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Sample records for basalis stimulation depends

  1. Changes in Nutritional Status after Deep Brain Stimulation of the Nucleus Basalis of Meynert in Alzheimer's Disease--Results of a Phase I Study.

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    Noreik, M; Kuhn, J; Hardenacke, K; Lenartz, D; Bauer, A; Bührle, C P; Häussermann, P; Hellmich, M; Klosterkötter, J; Wiltfang, J; Maarouf, M; Freund, H-J; Visser-Vandewalle, V; Sturm, V; Schulz, R-J

    2015-10-01

    The progression of Alzheimer's disease (AD) is associated with impaired nutritional status. New methods, such as deep brain stimulation (DBS), are currently being tested to decrease the progression of AD. DBS is an approved method in the treatment of Parkinson's disease, and its suitability for the treatment of AD patients is currently under experimental investigation. To evaluate the advantages and disadvantages of this new treatment, it is important to assess potential side effects of DBS regarding the nucleus basalis of Meynert; this new treatment is thought to positively affect cognition and might counteract the deterioration of nutritional status and progressive weight loss observed in AD. This study aims to assess the nutritional status of patients with AD before receiving DBS of the nucleus basalis of Meynert and after 1 year, and to analyze potential associations between changes in cognition and nutritional status. A 1-year phase I proof-of-concept study. The Department of Psychiatry and Psychotherapy at the University of Cologne. We assessed a consecutive sample of patients with mild to moderate AD (n=6) who fulfilled the inclusion criteria and provided written informed consent. Bilateral low-frequency DBS of the nucleus basalis of Meynert. Nutritional status was assessed using a modified Mini Nutritional Assessment, bioelectrical impedance analysis, a completed 3-day food diary, and analysis of serum levels of vitamin B12 and folate. With a normal body mass index (BMI) at baseline (mean 23.75 kg/m²) and after 1 year (mean 24.59 kg/m²), all but one patient gained body weight during the period of the pilot study (mean 2.38 kg, 3.81% of body weight). This was reflected in a mainly stable or improved body composition, assessed by bioelectrical impedance analysis, in five of the six patients. Mean energy intake increased from 1534 kcal/day (min 1037, max 2370) at baseline to 1736 kcal/day (min 1010, max 2663) after 1 year, leading to the improved fulfillment

  2. Deep brain stimulation of the nucleus basalis of Meynert attenuates early EEG components associated with defective sensory gating in patients with Alzheimer disease - a two-case study.

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    Dürschmid, Stefan; Reichert, Christoph; Kuhn, Jens; Freund, Hans-Joachim; Hinrichs, Hermann; Heinze, Hans-Jochen

    2017-10-20

    Alzheimer's disease (AD) is associated with deterioration of memory and cognitive function and a degeneration of neurons of the nucleus basalis of Meynert (NBM). The NBM is the major input source of acetylcholine (ACh) to the cortex. The decreasing cholinergic innervation of the cortex due to degeneration of the NBM might be the cause of loss of memory function. NBM-Deep brain stimulation (NBM-DBS) is considered to serve as a potential therapeutic option for patients with AD by supporting residual cholinergic transmission to stabilize oscillatory activity in memory-relevant circuits. However, whether DBS could improve sensory memory functions in patients with AD is not clear. Here, in a passive auditory oddball paradigm, patients with AD (N = 2) listened to repetitive background tones (standard tones) randomly interrupted by frequency deviants in two blocks with NBM-DBS OFF and then NBM-DBS ON, while age-matched healthy controls (N = 6) repeated the experiment twice. The mismatch negativity in NBM-DBS OFF significantly differed from controls in both blocks, but not under NBM-DBS, which was likely due to a pronounced P50 increase overlapping with the N1 in NBM-DBS OFF. This early complex of EEG components recovered under stimulation to a normal level as defined by responses in controls. In this temporal interval, we found in patients with NBM-DBS ON (but not with NBM-DBS OFF) and in controls a strong repetition suppression effect to standard tones - with more attenuated responses to frequently repeated standard tones. This highlights the role of NBM-DBS for sensory gating of familiar auditory information into sensory memory. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  3. Transcriptomic Insights into the Response of Placenta and Decidua Basalis to the CpG Oligodeoxynucleotide Stimulation in Non-Obese Diabetic Mice and Wild-Type Controls

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    Xiao-Rui Liu

    2016-08-01

    Full Text Available Intrauterine infection is one of the most frequent causes of miscarriage. CpG oligodeoxynucleotide (CpG ODN can mimic intrauterine infection. CpG ODN-induced embryo-resorption was observed consistently in the NK-cell deficient non-obese diabetic (NOD mice but not in the wild-type (WT mice. To elucidate the molecular mechanisms of differential pregnancy outcomes, differentially expressed genes (DEGs in the placenta and decidua basalis was revealed by RNA-Seq with CpG ODN or control ODN treatment. Common DEGs in the WT and NOD mice were enriched in antimicrobial/antibacterial humoral responses that may be activated as a primary response to bacterial infection. The susceptibility to CpG ODN-induced embryo-resorption in the NOD mice might mainly be attributed to M1 macrophage polarization and the immunodeficient status, such as the down-regulation in antigen processing and presentation, allograft rejection, and natural killer cell mediated cytotoxicity. In contrast, the WT mice with normal immune systems could activate multiple immune responses and be resistant to CpG ODN-induced embryo-resorption, such as M2 macrophage differentiation and activation regulated by complement component C1q and peroxisome proliferation-activated receptor (PPAR signaling pathways. Collectively, this study suggests that the immunodeficient status of NOD mice and the macrophage polarization regulated by C1q and PPAR signaling might be the basis for differential pregnancy outcomes between the NOD and WT mice.

  4. Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions.

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    Bartolini, L; Casamenti, F; Pepeu, G

    1996-02-01

    Object recognition was investigated in adult and aging male rats in a two-trials, unrewarded, test that assessed a form of working-episodic memory. Exploration time in the first trial, in which two copies of the same object were presented, was recorded. In the second trial, in which one of the familiar objects and a new object were presented, the time spent exploring the two objects was separately recorded and a discrimination index was calculated. Adult rats explored the new object longer than the familiar object when the intertrial time ranged from 1 to 60 min. Rats older than 20 months of age did not discriminate between familiar and new objects. Object discrimination was lost in adult rats after scopolamine (0.2 mg/kg SC) administration and with lesions of the nucleus basalis, resulting in a 40% decrease in cortical ChAT activity. Both aniracetam (25, 50, 100 mg/kg os) and oxiracetam (50 mg/kg os) restored object recognition in aging rats, in rats treated with scopolamine, and with lesions of the nucleus basalis. In the rat, object discrimination appears to depend on the integrity of the cholinergic system, and nootropic drugs can correct its disruption.

