cells after severe spinal cord injury

    Science.gov (United States)

    Sharp, Kelli G.; Yee, Kelly Matsudaira; Steward, Oswald

    2014-01-01

    As part of the NIH “Facilities of Research Excellence—Spinal Cord Injury” project to support independent replication, we repeated key parts of a study reporting robust engraftment of neural stem cells (NSCs) treated with growth factors after complete spinal cord transection in rats. Rats (n = 20) received complete transections at thoracic level 3 (T3) and 2 weeks later received NSC transplants in a fibrin matrix with a growth factor cocktail using 2 different transplantation methods (with and without removal of scar tissue). Control rats (n = 9) received transections only. Hindlimb locomotor function was assessed with the BBB scale. Nine weeks post injury, reticulospinal tract axons were traced in 6 rats by injecting BDA into the reticular formation. Transplants grew to fill the lesion cavity in most rats although grafts made with scar tissue removal had large central cavities. Grafts blended extensively with host tissue obliterating the astroglial boundary at the cut ends, but in most cases there was a well-defined partition within the graft that separated rostral and caudal parts of the graft. In some cases, the partition contained non-neuronal scar tissue. There was extensive outgrowth of GFP labeled axons from the graft, but there was minimal ingrowth of host axons into the graft revealed by tract tracing and immunocy-tochemistry for 5HT. There were no statistically significant differences between transplant and control groups in the degree of locomotor recovery. Our results confirm the previous report that NSC transplants can fill lesion cavities and robustly extend axons, but reveal that most grafts do not create a continuous bridge of neural tissue between rostral and caudal segments. PMID:24747827

  17. Insulin signaling is a modulator of muscle growth

    Science.gov (United States)

    The growth rate of skeletal muscle during the neonatal period is higher than at any other stage of postnatal development and is driven by an elevated rate of protein synthesis. The high rate of muscle protein synthesis in neonatal mammals is in part due to a marked stimulation of protein synthesis a...

  18. Spinal tumor

    Science.gov (United States)

    Tumor - spinal cord ... tissue) Myeloma (blood cancer that starts in the plasma cells of the bone marrow) A small number of spinal tumors occur in the nerves of the spinal cord itself. Tumors that start in spinal tissue are ...

  19. Initiation and modulation of locomotor circuitry output with multisite transcutaneous electrical stimulation of the spinal cord in noninjured humans.

    Science.gov (United States)

    Gerasimenko, Yury; Gorodnichev, Ruslan; Puhov, Aleksandr; Moshonkina, Tatiana; Savochin, Aleksandr; Selionov, Victor; Roy, Roland R; Lu, Daniel C; Edgerton, V Reggie

    2015-02-01

    The mammalian lumbar spinal cord has the capability to generate locomotor activity in the absence of input from the brain. Previously, we reported that transcutaneous electrical stimulation of the spinal cord at vertebral level T11 can activate the locomotor circuitry in noninjured subjects when their legs are placed in a gravity-neutral position (Gorodnichev RM, Pivovarova EA, Pukhov A, Moiseev SA, Savokhin AA, Moshonkina TR, Shcherbakova NA, Kilimnik VA, Selionov VA, Kozlovskaia IB, Edgerton VR, Gerasimenko IU. Fiziol Cheloveka 38: 46-56, 2012). In the present study we hypothesized that stimulating multiple spinal sites and therefore unique combinations of networks converging on postural and locomotor lumbosacral networks would be more effective in inducing more robust locomotor behavior and more selective control than stimulation of more restricted networks. We demonstrate that simultaneous stimulation at the cervical, thoracic, and lumbar levels induced coordinated stepping movements with a greater range of motion at multiple joints in five of six noninjured subjects. We show that the addition of stimulation at L1 and/or at C5 to stimulation at T11 immediately resulted in enhancing the kinematics and interlimb coordination as well as the EMG patterns in proximal and distal leg muscles. Sequential cessation of stimulation at C5 and then at L1 resulted in a progressive degradation of the stepping pattern. The synergistic and interactive effects of transcutaneous stimulation suggest a multisegmental convergence of descending and ascending, and most likely propriospinal, influences on the spinal neuronal circuitries associated with locomotor activity. The potential impact of using multisite spinal cord stimulation as a strategy to neuromodulate the spinal circuitry has significant implications in furthering our understanding of the mechanisms controlling posture and locomotion and for regaining significant sensorimotor function even after a severe spinal cord

  20. Glycan Sulfation Modulates Dendritic Cell Biology and Tumor Growth

    Directory of Open Access Journals (Sweden)

    Roland El Ghazal

    2016-05-01

    Full Text Available In cancer, proteoglycans have been found to play roles in facilitating the actions of growth factors, and effecting matrix invasion and remodeling. However, little is known regarding the genetic and functional importance of glycan chains displayed by proteoglycans on dendritic cells (DCs in cancer immunity. In lung carcinoma, among other solid tumors, tumor-associated DCs play largely subversive/suppressive roles, promoting tumor growth and progression. Herein, we show that targeting of DC glycan sulfation through mutation in the heparan sulfate biosynthetic enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1 in mice increased DC maturation and inhibited trafficking of DCs to draining lymph nodes. Lymphatic-driven DC migration and chemokine (CCL21-dependent activation of a major signaling pathway required for DC migration (as measured by phospho-Akt were sensitive to Ndst1 mutation in DCs. Lewis lung carcinoma tumors in mice deficient in Ndst1 were reduced in size. Purified CD11c+ cells from the tumors, which contain the tumor-infiltrating DC population, showed a similar phenotype in mutant cells. These features were replicated in mice deficient in syndecan-4, the major heparan sulfate proteoglycan expressed on the DC surface: Tumors were growth-impaired in syndecan-4–deficient mice and were characterized by increased infiltration by mature DCs. Tumors on the mutant background also showed greater infiltration by NK cells and NKT cells. These findings indicate the genetic importance of DC heparan sulfate proteoglycans in tumor growth and may guide therapeutic development of novel strategies to target syndecan-4 and heparan sulfate in cancer.

  1. Peripheral Nerve Transplantation Combined with Acidic Fibroblast Growth Factor and Chondroitinase Induces Regeneration and Improves Urinary Function in Complete Spinal Cord Transected Adult Mice.

    Science.gov (United States)

    DePaul, Marc A; Lin, Ching-Yi; Silver, Jerry; Lee, Yu-Shang

    2015-01-01

    The loss of lower urinary tract (LUT) control is a ubiquitous consequence of a complete spinal cord injury, attributed to a lack of regeneration of supraspinal pathways controlling the bladder. Previous work in our lab has utilized a combinatorial therapy of peripheral nerve autografts (PNG), acidic fibroblast growth factor (aFGF), and chondroitinase ABC (ChABC) to treat a complete T8 spinal cord transection in the adult rat, resulting in supraspinal control of bladder function. In the present study we extended these findings by examining the use of the combinatorial PNG+aFGF+ChABC treatment in a T8 transected mouse model, which more closely models human urinary deficits following spinal cord injury. Cystometry analysis and external urethral sphincter electromyograms reveal that treatment with PNG+aFGF+ChABC reduced bladder weight, improved bladder and external urethral sphincter histology, and significantly enhanced LUT function, resulting in more efficient voiding. Treated mice's injured spinal cord also showed a reduction in collagen scaring, and regeneration of serotonergic and tyrosine hydroxylase-positive axons across the lesion and into the distal spinal cord. Regeneration of serotonin axons correlated with LUT recovery. These results suggest that our mouse model of LUT dysfunction recapitulates the results found in the rat model and may be used to further investigate genetic contributions to regeneration failure.

  2. Semaphorin3A regulates axon growth independently of growth cone repulsion via modulation of TrkA signaling.

    Science.gov (United States)

    Ben-Zvi, A; Ben-Gigi, L; Yagil, Z; Lerman, O; Behar, O

    2008-03-01

    Regulation of axon growth is a critical event in neuronal development. Nerve growth factor (NGF) is a strong inducer of axon growth and survival in the dorsal root ganglia (DRG). Paradoxically, high concentrations of NGF are present in the target region where axon growth must slow down for axons to accurately identify their correct targets. Semaphorin3A (Sema3A), a powerful axonal repellent molecule for DRG neurons, is also situated in their target regions. NGF is a modulator of Sema3A-induced repulsion and death. We show that Sema3A is a regulator of NGF-induced neurite outgrowth via the TrkA receptor, independent of its growth cone repulsion activity. First, neurite outgrowth of DRG neurons is more sensitive to Sema3A than repulsion. Second, at concentrations sufficient to significantly inhibit Sema3A-induced repulsion, NGF has no effect on Sema3A-induced axon growth inhibition. Third, Sema3A-induced outgrowth inhibition, but not repulsion activity, is dependent on NGF stimulation. Fourth, Sema3A attenuates TrkA-mediated growth signaling, but not survival signaling, and over-expression of constitutively active TrkA blocks Sema3A-induced axon growth inhibition, suggesting that Sema3A activity is mediated via regulation of NGF/TrkA-induced growth. Finally, quantitative analysis of axon growth in vivo supports the possibility that Sema3A affects axon growth, in addition to its well-documented role in axon guidance. We suggest a model whereby NGF at high concentrations in the target region is important for survival, attraction and inhibition of Sema3A-induced repulsion, while Sema3A inhibits its growth-promoting activity. The combined and cross-modulatory effects of these two signaling molecules ensure the accuracy of the final stages in axon targeting.

  3. Pannexin 1 Modulates Axonal Growth in Mouse Peripheral Nerves

    Directory of Open Access Journals (Sweden)

    Steven M. Horton

    2017-11-01

    Full Text Available The pannexin family of channels consists of three members—pannexin-1 (Panx1, pannexin-2 (Panx2, and pannexin-3 (Panx3 that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Pannexin-mediated release of intracellular ATP into the extracellular space has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors. Previous work indicates that the opening of Panx1 channels and activation of purinergic receptors by extracellular ATP may cause inflammation and apoptosis. In the CNS (central nervous system and PNS (peripheral nervous system, coupled pannexin, and P2 functions have been linked to peripheral sensitization (pain pathways. Purinergic pathways are also essential for other critical processes in the PNS, including myelination and neurite outgrowth. However, whether such pathways are pannexin-dependent remains to be determined. In this study, we use a Panx1 knockout mouse model and pharmacological inhibitors of the Panx1 and the ATP-mediated signaling pathway to fill gaps in our understanding of Panx1 localization in peripheral nerves, roles for Panx1 in axonal outgrowth and myelination, and neurite extension. Our data show that Panx1 is localized to axonal, myelin, and vascular compartments of the peripheral nerves. Knockout of Panx1 gene significantly increased axonal caliber in vivo and axonal growth rate in cultured dorsal root ganglia (DRG neurons. Furthermore, genetic knockout of Panx1 or inhibition of components of purinergic signaling, by treatment with probenecid and apyrase, resulted in denser axonal outgrowth from cultured DRG explants compared to untreated wild-types. Our findings suggest that Panx1 regulates axonal growth in the peripheral nervous system.

  4. Increasing plant growth by modulating omega-amidase expression in plants

    Science.gov (United States)

    Unkefer, Pat J.; Anderson, Penelope S.; Knight, Thomas J.

    2015-06-30

    The present disclosure relates to compositions and methods for increasing the leaf-to-root ratio of the signal metabolite 2-oxoglutaramate and related proline molecules in plants by modulating levels of .omega.-amidase to increase nitrogen use efficiency, resulting in enhanced growth, faster growth rates, greater seed and fruit/pod yields, earlier and more productive flowering, increased tolerance to high salt conditions, and increased biomass yields.

  5. Growth modulation with a medial malleolar screw for ankle valgus deformity

    Science.gov (United States)

    Rupprecht, Martin; Spiro, Alexander S; Breyer, Sandra; Vettorazzi, Eik; Ridderbusch, Karsten; Stücker, Ralf

    2015-01-01

    Background and purpose Growth modulation with a medial malleolar screw is used to correct ankle valgus deformity in children with a wide spectrum of underlying etiologies. It is unclear whether the etiology of the deformity affects the angular correction rate with this procedure. Patients and methods 79 children (20 girls) with ankle valgus deformity had growth modulation by a medial malleolar screw (125 ankles). To be included, patients had to have undergone screw removal at the time of skeletal maturity or deformity correction, or a minimum follow-up of 18 months, and consistent radiographs preoperatively and at the time of screw removal and/or follow-up. The patients were assigned to 1 of 7 groups according to their underlying diagnoses. The lateral distal tibial angle (LDTA) was analyzed preoperatively, at screw removal, and at follow-up. Results Mean age at operation was 11.7 (7.4–16.5) years. The average lateral distal tibial angle normalized from 80° (67–85) preoperatively to 89° (73–97) at screw removal. The screws were removed after an average time of 18 (6–46) months, according to an average rate of correction of 0.65° (0.1–2.2) per month. No significant differences in the correction rate per month were found between the groups (p = 0.3). Interpretation Growth modulation with a medial malleolar screw is effective for the treatment of ankle valgus deformity in patients with a wide spectrum of underlying diagnoses. The individual etiology of the ankle valgus does not appear to affect the correction rate after growth modulation. Thus, the optimal timing of growth modulation mainly depends on the remaining individual growth and on the extent of the deformity. PMID:25909385

  6. Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR).

    Science.gov (United States)

    Rhudy, Jamie L; Martin, Satin L; Terry, Ellen L; Delventura, Jennifer L; Kerr, Kara L; Palit, Shreela

    2012-11-01

    Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n=46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS-pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain). Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  7. The multifaceted effects of agmatine on functional recovery after spinal cord injury through Modulations of BMP-2/4/7 expressions in neurons and glial cells.

    Directory of Open Access Journals (Sweden)

    Yu Mi Park

    Full Text Available Presently, few treatments for spinal cord injury (SCI are available and none have facilitated neural regeneration and/or significant functional improvement. Agmatine (Agm, a guanidinium compound formed from decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter/neuromodulator and been reported to exert neuroprotective effects in central nervous system injury models including SCI. The purpose of this study was to demonstrate the multifaceted effects of Agm on functional recovery and remyelinating events following SCI. Compression SCI in mice was produced by placing a 15 g/mm(2 weight for 1 min at thoracic vertebra (Th 9 segment. Mice that received an intraperitoneal (i.p. injection of Agm (100 mg/kg/day within 1 hour after SCI until 35 days showed improvement in locomotor recovery and bladder function. Emphasis was made on the analysis of remyelination events, neuronal cell preservation and ablation of glial scar area following SCI. Agm treatment significantly inhibited the demyelination events, neuronal loss and glial scar around the lesion site. In light of recent findings that expressions of bone morphogenetic proteins (BMPs are modulated in the neuronal and glial cell population after SCI, we hypothesized whether Agm could modulate BMP- 2/4/7 expressions in neurons, astrocytes, oligodendrocytes and play key role in promoting the neuronal and glial cell survival in the injured spinal cord. The results from computer assisted stereological toolbox analysis (CAST demonstrate that Agm treatment dramatically increased BMP- 2/7 expressions in neurons and oligodendrocytes. On the other hand, BMP- 4 expressions were significantly decreased in astrocytes and oligodendrocytes around the lesion site. Together, our results reveal that Agm treatment improved neurological and histological outcomes, induced oligodendrogenesis, protected neurons, and decreased glial scar formation through modulating the BMP- 2/4/7 expressions following

  8. An improved SWAT vegetation growth module and its evaluation for four tropical ecosystems

    Science.gov (United States)

    Alemayehu, Tadesse; van Griensven, Ann; Taddesse Woldegiorgis, Befekadu; Bauwens, Willy

    2017-09-01

    The Soil and Water Assessment Tool (SWAT) is a globally applied river basin ecohydrological model used in a wide spectrum of studies, ranging from land use change and climate change impacts studies to research for the development of the best water management practices. However, SWAT has limitations in simulating the seasonal growth cycles for trees and perennial vegetation in the tropics, where rainfall rather than temperature is the dominant plant growth controlling factor. Our goal is to improve the vegetation growth module of SWAT for simulating the vegetation variables - such as the leaf area index (LAI) - for tropical ecosystems. Therefore, we present a modified SWAT version for the tropics (SWAT-T) that uses a straightforward but robust soil moisture index (SMI) - a quotient of rainfall (P) and reference evapotranspiration (ETr) - to dynamically initiate a new growth cycle within a predefined period. Our results for the Mara Basin (Kenya/Tanzania) show that the SWAT-T-simulated LAI corresponds well with the Moderate Resolution Imaging Spectroradiometer (MODIS) LAI for evergreen forest, savanna grassland and shrubland. This indicates that the SMI is reliable for triggering a new annual growth cycle. The water balance components (evapotranspiration and streamflow) simulated by the SWAT-T exhibit a good agreement with remote-sensing-based evapotranspiration (ET-RS) and observed streamflow. The SWAT-T model, with the proposed vegetation growth module for tropical ecosystems, can be a robust tool for simulating the vegetation growth dynamics in hydrologic models in tropical regions.

  9. Macrophyte growth module for the SWAT model – impact of climate change and management on stream ecology

    DEFF Research Database (Denmark)

    Lu, Shenglan; Trolle, Dennis; Erfurt, Jytte

    To access how multiple stressors affect the water quantity and quality and stream ecology at catchment scale under various management and climate change scenarios, we implemented macrophyte growth modules for the Soil and Water Assessment Tool version 2012 (SWAT). The macrophyte growth module ori...

  10. Arctigenin induced gallbladder cancer senescence through modulating epidermal growth factor receptor pathway.

    Science.gov (United States)

    Zhang, Mingdi; Cai, Shizhong; Zuo, Bin; Gong, Wei; Tang, Zhaohui; Zhou, Di; Weng, Mingzhe; Qin, Yiyu; Wang, Shouhua; Liu, Jun; Ma, Fei; Quan, Zhiwei

    2017-05-01

    Gallbladder cancer has poor prognosis and limited therapeutic options. Arctigenin, a representative dibenzylbutyrolactone lignan, occurs in a variety of plants. However, the molecular mechanisms involved in the antitumor effect of arctigenin on gallbladder cancer have not been fully elucidated. The expression levels of epidermal growth factor receptor were examined in 100 matched pairs of gallbladder cancer tissues. A positive correlation between high epidermal growth factor receptor expression levels and poor prognosis was observed in gallbladder cancer tissues. Pharmacological inhibition or inhibition via RNA interference of epidermal growth factor receptor induced cellular senescence in gallbladder cancer cells. The antitumor effect of arctigenin on gallbladder cancer cells was primarily achieved by inducing cellular senescence. In gallbladder cancer cells treated with arctigenin, the expression level of epidermal growth factor receptor significantly decreased. The analysis of the activity of the kinases downstream of epidermal growth factor receptor revealed that the RAF-MEK-ERK signaling pathway was significantly inhibited. Furthermore, the cellular senescence induced by arctigenin could be reverted by pcDNA-epidermal growth factor receptor. Arctigenin also potently inhibited the growth of tumor xenografts, which was accompanied by the downregulation of epidermal growth factor receptor and induction of senescence. This study demonstrates arctigenin could induce cellular senescence in gallbladder cancer through the modulation of epidermal growth factor receptor pathway. These data identify epidermal growth factor receptor as a key regulator in arctigenin-induced gallbladder cancer senescence.

  11. Neurokinin-1 (NK-1 receptor and brain-derived neurotrophic factor (BDNF gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain

    Directory of Open Access Journals (Sweden)

    McCarson Kenneth E

    2007-10-01

    Full Text Available Abstract Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1 receptors and brain-derived neurotrophic factor (BDNF, known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB, while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

  12. A3 adenosine receptor agonist prevents the development of paclitaxel-induced neuropathic pain by modulating spinal glial-restricted redox-dependent signaling pathways.

    Science.gov (United States)

    Janes, Kali; Esposito, Emanuela; Doyle, Timothy; Cuzzocrea, Salvatore; Tosh, Dillip K; Jacobson, Kenneth A; Salvemini, Daniela

    2014-12-01

    Chemotherapy-induced peripheral neuropathy accompanied by chronic neuropathic pain is the major dose-limiting toxicity of several anticancer agents including the taxane paclitaxel (Taxol). A critical mechanism underlying paclitaxel-induced neuropathic pain is the increased production of peroxynitrite in spinal cord generated in response to activation of the superoxide-generating enzyme, NADPH oxidase. Peroxynitrite in turn contributes to the development of neuropathic pain by modulating several redox-dependent events in spinal cord. We recently reported that activation of the Gi/Gq-coupled A3 adenosine receptor (A3AR) with selective A3AR agonists (ie, IB-MECA) blocked the development of chemotherapy induced-neuropathic pain evoked by distinct agents, including paclitaxel, without interfering with anticancer effects. The mechanism or mechanisms of action underlying these beneficial effects has yet to be explored. We now demonstrate that IB-MECA attenuates the development of paclitaxel-induced neuropathic pain by inhibiting the activation of spinal NADPH oxidase and two downstream redox-dependent systems. The first relies on inhibition of the redox-sensitive transcription factor (NFκB) and mitogen activated protein kinases (ERK and p38) resulting in decreased production of neuroexcitatory/proinflammatory cytokines (TNF-α, IL-1β) and increased formation of the neuroprotective/anti-inflammatory IL-10. The second involves inhibition of redox-mediated posttranslational tyrosine nitration and modification (inactivation) of glia-restricted proteins known to play key roles in regulating synaptic glutamate homeostasis: the glutamate transporter GLT-1 and glutamine synthetase. Our results unravel a mechanistic link into biomolecular signaling pathways employed by A3AR activation in neuropathic pain while providing the foundation to consider use of A3AR agonists as therapeutic agents in patients with chemotherapy-induced peripheral neuropathy. Copyright © 2014

  13. Anatomical and functional evidence for trace amines as unique modulators of locomotor function in the mammalian spinal cord

    Directory of Open Access Journals (Sweden)

    Elizabeth A Gozal

    2014-11-01

    Full Text Available The trace amines (TAs, tryptamine, tyramine, and β-phenylethylamine, are synthesized from precursor amino acids via aromatic-L-amino acid decarboxylase (AADC. We explored their role in the neuromodulation of neonatal rat spinal cord motor circuits. We first showed that the spinal cord contains the substrates for TA biosynthesis (AADC and for receptor-mediated actions via trace amine-associated receptors (TAARs 1 and 4. We next examined the actions of the TAs on motor activity using the in vitro isolated neonatal rat spinal cord. Tyramine and tryptamine most consistently increased motor activity with prominent direct actions on motoneurons. In the presence of N-methyl-D-aspartate, all applied TAs supported expression of a locomotor-like activity (LLA that was indistinguishable from that ordinarily observed with serotonin, suggesting that the TAs act on common central pattern generating neurons. The TAs also generated distinctive complex rhythms characterized by episodic bouts of LLA. TA actions on locomotor circuits did not require interaction with descending monoaminergic projections since evoked LLA was maintained following block of all Na+-dependent monoamine transporters or the vesicular monoamine transporter. Instead, TA (tryptamine and tyramine actions depended on intracellular uptake via pentamidine-sensitive Na+-independent membrane transporters. Requirement for intracellular transport is consistent with the TAs having much slower LLA onset than serotonin and for activation of intracellular TAARs. To test for endogenous actions following biosynthesis, we increased intracellular amino acid levels with cycloheximide. LLA emerged and included distinctive TA-like episodic bouts. In summary, we provided anatomical and functional evidence of the TAs as an intrinsic spinal monoaminergic modulatory system capable of promoting recruitment of locomotor circuits independent of the descending monoamines. These actions support their known

  14. Overexpression of the Fibroblast Growth Factor Receptor 1 (FGFR1 in a Model of Spinal Cord Injury in Rats.

    Directory of Open Access Journals (Sweden)

    Barbara Haenzi

    Full Text Available Spinal cord injury (SCI is a severe condition that affects many people and results in high health care costs. Therefore, it is essential to find new targets for treatment. The fibroblast growth factor receptor 1 (FGFR1 signalling pathway has a history of being explored for SCI treatment. Several groups have examined the effect of high availability of different FGFR1 ligands at the injury site and reported corticospinal tract (CST regeneration as well as improved motor functions. In this study, we investigated overexpression of the FGFR1 in rat corticospinal neurons in vivo after injury (unilateral pyramidotomy and in cerebellar granule neurons (CGNs in vitro. We show that overexpression of FGFR1 using AAV1 intracortical injections did not increase sprouting of the treated corticospinal tract and did not improve dexterity or walking in a rat model of SCI. Furthermore, we show that overexpression of FGFR1 in vitro resulted in decreased neurite outgrowth compared to control. Thus, our results suggest that the FGFR1 is not a suitable therapeutic target after SCI.

  15. Nerve growth factor does not seem to be a biomarker for neurogenic lower urinary tract dysfunction after spinal cord injury.

    Science.gov (United States)

    Krebs, Jörg; Pavlicek, David; Stoyanov, Jivko; Pannek, Jürgen; Wöllner, Jens

    2017-03-01

    To prospectively investigate the association of bladder function with the nerve growth factor (NGF) concentration in the urine of individuals with neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI). Individuals with chronic SCI and NLUTD presenting for a routine urologic examination at a tertiary urologic referral center were recruited for the study. Patient characteristics, the current bladder evacuation method and urodynamic parameters were collected. As controls, individuals with normal bladder function were recruited from the staff of a SCI rehabilitation center. The urinary NGF concentration was measured in triplicates by enzyme linked immunosorbent assay with a minimal sensitivity of 10 pg/ml. The data of 10 and 37 individuals with normal bladder function and NLUTD, respectively, were analyzed. The urinary NGF concentration was below 10 pg/ml in all investigated samples. The urinary NGF concentration did not differentiate between individuals with normal bladder function and those with NLUTD. At least in patients with SCI, the urinary NGF concentration does not seem to be a clinically relevant biomarker for NLUTD. Neurourol. Urodynam. 36:659-662, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Overexpression of the Fibroblast Growth Factor Receptor 1 (FGFR1) in a Model of Spinal Cord Injury in Rats.

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    Haenzi, Barbara; Gers-Barlag, Katharina; Akhoundzadeh, Halima; Hutson, Thomas H; Menezes, Sean C; Bunge, Mary Bartlett; Moon, Lawrence D F

    2016-01-01

    Spinal cord injury (SCI) is a severe condition that affects many people and results in high health care costs. Therefore, it is essential to find new targets for treatment. The fibroblast growth factor receptor 1 (FGFR1) signalling pathway has a history of being explored for SCI treatment. Several groups have examined the effect of high availability of different FGFR1 ligands at the injury site and reported corticospinal tract (CST) regeneration as well as improved motor functions. In this study, we investigated overexpression of the FGFR1 in rat corticospinal neurons in vivo after injury (unilateral pyramidotomy) and in cerebellar granule neurons (CGNs) in vitro. We show that overexpression of FGFR1 using AAV1 intracortical injections did not increase sprouting of the treated corticospinal tract and did not improve dexterity or walking in a rat model of SCI. Furthermore, we show that overexpression of FGFR1 in vitro resulted in decreased neurite outgrowth compared to control. Thus, our results suggest that the FGFR1 is not a suitable therapeutic target after SCI.

  17. Intrathecal lidocaine pretreatment attenuates immediate neuropathic pain by modulating Nav1.3 expression and decreasing spinal microglial activation

    Science.gov (United States)

    2011-01-01

    Background Intrathecal lidocaine reverses tactile allodynia after nerve injury, but whether neuropathic pain is attenuated by intrathecal lidocaine pretreatment is uncertain. Methods Sixty six adult male Sprague-Dawley rats were divided into three treatment groups: (1) sham (Group S), which underwent removal of the L6 transverse process; (2) ligated (Group L), which underwent left L5 spinal nerve ligation (SNL); and (3) pretreated (Group P), which underwent L5 SNL and was pretreated with intrathecal 2% lidocaine (50 μl). Neuropathic pain was assessed based on behavioral responses to thermal and mechanical stimuli. Expression of sodium channels (Nav1.3 and Nav1.8) in injured dorsal root ganglia and microglial proliferation/activation in the spinal cord were measured on post-operative days 3 (POD3) and 7 (POD7). Results Group L presented abnormal behavioral responses indicative of mechanical allodynia and thermal hyperalgesia, exhibited up-regulation of Nav1.3 and down-regulation of Nav1.8, and showed increased microglial activation. Compared with ligation only, pretreatment with intrathecal lidocaine before nerve injury (Group P), as measured on POD3, palliated both mechanical allodynia (p lidocaine prior to SNL blunts the response to noxious stimuli by attenuating Nav1.3 up-regulation and suppressing activation of spinal microglia. Although its effects are limited to 3 days, intrathecal lidocaine pretreatment can alleviate acute SNL-induced neuropathic pain. PMID:21676267

  18. Spinal Stenosis

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    ... and allows you to stand and bend. Spinal stenosis causes narrowing in your spine. The narrowing puts ... and spinal cord and can cause pain. Spinal stenosis occurs mostly in people older than 50. Younger ...

  19. Repair of spinal cord injury by inhibition of astrocyte growth and inflammatory factor synthesis through local delivery of flavopiridol in PLGA nanoparticles.

    Science.gov (United States)

    Ren, Hao; Han, Min; Zhou, Jing; Zheng, Ze-Feng; Lu, Ping; Wang, Jun-Juan; Wang, Jia-Qiu; Mao, Qi-Jiang; Gao, Jian-Qing; Ouyang, Hong Wei

    2014-08-01

    The cell-cycle inhibitor flavopiridol has been shown to improve recovery from spinal cord injury in animal models. However, the systemic dose of flavopiridol has side-effects and the mechanism of action is not clear. This study aimed to develop a strategy for the local delivery of flavopiridol and investigate its mechanisms of action. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were used for the sustained delivery of flavopiridol. The spinal cord was right-hemisectioned and NPs were delivered into the injury site. Transparent spinal cord technology was used for the three-dimensional observation of anterograde tracing. The results showed that flavopiridol NPs had a sustained release of up to 3 days in vitro. Flavopiridol NPs significantly decreased inflammatory factor synthesis by astrocytes, including TNF-α, IL-1β, and IL-6, while the IL-10 expression was elevated. In vivo study demonstrated that flavopiridol NPs decreased cell-cycle activation, inflammatory expression and glial scarring, and facilitated neuronal survival and regeneration. The cavitation volume was decreased by ~90%. Administration of flavopiridol NPs also improved the motor recovery of injured animals. These findings demonstrated that local delivery of flavopiridol in PLGA NPs improves recovery from spinal cord injury by inhibiting astrocyte growth and inflammatory factor synthesis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Collagen-Binding Hepatocyte Growth Factor (HGF) alone or with a Gelatin- furfurylamine Hydrogel Enhances Functional Recovery in Mice after Spinal Cord Injury.

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    Yamane, Kentaro; Mazaki, Tetsuro; Shiozaki, Yasuyuki; Yoshida, Aki; Shinohara, Kensuke; Nakamura, Mariko; Yoshida, Yasuhiro; Zhou, Di; Kitajima, Takashi; Tanaka, Masato; Ito, Yoshihiro; Ozaki, Toshifumi; Matsukawa, Akihiro

    2018-01-17

    The treatment of spinal cord injury (SCI) is currently a significant challenge. Hepatocyte growth factor (HGF) is a multipotent neurotrophic and neuroregenerative factor that can be beneficial for the treatment of SCI. However, immobilized HGF targeted to extracellular matrix may be more effective than diffusible, unmodified HGF. In this study, we evaluated the neurorestorative effects of an engineered HGF with a collagen biding domain (CBD-HGF). CBD-HGF remained in the spinal cord for 7 days after a single administration, while unmodified HGF was barely seen at 1 day. When a gelatin-furfurylamine (FA) hydrogel was applied on damaged spinal cord as a scaffold, CBD-HGF was retained in gelatin-FA hydrogel for 7 days, whereas HGF had faded by 1 day. A single administration of CBD-HGF enhanced recovery from spinal cord compression injury compared with HGF, as determined by motor recovery, and electrophysiological and immunohistochemical analyses. CBD-HGF alone failed to improve recovery from a complete transection injury, however CBD-HGF combined with gelatin-FA hydrogel promoted endogenous repair and recovery more effectively than HGF with hydrogel. These results suggest that engineered CBD-HGF has superior therapeutic effects than naïve HGF. CBD-HGF combined with hydrogel scaffold may be promising for the treatment of serious SCI.

  1. Role of Growth Factors in Modulation of the Microvasculature in Adult Skeletal Muscle.

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    Smythe, Gayle

    2016-01-01

    Post-natal skeletal muscle is a highly plastic tissue that has the capacity to regenerate rapidly following injury, and to undergo significant modification in tissue mass (i.e. atrophy/hypertrophy) in response to global metabolic changes. These processes are reliant largely on soluble factors that directly modulate muscle regeneration and mass. However, skeletal muscle function also depends on an adequate blood supply. Thus muscle regeneration and changes in muscle mass, particularly hypertrophy, also demand rapid changes in the microvasculature. Recent evidence clearly demonstrates a critical role for soluble growth factors in the tight regulation of angiogenic expansion of the muscle microvasculature. Furthermore, exogenous modulation of these factors has the capacity to impact directly on angiogenesis and thus, indirectly, on muscle regeneration, growth and performance. This chapter reviews recent developments in understanding the role of growth factors in modulating the skeletal muscle microvasculature, and the potential therapeutic applications of exogenous angiogenic and anti-angiogenic mediators in promoting effective growth and regeneration, and ameliorating certain diseases, of skeletal muscle.

  2. Effects of (-)-epicatechin on molecular modulators of skeletal muscle growth and differentiation.

    Science.gov (United States)

    Gutierrez-Salmean, Gabriela; Ciaraldi, Theodore P; Nogueira, Leonardo; Barboza, Jonathan; Taub, Pam R; Hogan, Michael C; Henry, Robert R; Meaney, Eduardo; Villarreal, Francisco; Ceballos, Guillermo; Ramirez-Sanchez, Israel

    2014-01-01

    Sarcopenia is a notable and debilitating age-associated condition. Flavonoids are known for their healthy effects and limited toxicity. The flavanol (-)-epicatechin (Epi) enhances exercise capacity in mice, and Epi-rich cocoa improves skeletal muscle structure in heart failure patients. (-)-Epicatechin may thus hold promise as treatment for sarcopenia. We examined changes in protein levels of molecular modulators of growth and differentiation in young vs. old, human and mouse skeletal muscle. We report the effects of Epi in mice and the results of an initial proof-of-concept trial in humans, where muscle strength and levels of modulators of muscle growth were measured. In mice, myostatin and senescence-associated β-galactosidase levels increase with aging, while those of follistatin and Myf5 decrease. (-)-Epicatechin decreases myostatin and β-galactosidase and increases levels of markers of muscle growth. In humans, myostatin and β-galactosidase increase with aging while follistatin, MyoD and myogenin decrease. Treatment for 7 days with (-)-epicatechin increases hand grip strength and the ratio of plasma follistatin/myostatin. In conclusion, aging has deleterious effects on modulators of muscle growth/differentiation, and the consumption of modest amounts of the flavanol (-)-epicatechin can partially reverse these changes. This flavanol warrants its comprehensive evaluation for the treatment of sarcopenia. © 2014.

  3. Examination of the Combined Effects of Chondroitinase ABC, Growth Factors and Locomotor Training following Compressive Spinal Cord Injury on Neuroanatomical Plasticity and Kinematics

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    Alluin, Olivier; Fehlings, Michael G.; Rossignol, Serge; Karimi-Abdolrezaee, Soheila

    2014-01-01

    While several cellular and pharmacological treatments have been evaluated following spinal cord injury (SCI) in animal models, it is increasingly recognized that approaches to address the glial scar, including the use of chondroitinase ABC (ChABC), can facilitate neuroanatomical plasticity. Moreover, increasing evidence suggests that combinatorial strategies are key to unlocking the plasticity that is enabled by ChABC. Given this, we evaluated the anatomical and functional consequences of ChABC in a combinatorial approach that also included growth factor (EGF, FGF2 and PDGF-AA) treatments and daily treadmill training on the recovery of hindlimb locomotion in rats with mid thoracic clip compression SCI. Using quantitative neuroanatomical and kinematic assessments, we demonstrate that the combined therapy significantly enhanced the neuroanatomical plasticity of major descending spinal tracts such as corticospinal and serotonergic-spinal pathways. Additionally, the pharmacological treatment attenuated chronic astrogliosis and inflammation at and adjacent to the lesion with the modest synergistic effects of treadmill training. We also observed a trend for earlier recovery of locomotion accompanied by an improvement of the overall angular excursions in rats treated with ChABC and growth factors in the first 4 weeks after SCI. At the end of the 7-week recovery period, rats from all groups exhibited an impressive spontaneous recovery of the kinematic parameters during locomotion on treadmill. However, although the combinatorial treatment led to clear chronic neuroanatomical plasticity, these structural changes did not translate to an additional long-term improvement of locomotor parameters studied including hindlimb-forelimb coupling. These findings demonstrate the beneficial effects of combined ChABC, growth factors and locomotor training on the plasticity of the injured spinal cord and the potential to induce earlier neurobehavioral recovery. However, additional

  4. Examination of the combined effects of chondroitinase ABC, growth factors and locomotor training following compressive spinal cord injury on neuroanatomical plasticity and kinematics.

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    Olivier Alluin

    Full Text Available While several cellular and pharmacological treatments have been evaluated following spinal cord injury (SCI in animal models, it is increasingly recognized that approaches to address the glial scar, including the use of chondroitinase ABC (ChABC, can facilitate neuroanatomical plasticity. Moreover, increasing evidence suggests that combinatorial strategies are key to unlocking the plasticity that is enabled by ChABC. Given this, we evaluated the anatomical and functional consequences of ChABC in a combinatorial approach that also included growth factor (EGF, FGF2 and PDGF-AA treatments and daily treadmill training on the recovery of hindlimb locomotion in rats with mid thoracic clip compression SCI. Using quantitative neuroanatomical and kinematic assessments, we demonstrate that the combined therapy significantly enhanced the neuroanatomical plasticity of major descending spinal tracts such as corticospinal and serotonergic-spinal pathways. Additionally, the pharmacological treatment attenuated chronic astrogliosis and inflammation at and adjacent to the lesion with the modest synergistic effects of treadmill training. We also observed a trend for earlier recovery of locomotion accompanied by an improvement of the overall angular excursions in rats treated with ChABC and growth factors in the first 4 weeks after SCI. At the end of the 7-week recovery period, rats from all groups exhibited an impressive spontaneous recovery of the kinematic parameters during locomotion on treadmill. However, although the combinatorial treatment led to clear chronic neuroanatomical plasticity, these structural changes did not translate to an additional long-term improvement of locomotor parameters studied including hindlimb-forelimb coupling. These findings demonstrate the beneficial effects of combined ChABC, growth factors and locomotor training on the plasticity of the injured spinal cord and the potential to induce earlier neurobehavioral recovery. However

  5. Folic Acid Modulates Matrix Metalloproteinase-2 Expression, Alleviates Neuropathic Pain, and Improves Functional Recovery in Spinal Cord-Injured Rats

    Science.gov (United States)

    Miranpuri, Gurwattan S.; Meethal, Sivan Vadakkadath; Sampene, Emmanuel; Chopra, Abhishek; Buttar, Seah; Nacht, Carrie; Moreno, Neydis; Patel, Kush; Liu, Lisa; Singh, Anupama; Singh, Chandra K.; Hariharan, Nithya; Iskandar, Bermans; Resnick, Daniel K.

    2017-01-01

    Background The molecular underpinnings of spinal cord injury (SCI) associated with neuropathic pain (NP) are unknown. Recent studies have demonstrated that matrix metalloproteinases (MMPs) such as MMP2 play a critical role in inducing NP following SCI. Promoter methylation of MMPs is known to suppress their transcription and reduce NP. In this context, it has been shown in rodents that folic acid (FA), an FDA approved dietary supplement and key methyl donor in the central nervous system (CNS), increases axonal regeneration and repair of injured CNS in part via methylation. Purpose Based on above observations, in this study, we test whether FA could decrease MMP2 expression and thereby decrease SCI-induced NP. Methods Sprague-Dawley male rats weighing 250–270 g received contusion spinal cord injuries (cSCIs) with a custom spinal cord impactor device that drops a 10 g weight from a height of 12.5 mm. The injured rats received either i.p. injections of FA (80 µg/kg) or water (control) 3 days prior and 17 days post-cSCI (mid phase) or for 3 days pre-cSCI and 14 days post-cSCI ending on the 42nd day of cSCI (late phase). The functional neurological deficits due to cSCI were then assessed by Basso, Beattie, and Bresnahan (BBB) scores either on post-impaction days 0 through 18 post-cSCI (mid phase) or on days 0, 2, 7, 14, 21, 28, 35, and 42 (late phase). Baseline measurements were taken the day before starting treatments. Thermal hyperalgesia (TH) testing for pain was performed on 4 days pre-cSCI (baseline data) and on days 18, 21, 28, 35, and 42 post-cSCI. Following TH testing, animals were euthanized and spinal cords harvested for MMP-2 expression analysis. Result The FA-treated groups showed higher BBB scores during mid phase (day 18) and in late phase (day 42) of injury compared to controls, suggesting enhanced functional recovery. There is a transient decline in TH in animals from the FA-treated group compared to controls when tested on days 18, 21, 28, and 35

  6. Motor imagery in spinal cord injured people is modulated by somatotopic coding, perspective taking, and post-lesional chronic pain.

    Science.gov (United States)

    Scandola, Michele; Aglioti, Salvatore M; Pozeg, Polona; Avesani, Renato; Moro, Valentina

    2017-09-01

    Motor imagery (MI) allows one to mentally represent an action without necessarily performing it. Importantly, however, MI is profoundly influenced by the ability to actually execute actions, as demonstrated by the impairment of this ability as a consequence of lesions in motor cortices, limb amputations, movement limiting chronic pain, and spinal cord injury. Understanding MI and its deficits in patients with motor limitations is fundamentally important as development of some brain-computer interfaces and daily life strategies for coping with motor disorders are based on this ability. We explored MI in a large sample of patients with spinal cord injury (SCI) using a comprehensive battery of questionnaires to assess the ability to imagine actions from a first-person or a third-person perspective and also imagine the proprioceptive components of actions. Moreover, we correlated MI skills with personality measures and clinical variables such as the level and completeness of the lesion and the presence of chronic pain. We found that the MI deficits (1) concerned the body parts affected by deafferentation and deefferentation, (2) were present in first- but not in third-person perspectives, and (3) were more altered in the presence of chronic pain. MI is thus closely related to bodily perceptions and representations. Every attempt to devise tools and trainings aimed at improving autonomy needs to consider the cognitive changes due to the body-brain disconnection. © 2016 The British Psychological Society.

  7. Regulation of the Escherichia coli rmf gene encoding the ribosome modulation factor: growth phase- and growth rate-dependent control.

    Science.gov (United States)

    Yamagishi, M; Matsushima, H; Wada, A; Sakagami, M; Fujita, N; Ishihama, A

    1993-02-01

    Ribosome modulation factor (RMF) is a protein specifically associated with 100S ribosome dimers which start to accumulate in Escherichia coli cells upon growth transition from exponential to stationary phase. The structural gene, rmf, encoding the 55 amino acid residues RMF protein has been cloned from the 21.8 min region of the E. coli genome and sequenced. While rmf was silent in rapidly growing exponential phase cells, a high level of transcription took place concomitantly with the growth transition to stationary phase. Under slow growth conditions, rmf was expressed even in exponential phase and there was an inverse relationship between the expression of rmf and the cell growth rate. Thus, the expression profile of rmf is contrary to those of genes for ribosomal components and ribosome-associated proteins constituting the translational apparatus. The katF gene product, a stationary phase-specific sigma factor, was not required for the expression of rmf. Disruption of rmf resulted in loss of ribosome dimers and reduction of cell viability during stationary phase.

  8. Modulation of the growth and metabolic response of cyanobacteria by the multifaceted activity of naringenin.

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    Beata Żyszka

    Full Text Available The interactions between the plant-derived bioflavonoid, naringenin, and prokaryotic microalgae representatives (cyanobacteria, were investigated with respect to its influence on the growth and metabolic response of these microorganisms. To achieve reliable results, the growth of cyanobacteria was determined based on measurements of chlorophyll content, morphological changes were assessed through microscopic observations, and the chemical response of cells was determined using liquid and gas chromatography (HPLC; GC-FID. The results show that micromolar levels of naringenin stimulated the growth of cyanobacteria. Increased growth was observed for halophilic strains at naringenin concentrations below 40 mg L-1, and in freshwater strains at concentrations below 20 mg L-1. The most remarkable stimulation was observed for the freshwater species Nostoc muscorum, which had a growth rate that was up to 60% higher than in the control. When naringenin was examined at concentrations above 40 mg L-1, the growth of the tested microorganisms was inhibited. Simultaneously, an intensive excretion of exopolysaccharides was observed. Microscopic observations strongly suggest that these effects resulted from a structural disturbance of cyanobacterial cell walls that was exerted by naringenin. This phenomenon, in combination with the absorption of naringenin into cell wall structures, influenced cell permeability and thus the growth of bacteria. Fortunately, almost all the naringenin added to the culture was incorporated into to cell substructures and could be recovered through extraction, raising the possibility that this modulator could be recycled.

  9. An improved SWAT vegetation growth module and its evaluation for four tropical ecosystems

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    T. Alemayehu

    2017-09-01

    Full Text Available The Soil and Water Assessment Tool (SWAT is a globally applied river basin ecohydrological model used in a wide spectrum of studies, ranging from land use change and climate change impacts studies to research for the development of the best water management practices. However, SWAT has limitations in simulating the seasonal growth cycles for trees and perennial vegetation in the tropics, where rainfall rather than temperature is the dominant plant growth controlling factor. Our goal is to improve the vegetation growth module of SWAT for simulating the vegetation variables – such as the leaf area index (LAI – for tropical ecosystems. Therefore, we present a modified SWAT version for the tropics (SWAT-T that uses a straightforward but robust soil moisture index (SMI – a quotient of rainfall (P and reference evapotranspiration (ETr – to dynamically initiate a new growth cycle within a predefined period. Our results for the Mara Basin (Kenya/Tanzania show that the SWAT-T-simulated LAI corresponds well with the Moderate Resolution Imaging Spectroradiometer (MODIS LAI for evergreen forest, savanna grassland and shrubland. This indicates that the SMI is reliable for triggering a new annual growth cycle. The water balance components (evapotranspiration and streamflow simulated by the SWAT-T exhibit a good agreement with remote-sensing-based evapotranspiration (ET-RS and observed streamflow. The SWAT-T model, with the proposed vegetation growth module for tropical ecosystems, can be a robust tool for simulating the vegetation growth dynamics in hydrologic models in tropical regions.