  5. The effect of age on sperm stock and egg laying in the parasitoid wasp, Dinarmus basalis

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    D. Damiens

    2003-07-01

    Full Text Available Sperm quantity and quality during storage may be constraints acting on female fecundity and hence fitness. In Hymenoptera, the importance of sperm quality has rarely been considered, despite its central role in reproductive strategies and especially in sex ratio control. In these insects, fertilized eggs develop into females and unfertilized eggs into males. Experiments were conducted on the female wasp, Dinarmus basalis, in the laboratory with and without egg-laying resources (hosts. The first point was to test if sperm age influenced sperm storage by measuring sperm count and viability using a sperm viability test (SYBR-14 : propidium iodide. The second point was the influence of prolonged storage in the female genital tract on the quantity, sex ratio and fitness of offspring produced. Results show that sperm viability in the spermatheca does not change significantly with maternal age, and that the sperm stock is not affected when females are deprived of hosts. Egg-laying is gradually restored after 21 days of host deprivation but remains at a low level after 115 days. The fitness of mated D. basalis females is therefore not constrained by sperm quantity or quality and seems to depend on host availability and female age.

  6. Commonly used stimulants: Sleep problems, dependence and psychological distress.

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    Ogeil, Rowan P; Phillips, James G

    2015-08-01

    Caffeine and nicotine are commonly used stimulants that enhance alertness and mood. Discontinuation of both stimulants is associated with withdrawal symptoms including sleep and mood disturbances, which may differ in males and females. The present study examines changes in sleep quality, daytime sleepiness and psychological distress associated with use and dependence on caffeine and nicotine. An online survey comprising validated tools to assess sleep quality, excessive daytime sleepiness and psychological distress was completed by 166 participants (74 males, 96 females) with a mean age of 28 years. Participants completed the study in their own time, and were not offered any inducements to participate. Sleep quality was poorer in those dependent upon caffeine or nicotine, and there were also significant interaction effects with gender whereby females reported poorer sleep despite males reporting higher use of both stimulants. Caffeine dependence was associated with poorer sleep quality, increased daytime dysfunction, and increased levels of night time disturbance, while nicotine dependence was associated with poorer sleep quality and increased use of sleep medication and sleep disturbances. There were strong links between poor sleep and diminished affect, with psychological distress found to co-occur in the context of disturbed sleep. Stimulants are widely used to promote vigilance and mood; however, dependence on commonly used drugs including caffeine and nicotine is associated with decrements in sleep quality and increased psychological distress, which may be compounded in female dependent users. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Time-Dependent Increase in Network Response to Stimulation.

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    Franz Hamilton

    Full Text Available In vitro neuronal cultures have become a popular method with which to probe network-level neuronal dynamics and phenomena in controlled laboratory settings. One of the key dynamics of interest in these in vitro studies has been the extent to which cultured networks display properties indicative of learning. Here we demonstrate the effects of a high frequency electrical stimulation signal in training cultured networks of cortical neurons. Networks receiving this training signal displayed a time-dependent increase in the response to a low frequency probing stimulation, particularly in the time window of 20-50 ms after stimulation. This increase was found to be statistically significant as compared to control networks that did not receive training. The timing of this increase suggests potentiation of synaptic mechanisms. To further investigate this possibility, we leveraged the powerful Cox statistical connectivity method as previously investigated by our group. This method was used to identify and track changes in network connectivity strength.

  8. Confirmation on Status of Chaetocnema basalis (Coleoptera: Chrysomellidae as A Vector of Stewart Wilt Disease

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    Heri Widodo

    2017-12-01

    Full Text Available Chaetocnema pulicaria and C. denticulata are recognized as vectors of Stewart wilt disease caused by Pantoea stewartii on maize. These insects have not been reported yet in Indonesia, but Stewart wilt disease has been reported in Java and Sumatera Islands. Genus Chaetocnema which presented in Indonesia is C.basalis. It is not cleared whether C. basalis is a vector for Stewart wilt disease like C. pulicaria and C. denticulata. This reseach was aimed to conduct the confirmation on status whether C. basalis have a role as vector of Stewart wilt disease on maize or not. C. basalis imago were collected from maize growing areas in Yogyakarta, and then starved for 24 h. Treatments were applied by placing imago of C. basalis on infected-P. stewartii plants for 72 h. Five insects were then transferred to each plot of healthy plant (1 plot consisted of 5 plants for 72 h. For control, imago of C. basalis were put on healthy plants for 72 h and five insects were then transferred to other healthy plant (1 plot consisted of 5 plants for 72 h. Each treatment was repeated three times. On the fifteenth days after transmission, PCR assays were carried out on leaf samples and isolates of bacteria. All sampled leaves analysis showed that there were no Stewart wilt diseases transmission based on PCR assay and bacterial isolates. This concluded that C. basalis is not a vector for  Stewart wilt disease on maize.   Intisari Chaetocnema pulicaria dan C. denticulata merupakan serangga vektor penyakit layu stewart yang disebabkan oleh bakteri Pantoea stewartii pada tanaman jagung. Kedua serangga ini belum pernah dilaporkan keberadaannya di Indonesia tetapi penyakit layu stewart telah ditemukan di pulau Jawa dan pulau Sumatera. Serangga Genus Chaetocnema yang ada di Indonesia adalah Chaetocnema basalis. C. basalis belum diketahui secara pasti sebagai vektor penyakit layu stewart seperti halnya C. pulicaria dan C. denticulata. Penelitian ini bertujuan untuk melakukan

  9. Mesenchymal Stem/Multipotent Stromal Cells from Human Decidua Basalis Reduce Endothelial Cell Activation.

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    Alshabibi, Manal A; Al Huqail, Al Joharah; Khatlani, Tanvir; Abomaray, Fawaz M; Alaskar, Ahmed S; Alawad, Abdullah O; Kalionis, Bill; Abumaree, Mohamed Hassan

    2017-09-15

    Recently, we reported the isolation and characterization of mesenchymal stem cells from the decidua basalis of human placenta (DBMSCs). These cells express a unique combination of molecules involved in many important cellular functions, which make them good candidates for cell-based therapies. The endothelium is a highly specialized, metabolically active interface between blood and the underlying tissues. Inflammatory factors stimulate the endothelium to undergo a change to a proinflammatory and procoagulant state (ie, endothelial cell activation). An initial response to endothelial cell activation is monocyte adhesion. Activation typically involves increased proliferation and enhanced expression of adhesion and inflammatory markers by endothelial cells. Sustained endothelial cell activation leads to a type of damage to the body associated with inflammatory diseases, such as atherosclerosis. In this study, we examined the ability of DBMSCs to protect endothelial cells from activation through monocyte adhesion, by modulating endothelial proliferation, migration, adhesion, and inflammatory marker expression. Endothelial cells were cocultured with DBMSCs, monocytes, monocyte-pretreated with DBMSCs and DBMSC-pretreated with monocytes were also evaluated. Monocyte adhesion to endothelial cells was examined following treatment with DBMSCs. Expression of endothelial cell adhesion and inflammatory markers was also analyzed. The interaction between DBMSCs and monocytes reduced endothelial cell proliferation and monocyte adhesion to endothelial cells. In contrast, endothelial cell migration increased in response to DBMSCs and monocytes. Endothelial cell expression of adhesion and inflammatory molecules was reduced by DBMSCs and DBMSC-pretreated with monocytes. The mechanism of reduced endothelial proliferation involved enhanced phosphorylation of the tumor suppressor protein p53. Our study shows for the first time that DBMSCs protect endothelial cells from activation by

  10. Distinct subsets of nucleus basalis neurons exhibit similar sensitivity to excitotoxicity

    NARCIS (Netherlands)

    Harkany, Tibor; Varga, Csaba; Grosche, Jens; Mulder, Jan; Luiten, Paul G.M.; Hortobágyi, Tibor; Penke, Botond; Härtig, Wolfgang

    2002-01-01

    Excitotoxic lesions in the magnocellular nucleus basalis (MBN) lead to a significant damage of cholinergic neurons concomitant with increased amyloid precursor protein (APP) expression in the cerebral cortex. However, the sensitivity of non-cholinergic neurons to excitotoxicity, and changes of APP

  11. Developments in deep brain stimulation using time dependent magnetic fields

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    Crowther, L.J.; Nlebedim, I.C.; Jiles, D.C.

    2012-03-07

    The effect of head model complexity upon the strength of field in different brain regions for transcranial magnetic stimulation (TMS) has been investigated. Experimental measurements were used to verify the validity of magnetic field calculations and induced electric field calculations for three 3D human head models of varying complexity. Results show the inability for simplified head models to accurately determine the site of high fields that lead to neuronal stimulation and highlight the necessity for realistic head modeling for TMS applications.

  12. Histaminergic ligands injected into the nucleus basalis magnocellularis differentially affect fear conditioning consolidation.

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    Benetti, Fernando; Baldi, Elisabetta; Bucherelli, Corrado; Blandina, Patrizio; Passani, Maria Beatrice

    2013-04-01

    The role of the nucleus basalis magnocellularis (NBM) in fear conditioning encoding is well established. In the present report, we investigate the involvement of the NBM histaminergic system in consolidating fear memories. The NBM was injected bilaterally with ligands of histaminergic receptors immediately after contextual fear conditioning. Histaminergic compounds, either alone or in combination, were stereotaxically administered to different groups of adult male Wistar rats and memory was assessed as conditioned freezing duration 72 h after administration. This protocol prevents interference with NBM function during either acquisition or retrieval phases, hence restricting the effect of pharmacological manipulations to fear memory consolidation. The results presented here demonstrate that post-training H3 receptors (H3R) blockade with the antagonist/inverse agonist thioperamide or activation with immepip in the NBM potentiates or decreases, respectively, freezing response at retrieval. Thioperamide induced memory enhancement seems to depend on H2R, but not H1R activation, as the H2R antagonist zolantidine blocked the effect of thioperamide, whereas the H1R antagonist pyrilamine was ineffective. Furthermore, the H2R agonist ampthamine improved fear memory expression independently of the H3R agonist effect. Our results indicate that activation of post-synaptic H2R within the NBM by endogenous histamine is responsible for the potentiated expression of fear responses. The results are discussed in terms of activation of H3 auto- and heteroreceptors within the NBM and the differential effect of H3R ligands on fear memory consolidation in distinct brain regions.

  13. Coupling brain-machine interfaces with cortical stimulation for brain-state dependent stimulation: enhancing motor cortex excitability for neurorehabilitation

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    Alireza eGharabaghi

    2014-03-01

    Full Text Available Motor recovery after stroke is an unsolved challenge despite intensive rehabilitation training programs. Brain stimulation techniques have been explored in addition to traditional rehabilitation training to increase the excitability of the stimulated motor cortex. This modulation of cortical excitability augments the response to afferent input during motor exercises, thereby enhancing skilled motor learning by long-term potentiation-like plasticity. Recent approaches examined brain stimulation applied concurrently with voluntary movements to induce more specific use-dependent neural plasticity during motor training for neurorehabilitation. Unfortunately, such approaches are not applicable for the many severely affected stroke patients lacking residual hand function. These patients require novel activity-dependent stimulation paradigms based on intrinsic brain activity. Here, we report on such brain state-dependent stimulation (BSDS combined with haptic feedback provided by a robotic hand orthosis. Transcranial magnetic stimulation of the motor cortex and haptic feedback to the hand were controlled by sensorimotor desynchronization during motor-imagery and applied within a brain-machine interface environment in one healthy subject and one patient with severe hand paresis in the chronic phase after stroke. BSDS significantly increased the excitability of the stimulated motor cortex in both healthy and post-stroke conditions, an effect not observed in non-BSDS protocols. This feasibility study suggests that closing the loop between intrinsic brain state, cortical stimulation and haptic feedback provides a novel neurorehabilitation strategy for stroke patients lacking residual hand function, a proposal that warrants further investigation in a larger cohort of stroke patients.

  14. Age-dependent effects of brain stimulation on network centrality.

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    Antonenko, Daria; Nierhaus, Till; Meinzer, Marcus; Prehn, Kristin; Thielscher, Axel; Ittermann, Bernd; Flöel, Agnes

    2018-04-18

    Functional magnetic resonance imaging (fMRI) studies have suggested that advanced age may mediate the effects of transcranial direct current stimulation (tDCS) on brain function. However, studies directly comparing neural tDCS effects between young and older adults are scarce and limited to task-related imaging paradigms. Resting-state (rs-) fMRI, that is independent of age-related differences in performance, is well suited to investigate age-associated differential neural tDCS effects. Three "online" tDCS conditions (anodal, cathodal, sham) were compared in a cross-over, within-subject design, in 30 young and 30 older adults. Active stimulation targeted the left sensorimotor network (active electrode over left sensorimotor cortex with right supraorbital reference electrode). A graph-based rs-fMRI data analysis approach (eigenvector centrality mapping) and complementary seed-based analyses characterized neural tDCS effects. An interaction between anodal tDCS and age group was observed. Specifically, centrality in bilateral paracentral and posterior regions (precuneus, superior parietal cortex) was increased in young, but decreased in older adults. Seed-based analyses revealed that these opposing patterns of tDCS-induced centrality modulation were explained from differential effects of tDCS on functional coupling of the stimulated left paracentral lobule. Cathodal tDCS did not show significant effects. Our study provides first evidence for differential tDCS effects on neural network organization in young and older adults. Anodal stimulation mainly affected coupling of sensorimotor with ventromedial prefrontal areas in young and decoupling with posteromedial areas in older adults. Copyright © 2018. Published by Elsevier Inc.