  10. Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells

    Science.gov (United States)

    Rhode, Jennifer; Fogoros, Sarah; Zick, Suzanna; Wahl, Heather; Griffith, Kent A; Huang, Jennifer; Liu, J Rebecca

    2007-01-01

    Background Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro. Methods The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-κB and and production of VEGF and IL-8 was determined in the presence or absence of ginger. Results Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that in vitro, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8. Conclusion Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer. PMID:18096028

  11. Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells

    Directory of Open Access Journals (Sweden)

    Huang Jennifer

    2007-12-01

    Full Text Available Abstract Background Ginger (Zingiber officinale Rosc is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro. Methods The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-κB and and production of VEGF and IL-8 was determined in the presence or absence of ginger. Results Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that in vitro, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8. Conclusion Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer.

  12. Dysfunctional mitochondria modulate cAMP-PKA signaling and filamentous and invasive growth of Saccharomyces cerevisiae.

    Science.gov (United States)

    Aun, Anu; Tamm, Tiina; Sedman, Juhan

    2013-02-01

    Mitochondrial metabolism is targeted by conserved signaling pathways that mediate external information to the cell. However, less is known about whether mitochondrial dysfunction interferes with signaling and thereby modulates the cellular response to environmental changes. In this study, we analyzed defective filamentous and invasive growth of the yeast Saccharomyces cerevisiae strains that have a dysfunctional mitochondrial genome (rho mutants). We found that the morphogenetic defect of rho mutants was caused by specific downregulation of FLO11, the adhesin essential for invasive and filamentous growth, and did not result from general metabolic changes brought about by interorganellar retrograde signaling. Transcription of FLO11 is known to be regulated by several signaling pathways, including the filamentous-growth-specific MAPK and cAMP-activated protein kinase A (cAMP-PKA) pathways. Our analysis showed that the filamentous-growth-specific MAPK pathway retained functionality in respiratory-deficient yeast cells. In contrast, the cAMP-PKA pathway was downregulated, explaining also various phenotypic traits observed in rho mutants. Thus, our results indicate that dysfunctional mitochondria modulate the output of the conserved cAMP-PKA signaling pathway.

  13. Abbreviated exposure to hypoxia is sufficient to induce CNS dysmyelination, modulate spinal motor neuron composition, and impair motor development in neonatal mice.

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    Jens O Watzlawik

    Full Text Available Neonatal white matter injury (nWMI is an increasingly common cause of cerebral palsy that results predominantly from hypoxic injury to progenitor cells including those of the oligodendrocyte lineage. Existing mouse models of nWMI utilize prolonged periods of hypoxia during the neonatal period, require complex cross-fostering and exhibit poor growth and high mortality rates. Abnormal CNS myelin composition serves as the major explanation for persistent neuro-motor deficits. Here we developed a simplified model of nWMI with low mortality rates and improved growth without cross-fostering. Neonatal mice are exposed to low oxygen from postnatal day (P 3 to P7, which roughly corresponds to the period of human brain development between gestational weeks 32 and 36. CNS hypomyelination is detectable for 2-3 weeks post injury and strongly correlates with levels of body and brain weight loss. Immediately following hypoxia treatment, cell death was evident in multiple brain regions, most notably in superficial and deep cortical layers as well as the subventricular zone progenitor compartment. PDGFαR, Nkx2.2, and Olig2 positive oligodendrocyte progenitor cell were significantly reduced until postnatal day 27. In addition to CNS dysmyelination we identified a novel pathological marker for adult hypoxic animals that strongly correlates with life-long neuro-motor deficits. Mice reared under hypoxia reveal an abnormal spinal neuron composition with increased small and medium diameter axons and decreased large diameter axons in thoracic lateral and anterior funiculi. Differences were particularly pronounced in white matter motor tracts left and right of the anterior median fissure. Our findings suggest that 4 days of exposure to hypoxia are sufficient to induce experimental nWMI in CD1 mice, thus providing a model to test new therapeutics. Pathological hallmarks of this model include early cell death, decreased OPCs and hypomyelination in early postnatal life

  14. Modulation of CXCL-8 expression in human melanoma cells regulates tumor growth, angiogenesis, invasion, and metastasis.

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    Wu, Sheng; Singh, Seema; Varney, Michelle L; Kindle, Scott; Singh, Rakesh K

    2012-12-01

    CXCL-8, a chemokine secreted by melanoma and stromal cells, serves as a growth and angiogenic factor for melanoma progression. This study evaluated how modulation of CXCL-8 levels in melanoma cell lines with different tumorigenic and metastatic potentials affected multiple tumor phenotypes. A375P cells (CXCL-8 low expressor) were stably transfected with a CXCL-8 mammalian expression vector to overexpress CXCL-8, whereas A375SM cells (CXCL-8 high expressor) were transfected with a CXCL-8 antisense expression vector to suppress CXCL-8 expression. Subsequent cell proliferation, migration, invasion, and soft-agar colony formation were analyzed, and in vivo tumor growth and metastasis were evaluated using mouse xenograft models. Our data demonstrate that overexpression of CXCL-8 significantly enhanced primary tumor growth and lung metastasis, accompanied by increased microvessel density in vivo, as compared with vector control-transfected cells. We also observed increased clonogenic ability, growth, and invasive potential of CXCL-8 overexpressing cells in vitro. Knockdown of CXCL-8 using an antisense vector resulted in increased cell death and reduced tumor growth relative to control. Taken together, these data confirm that CXCL-8 expression plays a critical role in regulating multiple cellular phenotypes associated with melanoma growth and metastasis.

  15. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore Cattle Are Modulators of Growth.

    Directory of Open Access Journals (Sweden)

    Anirene G T Pereira

    Full Text Available Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS, were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1 as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1, IGF2 (insulin like growth factor 2, GH1 (growth hormone 1, IGF1R (insulin like growth factor 1 receptor and GHR (growth hormone receptor, suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway.

  16. Pleiotropic Genes Affecting Carcass Traits in Bos indicus (Nellore) Cattle Are Modulators of Growth.

    Science.gov (United States)

    G T Pereira, Anirene; Utsunomiya, Yuri T; Milanesi, Marco; Torrecilha, Rafaela B P; Carmo, Adriana S; Neves, Haroldo H R; Carvalheiro, Roberto; Ajmone-Marsan, Paolo; Sonstegard, Tad S; Sölkner, Johann; Contreras-Castillo, Carmen J; Garcia, José F

    2016-01-01

    Two complementary methods, namely Multi-Trait Meta-Analysis and Versatile Gene-Based Test for Genome-wide Association Studies (VEGAS), were used to identify putative pleiotropic genes affecting carcass traits in Bos indicus (Nellore) cattle. The genotypic data comprised over 777,000 single-nucleotide polymorphism markers scored in 995 bulls, and the phenotypic data included deregressed breeding values (dEBV) for weight measurements at birth, weaning and yearling, as well visual scores taken at weaning and yearling for carcass finishing precocity, conformation and muscling. Both analyses pointed to the pleomorphic adenoma gene 1 (PLAG1) as a major pleiotropic gene. VEGAS analysis revealed 224 additional candidates. From these, 57 participated, together with PLAG1, in a network involved in the modulation of the function and expression of IGF1 (insulin like growth factor 1), IGF2 (insulin like growth factor 2), GH1 (growth hormone 1), IGF1R (insulin like growth factor 1 receptor) and GHR (growth hormone receptor), suggesting that those pleiotropic genes operate as satellite regulators of the growth pathway.

  17. Gibbs–Thomson Effect in Planar Nanowires: Orientation and Doping Modulated Growth

    KAUST Repository

    Shen, Youde

    2016-06-02

    Epitaxy-enabled bottom-up synthesis of self-assembled planar nanowires via the vapor-liquid-solid mechanism is an emerging and promising approach toward large-scale direct integration of nanowire-based devices without postgrowth alignment. Here, by examining large assemblies of indium tin oxide nanowires on yttria-stabilized zirconia substrate, we demonstrate for the first time that the growth dynamics of planar nanowires follows a modified version of the Gibbs-Thomson mechanism, which has been known for the past decades to govern the correlations between thermodynamic supersaturation, growth speed, and nanowire morphology. Furthermore, the substrate orientation strongly influences the growth characteristics of epitaxial planar nanowires as opposed to impact at only the initial nucleation stage in the growth of vertical nanowires. The rich nanowire morphology can be described by a surface-energy-dependent growth model within the Gibbs-Thomson framework, which is further modulated by the tin doping concentration. Our experiments also reveal that the cutoff nanowire diameter depends on the substrate orientation and decreases with increasing tin doping concentration. These results enable a deeper understanding and control over the growth of planar nanowires, and the insights will help advance the fabrication of self-assembled nanowire devices. © 2016 American Chemical Society.

  18. Spermine Regulates Pollen Tube Growth by Modulating Ca2+-Dependent Actin Organization and Cell Wall Structure

    Science.gov (United States)

    Aloisi, Iris; Cai, Giampiero; Faleri, Claudia; Navazio, Lorella; Serafini-Fracassini, Donatella; Del Duca, Stefano

    2017-01-01

    Proper growth of the pollen tube depends on an elaborate mechanism that integrates several molecular and cytological sub-processes and ensures a cell shape adapted to the transport of gametes. This growth mechanism is controlled by several molecules among which cytoplasmic and apoplastic polyamines. Spermine (Spm) has been correlated with various physiological processes in pollen, including structuring of the cell wall and modulation of protein (mainly cytoskeletal) assembly. In this work, the effects of Spm on the growth of pear pollen tubes were analyzed. When exogenous Spm (100 μM) was supplied to germinating pollen, it temporarily blocked tube growth, followed by the induction of apical swelling. This reshaping of the pollen tube was maintained also after growth recovery, leading to a 30–40% increase of tube diameter. Apical swelling was also accompanied by a transient increase in cytosolic calcium concentration and alteration of pH values, which were the likely cause for major reorganization of actin filaments and cytoplasmic organelle movement. Morphological alterations of the apical and subapical region also involved changes in the deposition of pectin, cellulose, and callose in the cell wall. Thus, results point to the involvement of Spm in cell wall construction as well as cytoskeleton organization during pear pollen tube growth. PMID:29033970

  19. Modulators of inhibitor of growth (ING) family expression in development and disease.

    Science.gov (United States)

    Maher, Stacey K; Helbing, Caren C

    2009-05-01

    The inhibitor of growth (ING) gene family proteins regulate many critical cellular processes such as cell proliferation and growth, apoptosis, DNA repair, senescence, angiogenesis, and drug resistance. Their transcripts and proteins are differentially expressed in health and disease and there is evidence for developmental regulation. The vast majority of studies have characterized ING levels in the context of cancer. However, relatively little attention has been paid to the expression of ING family members in other contexts. This review summarizes the findings from human and animal model systems that provide insight into the factors influencing the expression of these important proteins. We examine the influence of cell cycle and aging as well as genotoxic stress on ING expression levels and evaluate several emerging areas of inquiry demonstrating that ING gene activity may be modulated by factors such as the p53 tumor suppressor, DNA methylation, and ING proteins themselves with external factors such as hormones, reactive oxygen species, TGFbeta signalling, and other proteins of pathological significance also influencing ING levels. We then briefly discuss the influence of post-translational modification and changes in subcellular localization as it pertains to modulation of ING expression. Understanding how ING expression is modulated represents a vital aspect of effective drug targeting strategies.

  20. Low-energy extracorporeal shock wave therapy promotes vascular endothelial growth factor expression and improves locomotor recovery after spinal cord injury.

    Science.gov (United States)

    Yamaya, Seiji; Ozawa, Hiroshi; Kanno, Haruo; Kishimoto, Koshi N; Sekiguchi, Akira; Tateda, Satoshi; Yahata, Kenichiro; Ito, Kenta; Shimokawa, Hiroaki; Itoi, Eiji

    2014-12-01

    Extracorporeal shock wave therapy (ESWT) is widely used for the clinical treatment of various human diseases. Recent studies have demonstrated that low-energy ESWT upregulates the expression of vascular endothelial growth factor (VEGF) and promotes angiogenesis and functional recovery in myocardial infarction and peripheral artery disease. Many previous reports suggested that VEGF produces a neuroprotective effect to reduce secondary neural tissue damage after spinal cord injury (SCI). The purpose of the present study was to investigate whether low-energy ESWT promotes VEGF expression and neuroprotection and improves locomotor recovery after SCI. Sixty adult female Sprague-Dawley rats were randomly divided into 4 groups: sham group (laminectomy only), sham-SW group (low-energy ESWT applied after laminectomy), SCI group (SCI only), and SCI-SW group (low-energy ESWT applied after SCI). Thoracic spinal cord contusion injury was inflicted using an impactor. Low-energy ESWT was applied to the injured spinal cord 3 times a week for 3 weeks. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan (BBB) Scale (open field locomotor score) at different time points over 42 days after SCI. Hematoxylin and eosin staining was performed to assess neural tissue damage in the spinal cord. Neuronal loss was investigated by immunostaining for NeuN. The mRNA expressions of VEGF and its receptor, Flt-1, in the spinal cord were assessed using real-time polymerase chain reaction. Immunostaining for VEGF was performed to evaluate VEGF protein expression in the spinal cord. In both the sham and sham-SW groups, no animals showed locomotor impairment on BBB scoring. Histological analysis of H & E and NeuN stainings in the sham-SW group confirmed that no neural tissue damage was induced by the low-energy ESWT. Importantly, animals in the SCI-SW group demonstrated significantly better locomotor improvement than those in the SCI group at 7, 35, and 42 days after injury (p

  1. Flexibilide Obtained from Cultured Soft Coral Has Anti-Neuroinflammatory and Analgesic Effects through the Upregulation of Spinal Transforming Growth Factor-β1 in Neuropathic Rats

    Directory of Open Access Journals (Sweden)

    Nan-Fu Chen

    2014-06-01

    Full Text Available Chronic neuroinflammation plays an important role in the development and maintenance of neuropathic pain. The compound flexibilide, which can be obtained from cultured soft coral, possesses anti-inflammatory and analgesic effects in the rat carrageenan peripheral inflammation model. In the present study, we investigated the antinociceptive properties of flexibilide in the rat chronic constriction injury (CCI model of neuropathic pain. First, we found that a single intrathecal (i.t. administration of flexibilide significantly attenuated CCI-induced thermal hyperalgesia at 14 days after surgery. Second, i.t. administration of 10-μg flexibilide twice daily was able to prevent the development of thermal hyperalgesia and weight-bearing deficits in CCI rats. Third, i.t. flexibilide significantly inhibited CCI-induced activation of microglia and astrocytes, as well as the upregulated proinflammatory enzyme, inducible nitric oxide synthase, in the ipsilateral spinal dorsal horn. Furthermore, flexibilide attenuated the CCI-induced downregulation of spinal transforming growth factor-β1 (TGF-β1 at 14 days after surgery. Finally, i.t. SB431542, a selective inhibitor of TGF-β type I receptor, blocked the analgesic effects of flexibilide in CCI rats. Our results suggest that flexibilide may serve as a therapeutic agent for neuropathic pain. In addition, spinal TGF-β1 may be involved in the anti-neuroinflammatory and analgesic effects of flexibilide.

  2. Intrathecal delivery of IL-6 reactivates the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex after spinal cord injury.

    Science.gov (United States)

    Yang, Ping; Qin, Yu; Bian, Chen; Zhao, Yandong; Zhang, Wen

    2015-01-01

    We have previously demonstrated the growth-promoting effect of intrathecal delivery of recombinant rat IL-6 immediately after corticospinal tract (CST) injury. Our present study aims to further clarify whether intrathecal delivery of IL-6 after CST injury could reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex which project long axons to the spinal cord. We examined, by ELISA, levels of cyclic adenosine monophosphate (cAMP), adenylyl cyclase (AC, which synthesizes cAMP), phosphodiesterases (PDE, which degrades cAMP), and, by RT-PCR, the expression of regeneration-associated genes in the rat sensorimotor cortex after intrathecal delivery of IL-6 for 7 days, started immediately after CST injury. Furthermore, we injected retrograde neuronal tracer Fluorogold (FG) to the spinal cord to label pyramidal cells in the sensorimotor cortex, layers V and VI, combined with βIII-tubulin immunostaining, then we analyzed by immunohistochemisty and western blot the expression of the co-receptor gp-130 of IL-6 family, and pSTAT3 and mTOR, downstream IL-6/JAK/STAT3 and PI3K/AKT/mTOR signaling pathways respectively. We showed that intrathecal delivery of IL-6 elevated cAMP level and upregulated the expression of regeneration-associated genes including GAP-43, SPRR1A, CAP-23 and JUN-B, and the expression of pSTAT3 and mTOR in pyramidal cells of the sensorimotor cortex. In contrast, AG490, an inhibitor of JAK, partially blocked these effects of IL-6. All these results indicate that intrathecal delivery of IL-6 immediately after spinal cord injury can reactivate the intrinsic growth capacity of pyramidal cells in the sensorimotor cortex and these effects of IL-6 were partially JAK/STAT3-dependent.

  3. Impact of helium ion energy modulation on tungsten surface morphology and nano-tendril growth

    Science.gov (United States)

    Woller, K. B.; Whyte, D. G.; Wright, G. M.

    2017-06-01

    Time-modulated helium (He) ion energy (e.g. V Bias  =  -50  +  25·sin(2πf RF · t), f RF  =  13.56 MHz) is demonstrated to strongly affect the development of tungsten (W) surface morphology that results from He plasma irradiation in the DIONISOS linear plasma experiment. Nano-tendril bundles (NTBs), which appear as isolated ‘islands’ of nano-tendrils, can rapidly grow on an otherwise smooth W surface. This is in contrast to previously seen full-surface coverage of nano-tendril growth known as ‘fuzz’. When tall NTBs form, less than 15% of the surface contains nano-tendrils. The NTB surface coverage changes with growth conditions and the total volume of nano-tendrils in the NTBs is observed to be up to a factor of 16 larger than when fuzz is grown. This indicates that long-range W surface transport underlies nano-tendril formation. Surface temperature 870-1220 K, the DC bias potential  -30 to  -70 V, and the ion flux density 4.4  ×  1021-1.1  ×  1022 He · m-2 · s-1 are varied in the experiments. NTBs form at similar conditions as fuzz with the critical difference being the RF modulation of the ion energy bombarding the W, another indication of the importance of W surface transport. Mass loss measurements indicate net erosion with a yield of 1-8  ×  10-4 W/He when NTBs form; erosion that is not attributable to chemical or physical sputtering by He or impurities in the plasma. The erosion is correlated to the NTB growth, based on post-exposure inspection by electron microscopy indicating that NTBs are prone to loss from the surface. NTB growth is compared to the empirical growth-erosion model of fuzz, showing NTBs grow up to a factor of 100 times taller than the expected fuzz layer depth under DC bias conditions. Insights into nano-tendril growth provided by this new growth regime are discussed. Strategies to mitigate W fuzz growth may inadvertently result in rapid localized nano-tendril bundle

  4. Intra-articular nerve growth factor regulates development, but not maintenance, of injury-induced facet joint pain & spinal neuronal hypersensitivity.

    Science.gov (United States)

    Kras, J V; Kartha, S; Winkelstein, B A

    2015-11-01

    The objective of the current study is to define whether intra-articular nerve growth factor (NGF), an inflammatory mediator that contributes to osteoarthritic pain, is necessary and sufficient for the development or maintenance of injury-induced facet joint pain and its concomitant spinal neuronal hyperexcitability. Male Holtzman rats underwent painful cervical facet joint distraction (FJD) or sham procedures. Mechanical hyperalgesia was assessed in the forepaws, and NGF expression was quantified in the C6/C7 facet joint. An anti-NGF antibody was administered intra-articularly in additional rats immediately or 1 day following facet distraction or sham procedures to block intra-articular NGF and test its contribution to initiation and/or maintenance of facet joint pain and spinal neuronal hyperexcitability. NGF was injected into the bilateral C6/C7 facet joints in separate rats to determine if NGF alone is sufficient to induce these behavioral and neuronal responses. NGF expression increases in the cervical facet joint in association with behavioral sensitivity after that joint's mechanical injury. Intra-articular application of anti-NGF immediately after a joint distraction prevents the development of both injury-induced pain and hyperexcitability of spinal neurons. Yet, intra-articular anti-NGF applied after pain has developed does not attenuate either behavioral or neuronal hyperexcitability. Intra-articular NGF administered to the facet in naïve rats also induces behavioral hypersensitivity and spinal neuronal hyperexcitability. Findings demonstrate that NGF in the facet joint contributes to the development of injury-induced joint pain. Localized blocking of NGF signaling in the joint may provide potential treatment for joint pain. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  5. Co-induction of cyclooxyenase-2 and early growth response gene (Egr-1 in spinal cord in a clinical model of persistent inflammation and hyperalgesia

    Directory of Open Access Journals (Sweden)

    Dolan Sharron

    2011-11-01

    Full Text Available Abstract Background This study characterised the effects of persistent peripheral inflammation of the foot on pain and spinal cord expression of cyclooxygenase-1 and -2 (COX-1 and COX-2 and early growth response gene 1 (Egr-1, known markers of neuronal plasticity, in a clinical model of naturally-occurring inflammatory disease and hyperalgesia in sheep ('footrot', before and after routine treatment (parenteral treatment with antibiotics and antiseptic footbathing. The temporal pattern of expression of COX-1, COX-2 and Egr-1 mRNA and protein were analysed using real-time PCR and Western blotting. Results Animals affected with persistent peripheral inflammation displayed significant hyperalgesia and lameness (a proxy indicator of spontaneous pain restricted to the inflamed limb. Hyperalgesia and lameness were significantly attenuated 1 day after treatment, and resolved further by day 7 and day 3, respectively. COX-2 but not COX-1, protein expression was up-regulated in spinal cord from lame animals on day 0, before treatment. Following treatment and attenuation of pain behaviours, levels of COX-2 returned to control levels. Significant induction of Egr-1 mRNA and protein were observed in spinal cord from lame animals. Three days after treatment, levels of Egr-1 mRNA returned to control levels, however, Egr-1 protein remained elevated. Conclusion Elevated levels of spinal COX-2 and Egr-1 protein correlate with the presence of pain and hyperalgesia, and may underlie persistent pain, although a direct causal link has still to be established. Understanding the temporal pattern of expression of key mediators in clinical pain states may lead to better strategies to manage pain.

  6. Spinal Cord Stimulation (SCS) and Functional Magnetic Resonance Imaging (fMRI): Modulation of Cortical Connectivity With Therapeutic SCS.

    Science.gov (United States)

    Deogaonkar, Milind; Sharma, Mayur; Oluigbo, Chima; Nielson, Dylan M; Yang, Xiangyu; Vera-Portocarrero, Louis; Molnar, Gregory F; Abduljalil, Amir; Sederberg, Per B; Knopp, Michael; Rezai, Ali R

    2016-02-01

    The neurophysiological basis of pain relief due to spinal cord stimulation (SCS) and the related cortical processing of sensory information are not completely understood. The aim of this study was to use resting state functional magnetic resonance imaging (rs-fMRI) to detect changes in cortical networks and cortical processing related to the stimulator-induced pain relief. Ten patients with complex regional pain syndrome (CRPS) or neuropathic leg pain underwent thoracic epidural spinal cord stimulator implantation. Stimulation parameters associated with "optimal" pain reduction were evaluated prior to imaging studies. Rs-fMRI was obtained on a 3 Tesla, Philips Achieva MRI. Rs-fMRI was performed with stimulator off (300TRs) and stimulator at optimum (Opt, 300 TRs) pain relief settings. Seed-based analysis of the resting state functional connectivity was conducted using seeds in regions established as participating in pain networks or in the default mode network (DMN) in addition to the network analysis. NCUT (normalized cut) parcellation was used to generate 98 cortical and subcortical regions of interest in order to expand our analysis of changes in functional connections to the entire brain. We corrected for multiple comparisons by limiting the false discovery rate to 5%. Significant differences in resting state connectivity between SCS off and optimal state were seen between several regions related to pain perception, including the left frontal insula, right primary and secondary somatosensory cortices, as well as in regions involved in the DMN, such as the precuneus. In examining changes in connectivity across the entire brain, we found decreased connection strength between somatosensory and limbic areas and increased connection strength between somatosensory and DMN with optimal SCS resulting in pain relief. This suggests that pain relief from SCS may be reducing negative emotional processing associated with pain, allowing somatosensory areas to become more

  7. Nerve tissue growth factors as markers of evaluation of neuro-genesis processes in traumatic spinal cord disease

    Directory of Open Access Journals (Sweden)

    Uljanov V.Yu.

    2014-09-01

    Full Text Available Objective: immunological differentiation effects regeneration of nerve tissue in the acute and early periods of traumatic spinal cord disease on the basis of assessment of the dynamics of content neurospecific proteins in serum affected. Material and Methods. Content of neurospecific proteins in the blood serum has been studied by enzyme immunoassay in 40 patients with spinal cord injuries. Results. Dynamics and quantitative changes in the content of chronometric neurospecific proteins in serum of patients in acute and early periods of traumatic spinal cord disease is characterized by two-phase increase in the concentration CNTF; monotonic increase in the content of NT-3 in all periods of observation; biphasic increase in the levels of NT-4 to 1-4th and 14-th day from the date of injury. Conclusion. Complex research of neurospecific levels of proteins in the serum allows one to evaluate selectively the individual components of the process of regeneration of nerve tissue in acute and early periods of traumatic spinal cord disease.

  8. Sodium hyaluronate-CNTF gelatinous particles promote axonal growth, neurogenesis and functional recovery after spinal cord injury.

    Science.gov (United States)

    Wang, N; Zhang, S; Zhang, A F; Yang, Z Y; Li, X G

    2014-07-01

    Currently, effective therapeutic strategy for spinal cord injury (SCI) is not clinically available. To establish a better method that may help repair the injured spinal cord, sodium hyaluronate-ciliary neurotrophic factor (CNTF) gelatinous particles were generated. A segment of spinal cord tissue was excised to form a 2.5-mm-long cavity at thoracic level in an adult rat, and sodium hyaluronate-CNTF gelatinous particles were implanted into the lesion cavity. The recovery of the injured spinal cord was evaluated by immunohistochemistry, nerve tracing, electrophysiological test and Basso-Beattie-Bresnahan locomotor rating scale. Open-field locomotion of the sodium hyaluronate-CNTF rats was significantly enhanced up to 12 weeks postoperation. Together with the evidence of enhanced cortical motor evoked potentials and cortical somatosensory evoked potentials in the sodium hyaluronate-CNTF group, these findings suggested a powerful functional recovery component. Immunohistochemical analyses suggested that the functional recovery might be attributable partly to an increase in axonal regrowth as well as in replenishment of β-tubulin-III-positive neuron-like cells. Sodium hyaluronate-CNTF gelatinous particles may provide an effective method for treating SCI.

  9. Monitoring surface roughness during film growth using modulated RHEED intensity oscillations

    Science.gov (United States)

    Braun, Wolfgang

    2017-11-01

    Separation of the high- and low-frequency components of Reflection High-Energy Electron Diffraction (RHEED) intensity oscillations during pulsed deposition allows the extraction of a signal that is in phase with the cyclic surface morphology evolution during layer-by-layer growth. Similar to a biased impedance measurement in electricity, the periodic modulation of surface roughness induced by the pulsed deposition probes the differential response of the growth front to changes in step density. This signal does not follow the complex variation of the RHEED oscillation phase with diffraction conditions and surface reconstruction and therefore allows a direct detection of monolayer completion. Off-Laue Circle oscillations show promise to probe the surface morphology evolution at sharply defined in-plane spatial frequencies.

  10. Dietary lutein modulates growth and survival genes in prostate cancer cells.

    Science.gov (United States)

    Rafi, Mohamed M; Kanakasabai, Saravanan; Gokarn, Sarita V; Krueger, Eric G; Bright, John J

    2015-02-01

    Lutein is a carotenoid pigment present in fruits and vegetables that has anti-inflammatory and antitumor properties. In this study, we examined the effect of lutein on proliferation and survival-associated genes in prostate cancer (PC-3) cells. We found that in vitro culture of PC-3 cells with lutein induced mild decrease in proliferation that improved in combination treatment with peroxisome proliferator-activated receptor gamma (PPARγ) agonists and other chemotherapeutic agents. Flow cytometry analyses showed that lutein improved drug-induced cell cycle arrest and apoptosis in prostate cancer. Gene array and quantitative reverse transcription-polymerase chain reaction analyses showed that lutein altered the expression of growth and apoptosis-associated biomarker genes in PC-3 cells. These findings highlight that lutein modulates the expression of growth and survival-associated genes in prostate cancer cells.

  11. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Spinal Cord Injury Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation Pediatric Spinal ... Spinal Cord Injury Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation Pediatric Spinal ...

  12. Modulations of the chicken cecal microbiome and metagenome in response to anticoccidial and growth promoter treatment.

    Directory of Open Access Journals (Sweden)

    Jessica L Danzeisen

    Full Text Available With increasing pressures to reduce or eliminate the use of antimicrobials for growth promotion purposes in production animals, there is a growing need to better understand the effects elicited by these agents in order to identify alternative approaches that might be used to maintain animal health. Antibiotic usage at subtherapeutic levels is postulated to confer a number of modulations in the microbes within the gut that ultimately result in growth promotion and reduced occurrence of disease. This study examined the effects of the coccidiostat monensin and the growth promoters virginiamycin and tylosin on the broiler chicken cecal microbiome and metagenome. Using a longitudinal design, cecal contents of commercial chickens were extracted and examined using 16S rRNA and total DNA shotgun metagenomic pyrosequencing. A number of genus-level enrichments and depletions were observed in response to monensin alone, or monensin in combination with virginiamycin or tylosin. Of note, monensin effects included depletions of Roseburia, Lactobacillus and Enterococcus, and enrichments in Coprococcus and Anaerofilum. The most notable effect observed in the monensin/virginiamycin and monensin/tylosin treatments, but not in the monensin-alone treatments, was enrichments in Escherichia coli. Analysis of the metagenomic dataset identified enrichments in transport system genes, type I fimbrial genes, and type IV conjugative secretion system genes. No significant differences were observed with regard to antimicrobial resistance gene counts. Overall, this study provides a more comprehensive glimpse of the chicken cecum microbial community, the modulations of this community in response to growth promoters, and targets for future efforts to mimic these effects using alternative approaches.

  13. Modulations of the chicken cecal microbiome and metagenome in response to anticoccidial and growth promoter treatment.

    Science.gov (United States)

    Danzeisen, Jessica L; Kim, Hyeun Bum; Isaacson, Richard E; Tu, Zheng Jin; Johnson, Timothy J

    2011-01-01

    With increasing pressures to reduce or eliminate the use of antimicrobials for growth promotion purposes in production animals, there is a growing need to better understand the effects elicited by these agents in order to identify alternative approaches that might be used to maintain animal health. Antibiotic usage at subtherapeutic levels is postulated to confer a number of modulations in the microbes within the gut that ultimately result in growth promotion and reduced occurrence of disease. This study examined the effects of the coccidiostat monensin and the growth promoters virginiamycin and tylosin on the broiler chicken cecal microbiome and metagenome. Using a longitudinal design, cecal contents of commercial chickens were extracted and examined using 16S rRNA and total DNA shotgun metagenomic pyrosequencing. A number of genus-level enrichments and depletions were observed in response to monensin alone, or monensin in combination with virginiamycin or tylosin. Of note, monensin effects included depletions of Roseburia, Lactobacillus and Enterococcus, and enrichments in Coprococcus and Anaerofilum. The most notable effect observed in the monensin/virginiamycin and monensin/tylosin treatments, but not in the monensin-alone treatments, was enrichments in Escherichia coli. Analysis of the metagenomic dataset identified enrichments in transport system genes, type I fimbrial genes, and type IV conjugative secretion system genes. No significant differences were observed with regard to antimicrobial resistance gene counts. Overall, this study provides a more comprehensive glimpse of the chicken cecum microbial community, the modulations of this community in response to growth promoters, and targets for future efforts to mimic these effects using alternative approaches.

  14. Spinal Stenosis

    Science.gov (United States)

    ... need to be considered. These include trauma, congenital spinal deformity such as scoliosis, and a genetic disease affecting bone and muscle development throughout the body. Spinal imaging can differentiate these causes. Complications Rarely, untreated ...

  15. Spinal fusion

    Science.gov (United States)

    ... Low back pain - fusion; Herniated disk - fusion; Spinal stenosis - fusion; Laminectomy - fusion ... be done: With other surgical procedures for spinal stenosis , such as foraminotomy or laminectomy After diskectomy in ...

  16. Spinal Tap

    Science.gov (United States)

    ... It? A spinal tap (also called a lumbar puncture) is a medical test that involves taking a small sample of cerebrospinal fluid (CSF) for examination. Cerebrospinal fluid is a clear, colorless liquid that delivers nutrients to the brain and spinal ...

  17. Spinal injury

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000029.htm Spinal injury To use the sharing features on this page, ... move anyone who you think may have a spinal injury, unless it is absolutely necessary. For example, if ...

  18. Acute granulocyte macrophage-colony stimulating factor treatment modulates neuroinflammatory processes and promotes tactile recovery after spinal cord injury.

    Science.gov (United States)

    Thomaty, Sandie; Pezard, Laurent; Xerri, Christian; Brezun, Jean-Michel

    2017-05-04

    Neuroinflammation is known to play a key role in the prognosis of functional recovery after spinal cord injury (SCI). The involvement of microglial and mast cells in early and late stages of inflammation has been receiving increasing attention. This study was aimed at determining the influence of a pro-inflammatory cytokine, the granulocyte macrophage-colony stimulating factor (GM-CSF), on microglia and mast cell activation, glial scar formation and functional recovery following SCI. Rats were randomly injected with saline or GM-CSF one hour after a C4-C5 medio-lateral hemisection. To assess functional impairment and recovery, the rats were subjected to sensorimotor tasks for one month. Then, responses evoked by forepaw stimulation in the primary somatosensory cortex were recorded. We also quantified the changes in GM-CSF, IL-1β, IL-6 and BDNF levels, the gliosis and lesion volume as well as microglial and mast cell density, and mast cell surface. Our findings show that GM-CSF promotes cortical reactivation and recovery of tactile abilities, whereas it does not influence motor performances. A transient decrease in pro-inflammatory cytokines after GM-CSF treatment was also observed, whereas the endogenous GM-CSF level was unchanged. While the beneficial role of GM-CSF in reducing glial scar is confirmed, our findings reveal that neuroinflammatory events mediated by microglial and mast cells as well as the alteration of IL-1β and IL-6 levels are paralleled with an improvement in tactile recovery. These mechanisms could limit the duration and intensity of homeostatic imbalance and promote the plasticity of spared tissues. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels.

    Science.gov (United States)

    Damoiseaux, Jessica S; Seeley, William W; Zhou, Juan; Shirer, William R; Coppola, Giovanni; Karydas, Anna; Rosen, Howard J; Miller, Bruce L; Kramer, Joel H; Greicius, Michael D

    2012-06-13

    We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

  20. Testosterone modulates platelet aggregation and endothelial cell growth through nitric oxide pathway.

    Science.gov (United States)

    Campelo, Adrián E; Cutini, Pablo H; Massheimer, Virginia L

    2012-04-01

    The aim of the present study was to investigate the effect of testosterone on the modulation of cellular events associated with vascular homeostasis. In rat aortic strips, 5-20 min treatment with physiological concentrations of testosterone significantly increased nitric oxide (NO) production. The rapid action of the steroid was suppressed by the presence of an androgen receptor antagonist (flutamide). We obtained evidence that the enhancement in NO synthesis was dependent on the influx of calcium from extracellular medium, because in the presence of a calcium channel blocker (verapamil) the effect of testosterone was reduced. Using endothelial cell (EC) cultures, we demonstrated that androgen directly acts at the endothelial level. Chelerythrine or PD98059 compound completely suppressed the increase in NO production, suggesting that the mechanism of action of the steroid involves protein kinase C and mitogen-activated protein kinase pathways. It is known that endothelial NO released into the vascular lumen serves as an inhibitor of platelet activation and aggregation. We showed that testosterone inhibited platelet aggregation and this effect was dependent on endothelial NO synthesis. Indeed, the enhancement of NO production elicited by androgen was associated with EC growth. The steroid significantly increased DNA synthesis after 24 h of treatment, and this mitogenic action was blunted in the presence of NO synthase inhibitor N-nitro-l-arginine methyl ester. In summary, testosterone modulates vascular EC growth and platelet aggregation through its direct action on endothelial NO production.

  1. Spinal Stenosis

    Science.gov (United States)

    ... Vasculitis Enfermedades y Condiciones I Am A Patient / Caregiver Diseases & Conditions Spinal Stenosis Spinal Stenosis Fast Facts Spinal ... weakness, since it greatly affects your ability to work and enjoy life. The natural course of the disease is one of slow progression over time. There ...

  2. Evolution of the postoperative sagittal spinal profile in early-onset scoliosis: is there a difference between rib-based and spine-based growth-friendly instrumentation?

    Science.gov (United States)

    Chen, Zhonghui; Li, Song; Qiu, Yong; Zhu, Zezhang; Chen, Xi; Xu, Liang; Sun, Xu

    2017-12-01

    OBJECTIVE Although the vertical expandable prosthetic titanium rib (VEPTR) and growing rod instrumentation (GRI) encourage spinal growth via regular lengthening, they can create different results because of their different fixation patterns and mechanisms in correcting scoliosis. Previous studies have focused comparisons on coronal plane deformity with minimal attention to the sagittal profile. In this retrospective study, the authors aimed to compare the evolution of the sagittal spinal profile in early-onset scoliosis (EOS) treated with VEPTR versus GRI. METHODS The data for 11 patients with VEPTR and 22 with GRI were reviewed. All patients had more than 2 years' follow-up with more than 2 lengthening procedures. Radiographic measurements were performed before and after the index surgery and at the latest follow-up. The complications in both groups were recorded. RESULTS Patients in both groups had similar diagnoses, age at the index surgery, and number of lengthening procedures. The changes in the major coronal Cobb angle and T1-S1 spinal height were not significantly different between the 2 groups. Compared with the GRI group, the VEPTR group had less correction in thoracic kyphosis (23% ± 12% vs 44% ± 16%, p < 0.001) after the index surgery and experienced a greater correction loss in thoracic kyphosis (46% ± 18% vs 11% ± 8%, p < 0.001) at the latest follow-up. Although the increase in the proximal junctional angle was not significantly different (VEPTR: 7° ± 4° vs GRI: 8° ± 5°, p = 0.569), the incidence of proximal junctional kyphosis was relatively lower in the VEPTR group (VEPTR: 18.2% vs GRI: 22.7%). No significant changes in the spinopelvic parameters were observed, while the sagittal vertical axis showed a tendency toward a neutral position in both groups. The overall complication rate was higher in the VEPTR group than in the GRI group (72.7% vs 54.5%). CONCLUSIONS The VEPTR had coronal correction and spinal growth results similar to those

  3. Metformin Reduces Prostate Tumor Growth, in a Diet-Dependent Manner, by Modulating Multiple Signaling Pathways.

    Science.gov (United States)

    Sarmento-Cabral, André; L-López, Fernando; Gahete, Manuel D; Castaño, Justo P; Luque, Raúl M

    2017-07-01

    Prostate-cancer is strongly influenced by obesity, wherein metformin could represent a promising treatment; however, the endocrine metabolic/cellular/molecular mechanisms underlying these associations and effects are still unclear. To determine the beneficial antitumoral effects of metformin on prostate cancer progression/aggressiveness and the relative contribution of high-fat diet (HFD; independently of obesity), we used HFD-fed immunosuppressed mice inoculated with PC3 cells (which exhibited partial resistance to diet-induced obesity) compared with low-fat diet (LFD)-fed control mice. Moreover, gene expression analysis was performed on cancer-associated genes in the xenografted tumors, and the antitumorigenic role of metformin on tumoral (PC3/22Rv1/LNCaP) and normal (RWPE1) prostate cells was evaluated. The results demonstrate that HFD is associated with enhanced prostate cancer growth irrespective of body weight gain and endocrine metabolic dysregulations and that metformin can reduce prostate cancer growth under LFD but more prominently under HFD, acting through the modulation of several tumoral-associated processes (e.g., cell cycle, apoptosis, and/or necrosis). Moreover, the actions observed in vivo could be mediated by the modulation of the local expression of GH/IGF1 axis components. Finally, it was demonstrated that metformin had disparate effects on proliferation, migration, and prostate-specific antigen secretion from different cell lines. Altogether, these data reveal that metformin inhibits prostate cancer growth under LFD and, specially, under HFD conditions through multiple metabolic/tumoral signaling pathways. Implications: The current study linking dietary influence on metformin-regulated signaling pathways and antitumoral response provides new and critical insight on environment-host interactions in cancer and therapy. Mol Cancer Res; 15(7); 862-74. ©2017 AACR . ©2017 American Association for Cancer Research.

  4. Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions.

    Directory of Open Access Journals (Sweden)

    Yuval Ramot

    Full Text Available BACKGROUND: Rapidly regenerating tissues need sufficient polyamine synthesis. Since the hair follicle (HF is a highly proliferative mini-organ, polyamines may also be important for normal hair growth. However, the role of polyamines in human HF biology and their effect on HF epithelial stem cells in situ remains largely unknown. METHODS AND FINDINGS: We have studied the effects of the prototypic polyamine, spermidine (0.1-1 µM, on human scalp HFs and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen. Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro. Inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboyxlase (ODC, downregulated intrafollicular K15 expression. In primary human epidermal keratinocytes, spermidine slightly promoted entry into the S/G2-M phases of the cell cycle. By microarray analysis of human HF mRNA extracts, spermidine upregulated several key target genes implicated e.g. in the control of cell adherence and migration (POP3, or endoplasmic reticulum and mitochondrial functions (SYVN1, NACA and SLC25A3. Excess spermidine may restrict further intrafollicular polyamine synthesis by inhibiting ODC gene and protein expression in the HF's companion layer in situ. CONCLUSIONS: These physiologically and clinically relevant data provide the first direct evidence that spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology.

  5. Cycle modulation of insulin-like growth factor-binding protein 1 in human endometrium

    Directory of Open Access Journals (Sweden)

    Corleta H.

    2000-01-01

    Full Text Available Endometrium is one of the fastest growing human tissues. Sex hormones, estrogen and progesterone, in interaction with several growth factors, control its growth and differentiation. Insulin-like growth factor 1 (IGF-1 interacts with cell surface receptors and also with specific soluble binding proteins. IGF-binding proteins (IGF-BP have been shown to modulate IGF-1 action. Of six known isoforms, IGF-BP-1 has been characterized as a marker produced by endometrial stromal cells in the late secretory phase and in the decidua. In the current study, IGF-1-BP concentration and affinity in the proliferative and secretory phase of the menstrual cycle were measured. Endometrial samples were from patients of reproductive age with regular menstrual cycles and taking no steroid hormones. Cytosolic fractions were prepared and binding of 125I-labeled IGF-1 performed. Cross-linking reaction products were analyzed by SDS-polyacrylamide gel electrophoresis (7.5% followed by autoradiography. 125I-IGF-1 affinity to cytosolic proteins was not statistically different between the proliferative and secretory endometrium. An approximately 35-kDa binding protein was identified when 125I-IGF-1 was cross-linked to cytosol proteins. Secretory endometrium had significantly more IGF-1-BP when compared to proliferative endometrium. The specificity of the cross-linking process was evaluated by the addition of 100 nM unlabeled IGF-1 or insulin. Unlabeled IGF-1 totally abolished the radioactivity from the band, indicating specific binding. Insulin had no apparent effect on the intensity of the labeled band. These results suggest that IGF-BP could modulate the action of IGF-1 throughout the menstrual cycle. It would be interesting to study this binding protein in other pathologic conditions of the endometrium such as adenocarcinomas and hyperplasia.

  6. Regulation of the Cdc42/Cdc24 GTPase module during Candida albicans hyphal growth.

    Science.gov (United States)

    Bassilana, Martine; Hopkins, Julie; Arkowitz, Robert A

    2005-03-01

    The Rho G protein Cdc42 and its exchange factor Cdc24 are required for hyphal growth of the human fungal pathogen Candida albicans. Previously, we reported that strains ectopically expressing Cdc24 or Cdc42 are unable to form hyphae in response to serum. Here we investigated the role of these two proteins in hyphal growth, using quantitative real-time PCR to measure induction of hypha-specific genes together with time lapse microscopy. Expression of the hypha-specific genes examined depends on the cyclic AMP-dependent protein kinase A pathway culminating in the Efg1 and Tec1 transcription factors. We show that strains with reduced levels of CDC24 or CDC42 transcripts induce hypha-specific genes yet cannot maintain their expression in response to serum. Furthermore, in serum these mutants form elongated buds compared to the wild type and mutant budding cells, as observed by time lapse microscopy. Using Cdc24 fused to green fluorescent protein, we also show that Cdc24 is recruited to and persists at the germ tube tip during hyphal growth. Altogether these data demonstrate that the Cdc24/Cdc42 GTPase module is required for maintenance of hyphal growth. In addition, overexpression studies indicate that specific levels of Cdc24 and Cdc42 are important for invasive hyphal growth. In response to serum, CDC24 transcript levels increase transiently in a Tec1-dependent fashion, as do the G-protein RHO3 and the Rho1 GTPase activating protein BEM2 transcript levels. These results suggest that a positive feedback loop between Cdc24 and Tec1 contributes to an increase in active Cdc42 at the tip of the germ tube which is important for hypha formation.

  7. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than...... the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR-ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1-Ig2 interaction....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...

  8. Obesity accelerates murine gastric cancer growth by modulating the Sirt1/YAP pathway.

    Science.gov (United States)

    Li, Hai-Jun; Fu, Jun-Ke; Che, Xiang-Ming; Fan, Lin; Zhang, Yong; Bai, E

    2017-10-01

    A previous study from our group using an in vivo model demonstrated that diet induced-obesity increases the risk of gastric cancer and may prompt its growth. However, the molecular mechanisms underlying this association remain unclear and require further investigation. The aim of the present study was to investigate the potential molecular mechanisms through which obesity affects gastric cancer growth. In a subcutaneous mouse model, tumors were significantly larger in obese mice compared with non-obese and lean mice. In addition, markedly increased levels of Sirt1 and YAP protein were observed in the nucleus of cells from subcutaneous tumors from obese mice compared with those from lean mice. Murine forestomach carcinoma (MFC) cells treated with 5% sera from obese mice exhibited significantly increased expression of Sirt1 and YAP compared with MFC cells treated with sera from lean mice. In addition, a positive correlation was observed between Sirt1 expression and YAP expression, and between Sirt1 expression and serum visfatin levels in mice. These results suggested that diet-induced obesity could promote murine gastric cancer growth by modulating the Sirt1/YAP signaling pathway.

  9. Glial fibrillary acidic protein (GFAP: modulation by growth factors and its implication in astrocyte differentiation

    Directory of Open Access Journals (Sweden)

    F.C.A. Gomes

    1999-05-01

    Full Text Available Intermediate filament (IF proteins constitute an extremely large multigene family of developmentally and tissue-regulated cytoskeleton proteins abundant in most vertebrate cell types. Astrocyte precursors of the CNS usually express vimentin as the major IF. Astrocyte maturation is followed by a switch between vimentin and glial fibrillary acidic protein (GFAP expression, with the latter being recognized as an astrocyte maturation marker. Levels of GFAP are regulated under developmental and pathological conditions. Upregulation of GFAP expression is one of the main characteristics of the astrocytic reaction commonly observed after CNS lesion. In this way, studies on GFAP regulation have been shown to be useful to understand not only brain physiology but also neurological disease. Modulators of GFAP expression include several hormones such as thyroid hormone, glucocorticoids and several growth factors such as FGF, CNTF and TGFß, among others. Studies of the GFAP gene have already identified several putative growth factor binding domains in its promoter region. Data obtained from transgenic and knockout mice have provided new insights into IF protein functions. This review highlights the most recent studies on the regulation of IF function by growth factors and hormones.

  10. Growth response modulation by putrescine in Indian mustard Brassica juncea L. under multiple stress.

    Science.gov (United States)

    Lakra, Nita; Tomar, Pushpa C; Mishra, S N

    2016-04-01

    Plants, in general, are put to various kinds of stress, biotic and abiotic, both natural and manmade. Infestation by insect pests and diseases, and extreme conditions such as salinity, temperature, etc., as well as heavy metal contamination affect their growth performance. Here, we studied the impact of salinity and heavy metal pollution on the growth performance of Indian Mustard Brassica juncea L. and its amelioration by the diamine, putrescine, a known media supplement. We evaluated the putrescine (Put) modulation potential on multiple stress effect in 7-day old Indian mustard. The germination, seedlings length and photosynthetic pigments decline under salinity and metal (Cd/Pb) stress condition, alone or in combination, were checked by putrescine. The stress induced increase in root-shoot ratio, RNA and total amino acids content, as well as Na⁺/K⁺ ratio in leaf tissues were also comparatively less. The increased endogenous Cd/Pb accumulation in plants exposed to either metal further elevated under salinity was also found decelerated. However, the multiple stressed seedlings showed increase in glutathione content, which was further elevated with putrescine application. The increase in protein contents in leaf under single or combined stresses in the presence of putrescine could be a qualitative change. The differential changes in parameters examined here resulted in improved growth (> 10%) suggests stress mitigation by the putrescine up to an extent.

  11. MODULATION OF GROWTH AND PROTON PUMPING ATPase ACTIVITY OF PROBIOTIC Lactobacilli BY DIETARY CUCURBITS

    Directory of Open Access Journals (Sweden)

    Irfan Ahmad

    2013-12-01

    Full Text Available Gastrointestinal tract predominantly harbor probiotic Lactobacilli which exert beneficial effects on human health. Aqueous extracts from fruits of Lagenaria siceraria (Ls, Luffa cylindrica (Lc and Cucurbita maxima (Cm were prepared and lyophilized. Fruit extracts were investigated for their effects on Lactobacillus rhamnosus (L. rhamnosus, Lactobacillus plantarum (L. plantarum and Lactobacillus acidophilus (L. acidophilus. Extracts were found to enhance growth of Lactobacilli without any toxic effect (up to 1000µg/mL concentration. Minimum concentration of extracts at which growth of probiotic strains were found to be enhanced significantly were determined (103.67 µg/mL-118µg/mL and considered as effective concentration (EC or growth stimulatory concentration (GSC. Proton pumping ATPase activity of Lactobacilli were examined and found to be enhanced significantly (29.89- 61.96% in extracts treated probiotics (Lactobacilli as compared to the normal control. Inulin used as positive control and found to enhance the proton efflux activity (28.06-37.72% with respect to the control. These dietary cucurbits enhance metabolic activity of probiotic Lactobacilli by modulating their proton pumping ATPase mechanism. This study suggested that the consumption of cucurbit fruits might be a natural source of enhancing the activities of probiotic Lactobacilli in the gut.

  12. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury

    NARCIS (Netherlands)

    Bartus, Katalin; James, Nicholas D; Didangelos, Athanasios; Bosch, Karen D; Verhaagen, J.; Yáñez-Muñoz, Rafael J; Rogers, John H; Schneider, Bernard L; Muir, Elizabeth M; Bradbury, Elizabeth J

    2014-01-01

    Chondroitin sulfate proteoglycans (CSPGs) inhibit repair following spinal cord injury. Here we use mammalian-compatible engineered chondroitinase ABC (ChABC) delivered via lentiviral vector (LV-ChABC) to explore the consequences of large-scale CSPG digestion for spinal cord repair. We demonstrate

  13. Neuroprotection by peptide growth factors against anoxia and nitric oxide toxicity requires modulation of protein kinase C.

    Science.gov (United States)

    Maiese, K; Boccone, L

    1995-05-01

    Basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) are neuroprotective during anoxia and nitric oxide (NO) toxicity. Signal transduction systems that modulate protein kinase C (PKC) also can modulate the toxic effects of anoxia and NO. We therefore examined whether PKC was involved in the protective effects of bFGF and EGF during anoxia and NO toxicity. Down-regulation or inhibition of PKC activity before anoxia or NO exposure prevented hippocampal neuronal degeneration. Yet, this protective effect of inhibition of PKC activity was not present with the coadministration of growth factors. Combined inhibition of PKC activity and application of bFGF or EGF lessened the protective mechanisms of the growth factors. In addition, the protective ability of the growth factors was lost during anoxia and NO exposure with the activation of PKC, suggesting that at least a minimal degree of PKC activation is necessary for growth factor protection. Although modulation of PKC activity may be a necessary prerequisite for protection against anoxia and NO toxicity by bFGF and EGF, only inhibition of PKC activity, rather than application of the growth factors, was protective following exposure to NO. These results suggest that the mechanism of protection by bFGF and EGF during anoxia and NO toxicity appears initially to be dependent on a minimum degree of PKC activation, but that other signal transduction pathways independent of PKC also may mediate protection by peptide growth factors.

  14. Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons.

    Science.gov (United States)

    Coste, Bertrand; Osorio, Nancy; Padilla, Françoise; Crest, Marcel; Delmas, Patrick

    2004-05-01

    The NaV1.9 subunit is expressed in nociceptive dorsal root ganglion (DRG) neurons and sensory myenteric neurons in which it generates 'persistent' tetrodotoxin-resistant (TTX-R) Na+ currents of yet unknown physiological functions. Here, we have analyzed these currents in details by combining single-channel and whole-cell recordings from cultured rat DRG and myenteric neurons. Comparison of single-channel with whole-cell data indicates that recording using internal CsCl best reflects the basic electrical features of NaV1.9 currents. Inclusion of fluoride in the pipette solution caused a negative shift in the activation and inactivation gates of NaV1.9 but not NaV1.8. Fluoride acts by promoting entry of NaV1.9 channels into a preopen closed state, which causes a strong bias towards opening and enhances the ability of sensory neurons to sustain spiking. Thus, the modulation of the resting-closed states of NaV1.9 channels strongly influences nociceptor excitability and may provide a mechanism by which inflammatory mediators alter pain threshold.

  15. Natural organic matter differently modulates growth of two closely related coccal green algal species.

    Science.gov (United States)

    Karasyova, Tatyana A; Klose, Edgar O; Menzel, Ralph; Steinberg, Christian E W

    2007-03-01

    Humic substances (HS) comprise the majority of dead and living organic carbon, including organisms. In the environment, they are considered to be chemically inert or at least refractory. Recent papers, however, show that HS (including natural organic matter-NOM, isolated by reverse osmosis) are natural chemicals which interact with aquatic organisms. They are taken up and cause a variety of stress defense reactions which are well known from man-made chemicals. These reactions include chaperon activation, induction and modulation of biotrans-formation enzymes, or induction of antioxidant defense enzymes. One specific reaction with freshwater plants is the reduction of photosynthetic oxygen release. In this contribution, we compare the susceptibilities (cell yield) of two closely related coccal green algae, Monoraphidium convolutum and M. minutum, towards various NOM isolates. Cultures of M. convolutum and M. minutum were obtained from the algal collection of the Leibniz Institute of Freshwater Ecology and Inland Fisheries, Berlin, and from the Culture Collection of Algae, Göttingen, and maintained in a common medium. The cultures were non-axenic. The algae were exposed to 5 mg L(-1) DOC of each humic material, an environmentally realistic concentration. Cell numbers were counted microscopically in Neugebauer cuvettes in 5 replicates on days 1, 4, 7, 10, 14, and 21. Almost all NOM isolates modulated the growth of the algae. Only the NOM of a Norwegian raised peat bog lake did not reveal any significant effect with M. convolutuim. In general, the results with two algal species are by no means uniform. For instance, Suwannee River NOM causes a decrease in cell density with M. minutum, but temporarily stimulates the growth of M. convolutum. The opposite applies to Aurevann NOM: Growth increase in M. minutum, but a bi-phasic response in M. convolutum. Different responses of both Monoraphidium species must be attributed to intrinsic factors of the algae rather than only

  16. Growth modulation and remodeling by means of posterior tethering technique for correction of early-onset scoliosis with thoracolumbar kyphosis.

    Science.gov (United States)

    Ahmad, Alaaeldin A; Aker, Loai; Hanbali, Yahia; Sbaih, Aesha; Nazzal, Zaher

    2017-06-01

    The aim of this study is to evaluate the role of the non-fusion instrumented procedure with compression adjunct to lengthening by distraction in facilitating spinal modulation of the wedged peak vertebra, in patients with congenital thoracolumbar kyphosis/kyphoscoliosis according to the Hueter-Volkmann law. The authors seek to address the progressive modulation of the most wedged vertebra by analyzing the subjects' pre-operative and latest follow-up sagittal radiograph. Ongoing data collection of 14 peak wedged vertebra modulation during surgical management of 13 patients with Type I congenital thoracolumbar kyphosis (5 patients) or kyphoscoliosis (8 patients). Age at initial surgery averaged 58.6 months, with mean follow-up of 55.6 months (24-78). All were done with hybrid rib construct with clawing fashion through a single posterior approach with at least 4 lengthenings. Two vertebral bodies were selected, the peaked deformed vertebrae within the instrumentation compression level (WICL) and the vertebrae nearest but outside the instrumentation compression process (OICL). Anterior vertebral body height (AVBH) and posterior vertebral body height (PVBH) were measured in both vertebral bodies. Regarding measured vertebrae (WICL), average preoperative AVBH/PVBH ratio significantly increased from 0.54 to 0.77 in the final follow-up. Regarding measured vertebrae (OICL), the average preoperative AVBH/PVBH ratio increased from 0.76 to 0.79 in the final follow-up. Modulation can be confirmed in the most deformed vertebrae (WICL) as the difference between the change in AVBH/PVBH ratio between vertebrae (OICL) and (WICL) was statistically significant (P modulation (WICL) in comparison with the (OICL). This calls for further studies on the impact of surgical correction of EOS on modulation of the vertebrae.

  17. Acute Putrescine Supplementation with Schwann Cell Implantation Improves Sensory and Serotonergic Axon Growth and Functional Recovery in Spinal Cord Injured Rats.

    Science.gov (United States)

    Iorgulescu, J Bryan; Patel, Samik P; Louro, Jack; Andrade, Christian M; Sanchez, Andre R; Pearse, Damien D

    2015-01-01

    Schwann cell (SC) transplantation exhibits significant potential for spinal cord injury (SCI) repair and its use as a therapeutic modality has now progressed to clinical trials for subacute and chronic human SCI. Although SC implants provide a receptive environment for axonal regrowth and support functional recovery in a number of experimental SCI models, axonal regeneration is largely limited to local systems and the behavioral improvements are modest without additional combinatory approaches. In the current study we investigated whether the concurrent delivery of the polyamine putrescine, started either 30 min or 1 week after SCI, could enhance the efficacy of SCs when implanted subacutely (1 week after injury) into the contused rat spinal cord. Polyamines are ubiquitous organic cations that play an important role in the regulation of the cell cycle, cell division, cytoskeletal organization, and cell differentiation. We show that the combination of putrescine with SCs provides a significant increase in implant size, an enhancement in axonal (sensory and serotonergic) sparing and/or growth, and improved open field locomotion after SCI, as compared to SC implantation alone. These findings demonstrate that polyamine supplementation can augment the effectiveness of SCs when used as a therapeutic approach for subacute SCI repair.

  18. Ferulic Acid Improves Functional Recovery after Acute Spinal Cord Injury in Rats by Inducing Hypoxia to Inhibit microRNA-590 and Elevate Vascular Endothelial Growth Factor Expressions.

    Science.gov (United States)

    Li, Zhenjie; Wang, Shengyun; Li, Wenfang; Yuan, Hongbin

    2017-01-01

    Spinal cord injury (SCI) is the leading cause of paralysis, disability and even death in severe cases, and neural stem cells (NSCs) transplant has been employed for repairing SCI. Ferulic acid (FA) is able to promote neurogenesis in various stem cell therapies. We aimed to investigate the effect of FA on NSC transplant therapy, and the underlying mechanism, in improving functional recovery in SCI rat model. A rat model of SCI was established, which then received transplant of NSCs with or without FA pre-treatment. Functional recovery of the SCI rats was then evaluated, in terms of spinal cord water content, myeloperoxidase activity and behavioral assessments. Effect of FA in inducing hypoxia in NSCs was also assessed, followed by identifying the hypoxic regulated microRNA and the subsequent target gene. Transplant of FA pre-treated NSCs improved functional recovery of SCI rats to a more significant extent than NSCs without FA pre-treatment. The beneficial effects of FA in repairing SCI was mediated by inducing hypoxia in NSCs, which in turn inhibited microRNA-590 to elevate vascular endothelial growth factor expression. Our findings support the clinical potential of FA in improving efficacy of NSC transplant therapy for treatment of SCI.

  19. The Arabidopsis SWI/SNF protein BAF60 mediates seedling growth control by modulating DNA accessibility

    KAUST Repository

    Jégu, Teddy

    2017-06-15

    Plant adaptive responses to changing environments involve complex molecular interplays between intrinsic and external signals. Whilst much is known on the signaling components mediating diurnal, light, and temperature controls on plant development, their influence on chromatin-based transcriptional controls remains poorly explored.In this study we show that a SWI/SNF chromatin remodeler subunit, BAF60, represses seedling growth by modulating DNA accessibility of hypocotyl cell size regulatory genes. BAF60 binds nucleosome-free regions of multiple G box-containing genes, opposing in cis the promoting effect of the photomorphogenic and thermomorphogenic regulator Phytochrome Interacting Factor 4 (PIF4) on hypocotyl elongation. Furthermore, BAF60 expression level is regulated in response to light and daily rhythms.These results unveil a short path between a chromatin remodeler and a signaling component to fine-tune plant morphogenesis in response to environmental conditions.

  20. A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth

    Science.gov (United States)

    Wang, Lei; Chang, Jianjun; Varghese, Diana; Dellinger, Michael; Kumar, Subodh; Best, Anne M.; Ruiz, Julio; Bruick, Richard; Peña-Llopis, Samuel; Xu, Junjie; Babinski, David J.; Frantz, Doug E.; Brekken, Rolf A.; Quinn, Amy M.; Simeonov, Anton; Easmon, Johnny; Martinez, Elisabeth D.

    2013-01-01

    The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signaling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) which specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumors in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumor burden and prolongs survival. Importantly, we find that patients with breast tumors that overexpress Jumonji demethylases have significantly lower survival. Thus JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance. PMID:23792809

  1. Metastases and Colon Cancer Tumor Growth Display Divergent Responses to Modulation of Canonical WNT Signaling.

    Directory of Open Access Journals (Sweden)

    Chandan Seth

    Full Text Available Human colon cancers commonly harbor loss of function mutations in APC, a repressor of the canonical WNT pathway, thus leading to hyperactive WNT-TCF signaling. Re-establishment of Apc function in mice, engineered to conditionally repress Apc through RNAi, resolve the intestinal tumors formed due to hyperactivated Wnt-Tcf signaling. These and other results have prompted the search for specific WNT pathway antagonists as therapeutics for clinically problematic human colon cancers and associated metastases, which remain largely incurable. This widely accepted view seems at odds with a number of findings using patient-derived material: Canonical TCF targets are repressed, instead of being hyperactivated, in advanced colon cancers, and repression of TCF function does not generally result in tumor regression in xenografts. The results of a number of genetic mouse studies have also suggested that canonical WNT-TCF signaling drives metastases, but direct in vivo tests are lacking, and, surprisingly, TCF repression can enhance directly seeded metastatic growth. Here we have addressed the abilities of enhanced and blocked WNT-TCF signaling to alter tumor growth and distant metastases using xenografts of advanced human colon cancers in mice. We find that endogenous WNT-TCF signaling is mostly anti-metastatic since downregulation of TCF function with dnTCF generally enhances metastatic spread. Consistently, elevating the level of WNT signaling, by increasing the levels of WNT ligands, is not generally pro-metastatic. Our present and previous data reveal a heterogeneous response to modulating WNT-TCF signaling in human cancer cells. Nevertheless, the findings that a fraction of colon cancers tested require WNT-TCF signaling for tumor growth but all respond to repressed signaling by increasing metastases beg for a reevaluation of the goal of blocking WNT-TCF signaling to universally treat colon cancers. Our data suggest that WNT-TCF blockade may be effective

  2. Gelatin Nanostructured Lipid Carriers Incorporating Nerve Growth Factor Inhibit Endoplasmic Reticulum Stress-Induced Apoptosis and Improve Recovery in Spinal Cord Injury.

    Science.gov (United States)

    Zhu, Si-Pin; Wang, Zhou-Guang; Zhao, Ying-Zheng; Wu, Jiang; Shi, Hong-Xue; Ye, Li-Bing; Wu, Fen-Zan; Cheng, Yi; Zhang, Hong-Yu; He, Songbin; Wei, Xiaojie; Fu, Xiao-Bing; Li, Xiao-Kun; Xu, Hua-Zi; Xiao, Jian

    2016-09-01

    Clinical translation of growth factor therapies faces multiple challenges; the most significant one is the short half-life of the naked protein. Gelatin nanostructured lipid carriers (GNLs) had previously been used to encapsulate the basic fibroblast growth factor to enhance the functional recovery in hemiparkinsonian rats. In this research, we comparatively study the enhanced therapy between nerve growth factor (NGF) loaded GNLs (NGF-GNLs) and NGF only in spinal cord injury (SCI). The effects of NGF-GNLs and NGF only were tested by the Basso-Beattie-Bresnahan (BBB) locomotion scale, inclined plane test, and footprint analysis. Western blot analysis and immunofluorescent staining were further performed to identify the expression of ER stress-related proteins, neuron-specific marker neuronal nuclei (NeuN), and growth-associated protein 43 (GAP43). Correlated downstream signals Akt/GSK-3β and ERK1/2 were also analyzed with or without inhibitors. Results showed that NGF-GNLs, compared to NGF only, enhanced the neuroprotection effect in SCI rats. The ER stress-induced apoptosis response proteins CHOP, GRP78 and caspase-12 inhibited by NGF-GNL treatment were more obvious. Meanwhile, NGF-GNLs in the recovery of SCI are related to the inhibition of ER stress-induced cell death via the activation of downstream signals PI3K/Akt/GSK-3β and ERK1/2.

  3. The oncoprotein HBXIP suppresses gluconeogenesis through modulating PCK1 to enhance the growth of hepatoma cells.

    Science.gov (United States)

    Shi, Hui; Fang, Runping; Li, Yinghui; Li, Leilei; Zhang, Weiying; Wang, Huawei; Chen, Fuquan; Zhang, Shuqin; Zhang, Xiaodong; Ye, Lihong

    2016-11-28

    Hepatitis B X-interacting protein (HBXIP) as an oncoprotein plays crucial roles in the development of cancer, involving glucose metabolism reprogramming. In this study, we are interested in whether the oncoprotein HBXIP is involved in the modulation of gluconeogenesis in liver cancer. Here, we showed that the expression level of phosphoenolpyruvate carboxykinase (PCK1), a key enzyme of gluconeogenesis, was lower in clinical hepatocellular carcinoma (HCC) tissues than that in normal tissues. Mechanistically, HBXIP inhibited the expression of PCK1 through down-regulating transcription factor FOXO1 in hepatoma cells, and up-regulated miR-135a targeting the 3'UTR of FOXO1 mRNA in the cells. In addition, HBXIP increased the phosphorylation levels of FOXO1 protein by activating PI3K/Akt pathway, leading to the export of FOXO1 from nucleus to cytoplasm. Strikingly, over-expression of PCK1 could abolish the HBXIP-promoted growth of hepatoma cells in vitro and in vivo. Thus, we conclude that the oncoprotein HBXIP is able to depress the gluconeogenesis through suppressing PCK1 to promote hepatocarcinogenesis, involving miR-135a/FOXO1 axis and PI3K/Akt/p-FOXO1 pathway. Our finding provides new insights into the mechanism by which oncoprotein HBXIP modulates glucose metabolism reprogramming in HCC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Growth of electronically distinct manganite thin films by modulating cation stoichiometry

    Science.gov (United States)

    Ryu, Sangkyun; Lee, Joonhyuk; Ahn, Eunyoung; Kim, Ji woong; Herklotz, Andreas; Bae, Jong-Seong; Lee, Ho Nyung; Kim, Young hak; Kim, Jae-Young; Jeon, Tae-Yeol; Cho, Jinhyung; Park, Sungkyun; Jeen, Hyoungjeen

    2017-06-01

    Nd1-xSrxMnO3 is a well-known manganite due to close connection among structure, transport, magnetism, and chemistry. Thus, it would be an ideal system to study the modification of physical properties by external stimuli including control of stoichiometry in growth. In this work, we show that an abrupt change of electronic and magnetic properties can be achieved by a subtle change of oxygen partial pressure in pulsed laser deposition. Interestingly, the pressure indeed modulates cation stoichiometry. We clearly observed that the films grown at 140 mTorr and higher showed clear insulator to metal transition and stronger magnetism, commonly found in less hole doping, while the films grown at 130 mTorr and lower showed insulating behavior and weak magnetism. From soft x-ray spectroscopic methods, we clearly observed the compositional difference in those thin films. This result is further supported by scattering of lighter elements in high oxygen partial pressure but not by anion deficiency in growth.

  5. Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.

    Directory of Open Access Journals (Sweden)

    Jingshan Zhao

    Full Text Available The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL, a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF signaling and angiogenesis in endothelial cells (ECs. We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.

  6. Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.

    Science.gov (United States)

    Zhao, Jingshan; Niu, Honglin; Li, Aiying; Nie, Lei

    2016-01-01

    The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL), a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF) signaling and angiogenesis in endothelial cells (ECs). We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day) recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.

  7. Nucleolin inhibitor GroA triggers reduction in epidermal growth factor receptor activation: Pharmacological implication for glial scarring after spinal cord injury.

    Science.gov (United States)

    Goldshmit, Yona; Schokoroy Trangle, Sari; Afergan, Fabian; Iram, Tal; Pinkas-Kramarski, Ronit

    2016-09-01

    Glial scarring, formed by reactive astrocytes, is one of the major impediments for regeneration after spinal cord injury (SCI). Reactive astrocytes become hypertrophic, proliferate and secrete chondroitin sulphate proteoglycans into the extracellular matrix (ECM). Many studies have demonstrated that epidermal growth factor receptors (EGFR) can mediate astrocyte reactivity after neurotrauma. Previously we showed that there is crosstalk between nucleolin and EGFR that leads to increased EGFR activation followed by increased cell proliferation. Treatment with the nucleolin inhibitor GroA (AS1411) prevented these effects in vitro and in vivo. In this study, we hypothesized that similar interactions may mediate astrogliosis after SCI. Our results demonstrate that nucleolin and EGFR interaction may play a pivotal role in mediating astrocyte proliferation and reactivity after SCI. Moreover, we demonstrate that treatment with GroA reduces EGFR activation, astrocyte proliferation and chondroitin sulphate proteoglycans secretion, therefore promoting axonal regeneration and sprouting into the lesion site. Our results identify, for the first time, a role for the interaction between nucleolin and EGFR in astrocytes after SCI, indicating that nucleolin inhibitor GroA may be used as a novel treatment after neurotrauma. A major barrier for axonal regeneration after spinal cord injury is glial scar created by reactive and proliferating astrocytes. EGFR mediate astrocyte reactivity. We showed that inhibition of nucleolin by GroA, reduces EGFR activation, which results in attenuation of astrocyte reactivity and proliferation in vivo and in vitro. EGFR, epidermal growth factor receptor. © 2016 International Society for Neurochemistry.

  8. Sustained delivery of activated Rho GTPases and BDNF promotes axon growth in CSPG-rich regions following spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Anjana Jain

    2011-01-01

    Full Text Available Spinal cord injury (SCI often results in permanent functional loss. This physical trauma leads to secondary events, such as the deposition of inhibitory chondroitin sulfate proteoglycan (CSPG within astroglial scar tissue at the lesion.We examined whether local delivery of constitutively active (CA Rho GTPases, Cdc42 and Rac1 to the lesion site alleviated CSPG-mediated inhibition of regenerating axons. A dorsal over-hemisection lesion was created in the rat spinal cord and the resulting cavity was conformally filled with an in situ gelling hydrogel combined with lipid microtubes that slowly released constitutively active (CA Cdc42, Rac1, or Brain-derived neurotrophic factor (BDNF. Treatment with BDNF, CA-Cdc42, or CA-Rac1 reduced the number of GFAP-positive astrocytes, as well as CSPG deposition, at the interface of the implanted hydrogel and host tissue. Neurofilament 160kDa positively stained axons traversed the glial scar extensively, entering the hydrogel-filled cavity in the treatments with BDNF and CA-Rho GTPases. The treated animals had a higher percentage of axons from the corticospinal tract that traversed the CSPG-rich regions located proximal to the lesion site.Local delivery of CA-Cdc42, CA-Rac1, and BDNF may have a significant therapeutic role in overcoming CSPG-mediated regenerative failure after SCI.

  9. In Vitro Morphogenesis of Arabidopsis to Search for Novel Endophytic Fungi Modulating Plant Growth.

    Directory of Open Access Journals (Sweden)

    Francesco Dovana

    Full Text Available Fungal endophytes have shown to affect plant growth and to confer stress tolerance to the host; however, effects of endophytes isolated from water plants have been poorly investigated. In this study, fungi isolated from stems (stem-E and roots (root-E of Mentha aquatica L. (water mint were identified, and their morphogenetic properties analysed on in vitro cultured Arabidopsis (L. Heynh., 14 and 21 days after inoculation (DAI. Nineteen fungi were analysed and, based on ITS analysis, 17 isolates showed to be genetically distinct. The overall effect of water mint endophytes on Arabidopsis fresh (FW and dry weight (DW was neutral and positive, respectively, and the increased DW, mainly occurring 14 DAI, was possibly related to plant defence mechanism. Only three fungi increased both FW and DW of Arabidopsis at 14 and 21 DAI, thus behaving as plant growth promoting (PGP fungi. E-treatment caused a reduction of root depth and primary root length in most cases and inhibition-to-promotion of root area and lateral root length, from 14 DAI. Only Phoma macrostoma, among the water mint PGP fungi, increased both root area and depth, 21 DAI. Root depth and area 14 DAI were shown to influence DWs, indicating that the extension of the root system, and thus nutrient uptake, was an important determinant of plant dry biomass. Reduction of Arabidopsis root depth occurred to a great extent when plants where treated with stem-E while root area decreased or increased under the effects of stem-E and root-E, respectively, pointing to an influence of the endophyte origin on root extension. M. aquatica and many other perennial hydrophytes have growing worldwide application in water pollution remediation. The present study provided a model for directed screening of endophytes able to modulate plant growth in the perspective of future field applications of these fungi.

  10. Histomorphological study of the spinal growth plates from the convex side and the concave side in adolescent idiopathic scoliosis

    Directory of Open Access Journals (Sweden)

    Ma Zhaolong

    2007-11-01

    Full Text Available Abstract Asymmetrical growth of the vertebrae has been implicated as one possible etiologic factor in the pathogenesis of adolescent idiopathic scoliosis. The longitudinal vertebral growth derives from the endochondral ossification of the vertebral growth plate. In the present study, the growth plates from the convex and concave side of the vertebrae were characterized by the method of histology and immunohistochemistry to evaluate the growth activity, cell proliferation, and apoptosis. Normal zoned architectures were observed in the convex side of the growth plate and disorganized architectures in the concave side. The histological grades were significantly different between the convex and the concave side of the growth plate in the apex vertebrae (P

  11. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle

    NARCIS (Netherlands)

    Pera, Tonio; Sami, Riham; Zaagsma, Johan; Meurs, Herman

    2011-01-01

    Pera T, Sami R, Zaagsma J, Meurs H. TAK1 plays a major role in growth factor-induced phenotypic modulation of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 301: L822-L828, 2011. First published August 26, 2011; doi:10.1152/ajplung.00017.2011.-Increased airway smooth muscle (ASM) mass is a

  12. Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia

    NARCIS (Netherlands)

    Kroening, Sven; Neubauer, Emily; Wullich, Bernd; Aten, Jan; Goppelt-Struebe, Margarete

    2010-01-01

    Kroening S, Neubauer E, Wullich B, Aten J, Goppelt-Struebe M. Characterization of connective tissue growth factor expression in primary cultures of human tubular epithelial cells: modulation by hypoxia. Am J Physiol Renal Physiol 298:F796-F806, 2010. First published December 23, 2009;

  13. Role of the placental Vitamin D receptor in modulating feto-placental growth in Fetal growth restriction and Preeclampsia-affected pregnancies.

    Directory of Open Access Journals (Sweden)

    Padma eMurthi

    2016-02-01

    Full Text Available Fetal growth restriction (FGR is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signalling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation.

  14. Effects of drought on leaf carbon source and growth of European beech are modulated by soil type

    Science.gov (United States)

    Liu, Jian-Feng; Arend, Matthias; Yang, Wen-Juan; Schaub, Marcus; Ni, Yan-Yan; Gessler, Arthur; Jiang, Ze-Ping; Rigling, Andreas; Li, Mai-He

    2017-02-01

    Drought potentially affects carbon balance and growth of trees, but little is known to what extent soil plays a role in the trade-off between carbon gain and growth investment. In the present study, we analyzed leaf non-structural carbohydrates (NSC) as an indicator of the balance of photosynthetic carbon gain and carbon use, as well as growth of European beech (Fagus sylvatica L.) saplings, which were grown on two different soil types (calcareous and acidic) in model ecosystems and subjected to a severe summer drought. Our results showed that drought led in general to increased total NSC concentrations and to decreased growth rate, and drought reduced shoot and stem growth of plants in acidic soil rather than in calcareous soil. This result indicated that soil type modulated the carbon trade-off between net leaf carbon gain and carbon investment to growth. In drought-stressed trees, leaf starch concentration and growth correlated negatively whereas soluble sugar:starch ratio and growth correlated positively, which may contribute to a better understanding of growth regulation under drought conditions. Our results emphasize the role of soil in determining the trade-off between the balance of carbon gain and carbon use on the leaf level and growth under stress (e.g. drought).

  15. Effects of liposome-based local suppression of nerve growth factor in the bladder on autonomic dysreflexia during urinary bladder distention in rats with spinal cord injury.

    Science.gov (United States)

    Kadekawa, Katsumi; Yoshizawa, Tsuyoshi; Wada, Naoki; Shimizu, Takahiro; Majima, Tsuyoshi; Tyagi, Pradeep; de Groat, William C; Sugaya, Kimio; Yoshimura, Naoki

    2017-05-01

    To examine (1) whether spinal cord injury (SCI) time-dependently increases the severity of autonomic dysreflexia (AD) and expression levels of bladder nerve growth factor (NGF) protein, and (2) whether local suppression of NGF in the bladder improves SCI-induced AD in rats. SCI was produced by the transection of the T2/3 spinal cord in female Sprague-Dawley rats. At 4 or 8weeks after SCI, differences in the mean arterial blood pressure (ΔMAP) and heart rate (ΔMHR) during graded increases in intravesical pressure to 20, 40 and 60cm H2O from those before bladder distention and NGF protein levels in the bladder wall were evaluated in spinal intact and SCI rats under urethane anesthesia. Seven weeks after SCI liposome-NGF antisense conjugates were administered intravesically to the animals. At 1week after intravesical treatment (8weeks after SCI), ΔMAP and ΔMHR during bladder distention and bladder NGF protein expression were evaluated. The ΔMAP and ΔMHR were increased in a graded manner in response to bladder distention at intravesical pressures of 20, 40 and 60cm H2O in SCI rats. These AD-like cardiovascular responses and NGF protein expression in the bladder mucosal and muscle layers were increased after SCI in a time-dependent manner. The liposome-NGF antisense treatment significantly reduced the NGF protein overexpression in the mucosal layer of SCI rat bladder and reduced ΔMAP and ΔMHR elicited by bladder distention. These results indicate that the duration of the post-SCI recovery period affects the severity of AD induced by bladder distention as well as the level of bladder NGF protein, and that local suppression of NGF expression in the bladder reduces SCI-induced AD. Thus, Intravesical application of liposome-NGF antisense conjugates can be a new effective therapy for bladder distention-induced AD after SCI. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Plasmodium P-Type Cyclin CYC3 Modulates Endomitotic Growth during Oocyst Development in Mosquitoes

    KAUST Repository

    Roques, Magali

    2015-11-13

    Cell-cycle progression and cell division in eukaryotes are governed in part by the cyclin family and their regulation of cyclin-dependent kinases (CDKs). Cyclins are very well characterised in model systems such as yeast and human cells, but surprisingly little is known about their number and role in Plasmodium, the unicellular protozoan parasite that causes malaria. Malaria parasite cell division and proliferation differs from that of many eukaryotes. During its life cycle it undergoes two types of mitosis: endomitosis in asexual stages and an extremely rapid mitotic process during male gametogenesis. Both schizogony (producing merozoites) in host liver and red blood cells, and sporogony (producing sporozoites) in the mosquito vector, are endomitotic with repeated nuclear replication, without chromosome condensation, before cell division. The role of specific cyclins during Plasmodium cell proliferation was unknown. We show here that the Plasmodium genome contains only three cyclin genes, representing an unusual repertoire of cyclin classes. Expression and reverse genetic analyses of the single Plant (P)-type cyclin, CYC3, in the rodent malaria parasite, Plasmodium berghei, revealed a cytoplasmic and nuclear location of the GFP-tagged protein throughout the lifecycle. Deletion of cyc3 resulted in defects in size, number and growth of oocysts, with abnormalities in budding and sporozoite formation. Furthermore, global transcript analysis of the cyc3-deleted and wild type parasites at gametocyte and ookinete stages identified differentially expressed genes required for signalling, invasion and oocyst development. Collectively these data suggest that cyc3 modulates oocyst endomitotic development in Plasmodium berghei.

  17. Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration

    Science.gov (United States)

    Brissova, Marcela; Aamodt, Kristie; Brahmachary, Priyanka; Prasad, Nripesh; Hong, Ji-Young; Dai, Chunhua; Mellati, Mahnaz; Shostak, Alena; Poffenberger, Greg; Aramandla, Radhika; Levy, Shawn E.; Powers, Alvin C.

    2014-01-01

    SUMMARY Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion. PMID:24561261

  18. BET protein inhibitor JQ1 inhibits growth and modulates WNT signaling in mesenchymal stem cells.

    Science.gov (United States)

    Alghamdi, Saeed; Khan, Irfan; Beeravolu, Naimisha; McKee, Christina; Thibodeau, Bryan; Wilson, George; Chaudhry, G Rasul

    2016-02-01

    Efficacy and safety of anticancer drugs are traditionally studied using cancer cell lines and animal models. The thienodiazepine class of BET inhibitors, such as JQ1, has been extensively studied for the potential treatment of hematological malignancies and several small molecules belonging to this class are currently under clinical investigation. While these compounds are well known to inhibit cancer cell growth and cause apoptosis, their effects on stem cells, particularly mesenchymal stem cells (MSCs), which are important for regeneration of damaged cells and tissues, are unknown. In this study we employed umbilical cord derived MSCs as a model system to evaluate the safety of JQ1. Cord derived MSCs were treated with various doses of JQ1 and subjected to cell metabolic activity, apoptosis, and cell cycle analyses using MTT assay, Annexin-V/FITC and PI staining, and flow cytometry, respectively. The effect of JQ1 on gene expression was determined using microarray and quantitative real-time reverse transcriptase polymerase chain reaction analysis. Furthermore, protein expression of apoptotic and neuronal markers was carried out using western blot and immunostaining, respectively. Our results showed that JQ1 inhibited cell growth and caused cell cycle arrest in G1 phase but did not induce apoptosis or senescence. JQ1 also down-regulated genes involved in self-renewal, cell cycle, DNA replication, and mitosis, which may have negative implications on the regenerative potential of MSCs. In addition, JQ1 interfered with signaling pathways by down regulating the expression of WNT, resulting in limiting the self-renewal. These results suggest that anticancer agents belonging to the thienodiazepine class of BET inhibitors should be carefully evaluated before their use in cancer therapy. This study revealed for the first time that JQ1 adversely affected MSCs, which are important for repair and regeneration. JQ1 specifically modulated signal transduction and inhibited

  19. Noninvasive Spinal Cord Stimulation: Technical Aspects and Therapeutic Applications.

    Science.gov (United States)

    Nardone, Raffaele; Höller, Yvonne; Taylor, Alexandra; Thomschewski, Aljoscha; Orioli, Andrea; Frey, Vanessa; Trinka, Eugen; Brigo, Francesco

    2015-10-01

    Electrical and magnetic trans-spinal stimulation can be used to increase the motor output of multiple spinal segments and modulate cortico-spinal excitability. The application of direct current through the scalp as well as repetitive transcranial magnetic stimulation are known to influence brain excitability, and hence can also modulate other central nervous system structures, including spinal cord. This study aimed to evaluate the effects and the therapeutic usefulness of these noninvasive neuromodulatory techniques in healthy subjects and in the neurorehabilitation of patients with spinal cord disorders, as well as to discuss the possible mechanisms of action. A comprehensive review that summarizes previous studies using noninvasive spinal cord stimulation is lacking. PubMed (MEDLINE) and EMBASE were systematically searched to identify the most relevant published studies. We performed here an extensive review in this field. By decreasing the spinal reflex excitability, electrical and magnetic trans-spinal stimulation could be helpful in normalizing reflex hyperexcitability and treating hypertonia in subjects with lesions to upper motor neurons. Transcutaneous spinal direct current stimulation, based on applying direct current through the skin, influences the ascending and descending spinal pathways as well as spinal reflex excitability, and there is increasing evidence that it also can induce prolonged functional neuroplastic changes. When delivered repetitively, magnetic stimulation could also modulate spinal cord functions; however, at present only a few studies have documented spastic-reducing effects induced by repetitive spinal magnetic stimulation. Moreover, paired peripheral and transcranial stimulation can be used to target the spinal cord and may have potential for neuromodulation in spinal cord-injured subjects. Noninvasive electrical and magnetic spinal stimulation may provide reliable means to characterize important neurophysiologic and

  20. 6-Gingerol inhibits hair shaft growth in cultured human hair follicles and modulates hair growth in mice.

    Science.gov (United States)

    Miao, Yong; Sun, Yabin; Wang, Wenjun; Du, Benjun; Xiao, Shun-e; Hu, Yijue; Hu, Zhiqi

    2013-01-01

    Ginger (Zingiber officinale) has been traditionally used to check hair loss and stimulate hair growth in East Asia. Several companies produce shampoo containing an extract of ginger claimed to have anti-hair loss and hair growth promotion properties. However, there is no scientific evidence to back up these claims. This study was undertaken to measure 6-gingerol, the main active component of ginger, on hair shaft elongation in vitro and hair growth in vivo, and to investigate its effect on human dermal papilla cells (DPCs) in vivo and in vitro. 6-Gingerol suppressed hair growth in hair follicles in culture and the proliferation of cultured DPCs. The growth inhibition of DPCs by 6-gingerol in vitro may reflect a decrease in the Bcl-2/Bax ratio. Similar results were obtained in vivo. The results of this study showed that 6-gingerol does not have the ability to promote hair growth, on the contrary, can suppress human hair growth via its inhibitory and pro-apoptotic effects on DPCs in vitro, and can cause prolongation of telogen phase in vivo. Thus, 6-gingerol rather than being a hair growth stimulating drug, it is a potential hair growth suppressive drug; i.e. for hair removal.

  1. 6-Gingerol inhibits hair shaft growth in cultured human hair follicles and modulates hair growth in mice.

    Directory of Open Access Journals (Sweden)

    Yong Miao

    Full Text Available Ginger (Zingiber officinale has been traditionally used to check hair loss and stimulate hair growth in East Asia. Several companies produce shampoo containing an extract of ginger claimed to have anti-hair loss and hair growth promotion properties. However, there is no scientific evidence to back up these claims. This study was undertaken to measure 6-gingerol, the main active component of ginger, on hair shaft elongation in vitro and hair growth in vivo, and to investigate its effect on human dermal papilla cells (DPCs in vivo and in vitro. 6-Gingerol suppressed hair growth in hair follicles in culture and the proliferation of cultured DPCs. The growth inhibition of DPCs by 6-gingerol in vitro may reflect a decrease in the Bcl-2/Bax ratio. Similar results were obtained in vivo. The results of this study showed that 6-gingerol does not have the ability to promote hair growth, on the contrary, can suppress human hair growth via its inhibitory and pro-apoptotic effects on DPCs in vitro, and can cause prolongation of telogen phase in vivo. Thus, 6-gingerol rather than being a hair growth stimulating drug, it is a potential hair growth suppressive drug; i.e. for hair removal.

  2. Rebound Deformity After Growth Modulation in Patients With Coronal Plane Angular Deformities About the Knee: Who Gets It and How Much?

    Science.gov (United States)

    Leveille, Lise A; Razi, Ozan; Johnston, Charles E

    2017-05-18

    With observed success and increased popularity of growth modulation techniques, there has been a trend toward use in progressively younger patients. Younger age at growth modulation increases the likelihood of complete deformity correction and need for implant removal before skeletal maturity introducing the risk of rebound deformity. The purpose of this study was to quantify magnitude and identify risk factors for rebound deformity after growth modulation. We performed a retrospective review of all patients undergoing growth modulation with a tension band plate for coronal plane deformity about the knee with subsequent implant removal. Exclusion criteria included completion epiphysiodesis or osteotomy at implant removal, ongoing growth modulation, and modulation, before implant removal, and at final follow-up. In total, 67 limbs in 45 patients met the inclusion criteria. Mean age at growth modulation was 9.8 years (range, 3.4 to 15.4 y) and mean age at implant removal was 11.4 years (range, 5.3 to 16.4 y). Mean change in HKA after implant removal was 6.9 degrees (range, 0 to 23 degrees). In total, 52% of patients had >5 degrees rebound and 30% had >10 degrees rebound in HKA after implant removal. Females below 10 years and males below 12 years at time of growth modulation had greater mean change in HKA after implant removal compared with older patients (8.4 vs. 4.7 degrees, P=0.012). Patients with initial deformity >20 degrees had an increased frequency of rebound >10 degrees compared with patients with less severe initial deformity (78% vs. 22%, P=0.002). Rebound deformity after growth modulation is common. Growth modulation at a young age and large initial deformity increases risk of rebound. However, rebound does not occur in all at risk patients, therefore, we recommend against routine overcorrection. Level IV-retrospective study.

  3. Spinal Fusion

    Science.gov (United States)

    ... concept of fusion is similar to that of welding in industry. Spinal fusion surgery, however, does not ... are taking for other conditions, and your overall health can affect the rate of healing and fusion, ...

  4. Sustained Partial Sleep Deprivation: Effects on Immune Modulation and Growth Factors

    Science.gov (United States)

    Mullington, Janet M.

    1999-01-01

    from this larger study: a 4.2 hour per night condition, and a 8.2 hour per night condition. During space flight, muscle mass and bone density are reduced, apparently due to loss of GH and IGF-I, associated with microgravity. Since >70% of growth hormone (GH) is secreted at night in normal adults, we hypothesized that the chronic sleep restriction to 4 hours per night would reduce GH levels as measured in the periphery. In this synergy project, in collaboration with the "Muscle Alterations and Atrophy Team ", we are measuring insulin-like growth factor-I (IGF-I) in peripheral circulation to test the prediction that it will be reduced by chronic sleep restriction. In addition to stress modulation of immune function, recent research suggests that sleep is also involved. While we all have the common experience of being sleepy when suffering from infection, and being susceptible to infection when not getting enough sleep, the mechanisms involved in this process are not understood and until recently have gone largely overlooked. We believe that the immune function changes seen in spaceflight may also be related to the cumulative effects of sleep loss. Moreover, in space flight, the possibility of compromised immune function or of the reactivation of latent viruses are serious potential hazards for the success of long term missions. Confined living conditions, reduced sleep, altered diet and stress are all factors that may compromise immune function, thereby increasing the risks of developing and transmitting disease. Medical complications, which would not pose serious problems on earth, may be disastrous if they emerged in space.

  5. Spinal vascular malformations; Spinale Gefaessmalformationen

    Energy Technology Data Exchange (ETDEWEB)

    Yilmaz, U. [Universitaetsklinikum des Saarlandes, Klinik fuer Diagnostische und Interventionelle Neuroradiologie, Homburg/Saar (Germany)

    2012-05-15

    Spinal vascular malformations are a group of rare diseases with different clinical presentations ranging from incidental asymptomatic findings to progressive tetraplegia. This article provides an overview about imaging features as well as clinical and therapeutic aspects of spinal arteriovenous malformations, cavernomas and capillary telangiectasia. (orig.) [German] Spinale Gefaessmalformationen sind eine Gruppe seltener Erkrankungen mit unterschiedlichen klinischen Praesentationen, die vom asymptomatischen Zufallsbefund bis zur progredienten Tetraparese reichen. Dieser Artikel gibt einen Ueberblick ueber radiologische Befunde sowie klinische und therapeutische Aspekte von spinalen arteriovenoesen Malformationen, Kavernomen und kapillaeren Teleangiektasien. (orig.)