  15. Cobalt stimulates HIF-1-dependent but inhibits HIF-2-dependent gene expression in liver cancer cells

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    Befani, Christina; Mylonis, Ilias; Gkotinakou, Ioanna-Maria; Georgoulias, Panagiotis; Hu, Cheng-Jun; Simos, George; Liakos, Panagiotis

    2013-01-01

    Hypoxia-inducible factors (HIFs) are transcriptional regulators that mediate the cellular response to low oxygen. Although HIF-1 is usually considered as the principal mediator of hypoxic adaptation, several tissues and different cell types express both HIF-1 and HIF-2 isoforms under hypoxia or when treated with hypoxia mimetic chemicals such as cobalt. However, the similarities or differences between HIF-1 and HIF-2, in terms of their tissue- and inducer-specific activation and function, are not adequately characterized. To address this issue, we investigated the effects of true hypoxia and hypoxia mimetics on HIF-1 and HIF-2 induction and specific gene transcriptional activity in two hepatic cancer cell lines, Huh7 and HepG2. Both hypoxia and cobalt caused rapid induction of both HIF-1α and HIF-2α proteins. Hypoxia induced erythropoietin (EPO) expression and secretion in a HIF-2-dependent way. Surprisingly, however, EPO expression was not induced when cells were treated with cobalt. In agreement, both HIF-1- and HIF-2-dependent promoters (of PGK and SOD2 genes, respectively) were activated by hypoxia while cobalt only activated the HIF-1-dependent PGK promoter. Unlike cobalt, other hypoxia mimetics such as DFO and DMOG activated both types of promoters. Furthermore, cobalt impaired the hypoxic stimulation of HIF-2, but not HIF-1, activity and cobalt-induced HIF-2α interacted poorly with USF-2, a HIF-2-specific co-activator. These data show that, despite similar induction of HIF-1α and HIF-2α protein expression, HIF-1 and HIF-2 specific gene activating functions respond differently to different stimuli and suggest the operation of oxygen-independent and gene- or tissue-specific regulatory mechanisms involving additional transcription factors or co-activators. PMID:23958427

  16. dependent/calmodulin- stimulated protein kinase from moss

    Indian Academy of Sciences (India)

    Unknown

    lin-dependent protein kinase homolog; Planta 203 S91–. S97. Lu Y-T, Hidaka H and Feldman L J 1996 Characterization of a calcium/calmodulin-dependent protein kinase homolog from maize roots showing light-regulated gravitropism; Planta. 199 18–24. Mitra D and Johri M M 2000 Enhanced expression of a cal-.

  17. Time-dependent effects of neuromuscular electrical stimulation on changes in spinal excitability are dependent on stimulation frequency: a preliminary study in healthy adults.

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    Koyama, Soichiro; Tanabe, Shigeo; Ishikawa, Takuma; Itoh, Syunpei; Kubota, Shinji; Sakurai, Hiroaki; Kanada, Yoshikiyo

    2014-12-01

    Neuromuscular electrical stimulation (NMES) can be used as treatment for spasticity. The present study examined differences in time-dependent effects of NMES depending on stimulation frequency. Forty healthy subjects were separated into four groups (no-stim, NMES of 50, 100, and 200 Hz). The un-conditioned H-reflex amplitude and the H-reflex conditioning-test paradigm were used to measure the effectiveness on monosynaptic Ia excitation of motoneurons in the soleus (SOL) muscle, disynaptic reciprocal Ia inhibition from tibialis anterior (TA) to SOL, and presynaptic inhibition of SOL Ia afferents. Each trial consisted of a 30-min period of NMES applied to the deep peroneal nerve followed by a 30-min period with no stimulation to measure prolonged effects. Measurements were performed periodically. Stimulation applied at all frequencies produced a significant reduction in monosynaptic Ia excitation of motoneurons in the SOL muscle, however, only stimulation with 50 Hz showed prolonged reduction after NMES. NMES frequency did not affect the amount of disynaptic reciprocal Ia inhibition and presynaptic inhibition of Ia afferents. The results show a frequency-dependent effect of NMES on the monosynaptic Ia excitation of motoneurons. This result has implications for selecting the optimal NMES frequency for treatment in patients with spasticity.

  18. Age-dependent effects of brain stimulation on network centrality

    DEFF Research Database (Denmark)

    Antonenko, Daria; Nierhaus, Till; Meinzer, Marcus

    2018-01-01

    Functional magnetic resonance imaging (fMRI) studies have suggested that advanced age may mediate the effects of transcranial direct current stimulation (tDCS) on brain function. However, studies directly comparing neural tDCS effects between young and older adults are scarce and limited to task......-related imaging paradigms. Resting-state (rs-) fMRI, that is independent of age-related differences in performance, is well suited to investigate age associated differential neural tDCS effects. Three “online” tDCS conditions (anodal, cathodal, sham) were compared in a cross-over, within-subject design, in 30...... characterized neural tDCS effects. An interaction between anodal tDCS and age group was observed. Specifically, centrality in bilateral paracentral and posterior regions (precuneus, superior parietal cortex) was increased in young, but decreased in older adults. Seed-based analyses revealed that these opposing...

  19. Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity.

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    Moran, Fidelma; Leonard, Tracey; Hawthorne, Stephanie; Hughes, Ciara M; McCrum-Gardner, Evie; Johnson, Mark I; Rakel, Barbara A; Sluka, Kathleen A; Walsh, Deirdre M

    2011-08-01

    Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS naïve healthy individuals (18-64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r(2) = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

  20. Comparison of Experienced Violence in Women with Opiate-Dependent and Stimulant-Dependent Husbands

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    Neda Ahmadpour

    2013-01-01

    Full Text Available Objective: Opium and stimulants are two kinds of illegal substances which are different from each other in chemical structure, psychological and biological effects (material, and their potential adverse effects on consumers. The present study compares the effect of abuse of each of the two (opium and stimulants on violent behavior against wives. Materials & Methods: The present study was a non-experimental and comparative study. The study sample included 100 spouses of men addicted to opium and stimulants (50 opium and 50 stimulant addicts who attended governmental or non-governmental centers or camps in Tehran city (from October 2011 to January 2012, in order to receive professional assistances. (Both groups of subjects were selected by convenient sampling method to ensure the compatibility with input and output data. The “revised conflict tactics scale” was used to assess the rates of violence (psychological, sexual coercion, negotiation, injury and physical assault exerted by men. Results were analyzed using multi-variety analysis of variance and covariance. Results: Results showed that after controlling the age as a covariate, consumers of stimulants (especially methamphetamine were more violent toward their wives than were consumers of opium (P&le0.001. There were also significant differences between the two groups in the psychological, sexual coercion, injury and physical assault subscales, but not in the negotiation subscale (P&le0.05. Conclusion: It seems that the psychopharmacological effect of stimulants leads to more violent behaviors in its consumers (especially by methamphetamine than in consumers of opium.

  1. Abscisic acid stimulates a calcium-dependent protein kinase in grape berry.

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    Yu, Xiang-Chun; Li, Mei-Jun; Gao, Gui-Feng; Feng, Hai-Zhong; Geng, Xue-Qing; Peng, Chang-Cao; Zhu, Sai-Yong; Wang, Xiao-Jing; Shen, Yuan-Yue; Zhang, Da-Peng

    2006-02-01

    It has been demonstrated that calcium plays a central role in mediating abscisic acid (ABA) signaling, but many of the Ca2+-binding sensory proteins as the components of the ABA-signaling pathway remain to be elucidated. Here we identified, characterized, and purified a 58-kD ABA-stimulated calcium-dependent protein kinase from the mesocarp of grape berries (Vitis vinifera x Vitis labrusca), designated ACPK1 (for ABA-stimulated calcium-dependent protein kinase1). ABA stimulates ACPK1 in a dose-dependent manner, and the ACPK1 expression and enzyme activities alter accordantly with the endogenous ABA concentrations during fruit development. The ABA-induced ACPK1 stimulation appears to be transient with a rapid effect in 15 min but also with a slow and steady state of induction after 60 min. ABA acts on ACPK1 indirectly and dependently on in vivo state of the tissues. Two inactive ABA isomers, (-)-2-cis, 4-trans-ABA and 2-trans, 4-trans-(+/-)-ABA, are ineffective for inducing ACPK1 stimulation, revealing that the ABA-induced effect is stereo specific to physiological active (+)-2-cis, 4-trans-ABA. The other phytohormones such as auxin indoleacetic acid, gibberellic acid, synthetic cytokinin N-benzyl-6-aminopurine, and brassinolide are also ineffective in this ACPK1 stimulation. Based on sequencing of the two-dimensional electrophoresis-purified ACPK1, we cloned the ACPK1 gene. The ACPK1 is expressed specifically in grape berry covering a fleshy portion and seeds, and in a developmental stage-dependent manner. We further showed that ACPK1 is localized in both plasma membranes and chloroplasts/plastids and positively regulates plasma membrane H+-ATPase in vitro, suggesting that ACPK1 may be involved in the ABA-signaling pathway.

  2. Occurrence of Dinarmus basalis in Callosobruchus analis in stored soybean in São Paulo, Brazil Ocorrência de Dinarmus basalis (Rondani em Callosobruchus analis (F. em soja armazenada em São Paulo, Brasil

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    Valmir Antonio Costa

    2007-06-01

    Full Text Available Callosobruchus analis (F. is considered an important pest in several countries in Africa, Asia and Oceania. It has been observed infesting seeds belonging to 15 Leguminosae genera, including peanut, bean, chickpea, pea, cowpea, and soybean. One of its main natural enemies is the parasitoid Dinarmus basalis (Rondani (Hymenoptera: Pteromalidae, whose control efficiency has already been demonstrated in several studies. This paper records the occurrence of C. analis and its parasitoid, D. basalis, in stored soybean of the state of São Paulo, Brazil.Callosobruchus analis (F. é uma praga de expressão econômica em diversos países da África, Ásia e Oceania. Já foi observado infestando sementes de espécies de leguminosas pertencentes a 15 gêneros, incluindo-se culturas como amendoim, grão-de-bico, feijão, ervilha, caupi e soja. Um de seus inimigos naturais mais importantes é o parasitóide Dinarmus basalis (Rondani (Hymenoptera: Pteromalidae, cuja eficiência de controle já foi demonstrada em vários estudos. Neste trabalho registra-se a ocorrência de C. analis e de seu parasitóide, D. basalis, em grãos armazenados de soja no estado de São Paulo.

  3. Luminol-dependent chemiluminescence in antibody-sensitized neutrophils stimulated with protein A-bearing staphylococci.

    Science.gov (United States)

    Nishihara, S; Seki, K; Ikigai, H; Masuda, S

    1988-01-01

    When mouse polymorphonuclear leukocytes (PMNs) sensitized with rabbit antibody to mouse Ehrlich ascites tumor cells were stimulated by Staphylococcus aureus Cowan I cells, a conspicuous luminol-dependent chemiluminescence was observed in the absence of opsonin. The profile of the chemiluminescence (CL) response evoked by staphylococcal cells from antibody-sensitized PMNs had two peaks. An initial peak, observed within 1 min after stimulation, was sharp and high and a second peak, observed about 5 min after stimulation, was low and extended. The CL response of antibody-sensitized PMNs stimulated by S. aureus Cowan I cells was dose-dependently blocked by preincubation with soluble SpA. Cells of a mutant derived from S. aureus Cowan I strain with trace amounts of cell-bound SpA failed to stimulate the antibody-sensitized PMNs to generate the CL response. The antibody-sensitized PMNs were found to phagocytize SpA-bearing S. aureus cells even in the absence of opsonic serum. These results suggest that the observation presented here might provide a useful tool for the investigation of CL response of PMNs.

  4. Nobiletin Stimulates Chloride Secretion in Human Bronchial Epithelia via a cAMP/PKA-Dependent Pathway

    Directory of Open Access Journals (Sweden)

    Yuan Hao

    2015-08-01

    Full Text Available Background/Aims: Nobiletin, a citrus flavonoid isolated from tangerines, alters ion transport functions in intestinal epithelia, and has antagonistic effects on eosinophilic airway inflammation of asthmatic rats. The present study examined the effects of nobiletin on basal short-circuit current (ISC in a human bronchial epithelial cell line (16HBE14o-, and characterized the signal transduction pathways that allowed nobiletin to regulate electrolyte transport. Methods: The ISC measurement technique was used for transepithelial electrical measurements. Intracellular calcium ([Ca2+]i and cAMP were also quantified. Results: Nobiletin stimulated a concentration-dependent increase in ISC, which was due to Cl- secretion. The increase in ISC was inhibited by a cystic fibrosis transmembrane conductance regulator inhibitor (CFTRinh-172, but not by 4,4'-diisothiocyano-stilbene-2,2'-disulphonic acid (DIDS, Chromanol 293B, clotrimazole, or TRAM-34. Nobiletin-stimulated ISC was also sensitive to a protein kinase A (PKA inhibitor, H89, and an adenylate cyclase inhibitor, MDL-12330A. Nobiletin could not stimulate any increase in ISC in a cystic fibrosis (CF cell line, CFBE41o-, which lacked a functional CFTR. Nobiletin stimulated a real-time increase in cAMP, but not [Ca2+]i. Conclusion: Nobiletin stimulated transepithelial Cl- secretion across human bronchial epithelia. The mechanisms involved activation of adenylate cyclase- and cAMP/PKA-dependent pathways, leading to activation of apical CFTR Cl- channels.