  6. Hepatocyte growth factor modulates in vitro survival and proliferation of germ cells during postnatal testis development.

    Science.gov (United States)

    Catizone, A; Ricci, G; Del Bravo, J; Galdieri, M

    2006-04-01

    The hepatocyte growth factor (HGF) is a pleiotropic cytokine that influences mitogenesis, motility and differentiation of many different cell types by its tyrosine kinase receptor c-Met. We previously demonstrated that the c-Met/HGF system is present and functionally active during postnatal testis development. We found also that spermatozoa express c-Met and that HGF has a positive effect on the maintenance of sperm motility. In the present paper, we extend our study on the germ cells at different stages of differentiation during the postnatal development of the testis. We demonstrate that c-met is present in rat spermatogonia, pachytene spermatocytes and round spermatids and that HGF significantly increases spermatogonial proliferation in 8- to 10-day-old pre-pubertal rats. At this age HGF does not affect Sertoli cells and peritubular myoid cells proliferation. In addition, we studied the effect of the factor on germ cell apoptosis and we show that HGF prevents the germ cell apoptotic process. We also studied the effect of HGF on 18- to 20-day-old and 28- to 30-day-old rat testes. At these ages also the factor significantly increases germ cell duplication and decreases the number of apoptotic cells. However, the effect on programmed cell death is higher in the 8- to 10-day-old rats and declines in the older animals. In conclusion, we report that rat germ cells (spermatogonia, pachytene spermatocytes and round spermatids) express c-met and that HGF modulates germ cell proliferating activity and apoptosis in vitro. These data indicate that the c-Met/HGF system is involved in male germ cell homeostasis and, consequently, has a role in male fertility.

  7. Modulation Analysis of Whistler Mode Sidebands in VLF-Triggered Emissions and Implications for Conditions of Nonlinear Growth

    Science.gov (United States)

    Costabile, Jamie D.; Gołkowski, Mark; Wall, Randall E.

    2017-12-01

    Experimental observations of very low frequency (VLF) triggered emissions are an important resource in investigation of nonlinear wave-particle interactions between whistler mode waves and energetic electrons in the Earth's radiation belts. Magnetospherically generated whistler mode sidebands observed during the Siple Station wave injection experiment are analyzed using a mixed modulation model and the MINUIT minimization package. The observed sidebands are found to exhibit features of both amplitude and frequency modulation of the input carrier wave with frequency modulation becoming more prominent as the observed amplitudes of the carrier and sidebands increase. A nonlinear whistler mode wave growth formulation based on phase bunching of counterstreaming electrons within a well-defined phase trap is shown to reproduce the salient features of the sideband observations. Whistler mode sideband amplitude is shown to be affected by the shape and uniformity of the trap.

  8. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Life After Pediatric Spinal Injury Dawn Sheaffer, MSW Rehabilitation Psychological Realities after Spinal Cord Injury Toby Huston, ... Rose, PhD The Basics of Spinal Cord Injury Rehabilitation Kristine Cichowski, MS Occupational Therapy after Spinal Cord ...

  9. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... and What They Mean Animated Spinal Cord Injury Chart Spinal Cord Injury Facts and Figures Care and ... and What They Mean Animated Spinal Cord Injury Chart Spinal Cord Injury Facts and Figures Care and ...

  10. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Injury Chart Spinal Cord Injury Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation ... Injury Chart Spinal Cord Injury Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation ...

  11. Spinal Cord Injury 101

    Medline Plus

    Full Text Available menu Understanding Spinal Cord Injury What is a Spinal Cord Injury Levels of Injury and What They Mean Animated Spinal Cord Injury Chart Spinal Cord Injury Facts and Figures Care and ...

  12. Genetic selection for modulators of the MAP kinase and beta-catenin growth-control pathways in mammalian cells.

    Science.gov (United States)

    Wheatley, William; Yoo, Sanghee; Pierce, Michael; Rebentisch, Matthew; Endo, Mark; Peterson, Isaac; Stump, Mark; McCormack, Ken; Garcia-Guzman, Miguel; Kamb, Alexander

    2002-12-01

    Transdominant genetic selections can yield protein fragment and peptide modulators of specific biochemical pathways. In yeast, such screens have been highly successful in targeting the MAP (mitogen-activated protein) kinase growth-control pathway. We performed a similar type of selection aimed at recovery of modulators of the mammalian MAP kinase cascade. Two pathway activators were identified, fragments of the TrkB and Raf-1 kinases. In a second selection directed at the beta-catenin growth-control pathway, three different clones encoding cadherin fragments were recovered. In neither selection were peptide inhibitors observed. We conclude that some transdominant selections in mammalian cells can readily yield high-penetrance protein fragments, but may be less amenable to isolation of peptide inhibitors.

  13. Evapotranspiration modules for crop growth simulation. Implementation of the algorithms from Penman, Makkink and Priestley-Taylor

    OpenAIRE

    Kraalingen, van, D.W.G.; Stol, W.

    1997-01-01

    Calculation of evapotranspiration is essential for the estimation of crop water use or for studying the effect of drought stress on crop performance with simulation models. Several methods are available for calculation of evapotranspiration. This report describes three different methods : the Penman method (1948) and the approaches of Makkink (1957) and Priestley -Taylor (1972). The modules described in this report are developed for use in general crop growth models for water-limited conditio...

  14. Nerve growth factor in the hippocamposeptal system: Evidence for activity-dependent anterograde delivery and modulation of synaptic activity

    OpenAIRE

    Guo, Lan; Yeh, Mason L.; Cuzon Carlson, Verginia C.; Johnson-Venkatesh, Erin M; Yeh, Hermes H.

    2012-01-01

    Neurotrophins have been implicated in regulating neuronal differentiation, promoting neuronal survival, and modulating synaptic efficacy and plasticity. Depending on the target and mode of action, the prevailing view is that most neurotrophins can be trafficked and released either anterogradely or retrogradely in an activity-dependent manner. However, the prototypic neurotrophin, nerve growth factor (NGF), is not thought to be anterogradely delivered. Here we provide the neuroanatomical subst...

  15. Astrocyte sigma-1 receptors modulate connexin 43 expression leading to the induction of below-level mechanical allodynia in spinal cord injured mice.

    Science.gov (United States)

    Choi, Sheu-Ran; Roh, Dae-Hyun; Yoon, Seo-Yeon; Kwon, Soon-Gu; Choi, Hoon-Seong; Han, Ho-Jae; Beitz, Alvin J; Lee, Jang-Hern

    2016-12-01

    We have previously shown using a spinal cord injury (SCI) model that gap junctions contribute to the early spread of astrocyte activation in the lumbar spinal cord and that this astrocyte communication plays critical role in the induction of central neuropathic pain. Sigma-1 receptors (Sig-1Rs) have been implicated in spinal astrocyte activation and the development of peripheral neuropathic pain, yet their contribution to central neuropathic pain remains unknown. Thus, we investigated whether SCI upregulates spinal Sig-1Rs, which in turn increase the expression of the astrocytic gap junction protein, connexin 43 (Cx43) leading to the induction of central neuropathic pain. A thoracic spinal cord hemisection significantly increased both astrocyte activation and Cx43 expression in lumbar dorsal horn. Sig-1Rs were also increased in lumbar dorsal horn astrocytes, but not neurons or microglia. Intrathecal injection of an astrocyte metabolic inhibitor (fluorocitrate); a gap junction/hemichannel blocker (carbenoxolone); or a Cx43 mimetic peptide (43Gap26) significantly reduced SCI-induced bilateral below-level mechanical allodynia. Blockade of Sig-1Rs with BD1047 during the induction phase of pain significantly suppressed the SCI-induced development of mechanical allodynia, astrocyte activation, increased expression of Cx43 in both total and membrane levels, and increased association of Cx43 with Sig-1R. However, SCI did not change the expression of oligodendrocyte (Cx32) or neuronal (Cx36) gap junction proteins. These findings demonstrate that SCI activates astrocyte Sig-1Rs leading to increases in the expression of the gap junction protein, Cx43 and astrocyte activation in the lumbar dorsal horn, and ultimately contribute to the induction of bilateral below-level mechanical allodynia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Modulation of growth factors by growth hormone in children with chronic renal failure. The Southwest Pediatric Nephrology Study Group.

    Science.gov (United States)

    Powell, D R; Liu, F; Baker, B K; Hintz, R L; Lee, P D; Durham, S K; Brewer, E D; Frane, J W; Watkins, S L; Hogg, R J

    1997-06-01

    Anthropometric measurements and circulating growth factors were studied serially in 44 prepubertal children with growth failure and chronic renal failure (GFR = 10 to 40 ml/min/1.73 m2) who were randomized to receive either recombinant human growth hormone (rhGH; N = 30) or no treatment (N = 14). RhGH was given as Nutropin, 0.05 mg/kg/day, and the studies were carried out at baseline and after 3 and 12 months. At baseline, serum insulin-like growth factor binding protein (IGFBP)-1 and -2 levels were, while IGFBP-3 levels were not, higher than those of children with normal renal function. In addition, height SDS at baseline correlated inversely with serum IGFBP-2 levels (r = -0.461, P = 0.0016), but did not correlate significantly with any other factor. After 12 months of study, the 30 children receiving rhGH showed: (i) greater increase in height (9.1 +/- 2.8 vs. 5.5 +/- 1.9 cm, P < 0.0001); (ii) increases in serum levels of IGF-I, IGF-II, free IGF-I, IGFBP-3 and acid labile subunit (ALS); (iii) a greater decrease in serum IGFBP-1 levels; and (iv) no significant difference in serum IGFBP-2 levels, when compared to the 14 control patients. The change in height SDS after 12 months of rhGH (+0.8) in the 30 treated children correlated significantly and positively with serum ALS, IGFBP-3, total IGF, IGF-I, IGF-II and free IGF-I levels measured during treatment. These observations suggest that, in children with growth failure associated with chronic renal failure: (i) IGFBP-2, and not IGFBP-3, is likely to be a growth inhibitor; (ii) rhGH stimulates catch-up growth in part by increasing serum levels of IGF peptides; and (iii) linear growth is influenced by the balance between growth stimulating IGFs and growth inhibitory IGFBPs.

  17. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth

    Energy Technology Data Exchange (ETDEWEB)

    Stagg, Brian C., E-mail: briancstagg@gmail.com; Uehara, Hironori; Lambert, Nathan; Rai, Ruju; Gupta, Isha; Radmall, Bryce; Bates, Taylor; Ambati, Balamurali K. [John A Moran Eye Center, University of Utah, Salt Lake City, UT, 65 Mario Capecchi Drive, Salt Lake City, UT 84132 (United States)

    2014-11-26

    Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.

  18. Modulation of the cardiac sodium channel Nav1.5 by fibroblast growth factor homologous factor 1B.

    Science.gov (United States)

    Liu, Chuan-ju; Dib-Hajj, Sulayman D; Renganathan, Muthukrishnan; Cummins, Theodore R; Waxman, Stephen G

    2003-01-10

    We have previously shown that fibroblast growth factor homologous factor 1B (FHF1B), a cytosolic member of the fibroblast growth factor family, associates with the sensory neuron-specific channel Na(v)1.9 but not with the other sodium channels present in adult rat dorsal root ganglia neurons. We show in this study that FHF1B binds to the C terminus of the cardiac voltage-gated sodium channel Na(v)1.5 and modulates the properties of the channel. The N-terminal 41 amino acid residues of FHF1B are essential for binding to Na(v)1.5, and the conserved acidic rich domain (amino acids 1773-1832) in the C terminus of Na(v)1.5 is sufficient for association with this factor. Binding of the growth factor to recombinant wild type human Na(v)1.5 in human embryonic kidney 293 cells produces a significant hyperpolarizing shift in the voltage dependence of channel inactivation. An aspartic acid to glycine substitution at position 1790 of the channel, which underlies one of the LQT-3 phenotypes of cardiac arrythmias, abolishes the interaction of the Na(v)1.5 channel with FHF1B. This is the first report showing that interaction with a growth factor can modulate properties of a voltage-gated sodium channel.

  19. Exercise dependent increase in axon regeneration into peripheral nerve grafts by propriospinal but not sensory neurons after spinal cord injury is associated with modulation of regeneration-associated genes.

    Science.gov (United States)

    Sachdeva, Rahul; Theisen, Catherine C; Ninan, Vinu; Twiss, Jeffery L; Houlé, John D

    2016-02-01

    Insufficient regeneration of central nervous system (CNS) axons contributes to persisting neurological dysfunction after spinal cord injury (SCI). Peripheral nerve grafts (PNGs) support regeneration by thousands of injured intraspinal axons and help them bypass some of the extracellular barriers that form after SCI. However this number represents but a small portion of the total number of axons that are injured. Here we tested if rhythmic sensory stimulation during cycling exercise would boost the intrinsic regenerative state of neurons to enhance axon regeneration into PNGs after a lower thoracic (T12) spinal transection of adult rats. Using True Blue retrograde tracing, we show that 4 weeks of cycling improves regeneration into a PNG from lumbar interneurons but not by primary sensory neurons. The majority of neurons that regenerate their axon are within 5 mm of the lesion and their number increased 70% with exercise. Importantly propriospinal neurons in more distant regions (5-20 mm from the lesion) that routinely exhibit very limited regeneration responded to exercise by increasing the number of regenerating neurons by 900%. There was no exercise-associated increase in regeneration from sensory neurons. Analyses using fluorescent in situ hybridization showed that this increase in regenerative response is associated with changes in levels of mRNAs encoding the regeneration associated genes (RAGs) GAP43, β-actin and Neuritin. While propriospinal neurons showed increased mRNA levels in response to SCI alone and then to grafting and exercise, sensory neurons did not respond to SCI, but there was a response to the presence of a PNG. Thus, exercise is a non-invasive approach to modulate gene expression in injured neurons leading to an increase in regeneration. This sets the stage for future studies to test whether exercise will promote axon outgrowth beyond the PNG and reconnection with spinal cord neurons, thereby demonstrating a potential clinical application of

  20. Crosstalk between chemokine receptor CXCR4 and cannabinoid receptor CB2 in modulating breast cancer growth and invasion.

    Directory of Open Access Journals (Sweden)

    Mohd W Nasser

    Full Text Available BACKGROUND: Cannabinoids bind to cannabinoid receptors CB(1 and CB(2 and have been reported to possess anti-tumorigenic activity in various cancers. However, the mechanisms through which cannabinoids modulate tumor growth are not well known. In this study, we report that a synthetic non-psychoactive cannabinoid that specifically binds to cannabinoid receptor CB(2 may modulate breast tumor growth and metastasis by inhibiting signaling of the chemokine receptor CXCR4 and its ligand CXCL12. This signaling pathway has been shown to play an important role in regulating breast cancer progression and metastasis. METHODOLOGY/PRINCIPAL FINDINGS: We observed high expression of both CB(2 and CXCR4 receptors in breast cancer patient tissues by immunohistochemical analysis. We further found that CB(2-specific agonist JWH-015 inhibits the CXCL12-induced chemotaxis and wound healing of MCF7 overexpressing CXCR4 (MCF7/CXCR4, highly metastatic clone of MDA-MB-231 (SCP2 and NT 2.5 cells (derived from MMTV-neu by using chemotactic and wound healing assays. Elucidation of the molecular mechanisms using various biochemical techniques and confocal microscopy revealed that JWH-015 treatment inhibited CXCL12-induced P44/P42 ERK activation, cytoskeletal focal adhesion and stress fiber formation, which play a critical role in breast cancer invasion and metastasis. In addition, we have shown that JWH-015 significantly inhibits orthotopic tumor growth in syngenic mice in vivo using NT 2.5 cells. Furthermore, our studies have revealed that JWH-015 significantly inhibits phosphorylation of CXCR4 and its downstream signaling in vivo in orthotopic and spontaneous breast cancer MMTV-PyMT mouse model systems. CONCLUSIONS/SIGNIFICANCE: This study provides novel insights into the crosstalk between CB(2 and CXCR4/CXCL12-signaling pathways in the modulation of breast tumor growth and metastasis. Furthermore, these studies indicate that CB(2 receptors could be used for developing

  1. Growth Hormone differentially modulates chemoresistance in human endometrial adenocarcinoma cell lines.

    Science.gov (United States)

    Gentilin, Erica; Minoia, Mariella; Bondanelli, Marta; Tagliati, Federico; Degli Uberti, Ettore C; Zatelli, Maria Chiara

    2017-06-01

    Growth Hormone may influence neoplastic development of endometrial epithelium towards endometrial adenocarcinoma, which is one of the most occurring tumors in acromegalic patients. Since chemoresistance often develops in advanced endometrial adenocarcinoma, we investigated whether Growth Hormone might influence the development of chemoresistance to drugs routinely employed in endometrial adenocarcinoma treatment, such as Doxorubicin, Cisplatin, and Paclitaxel. Growth Hormone and Growth Hormone receptor expression was assessed by immunofluorescence in two endometrial adenocarcinoma cell lines, AN3 CA and HEC-1-A cells. Growth Hormone effects were assessed investigating cell viability, caspase3/7 activation, ERK1/2, and protein kinase C delta protein expression. AN3 CA and HEC-1-A cells display Growth Hormone and Growth Hormone receptor. Growth Hormone does not influence cell viability in both cells lines, but significantly reduces caspase 3/7 activation in AN3 CA cells, an effect blocked by a Growth Hormone receptor antagonist. Growth Hormone rescues AN3 CA cells from the inhibitory effects of Doxorubicin and Cisplatin on cell viability, while it has no effect on Paclitaxel. Growth Hormone does not influence the pro-apoptotic effects of Doxorubicin, but is capable of rescuing AN3 CA cells from the pro-apoptotic effects of Cisplatin. On the other hand, Growth Hormone did not influence the effects of Doxorubicin and Paclitaxel on HEC-1A cell viability. The protective action of Growth Hormone towards the effects of Doxorubicin may be mediated by ERK1/2 activation, while the pro-apoptotic effects of Cisplatin may be mediated by protein kinase C delta inhibition. All together our results indicate that Growth Hormone may differentially contribute to endometrial adenocarcinoma chemoresistance. This may provide new insights on novel therapies against endometrial adenocarcinoma chemoresistant aggressive tumors.

  2. Conventionally-fractionated image-guided intensity modulated radiotherapy (IG-IMRT: a safe and effective treatment for cancer spinal metastasis

    Directory of Open Access Journals (Sweden)

    Jiang Xiaoqin

    2008-04-01

    Full Text Available Abstract Background Treatments for cancer spinal metastasis were always palliative. This study was conducted to investigate the safety and effectiveness of IG-IMRT for these patients. Methods 10 metastatic lesions were treated with conventionally-fractionated IG-IMRT. Daily kilovoltage cone-beam computed tomography (kV-CBCT scan was applied to ensure accurate positioning. Plans were evaluated by the dose-volume histogram (DVH analysis. Results Before set-up correction, the positioning errors in the left-right (LR, superior-inferior (SI and anterior-posterior (AP axes were 0.3 ± 3.2, 0.4 ± 4.5 and -0.2 ± 3.9 mm, respectively. After repositioning, those errors were 0.1 ± 0.7, 0 ± 0.8 and 0 ± 0.7 mm, respectively. The systematic/random uncertainties ranged 1.4–2.3/3.0–4.1 before and 0.1–0.2/0.7–0.8 mm after online set-up correction. In the original IMRT plans, the average dose of the planning target volume (PTV was 61.9 Gy, with the spinal cord dose less than 49 Gy. Compared to the simulated PTVs based on the pre-correction CBCT, the average volume reduction of PTVs was 42.3% after online correction. Also, organ at risk (OAR all benefited from CBCT-based set-up correction and had significant dose reduction with IGRT technique. Clinically, most patients had prompt pain relief within one month of treatment. There was no radiation-induced toxicity detected clinically during a median follow-up of 15.6 months. Conclusion IG-IMRT provides a new approach to treat cancer spinal metastasis. The precise positioning ensures the implementation of optimal IMRT plan, satisfying both the dose escalation of tumor targets and the radiation tolerance of spinal cord. It might benefit the cancer patient with spinal metastasis.

  3. Synergistic action of heparin and serum on basic fibroblast growth factor-modulated DNA synthesis and mitochondrial activity of cultured bovine corneal endothelial cells

    NARCIS (Netherlands)

    Hoppenreijs, V. P.; Pels, E.; Felten, P. C.; Ruijter, J. M.; Vrensen, G. F.; Treffers, W. F.

    1996-01-01

    Basic fibroblast growth factor (bFGF) is a major mitogen and chemoattractant for many cell types. The synergistic role of fetal bovine serum (FBS) and heparin on the modulation of tissue-cultured bovine corneal endothelial cells by bFGF was studied. Cell modulation was assessed by DNA synthesis

  4. Novel small molecule modulators of plant growth and development identified by high-content screening with plant pollen.

    Science.gov (United States)

    Chuprov-Netochin, Roman; Neskorodov, Yaroslav; Marusich, Elena; Mishutkina, Yana; Volynchuk, Polina; Leonov, Sergey; Skryabin, Konstantin; Ivashenko, Andrey; Palme, Klaus; Touraev, Alisher

    2016-09-06

    Small synthetic molecules provide valuable tools to agricultural biotechnology to circumvent the need for genetic engineering and provide unique benefits to modulate plant growth and development. We developed a method to explore molecular mechanisms of plant growth by high-throughput phenotypic screening of haploid populations of pollen cells. These cells rapidly germinate to develop pollen tubes. Compounds acting as growth inhibitors or stimulators of pollen tube growth are identified in a screen lasting not longer than 8 h high-lighting the potential broad applicability of this assay to prioritize chemicals for future mechanism focused investigations in plants. We identified 65 chemical compounds that influenced pollen development. We demonstrated the usefulness of the identified compounds as promotors or inhibitors of tobacco and Arabidopsis thaliana seed growth. When 7 days old seedlings were grown in the presence of these chemicals twenty two of these compounds caused a reduction in Arabidopsis root length in the range from 4.76 to 49.20 % when compared to controls grown in the absence of the chemicals. Two of the chemicals sharing structural homology with thiazolidines stimulated root growth and increased root length by 129.23 and 119.09 %, respectively. The pollen tube growth stimulating compound (S-02) belongs to benzazepin-type chemicals and increased Arabidopsis root length by 126.24 %. In this study we demonstrate the usefulness of plant pollen tube based assay for screening small chemical compound libraries for new biologically active compounds. The pollen tubes represent an ultra-rapid screening tool with which even large compound libraries can be analyzed in very short time intervals. The broadly applicable high-throughput protocol is suitable for automated phenotypic screening of germinating pollen resulting in combination with seed germination assays in identification of plant growth inhibitors and stimulators.

  5. Stability of skeletal changes induced by growth modulation procedures in the treatment of skeletal Class II malocclusion

    Directory of Open Access Journals (Sweden)

    Prashantha Govinakovi Shivamurthy

    2016-01-01

    Full Text Available Objective: Objective of this study, based on an evaluation of lateral cephalograms, was to evaluate the degree of skeletal changes produced by the various growth modulative procedures in the treatment of skeletal Class II malocclusion and to characterize the stability of these changes in the years after treatment. Materials and Methods: Total of 40 patients with Class II malocclusion was divided into three groups according to appliance used, i.e. removable or fixed functional appliances (n = 10, combination of functional appliance with headgear (n = 10, and only headgear (n = 10. In addition, almost a matched control group (n = 10 also characterized by skeletal Class II pattern and were under observation, for more than 2 years was also selected. Lateral cephalograms of each patient were taken at the start of treatment (T1, at its completion (T2, and long-term posttreatment (T3. Results: This study showed significant improvement in maxillomandibular relationship in treated group compared to control group, and the changes remained stable in posttreatment phase. Restriction of maxillary growth was evident in headgear and combination groups whereas significant forward movement of the mandible was seen in functional group. Conclusion: Analysis of lateral cephalograms indicates that growth modulation therapy in angle Class II malocclusion brings about desired skeletal changes which remain relatively stable over a long-term period.

  6. Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

    Science.gov (United States)

    Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

    2015-01-01

    It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+ Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL. PMID:26137413

  7. Nutritional modulation of mouse and human liver bud growth through a branched-chain amino acid metabolism.

    Science.gov (United States)

    Koike, Hiroyuki; Zhang, Ran-Ran; Ueno, Yasuharu; Sekine, Keisuke; Zheng, Yun-Wen; Takebe, Takanori; Taniguchi, Hideki

    2017-03-15

    Liver bud progenitors experience a transient amplification during the early organ growth phase, yet the mechanism responsible is not fully understood. Collective evidence highlights the specific requirements in stem cell metabolism for expanding organ progenitors during organogenesis and regeneration. Here, transcriptome analyses show that progenitors of the mouse and human liver bud growth stage specifically express the gene branched chain aminotransferase 1, encoding a known breakdown enzyme of branched-chain amino acids (BCAAs) for energy generation. Global metabolome analysis confirmed the active consumption of BCAAs in the growing liver bud, but not in the later fetal or adult liver. Consistently, maternal dietary restriction of BCAAs during pregnancy significantly abrogated the conceptus liver bud growth capability through a striking defect in hepatic progenitor expansion. Under defined conditions, the supplementation of L-valine specifically among the BCAAs promoted rigorous growth of the human liver bud organoid in culture by selectively amplifying self-renewing bi-potent hepatic progenitor cells. These results highlight a previously underappreciated role of branched-chain amino acid metabolism in regulating mouse and human liver bud growth that can be modulated by maternal nutrition in vivo or cultural supplement in vitro. © 2017. Published by The Company of Biologists Ltd.

  8. Chronic activity-based therapy does not improve body composition, insulin-like growth factor-I, adiponectin, or myostatin in persons with spinal cord injury

    Science.gov (United States)

    Harness, Eric T.; Witzke, Kara A.

    2015-01-01

    Spinal cord injury (SCI) induces dramatic changes in body composition including reductions in fat-free mass (FFM) and increases in fat mass (FM). Objective To examine changes in body composition in response to chronic activity-based therapy (ABT) in persons with SCI. Design Longitudinal exercise intervention. Methods Seventeen men and women with SCI (mean age = 36.1 ± 11.5 years) completed 6 months of supervised ABT consisting of load bearing, resistance training, locomotor training, and functional electrical stimulation. At baseline and after 3 and 6 months of ABT, body weight, body fat, and FFM were assessed using dual-energy X-ray absorptiometry, and fasting blood samples were obtained to assess changes in insulin-like growth factor-I (IGF-I), adiponectin, and myostatin. Results Across all subjects, there was no change (P > 0.05) in body weight, percent body fat, or FFM of the leg, arm, or trunk, whereas whole-body FFM declined (P = 0.02, 50.4 ± 8.4 to 49.2 ± 7.4 kg). No changes (P = 0.21–0.41) were demonstrated in IGF-I, adiponectin, or myostatin during the study. Conclusions Chronic ABT focusing on the lower extremity does not slow muscle atrophy or alter body fat, body mass, or regional depots of FFM in persons with SCI. Further, it does not induce beneficial changes in adiponectin, myostatin, or IGF-I. Alternative exercise-based therapies are needed in SCI to reverse muscle atrophy and minimize the onset of related health risks. PMID:25130192

  9. Regulation and modulation of growth : insights from human and animal studies

    NARCIS (Netherlands)

    Gool, Sandy Agathe van

    2011-01-01

    Growth disorders are a major concern for patients, their parents, and health care professionals. our understanding of growth failure in the presence of normal GH secretion remains primitive, hampering the development of new treatment strategies for children with short stature. Final height gain in

  10. Computational modeling of the mechanical modulation of the growth plate by sustained loading

    Directory of Open Access Journals (Sweden)

    Narváez-Tovar Carlos A

    2012-09-01

    Full Text Available Abstract This paper presents a computational model that describes the growth of the bone as a function of the proliferation and hypertrophy of chondrocytes in the growth plate. We have included the effects of the mechanical loads on the sizes of the proliferative and hypertrophic areas, the number of proliferative chondrocytes and the final size of the hypertrophic chondrocytes. The validation of the model was performed with experimental data published on other investigations about proximal tibia of rats, subjected to sustained axial stresses of 0.1 MPa, 0.0 MPa, -0.1 MPa and −0.2 MPa. Growth was simulated during 23 days, obtaining numerical errors between 2.77% and 3.73% with respect to experimental growth rates. The results obtained show that the model adequately simulates the behavior of the growth plate and the effect of mechanical loads over its cellular activity.

  11. The hemodynamic repercussions of the autonomic modulations in growth-restricted fetuses

    Directory of Open Access Journals (Sweden)

    Igor Victorovich Lakhno

    2017-12-01

    Conclusion: Fetal heart rate pattern was influenced by maternal and fetal autonomic tone. Maternal cardiovascular oscillations were reflected in the umbilical circulation in healthy pregnancy Fetal distress was featured by sympathetic overactivity and the reduction of vagal tone. Such autonomic modulations was manifested by the decelerative pattern of CTG and deteriorated umbilical hemodynamics.

  12. Chemical Tumor Promoters, Oncogenes and Growth Factors: Modulators of Gap Junctional Intercellular Communication

    Science.gov (United States)

    1991-01-01

    tives ( saccharin ), solvents (heptanol), pollutants (PCBs, PBBs), pesticides and herbicides (DDT, 2,3,5-T), nutritional factors (unsaturated fatty acids...acids and saccharin could inhibit gap junctional intercellular communication (41). Oncogenes as modulators of gap junctional intercellular communication...phosphorylation reactions, could (a) prepare the plasma membrane for active transport of regulatory ions and substrates for macromolecular synthesis

  13. Insulin and insulin-like growth factor-1 modulate the lipolytic action of growth hormone by altering signal pathway linkages.

    Science.gov (United States)

    Bergan-Roller, Heather E; Ickstadt, Alicia T; Kittilson, Jeffrey D; Sheridan, Mark A

    2017-07-01

    Growth hormone (GH) has many actions in vertebrates, including the regulation of two disparate metabolic processes: growth promotion (anabolic) and the mobilization of stored lipids (catabolic). Our previous studies showed that GH stimulated IGF-1 production in hepatocytes from fed rainbow trout, but in cells from fasted fish GH stimulated lipolysis. In this study, we used rainbow trout (Oncorhynchus mykiss) to elucidate regulation of the mechanisms that enable cells to alter their lipolytic responsiveness to GH. In the first experiment, cells were removed from either fed or fasted fish, conditioned in medium containing serum (10%) from either fed or fasted fish, then challenged with GH. GH stimulated the expression of hormone sensitive lipase (HSL), the primary lipolytic enzyme, in cells from fasted fish conditioned with "fasted serum" but not in cells from fasted fish conditioned in "fed serum." Pretreatment of cells from fed fish with "fasted serum" resulted in GH-stimulated HSL expression, whereas GH-stimulated HSL expression in cells from fasted fish was blocked by conditioning in "fed serum." The nature of the conditioning serum governed the signaling pathways activated by GH irrespective of the nutritional state of the animals from which the cells were removed. When hepatocytes were pretreated with "fed serum," GH activated JAK2, STAT5, Akt, and ERK pathways; when cells were pretreated with "fasted serum," GH activated PKC and ERK. In the second study, we examined the direct effects of insulin (INS) and insulin-like growth factor (IGF-1), two nutritionally-regulated hormones, on GH-stimulated lipolysis and signal transduction in isolated hepatocytes. GH only stimulated HSL mRNA expression in cells from fasted fish. Pretreatment with INS and/or IGF-1 abolished this lipolytic response to GH. INS and/or IGF-1 augmented GH activation of JAK2 and STAT5 in cells from fed and fasted fish. However, INS and/or IGF-1 eliminated the ability of GH to activate PKC and

  14. [Metabolic and immune response to spinal vs intravenous morphine for analgesia after radical prostatectomy].

    Science.gov (United States)

    Longás Valién, J; Abengochea Beisty, J M; Martínez Ubieto, J R; Giron Mombiela, J A; Rodríguez Zazo, A; Cuartero Lobera, J

    2005-12-01

    To study differences between the endocrine-metabolic and immune cell responses to spinal or intravenous administration of morphine for analgesia after radical prostatectomy. Prospective study of 60 patients randomized to 2 groups: in group A (n=30) morphine for postoperative analgesia was infused intravenously and in group B (n=30) morphine was infused into the spinal canal. Changes in leukocyte populations and lymphocyte subpopulations in peripheral blood and blood from surgical drains (local) were analyzed to study immune cell response to morphine administration. Cortisol, corticotropin, growth hormone, glucose, and immunoglobulin levels in peripheral blood were measured as indicators of metabolic and humoral immune responses. Both groups developed lymphopenia in peripheral blood. The group treated with spinal morphine had significantly lower CD4+ cell counts in peripheral blood Presponse in either group. Significant differences were found in natural killer and CD4+ cell counts both locally and in peripheral blood Pimmune response suppression in both groups; however, it was more marked in the group treated with spinal morphine and the difference was significant Pmetabolic response was greater in the group treated with intravenous morphine. Patients who received morphine by spinal infusion had a less marked endocrine-metabolic response. Although local cell responses were similar in the 2 groups, the response in peripheral blood was different, possibly reflecting different mechanisms of central modulation of the inflammatory response to stress.

  15. Myelin Lipids Inhibit Axon Regeneration Following Spinal Cord Injury: a Novel Perspective for Therapy.

    Science.gov (United States)

    Mar, Fernando M; da Silva, Tiago F; Morgado, Marlene M; Rodrigues, Lorena G; Rodrigues, Daniel; Pereira, Marta I L; Marques, Ana; Sousa, Vera F; Coentro, João; Sá-Miranda, Clara; Sousa, Mónica M; Brites, Pedro

    2016-03-01

    Lack of axon regeneration following spinal cord injury has been mainly ascribed to the inhibitory environment of the injury site, i.e., to chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs). Here, we used shiverer (shi) mice to assess axon regeneration following spinal cord injury in the presence of MAIs and CSPG but in the absence of compact myelin. Although in vitro shi neurons displayed a similar intrinsic neurite outgrowth to wild-type neurons, in vivo, shi fibers had increased regenerative capacity, suggesting that the wild-type spinal cord contains additional inhibitors besides MAIs and CSPG. Our data show that besides myelin protein, myelin lipids are highly inhibitory for neurite outgrowth and suggest that this inhibitory effect is released in the shi spinal cord given its decreased lipid content. Specifically, we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that operate through a Rho-dependent mechanism and have inhibitory activity in multiple neuron types. We further demonstrated the inhibitory action of myelin lipids in vivo, by showing that delivery of 2-hydroxypropyl-β-cyclodextrin, a drug that reduces the levels of lipids specifically in the injury site, leads to increased axon regeneration of wild-type (WT) dorsal column axons following spinal cord injury. In summary, our work shows that myelin lipids are important modulators of axon regeneration that should be considered together with protein MAIs as critical targets in strategies aiming at improving axonal growth following injury.

  16. New Therapeutics in Promoting and Modulating Mandibular Growth in Cases with Mandibular Hypoplasia

    Directory of Open Access Journals (Sweden)

    Tarek El-Bialy

    2013-01-01

    Full Text Available Children with mandibular growth deficiency may develop airway obstruction. The standard treatment of severe airway obstruction involves invasive procedures such as tracheostomy. Mandibular distraction osteogenesis has been proposed in neonates with mandibular deficiency as a treatment option to avoid tracheostomy procedure later in life. Both tracheostomy and distraction osteogenesis procedures suffer from substantial shortcomings including scarring, unpredictability, and surgical complications. Forward jaw positioning appliances have been also used to enhance mandible growth. However, the effectiveness of these appliances is limited and lacks predictability. Current and future approaches to enhance mandibular growth, both experimental and clinical trials, and their effectiveness are presented and discussed.

  17. Halofuginone has anti-proliferative effects in acute promyelocytic leukemia by modulating the transforming growth factor beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Lorena L de Figueiredo-Pontes

    Full Text Available Promyelocytic leukemia-retinoic acid receptor alpha (PML-RARα expression in acute promyelocytic leukemia (APL impairs transforming growth factor beta (TGFβ signaling, leading to cell growth advantage. Halofuginone (HF, a low-molecular-weight alkaloid that modulates TGFβ signaling, was used to treat APL cell lines and non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice subjected to transplantation with leukemic cells from human chorionic gonadotrophin-PML-RARα transgenic mice (TG. Cell cycle analysis using incorporated bromodeoxyuridine and 7-amino-actinomycin D showed that, in NB4 and NB4-R2 APL cell lines, HF inhibited cellular proliferation (P<0.001 and induced apoptosis (P = 0.002 after a 24-hour incubation. Addition of TGFβ revealed that NB4 cells were resistant to its growth-suppressive effects and that HF induced these effects in the presence or absence of the cytokine. Cell growth inhibition was associated with up-regulation of TGFβ target genes involved in cell cycle regulation (TGFB, TGFBRI, SMAD3, p15, and p21 and down-regulation of MYC. Additionally, TGFβ protein levels were decreased in leukemic TG animals and HF in vivo could restore TGFβ values to normal. To test the in vivo anti-leukemic activity of HF, we transplanted NOD/SCID mice with TG leukemic cells and treated them with HF for 21 days. HF induced partial hematological remission in the peripheral blood, bone marrow, and spleen. Together, these results suggest that HF has anti-proliferative and anti-leukemic effects by reversing the TGFβ blockade in APL. Since loss of the TGFβ response in leukemic cells may be an important second oncogenic hit, modulation of TGFβ signaling may be of therapeutic interest.

  18. Factors modulating cottongrass seedling growth stimulation to enhanced nitrogen and carbon dioxide: compensatory tradeoffs in leaf dynamics and allocation to meet potassium-limited growth.

    Science.gov (United States)

    Siegenthaler, Andy; Buttler, Alexandre; Grosvernier, Philippe; Gobat, Jean-Michel; Nilsson, Mats B; Mitchell, Edward A D

    2013-02-01

    Eriophorum vaginatum is a characteristic species of northern peatlands and a keystone plant for cutover bog restoration. Understanding the factors affecting E. vaginatum seedling establishment (i.e. growth dynamics and allocation) under global change has practical implications for the management of abandoned mined bogs and restoration of their C-sequestration function. We studied the responses of leaf dynamics, above- and belowground biomass production of establishing seedlings to elevated CO(2) and N. We hypothesised that nutrient factors such as limitation shifts or dilutions would modulate growth stimulation. Elevated CO(2) did not affect biomass, but increased the number of young leaves in spring (+400 %), and the plant vitality (i.e. number of green leaves/total number of leaves) (+3 %), both of which were negatively correlated to [K(+)] in surface porewater, suggesting a K-limited production of young leaves. Nutrient ratios in green leaves indicated either N and K co-limitation or K limitation. N addition enhanced the number of tillers (+38 %), green leaves (+18 %), aboveground and belowground biomass (+99, +61 %), leaf mass-to-length ratio (+28 %), and reduced the leaf turnover (-32 %). N addition enhanced N availability and decreased [K(+)] in spring surface porewater. Increased tiller and leaf production in July were associated with a doubling in [K(+)] in surface porewater suggesting that under enhanced N production is K driven. Both experiments illustrate the importance of tradeoffs in E. vaginatum growth between: (1) producing tillers and generating new leaves, (2) maintaining adult leaves and initiating new ones, and (3) investing in basal parts (corms) for storage or in root growth for greater K uptake. The K concentration in surface porewater is thus the single most important factor controlling the growth of E. vaginatum seedlings in the regeneration of selected cutover bogs.

  19. [Modulation of scoliotic spine growth in experimental animals using intelligent metal bars].

    Science.gov (United States)

    Sánchez-Márquez, J M; Sánchez Pérez-Grueso, F J; Fernández-Baíllo, N; Gil-Garay, E; Antuña-Antuña, S

    2013-01-01

    To create an experimental structural scoliosis model in mice to evaluate the efficacy of shape-memory metals to gradually correct the deformity over time. Experimental scoliosis was generated in 3 week-old mice by means of a suture between the left scapula and pelvis for 8 weeks. They were then randomised into two groups: a control group, in which the suture was cut, and another, in those that also had a Nitinol straight memory-wire implant fixed to the column. Serial X-rays were performed to determine the efficacy of the Nitinol in the correction of the scoliosis. In a second time, the histological changes at apical vertical body level and the adjacent discs were evaluated pre- and post-correction. A mean 81.5° kyphoscoliosis was gradually induced. In the control group, after cutting the suture, an initial reduction in the deformity was observed, but later it remained stable throughout the time (54° at two weeks). In the Nitinol group, a gradual reduction was observed in the scoliosis angle value, to a mean of 8.7° at two weeks. The curvature of the apical vertebral body and adjacent discs were partially corrected after two weeks of correcting the deformity. This scoliosis model has demonstrated the efficacy of a straight Nitinol wire fixed to the spinal column in the gradual correction of kyphoscoliosis and in the changes in its adjacent structures. Copyright © 2013 SECOT. Published by Elsevier Espana. All rights reserved.

  20. Obesity accelerates murine gastric cancer growth by modulating the Sirt1/YAP pathway

    OpenAIRE

    Li, Hai-jun; Fu, Jun-Ke; Che, Xiang-Ming; Fan, Lin; Zhang, Yong; Bai, E.

    2017-01-01

    A previous study from our group using an in vivo model demonstrated that diet induced-obesity increases the risk of gastric cancer and may prompt its growth. However, the molecular mechanisms underlying this association remain unclear and require further investigation. The aim of the present study was to investigate the potential molecular mechanisms through which obesity affects gastric cancer growth. In a subcutaneous mouse model, tumors were significantly larger in obese mice compared with...

  1. Pollution Critical Load Exceedance and an Extended Growing Season as Modulators of Red Spruce Radial Growth

    Science.gov (United States)

    Kosiba, A. M.; Schaberg, P. G.; Engel, B. J.; Rayback, S. A.; Hawley, G. J.; Pontius, J.; Miller, E. K.

    2016-12-01

    Acidic sulfur (S) and nitrogen (N) deposition depletes cations such as calcium (Ca) from forest soils and has been linked to increases in foliar winter injury that led to the decline of red spruce (Picea rubens Sarg.) in the northeastern United States. We used results from a 30 m resolution steady-state S and N critical load exceedance model for New England to better understand the spatial connections between Ca depletion and red spruce productivity. To calculate exceedance, atmospheric deposition was estimated for a 5-year period (1984-1988) because tree health and productivity declines were expected to be most responsive to high acid loading. We examined how radial growth (basal area increment) of 441 dominant and co-dominant red spruce trees from 37 sites across Vermont and New Hampshire was related to modeled estimates of S and N critical load exceedance. We assessed growth using statistical models with exceedance as a source of variation, but which also included "year" and "elevation class" (to help account for climatic variability) and interactions among factors. Exceedance was significantly and negatively associated with mean growth for the study period (1951-2010) overall, and particularly for the 1980s and 2000s - periods of numerous and/or severe foliar winter injury events. However, climate-related sources of variation (year and elevation) accounted for most of the differences in growth over the chronology. Interestingly, recent growth for red spruce is now the highest recorded over our dendrochronological record for the species - suggesting that the factors shaping growth may be changing. Because red spruce is a temperate conifer that has the capacity to photosynthesize year-round, it is possible that warmer temperatures may be extending the functional growing season of the species thereby fostering increased growth. Data from elevational transects on Mount Mansfield (Vermont's tallest mountain) indicate that warmer spring, summer, fall and even winter

  2. HDAC4 Represses Vascular Endothelial Growth Factor Expression in Chondrosarcoma by Modulating RUNX2 Activity*

    OpenAIRE

    Sun, Xiaojuan; Wei, Lei; Chen, Qian; Terek, Richard M.

    2009-01-01

    Chondrosarcoma is a primary bone tumor with a dismal prognosis; most patients with this disease develop fatal pulmonary metastases, suggesting the need for a better systemic treatment. Anti-angiogenesis treatment may be useful, because angiogenesis is critical for both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is regulated by pathways related to the normal physiologic response to hypoxia and genetic alterations related ...

  3. Melanoma Angiogenesis and Metastasis Modulated by Ribozyme Targeting of the Secreted Growth Factor Pleiotrophin

    Science.gov (United States)

    Czubayko, Frank; Schulte, Anke M.; Berchem, Guy J.; Wellstein, Anton

    1996-12-01

    Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.

  4. Glycoprotein composition along the pistil of Malus x domestica and the modulation of pollen tube growth.

    Science.gov (United States)

    Losada, Juan M; Herrero, Maria

    2014-01-03

    The characteristics of pollen tube growth are not constant, but display distinct patterns of growth within the different tissues of the pistil. In the stigma, the growth rate is slow and autotrophic, whereas in the style, it is rapid and heterotrophic. Very little is known about the interactions between these distinct maternal tissues and the traversing pollen tube and the role of this interaction on the observed metabolism. In this work we characterise pollen tube growth in the apple flower and look for differences in glycoprotein epitope localization between two different maternal tissues, the stigma and the style. While immunocytochemically-detected arabinogalactan proteins were present at high levels in the stigma, they were not detected in the transmitting tissue of the style, where extensins were abundant. Whereas extensins remained at high levels in unpollinated pistils, they were no longer present in the style following pollen tube passage. Similarily, while abundant in unpollinated styles, insoluble polysaccharides such as β-glucans, were depleted in pollinated pistils. The switch from autotropic to heterotrophic pollen tube growth correlates spatially with a change of glycoprotein epitopes between the stigma and the style. The depletion of extensins and polysaccharides following pollen tube passage in the style suggest a possible contribution to the acceleration of heterotrophic pollen tube growth, which would imply an active contribution of female tissues on prezygotic male-female crosstalk.

  5. FOST 2 Upgrade with Hollow-Fiber CTA FO Module and Generation of Osmotic Agent for Microorganism Growth Studies

    Science.gov (United States)

    Parodi, Jurek; Mangado, Jaione Romero; Stefanson, Ofir; Flynn, Michael; Shaw, Hali; Beeler, David

    2016-01-01

    FOST 2 is an integrated membrane system that incorporates a forward osmosis subsystem and a reverse osmosis subsystem working in series. It has been designed as a post treatment system to process the effluent from the Membrane Aerated Biological Reactor developed at NASA Johnson Space Center and Texas Tech University. Its function is to remove dissolved solids residual such as ammonia and suspended solids, as well as to provide a physical barrier to microbial and viral contamination. A tubular CTA membrane module from HTI and a flat-sheet lipid-base membrane module from Porifera were integrated and tested on FOST 2 in the past, using both a bioreactor's effluent and greywater as the feed solution. This paper documents the performance of FOST 2 after its upgrade with a hollow-fiber CTA membrane module from Toyobo, treating real black-water to generate the osmotic agent solution necessary to conduct growth studies of genetically engineered microorganism for the Synthetic Biological Membrane project.

  6. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Cord Injury Diane M. Rowles, MS, NP How Family Life Changes After Spinal Cord Injury Nancy Rosenberg, ... Children with Spinal Cord Injury Patricia Mucia, RN Family Life After Pediatric Spinal Injury Dawn Sheaffer, MSW ...

  7. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... spinal cord injury? play_arrow What kind of surgery is common after a spinal cord injury? play_ ... How soon after a spinal cord injury should surgery be performed? play_arrow Is it common to ...

  8. Spinal Cord Injury 101

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    Full Text Available ... L Sarah Harrison, OT Anne Bryden, OT The Role of the Social Worker after Spinal Cord Injury ... a spinal cord injury important? play_arrow What role does “compression” play in a spinal cord injury? ...

  9. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Counseling Blog About Media Donate Spinal Cord Injury Medical Expert Videos Topics menu Topics Spinal Cord Injury ... Jennifer Piatt, PhD David Chen, MD Read Bio Medical Director, Spinal Cord Injury Rehabilitation Program, Rehabilitation Institute ...

  10. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Spinal Cord Injury Diane M. Rowles, MS, NP How Family Life Changes After Spinal Cord Injury Nancy ... Abuse and Spinal Cord Injury Allen Heinemann, PhD How Peer Counseling Works Julie Gassaway, MS, RN Pediatric ...

  11. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... About Media Donate Spinal Cord Injury Medical Expert Videos Topics menu Topics Spinal Cord Injury 101 Adult ... LLC Understanding Spinal Cord Injury About Us Expert Videos Contact Us Personal Experience Videos Blog Videos By ...

  12. Spinal Cord Diseases

    Science.gov (United States)

    Your spinal cord is a bundle of nerves that runs down the middle of your back. It carries signals back and ... the spine, this can also injure the spinal cord. Other spinal cord problems include Tumors Infections such ...

  13. Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Eun Hyang; Jang, Soon Young; Cho, In-Hye [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Hong, Darong [Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Jung, Bom; Park, Min-Ju [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of); Kim, Jong-Ho, E-mail: jonghokim@khu.ac.kr [Department of Pharmacy, Graduate School, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701 (Korea, Republic of)

    2015-08-07

    Human estrogen receptor α (ERα) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERα is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERα regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERα at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERα. Hispolon treatment also inhibited expression of the ERα target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERα in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. - Highlights: • Hispolon decreased ERα expression at both mRNA and protein levels. • Hispolon decreased ERα transcriptional activity. • Hispolon treatment inhibited expression of ERα target gene pS2. • Shikonin is a candidate chemotherapeutic target in the treatment of human breast cancer.

  14. Tumour cell–derived extracellular vesicles interact with mesenchymal stem cells to modulate the microenvironment and enhance cholangiocarcinoma growth

    Directory of Open Access Journals (Sweden)

    Hiroaki Haga

    2015-01-01

    Full Text Available The contributions of mesenchymal stem cells (MSCs to tumour growth and stroma formation are poorly understood. Tumour cells can transfer genetic information and modulate cell signalling in other cells through the release of extracellular vesicles (EVs. We examined the contribution of EV-mediated inter-cellular signalling between bone marrow MSCs and tumour cells in human cholangiocarcinoma, highly desmoplastic cancers that are characterized by tumour cells closely intertwined within a dense fibrous stroma. Exposure of MSCs to tumour cell–derived EVs enhanced MSC migratory capability and expression of alpha-smooth muscle actin mRNA, in addition to mRNA expression and release of CXCL-1, CCL2 and IL-6. Conditioned media from MSCs exposed to tumour cell–derived EVs increased STAT-3 phosphorylation and proliferation in tumour cells. These effects were completely blocked by anti-IL-6R antibody. In conclusion, tumour cell–derived EVs can contribute to the generation of tumour stroma through fibroblastic differentiation of MSCs, and can also selectively modulate the cellular release of soluble factors such as IL-6 by MSCs that can, in turn, alter tumour cell proliferation. Thus, malignant cells can “educate” MSCs to induce local microenvironmental changes that enhance tumour cell growth.

  15. Spinal cord contusion

    OpenAIRE

    Ju, Gong; Wang, Jian; Wang, Yazhou; Zhao, Xianghui

    2014-01-01

    Spinal cord injury is a major cause of disability with devastating neurological outcomes and limited therapeutic opportunities, even though there are thousands of publications on spinal cord injury annually. There are two major types of spinal cord injury, transaction of the spinal cord and spinal cord contusion. Both can theoretically be treated, but there is no well documented treatment in human being. As for spinal cord contusion, we have developed an operation with fabulous result.

  16. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Pediatric SCI Rehabilitation Sara Klaas, MSW Transitions for Children with Spinal Cord Injury Patricia Mucia, RN Family Life After Pediatric Spinal Injury Dawn Sheaffer, MSW ...

  17. Laser intensity modulated real time monitoring cell growth sensor for bioprocess applications

    Science.gov (United States)

    Kishore, P.; Babu, P. Ravindra; Devi, V. Rama; Maunika, T.; Soujanya, P.; Kishore, P. V. N.; Dinakar, D.

    2016-04-01

    This article proposes an optical method for monitoring the growth of Escherichia coli in Luria Bertani medium and Saccharomyces cereviciae in YPD. Suitable light is selected which on interaction with the analyte under consideration, gets adsorption / scattered. Required electronic circuitry is designed to drive the laser source and to detect the intensity of light using Photo-detector. All these components are embedded and arranged in a proper way and monitored the growth of the microbs in real time. The sensors results are compared with standard techniques such as colorimeter, Nephelometer and hemocytometer. The experimental results are in good agreement with the existed techniques and well suitable for real time monitoring applications of the growth of the microbs.

  18. GROWTH MODULATING PROPERTIES OF POLYPHENOLIC APPLE POMACE EXTRACT ON FOOD ASSOCIATED MICROORGANISMS

    Directory of Open Access Journals (Sweden)

    Christopher Beermann

    2013-10-01

    Full Text Available Bacteriostatic effects of plant derived polyphenols are generally proposed for food protection against microbial spoiling. This study aimed at characterizing distinct growth modification and cell-lytic properties of an apple pomace extract (APE containing short-chain and long-chain PP on food spoiling and fermenting starter bacteria. APE contained 6.76 wt % PP, 0.46 wt % glucose, 1.69 wt % fructose, 1.26 wt % starch, 3.8 wt % sorbitol, and 0.64 wt % nitrogen with a pH-value of 4.1. APE caused growth modification of prominent bacterial food spoilers, yeasts, moulds and food fermenting starter bacteria was analyzed turbidometry (180° light absorption measurement at 600 nm wavelength. Cell-lytic activity of APE was measured by a SYTOX® Green fluorescence cell viability assay. APE 1.5 w/w % reduced the growth of gram-positive and gram-negative food spoiling bacteria in dose-dependent manner up to 35.00%. Bacillus subtilis growth was reduced up to 10.53% comparable to 1.01 µg/ mL ampicillin or 0.144 mg/ mL sulfamethoxazol. In contrast, the growth of several fermenting starter bacteria increased at 1.5 w/w % APE up to 167.65% whereas expansion of yeasts and moulds were unaffected. Neither specific cell-lytic activities of APE could be examined on gram-positive and gram-negative food spoiler nor food fermenting starter bacteria. This study indicates that APE is a bacteriostatic but not a cell-lytic agent against food spoiling bacteria. Instead, the growth of specific lactic acid bacteria was supported by APE. Therefore, APE might stabilize explicit food fermentation processes.

  19. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression.

    Science.gov (United States)

    Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning; Ehrnhoefer, Dagmar E; Graham, Rona K; Kim, Jeong Eun; Bissada, Nagat; Yang, X William; Paganetti, Paolo; Friedlander, Robert M; Leavitt, Blair R; Hayden, Michael R

    2010-04-15

    Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.

  20. Expression of galectin-3 modulates T-cell growth and apoptosis.

    OpenAIRE

    Yang, R.Y.; Hsu, D K; Liu, F T

    1996-01-01

    Galectin-3 is a member (if a large family of beta-galactoside-binding animal lectins. It has been shown that the expression of galectin-3 is upregulated in proliferating cells, suggesting a possible role for this lectin in regulation of cell growth. Previously, we have shown that T cells infected with human T-cell leukemia virus type I express high levels of galectin-3, in contrast to uninfected cells, which do not express detectable amounts of this protein. In this study, we examined growth ...

  1. Epidermal growth factor receptor inhibitor ameliorates excessive astrogliosis and improves the regeneration microenvironment and functional recovery in adult rats following spinal cord injury.

    Science.gov (United States)

    Li, Zai-Wang; Li, Ji-Jun; Wang, Lan; Zhang, Jian-Ping; Wu, Jing-Jing; Mao, Xu-Qiang; Shi, Guo-Feng; Wang, Qian; Wang, Feng; Zou, Jian

    2014-04-05

    Astrogliosis is a common phenomenon after spinal cord injury (SCI). Although this process exerts positive effects on axonal regeneration, excessive astrogliosis imparts negative effects on neuronal repair and recovery. Epidermal growth factor receptor (EGFR) pathway is critical to the regulation of reactive astrogliosis, and therefore is a potential target of therapeutics to better control the response. In this report, we aim to investigate whether blocking EGFR signaling using an EGFR tyrosine kinase specific inhibitor can attenuate reactive astrogliosis and promote functional recovery after a traumatic SCI. The astrocyte scratch injury model in vitro and the weight-drop SCI model in vivo were used as model systems. PD168393 was used to inhibit EGFR signaling activation. Astrocytic activation and phosphorylated EGFR (pEGFR) were observed after immunofluorescence staining and Western blot analysis. The rate of proliferation was determined by immunofluorescence detection of BrdU-incorporating cells located next to the wound. The levels of TNF-α, iNOS, COX-2 and IL-1β in the culture medium under different conditions were assayed by ELISA. Western blot was performed to semi-quantify the expression of EGFR/pEGFR, glial fibrillary acid protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs). Myelin was stained by Luxol Fast Blue Staining. Cresyl violet eosin staining was performed to analyze the lesion cavity volume and neuronal survival following injury. Finally, functional scoring and residual urine recording were performed to show the rats' recovery. EGFR phosphorylation was found to parallel astrocyte activation, and EGFR inhibitor PD168393 potently inhibited scratch-induced reactive astrogliosis and proinflammatory cytokine/mediator secretion of reactive astrocytes in vitro. Moreover, local administration of PD168393 in the injured area suppressed CSPGs production and glial scar formation, and resulted in reduced demyelination and neuronal loss, which

  2. Increased cavernous expression of transforming growth factor-β1 and activation of the Smad signaling pathway affects erectile dysfunction in men with spinal cord injury.

    Science.gov (United States)

    Shin, Tae-Young; Ryu, Ji-Kan; Jin, Hai-Rong; Piao, Shuguang; Tumurbaatar, Munkhbayar; Yin, Guo Nan; Shin, Sun Hwa; Kwon, Mi-Hye; Song, Kang-Moon; Fang, Zheng-Huan; Han, Jee-Young; Kim, Woo Jean; Suh, Jun-Kyu

    2011-05-01

    Transforming growth factor-β1 (TGF-β1) is implicated in bladder fibrosis after spinal cord injury (SCI) and in the fibrosis in the corpus cavernosum tissue after cavernous nerve injury. We investigated the differential expression of TGF-β1 and the Smad transcription factor, the key molecule for the initiation of TGF-β-mediated fibrosis, in cavernous tissue from SCI patients. After obtaining informed consent and approval from the patients and our institutional review board, we enrolled 5 patients with psychogenic erectile dysfunction (ED) (mean age 36.8 years; range 20-50 years) and 10 patients with neurogenic ED from SCI (mean age 38.8 years; range 18-50 years). Cavernous tissues were obtained by percutaneous biopsy and stained with Masson trichrome, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL), or antibodies to TGF-β1 and phospho-Smad2. Semi-quantitative analysis of TGF-β1 and phospho-Smad2 was performed, and the numbers of apoptotic cells were counted. We also quantified the cavernous collagen area with the use of an image analyzer system. The expression of TGF-β1 and phospho-Smad2 protein was significantly higher in the SCI group than in the psychogenic group. The TUNEL assay revealed a higher apoptotic index in the SCI group than in the psychogenic group. Higher TGF-β1 and phospho-Smad2 expression and more apoptotic cells were noted mainly in endothelial cells, smooth muscle cells, and fibroblasts of the SCI group. Double labeling of cavernous tissue with TUNEL and antibody to phospho-Smad2 revealed that most TUNEL-positive cells showed immunoreactivity to phospho-Smad2 staining. Cavernous collagen content was significantly greater in the SCI group than in the psychogenic group. Upregulation of TGF-β1 and activation of the Smad signaling pathway may play important roles in SCI-induced cavernous fibrosis and deterioration of erectile function, which warrants early pharmacological intervention to

  3. Nerve Growth Factor Activation of the Extracellular Signal-Regulated Kinase Pathway Is Modulated by Ca2+ and Calmodulin

    Science.gov (United States)

    Egea, Joaquim; Espinet, Carme; Soler, Rosa M.; Peiró, Sandra; Rocamora, Nativitat; Comella, Joan X.

    2000-01-01

    Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons. Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA, which leads to the activation of several intracellular signaling pathways. Once activated, TrkA also allows for a rapid and moderate increase in intracellular calcium levels, which would contribute to the effects triggered by nerve growth factor in neurons. In this report, we analyzed the relationship of calcium to the activation of the Ras/extracellular signal-regulated kinase pathway in PC12 cells. We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal-regulated kinases after TrkA stimulation. We analyzed the elements of the pathway that lead to this activation, and we observed that calmodulin antagonists completely block the initial Raf-1 activation without affecting the function of upstream elements, such as Ras, Grb2, Shc, and Trk. We have broadened our study to other stimuli that activate extracellular signal-regulated kinases through tyrosine kinase receptors, and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons. Calmodulin seems to regulate the full activation of Raf-1 after Ras activation, since functional Ras is necessary for Raf-1 activation after nerve growth factor stimulation and calmodulin-Sepharose is able to precipitate Raf-1 in a calcium-dependent manner. PMID:10688641

  4. Phosphorus and magnesium interactively modulate the elongation and directional growth of primary roots in Arabidopsis thaliana (L.) Heynh.

    Science.gov (United States)

    Niu, Yaofang; Jin, Gulei; Li, Xin; Tang, Caixian; Zhang, Yongsong; Liang, Yongchao; Yu, Jingquan

    2015-07-01

    A balanced supply of essential nutrients is an important factor influencing root architecture in many plants, yet data related to the interactive effects of two nutrients on root growth are limited. Here, we investigated the interactive effect between phosphorus (P) and magnesium (Mg) on root growth of Arabidopsis grown in pH-buffered agar medium at different P and Mg levels. The results showed that elongation and deviation of primary roots were directly correlated with the amount of P added to the medium but could be modified by the Mg level, which was related to the root meristem activity and stem-cell division. High P enhanced while low P decreased the tip-focused fluorescence signal of auxin biosynthesis, transport, and redistribution during elongation of primary roots; these effects were greater under low Mg than under high Mg. The altered root growth in response to P and Mg supply was correlated with AUX1, PIN2, and PIN3 mRNA abundance and expression and the accumulation of the protein. Application of either auxin influx inhibitor or efflux inhibitor inhibited the elongation and increased the deviation angle of primary roots, and decreased auxin level in root tips. Furthermore, the auxin-transport mutants aux1-22 and eir1-1 displayed reduced root growth and increased the deviation angle. Our data suggest a profound effect of the combined supply of P and Mg on the development of root morphology in Arabidopsis through auxin signals that modulate the elongation and directional growth of primary root and the expression of root differentiation and development genes. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  5. Gut symbiotic bacteria stimulate insect growth and egg production by modulating hexamerin and vitellogenin gene expression.

    Science.gov (United States)

    Lee, Jun Beom; Park, Kyoung-Eun; Lee, Seung Ah; Jang, Seong Han; Eo, Ho Jeong; Jang, Ho Am; Kim, Chan-Hee; Ohbayashi, Tsubasa; Matsuura, Yu; Kikuchi, Yoshitomo; Futahashi, Ryo; Fukatsu, Takema; Lee, Bok Luel

    2017-04-01

    Recent studies have suggested that gut symbionts modulate insect development and reproduction. However, the mechanisms by which gut symbionts modulate host physiologies and the molecules involved in these changes are unclear. To address these questions, we prepared three different groups of the insect Riptortus pedestris: Burkholderia gut symbiont-colonized (Sym) insects, Burkholderia-non-colonized (Apo) insects, and Burkholderia-depleted (Sym(Burk-)) insects, which were fed tetracycline. When the hemolymph proteins of three insects were analyzed by SDS-PAGE, the hexamerin-α, hexamerin-β and vitellogenin-1 proteins of Sym-adults were highly expressed compared to those of Apo- and Sym(Burk-)-insects. To investigate the expression patterns of these three genes during insect development, we measured the transcriptional levels of these genes. The hexamerin-β gene was specifically expressed at all nymphal stages, and its expression was detected 4-5 days earlier in Sym-insect nymphs than that in Apo- and Sym(Burk-)-insects. However, the hexamerin-α and vitellogenin-1 genes were only expressed in adult females, and they were also detected 6-7 days earlier and were 2-fold higher in Sym-adult females than those in the other insects. Depletion of hexamerin-β by RNA interference in 2nd instar Sym-nymphs delayed adult emergence, whereas hexamerin-α and vitellogenin-1 RNA interference in 5th instar nymphs caused loss of color of the eggs of Sym-insects. These results demonstrate that the Burkholderia gut symbiont modulates host development and egg production by regulating production of these three hemolymph storage proteins. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Spinal cord infarction; Spinaler Infarkt

    Energy Technology Data Exchange (ETDEWEB)

    Naumann, N.; Shariat, K.; Ulmer, S.; Stippich, C.; Ahlhelm, F.J. [Universitaetsspital Basel, Abteilung fuer Diagnostische und Interventionelle Neuroradiologie, Klinik fuer Radiologie und Nuklearmedizin, Basel (Switzerland)

    2012-05-15

    Infarction of the spinal cord can cause a variety of symptoms and neurological deficits because of the complex vascular supply of the myelon. The most common leading symptom is distal paresis ranging from paraparesis to tetraplegia caused by arterial ischemia or infarction of the myelon. Venous infarction, however, cannot always be distinguished from arterial infarction based on the symptoms alone. Modern imaging techniques, such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA) assist in preoperative planning of aortic operations to reliably identify not only the most important vascular structure supplying the spinal cord, the artery of Adamkiewicz, but also other pathologies such as tumors or infectious disorders. In contrast to CT, MRI can reliably depict infarction of the spinal cord. (orig.) [German] Die durch einen Rueckenmarkinfarkt verursachte Symptomatik kann aufgrund der komplexen Blutversorgung des Myelons zu unterschiedlichen neurologischen Ausfaellen fuehren. Dabei steht haeufig die durch eine arterielle Minderperfusion des Myelons bedingte Querschnittssymptomatik im Vordergrund. Venoes induzierte Mikrozirkulationsstoerungen sind anhand des neurologischen Befundes klinisch nicht immer von arteriellen Infarkten zu unterscheiden. Die moderne Bildgebung unter Einsatz der CT- (CTA) und MR-Angiographie (MRA) dient dem Ausschluss nichtvaskulaerer Ursachen fuer die Symptomatik wie Entzuendungen und Tumoren sowie der praeoperativen Planung vor der Aortenchirurgie zum Nachweis der fuer die Myelondurchblutung entscheidenden A. Adamkiewicz. Im Gegensatz zur CT kann mittels MRT ein Infarkt im Myelon mit hoher Verlaesslichkeit nachgewiesen werden. (orig.)

  7. Renal heparan sulfate proteoglycans modulate fibroblast growth factor 2 signaling in experimental chronic transplant dysfunction.

    Science.gov (United States)

    Katta, Kirankumar; Boersema, Miriam; Adepu, Saritha; Rienstra, Heleen; Celie, Johanna W A M; Mencke, Rik; Molema, Grietje; van Goor, Harry; Berden, Jo H M; Navis, Gerjan; Hillebrands, Jan-Luuk; van den Born, Jacob

    2013-11-01

    Depending on the glycan structure, proteoglycans can act as coreceptors for growth factors. We hypothesized that proteoglycans and their growth factor ligands orchestrate tissue remodeling in chronic transplant dysfunction. We have previously shown perlecan to be selectively up-regulated in the glomeruli and arteries in a rat renal transplantation model. Using the same model, here we present quantitative RT-PCR profiling data on proteoglycans and growth factors from laser-microdissected glomeruli, arterial tunicae mediae, and neointimae at 12 weeks after transplantation. In glomeruli and neointimae of allografts, selective induction of the matrix heparan sulfate proteoglycan perlecan was observed, along with massive accumulation of fibroblast growth factor 2 (FGF2). Profiling the heparan sulfate polysaccharide side chains revealed conversion from a non-FGF2-binding heparan sulfate phenotype in control and isografted kidneys toward a FGF2-binding phenotype in allografts. In vitro experiments with perlecan-positive rat mesangial cells showed that FGF2-induced proliferation is dependent on sulfation and can be inhibited by exogenously added heparan sulfate. These findings indicate that matrix proteoglycans such as perlecan serve as functional docking platforms for FGF2 in chronic transplant dysfunction. We speculate that heparin-like glycomimetics could be a promising intervention to retard development of glomerulosclerosis and neointima formation in chronic transplant dysfunction. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation

    NARCIS (Netherlands)

    Karpanen, Terhi; Wirzenius, Maria; Mäkinen, Taija; Veikkola, Tanja; Haisma, Hidde J; Achen, Marc G; Stacker, Steven A; Pytowski, Bronislaw; Ylä-Herttuala, Seppo; Alitalo, Kari

    Lymphatic vessel plasticity and stability are of considerable importance when attempting to treat diseases associated with the lymphatic vasculature. Development of lymphatic vessels during embryogenesis is dependent on vascular endothelial growth factor (VEGF)-C but not VEGF-D. Using a recombinant

  9. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Seung Min, E-mail: smjeong@catholic.ac.kr [Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul 137-701 (Korea, Republic of); Hwang, Sunsook; Seong, Rho Hyun [School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2016-03-11

    The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer. - Highlights: • Pancreatic ductal adenocarcinoma (PDAC) exhibits an elevated transferrin receptor (TfR1) expression in comparison with non-transformed pancreatic cells. • TfR1 is required for PDAC growth by regulating mitochondrial respiration and ROS production. • TfR1 functions as a determinant of cell viability to oxidative stress in PDAC cells.

  10. Progesterone and HMOX-1 promote fetal growth by CD8(+) T cell modulation

    NARCIS (Netherlands)

    Solana, Maria Emilia; Kowal, Mirka Katharine; O'Rourke, Greta Eugenia; Horst, Andrea Kristina; Modest, Kathrin; Ploesch, Torsten; Barikbin, Roja; Remus, Chressen Catharina; Berger, Robert G.; Jago, Caitlin; Ho, Hoang; Sass, Gabriele; Parker, Victoria J.; Lydon, John P.; DeMayo, Francesco J.; Hecher, Kurt; Karimi, Khalil; Arck, Petra Clara

    Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved

  11. Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

    NARCIS (Netherlands)

    Solano, María Emilia; Kowal, Mirka Katharina; O'Rourke, Greta Eugenia; Horst, Andrea Kristina; Modest, Kathrin; Plösch, Torsten; Barikbin, Roja; Remus, Chressen Catharina; Berger, Robert G; Jago, Caitlin; Ho, Hoang; Sass, Gabriele; Parker, Victoria J; Lydon, John P; DeMayo, Francesco J; Hecher, Kurt; Karimi, Khalil; Arck, Petra Clara

    Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children. Placental insufficiency is often associated with IUGR; however, the molecular mechanisms involved

  12. Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells.

    Directory of Open Access Journals (Sweden)

    Alisha M Mendonsa

    Full Text Available Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.

  13. Modulation of the leptin receptor mediates tumor growth and migration of pancreatic cancer cells.

    Science.gov (United States)

    Mendonsa, Alisha M; Chalfant, Madeleine C; Gorden, Lee D; VanSaun, Michael N

    2015-01-01

    Obesity has been implicated as a significant risk factor for development of pancreatic cancer. In the setting of obesity, a systemic chronic inflammatory response is characterized by alterations in the production and secretion of a wide variety of growth factors. Leptin is a hormone whose level increases drastically in the serum of obese patients. High fat diet induced obesity in mice leads to an overall increased body weight, pancreatic weight, serum leptin, and pancreatic tissue leptin levels. Here we report the contribution of obesity and leptin to pancreatic cancer growth utilizing an in vivo orthotopic murine pancreatic cancer model, which resulted in increased tumor proliferation with concomitant increased tumor burden in the diet induced obese mice compared to lean mice. Human and murine pancreatic cancer cell lines were found to express the short as well as the long form of the leptin receptor and functionally responded to leptin induced activation through an increased phosphorylation of AKT473. In vitro, leptin stimulation increased cellular migration which was blocked by addition of a PI3K inhibitor. In vivo, depletion of the leptin receptor through shRNA knockdown partially abrogated increased orthotopic tumor growth in obese mice. These findings suggest that leptin contributes to pancreatic tumor growth through activation of the PI3K/AKT pathway, which promotes pancreatic tumor cell migration.

  14. Volatiles emitted by Bacillus sp. BCT9 act as growth modulating agents on Lactuca sativa seedlings.

    Science.gov (United States)

    Fincheira, Paola; Parra, Leonardo; Mutis, Ana; Parada, Maribel; Quiroz, Andrés

    2017-10-01

    Chemical products are applied during horticulture to increase food production, but the environmental problems resulting from these applications have led to a search for more sustainable products. Volatile organic compounds (VOCs) demonstrating plant growth promoter (PGP) activity released by bacterial species have emerged as alternatives, but their effects on Lactuca sativa growth are unknown. In this study, VOCs released by Bacillus sp. BCT9 cultures grown in different media (Methyl Red & Voges Proskauer, Murashige & Skoog and nutrient media) at concentrations of 0.1, 0.2, 0.5 and 0.7 (measured as the absorbance, λ=600nm) were tested to evaluate their activity as growth inducers of L. sativa after 10days of exposure. Lower concentrations of BCT9 increased root length, and higher concentrations induced shoot length and lateral root length. The dry weight and number of lateral roots increased similarly, independent of concentration, for VOCs produced in all culture media. BCT9 cultures grown in Methyl Red & Voges Proskauer medium as bioactive compounds with or without lanolin. These VOCs increased shoot length, root length and dry weight at low concentrations, independent of the presence of lanolin. Lateral root length increased with the application of 2-nonanone (50ppm) and 2-undecanone (0.05ppm). Based on these results, the use of bioactive volatiles as growth inducers of horticultural species represents an alternative or complementary strategy. Copyright © 2017 Elsevier GmbH. All rights reserved.

  15. Transient energy growth modulation by temperature dependent transport properties in a stratified plane Poiseuille flow

    NARCIS (Netherlands)

    Rinaldi, E.; Boersma, B.J.; Pecnik, R.

    2015-01-01

    We investigate the effect of temperature dependent thermal conductivity ? and isobaric specific heat c_P on the transient amplification of perturbations in a thermally stratified laminar plane Poiseuille flow. It is shown that for decreasing thermal conductivity the maximum transient energy growth

  16. Analysis of collagen and glucose modulated cell growth within tissue engineered scaffolds.

    Science.gov (United States)

    Chung, C A; Ho, Szu-Ying

    2010-04-01

    The strategy of tissue engineering includes seeding cells onto porous scaffolds. The cellular construct is cultured in vitro for a period of time before transplantation for the patient. Because of the intrinsic complexity of biological systems, it is valuable to have models of simulation that can assess the culture conditions and optimize experiments. This work presents a mathematical model to account for the effects of glucose and type II collagen on chondrocyte growth under static culture conditions. Dependence of cell growth on collagen was assumed as a biphasic function of collagen quantity, whereby the cell growth rate increases and then decreases with increasing collagen content. Results from simulation were compared with experimental data in literature. The model was then applied to investigate the effects of cell seeding area, demonstrating the spatiotemporal evolution of cell distribution in scaffolds. Results show that the conventional uniform seeding method may not be a good way of gaining uniform and large cell number densities at the final stage of cultivation. A seeding mode that has cells reside initially in the middle area of scaffold was shown to be able to not only reduce the diffusion limitation of nutrients but also weaken the inhibiting impact of aggregated collagen on cell growth. Therefore the middle seeding mode may result in better cell amounts and uniformities for developing tissue engineered constructs.

  17. Nutritional modulation of IGF-1 in relation to growth and body condition in Sceloporus lizards.

    Science.gov (United States)

    Duncan, Christine A; Jetzt, Amanda E; Cohick, Wendie S; John-Alder, Henry B

    2015-05-15

    Nutrition and energy balance are important regulators of growth and the growth hormone/insulin-like growth factor (GH/IGF) axis. However, our understanding of these functions does not extend uniformly to all classes of vertebrates and is mainly limited to controlled laboratory conditions. Lizards can be useful models to improve our understanding of the nutritional regulation of the GH/IGF-1 axis because many species are relatively easy to observe and manipulate both in the laboratory and in the field. In the present study, the effects of variation in food intake on growth, body condition, and hepatic IGF-1 mRNA levels were measured in (1) juveniles of Sceloporus jarrovii maintained on a full or 1/3 ration and (2) hatchlings of Sceloporus undulatus subjected to full or zero ration with or without re-feeding. These parameters plus plasma IGF-1 were measured in a third experiment using adults of S. undulatus subjected to full or zero ration with or without re-feeding. In all experiments, plasma corticosterone was measured as an anticipated indicator of nutritional stress. In S. jarrovii, growth and body condition were reduced but lizards remained in positive energy balance on 1/3 ration, and hepatic IGF-1 mRNA and plasma corticosterone were not affected in comparison to full ration. In S. undulatus, growth, body condition, hepatic IGF-1 mRNA, and plasma IGF-1 were all reduced by zero ration and restored by refeeding. Plasma corticosterone was increased in response to zero ration and restored by full ration in hatchlings but not adults of S. undulatus. These data indicate that lizards conform to the broader vertebrate model in which severe food deprivation and negative energy balance is required to attenuate systemic IGF-1 expression. However, when animals remain in positive energy balance, reduced food intake does not appear to affect systemic IGF-1. Consistent with other studies on lizards, the corticosterone response to reduced food intake is an unreliable indicator

  18. Sphingosine 1-Phosphate Receptor 1 Modulates CNTF-Induced Axonal Growth and Neuroprotection in the Mouse Visual System

    Directory of Open Access Journals (Sweden)

    Sandrine Joly

    2017-01-01

    Full Text Available The lack of axonal regeneration and neuronal cell death causes permanent neurological deficits in the injured CNS. Using the classical CNS injury model of optic nerve crush in mice, ciliary neurotrophic factor (CNTF was found to stimulate retinal ganglion cell (RGC survival and axonal growth, but in an incomplete fashion. The elucidation of molecular mechanisms impairing CNTF-induced axonal regeneration is paramount to promote visual recovery. In the present study, we sought to evaluate the contribution of sphingosine 1-phosphate receptor 1 (S1PR1 to the neuroprotective and regenerative effects of CNTF. The transduction of retinal cells with adeno-associated viruses (AAV allowed to activate CNTF/signal transducer and activator of transcription 3 (Stat3 signaling and to modulate S1PR1 expression in RGCs. Our results showed that CNTF/Stat3 prevented injury-induced S1PR1 downregulation. Silencing S1PR1 in RGCs significantly enhanced CNTF-induced axonal growth in the injured optic nerve. In contrast, RGC survival was markedly decreased when S1PR1 was repressed with viral vectors. The level of phosphorylated Stat3 (P-Stat3, an intracellular mediator of CNTF, did not fluctuate after S1PR1 inhibition and CNTF stimulation. Collectively, these results suggest that S1PR1 acts as a major regulator of retinal neuron survival and restricts the RGC growth response induced by CNTF.

  19. Spinal cord injury reveals multilineage differentiation of ependymal cells.

    Directory of Open Access Journals (Sweden)

    Konstantinos Meletis

    2008-07-01

    Full Text Available Spinal cord injury often results in permanent functional impairment. Neural stem cells present in the adult spinal cord can be expanded in vitro and improve recovery when transplanted to the injured spinal cord, demonstrating the presence of cells that can promote regeneration but that normally fail to do so efficiently. Using genetic fate mapping, we show that close to all in vitro neural stem cell potential in the adult spinal cord resides within the population of ependymal cells lining the central canal. These cells are recruited by spinal cord injury and produce not only scar-forming glial cells, but also, to a lesser degree, oligodendrocytes. Modulating the fate of ependymal progeny after spinal cord injury may offer an alternative to cell transplantation for cell replacement therapies in spinal cord injury.

  20. The composition of Camembert cheese-ripening cultures modulates both mycelial growth and appearance.

    Science.gov (United States)

    Lessard, Marie-Hélène; Bélanger, Gaétan; St-Gelais, Daniel; Labrie, Steve

    2012-03-01

    The fungal microbiota of bloomy-rind cheeses, such as Camembert, forms a complex ecosystem that has not been well studied, and its monitoring during the ripening period remains a challenge. One limitation of enumerating yeasts and molds on traditional agar media is that hyphae are multicellular structures, and colonies on a petri dish rarely develop from single cells. In addition, fungi tend to rapidly invade agar surfaces, covering small yeast colonies and resulting in an underestimation of their number. In this study, we developed a real-time quantitative PCR (qPCR) method using TaqMan probes to quantify a mixed fungal community containing the most common dairy yeasts and molds: Penicillium camemberti, Geotrichum candidum, Debaryomyces hansenii, and Kluyveromyces lactis on soft-cheese model curds (SCMC). The qPCR method was optimized and validated on pure cultures and used to evaluate the growth dynamics of a ripening culture containing P. camemberti, G. candidum, and K. lactis on the surface of the SCMC during a 31-day ripening period. The results showed that P. camemberti and G. candidum quickly dominated the ecosystem, while K. lactis remained less abundant. When added to this ecosystem, D. hansenii completely inhibited the growth of K. lactis in addition to reducing the growth of the other fungi. This result was confirmed by the decrease in the mycelium biomass on SCMC. This study compares culture-dependent and qPCR methods to successfully quantify complex fungal microbiota on a model curd simulating Camembert-type cheese.

  1. The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.

    Directory of Open Access Journals (Sweden)

    Jacques Montagne

    2010-05-01

    Full Text Available S6 kinases (S6Ks act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR, Drosophila hormone receptor 3 (DHR3, a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

  2. The effect of radiation of LED modules on the growth of dill (Anethum graveolens L.

    Directory of Open Access Journals (Sweden)

    Frąszczak Barbara

    2016-01-01

    Full Text Available Light quality is thought to affect the growth and development of plants. We examined how light influences the growth and content of some chemical compounds in dill (Anethum graveolens L.. The plants were grown under different light quality. The share of orange and green light in the spectrum was constant and amounted to 10% for either colour. In the first combination (A, 70/10, there was 70% of red light and 10% of blue light. Other combinations had the following proportions: B 60/20, C 50/30, D 40/40 and E 30/50 of red and blue light. The PPFD was about 155 μmol m-2 s-1. Blue light inhibited the elongation growth as well as leaf area. It had positive influence on the accumulation of dry mass, glucose and fructose in the herb. In the combinations with higher percentage of red light the plants were characterised by higher content of essential oils, macronutrients and zinc. To sum up, we can say that the proportion of red and blue light has significant influence on the morphological qualities, chemical composition and dynamics of photosynthesis in these plants. On the other hand, the selection of spectral composition of LEDs will depend on the result we want to achieve.

  3. Transferrin receptor regulates pancreatic cancer growth by modulating mitochondrial respiration and ROS generation.

    Science.gov (United States)

    Jeong, Seung Min; Hwang, Sunsook; Seong, Rho Hyun

    2016-03-11

    The transferrin receptor (TfR1) is upregulated in malignant cells and its expression is associated with cancer progression. Because of its pre-eminent role in cell proliferation, TfR1 has been an important target for the development of cancer therapy. Although TfR1 is highly expressed in pancreatic cancers, what it carries out in these refractory cancers remains poorly understood. Here we report that TfR1 supports mitochondrial respiration and ROS production in human pancreatic ductal adenocarcinoma (PDAC) cells, which is required for their tumorigenic growth. Elevated TfR1 expression in PDAC cells contributes to oxidative phosphorylation, which allows for the generation of ROS. Importantly, mitochondrial-derived ROS are essential for PDAC growth. However, exogenous iron supplement cannot rescue the defects caused by TfR1 knockdown. Moreover, we found that TfR1 expression determines PDAC cells sensitivity to oxidative stress. Together, our findings reveal that TfR1 can contribute to the mitochondrial respiration and ROS production, which have essential roles in growth and survival of pancreatic cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Increasing carbon availability stimulates growth and secondary metabolites via modulation of phytohormones in winter wheat.

    Science.gov (United States)

    Huang, Jianbei; Reichelt, Michael; Chowdhury, Somak; Hammerbacher, Almuth; Hartmann, Henrik

    2017-02-01

    Phytohormones play important roles in plant acclimation to changes in environmental conditions. However, their role in whole-plant regulation of growth and secondary metabolite production under increasing atmospheric CO2 concentrations ([CO2]) is uncertain but crucially important for understanding plant responses to abiotic stresses. We grew winter wheat (Triticum aestivum) under three [CO2] (170, 390, and 680 ppm) over 10 weeks, and measured gas exchange, relative growth rate (RGR), soluble sugars, secondary metabolites, and phytohormones including abscisic acid (ABA), auxin (IAA), jasmonic acid (JA), and salicylic acid (SA) at the whole-plant level. Our results show that, at the whole-plant level, RGR positively correlated with IAA but not ABA, and secondary metabolites positively correlated with JA and JA-Ile but not SA. Moreover, soluble sugars positively correlated with IAA and JA but not ABA and SA. We conclude that increasing carbon availability stimulates growth and production of secondary metabolites via up-regulation of auxin and jasmonate levels, probably in response to sugar-mediated signalling. Future low [CO2] studies should address the role of reactive oxygen species (ROS) in leaf ABA and SA biosynthesis, and at the transcriptional level should focus on biosynthetic and, in particular, on responsive genes involved in [CO2]-induced hormonal signalling pathways. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  5. The cytokinin response factors modulate root and shoot growth and promote leaf senescence in Arabidopsis.

    Science.gov (United States)

    Raines, Tracy; Shanks, Carly; Cheng, Chia-Yi; McPherson, Duncan; Argueso, Cristiana T; Kim, Hyo J; Franco-Zorrilla, José M; López-Vidriero, Irene; Solano, Roberto; Vaňková, Radomíra; Schaller, G Eric; Kieber, Joseph J

    2016-01-01

    The cytokinin response factors (CRFs) are a group of related AP2/ERF transcription factors that are transcriptionally induced by cytokinin. Here we explore the role of the CRFs in Arabidopsis thaliana growth and development by analyzing lines with decreased and increased CRF function. While single crf mutations have no appreciable phenotypes, disruption of multiple CRFs results in larger rosettes, delayed leaf senescence, a smaller root apical meristem (RAM), reduced primary and lateral root growth, and, in etiolated seedlings, shorter hypocotyls. In contrast, overexpression of CRFs generally results in the opposite phenotypes. The crf1,2,5,6 quadruple mutant is embryo lethal, indicating that CRF function is essential for embryo development. Disruption of the CRFs results in partially insensitivity to cytokinin in a root elongation assay and affects the basal expression of a significant number of cytokinin-regulated genes, including the type-A ARRs, although it does not impair the cytokinin induction of the type-A ARRs. Genes encoding homeobox transcription factors are mis-expressed in the crf1,3,5,6 mutant, including STIMPY/WOX9 that is required for root and shoot apical meristem maintenance roots and which has previously been linked to cytokinin. These results indicate that the CRF transcription factors play important roles in multiple aspects of plant growth and development, in part through a complex interaction with cytokinin signaling. © 2015 The Authors The Plant Journal © 2015 John Wiley & Sons Ltd.

  6. Prostate-Specific Antigen Modulates the Expression of Genes Involved in Prostate Tumor Growth

    Directory of Open Access Journals (Sweden)

    B. Bindukumar

    2005-03-01

    Full Text Available Prostate-specific antigen (PSA is a serine protease that is widely used as a surrogate marker in the early diagnosis and management of prostate cancer. The physiological relevance of tissue PSA levels and their role in prostate tumor growth and metastasis are not known. Free-PSA (f-PSA was purified to homogeneity from human seminal plasma by column chromatography, eliminating hk2 and all known PSA complexes and retaining its protease activity. Confluent monolayers of prostate cancer cell lines, PC-3M and LNCaP, were treated with f-PSA in a series of in vitro experiments to determine the changes in expression of various genes that are known to regulate tumor growth and metastasis. Gene array, quantitative polymerase chain reaction (QPCR, enzyme-linked immunosorbent assay (ELISA results show significant changes in the expression of various cancer-related genes in PC-3M and LNCaP cells treated with f-PSA. In a gene array analysis of PC-3M cells treated with 10 4tM f-PSA, 136 genes were upregulated and 137 genes were downregulated. In LNCaP cells treated with an identical concentration of f-PSA, a total of 793 genes was regulated. QPCR analysis reveals that the genes for urokinase-type plasminogen activator (uPA, VEGF, Pim-1 oncogene, known to promote tumor growth, were significantly downregulated, whereas IFN-γ, known to be a tumor-suppressor gene, was significantly upregulated in f-PSA-treated PC-3M cells. The effect of f-PSA on VEGF and IFN-γ gene expression and on protein release in PC-3M cells was distinctly dose-dependent. In vivo studies showed a significant reduction (P = .03 in tumor load when fPSA was administered in the tumor vicinity of PC-3M tumor-bearing BALB/c nude mice. Our data support the hypothesis that f-PSA plays a significant role in prostate tumor growth by regulating various proangiogenic and antiangiogenic growth factors.

  7. Transforming growth factor beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.

    Science.gov (United States)

    Chen, Kui; Mehta, Jawahar L; Li, Dayuan; Joseph, Lija; Joseph, Jacob

    2004-12-10

    Angiotensin II (Ang II) is a powerful mediator of adverse cardiac remodeling and fibrosis. However, the mechanisms of Ang II-induced myocardial fibrosis remain to be clarified. We postulated that Ang II alters transforming growth factor beta (TGF-beta) receptor expression, specifically that of endoglin, and thereby modulates cardiac fibroblast (CF) collagen metabolism. Experiments were conducted using CF from adult Sprague Dawley rats to determine the expression of TGF-beta1 receptors including endoglin, and the role of Ang II type 1 (AT1) and type 2 (AT2) receptors, and MAPK p42/44 in this process. The functional role of endoglin in modulating Ang II effects on matrix metalloproteinase-1 (MMP-1) and type I collagen expression was also analyzed. Endoglin gene and protein expression were consistently identified in quiescent CFs. Ang II increased the expression of endoglin mRNA and protein in a concentration and time-dependent manner, with no effect on TGF-beta receptors I and II expression. This effect was AT1 receptor mediated, because AT1 receptor antagonists valsartan, candesartan, and losartan inhibited Ang II-induced endoglin expression, whereas the AT2 receptor antagonist PD123319 had no effect. MAPKp42/44 inhibition attenuated Ang II-induced endoglin expression. Ang II-induced decrease in MMP-1 protein expression and increase in type I collagen protein expression were both blocked by a specific endoglin antibody. Hence, our results indicate that endoglin is upregulated in CFs by Ang II via the AT1 receptor and modulates profibrotic effects of Ang II. These findings provide novel insights into Ang II-induced cardiac remodeling.

  8. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation Pediatric Spinal Cord Injuries Video Library SCI Medical ... Facts and Figures Care and Treatment After SCI Spinal Cord Injury Rehabilitation Pediatric Spinal Cord Injuries Video Library SCI Medical ...

  9. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... is a spinal cord injury? play_arrow How does the spinal cord work? play_arrow Why is ... spinal cord injury important? play_arrow What role does “compression” play in a spinal cord injury? play_ ...

  10. Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

    Science.gov (United States)

    Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

    2016-08-01

    Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

  11. Flow-induced morphological instabilities due to temporally-modulated stagnation-point flow. [in single crystals growth by directionally-solidifying interface

    Science.gov (United States)

    Merchant, G. J.; Davis, S. H.

    1989-01-01

    The influence of periodically-modulated planar stagnation-point flow on the morphological stability of a directionally-solidifying interface is presently considered with a view to the effect of unsteady nonparallel flows on single-crystal growth. The modeling of the system assumes that the viscous boundary layer thickness is much greater than that of the solute boundary layer, and that the modulation frequency is much smaller than the strength of plane stagnation-point flow. The solidifying interface is either stabilized or destabilized depending on the ratio of the period of modulation to the solute-diffusion time.

  12. Alternative Growth Promoters Modulate Broiler Gut Microbiome and Enhance Body Weight Gain.

    Science.gov (United States)

    Salaheen, Serajus; Kim, Seon-Woo; Haley, Bradd J; Van Kessel, Jo Ann S; Biswas, Debabrata

    2017-01-01

    Antibiotic growth promoters (AGPs) are frequently used to enhance weight-gain in poultry production. However, there has been increasing concern over the impact of AGP on the emergence of antibiotic resistance in zoonotic bacterial pathogens in the microbial community of the poultry gut. In this study, we adopted mass-spectrophotometric, phylogenetic, and shotgun-metagenomic approaches to evaluate bioactive phenolic extracts (BPE) from blueberry (Vaccinium corymbosum) and blackberry (Rubus fruticosus) pomaces as AGP alternatives in broilers. We conducted two trials with 100 Cobb-500 broiler chicks (in each trial) in four equal groups that were provided water with no supplementation, supplemented with AGP (tylosin, neomycin sulfate, bacitracin, erythromycin, and oxytetracycline), or supplemented with 0.1 g Gallic acid equivalent (GAE)/L or 1.0 g GAE/L (during the last 72 h before euthanasia) of BPE for 6 weeks. When compared with the control group (water only), the chickens supplemented with AGP and 0.1 g GAE/L of BPE gained 9.5 and 5.8% more body weight, respectively. The microbiomes of both the AGP- and BPE-treated chickens had higher Firmicutes to Bacteroidetes ratios. AGP supplementation appeared to be associated with higher relative abundance of bacteriophages and unique cecal resistomes compared with BPE supplementation or control. Functional characterization of cecal microbiomes revealed significant animal-to-animal variation in the relative abundance of genes involved in energy and carbohydrate metabolism. These findings established a baseline upon which mechanisms of plant-based performance enhancers in regulation of animal growth can be investigated. In addition, the data will aid in designing alternate strategies to improve animal growth performance and consequently production.