  5. The Effect of Lamotrigine and Levetiracetam on TMS-Evoked EEG Responses Depends on Stimulation Intensity

    Directory of Open Access Journals (Sweden)

    Isabella Premoli

    2017-10-01

    Full Text Available The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG has uncovered underlying mechanisms of two anti-epileptic medications: levetiracetam and lamotrigine. Despite their different mechanism of action, both drugs modulated TMS-evoked EEG potentials (TEPs in a similar way. Since both medications increase resting motor threshold (RMT, the current aim was to examine the similarities and differences in post-drug TEPs, depending on whether stimulation intensity was adjusted to take account of post-drug RMT increase. The experiment followed a placebo controlled, double blind, crossover design, involving a single dose of either lamotrigine or levetiracetam. When a drug-induced increase of RMT occurred, post-drug measurements involved two blocks of stimulations, using unadjusted and adjusted stimulation intensity. A cluster based permutation analysis of differences in TEP amplitude between adjusted and unadjusted stimulation intensity showed that lamotrigine induced a stronger modulation of the N45 TEP component compared to levetiracetam. Results highlight the impact of adjusting stimulation intensity.

  6. Mindfulness Based Relapse Prevention for Stimulant Dependent Adults: A Pilot Randomized Clinical Trial.

    Science.gov (United States)

    Glasner-Edwards, Suzette; Mooney, Larissa J; Ang, Alfonso; Garneau, Hélène Chokron; Hartwell, Emily; Brecht, Mary-Lynn; Rawson, Richard A

    2017-02-01

    In light of the known associations between stress, negative affect, and relapse, mindfulness strategies hold promise as a means of reducing relapse susceptibility. In a pilot randomized clinical trial, we evaluated the effects of Mindfulness Based Relapse Prevention (MBRP), relative to a health education control condition (HE) among stimulant dependent adults receiving contingency management. All participants received a 12-week contingency management (CM) intervention. Following a 4-week CM-only lead in phase, participants were randomly assigned to concurrently receive MBRP (n=31) or HE (n=32). Stimulant dependent adults age 18 and over. A university based clinical research center. The primary outcomes were stimulant use, measured by urine drug screens weekly during the intervention and at 1-month post-treatment, negative affect, measured by the Beck Depression Inventory and Beck Anxiety Inventory, and psychiatric severity, measured by the Addiction Severity Index. Medium effect sizes favoring MBRP were observed for negative affect and overall psychiatric severity outcomes. Depression severity changed differentially over time as a function of group, with MBRP participants reporting greater reductions through follow-up (p=0.03; Effect Size=0.58). Likewise, the MBRP group evidenced greater declines in psychiatric severity, (p=0.01; Effect Size=0.61 at follow-up). Among those with depressive and anxiety disorders, MBRP was associated with lower odds of stimulant use relative to the control condition (Odds Ratio= 0.78, p=0.03 and OR=0.68, p=0.04). MBRP effectively reduces negative affect and psychiatric impairment, and is particularly effective in reducing stimulant use among stimulant dependent adults with mood and anxiety disorders.

  7. Calcium dependent plasticity applied to repetitive transcranial magnetic stimulation with a neural field model.

    Science.gov (United States)

    Wilson, M T; Fung, P K; Robinson, P A; Shemmell, J; Reynolds, J N J

    2016-08-01

    The calcium dependent plasticity (CaDP) approach to the modeling of synaptic weight change is applied using a neural field approach to realistic repetitive transcranial magnetic stimulation (rTMS) protocols. A spatially-symmetric nonlinear neural field model consisting of populations of excitatory and inhibitory neurons is used. The plasticity between excitatory cell populations is then evaluated using a CaDP approach that incorporates metaplasticity. The direction and size of the plasticity (potentiation or depression) depends on both the amplitude of stimulation and duration of the protocol. The breaks in the inhibitory theta-burst stimulation protocol are crucial to ensuring that the stimulation bursts are potentiating in nature. Tuning the parameters of a spike-timing dependent plasticity (STDP) window with a Monte Carlo approach to maximize agreement between STDP predictions and the CaDP results reproduces a realistically-shaped window with two regions of depression in agreement with the existing literature. Developing understanding of how TMS interacts with cells at a network level may be important for future investigation.

  8. TFCP2 Is Required for YAP-Dependent Transcription to Stimulate Liver Malignancy

    Directory of Open Access Journals (Sweden)

    Xiao Zhang

    2017-10-01

    Full Text Available Summary: Although YAP-dependent transcription is closely associated with liver tumorigenesis, the mechanism by which YAP maintains its function is poorly understood. Here, we show that TFCP2 is required for YAP-dependent transcription and liver malignancy. Mechanistically, YAP function is stimulated by TFCP2 via a WW-PSY interaction. TFCP2 also maintains YAP stability by inhibiting βTrCP. Notably, genomic co-occupancy of YAP and TFCP2 is revealed. TFCP2 acts as a transcription co-factor that stimulates YAP transcription by facilitating YAP binding with YAP binding motif (YBF-containing transcription factors. Interestingly, TFCP2 also stimulated the YAP-TEAD interaction and TEAD target gene expression. Finally, several genes co-regulated by YAP and TFCP2 that contribute to YAP-dependent tumorigenesis are identified and verified. Thus, we establish a model showing that TFCP2 acts as a YAP co-factor to maintain YAP-dependent transcription in liver cancer cells, suggesting that simultaneous targeting of both YAP and TFCP2 may be an effective therapeutic approach. : Zhang et al. reveal that TFCP2 acts as a YAP co-factor to stimulate YAP-dependent liver malignancy. YAP binds to TFCP2 via a WW-PSY interaction, which facilitates the binding of YAP to transcription factors that contain the YAP binding motif. These effects lead to the enhanced transcription of downstream co-regulated proto-oncogenes. Keywords: gene regulation, enhancer, YAP-dependent transcription factors, protein stability, βTrCP

  9. Time and frequency-dependent modulation of local field potential synchronization by deep brain stimulation.

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    Clinton B McCracken

    Full Text Available High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS, is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP, the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson's disease (PD. We performed simultaneous multi-site local field potential (LFP recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective, low-frequency (LF, 15 Hz; ineffective and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR, ventroanterior thalamus (VA, primary motor cortex (M1, and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic

  10. Depolarization-stimulated 42K+ efflux in rat aorta is calcium- and cellular volume-dependent

    International Nuclear Information System (INIS)

    Magliola, L.; Jones, A.W.