  13. Alternative Growth Promoters Modulate Broiler Gut Microbiome and Enhance Body Weight Gain

    Directory of Open Access Journals (Sweden)

    Serajus Salaheen

    2017-10-01

    Full Text Available Antibiotic growth promoters (AGPs are frequently used to enhance weight-gain in poultry production. However, there has been increasing concern over the impact of AGP on the emergence of antibiotic resistance in zoonotic bacterial pathogens in the microbial community of the poultry gut. In this study, we adopted mass-spectrophotometric, phylogenetic, and shotgun-metagenomic approaches to evaluate bioactive phenolic extracts (BPE from blueberry (Vaccinium corymbosum and blackberry (Rubus fruticosus pomaces as AGP alternatives in broilers. We conducted two trials with 100 Cobb-500 broiler chicks (in each trial in four equal groups that were provided water with no supplementation, supplemented with AGP (tylosin, neomycin sulfate, bacitracin, erythromycin, and oxytetracycline, or supplemented with 0.1 g Gallic acid equivalent (GAE/L or 1.0 g GAE/L (during the last 72 h before euthanasia of BPE for 6 weeks. When compared with the control group (water only, the chickens supplemented with AGP and 0.1 g GAE/L of BPE gained 9.5 and 5.8% more body weight, respectively. The microbiomes of both the AGP- and BPE-treated chickens had higher Firmicutes to Bacteroidetes ratios. AGP supplementation appeared to be associated with higher relative abundance of bacteriophages and unique cecal resistomes compared with BPE supplementation or control. Functional characterization of cecal microbiomes revealed significant animal-to-animal variation in the relative abundance of genes involved in energy and carbohydrate metabolism. These findings established a baseline upon which mechanisms of plant-based performance enhancers in regulation of animal growth can be investigated. In addition, the data will aid in designing alternate strategies to improve animal growth performance and consequently production.

  14. Arabidopsis growth and defense are modulated by bacterial quorum sensing molecules.

    Science.gov (United States)

    Schenk, Sebastian T; Stein, Elke; Kogel, Karl-Heinz; Schikora, Adam

    2012-02-01

    N-acyl-homoserine lactones (AHLs) play an important role in the communication within the rhizosphere; they serve as a chemical base for interactions within and between different species of Gram-negative bacteria. Not only bacteria, also plants perceive and react to AHLs with diverse responses. Here we describe a negative correlation between the length of AHLs' lipid chains and the observed growth promotion in Arabidopsis thaliana. Moreover, we speculate on a positive correlation between the reinforcement of defense mechanisms and the length of the lipid moieties. Observation presented here may be of great importance for understanding of the complex interplay between plants and their environment, as well as for agronomic applications.

  15. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury

    NARCIS (Netherlands)

    F. Hellal (Farida); A. Hurtado (Andres); J. Ruschel (Jörg); K.C. Flynn (Kevin); C.J. Laskowski (Claudia); M. Umlauf (Martina); L.C. Kapitein (Lukas); D. Strikis (Dinara); V. Lemmon (Vance); J. Bixby (John); C.C. Hoogenraad (Casper); F. Bradke (Frank)

    2011-01-01

    textabstractHypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents through

  16. Epidermal Growth Factor Receptor Expression Modulates Antitumor Efficacy of Vandetanib or Cediranib Combined With Radiotherapy in Human Glioblastoma Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Wachsberger, Phyllis R., E-mail: Phyllis.wachsberger@jeffersonhospital.org [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Lawrence, Yaacov R.; Liu Yi; Daroczi, Borbala [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Xu Xia [Merck Research Laboratories, North Wales, Pennsylvania (United States); Dicker, Adam P. [Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2012-01-01

    Purpose: The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression. Methods and Materials: Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers. Results: In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib. Conclusions: EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a &apos

  17. Antimicrobial growth promoters modulate host responses in mice with a defined intestinal microbiota.

    Science.gov (United States)

    Brown, Kirsty; Zaytsoff, Sarah J M; Uwiera, Richard R E; Inglis, G Douglas

    2016-12-08

    Antibiotics can promote growth in livestock (antimicrobial growth promoters, AGPs), however lack of knowledge regarding mechanisms has hampered the development of effective non-antibiotic alternatives. Antibiotics affect eukaryotic cells at therapeutic concentrations, yet effects of AGPs on host physiology are relatively understudied, partially due to the complexity of host-microorganism interactions within the gastrointestinal tract. To determine the direct effects of AGPs on the host, we generated Altered Schaedler Flora (ASF) mice, and administered chlortetracycline (CTC) and tylosin phosphate (TYL) in feed. Mice were challenged with Citrobacter rodentium to determine how AGPs alter host responses to physiological stress. Although CTC and TYL had inconsistent effects on the ASF taxa, AGPs protected mice from weight loss following C. rodentium inoculation. Mice treated with either CTC or TYL had lower expression of βd1 and Il17a in the intestine and had a robust induction of Il17a and Il10. Furthermore, AGP administration resulted in a lower hepatic expression of acute phase proteins (Saa1, Hp, and Cp) in liver tissue, and ameliorated C. rodentium-induced reductions in the expression of genes involved in lipogenesis (Hmgcl and Fabp1). Collectively, this indicates that AGPs directly affect host physiology, and highlights important considerations in the development of non-antibiotic alternatives.

  18. Production of fungal and bacterial growth modulating secondary metabolites is widespread among mycorrhiza-associated streptomycetes

    Science.gov (United States)

    2012-01-01

    Background Studies on mycorrhiza associated bacteria suggest that bacterial-fungal interactions play important roles during mycorrhiza formation and affect plant health. We surveyed Streptomyces Actinobacteria, known as antibiotic producers and antagonists of fungi, from Norway spruce mycorrhizas with predominantly Piloderma species as the fungal partner. Results Fifteen Streptomyces isolates exhibited substantial variation in inhibition of tested mycorrhizal and plant pathogenic fungi (Amanita muscaria, Fusarium oxysporum, Hebeloma cylindrosporum, Heterobasidion abietinum, Heterobasidion annosum, Laccaria bicolor, Piloderma croceum). The growth of the mycorrhiza-forming fungus Laccaria bicolor was stimulated by some of the streptomycetes, and Piloderma croceum was only moderately affected. Bacteria responded to the streptomycetes differently than the fungi. For instance the strain Streptomyces sp. AcM11, which inhibited most tested fungi, was less inhibitory to bacteria than other tested streptomycetes. The determined patterns of Streptomyces-microbe interactions were associated with distinct patterns of secondary metabolite production. Notably, potentially novel metabolites were produced by strains that were less antagonistic to fungi. Most of the identified metabolites were antibiotics (e.g. cycloheximide, actiphenol) and siderophores (e.g. ferulic acid, desferroxiamines). Plant disease resistance was activated by a single streptomycete strain only. Conclusions Mycorrhiza associated streptomycetes appear to have an important role in inhibiting the growth of fungi and bacteria. Additionally, our study indicates that the Streptomyces strains, which are not general antagonists of fungi, may produce still un-described metabolites. PMID:22852578

  19. Production of fungal and bacterial growth modulating secondary metabolites is widespread among mycorrhiza-associated streptomycetes

    Directory of Open Access Journals (Sweden)

    Schrey Silvia D

    2012-08-01

    Full Text Available Abstract Background Studies on mycorrhiza associated bacteria suggest that bacterial-fungal interactions play important roles during mycorrhiza formation and affect plant health. We surveyed Streptomyces Actinobacteria, known as antibiotic producers and antagonists of fungi, from Norway spruce mycorrhizas with predominantly Piloderma species as the fungal partner. Results Fifteen Streptomyces isolates exhibited substantial variation in inhibition of tested mycorrhizal and plant pathogenic fungi (Amanita muscaria, Fusarium oxysporum, Hebeloma cylindrosporum, Heterobasidion abietinum, Heterobasidion annosum, Laccaria bicolor, Piloderma croceum. The growth of the mycorrhiza-forming fungus Laccaria bicolor was stimulated by some of the streptomycetes, and Piloderma croceum was only moderately affected. Bacteria responded to the streptomycetes differently than the fungi. For instance the strain Streptomyces sp. AcM11, which inhibited most tested fungi, was less inhibitory to bacteria than other tested streptomycetes. The determined patterns of Streptomyces-microbe interactions were associated with distinct patterns of secondary metabolite production. Notably, potentially novel metabolites were produced by strains that were less antagonistic to fungi. Most of the identified metabolites were antibiotics (e.g. cycloheximide, actiphenol and siderophores (e.g. ferulic acid, desferroxiamines. Plant disease resistance was activated by a single streptomycete strain only. Conclusions Mycorrhiza associated streptomycetes appear to have an important role in inhibiting the growth of fungi and bacteria. Additionally, our study indicates that the Streptomyces strains, which are not general antagonists of fungi, may produce still un-described metabolites.

  20. Cyanobacterial Alkanes Modulate Photosynthetic Cyclic Electron Flow to Assist Growth under Cold Stress.

    Science.gov (United States)

    Berla, Bertram M; Saha, Rajib; Maranas, Costas D; Pakrasi, Himadri B

    2015-10-13

    All cyanobacterial membranes contain diesel-range C15-C19 hydrocarbons at concentrations similar to chlorophyll. Recently, two universal but mutually exclusive hydrocarbon production pathways in cyanobacteria were discovered. We engineered a mutant of Synechocystis sp. PCC 6803 that produces no alkanes, which grew poorly at low temperatures. We analyzed this defect by assessing the redox kinetics of PSI. The mutant exhibited enhanced cyclic electron flow (CEF), especially at low temperature. CEF raises the ATP:NADPH ratio from photosynthesis and balances reductant requirements of biosynthesis with maintaining the redox poise of the electron transport chain. We conducted in silico flux balance analysis and showed that growth rate reaches a distinct maximum for an intermediate value of CEF equivalent to recycling 1 electron in 4 from PSI to the plastoquinone pool. Based on this analysis, we conclude that the lack of membrane alkanes causes higher CEF, perhaps for maintenance of redox poise. In turn, increased CEF reduces growth by forcing the cell to use less energy-efficient pathways, lowering the quantum efficiency of photosynthesis. This study highlights the unique and universal role of medium-chain hydrocarbons in cyanobacterial thylakoid membranes: they regulate redox balance and reductant partitioning in these oxygenic photosynthetic cells under stress.

  1. G Protein-Coupled Estrogen Receptor-Selective Ligands Modulate Endometrial Tumor Growth

    Directory of Open Access Journals (Sweden)

    Whitney K. Petrie

    2013-01-01

    Full Text Available Endometrial carcinoma is the most common cancer of the female reproductive tract. GPER/GPR30 is a 7-transmembrane spanning G protein-coupled receptor that has been identified as the third estrogen receptor, in addition to ERα and ERβ. High GPER expression is predictive of poor survival in endometrial and ovarian cancer, but despite this, the estrogen-mediated signaling pathways and specific estrogen receptors involved in endometrial cancer remain unclear. Here, employing ERα-negative Hec50 endometrial cancer cells, we demonstrate that GPER mediates estrogen-stimulated activation of ERK and PI3K via matrix metalloproteinase activation and subsequent transactivation of the EGFR and that ER-targeted therapeutic agents (4-hydroxytamoxifen, ICI182,780/fulvestrant, and Raloxifene, the phytoestrogen genistein, and the “ERα-selective” agonist propylpyrazole triol also function as GPER agonists. Furthermore, xenograft tumors of Hec50 cells yield enhanced growth with G-1 and estrogen, the latter being inhibited by GPER-selective pharmacologic antagonism with G36. These results have important implications with respect to the use of putatively ER-selective ligands and particularly for the widespread long-term use of “ER-targeted” therapeutics. Moreover, our findings shed light on the potential mechanisms of SERM/SERD side effects reported in many clinical studies. Finally, our results provide the first demonstration that pharmacological inhibition of GPER activity in vivo prevents estrogen-mediated tumor growth.

  2. Production of fungal and bacterial growth modulating secondary metabolites is widespread among mycorrhiza-associated streptomycetes.

    Science.gov (United States)

    Schrey, Silvia D; Erkenbrack, Eric; Früh, Elisabeth; Fengler, Svenja; Hommel, Kerstin; Horlacher, Nadine; Schulz, Dirk; Ecke, Margret; Kulik, Andreas; Fiedler, Hans-Peter; Hampp, Rüdiger; Tarkka, Mika T

    2012-08-02

    Studies on mycorrhiza associated bacteria suggest that bacterial-fungal interactions play important roles during mycorrhiza formation and affect plant health. We surveyed Streptomyces Actinobacteria, known as antibiotic producers and antagonists of fungi, from Norway spruce mycorrhizas with predominantly Piloderma species as the fungal partner. Fifteen Streptomyces isolates exhibited substantial variation in inhibition of tested mycorrhizal and plant pathogenic fungi (Amanita muscaria, Fusarium oxysporum, Hebeloma cylindrosporum, Heterobasidion abietinum, Heterobasidion annosum, Laccaria bicolor, Piloderma croceum). The growth of the mycorrhiza-forming fungus Laccaria bicolor was stimulated by some of the streptomycetes, and Piloderma croceum was only moderately affected. Bacteria responded to the streptomycetes differently than the fungi. For instance the strain Streptomyces sp. AcM11, which inhibited most tested fungi, was less inhibitory to bacteria than other tested streptomycetes. The determined patterns of Streptomyces-microbe interactions were associated with distinct patterns of secondary metabolite production. Notably, potentially novel metabolites were produced by strains that were less antagonistic to fungi. Most of the identified metabolites were antibiotics (e.g. cycloheximide, actiphenol) and siderophores (e.g. ferulic acid, desferroxiamines). Plant disease resistance was activated by a single streptomycete strain only. Mycorrhiza associated streptomycetes appear to have an important role in inhibiting the growth of fungi and bacteria. Additionally, our study indicates that the Streptomyces strains, which are not general antagonists of fungi, may produce still un-described metabolites.

  3. Modulation of radiation effects in tissues by keratinocyte growth factor (KGF); Modulation der Strahlenwirkung an Plattenepithelien durch Keratinozyten-Wachstumsfaktor (KGF)

    Energy Technology Data Exchange (ETDEWEB)

    Doerr, W.; Lacmann, A.; Noack, R.; Spekl, K. [Dresden Technische Univ. (Germany). Medizinische Fakultaet Carl Gustav Carus, Klinik und Poliklinik fuer Strahlentherapie und Radioonkologie; Rex, K.; Farrell, C.L. [AMGEN Inc., Thousand Oaks, CA (United States)

    2000-07-01

    Keratinocyte Growth Factor (KGF) is a member of the fibroblast growth factor family. KGF is produced by mesenchymal cells, predominantly fibroblasts; target cells are epithelial cells in a variety of tissues. Hence, KGF is a mediator of the mesenchymal-epithelial communication and a regulator of tissue homeostasis in epithelia. Systemic administration of KGF in animal models induces stimulation of proliferation and modulation of migration and differentiation processes in squamous epithelia. This results in a transient increase in cell numbers and epithelial thickness. Radiation exposure of epithelia causes an imbalance between cell production and cell loss, which in consequence causes progressive cell depletion and eventually complete denudation. Systemic application of KGF reduces the radiation-induced cell loss. This effect is most pronounced when KGF is given after the radiation exposure. With regard to epithelial radiation tolerance, KGF-application in animal models results in a significant increase, by a factor of 1.7-2.3, in the doses required to induce epithelial ulceration as a clinically most relevant endpoint. After exposure with a given dose, this translates into a significant reduction of the clinical manifestation of the acute radiation sequelae. This effect is accompanied by a modification of the time course of the response. In conclusion, although the mechanisms underlying the protective efficacy remain unclear, KGF may represent an effective approach for amelioration of radiation effects in oral, gastrointestinal and cutaneous epithelia. Results from a clinical pilot study indicate that KGF is well tolerated and effective in humans. (orig.) [German] Keratinozyten-Wachstumsfaktor (KGF) ist ein Mitglied der Familie der Fibroblasten-Wachstumsfaktoren. KGF wird von mesenchymalen Zellen, v.a. Fibroblasten, gebildet; Zielzellen sind epitheliale Zellen in einer Vielzahl von Geweben. Dieser Wachstumsfaktor stellt somit einen Mediator der mesenchymal

  4. miRNAs: Major modulators for crop growth and development under abiotic stresses.

    Science.gov (United States)

    Noman, Ali; Fahad, Shah; Aqeel, Muhammad; Ali, Usman; Amanullah; Anwar, Sumera; Baloch, Shahbaz Khan; Zainab, Madiha

    2017-05-01

    Cumulatively, biotic and abiotic stresses of various magnitudes can decrease the production of crops by 70%. miRNAs have emerged as a genetic tool with enormous potential that can be exploited to understand stress tolerance at the molecular level and eventually regulate stress in crops. Plant miRNA targets frequently fit into diverse families of TFs that control the expression of genes related to a certain trait. As key machinery in gene regulatory networks, it is agreed that a broad understanding of miRNAs will greatly increase our understanding of plant responses to environmental stresses. miRNA-led stress regulatory networks are being considered as novel tools for the development of abiotic stress tolerance in crops. At this time, we need to expand our knowledge about the modulatory role of miRNAs during environmental fluctuations. It has become exceedingly clear that with increased understanding of the role of miRNAs during stress, the techniques for using miRNA-mediated gene regulation to enhance plant stress tolerance will become more effective and reliable. In this review we present: (1) miRNAs as a potential avenue for the modulation of abiotic stresses, and (2) summarize the research progress regarding plant responses to stress. Current progress is explained through discussion of the identification and validation of several miRNAs that enhance crop tolerance of salinity, drought, etc., while missing links on different aspects of miRNAs related to abiotic stress tolerance are noted.

  5. Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis.

    Directory of Open Access Journals (Sweden)

    Chiara Corrado

    Full Text Available The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeutic options are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel density was also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors, suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenic process thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO is the orotate salt form of carboxyamidotriazole (CAI, an orally bioavailable signal transduction inhibitor that in vitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when compared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth in a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated the effects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients.

  6. A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain.

    Science.gov (United States)

    Liem, Liong; Russo, Marc; Huygen, Frank J P M; Van Buyten, Jean-Pierre; Smet, Iris; Verrills, Paul; Cousins, Michael; Brooker, Charles; Levy, Robert; Deer, Timothy; Kramer, Jeffery

    2013-01-01

    This multicenter prospective trial was conducted to evaluate the clinical performance of a new neurostimulation system designed to treat chronic pain through the electrical neuromodulation of the dorsal root ganglia (DRG) neurophysiologically associated with painful regions of the limbs and/or trunk. Thirty-two subjects were implanted with a novel neuromodulation device. Pain ratings during stimulation were followed up to six months and compared with baseline ratings. Subjects also completed two separate reversal periods in which stimulation was briefly stopped in order to establish the effects of the intervention. At all assessments, more than half of subjects reported pain relief of 50% or better. At six months postimplant, average overall pain ratings were 58% lower than baseline (p reduction in pain specific to back, leg, and foot regions were 57%, 70%, and 89%, respectively. When stimulation was discontinued for a short time, pain returned to baseline levels. Discrete coverage of hard-to-treat areas was obtained across a variety of anatomical pain distributions. Paresthesia intensity remained stable over time and there was no significant difference in the paresthesia intensity perceived during different body postures/positions (standing up vs. lying down). Results of this clinical trial demonstrate that neurostimulation of the DRG is a viable neuromodulatory technique for the treatment of chronic pain. Additionally, the capture of discrete painful areas such as the feet combined with stable paresthesia intensities across body positions suggest that this stimulation modality may allow more selective targeting of painful areas and reduce unwanted side-effects observed in traditional spinal cord stimulation (SCS). © 2013 International Neuromodulation Society.

  7. Transition from isotropic to digitated growth modulates network formation in Physarum polycephalum

    Science.gov (United States)

    Vogel, David; Gautrais, Jacques; Perna, Andrea; Sumpter, David J. T.; Deneubourg, Jean-Louis; Dussutour, Audrey

    2017-01-01

    Some organisms, including fungi, ants, and slime molds, explore their environment and forage by forming interconnected networks. The plasmodium of the slime mold Physarum polycephalum is a large unicellular amoeboid organism that grows a tubular spatial network through which nutrients, body mass, and chemical signals are transported. Individual plasmodia are capable of sophisticated behaviours such as optimizing their network connectivity and dynamics using only decentralized information processing. In this study, we used a population of plasmodia that interconnect through time to analyse the dynamical interactions between growth of individual plasmodia and global network formation. Our results showed how initial conditions, such as the distance between plasmodia, their size, or the presence and quality of food, affect the emerging network connectivity.

  8. Spinal pain

    Energy Technology Data Exchange (ETDEWEB)

    Izzo, R., E-mail: roberto1766@interfree.it [Neuroradiology Department, A. Cardarelli Hospital, Naples (Italy); Popolizio, T., E-mail: t.popolizio1@gmail.com [Radiology Department, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo (Fg) (Italy); D’Aprile, P., E-mail: paoladaprile@yahoo.it [Neuroradiology Department, San Paolo Hospital, Bari (Italy); Muto, M., E-mail: mutomar@tiscali.it [Neuroradiology Department, A. Cardarelli Hospital, Napoli (Italy)

    2015-05-15

    Highlights: • Purpose of this review is to address the current concepts on the pathophysiology of discogenic, radicular, facet and dysfunctional spinal pain, focusing on the role of the imaging in the diagnostic setting, to potentially address a correct approach also to minimally invasive interventional techniques. • Special attention will be given to the discogenic pain, actually considered as the most frequent cause of chronic low back pain. • The correct distinction between referred pain and radicular pain contributes to give a more correct approach to spinal pain. • The pathogenesis of chronic pain renders this pain a true pathology requiring a specific management. - Abstract: The spinal pain, and expecially the low back pain (LBP), represents the second cause for a medical consultation in primary care setting and a leading cause of disability worldwide [1]. LBP is more often idiopathic. It has as most frequent cause the internal disc disruption (IDD) and is referred to as discogenic pain. IDD refers to annular fissures, disc collapse and mechanical failure, with no significant modification of external disc shape, with or without endplates changes. IDD is described as a separate clinical entity in respect to disc herniation, segmental instability and degenerative disc desease (DDD). The radicular pain has as most frequent causes a disc herniation and a canal stenosis. Both discogenic and radicular pain also have either a mechanical and an inflammatory genesis. For to be richly innervated, facet joints can be a direct source of pain, while for their degenerative changes cause compression of nerve roots in lateral recesses and in the neural foramina. Degenerative instability is a common and often misdiagnosed cause of axial and radicular pain, being also a frequent indication for surgery. Acute pain tends to extinguish along with its cause, but the setting of complex processes of peripheral and central sensitization may influence its evolution in chronic

  9. Acetaminophen and DMSO modulate growth and gemcitabine cytotoxicity in FM3A breast cancer cells in vitro.

    Science.gov (United States)

    Bilir, A; Guneri, A D; Altinoz, M A

    2004-01-01

    Addition of antioxidants to chemotherapy is an unresolved problem in oncology. It is still an issue of debate, whether antioxidants may reduce rough cellular toxicity and thereby the systemic side effects of the chemotherapy, without sacrificing the anti-tumor efficacy. Gemcitabine is a rather new anti-cancer agent, which is quite potent against a range of drug resistant tumors, particularly breast cancer. Tumor-sensitivity towards gemcitabine can be increased with COX inhibitory anti-inflammatory agents and ribonucleotide reductase (RR) inhibitor flavopiridol. Acetaminophen and DMSO are two unique anti-inflammatory and anti- oxidant agents with unrelated structures, yet both capable to block RR and COX, simultaneously. Using plating efficacy and 3H- thymidine labeling, we monitored efficacy of acetaminophen and DMSO to modulate growth and gemcitabine sensitivity in FM3A breast tumor cells, which is highly used to study thymineless death induced by nucleotide-metabolism hemming drugs. Peculiarly, acetaminophen alone stimulated S-phase, which was not accompanied with enhanced plating, rather resulting in 40.3% growth inhibition at the 96 hour. DMSO alone significantly diminished both the plating and S-phase, which resulted in 71.7% growth inhibition at the 96 hour. Gemcitabine drastically reduced S-phase and plating until 72 hours, yet at 96 hours it lost its efficacy to suppress the S-phase with concomitant 2-fold rise in cell numbers in comparison to 72 hour time point. Both DMSO and acetaminophen brought S-phase to around zero percent in combination with gemcitabine until 48 hours, yet they both reduced early cytotoxicity of gemcitabine at the same time interval. However, at the 96 hour, they both strongly augmented gemcitabine efficacy to block S-phase and prevented the rise in plating. Acetaminophen and DMSO should be tested in animal models, whether they could augment efficacy and reduce the toxicity of gemcitabine.

  10. Spinal infections

    Energy Technology Data Exchange (ETDEWEB)

    Tali, E. Turgut E-mail: turguttali@gazi.edu.tr

    2004-05-01

    Spinal infections can be thought of as a spectrum of disease comprising spondylitis, discitis, spondylodiscitis, pyogenic facet arthropathy, epidural infections, meningitis, polyradiculopathy and myelitis. Radiological evaluations have gained importance in the diagnosis, treatment planning, treatment and treatment monitoring of the spinal infections. Conventional radiographs are usually the initial imaging study. The sensitivity and specificity of the plain radiographs are very low. The sensitivity of CT is higher while it lacks of specificity. Conventional CT has played minor role for the diagnosis of early spondylitis and disc space infection and for follow-up, researches are going on the value of MDCT. MRI is as sensitive, specific and accurate as combined nuclear medicine studies and the method of choice for the spondylitis. Low signal areas of the vertebral body, loss of definition of the end plates and interruption of the cortical continuity, destruction of the cortical margins are typical on T1WI whereas high signal of affected areas of the vertebral body and disc is typical on T2WI. Contrast is mandatory and increases conspicuity, specificity, and observer confidence in the diagnosis and facilitates the treatment planning. Contrast enhancement is the earliest sign and pathognomonic in the acute inflammatory episode and even in the subtle infection then persists to a varying degree for several weeks or months. The outcome of the treatment is influenced by the type of infection and by the degree of neurologic compromise before treatment. There is an increasing move away from surgical intervention towards conservative therapy, percutaneous drainage of abscess or both. It is therefore critical to monitor treatment response, particularly in the immuno-deficient population.

  11. Growth modulation with a medial malleolar screw for ankle valgus deformity. 79 children with 125 affected ankles followed until correction or physeal closure.

    Science.gov (United States)

    Rupprecht, Martin; Spiro, Alexander S; Breyer, Sandra; Vettorazzi, Eik; Ridderbusch, Karsten; Stücker, Ralf

    2015-01-01

    Growth modulation with a medial malleolar screw is used to correct ankle valgus deformity in children with a wide spectrum of underlying etiologies. It is unclear whether the etiology of the deformity affects the angular correction rate with this procedure. 79 children (20 girls) with ankle valgus deformity had growth modulation by a medial malleolar screw (125 ankles). To be included, patients had to have undergone screw removal at the time of skeletal maturity or deformity correction, or a minimum follow-up of 18 months, and consistent radiographs preoperatively and at the time of screw removal and/or follow-up. The patients were assigned to 1 of 7 groups according to their underlying diagnoses. The lateral distal tibial angle (LDTA) was analyzed preoperatively, at screw removal, and at follow-up. Mean age at operation was 11.7 (7.4-16.5) years. The average lateral distal tibial angle normalized from 80° (67-85) preoperatively to 89° (73-97) at screw removal. The screws were removed after an average time of 18 (6-46) months, according to an average rate of correction of 0.65° (0.1-2.2) per month. No significant differences in the correction rate per month were found between the groups (p = 0.3). Growth modulation with a medial malleolar screw is effective for the treatment of ankle valgus deformity in patients with a wide spectrum of underlying diagnoses. The individual etiology of the ankle valgus does not appear to affect the correction rate after growth modulation. Thus, the optimal timing of growth modulation mainly depends on the remaining individual growth and on the extent of the deformity.

  12. High expression of G-protein signaling modulator 2 in hepatocellular carcinoma facilitates tumor growth and metastasis by activating the PI3K/AKT signaling pathway.

    Science.gov (United States)

    He, Xiao-Qin; Zhang, Yue-Feng; Yu, Jia-Jun; Gan, Yuan-Yuan; Han, Na-Na; Zhang, Mei-Xia; Ge, Wei; Deng, Jun-Jian; Zheng, Yong-Fa; Xu, Xi-Ming

    2017-03-01

    The aim of this study was to investigate the role of G-protein signaling modulator 2 in the carcinogenesis and progression of hepatocellular carcinoma. We previously showed that G-protein signaling modulator 2 was upregulated in hepatitis B virus-related hepatocellular carcinoma tissues through a hierarchical clustering analysis. With this study, we first assessed the expression pattern of G-protein signaling modulator 2 in hepatocellular carcinoma specimens and adjacent noncancerous tissues; clinical data were analyzed, along survival times, utilizing the Kaplan-Meier method. Moreover, the functions of G-protein signaling modulator 2 were examined using small-interfering RNAs in vitro. The results showed that G-protein signaling modulator 2 was clearly overexpressed in hepatocellular carcinoma tissues and cell lines and that the G-protein signaling modulator 2 expression level was related to tumor size and hepatitis B virus infection. Furthermore, G-protein signaling modulator 2 knockdown studies suggested that G-protein signaling modulator 2 accelerates cell growth, cell cycle, migration, and invasion and inhibits apoptosis, acting as an oncogene in hepatocellular carcinoma. Western blotting indicated that silencing of G-protein signaling modulator 2 in HepG2 and SMMC-7721 cells increased the expression levels of Bax, caspase-3, and E-cadherin, while notably suppressing the cyclin-dependent kinase 4, cyclin-dependent kinase 6, CyclinD1, Snail1, Vimentin, and matrix metallopeptidase 9 expression levels, compared with that in the control groups. In addition, we found that G-protein signaling modulator 2 can affect the expression of key proteins involved in protein kinase B activation. In conclusion, high expression of G-protein signaling modulator 2 was involved in the pathological processes of hepatocellular carcinoma through activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, which may provide an attractive potential diagnostic

  13. Phytase modulates ileal microbiota and enhances growth performance of the broiler chickens.

    Directory of Open Access Journals (Sweden)

    Anna Ptak

    Full Text Available Phytase is well studied and explored, however, little is known about its effects on the microbial ecology of the gastrointestinal tract. In total, 400 one-day-old female Ross 308 chicks were randomly distributed to four experimental groups. The dietary treatments were arranged as a 2 × 2 complete factorial design, with the factors being adequate (PC or insufficient calcium (Ca and digestible phosphor (dP(NC and with or without 5000 phytase units (FTU/kg of Escherichia coli 6-phytase. The gastrointestinal tract pH values, ileal microbial communities and short-chain fatty acid concentrations in the digesta were determined. The reduction in Ca and dP concentration significantly affected pH in the crop and caeca, and addition of phytase to the NC resulted in a pH increase in the ileum. The reduction in Ca and dP concentration significantly lowered, while phytase supplementation increased ileal total bacterial counts. Additionally, the deficient diet reduced butyrate- but increased lactate-producing bacteria. The addition of phytase increased Lactobacillus sp./Enterococcus sp. whereas in case of Clostridium leptum subgroup, Clostridium coccoides-Eubacterium rectale cluster, Bifidobacterium sp. and Streptococcus/Lactococcus counts, a significant Ca and dP level x phytase interaction was found. However, the recorded interactions indicated that the effects of phytase and Ca and dP levels were not consistent. Furthermore, the reduction of Ca and dP level lowered Clostridium perfringens and Enterobacteriaceae counts. The analysis of fermentation products showed that reducing the Ca and dP content in the diet reduced total SCFA, DL-lactate, and acetic acid in the ileum whereas phytase increased concentrations of these acids in the NC group. This suggests that P is a factor which limits fermentation in the ileum. It may be concluded that phytase plays a role in modulating the gut microbiota of chicken, however, this is clearly linked with the levels of P

  14. Modulation of cortisol metabolism by low-dose growth hormone replacement in elderly hypopituitary patients.

    Science.gov (United States)

    Toogood, A A; Taylor, N F; Shalet, S M; Monson, J P

    2000-04-01

    11 beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) functions as a net reductase converting cortisone to cortisol. GH inhibits 11beta-HSD1, resulting in a shift in cortisol metabolism favoring cortisone, an observation that may have significance in patients with ACTH deficiency who are unable to compensate for such changes. We have studied the effect of three doses of GH replacement (0.17, 0.33, and 0.5 mg each given for 12 weeks in ascending order) on cortisol metabolism in nine patients, aged 62-70 yr, with hypopituitarism who were receiving fixed doses of oral hydrocortisone. Serum insulin-like growth factor I levels rose in a dose-dependent manner over the course of the study. Fat mass decreased significantly at 24 weeks (P = 0.02), a change that was maintained at 36 weeks. Fasting serum insulin levels did not change significantly over the course of the study. The ratio of urine cortisol to cortisone metabolites (Fm/Em) fell significantly at 12 weeks (GH dose, 0.17 mg/day) from 1.32 (0.91-2.20) at baseline to 1.08 (0.89-2.11) (P cortisol replacement is suboptimal, may be at risk of the clinical manifestations of cortisol deficiency when they are commenced on GH therapy.

  15. Pheromone-modulated behavioral suites influence colony growth in the honey bee (Apis mellifera)

    Science.gov (United States)

    Pankiw, Tanya; Roman, Roman; Sagili, Ramesh R.; Zhu-Salzman, Keyan

    2004-12-01

    The success of a species depends on its ability to assess its environment and to decide accordingly which behaviors are most appropriate. Many animal species, from bacteria to mammals, are able to communicate using interspecies chemicals called pheromones. In addition to exerting physiological effects on individuals, for social species, pheromones communicate group social structure. Communication of social structure is important to social insects for the allocation of its working members into coordinated suites of behaviors. We tested effects of long-term treatment with brood pheromone on suites of honey bee brood rearing and foraging behaviors. Pheromone-treated colonies reared significantly greater brood areas and more adults than controls, while amounts of stored pollen and honey remained statistically similar. Brood pheromone increased the number of pollen foragers and the pollen load weights they returned. It appeared that the pheromone-induced increase in pollen intake was directly canalized into more brood rearing. A two-way pheromone priming effect was observed, such that some workers from the same age cohorts showed an increased and extended capacity to rear larvae, while others were recruited at significantly younger ages into pollen-specific foraging. Brood pheromone affected suites of nursing and foraging behaviors allocating worker and pollen resources associated with an important fitness trait, colony growth.

  16. Laser-induced immune modulation inhibits tumor growth in vivo (Conference Presentation)

    Science.gov (United States)

    Ottaviani, Giulia; Martinelli, Valentina; Rupel, Katia; Caronni, Nicoletta; Naseem, Asma; Zandonà, Lorenzo; Perinetti, Giuseppe; Gobbo, Margherita; Di Lenarda, Roberto; Bussani, Rossana; Benvenuti, Federica; Giacca, Mauro; Biasotto, Matteo; Zacchigna, Serena

    2017-02-01

    Photobiomodulation stands as a recommended therapy for oral mucositis induced by oncological therapies. However, its mechanisms of action and, more importantly, its safety in cancer patients, are still unclear. We assessed cancer cell metabolism and proliferation in vitro and in vivo after exposure to different laser protocols. We exploited both ectopic melanoma and a more physiological oral carcinogenesis mouse model, followed by molecular, histological and immunohistochemical characterization. Laser irradiation resulted in a slightly increase in cell metabolism and proliferation in vitro, albeit each protocol exerted a difference response. Of notice, in vivo laser light reduced tumour growth and invasiveness, indicating e beneficial effect on tumor microenvironment. Laser-treated tumors were surrounded and infiltrated by immune cells, mainly lymphocytes and dendritic cells, paralleled by an enhanced secretion of type I interferons. In contrast, the number of pro-angiogenic macrophages was reduced in response to laser irradiation, with consequent normalization of the tumor vasculature. Based on these finding we have also started exploring the effect of photobiomodulation on lymphocyte response in an experimental model of vaccination. Preliminary data indicate that laser light induced antigen-specific CD8+ and CD4+ T cell responses. In conclusion, our data point toward photobiomodulation as an effective strategy to boost the immune response in vivo, with relevant, therapeutic activities in both cancer and vaccination experimental models. These results support the safe use of laser light on cancer patients and open the way to innovative therapeutic opportunities.

  17. Population Growth, Energy Use, and Pollution: Understanding the Driving Forces of Global Change. Hands-On! Developing Active Learning Modules on the Human Dimensions of Global Change.

    Science.gov (United States)

    Kuby, Michael

    Since the beginning of the scientific revolution in the 1700s, the absolute scale of the human economy has increased many times over, and, with it, the impact on the natural environment. This learning module's activities introduce the student to linkages among population growth, energy use, level of economic and technological development and their…

  18. Phytoecdysteroids as modulators of the Toxoplasma gondii growth rate in human and mouse cells.

    Science.gov (United States)

    Dzitko, Katarzyna; Grzybowski, Marcin Mikołaj; Pawełczyk, Jakub; Dziadek, Bożena; Gatkowska, Justyna; Stączek, Paweł; Długońska, Henryka

    2015-08-15

    Searching for new effective drugs against human and animal toxoplasmosis we decided to test the anti-Toxoplasma potential of phytoecdysteroids (α-ecdysone and 20-hydroxyecdysone) characterized by the pleiotropic activity on mammalian organisms including the enhancement of host's anti-parasitic defence. This objective was accomplished by the in vitro evaluation of T. gondii growth in phytoecdysteroid-treated immunocompetent cells of selected hosts: humans and two strains of inbred mice with genetically determined different susceptibility to toxoplasmosis. Peripheral mononuclear blood cells were isolated from Toxoplasma-positive and Toxoplasma-negative women (N = 43) and men (N = 21). Non-infected mice (C57BL/6, N = 10 and BALB/c, N = 14) and mice (BALB/c, N = 10) challenged intraperitoneally with 5 tissue cysts of the T. gondii DX strain were also used in this study as a source of splenocytes. The effects of phytoecdysteroids on the viability of human PBMC and mouse splenocytes were evaluated using the MTT assay. The influence of phytoecdysteroids on PBMCs, splenocytes and T. gondii proliferation was measured using radioactivity tests (the level of 3[H] uracil incorporation by toxoplasms or 3[H] thymidine by PBMCs and splenocytes), which was confirmed by quantitative Real-Time PCR. Statistical analysis was performed using SigmaStat 3.5 (Systat Software GmbH). The best-fit IC50 curves were plotted using GraphPad Prism 6.0 (GraphPad Software, Inc.). Our results showed that phytoecdysteroids promote the multiplication of Toxoplasma in cultures of human or murine immune cells, in contrast to another apicomplexan parasite, Babesia gibsoni. Additionally, the tested phytoecdysteroids did not stimulate the in vitro secretion of the essential protective cytokines (IFN-γ, IL-2 and IL-10), neither by human nor by murine immune cells involved in an effective intracellular killing of the parasite. Judging by the effect of phytoecdysteroids on the T. gondii

  19. Growth hormone is protective against acute methadone-induced toxicity by modulating the NMDA receptor complex.

    Science.gov (United States)

    Nylander, Erik; Grönbladh, Alfhild; Zelleroth, Sofia; Diwakarla, Shanti; Nyberg, Fred; Hallberg, Mathias

    2016-12-17

    Human growth hormone (GH) displays promising protective effects in the central nervous system after damage caused by various insults. Current evidence suggests that these effects may involve N-methyl-d-aspartate (NMDA) receptor function, a receptor that also is believed to play a role in opioid-induced neurotoxicity. The aims of the present study were to examine the acute toxic effects of methadone, an opioid receptor agonist and NMDA receptor antagonist, as well as to evaluate the protective properties of recombinant human GH (rhGH) on methadone-induced toxicity. Primary cortical cell cultures from embryonic day 17 rats were grown for 7days in vitro. Cells were treated with methadone for 24h and the 50% lethal dose was calculated and later used for protection studies with rhGH. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase release, and caspase activation. Furthermore, the mRNA expression levels of NMDA receptor subunits were investigated following methadone and rhGH treatment using quantitative PCR (qPCR) analysis. A significant protective effect was observed with rhGH treatment on methadone-induced mitochondrial dysfunction and in methadone-induced LDH release. Furthermore, methadone significantly increased caspase-3 and -7 activation but rhGH was unable to inhibit this effect. The mRNA expression of the NMDA receptor subunit GluN1, GluN2a, and GluN2b increased following methadone treatment, as assessed by qPCR, and rhGH treatment effectively normalized this expression to control levels. We have demonstrated that rhGH can rescue cells from methadone-induced toxicity by maintaining mitochondrial function, cellular integrity, and NMDA receptor complex expression. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  20. Dietary nisin modulates the gastrointestinal microbial ecology and enhances growth performance of the broiler chickens.

    Directory of Open Access Journals (Sweden)

    Damian Józefiak

    Full Text Available Due to antimicrobial properties, nisin is one of the most commonly used and investigated bacteriocins for food preservation. Surprisingly, nisin has had limited use in animal feed as well as there are only few reports on its influence on microbial ecology of the gastrointestinal tract (GIT. The present study therefore aimed at investigating effects of dietary nisin on broiler chicken GIT microbial ecology and performance in comparison to salinomycin, the widely used ionophore coccidiostat. In total, 720 one-day-old male Ross 308 chicks were randomly distributed to six experimental groups. The positive control (PC diet was supplemented with salinomycin (60 mg/kg. The nisin (NI diets were supplemented with increasing levels (100, 300, 900 and 2700 IU nisin/g, respectively of the bacteriocin. The negative control (NC diet contained no additives. At slaughter (35 days of age, activity of specific bacterial enzymes (α- and β-glucosidases, α-galactosidases and β-glucuronidase in crop, ileum and caeca were significantly higher (P<0.05 in the NC group, and nisin supplementation decreased the enzyme activities to levels observed for the PC group. A similar inhibitory influence on bacterial activity was reflected in the levels of short-chain fatty acids (SCFA and putrefactive SCFA (PSCFA in digesta from crop and ileum; no effect was observed in caeca. Counts of Bacteroides and Enterobacteriacae in ileum digesta were significantly (P<0.001 decreased by nisin and salinomycin, but no effects were observed on the counts of Clostridium perfringens, Lactobacillus/Enterococcus and total bacteria. Like salinomycin, nisin supplementation improved broiler growth performance in a dose-dependent manner; compared to the NC group, the body weight gain of the NI₉₀₀ and NI₂₇₀₀ groups was improved by 4.7 and 8.7%, respectively. Our findings suggest that dietary nisin exerts a mode of action similar to salinomycin and could be considered as a dietary

  1. Dietary nisin modulates the gastrointestinal microbial ecology and enhances growth performance of the broiler chickens.

    Science.gov (United States)

    Józefiak, Damian; Kierończyk, Bartosz; Juśkiewicz, Jerzy; Zduńczyk, Zenon; Rawski, Mateusz; Długosz, Jakub; Sip, Anna; Højberg, Ole

    2013-01-01

    Due to antimicrobial properties, nisin is one of the most commonly used and investigated bacteriocins for food preservation. Surprisingly, nisin has had limited use in animal feed as well as there are only few reports on its influence on microbial ecology of the gastrointestinal tract (GIT). The present study therefore aimed at investigating effects of dietary nisin on broiler chicken GIT microbial ecology and performance in comparison to salinomycin, the widely used ionophore coccidiostat. In total, 720 one-day-old male Ross 308 chicks were randomly distributed to six experimental groups. The positive control (PC) diet was supplemented with salinomycin (60 mg/kg). The nisin (NI) diets were supplemented with increasing levels (100, 300, 900 and 2700 IU nisin/g, respectively) of the bacteriocin. The negative control (NC) diet contained no additives. At slaughter (35 days of age), activity of specific bacterial enzymes (α- and β-glucosidases, α-galactosidases and β-glucuronidase) in crop, ileum and caeca were significantly higher (Pnisin supplementation decreased the enzyme activities to levels observed for the PC group. A similar inhibitory influence on bacterial activity was reflected in the levels of short-chain fatty acids (SCFA) and putrefactive SCFA (PSCFA) in digesta from crop and ileum; no effect was observed in caeca. Counts of Bacteroides and Enterobacteriacae in ileum digesta were significantly (Pnisin and salinomycin, but no effects were observed on the counts of Clostridium perfringens, Lactobacillus/Enterococcus and total bacteria. Like salinomycin, nisin supplementation improved broiler growth performance in a dose-dependent manner; compared to the NC group, the body weight gain of the NI₉₀₀ and NI₂₇₀₀ groups was improved by 4.7 and 8.7%, respectively. Our findings suggest that dietary nisin exerts a mode of action similar to salinomycin and could be considered as a dietary supplement for broiler chickens.

  2. Prohexadione, a plant growth regulator, inhibits histone lysine demethylases and modulates epigenetics.

    Science.gov (United States)

    Vavilala, Divya Teja; Reddy, Sujatha; Sachchidanand; Prakash, Swami; Ponnaluri, V K Chaithanya; Kumar, Arvind; Mukherji, Mridul

    2014-01-01

    Epigenetic modifications, particularly DNA methylation and posttranslational histone modifications regulate heritable changes in transcription without changes in the DNA sequence. Despite a number of studies showing clear links between environmental factors and DNA methylation, little is known about the effect of environmental factors on the recently identified histone lysine methylation. Since their identification numerous studies have establish critical role played by these enzymes in mammalian development. Identification of the Jumonji (Jmj) domain containing histone lysine demethylase have added a new dimension to epigenetic control of gene expression by dynamic regulation of histone methylation marks. The objective of our study was to evaluate the effect of prohexadione and trinexapac, widely used plant growth regulators of the acylcyclohexanediones class, on the enzymatic activity of histone lysine demethylases and histone modifications during the neural stem/progenitor cell differentiation. Here we show that prohexadione, but not trinexapac, directly inhibits non-heme iron (II), 2-oxoglutarate-dependent histone lysine demethylase such as Jmjd2a. We used molecular modeling to show binding of prohexadione to Jmjd2a. We also performed in vitro demethylation assays to show the inhibitory effect of prohexadione on Jmjd2a. Further we tested this molecule in cell culture model of mouse hippocampal neural stem/progenitor cells to demonstrate its effect toward neuronal proliferation and differentiation. Molecular modeling studies suggest that prohexadione binds to the 2-oxoglutarate binding site of Jmjd2a demethylase. Treatment of primary neural stem/progenitor cells with prohexadione showed a concentration dependent reduction in their proliferation. Further, the prohexadione treated neurospheres were induced toward neurogenic lineage upon differentiation. Our results describe an important chemico-biological interaction of prohexadione, in light of critical roles

  3. The rice YABBY4 gene regulates plant growth and development through modulating the gibberellin pathway.

    Science.gov (United States)

    Yang, Chao; Ma, Yamei; Li, Jianxiong

    2016-10-01

    YABBY genes encode seed plant-specific transcription factors that play pivotal roles in diverse aspects of leaf, shoot, and flower development. Members of the YABBY gene family are primarily expressed in lateral organs in a polar manner and function to specify abaxial cell fate in dicotyledons, but this polar expression is not conserved in monocotyledons. The function of YABBY genes is therefore not well understood in monocotyledons. Here we show that overexpression of the rice (Oryza sativa L.) YABBY4 gene (OsYABBY4) leads to a semi-dwarf phenotype, abnormal development in the uppermost internode, an increased number of floral organs, and insensitivity to gibberellin (GA) treatment. We report on an important role for OsYABBY4 in negative control of the expression of a GA biosynthetic gene by binding to the promoter region of the gibberellin 20-oxidase 2 gene (GA20ox2), which is a direct target of SLR1 (the sole DELLA protein negatively controlling GA responses in rice). OsYABBY4 also suppresses the expression level of SLR1 and interacts with SLR1 protein. The interaction inhibits GA-dependent degradation of SLR1 and therefore leads to GA insensitivity. These data together suggest that OsYABBY4 serves as a DNA-binding intermediate protein for SLR1 and is associated with the GA signaling pathway regulating gene expression during plant growth and development. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. PPARα inhibition modulates multiple reprogrammed metabolic pathways in kidney cancer and attenuates tumor growth.

    Science.gov (United States)

    Abu Aboud, Omran; Donohoe, Dallas; Bultman, Scott; Fitch, Mark; Riiff, Tim; Hellerstein, Marc; Weiss, Robert H

    2015-06-01

    Kidney cancer [renal cell carcinoma (RCC)] is the sixth-most-common cancer in the United States, and its incidence is increasing. The current progression-free survival for patients with advanced RCC rarely extends beyond 1-2 yr due to the development of therapeutic resistance. We previously identified peroxisome proliferator-activating receptor-α (PPARα) as a potential therapeutic target for this disease and showed that a specific PPARα antagonist, GW6471, induced apoptosis and cell cycle arrest at G0/G1 in RCC cell lines associated with attenuation of cell cycle regulatory proteins. We now extend that work and show that PPARα inhibition attenuates components of RCC metabolic reprogramming, capitalizing on the Warburg effect. The specific PPARα inhibitor GW6471, as well as a siRNA specific to PPARα, attenuates the enhanced fatty acid oxidation and oxidative phosphorylation associated with glycolysis inhibition, and PPARα antagonism also blocks the enhanced glycolysis that has been observed in RCC cells; this effect did not occur in normal human kidney epithelial cells. Such cell type-specific inhibition of glycolysis corresponds with changes in protein levels of the oncogene c-Myc and has promising clinical implications. Furthermore, we show that treatment with GW6471 results in RCC tumor growth attenuation in a xenograft mouse model, with minimal obvious toxicity, a finding associated with the expected on-target effects on c-Myc. These studies demonstrate that several pivotal cancer-relevant metabolic pathways are inhibited by PPARα antagonism. Our data support the concept that targeting PPARα, with or without concurrent inhibition of glycolysis, is a potential novel and effective therapeutic approach for RCC that targets metabolic reprogramming in this tumor.

  5. Differential role of entorhinal and hippocampal nerve growth factor in short- and long-term memory modulation

    Directory of Open Access Journals (Sweden)

    Walz R.

    2005-01-01

    Full Text Available We studied the effects of infusion of nerve growth factor (NGF into the hippocampus and entorhinal cortex of male Wistar rats (250-300 g, N = 11-13 per group on inhibitory avoidance retention. In order to evaluate the modulation of entorhinal and hippocampal NGF in short- and long-term memory, animals were implanted with cannulae in the CA1 area of the dorsal hippocampus or entorhinal cortex and trained in one-trial step-down inhibitory avoidance (foot shock, 0.4 mA. Retention tests were carried out 1.5 h or 24 h after training to measure short- and long-term memory, respectively. Immediately after training, rats received 5 µl NGF (0.05, 0.5 or 5.0 ng or saline per side into the CA1 area and entorhinal cortex. The correct position of the cannulae was confirmed by histological analysis. The highest dose of NGF (5.0 ng into the hippocampus blocked short-term memory (P < 0.05, whereas the doses of 0.5 (P < 0.05 and 5.0 ng (P < 0.01 NGF enhanced long-term memory. NGF administration into the entorhinal cortex improved long-term memory at the dose of 5.0 ng (P < 0.05 and did not alter short-term memory. Taken as a whole, our results suggest a differential modulation by entorhinal and hippocampal NGF of short- and long-term memory.

  6. Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

    Science.gov (United States)

    Tang, Lisha; Zhu, Hengrui; Yang, Xianmei; Xie, Fang; Peng, Jingtao; Jiang, Deke; Xie, Jun; Qi, Meiyan; Yu, Long

    2016-01-01

    Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

  7. Modulation of thyroid hormone-dependent gene expression in Xenopus laevis by INhibitor of Growth (ING) proteins.

    Science.gov (United States)

    Helbing, Caren C; Wagner, Mary J; Pettem, Katherine; Johnston, Jill; Heimeier, Rachel A; Veldhoen, Nik; Jirik, Frank R; Shi, Yun-Bo; Browder, Leon W

    2011-01-01

    INhibitor of Growth (ING) proteins belong to a large family of plant homeodomain finger-containing proteins important in epigenetic regulation and carcinogenesis. We have previously shown that ING1 and ING2 expression is regulated by thyroid hormone (TH) during metamorphosis of the Xenopus laevis tadpole. The present study investigates the possibility that ING proteins modulate TH action. Tadpoles expressing a Xenopus ING2 transgene (Trans(ING2)) were significantly smaller than tadpoles not expressing the transgene (Trans(GFP)). When exposed to 10 nM 3,5,3'-triiodothyronine (T(3)), premetamorphic Trans(ING2) tadpoles exhibited a greater reduction in tail, head, and brain areas, and a protrusion of the lower jaw than T(3)-treated Trans(GFP) tadpoles. Quantitative real time polymerase chain reaction (QPCR) demonstrated elevated TH receptor β (TRβ) and TH/bZIP transcript levels in Trans(ING2) tadpole tails compared to Trans(GFP) tadpoles while TRα mRNAs were unaffected. In contrast, no difference in TRα, TRβ or insulin-like growth factor (IGF2) mRNA abundance was observed in the brain between Trans(ING2) and Trans(GFP) tadpoles. All of these transcripts, except for TRα mRNA in the brain, were inducible by the hormone in both tissues. Oocyte transcription assays indicated that ING proteins enhanced TR-dependent, T(3)-induced TRβ gene promoter activity. Examination of endogenous T(3)-responsive promoters (TRβ and TH/bZIP) in the tail by chromatin immunoprecipitation assays showed that ING proteins were recruited to TRE-containing regions in T(3)-dependent and independent ways, respectively. Moreover, ING and TR proteins coimmunoprecipitated from tail protein homogenates derived from metamorphic climax animals. We show for the first time that ING proteins modulate TH-dependent responses, thus revealing a novel role for ING proteins in hormone signaling. This has important implications for understanding hormone influenced disease states and suggests that the

  8. The endophytic fungus Piriformospora indica enhances Arabidopsis thaliana growth and modulates Na + /K + homeostasis under salt stress conditions

    KAUST Repository

    Abdelaziz, Mohamed Ewis

    2017-07-13

    The mutualistic, endophytic fungus Piriformospora indica has been shown to confer biotic and abiotic stress tolerance to host plants. In this study, we investigated the impact of P. indica on the growth of Arabidopsis plants under normal and salt stress conditions. Our results demonstrate that P. indica colonization increases plant biomass, lateral roots density, and chlorophyll content under both conditions. Colonization with P. indica under salt stress was accompanied by a lower Na+/K+ ratio and less pronounced accumulation of anthocyanin, compared to control plants. Moreover, P. indica colonized roots under salt stress showed enhanced transcript levels of the genes encoding the high Affinity Potassium Transporter 1 (HKT1) and the inward-rectifying K+ channels KAT1 and KAT2, which play key roles in regulating Na+ and K+ homeostasis. The effect of P. indica colonization on AtHKT1;1 expression was also confirmed in the Arabidopsis line gl1-HKT:AtHKT1;1 that expresses an additional AtHKT1;1 copy driven by the native promoter. Colonization of the gl1-HKT:AtHKT1;1 by P. indica also increased lateral roots density and led to a better Na+/K+ ratio, which may be attributed to the observed increase in KAT1 and KAT2 transcript levels. Our findings demonstrate that P. indica colonization promotes Arabidopsis growth under salt stress conditions and that this effect is likely caused by modulation of the expression levels of the major Na+ and K+ ion channels, which allows establishing a balanced ion homeostasis of Na+/K+ under salt stress conditions.

  9. Abalone visceral extract inhibit tumor growth and metastasis by modulating Cox-2 levels and CD8+ T cell activity

    Directory of Open Access Journals (Sweden)

    II Kim Jae

    2010-10-01

    Full Text Available Abstract Background Abalone has long been used as a valuable food source in East Asian countries. Although the nutritional importance of abalone has been reported through in vitro and in vivo studies, there is little evidence about the potential anti-tumor effects of abalone visceral extract. The aim of the present study is to examine anti-tumor efficacy of abalone visceral extract and to elucidate its working mechanism. Methods In the present study, we used breast cancer model using BALB/c mouse-derived 4T1 mammary carcinoma and investigated the effect of abalone visceral extract on tumor development. Inhibitory effect against tumor metastasis was assessed by histopathology of lungs. Cox-2 productions by primary and secondary tumor were measured by real-time RT-PCR and immunoblotting (IB. Proliferation assay based on [3H]-thymidine incorporation and measurement of cytokines and effector molecules by RT-PCR were used to confirm tumor suppression efficacy of abalone visceral extract by modulating cytolytic CD8+ T cells. The cytotoxicity of CD8+ T cell was compared by JAM test. Results Oral administration of abalone visceral extract reduced tumor growth (tumor volume and weight and showed reduced metastasis as confirmed by decreased level of splenomegaly (spleen size and weight and histological analysis of the lung metastasis (gross analysis and histological staining. Reduced expression of Cox-2 (mRNA and protein from primary tumor and metastasized lung was also detected. In addition, treatment of abalone visceral extract increased anti-tumor activities of CD8+ T cells by increasing the proliferation capacity and their cytolytic activity. Conclusions Our results suggest that abalone visceral extract has anti-tumor effects by suppressing tumor growth and lung metastasis through decreasing Cox-2 expression level as well as promoting proliferation and cytolytic function of CD8+ T cells.

  10. The endophytic fungus Piriformospora indica enhances Arabidopsis thaliana growth and modulates Na+/K+ homeostasis under salt stress conditions.

    Science.gov (United States)

    Abdelaziz, Mohamed E; Kim, Dongjin; Ali, Shawkat; Fedoroff, Nina V; Al-Babili, Salim

    2017-10-01

    The mutualistic, endophytic fungus Piriformospora indica has been shown to confer biotic and abiotic stress tolerance to host plants. In this study, we investigated the impact of P. indica on the growth of Arabidopsis plants under normal and salt stress conditions. Our results demonstrate that P. indica colonization increases plant biomass, lateral roots density, and chlorophyll content under both conditions. Colonization with P. indica under salt stress was accompanied by a lower Na+/K+ ratio and less pronounced accumulation of anthocyanin, compared to control plants. Moreover, P. indica colonized roots under salt stress showed enhanced transcript levels of the genes encoding the high Affinity Potassium Transporter 1 (HKT1) and the inward-rectifying K+ channels KAT1 and KAT2, which play key roles in regulating Na+ and K+ homeostasis. The effect of P. indica colonization on AtHKT1;1 expression was also confirmed in the Arabidopsis line gl1-HKT:AtHKT1;1 that expresses an additional AtHKT1;1 copy driven by the native promoter. Colonization of the gl1-HKT:AtHKT1;1 by P. indica also increased lateral roots density and led to a better Na+/K+ ratio, which may be attributed to the observed increase in KAT1 and KAT2 transcript levels. Our findings demonstrate that P. indica colonization promotes Arabidopsis growth under salt stress conditions and that this effect is likely caused by modulation of the expression levels of the major Na+ and K+ ion channels, which allows establishing a balanced ion homeostasis of Na+/K+ under salt stress conditions. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Hydrodynamic instability growth of three-dimensional modulations in radiation-driven implosions with "low-foot" and "high-foot" drives at the National Ignition Facility

    Science.gov (United States)

    Smalyuk, V. A.; Weber, C. R.; Robey, H. F.; Casey, D. T.; Chen, K.-C.; Clark, D. S.; Farrell, M.; Felker, S.; Field, J. E.; Haan, S. W.; Hammel, B. A.; Hamza, A. V.; Hoover, D.; Kroll, J. J.; Landen, O. L.; MacPhee, A. G.; Martinez, D.; Nikroo, A.; Rice, N.

    2017-04-01

    Hydrodynamic instability growth has been studied using three-dimensional (3-D) broadband modulations by comparing "high-foot" and "low-foot" spherical plastic (CH) capsule implosions at the National Ignition Facility (NIF) [E. M. Campbell et al., AIP Conf. Proc. 429, 3 (1998)]. The initial perturbations included capsule outer-surface roughness and capsule-mounting membranes ("tents") that were similar to those used in a majority of implosions on NIF. The tents with thicknesses of 31-nm, 46-nm, and 109-nm were used in the experiments. The outer-surface roughness in the "low-foot" experiment was similar to the standard specification, while it was increased by ˜4 times in the "high-foot" experiment to compensate for the reduced growth. The ablation-front instability growth was measured using a Hydrodynamic Growth Radiography platform at a convergence ratio of ˜3. The dominant capsule perturbations, generated by the tent mountings, had measured perturbation amplitudes comparable to the capsule thickness with the "low-foot" drive. These tent perturbations were reduced by ˜3 to 10 times in implosions with the "high-foot" drive. Unexpectedly, the measured perturbations with initially thinner tents were either larger or similar to the measured perturbations with thicker tents for both "high-foot" and "low-foot" drives. While the measured instability growth of 3-D broadband perturbations was also significantly reduced by ˜5 to 10 times with the "high-foot" drive, compared to the "low-foot" drive, the growth mitigation was stronger than expected based on previous "growth-factor" results measured with two-dimensional modulations [D. T. Casey et al., Phys. Rev. E 90, 011102 (2014)]. One of the hypotheses to explain the results is based on the 3-D modulations of the oxygen content in the bulk of the capsule having a stronger effect on the overall growth of capsule perturbations than the outer-surface capsule roughness.

  12. Biomaterials for revascularization and immunomodulation after spinal cord injury.

    Science.gov (United States)

    Haggerty, Agnes E; Maldonado-Lasuncion, Ines; Oudega, Martin

    2018-01-23

    Spinal cord injury causes immediate damage to the nervous tissue accompanied by loss of motor and sensory function. The limited self-repair competence of injured nervous tissue underscores the need for reparative interventions to recover function after spinal cord injury. The vasculature of the spinal cord plays a crucial role in spinal cord injury and repair. Ruptured and sheared blood vessels in the injury epicenter and blood vessels with a breached blood-spinal cord barrier in the surrounding tissue cause bleeding and inflammation, which contribute to the overall tissue damage. The insufficient formation of new functional vasculature in and near the injury impedes endogenous tissue repair and limits the prospect of repair approaches. Limiting the loss of blood vessels, stabilizing the blood-spinal cord barrier, and promoting the formation of new blood vessels are therapeutic targets for spinal cord repair. Inflammation is an integral part of injury-mediated vascular damage, with deleterious and reparative consequences. Inflammation and the formation of new blood vessels are intricately interwoven. Biomaterials can be effectively used for promoting and guiding blood vessel formation or modulating the inflammatory response after spinal cord injury, thereby governing the extent of damage and the success of reparative interventions. This review deals with the vasculature after spinal cord injury, the reciprocal interactions between inflammation and blood vessel formation, and the potential of biomaterials to support revascularization and immunomodulation in damaged spinal cord nervous tissue. © 2018 IOP Publishing Ltd.

  13. Anti-Vascular Endothelial Growth Factors Protect Retinal Pigment Epithelium Cells Against Oxidation by Modulating Nitric Oxide Release and Autophagy

    Directory of Open Access Journals (Sweden)

    Stefano De Cillà

    2017-07-01

    Full Text Available Background/Aims: the anti-vascular endothelial growth factors (VEGF, Aflibercept and Ranibizumab, are used for the treatment of macular degeneration. Here we examined the involvement of nitric oxide (NO, mitochondria function and of apoptosis/autophagy in their antioxidant effects in human retinal pigment epithelium cells (RPE. Methods: RPE were exposed to Ranibizumab/Aflibercept in the absence or presence of NO synthase (NOS inhibitor and of autophagy activator/blocker, rapamicyn/3-methyladenine. Specific kits were used for cell viability, NO and reactive oxygen species detection and mitochondrial membrane potential measurement, whereas Western Blot was performed for apoptosis/ autophagy markers and other kinases detection. Results: In RPE cultured in physiological conditions, Aflibercept/Ranibizumab increased NO release in a dose and time-dependent way. Opposite results were obtained in RPE pretreated with hydrogen peroxide. Moreover, both the anti-VEGF agents were able to prevent the fall of cell viability and of mitochondrial membrane potential. Those effects were reduced by the NOS inhibitor and 3-methyladenine and were potentiated by rapamycin. Finally, Aflibercept and Ranibizumab counteracted the changes of apoptosis/autophagy markers, NOS, Phosphatidylinositol-3-Kinase/Protein Kinase B and Extracellular signal–regulated kinases 1/2 caused by peroxidation. Conclusion: Aflibercept and Ranibizumab protect RPE against peroxidation through the modulation of NO release, apoptosis and autophagy.

  14. Nerve growth factor in the hippocamposeptal system: evidence for activity-dependent anterograde delivery and modulation of synaptic activity.

    Science.gov (United States)

    Guo, Lan; Yeh, Mason L; Cuzon Carlson, Verginia C; Johnson-Venkatesh, Erin M; Yeh, Hermes H

    2012-05-30

    Neurotrophins have been implicated in regulating neuronal differentiation, promoting neuronal survival, and modulating synaptic efficacy and plasticity. The prevailing view is that, depending on the target and mode of action, most neurotrophins can be trafficked and released either anterogradely or retrogradely in an activity-dependent manner. However, the prototypic neurotrophin, nerve growth factor (NGF), is not thought to be anterogradely delivered. Here we provide the neuroanatomical substrate for an anterograde hippocamposeptal transport of NGF by demonstrating its presence in mouse hippocampal GABAergic neurons and in their hippocamposeptal axons that ramify densely and abut neurons in the medial septum/diagonal band of Broca (MS/DB). We also demonstrate an activity-dependent increase in septal NGF levels that is dependent on the pattern of intrahippocampal stimulation. In addition, we show that acute exposure to NGF, via activation of TrkA, attenuates GABA(A) receptor-mediated inhibitory synaptic currents and reduces sensitivity to exogenously applied GABA. These acute actions of NGF display cell type and functional selectivity insofar as (1) they were found in cholinergic, but not GABAergic, MS/DB neurons, and (2) glutamate-mediated excitatory synaptic activity as well as AMPA-activated current responses were unaffected. Our results advocate a novel anterograde, TrkA-mediated NGF signaling in the CNS.

  15. The Vip1 inositol polyphosphate kinase family regulates polarized growth and modulates the microtubule cytoskeleton in fungi.

    Directory of Open Access Journals (Sweden)

    Jennifer Pöhlmann

    2014-09-01

    Full Text Available Microtubules (MTs are pivotal for numerous eukaryotic processes ranging from cellular morphogenesis, chromosome segregation to intracellular transport. Execution of these tasks requires intricate regulation of MT dynamics. Here, we identify a new regulator of the Schizosaccharomyces pombe MT cytoskeleton: Asp1, a member of the highly conserved Vip1 inositol polyphosphate kinase family. Inositol pyrophosphates generated by Asp1 modulate MT dynamic parameters independent of the central +TIP EB1 and in a dose-dependent and cellular-context-dependent manner. Importantly, our analysis of the in vitro kinase activities of various S. pombe Asp1 variants demonstrated that the C-terminal phosphatase-like domain of the dual domain Vip1 protein negatively affects the inositol pyrophosphate output of the N-terminal kinase domain. These data suggest that the former domain has phosphatase activity. Remarkably, Vip1 regulation of the MT cytoskeleton is a conserved feature, as Vip1-like proteins of the filamentous ascomycete Aspergillus nidulans and the distantly related pathogenic basidiomycete Ustilago maydis also affect the MT cytoskeleton in these organisms. Consistent with the role of interphase MTs in growth zone selection/maintenance, all 3 fungal systems show aspects of aberrant cell morphogenesis. Thus, for the first time we have identified a conserved biological process for inositol pyrophosphates.

  16. Glutamate receptor antagonists and growth factors modulate dentate granule cell neurogenesis in organotypic, rat hippocampal slice cultures

    DEFF Research Database (Denmark)

    Poulsen, Frantz Rom; Blaabjerg, Morten; Montero, Maria

    2005-01-01

    Generation of dentate granule cells and its modulation by glutamate receptor antagonists, growth factors and pilocarpine-induced seizure-like activity was investigated in rat hippocampal slice cultures derived from 1-week-old rats and grown for 2 weeks. Focussing on the dentate granule cell layer...... facing CA1 and the immediate subgranular zone, exposure for 3 days to the NMDA receptor blocking agents MK-801 (10 microM) or APV (25 microM) in the culture medium, increased the number of TOAD-64/Ulip/CRMP-4 (TUC-4)-positive cells as counted in the slice cultures at the end of the 3-day treatment period....... Exposure to IGF-I (200 ng/ml) and EGF (20 ng/ml) also increased the number of TUC-4-positive cells. Combining APV with IGF-I/EGF had an additive effect. Similar results were obtained by 3 days treatment with the AMPA receptor antagonist CNQX (25 microM). Surprisingly, addition of 5 mM pilocarpine reduced...

  17. Spinal Cord Injury 101

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    Full Text Available ... with SCI Personal Experiences by Topic Resources Peer Counseling Blog About Media Donate close search Understanding Spinal ... with SCI Personal Experiences by Topic Resources Peer Counseling Blog About Media Donate Spinal Cord Injury Medical ...

  18. Spinal Cord Injury 101

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    Full Text Available ... After Pediatric Spinal Injury Dawn Sheaffer, MSW Rehabilitation Psychological Realities after Spinal Cord Injury Toby Huston, PhD ... not provide medical advice, recommend or endorse health care products or services, or control the information found ...

  19. Tethered Spinal Cord Syndrome

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    ... SEARCH Definition Treatment Prognosis Clinical Trials Organizations Publications Definition Tethered spinal cord syndrome is a neurological disorder caused by tissue attachments that limit the movement of the spinal cord within the ...

  20. Spinal Cord Injury 101

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    Full Text Available ... OT Anne Bryden, OT The Role of the Social Worker after Spinal Cord Injury Patti Rogers, SW Marguerite ... play_arrow What are the latest developments in the use of electrical stimulation for spinal ...

  1. Spinal Cord Injury 101

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  2. Spinal Cord Injury 101

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    Full Text Available ... of spinal cord injuries? play_arrow What does stem-cell research on animals tell us? play_arrow When can we expect stem-cell treatments to become available for spinal cord injuries? ...

  3. Spinal Cord Tumor

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    ... that may be more likely to affect the spine include breast, lung, prostate and multiple myeloma. Complications Both noncancerous and cancerous spinal tumors can compress the spinal cord and nerves, leading ...

  4. Spinal Cord Infarction

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    ... Information from the National Library of Medicine’s MedlinePlus Spinal Cord Injuries Show More Show Less Search Disorders Search NINDS SEARCH SEARCH Definition Treatment Prognosis Clinical Trials Organizations Publications Definition Spinal ...

  5. Spinal Cord Injury 101

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  6. Spinal Cord Injury 101

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  7. Spinal cord stimulation

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    ... this page: //medlineplus.gov/ency/article/007560.htm Spinal cord stimulation To use the sharing features on this page, please enable JavaScript. Spinal cord stimulation is a treatment for pain that uses a ...

  8. Spinal Cord Injury 101

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    Full Text Available ... Disabilities Photography by Rona Talcott Website by Mobile Marketing LLC Understanding Spinal Cord Injury About Us Expert Videos Contact Us Personal Experience Videos Blog Videos By Topic Media Resources Donate to support families facing spinal cord ...

  9. Spinal Cord Injury 101

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    Full Text Available ... Gravity Forms. FacingDisability.com is an informational and support website for families facing spinal cord injuries. The ... Blog Videos By Topic Media Resources Donate to support families facing spinal cord injuries Peer Counseling 312- ...

  10. Spinal Cord Injury

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    ... hips, legs, and feet. If you have a spinal injury you may need surgery, physical therapy , and other ... your health on a daily basis. Living with spinal cord injury — your questions answered top What are pediatric ...

  11. Spinal Cord Injury 101

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    Full Text Available ... long does it usually take for feeling and movement to return after a spinal cord injury? play_ ... LLC Understanding Spinal Cord Injury About Us Expert Videos Contact Us Personal Experience Videos Blog Videos By ...

  12. Spinal Cord Injury 101

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  13. Spinal Cord Injury 101

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  14. Radiosurgery for spinal malignant tumors.

    Science.gov (United States)

    Wowra, Berndt; Muacevic, Alexander; Zausinger, Stefan; Tonn, Jörg-Christian

    2009-02-01

    Radiosurgery is a special treatment method that employs highly focused radiation to destroy tumors with high precision in a single session. A broad base of scientific evidence already exists for the radiosurgical treatment of brain metastases. Recent advances in medical technology now allow radiosurgery to be extended to the spine as well. Selective literature review based on a PubMed search using the search terms stereotaxis, radiosurgery, stereotactic radiotherapy, accuracy, quality assurance, spine, spine metastasis, pain, Novalis, CyberKnife, Synergy, and robotics. We also present and analyze our own data as an illustration of the application of spinal radiosurgery. The literature search identified 20 scientific original publications and one recent review. The data indicate that, within the specific constraints of the method, radiosurgery can arrest the growth of up to 96% of spinal metastases. Durable pain relief can be achieved in patients with tumor-associated pain syndromes. The morbidity of spinal radiosurgery is low, with a less than 1% risk of myelopathy. Spinal radiosurgery is an independent, essentially noninvasive method of treatment. Different types of radiosurgical treatment apparatus are available. For properly selected patients, radiosurgery offers a good chance of therapeutic success with relatively rare complications.

  15. Article Commentary: Spinal Tuberculosis

    Directory of Open Access Journals (Sweden)

    Safak Ekinci

    2015-01-01

    Full Text Available Spinal tuberculosis (TB is a significant form of TB, causing spinal deformity and paralysis. Early diagnosis and treatment are crucial for avoiding multivertebral destruction and are critical for improving outcomes in spinal TB. We believe that appropriate treatment method should be implemented at the early stage of this disease and that the Gulhane Askeri Tip Akademisi classification system can be considered a practical guide for spinal TB treatment planning in all countries.

  16. The expression of spinal methyl-CpG-binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states

    Directory of Open Access Journals (Sweden)

    Tochiki Keri K

    2012-02-01

    Full Text Available Abstract Background DNA CpG methylation is carried out by DNA methyltransferases and induces chromatin remodeling and gene silencing through a transcription repressor complex comprising the methyl-CpG-binding protein 2 (MeCP2 and a subset of histone deacetylases. Recently, we have found that MeCP2 activity had a crucial role in the pattern of gene expression seen in the superficial dorsal horn rapidly after injection of Complete Freund's Adjuvant (CFA in the rat ankle joint. The aim of the present study was to analyse the changes in expression of MeCP2, DNA methyltransferases and a subset of histone deacetylases in the superficial dorsal horn during the maintenance phase of persistent pain states. In this process, the cell specific expression of MeCP2 was also investigated. Results Using immunohistochemistry, we found that neurones, oligodendrocytes and astrocytes expressed MeCP2. Microglia, oligodendrocyte precursor cells and Schwann cells never showed any positive stain for MeCP2. Quantitative analyses showed that MeCP2 expression was increased in the superficial dorsal horn 7 days following CFA injection in the ankle joint but decreased 7 days following spared nerve injury. Overall, the expression of DNA methyltransferases and a subset of histone deacetylases followed the same pattern of expression. However, there were no significant changes in the expression of the MeCP2 targets that we had previously shown are regulated in the early time points following CFA injection in the ankle joint. Finally, the expression of MeCP2 was also down regulated in damaged dorsal root ganglion neurones following spared nerve injury. Conclusion Our results strongly suggest that changes in chromatin compaction, regulated by the binding of MeCP2 complexes to methylated DNA, are involved in the modulation of gene expression in the superficial dorsal horn and dorsal root ganglia during the maintenance of persistent pain states.

  17. Spinal Cord Injury 101

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  18. Spinal Cord Injuries

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    ... forth between your body and your brain. A spinal cord injury disrupts the signals. Spinal cord injuries usually begin with a blow that fractures or ... down on the nerve parts that carry signals. Spinal cord injuries can be complete or incomplete. With a complete ...

  19. Spinal Cord Injury 101

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  1. Adhesion to carbon nanotube conductive scaffolds forces action-potential appearance in immature rat spinal neurons.

    Directory of Open Access Journals (Sweden)

    Alessandra Fabbro

    Full Text Available In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiological and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiological studies associated to gene expression analysis. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray experiments suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural regeneration strategies.

  2. Adhesion to carbon nanotube conductive scaffolds forces action-potential appearance in immature rat spinal neurons.

    Science.gov (United States)

    Fabbro, Alessandra; Sucapane, Antonietta; Toma, Francesca Maria; Calura, Enrica; Rizzetto, Lisa; Carrieri, Claudia; Roncaglia, Paola; Martinelli, Valentina; Scaini, Denis; Masten, Lara; Turco, Antonio; Gustincich, Stefano; Prato, Maurizio; Ballerini, Laura

    2013-01-01

    In the last decade, carbon nanotube growth substrates have been used to investigate neurons and neuronal networks formation in vitro when guided by artificial nano-scaled cues. Besides, nanotube-based interfaces are being developed, such as prosthesis for monitoring brain activity. We recently described how carbon nanotube substrates alter the electrophysiological and synaptic responses of hippocampal neurons in culture. This observation highlighted the exceptional ability of this material in interfering with nerve tissue growth. Here we test the hypothesis that carbon nanotube scaffolds promote the development of immature neurons isolated from the neonatal rat spinal cord, and maintained in vitro. To address this issue we performed electrophysiological studies associated to gene expression analysis. Our results indicate that spinal neurons plated on electro-conductive carbon nanotubes show a facilitated development. Spinal neurons anticipate the expression of functional markers of maturation, such as the generation of voltage dependent currents or action potentials. These changes are accompanied by a selective modulation of gene expression, involving neuronal and non-neuronal components. Our microarray experiments suggest that carbon nanotube platforms trigger reparative activities involving microglia, in the absence of reactive gliosis. Hence, future tissue scaffolds blended with conductive nanotubes may be exploited to promote cell differentiation and reparative pathways in neural regeneration strategies.

  3. Spinal cord evolution in early Homo.

    Science.gov (United States)

    Meyer, Marc R; Haeusler, Martin

    2015-11-01

    The discovery at Nariokotome of the Homo erectus skeleton KNM-WT 15000, with a narrow spinal canal, seemed to show that this relatively large-brained hominin retained the primitive spinal cord size of African apes and that brain size expansion preceded postcranial neurological evolution. Here we compare the size and shape of the KNM-WT 15000 spinal canal with modern and fossil taxa including H. erectus from Dmanisi, Homo antecessor, the European middle Pleistocene hominins from Sima de los Huesos, and Pan troglodytes. In terms of shape and absolute and relative size of the spinal canal, we find all of the Dmanisi and most of the vertebrae of KNM-WT 15000 are within the human range of variation except for the C7, T2, and T3 of KNM-WT 15000, which are constricted, suggesting spinal stenosis. While additional fossils might definitively indicate whether H. erectus had evolved a human-like enlarged spinal canal, the evidence from the Dmanisi spinal canal and the unaffected levels of KNM-WT 15000 show that unlike Australopithecus, H. erectus had a spinal canal size and shape equivalent to that of modern humans. Subadult status is unlikely to affect our results, as spinal canal growth is complete in both individuals. We contest the notion that vertebrae yield information about respiratory control or language evolution, but suggest that, like H. antecessor and European middle Pleistocene hominins from Sima de los Huesos, early Homo possessed a postcranial neurological endowment roughly commensurate to modern humans, with implications for neurological, structural, and vascular improvements over Pan and Australopithecus. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Trauma: Spinal Cord Injury.

    Science.gov (United States)

    Eckert, Matthew J; Martin, Matthew J

    2017-10-01

    Injuries to the spinal column and spinal cord frequently occur after high-energy mechanisms of injury, or with lower-energy mechanisms, in select patient populations like the elderly. A focused yet complete neurologic examination during the initial evaluation will guide subsequent diagnostic procedures and early supportive measures to help prevent further injury. For patients with injury to bone and/or ligaments, the initial focus should be spinal immobilization and prevention of inducing injury to the spinal cord. Spinal cord injury is associated with numerous life-threatening complications during the acute and long-term phases of care that all acute care surgeons must recognize. Published by Elsevier Inc.

  5. Biomechanical analysis and modeling of different vertebral growth patterns in adolescent idiopathic scoliosis and healthy subjects

    Directory of Open Access Journals (Sweden)

    Driscoll Mark

    2011-05-01

    Full Text Available Abstract Background The etiology of AIS remains unclear, thus various hypotheses concerning its pathomechanism have been proposed. To date, biomechanical modeling has not been used to thoroughly study the influence of the abnormal growth profile (i.e., the growth rate of the vertebral body during the growth period on the pathomechanism of curve progression in AIS. This study investigated the hypothesis that AIS progression is associated with the abnormal growth profiles of the anterior column of the spine. Methods A finite element model of the spinal column including growth dynamics was utilized. The initial geometric models were constructed from the bi-planar radiographs of a normal subject. Based on this model, five other geometric models were generated to emulate different coronal and sagittal curves. The detailed modeling integrated vertebral body growth plates and growth modulation spinal biomechanics. Ten years of spinal growth was simulated using AIS and normal growth profiles. Sequential measures of spinal alignments were compared. Results (1 Given the initial lateral deformity, the AIS growth profile induced a significant Cobb angle increase, which was roughly between three to five times larger compared to measures utilizing a normal growth profile. (2 Lateral deformities were absent in the models containing no initial coronal curvature. (3 The presence of a smaller kyphosis did not produce an increase lateral deformity on its own. (4 Significant reduction of the kyphosis was found in simulation results of AIS but not when using the growth profile of normal subjects. Conclusion Results from this analysis suggest that accelerated growth profiles may encourage supplementary scoliotic progression and, thus, may pose as a progressive risk factor.

  6. Monocarboxylate transporter 8 modulates the viability and invasive capacity of human placental cells and fetoplacental growth in mice.

    Directory of Open Access Journals (Sweden)

    Elisavet Vasilopoulou

    Full Text Available Monocarboxylate transporter 8 (MCT8 is a well-established thyroid hormone (TH transporter. In humans, MCT8 mutations result in changes in circulating TH concentrations and X-linked severe global neurodevelopmental delay. MCT8 is expressed in the human placenta throughout gestation, with increased expression in trophoblast cells from growth-restricted pregnancies. We postulate that MCT8 plays an important role in placental development and transplacental TH transport. We investigated the effect of altering MCT8 expression in human trophoblast in vitro and in a Mct8 knockout mouse model. Silencing of endogenous MCT8 reduced T3 uptake into human extravillous trophoblast-like cells (SGHPL-4; 40%, P<0.05 and primary cytotrophoblast (15%, P<0.05. MCT8 over-expression transiently increased T3 uptake (SGHPL-4∶30%, P<0.05; cytotrophoblast: 15%, P<0.05. Silencing MCT8 did not significantly affect SGHPL-4 invasion, but with MCT8 over-expression T3 treatment promoted invasion compared with no T3 (3.3-fold; P<0.05. Furthermore, MCT8 silencing increased cytotrophoblast viability (∼20%, P<0.05 and MCT8 over-expression reduced cytotrophoblast viability independently of T3 (∼20%, P<0.05. In vivo, Mct8 knockout reduced fetal:placental weight ratios compared with wild-type controls at gestational day 18 (25%, P<0.05 but absolute fetal and placental weights were not significantly different. The volume fraction of the labyrinthine zone of the placenta, which facilitates maternal-fetal exchange, was reduced in Mct8 knockout placentae (10%, P<0.05. However, there was no effect on mouse placental cell proliferation in vivo. We conclude that MCT8 makes a significant contribution to T3 uptake into human trophoblast cells and has a role in modulating human trophoblast cell invasion and viability. In mice, Mct8 knockout has subtle effects upon fetoplacental growth and does not significantly affect placental cell viability probably due to compensatory mechanisms in

  7. Genetic variation in the nuclear and organellar genomes modulates stochastic variation in the metabolome, growth, and defense.

    Directory of Open Access Journals (Sweden)

    Bindu Joseph

    2015-01-01

    Full Text Available Recent studies are starting to show that genetic control over stochastic variation is a key evolutionary solution of single celled organisms in the face of unpredictable environments. This has been expanded to show that genetic variation can alter stochastic variation in transcriptional processes within multi-cellular eukaryotes. However, little is known about how genetic diversity can control stochastic variation within more non-cell autonomous phenotypes. Using an Arabidopsis reciprocal RIL population, we showed that there is significant genetic diversity influencing stochastic variation in the plant metabolome, defense chemistry, and growth. This genetic diversity included loci specific for the stochastic variation of each phenotypic class that did not affect the other phenotypic classes or the average phenotype. This suggests that the organism's networks are established so that noise can exist in one phenotypic level like metabolism and not permeate up or down to different phenotypic levels. Further, the genomic variation within the plastid and mitochondria also had significant effects on the stochastic variation of all phenotypic classes. The genetic influence over stochastic variation within the metabolome was highly metabolite specific, with neighboring metabolites in the same metabolic pathway frequently showing different levels of noise. As expected from bet-hedging theory, there was more genetic diversity and a wider range of stochastic variation for defense chemistry than found for primary metabolism. Thus, it is possible to begin dissecting the stochastic variation of whole organismal phenotypes in multi-cellular organisms. Further, there are loci that modulate stochastic variation at different phenotypic levels. Finding the identity of these genes will be key to developing complete models linking genotype to phenotype.

  8. Induction of angiogenesis and modulation of vascular endothelial growth factor receptor-2 by simvastatin after traumatic brain injury.

    Science.gov (United States)

    Wu, Hongtao; Jiang, Hao; Lu, Dunyue; Qu, Changsheng; Xiong, Ye; Zhou, Dong; Chopp, Michael; Mahmood, Asim

    2011-05-01

    Our previous studies demonstrated that simvastatin reduced neuronal death, increased neurogenesis, and promoted functional recovery after traumatic brain injury (TBI). To investigate the effect of simvastatin on angiogenesis after TBI and the related signaling pathways. Saline or simvastatin (1 mg/kg) was administered orally to rats starting at day 1 after TBI or sham surgery and then daily for 14 days. Rats were sacrificed at 3 and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining, enzyme-linked immunosorbent assay, and Western blot analysis. Cultured rat brain microvascular endothelial cells were subjected to oxygen-glucose deprivation followed by immunocytochemical staining with phallotoxins and vascular endothelial growth factor receptor-2 (VEGFR-2). Western blot analysis was carried out to examine the simvastatin-induced activation of the v-akt murine thymoma viral oncogene homolog (Akt) signaling pathway. The expression of VEGFR-2 was detected by enzyme-linked immunosorbent assay. Simvastatin significantly increased the length of vascular perimeter, promoted the proliferation of endothelial cells, and improved the sensorimotor function after TBI. Simvastatin stimulated endothelial cell tube formation after oxygen-glucose deprivation in vitro. VEGFR-2 expression in both brain tissues and cultured rat brain microvascular endothelial cells was enhanced after simvastatin treatment, which may be modulated by activation of Akt. Akt-dependent endothelial nitric oxide synthase phosphorylation was also induced by simvastatin in vivo and in vitro. Simvastatin augments TBI-induced angiogenesis in the lesion boundary zone and hippocampus and improves functional recovery. Simvastatin also promotes angiogenesis in vitro. These beneficial effects on angiogenesis may be related to simvastatin-induced activation of the VEGFR-2/Akt/endothelial nitric oxide synthase signaling pathway.

  9. Modulation of fibroblast growth factor 19 expression by bile acids, meal replacement and energy drinks, milk, and coffee.

    Science.gov (United States)

    Styer, Amanda M; Roesch, Stephen L; Argyropoulos, George

    2014-01-01

    The enterohepatic pathway involving the fibroblast growth factor 19 (FGF19) and bile acids (BA) has been linked with the etiology and remission of type 2 diabetes (T2D) following Roux-en-Y gastric bypass (RYGB) surgery. Specifically, diabetic patients had lower FGF19 circulating levels but postoperative FGF19 and BA levels were higher in diabetic patients that experience remission of T2D, as compared to non-diabetic patients and diabetic patients that do not experience remission. It has been proposed that this may be due to the direct flow of digestate-free bile acids into the ileum benefiting mostly T2D patients without severe diabetes. We used a human colorectal cell line (LS174T) that endogenously expresses FGF19, real time PCR, and Elisas for precise quantitation of FGF19 mRNA and secreted protein levels. We report here that BA and fractions of BA stimulated FGF19 in vitro but this effect was partially blocked when BA were pre-incubated with a lipoprotein mix which emulates digested food. In addition, we show that FGF19 mRNA was stimulated by meal replacement drinks (Ensure, Glucerna, SlimFast), non-fat milk, and coffee which has been linked with reduced risk for developing diabetes. Pure caffeine and the 5-hour Energy drink, on the other hand, decreased FGF19 mRNA. In summary, FGF19 expression in vitro is modifiable by popular drinks suggesting that such approaches could potentially be used for modulating FGF19 expression in humans.

  10. Selective androgen receptor modulators (SARMs negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    Full Text Available The androgen receptor (AR is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer.Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC co-culture signaling studies were performed to understand the mechanisms of action.Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures.1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

  11. Insulin-like growth factor-1 inhibits adult supraoptic neurons via complementary modulation of mechanoreceptors and glycine receptors.

    Science.gov (United States)

    Ster, Jeanne; Colomer, Claude; Monzo, Cécile; Duvoid-Guillou, Anne; Moos, Françoise; Alonso, Gérard; Hussy, Nicolas

    2005-03-02

    In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons. In vivo application of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl- currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.

  12. Modulation of fibroblast growth factor 19 expression by bile acids, meal replacement and energy drinks, milk, and coffee.

    Directory of Open Access Journals (Sweden)

    Amanda M Styer

    Full Text Available BACKGROUND: The enterohepatic pathway involving the fibroblast growth factor 19 (FGF19 and bile acids (BA has been linked with the etiology and remission of type 2 diabetes (T2D following Roux-en-Y gastric bypass (RYGB surgery. Specifically, diabetic patients had lower FGF19 circulating levels but postoperative FGF19 and BA levels were higher in diabetic patients that experience remission of T2D, as compared to non-diabetic patients and diabetic patients that do not experience remission. It has been proposed that this may be due to the direct flow of digestate-free bile acids into the ileum benefiting mostly T2D patients without severe diabetes. METHODS/RESULTS: We used a human colorectal cell line (LS174T that endogenously expresses FGF19, real time PCR, and Elisas for precise quantitation of FGF19 mRNA and secreted protein levels. We report here that BA and fractions of BA stimulated FGF19 in vitro but this effect was partially blocked when BA were pre-incubated with a lipoprotein mix which emulates digested food. In addition, we show that FGF19 mRNA was stimulated by meal replacement drinks (Ensure, Glucerna, SlimFast, non-fat milk, and coffee which has been linked with reduced risk for developing diabetes. Pure caffeine and the 5-hour Energy drink, on the other hand, decreased FGF19 mRNA. CONCLUSIONS: In summary, FGF19 expression in vitro is modifiable by popular drinks suggesting that such approaches could potentially be used for modulating FGF19 expression in humans.

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

    Science.gov (United States)

    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.

  14. Dietary Energy Balance Modulation of Kras– and Ink4a/Arf+/-–Driven Pancreatic Cancer: The Role of Insulin-like Growth Factor-1

    OpenAIRE

    Lashinger, Laura M.; Harrison, Lauren M.; Rasmussen, Audrey J.; Logsdon, Craig D.; Fischer, Susan M.; McArthur, Mark J.; Hursting, Stephen D.

    2013-01-01

    New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-1–dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+ mice, calorie restriction, versus overweight- or obesity-...

  15. Insulin-like and fibroblast growth factors in spinal cords, nerve roots and skeletal muscle of human controls and patients with amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    Kerkhoff, H.; Hassan, S. M.; Troost, D.; van Etten, R. W.; Veldman, H.; Jennekens, F. G.

    1994-01-01

    Insulin-like growth factors (IGF-I and IGF-II) and fibroblast growth factors [acidic FGF (aFGF) and basic FGF (bFGF)] are trophic for motor neurones in vitro and (in laboratory animals) in vivo. An immunohistochemical investigation was performed on the distribution of these factors in the

  16. Abscisic acid accumulation modulates auxin transport in the root tip to enhance proton secretion for maintaining root growth under moderate water stress.

    Science.gov (United States)

    Xu, Weifeng; Jia, Liguo; Shi, Weiming; Liang, Jiansheng; Zhou, Feng; Li, Qianfeng; Zhang, Jianhua

    2013-01-01

    Maintenance of root growth is essential for plant adaptation to soil drying. Here, we tested the hypothesis that auxin transport is involved in mediating ABA's modulation by activating proton secretion in the root tip to maintain root growth under moderate water stress. Rice and Arabidopsis plants were raised under a hydroponic system and subjected to moderate water stress (-0.47 MPa) with polyethylene glycol (PEG). ABA accumulation, auxin transport and plasma membrane H(+)-ATPase activity at the root tip were monitored in addition to the primary root elongation and root hair density. We found that moderate water stress increases ABA accumulation and auxin transport in the root apex. Additionally, ABA modulation is involved in the regulation of auxin transport in the root tip. The transported auxin activates the plasma membrane H(+)-ATPase to release more protons along the root tip in its adaption to moderate water stress. The proton secretion in the root tip is essential in maintaining or promoting primary root elongation and root hair development under moderate water stress. These results suggest that ABA accumulation modulates auxin transport in the root tip, which enhances proton secretion for maintaining root growth under moderate water stress. © 2012 The Authors. New Phytologist © 2012 New Phytologist Trust.