    1987-01-01

    The purpose of this study was to investigate the factors controlling membrane permeability to potassium of smooth muscle cells from rat aorta stimulated by depolarization. The increase 42 K+ efflux (change in the rate constant) induced by depolarization (application of high concentrations of potassium chloride) was inhibited significantly by the calcium antagonists diltiazem and nisoldipine. Parallel inhibitory effects on contraction were observed. Diltiazem also inhibited potassium-stimulated 36 Cl- efflux. The addition of 25-150 mM KCl to normal physiologic solution stimulated 42 K+ efflux in a concentration-dependent manner. Diltiazem suppressed potassium-stimulated 42 K+ efflux approximately 90% at 25 mM KCl and approximately 40% at 150 mM KCl. The ability of nisoldipine to inhibit 42 K+ efflux also diminished as the potassium chloride concentration was elevated. The component of efflux that was resistant to calcium antagonists probably resulted from a decrease in the electrochemical gradient for potassium. Cellular water did not change during potassium addition. Substitution of 80 and 150 mM KCl for sodium chloride produced cellular swelling and enhanced potassium-stimulated 42 K+ efflux compared with potassium chloride addition. The addition of sucrose to prevent cellular swelling reduced efflux response to potassium substitution toward that of potassium addition. A hypoosmolar physiologic solution produced an increase in the 42 K+ efflux and a contracture that were both prevented by the addition of sucrose. We concluded that the depolarization-mediated 42 K+ efflux has three components: one is calcium dependent; a second is dependent on cellular volume; and a third is resistant to inhibition by calcium antagonists

  11. Delay-Dependent Response in Weakly Electric Fish under Closed-Loop Pulse Stimulation.

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    Caroline Garcia Forlim

    Full Text Available In this paper, we apply a real time activity-dependent protocol to study how freely swimming weakly electric fish produce and process the timing of their own electric signals. Specifically, we address this study in the elephant fish, Gnathonemus petersii, an animal that uses weak discharges to locate obstacles or food while navigating, as well as for electro-communication with conspecifics. To investigate how the inter pulse intervals vary in response to external stimuli, we compare the response to a simple closed-loop stimulation protocol and the signals generated without electrical stimulation. The activity-dependent stimulation protocol explores different stimulus delivery delays relative to the fish's own electric discharges. We show that there is a critical time delay in this closed-loop interaction, as the largest changes in inter pulse intervals occur when the stimulation delay is below 100 ms. We also discuss the implications of these findings in the context of information processing in weakly electric fish.

  12. Blue-yellow colour vision impairment and cognitive deficits in occasional and dependent stimulant users.

    Science.gov (United States)

    Hulka, Lea M; Wagner, Michael; Preller, Katrin H; Jenni, Daniela; Quednow, Boris B

    2013-04-01

    Specific blue-yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug-induced changes in retinal dopamine neurotransmission are responsible. However, it is unclear whether these changes are confined to chronic cocaine users, whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory, encoding and consolidation. In 47 occasional and 29 dependent cocaine users, 23 MDMA (commonly known as 'ecstasy') users and 47 stimulant-naive controls, colour vision discrimination was measured with the Lanthony Desaturated Panel D-15 Test and memory performance with the Auditory Verbal Learning Test. Both occasional and dependent cocaine users showed higher colour confusion indices than controls. Users of the serotonergic stimulant MDMA (26%), occasional (30%) and dependent cocaine users (34%) exhibited more frequent blue-yellow colour vision disorders compared to controls (9%). Inferior performance of MDMA users was caused by a subgroup with high amphetamine co-use (55%), while MDMA use alone was not associated with decreased blue-yellow discrimination (0%). Cognitive performance was worse in cocaine users with colour vision disorder compared to users and controls with intact colour vision and both colour vision impairment and cognitive deficits were related to cocaine use. Occasional cocaine and amphetamine use might induce blue-yellow colour vision impairment, whereas the serotonergic stimulant MDMA does not impair colour vision. The association between colour vision impairment and cognitive deficits in cocaine users may reflect that retinal and cerebral dopamine alterations are linked to a certain degree.

  13. Dependence of (anomalous) fading of infra-red stimulated luminescence on trap occupancy in feldspars

    DEFF Research Database (Denmark)

    Morthekai, P.; Jain, Mayank; Gach, Grzegorz

    2013-01-01

    Dose dependency of anomalous fading of infra-red stimulated luminescence (IRSL) from feldspars has been investigated using radiations of different ionisation qualities. The rate of fading of the IRSL signal after proton irradiation (9.4–30%/decade) is on an average almost twice compared to that a...... on the number density of the trapped charge carriers. These results support the hypothesis that anomalous fading occurs across randomly distributed donor-acceptor distances as opposed to pairs with a fixed distance....

  14. Blue-yellow colour vision impairment and cognitive deficits in occasional and dependent stimulant users

    OpenAIRE

    Hulka, Lea M; Wagner, Michael; Preller, Katrin H; Jenni, Daniela; Quednow, Boris B

    2013-01-01

    Specific blue yellow colour vision impairment has been reported in dependent cocaine users and it was postulated that drug induced changes in retinal dopamine neurotransmission are responsible. However it is unclear whether these changes are confined to chronic cocaine users whether they are specific for dopaminergic stimulants such as cocaine and amphetamine and whether they are related to cognitive functions such as working memory encoding and consolidation. In 47 occasional and 29 dependen...

  15. Emergence, longevity and fecundity of Trissolcus basalis and Telenomus podisi after cold storage in the pupal stage Emergência, longevidade e fecundidade de Trissolcus basalis e Telenomus podisi após estocagem no estágio pupal

    Directory of Open Access Journals (Sweden)

    Luís Amilton Foerster

    2004-09-01

    Full Text Available Pupae of Trissolcus basalis (Wollaston and Telenomus podisi Ashmead (Hymenoptera: Scelionidae were stored at 12ºC and 15ºC for 120-210 days, after different periods of parasitism at 18ºC in order to evaluate adult emergence, longevity and ovipositional capacity. There was no emergence of adults at 12ºC. The rate of emergence of parasitoids transferred to 15ºC at the beginning of the pupal stage was 1.5% and 26.3%, for T. basalis and T. podisi respectively, whereas those parasitoids transferred one day before the expected date of emergence at 18ºC showed 86.4% of emergence for T. basalis and 59.9% for T. podisi. Mean adult longevity was also significantly lower when pupae were transferred to 15ºC at the beginning of the pupal stage. Females emerged after storage and maintained for 120 to 210 days at 15ºC parasitized host eggs after transference to 25ºC; however, fecundity of T. podisi was reduced in about 80% after cold storage.Pupas de Trissolcus basalis (Wollaston e Telenomus podisi Ashmead (Hymenoptera: Scelionidae armazenadas a 12ºC e 15ºC por 120 a 210 dias, após diferentes períodos de parasitismo a 18ºC, foram avaliadas quanto à emergência, longevidade e capacidade de parasitismo dos adultos. Não houve emergência de adultos a 12ºC. Os índices de emergência de parasitóides transferidos a 15ºC no início do estágio pupal foram 1,5% e 26,3%, em T. basalis e T. podisi, respectivamente, enquanto os transferidos um dia antes da data prevista para a emergência dos adultos a 18ºC apresentaram índices de emergência de 86,4% em T. basalis e 59,9% em T. podisi. De forma semelhante, a longevidade média dos adultos foi significativamente menor quando a transferência para 15ºC foi realizada no início do estágio pupal. Fêmeas emergidas após estocagem das pupas e mantidas por 120 a 210 dias a 15ºC parasitaram ovos hospedeiros após transferência para 25ºC; no entanto, a fecundidade de T. podisi foi reduzida em cerca de

  16. Development of Eye Position Dependency of Slow Phase Velocity during Caloric Stimulation

    Science.gov (United States)

    Bockisch, Christopher J.; Khojasteh, Elham; Straumann, Dominik; Hegemann, Stefan C. A.