  17. International Spinal Cord Injury

    DEFF Research Database (Denmark)

    Dvorak, M F; Itshayek, E; Fehlings, M G

    2015-01-01

    STUDY DESIGN: Survey of expert opinion, feedback and final consensus. OBJECTIVE: To describe the development and the variables included in the International Spinal Cord Injury (SCI) Spinal Interventions and Surgical Procedures Basic Data set. SETTING: International working group. METHODS......: A committee of experts was established to select and define data elements. The data set was then disseminated to the appropriate committees and organizations for comments. All suggested revisions were considered and both the International Spinal Cord Society and the American Spinal Injury Association endorsed...... the final version. RESULTS: The data set consists of nine variables: (1) Intervention/Procedure Date and start time (2) Non-surgical bed rest and external immobilization, (3) Spinal intervention-closed manipulation and/or reduction of spinal elements, (4) Surgical procedure-approach, (5) Date and time...

  18. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression

    DEFF Research Database (Denmark)

    Pouladi, Mahmoud A; Xie, Yuanyun; Skotte, Niels Henning

    2010-01-01

    Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement...

  19. Shizukaol D, a Dimeric Sesquiterpene Isolated from Chloranthus serratus, Represses the Growth of Human Liver Cancer Cells by Modulating Wnt Signalling Pathway.

    Directory of Open Access Journals (Sweden)

    Lisha Tang

    Full Text Available Natural products have become sources of developing new drugs for the treatment of cancer. To seek candidate compounds that inhibit the growth of liver cancer, components of Chloranthus serratus were tested. Here, we report that shizukaol D, a dimeric sesquiterpene from Chloranthus serratus, exerted a growth inhibition effect on liver cancer cells in a dose- and time-dependent manner. We demonstrated that shizukaol D induced cells to undergo apoptosis. More importantly, shizukaol D attenuated Wnt signalling and reduced the expression of endogenous Wnt target genes, which resulted in decreased expression of β-catenin. Collectively, this study demonstrated that shizukaol D inhibited the growth of liver cancer cells by modulating Wnt pathway.

  20. The transformation of spinal curvature into spinal deformity: pathological processes and implications for treatment

    Directory of Open Access Journals (Sweden)

    Hawes Martha C

    2006-03-01

    Full Text Available Abstract Background This review summarizes what is known about the pathological processes (e.g. structural and functional changes, by which spinal curvatures develop and evolve into spinal deformities. Methods Comprehensive review of articles (English language only published on 'scoliosis,' whose content yielded data on the pathological changes associated with spinal curvatures. Medline, Science Citation Index and other searches yielded > 10,000 titles each of which was surveyed for content related to 'pathology' and related terms such as 'etiology,' 'inheritance,' 'pathomechanism,' 'signs and symptoms.' Additional resources included all books published on 'scoliosis' and available through the Arizona Health Sciences Library, Interlibrary Loan, or through direct contact with the authors or publishers. Results A lateral curvature of the spine–'scoliosis'–can develop in association with postural imbalance due to genetic defects and injury as well as pain and scarring from trauma or surgery. Irrespective of the factor that triggers its appearance, a sustained postural imbalance can result, over time, in establishment of a state of continuous asymmetric loading relative to the spinal axis. Recent studies support the longstanding hypothesis that spinal deformity results directly from such postural imbalance, irrespective of the primary trigger, because the dynamics of growth within vertebrae are altered by continuous asymmetric mechanical loading. These data suggest that, as long as growth potential remains, evolution of a spinal curvature into a spinal deformity can be prevented by reversing the state of continuous asymmetric loading. Conclusion Spinal curvatures can routinely be diagnosed in early stages, before pathological deformity of the vertebral elements is induced in response to asymmetric loading. Current clinical approaches involve 'watching and waiting' while mild reversible spinal curvatures develop into spinal deformities with

  1. The transformation of spinal curvature into spinal deformity: pathological processes and implications for treatment

    Science.gov (United States)

    Hawes, Martha C; O'Brien, Joseph P

    2006-01-01

    Background This review summarizes what is known about the pathological processes (e.g. structural and functional changes), by which spinal curvatures develop and evolve into spinal deformities. Methods Comprehensive review of articles (English language only) published on 'scoliosis,' whose content yielded data on the pathological changes associated with spinal curvatures. Medline, Science Citation Index and other searches yielded > 10,000 titles each of which was surveyed for content related to 'pathology' and related terms such as 'etiology,' 'inheritance,' 'pathomechanism,' 'signs and symptoms.' Additional resources included all books published on 'scoliosis' and available through the Arizona Health Sciences Library, Interlibrary Loan, or through direct contact with the authors or publishers. Results A lateral curvature of the spine–'scoliosis'–can develop in association with postural imbalance due to genetic defects and injury as well as pain and scarring from trauma or surgery. Irrespective of the factor that triggers its appearance, a sustained postural imbalance can result, over time, in establishment of a state of continuous asymmetric loading relative to the spinal axis. Recent studies support the longstanding hypothesis that spinal deformity results directly from such postural imbalance, irrespective of the primary trigger, because the dynamics of growth within vertebrae are altered by continuous asymmetric mechanical loading. These data suggest that, as long as growth potential remains, evolution of a spinal curvature into a spinal deformity can be prevented by reversing the state of continuous asymmetric loading. Conclusion Spinal curvatures can routinely be diagnosed in early stages, before pathological deformity of the vertebral elements is induced in response to asymmetric loading. Current clinical approaches involve 'watching and waiting' while mild reversible spinal curvatures develop into spinal deformities with potential to cause symptoms

  2. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... After Pediatric Spinal Injury Dawn Sheaffer, MSW Rehabilitation Psychological Realities ... play_arrow What factors are important in choosing a rehabilitation facility after ...

  3. Transcription factor Nrf2 protects the spinal cord from inflammation produced by spinal cord injury.

    Science.gov (United States)

    Mao, Lei; Wang, Handong; Wang, Xiaoliang; Liao, Hong; Zhao, Xianzhong

    2011-09-01

    Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI). Previous studies have suggested that nuclear factor-erythroid 2-related factor 2 (Nrf2), a pleiotropic transcription factor, may play a key role in modulating inflammation in a variety of experimental models. This study evaluated the neuroprotective role of Nrf2 in the inflammatory response after SCI in mice. Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice spinal cord compression injury was induced by the application of vascular clips (force of 10 g) to the dura. Sulforaphane (SFN) was used to activate Nrf2 after SCI. Inflammatory cytokines, NF-κB activity, histologic injury score, dying neurons count in grey matter, water content of impaired spinal cord, and Basso open-field motor score (BMS) were assessed to determine the extent of SCI-mediated damage. The results showed that SFN activated Nrf2 in impaired spinal cord tissue, improved hindlimb locomotor function assessed by BMS, reduced inflammatory damage, histologic injury, dying neurons count, and spinal cord edema caused by SCI. Nrf2(-/-) mice demonstrated more severe neurologic deficit and spinal cord edema after SCI and did not benefit from the protective effect of SFN. Taken together, our results suggest that Nrf2 may represent a strategic target for SCI therapies. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Concise review: reactive astrocytes and stem cells in spinal cord injury: good guys or bad guys?

    Science.gov (United States)

    Lukovic, Dunja; Stojkovic, Miodrag; Moreno-Manzano, Victoria; Jendelova, Pavla; Sykova, Eva; Bhattacharya, Shomi S; Erceg, Slaven

    2015-04-01

    Spinal cord injury (SCI) usually results in long lasting locomotor and sensory neuron degeneration below the injury. Astrocytes normally play a decisive role in mechanical and metabolic support of neurons, but in the spinal cord they cause injury, exerting well-known detrimental effects that contribute to glial scar formation and inhibition of axon outgrowth. Cell transplantation is considered a promising approach for replacing damaged cells and promoting neuroprotective and neuroregenerative repair, but the effects of the grafted cells on local tissue and the regenerative properties of endogenous neural stem cells in the injured spinal cord are largely unknown. During the last 2 decades cumulative evidence from diverse animal models has indicated that reactive astrocytes in synergy with transplanted cells could be beneficial for injury in multiple ways, including neuroprotection and axonal growth. In this review, we specifically focus on the dual opposing roles of reactive astrocytes in SCI and how they contribute to the creation of a permissive environment when combined with transplanted cells as the influential components for a local regenerative niche. Modulation of reactive astrocyte function might represent an extremely attractive new therapy to enhance the functional outcomes in patients. © 2015 AlphaMed Press.

  5. Thermal Stimulation Alters Cervical Spinal Cord Functional Connectivity in Humans.

    Science.gov (United States)

    Weber, Kenneth A; Sentis, Amy I; Bernadel-Huey, Olivia N; Chen, Yufen; Wang, Xue; Parrish, Todd B; Mackey, Sean

    2018-01-15

    The spinal cord has an active role in the modulation and transmission of the neural signals traveling between the body and the brain. Recent advancements in functional magnetic resonance imaging (fMRI) have made the in vivo examination of spinal cord function in humans now possible. This technology has been recently extended to the investigation of resting state functional networks in the spinal cord, leading to the identification of distinct patterns of spinal cord functional connectivity. In this study, we expand on the previous work and further investigate resting state cervical spinal cord functional connectivity in healthy participants (n = 15) using high resolution imaging coupled with both seed-based functional connectivity analyses and graph theory-based metrics. Within spinal cord segment functional connectivity was present between the left and right ventral horns (bilateral motor network), left and right dorsal horns (bilateral sensory network), and the ipsilateral ventral and dorsal horns (unilateral sensory-motor network). Functional connectivity between the spinal cord segments was less apparent with the connectivity centered at the region of interest and spanning spinal cord functional network was demonstrated to be state-dependent as thermal stimulation of the right ventrolateral forearm resulted in significant disruption of the bilateral sensory network, increased network global efficiency, and decreased network modularity. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. Common surgical complications in degenerative spinal surgery.

    Science.gov (United States)

    Papadakis, Michael; Aggeliki, Lianou; Papadopoulos, Elias C; Girardi, Federico P

    2013-04-18

    The rapid growth of spine degenerative surgery has led to unrelenting efforts to define and prevent possible complications, the incidence of which is probably higher than that reported and varies according to the region of the spine involved (cervical and thoracolumbar) and the severity of the surgery. Several issues are becoming progressively clearer, such as complication rates in primary versus revision spinal surgery, complications in the elderly, the contribution of minimally invasive surgery to the reduction of complication rate. In this paper the most common surgical complications in degenerative spinal surgery are outlined and discussed.

  7. The effect of application site of spinal manipulative therapy (SMT) on spinal stiffness.

    Science.gov (United States)

    Edgecombe, Tiffany L; Kawchuk, Greg N; Long, Cynthia R; Pickar, Joel G

    2015-06-01

    Like other factors that can influence treatment efficacy (eg, dosage, frequency, time of day), the site of treatment application is known to affect various physical interventions such as topical anesthetics and cardiopulmonary resuscitation. Like these examples, spinal manipulative therapy (SMT) is a physical intervention that may exhibit maximal benefit when directed to a specific site. Whereas numerous studies of SMT efficacy have produced mixed results, few studies have taken into account the site of SMT application. To determine if the site of SMT application modulates the effect of SMT in an anesthetized feline model. Spinal manipulative therapy applied to specific anatomic locations randomized in a Latin square design with a no-SMT control. Physiologic measures (spinal stiffness). Simulated SMT was delivered by a validated mechanical apparatus to the intact lumbar spine of eight anesthetized felines at four unique sites: L6 spinous process, left L6 lamina, left L6 mammillary process, and L7 spinous process. To measure spinal stiffness, a separate indentation load was applied mechanically to the L6 spinous process before and after each SMT application. Spinal stiffness was calculated from the resulting force-displacement curve as the average stiffness (k) and terminal instantaneous stiffness (TIS). Relative to the no-SMT control, significant decreases in spinal stiffness followed the SMT when L6 spinous and L6 lamina were used as the contact site. Terminal instantaneous stiffness significantly decreased -0.48 N/mm (upper, lower 95% confidence interval [-0.86, -0.09]) with L6 spinous as the contact site and decreased -0.44 N/mm (-0.82, -0.05), with the L6 lamina as the contact site. k increased 0.44 N/mm (-0.01, 088), using L6 spinous as the contact site. Decreases in terminal spinal stiffness were observed after SMT delivered at some application sites but not the others. The results suggest that SMT contact site modulates SMT's effect on spinal stiffness in a

  8. Synergistic action of protease-modulating matrix and autologous growth factors in healing of diabetic foot ulcers. A prospective randomized trial.

    Science.gov (United States)

    Kakagia, Despoina D; Kazakos, Konstantinos J; Xarchas, Konstantinos C; Karanikas, Michael; Georgiadis, George S; Tripsiannis, Gregory; Manolas, Constantinos

    2007-01-01

    This study tests the hypothesis that addition of a protease-modulating matrix enhances the efficacy of autologous growth factors in diabetic ulcers. Fifty-one patients with chronic diabetic foot ulcers were managed as outpatients at the Democritus University Hospital of Alexandroupolis and followed up for 8 weeks. All target ulcers were > or = 2.5 cm in any one dimension and had been previously treated only with moist gauze. Patients were randomly allocated in three groups of 17 patients each: Group A was treated only with the oxidized regenerated cellulose/collagen biomaterial (Promogran, Johnson & Johnson, New Brunswick, NJ), Group B was treated only with autologous growth factors delivered by Gravitational Platelet Separation System (GPS, Biomet), and Group C was managed by a combination of both. All ulcers were digitally photographed at initiation of the study and then at change of dressings once weekly. Computerized planimetry (Texas Health Science Center ImageTool, Version 3.0) was used to assess ulcer dimensions that were analyzed for homogeneity and significance using the Statistical Package for Social Sciences, Version 13.0. Post hoc analysis revealed that there was significantly greater reduction of all three dimensions of the ulcers in Group C compared to Groups A and B (all P<.001). Although reduction of ulcer dimensions was greater in Group A than in Group B, these differences did not reach statistical significance. It is concluded that protease-modulating dressings act synergistically with autologous growth factors and enhance their efficacy in diabetic foot ulcers.

  9. Transforming growth factor-beta and epidermal growth factor modulate basal and interleukin-6-induced amino acid uptake and acute phase protein synthesis in cultured rat hepatocytes.

    Science.gov (United States)

    Bereta, J; Szuba, K; Fiers, W; Gauldie, J; Koj, A

    1990-06-18

    Rat hepatocytes cultured for 2 days with interleukin-6 show increased synthesis of acute phase proteins and enhanced accumulation of 14C-labelled alpha-aminoisobutyric acid. Transforming growth factor-beta 1 (0.1-10 ng/ml) inhibits whereas epidermal growth factor (1-100 ng/ml) enhances both basal and interleukin-6-induced amino acid uptake by rat hepatocytes with only a slight alteration of acute phase protein synthesis.

  10. Afferent electrical stimulation during cycling improves spinal processing of sensorimotor function after incomplete spinal cord injury.

    Science.gov (United States)

    Piazza, Stefano; Serrano-Muñoz, Diego; Gómez-Soriano, Julio; Torricelli, Diego; Segura-Fragosa, Antonio; Pons, José Luis; Taylor, Julian

    2017-01-01

    Appropriate afferent feedback delivery during the execution of motor tasks is important for rehabilitation after incomplete spinal cord injury (iSCI). However, during leg-cycling therapy, the plantar afferent feedback is minimal. We hypothesize that the augmentation of sensory input by combining cycling with a locomotor-like stimulation of plantar cutaneous innervations (ES-cycling), might help to restore proper spinal processing of sensorimotor function. Thirteen non-injured subjects and 10 subjects with iSCI performed 10 minutes of cycling and, on another session, of ES-cycling. To assess spinal processing of sensorimotor function, soleus H-reflex response was tested following a conditioning plantar electrical stimulation applied at 25-100 ms inter-stimulus intervals (ISI's), measured before and after the execution of the tasks. Before tasks execution, the conditioned H-reflex response was modulated in non-injured subjects, and absent in subjects with iSCI; after cycling, modulation profiles were unchanged. However, after ES-cycling a significant increase in H-reflex excitability was observed in the non-injured group at 100 ms ISI (p spinal processing of sensorimotor function. Reflex modulation recovery after ES-cycling may indicate the partial reactivation of these mechanisms.

  11. Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury.

    Science.gov (United States)

    Bauman, William A; La Fountaine, Michael F; Cirnigliaro, Christopher M; Kirshblum, Steven C; Spungen, Ann M

    2013-09-01

    To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study. The subjects were 43 ± 12 years old, had duration of injury of 20 ± 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 ± 63 vs. 217 ± 69 ng/ml; P plasma IGF-1 concentrations in the physiological range in men with chronic SCI.

  12. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Spinal Cord Injury 101 Lawrence Vogel, MD The Basics of Pediatric SCI Rehabilitation Sara Klaas, MSW Transitions ... PhD Michelle Meade, PhD Jonathon Rose, PhD The Basics of Spinal Cord Injury Rehabilitation Kristine Cichowski, MS ...

  13. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... in a Wheelchair Lisa Rosen, MS Spasticity, Physical Therapy-Lokomat T. George Hornby, PhD, PT Empowering the Patient After Spinal Cord Injury Guy W. Fried, MD Substance Abuse and Spinal Cord Injury Allen Heinemann, PhD How ...

  14. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Read Bio Medical Director, Spinal Cord Injury Rehabilitation Program, Rehabilitation Institute of Chicago play_arrow What is ... What is the “Spinal Cord Injury Model Systems” program? play_arrow What are the most promising new ...

  15. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Cord Injury Allen Heinemann, PhD How Peer Counseling Works Julie Gassaway, MS, RN Pediatric Injuries Pediatric Spinal Cord Injury 101 Lawrence Vogel, MD The Basics of Pediatric SCI Rehabilitation Sara Klaas, MSW Transitions for Children with Spinal Cord Injury Patricia Mucia, RN Family ...

  16. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Blog Videos By Topic Media Resources Donate to support families facing spinal cord injuries Peer Counseling 312-284- ... of Use FacingDisability.com is an informational and support website for families facing spinal cord injuries. The website does not ...

  17. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... MS Spasticity, Physical Therapy-Lokomat T. George Hornby, PhD, PT Empowering the Patient After Spinal Cord Injury ... Substance Abuse and Spinal Cord Injury Allen Heinemann, PhD How Peer Counseling Works Julie Gassaway, MS, RN ...

  18. Glioblastoma with spinal seeding

    Energy Technology Data Exchange (ETDEWEB)

    Fakhrai, N.; Fazeny-Doerner, B.; Marosi, C. [Clinical Div. of Oncology, Dept. of Medicine I, Univ. of Vienna (Austria); Czech, T. [Dept. of Neurosurgery, Univ. of Vienna (Austria); Diekmann, K. [Dept. of Radiooncology, Univ. of Vienna (Austria); Birner, P.; Hainfellner, J.A. [Clinical Inst. for Neurology, Univ. of Vienna (Austria); Prayer, D. [Dept. of Neuroradiology, Univ. of Vienna (Austria)

    2004-07-01

    Background: extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding. Case reports: two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding. Results: in both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state. Conclusion: because of short survival periods, patients deserve optimal pain management and dedicated palliative care. (orig.)

  19. The safe spinal anaesthetic

    African Journals Online (AJOL)

    and complications. To perform a safe procedure, the anaesthetist must have adequate knowledge of the indications and contra-indications, and of the relevant anatomy, physiology and pharmacology of spinal anaesthesia. The patient must be assessed before administration of the spinal anaesthetic and the theatre must be.

  20. Conventional Spinal Anaesthesia

    African Journals Online (AJOL)

    Blood pressure, heart rate, respiratory rate and oxygen saturation were monitored over 1hour. RESULTS: Three ... Patients in the conventional group had statistically significant greater fall in the systolic blood pressures at 15, 30 and 45 ..... cardiovascular homeostasis during spinal anaesthesia, unilateral spinal anaesthesia ...

  1. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... Life in a Wheelchair Lisa Rosen, MS Spasticity, Physical Therapy-Lokomat T. George Hornby, PhD, PT Empowering the Patient After Spinal Cord Injury Guy W. Fried, MD Substance Abuse and Spinal Cord Injury Allen Heinemann, PhD How ...

  2. Spinal Cord Injury 101

    Medline Plus

    Full Text Available ... cord injuries? play_arrow What are the latest developments in the use of electrical stimulation for spinal cord injuries? play_arrow What is “Braingate” research? play_arrow How would stem-cell therapies work in the treatment of spinal cord injuries? play_ ...

  3. An unusual spinal arachnoiditis.

    Science.gov (United States)

    Agrawal, Abhishek; Agrawal, Anushree; Agrawal, Chandrashekhar; Rohtagi, Anshu

    2006-12-01

    Cryptococcal spinal arachnoiditis occurs in patients with meningitis and usually when they are immunocompromised. Spinal symptoms in cryptococcosis are rare and a very exceptional entity in the immunocompetent population. We present a young immunocompetent male who developed progressively increasing paraparesis due to primary cryptococcal arachnoiditis, who showed significant improvement after antifungal therapy. Although extremely rare, spinal arachnoiditis in an immunocompetent individual can be caused due to cryptococcus, as in our case. This case illustrates and emphasizes the necessity for an exhaustive and complete investigation, with a high index of suspicion for fungal etiology in patients presenting with spinal arachnoiditis or other disabling, progressive spinal cord syndromes of unknown etiology. Awareness of this presentation is necessary to avoid delay in diagnosis and management of this potentially curable condition.

  4. Human spinal motor control

    DEFF Research Database (Denmark)

    Nielsen, Jens Bo

    2016-01-01

    interneurons and exert a direct (willful) muscle control with the aid of a context-dependent integration of somatosensory and visual information at cortical level. However, spinal networks also play an important role. Sensory feedback through spinal circuitries is integrated with central motor commands...... and contributes importantly to the muscle activity underlying voluntary movements. Regulation of spinal interneurons is used to switch between motor states such as locomotion (reciprocal innervation) and stance (coactivation pattern). Cortical regulation of presynaptic inhibition of sensory afferents may focus...... the central motor command by opening or closing sensory feedback pathways. In the future, human studies of spinal motor control, in close collaboration with animal studies on the molecular biology of the spinal cord, will continue to document the neural basis for human behavior. Expected final online...

  5. Dlk1/FA1 Is a Novel Endocrine Regulator of Bone and Fat Mass and Its Serum Level Is Modulated By Growth Hormone

    DEFF Research Database (Denmark)

    Abdallah, B.M.; Ding, M.; Jensen, C.H.

    2007-01-01

    modulation of serum FA1 by GH. Serum levels of insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBPs) did not change in FA1-mice, while increasing serum GH in normal mice using HGTP, dramatically reduced serum FA1 levels by 60%. On the other hand, serum FA1 was increased 450......% in hypophysectomized mice and this high level was reduced by 40% during GH treatment. In conclusion, our data identify the FA1 as a novel endocrine factor regulating bone mass and fat mass in vivo and its serum levels are regulated by GH. FA1 thus, provides a novel class of developmental molecules that regulate...

  6. Growing in times of grief: attachment modulates bereaved adults' posttraumatic growth after losing a family member to cancer.

    Science.gov (United States)

    Xu, Wei; Fu, Zhongfang; He, Li; Schoebi, Dominik; Wang, Jianping

    2015-11-30

    This study explored whether attachment moderated the relationship between grief and posttraumatic growth. A total of 240 Chinese adults who have lost a family member to cancer reported on their grief (Prolonged Grief Questionnaire-13; PG-13), posttraumatic growth (Posttraumatic Growth Inventory; PTGI) and attachment (Experiences in Close Relationships; ECR). The results suggested that bereaved individuals who scored high on attachment anxiety showed a substantial and positive relationship between grief and posttraumatic growth, while their less anxiously attached counterparts showed no such association. Attachment avoidance was not significantly related to the association between grief and posttraumatic growth. Findings indicated that individuals high in attachment anxiety have the potential to benefit and gain from the process of adapting to the loss. The implications of the results for relevant research and grief counseling were discussed. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Extracellular cathepsin L stimulates axonal growth in neurons.

    Science.gov (United States)

    Tohda, Chihiro; Tohda, Michihisa

    2017-11-23

    Cathepsin L, a lysosomal endopeptidase expressed in most eukaryotic cells, is a member of the papain-like family of cysteine proteases. Although commonly recognized as a lysosomal protease, cathepsin L is also secreted and involved in the degradation of extracellular matrix proteins. Previous studies demonstrated that the secretion of cathepsin L was stimulated by basic fibroblast growth factor (bFGF) and bFGF-enhanced axonal terminal sprouting of motor neurons. Based on these results, although it has never been directly investigated, we hypothesized that extracellular cathepsin L may induce axonal growth. To confirm the hypothesis, the axonal growth activity of recombinant cathepsin L was evaluated in cultured cortical and spinal cord neurons. Treatment with recombinant cathepsin L significantly enhanced axonal growth, but not dendritic growth. This result indicated that extracellular cathepsin L may act as a new neuronal network modulator.

  8. Body segments and growth hormone.

    OpenAIRE

    Bundak, R; Hindmarsh, P C; Brook, C G

    1988-01-01

    The effects of human growth hormone treatment for five years on sitting height and subischial leg length of 35 prepubertal children with isolated growth hormone deficiency were investigated. Body segments reacted equally to treatment with human growth hormone; this is important when comparing the effect of growth hormone on the growth of children with skeletal dysplasias or after spinal irradiation.

  9. Extramedullary spinal teratoma presenting with recurrent aseptic meningitis.

    Science.gov (United States)

    Mpayo, Lucy L; Liu, Xiao-Hong; Xu, Man; Wang, Kai; Wang, Jiao; Yang, Li

    2014-06-01

    Spinal teratomas are extremely rare; they constitute meningitis. A 7-year-old boy presented with paroxysmal abdominal pain and a history of recurrent aseptic meningitis. Kernig and Brudzinski signs were present. Lumber puncture revealed pleocytosis with no evidence of bacteria growth. Imaging of the spine revealed a cystic lesion in spinal cord at thoracic level 9-11. Endoscopic excision of the cyst was successfully performed. Surgical and histopathological findings confirmed extramedullary matured teratoma. As the symptomatic attacks of spontaneous rupture of spinal teratoma resemble presentations of Mollaret meningitis, spinal teratoma should be considered in the differential diagnosis of Mollaret meningitis. We describe a rare example of spinal teratoma causing recurrent meningitis. Spine imaging should be considered in individuals with recurrent aseptic meningitis as this promotes earlier diagnosis, more appropriate treatment, and improved neurological outcome. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Collagen and Stretch Modulate Autocrine Secretion of Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Proteins from Differentiated Skeletal Muscle Cells

    Science.gov (United States)

    Perrone, Carmen E.; Fenwick-Smith, Daniela; Vandenburgh, Herman H.

    1995-01-01

    Stretch-induced skeletal muscle growth may involve increased autocrine secretion of insulin-like growth factor-1 (IGF-1) since IGF-1 is a potent growth factor for skeletal muscle hypertrophy, and stretch elevates IGF-1 mRNA levels in vivo. In tissue cultures of differentiated avian pectoralis skeletal muscle cells, nanomolar concentrations of exogenous IGF-1 stimulated growth in mechanically stretched but not static cultures. These cultures released up to 100 pg of endogenously produced IGF-1/micro-g of protein/day, as well as three major IGF binding proteins of 31, 36, and 43 kilodaltons (kDa). IGF-1 was secreted from both myofibers and fibroblasts coexisting in the muscle cultures. Repetitive stretch/relaxation of the differentiated skeletal muscle cells stimulated the acute release of IGF-1 during the first 4 h after initiating mechanical activity, but caused no increase in the long-term secretion over 24-72 h of IGF-1, or its binding proteins. Varying the intensity and frequency of stretch had no effect on the long-term efflux of IGF-1. In contrast to stretch, embedding the differentiated muscle cells in a three-dimensional collagen (Type I) matrix resulted in a 2-5-fold increase in long-term IGF-1 efflux over 24-72 h. Collagen also caused a 2-5-fold increase in the release of the IGF binding proteins. Thus, both the extracellular matrix protein type I collagen and stretch stimulate the autocrine secretion of IGF-1, but with different time kinetics. This endogenously produced growth factor may be important for the growth response of skeletal myofibers to both types of external stimuli.

  11. Epidermal growth factor and transforming growth factor-beta differently modulate the acute phase response elicited by interleukin-6 in cultured liver cells from man, rat and mouse.

    Science.gov (United States)

    Rokita, H; Bereta, J; Koj, A; Gordon, A H; Gauldie, J

    1990-01-01

    1. Complex effects of principal inflammatory cytokines (IL-6, IL-1, TNF, IFN-gamma) on acute phase protein synthesis and other metabolic processes in cultured liver cells are briefly reviewed. 2. Molecular properties and biological functions of transforming growth factor-beta and epidermal growth factor are compared. 3. The effects of these factors with respect to both amino acid uptake and acute phase protein synthesis are described in detail. The results are found to be different for rat or mouse hepatocytes and human hepatoma cells.

  12. Modulation of ethylene responses by OsRTH1 overexpression reveals the biological significance of ethylene in rice seedling growth and development

    Science.gov (United States)

    Zhang, Wei; Zhou, Xin; Wen, Chi-Kuang

    2012-01-01

    Overexpression of Arabidopsis Reversion-To-ethylene Sensitivity1 (RTE1) results in whole-plant ethylene insensitivity dependent on the ethylene receptor gene Ethylene Response1 (ETR1). However, overexpression of the tomato RTE1 homologue Green Ripe (GR) delays fruit ripening but does not confer whole-plant ethylene insensitivity. It was decided to investigate whether aspects of ethylene-induced growth and development of the monocotyledonous model plant rice could be modulated by rice RTE1 homologues (OsRTH genes). Results from a cross-species complementation test in Arabidopsis showed that OsRTH1 overexpression complemented the rte1-2 loss-of-function mutation and conferred whole-plant ethylene insensitivity in an ETR1-dependent manner. In contrast, OsRTH2 and OsRTH3 overexpression did not complement rte1-2 or confer ethylene insensitivity. In rice, OsRTH1 overexpression substantially prevented ethylene-induced alterations in growth and development, including leaf senescence, seedling leaf elongation and development, coleoptile elongation or curvature, and adventitious root development. Results of subcellular localizations of OsRTHs, each fused with the green fluorescent protein, in onion epidermal cells suggested that the three OsRTHs were predominantly localized to the Golgi. OsRTH1 may be an RTE1 orthologue of rice and modulate rice ethylene responses. The possible roles of auxins and gibberellins in the ethylene-induced alterations in growth were evaluated and the biological significance of ethylene in the early stage of rice seedling growth is discussed. PMID:22451723

  13. Modulation of ethylene responses by OsRTH1 overexpression reveals the biological significance of ethylene in rice seedling growth and development.

    Science.gov (United States)

    Zhang, Wei; Zhou, Xin; Wen, Chi-Kuang

    2012-06-01

    Overexpression of Arabidopsis Reversion-To-ethylene Sensitivity1 (RTE1) results in whole-plant ethylene insensitivity dependent on the ethylene receptor gene Ethylene Response1 (ETR1). However, overexpression of the tomato RTE1 homologue Green Ripe (GR) delays fruit ripening but does not confer whole-plant ethylene insensitivity. It was decided to investigate whether aspects of ethylene-induced growth and development of the monocotyledonous model plant rice could be modulated by rice RTE1 homologues (OsRTH genes). Results from a cross-species complementation test in Arabidopsis showed that OsRTH1 overexpression complemented the rte1-2 loss-of-function mutation and conferred whole-plant ethylene insensitivity in an ETR1-dependent manner. In contrast, OsRTH2 and OsRTH3 overexpression did not complement rte1-2 or confer ethylene insensitivity. In rice, OsRTH1 overexpression substantially prevented ethylene-induced alterations in growth and development, including leaf senescence, seedling leaf elongation and development, coleoptile elongation or curvature, and adventitious root development. Results of subcellular localizations of OsRTHs, each fused with the green fluorescent protein, in onion epidermal cells suggested that the three OsRTHs were predominantly localized to the Golgi. OsRTH1 may be an RTE1 orthologue of rice and modulate rice ethylene responses. The possible roles of auxins and gibberellins in the ethylene-induced alterations in growth were evaluated and the biological significance of ethylene in the early stage of rice seedling growth is discussed.

  14. A novel rodent model of spinal metastasis and spinal cord compression

    Directory of Open Access Journals (Sweden)

    Zibly Zion

    2012-11-01

    Full Text Available Abstract Background Spinal cord metastatic lesions affect a high number of cancer patients usually resulting in spinal cord compression syndrome. A major obstacle in the research of spinal metastatic disease is the lack of a simple reproducible animal model that mimics the natural course of the disease. In this study, we present a highly reproducible rodent model that can be used for different types of cancers while mimicking the natural course of human metastatic spinal cord compression syndrome. Results All sixteen Fisher 344 rats survived the dorsal approach intraosseous implantation of CRL-1666 adenocarcinoma cells and both rats survived the sham control surgery. By Day 13 functional analysis via the modified Basso-Beattie-Bresnahan (BBB locomotor rating scale showed significant decrease in motor function; median functional score was 3 for the tumor group (p = 0.0011. Median time to paresis was 8.7 days post-operatively. MR imaging illustrated repeated and consistent tumor formation, furthermore, onset of neurological sequale was the result of tumor formation and cord compression as confirmed by histological examination. Conclusions Analysis of these findings demonstrates a repeatable and consistent tumor growth model for cancer spinal metastases in rats. This novel rat model requires a less intricate surgical procedure, and as a result minimizes procedure time while subsequently increasing consistency. Therefore, this model allows for the preclinical evaluation of therapeutics for spinal metastases that more closely replicates physiological findings.

  15. Tapentadol increases levels of noradrenaline in the rat spinal cord as measured by in vivo microdialysis

    NARCIS (Netherlands)

    Tzschentke, Thomas M; Folgering, Joost H A; Flik, Gunnar; De Vry, Jean

    2012-01-01

    Spinal noradrenaline is thought to play an important role in descending pain inhibitory pathways and the modulation of nociceptive information at the spinal level. Tapentadol is a μ-opioid receptor (MOR) agonist and noradrenaline reuptake inhibitor (NRI). We showed previously that tapentadol, in

  16. Role of plant growth promoting rhizobacteria in modulating the efficiency of poultry litter composting with rock phosphate and its effect on growth and yield of wheat.

    Science.gov (United States)

    Billah, Motsim; Bano, Asghari

    2015-01-01

    The present study was aimed to evaluate the role of Plant Growth Promoting Rhizobacteria (PGPR) in P solubilisation from rock phosphate through composting with poultry litter, and further to study the effects of prepared enriched composts on growth, yield, and phosphorus uptake of wheat crop. Various phosphorus-enriched composts were prepared from rock phosphate and poultry litter (1:10) with and without inoculation of plant growth promoting rhizobacterias (Pseudomonas sp. and Proteus sp.). Results showed that the rock-phosphate-added poultry litter had higher total phosphorus, available (Mehlic-3 extracted) phosphorus, microbial biomass (carbon and phosphorus), and lower total organic carbon, total nitrogen, and carbon/nitrogen ratio over poultry litter alone. Inoculation of Pseudomonas sp. with rock phosphate-added poultry litter showed maximum increase in available phosphorus (41% of total phosphorus) followed by Proteus sp. inoculation (30% of total phosphorus) over uninoculated treatment (23% of total phosphorus) on the 120th day of composting. Microbial biomass (carbon and phosphorus) increased up to Day 45 and tended to decrease till the 120th day of composting, irrespective of the treatments. However, in pot experiments, wheat seeds receiving inoculation with plant growth promoting rhizobacterias, subsequently treated with rock phosphate-enriched compost proved highly stimulatory to plant height, phosphorus uptake, grain yield, and seed phosphorus content over uninoculated untreated control. The plant growth promoting rhizobacterias inoculation can be a sustainable source releasing phosphorus from low grade rock phosphate through composting and application of rock phosphate-enriched compost can be an alternative to chemical fertilisers for better crop production. © The Author(s) 2014.

  17. pH modulates the binding of early growth response protein 1 transcription factor to DNA

    National Research Council Canada - National Science Library

    Mikles, David C; Bhat, Vikas; Schuchardt, Brett J; Deegan, Brian J; Seldeen, Kenneth L; McDonald, Caleb B; Farooq, Amjad

    2013-01-01

    The transcription factor early growth response protein ( EGR )1 orchestrates a plethora of signaling cascades involved in cellular homeostasis, and its downregulation has been implicated in the development of prostate cancer...

  18. Anticancer bioactive peptides suppress human colorectal tumor cell growth and induce apoptosis via modulating the PARP-p53-Mcl-1 signaling pathway.

    Science.gov (United States)

    Su, Li-ya; Shi, Ying-xu; Yan, Mei-rong; Xi, Yaguang; Su, Xiu-lan

    2015-12-01

    We have reported novel anticancer bioactive peptides (ACBPs) that show tumor-suppressive activities in human gastric cancer, leukemia, nasopharyngeal cancer, and gallbladder cancer. In this study, we investigated the effects of ACBPs on human colorectal cancer and the underlying mechanisms. Cell growth and apoptosis of human colorectal tumor cell line HCT116 were measured using cell proliferation assay and flow cytometry, respectively. The expression levels of PARP, p53 and Mcl1A were assessed with Western blotting and immunohistochemistry. For evaluation of the in vivo antitumor activity of ACBPs, HCT116 xenograft nude mice were treated with ACBPs (35 μg/mL, ip) for 10 days. Treatment of HCT116 cells with ACBPs (35 μg/mL) for 4-6 days significantly inhibited the cell growth. Furthermore, treatment of HCT116 cells with ACBPs (35 μg/mL) for 6-12 h significantly enhanced UV-induced apoptosis, increased the expression of PARP and p53, and decreased the expression of Mcl-1. Administration of ACBPs did not change the body weight of HCT116 xenograft nude mice, but decreased the tumor growth by approximately 43%, and increased the expression of PARP and p53, and decreased the expression of Mcl-1 in xenograft mouse tumor tissues. Administration of ACBPs inhibits human colorectal tumor cell growth and induces apoptosis in vitro and in vivo through modulating the PARP-p53-Mcl-1 signaling pathway.

  19. Spinal tumors in children.

    Science.gov (United States)

    Joaquim, Andrei Fernandes; Ghizoni, Enrico; Valadares, Marcelo Gomes Cordeiro; Appenzeller, Simone; Aguiar, Simone Dos Santos; Tedeschi, Helder

    2017-05-01

    Spinal tumors are rare in the pediatric population, presenting many specific peculiarities when compared to adults. We have performed a broad narrative review to describe the most common spinal tumors in children, discussing their main characteristics and management options. The authors have performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Multimodality radiological studies (plain films, 3D computed tomography scan and magnetic resonance imaging) are necessary for proper evaluation and differential diagnosis of spinal tumors in children. In selected cases nuclear medicine imaging is used to improve the chances of a more accurate diagnosis. As a general rule, a fine needle biopsy is recommended after radiological evaluation to confirm the tumor's histology. Primary bone tumors can be divided into benign bone tumors, mostly represented by vertebral hemangiomas, osteoid osteomas, osteoblastomas, aneurismal bone cysts, and eosinophilic granulomas, and malign or aggressive tumors, such as Ewing's or osteogenic sarcomas. Secondary bone tumors (spinal metastases) comprise different tumor histologies, and treatment is mainly based on tumor's radiosensitivity. The characteristics and treatment options of the main spinal tumors are discussed in details. Spinal tumors in children are rare lesions that demand a thorough understanding of their main characteristics for their proper management. Understanding the nuances of spinal tumors in children is of paramount importance for improving outcomes and chances of cure.

  20. Spinal tumors in children

    Directory of Open Access Journals (Sweden)

    Andrei Fernandes Joaquim

    Full Text Available Summary Introduction: Spinal tumors are rare in the pediatric population, presenting many specific peculiarities when compared to adults. We have performed a broad narrative review to describe the most common spinal tumors in children, discussing their main characteristics and management options. Method: The authors have performed an extensive review of the peer-reviewed literature addressing the aforementioned objectives. Results: Multimodality radiological studies (plain films, 3D computed tomography scan and magnetic resonance imaging are necessary for proper evaluation and differential diagnosis of spinal tumors in children. In selected cases nuclear medicine imaging is used to improve the chances of a more accurate diagnosis. As a general rule, a fine needle biopsy is recommended after radiological evaluation to confirm the tumor's histology. Primary bone tumors can be divided into benign bone tumors, mostly represented by vertebral hemangiomas, osteoid osteomas, osteoblastomas, aneurismal bone cysts, and eosinophilic granulomas, and malign or aggressive tumors, such as Ewing's or osteogenic sarcomas. Secondary bone tumors (spinal metastases comprise different tumor histologies, and treatment is mainly based on tumor's radiosensitivity. The characteristics and treatment options of the main spinal tumors are discussed in details. Conclusion: Spinal tumors in children are rare lesions that demand a thorough understanding of their main characteristics for their proper management. Understanding the nuances of spinal tumors in children is of paramount importance for improving outcomes and chances of cure.

  1. Modulation of fatty acid composition and growth in Sporosarcina species in response to temperatures and exogenous branched-chain amino acids.

    Science.gov (United States)

    Tsuda, Kentaro; Nagano, Hideaki; Ando, Akinori; Shima, Jun; Ogawa, Jun

    2017-06-01

    Psychrotolerant endospore-forming Sporosarcina species have been predominantly isolated from minced fish meat (surimi), which is stored under refrigeration after heat treatment. To develop a better method for preserving surimi-based food products, we studied the growth and fatty acid compositions of the isolated strain S92h as well as Sporosarcina koreensis and Sporosarcina aquimarina at cold and moderate temperatures. The growth rates of strain S92h and S. koreensis were the fastest and slowest at cold temperatures, respectively, although these strains grew at a similar rate at moderate temperatures. In all three strains, the proportions of anteiso-C 15:0 and unsaturated fatty acids (UFAs) were significantly higher at cold temperatures than at moderate temperatures. Furthermore, supplementation with valine, leucine, and isoleucine resulted in proportional increases in iso-C 16:0 , iso-C 15:0 , and anteiso-C 15:0 , respectively, among the fatty acid compositions of these strains. The proportions of the UFAs were also altered by the supplementation. At cold temperatures, the growth rates of strain S92h and S. koreensis, but not of S. aquimarina, were affected by supplementation with leucine. Supplementation with isoleucine enhanced the growth of S. koreensis at cold temperatures but not that of the other strains. Valine did not affect the growth of any strain. These results indicate that anteiso-C 15:0 and UFAs both play important roles in the cold tolerance of the genus Sporosarcina and that these bacteria modulate their fatty acid compositions in response to the growth environment.

  2. Dietary energy balance modulation of Kras- and Ink4a/Arf+/--driven pancreatic cancer: the role of insulin-like growth factor-I.

    Science.gov (United States)

    Lashinger, Laura M; Harrison, Lauren M; Rasmussen, Audrey J; Logsdon, Craig D; Fischer, Susan M; McArthur, Mark J; Hursting, Stephen D

    2013-10-01

    New molecular targets and intervention strategies for breaking the obesity-pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-I-dependent mechanism. In LSL-Kras(G12D)/Pdx-1-Cre/Ink4a/Arf(lox/+) mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I-deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity-pancreatic cancer link.

  3. The identification and characterization of specific ARF-Aux/IAA regulatory modules in plant growth and development.

    Science.gov (United States)

    Krogan, Naden T; Berleth, Thomas

    2015-01-01

    The current model of auxin-inducible transcription describes numerous regulatory interactions between AUXIN RESPONSE FACTORs (ARFs) and Aux/IAAs. However, specific relationships between individual members of these families in planta remain largely uncharacterized. Using a systems biology approach, the entire suite of Aux/IAA genes directly regulated by the developmentally pivotal ARF MONOPTEROS (MP) was recently determined for multiple Arabidopsis tissue types. This study showed that MP directly targets distinct subclades of Aux/IAAs, revealing potential regulatory modules of redundantly acting Aux/IAAs involved in MP-dependent processes. Further, functional analyses indicated that the protein products of these targeted Aux/IAAs negatively feedback on MP. Thus, comprehensive identification of Aux/IAAs targeted by individual ARFs will generate biologically meaningful networks of ARF-Aux/IAA regulatory modules controlling distinct plant pathways.

  4. Spinal injuries in sports.

    Science.gov (United States)

    Boden, Barry P; Jarvis, Christopher G

    2009-02-01

    Athletic competition has long been a known source of spinal injuries. Approximately 8.7% of all new cases of spinal cord injuries in the United States are related to sports activities. The sports activities that have the highest risk of catastrophic spinal injuries are football, ice hockey, wrestling, diving, skiing, snowboarding, rugby, and cheerleading. Axial compression forces to the top of the head can lead to cervical fracture and quadriplegia in any sport. It is critical for any medical personnel responsible for athletes in team sports to have a plan for stabilization and transfer of an athlete who sustains a cervical spine injury.

  5. Insulin sensitivity modulates the growth response during the first year of high-dose growth hormone treatment in short prepubertal children born small for gestational age.

    Science.gov (United States)

    Gies, Inge; Thomas, Muriel; Tenoutasse, Sylvie; De Waele, Kathleen; Lebrethon, Marie-Christine; Beckers, Dominique; Francois, Inge; Maes, Marc; Rooman, Raoul; de Beaufort, Carine; Massa, Guy; De Schepper, Jean

    2012-01-01

    To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. Mean height SDS increased from -3.3 ± 0.7 to -2.3 ± 0.7 after 1 year, and to -1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies. Copyright © 2012 S. Karger AG, Basel.

  6. Antagonistic interactions between the cAMP-dependent protein kinase and Tor signaling pathways modulate cell growth in Saccharomyces cerevisiae.

    Science.gov (United States)

    Ramachandran, Vidhya; Herman, Paul K

    2011-02-01

    Eukaryotic cells integrate information from multiple sources to respond appropriately to changes in the environment. Here, we examined the relationship between two signaling pathways in Saccharomyces cerevisiae that are essential for the coordination of cell growth with nutrient a