    2012-01-01

    The nystagmus in patients with vestibular disorders often has an eye position dependency, called Alexander’s law, where the slow phase velocity is higher with gaze in the fast phase direction compared with gaze in the slow phase direction. Alexander’s law has been hypothesized to arise either due to adaptive changes in the velocity-to-position neural integrator, or as a consequence of processing of the vestibular-ocular reflex. We tested whether Alexander’s law arises only as a consequence of non-physiologic vestibular stimulation. We measured the time course of the development of Alexander’s law in healthy humans with nystagmus caused by three types of caloric vestibular stimulation: cold (unilateral inhibition), warm (unilateral excitation), and simultaneous bilateral bithermal (one side cold, the other warm) stimulation, mimicking the normal push-pull pattern of vestibular stimulation. Alexander’s law, measured as a negative slope of the velocity versus position curve, was observed in all conditions. A reversed pattern of eye position dependency (positive slope) was found <10% of the time. The slope often changed with nystagmus velocity (cross-correlation of nystagmus speed and slope was significant in 50% of cases), and the average lag of the slope with the speed was not significantly different from zero. Our results do not support the hypothesis that Alexander’s law can only be observed with non-physiologic vestibular stimulation. Further, the rapid development of Alexander’s law, while possible for an adaptive mechanism, is nonetheless quite fast compared to most other ocular motor adaptations. These results suggest that Alexander’s law may not be a consequence of a true adaptive mechanism. PMID:23251522

  17. Development of eye position dependency of slow phase velocity during caloric stimulation.

    Directory of Open Access Journals (Sweden)

    Christopher J Bockisch

    Full Text Available The nystagmus in patients with vestibular disorders often has an eye position dependency, called Alexander's law, where the slow phase velocity is higher with gaze in the fast phase direction compared with gaze in the slow phase direction. Alexander's law has been hypothesized to arise either due to adaptive changes in the velocity-to-position neural integrator, or as a consequence of processing of the vestibular-ocular reflex. We tested whether Alexander's law arises only as a consequence of non-physiologic vestibular stimulation. We measured the time course of the development of Alexander's law in healthy humans with nystagmus caused by three types of caloric vestibular stimulation: cold (unilateral inhibition, warm (unilateral excitation, and simultaneous bilateral bithermal (one side cold, the other warm stimulation, mimicking the normal push-pull pattern of vestibular stimulation. Alexander's law, measured as a negative slope of the velocity versus position curve, was observed in all conditions. A reversed pattern of eye position dependency (positive slope was found <10% of the time. The slope often changed with nystagmus velocity (cross-correlation of nystagmus speed and slope was significant in 50% of cases, and the average lag of the slope with the speed was not significantly different from zero. Our results do not support the hypothesis that Alexander's law can only be observed with non-physiologic vestibular stimulation. Further, the rapid development of Alexander's law, while possible for an adaptive mechanism, is nonetheless quite fast compared to most other ocular motor adaptations. These results suggest that Alexander's law may not be a consequence of a true adaptive mechanism.

  18. Attenuated Neural Processing of Risk in Young Adults at Risk for Stimulant Dependence.

    Directory of Open Access Journals (Sweden)

    Martina Reske

    Full Text Available Approximately 10% of young adults report non-medical use of stimulants (cocaine, amphetamine, methylphenidate, which puts them at risk for the development of dependence. This fMRI study investigates whether subjects at early stages of stimulant use show altered decision making processing.158 occasional stimulants users (OSU and 50 comparison subjects (CS performed a "risky gains" decision making task during which they could select safe options (cash in 20 cents or gamble them for double or nothing in two consecutive gambles (win or lose 40 or 80 cents, "risky decisions". The primary analysis focused on risky versus safe decisions. Three secondary analyses were conducted: First, a robust regression examined the effect of lifetime exposure to stimulants and marijuana; second, subgroups of OSU with >1000 (n = 42, or <50 lifetime marijuana uses (n = 32, were compared to CS with <50 lifetime uses (n = 46 to examine potential marijuana effects; third, brain activation associated with behavioral adjustment following monetary losses was probed.There were no behavioral differences between groups. OSU showed attenuated activation across risky and safe decisions in prefrontal cortex, insula, and dorsal striatum, exhibited lower anterior cingulate cortex (ACC and dorsal striatum activation for risky decisions and greater inferior frontal gyrus activation for safe decisions. Those OSU with relatively more stimulant use showed greater dorsal ACC and posterior insula attenuation. In comparison, greater lifetime marijuana use was associated with less neural differentiation between risky and safe decisions. OSU who chose more safe responses after losses exhibited similarities with CS relative to those preferring risky options.Individuals at risk for the development of stimulant use disorders presented less differentiated neural processing of risky and safe options. Specifically, OSU show attenuated brain response in regions critical for performance monitoring

  19. Side effect of grain protectants on biological control agents: How Hyptis plant extracts affect parasitism and larval development of Dinarmus basalis

    OpenAIRE

    Sanon, A.; BA, N.; Dabire, L. C. B.; NIBIE, R.C.H.; Monge, Jean Paul

    2011-01-01

    International audience; Dinarmus basalis Rondani (Hymenoptera: Pteromalidae), an ectoparasitoid of Bruchid pest of stored cowpeas, is a potential biological control agent. We investigated whether grain protectants from Hyptis spicigera and H. suaveolens (Lamiaceae) disturb parasitism and post embryonic growth of the parasitoid. When cowpeas containing bruchid larvae were treated before being placed in the presence of D. basalis females, the rate of parasitism decreased on average up to 24 and...

  20. Personality Disorders, Narcotics, and Stimulants; Relationship in Iranian Male Substance Dependents Population.

    Science.gov (United States)

    Noorbakhsh, Simasadat; Zeinodini, Zahra; Khanjani, Zeynab; Poorsharifi, Hamid; Rajezi Esfahani, Sepideh

    2015-06-01

    Individuals with certain personality disorders, especially the antisocial and borderline personality disorders, are more prone to substance use disorders. Regarding the importance of substance use disorders, this study aimed to explore the association between personality disorders and types of used drugs (narcotics and stimulants) in Iranian male substance users. The current study was a correlation study. We evaluated 285 male substance users and excluded 25 according to exclusion criteria. A total of 130 narcotic users and 130 stimulant users were recruited randomly in several phases from January 2013 to October 2013. All participants were referred to Substance Dependency Treatment Clinics in Tehran, Iran. Data collection process was accomplished by means of clinical interview based on DSM-V criteria for substance use disorders, Iranian version of addiction severity index (ASI), and Millon clinical multi-axial inventory-III (MCMI-III). Data were analyzed by SPSS 21 using Pearson correlation coefficient and regression, the. There was a significant correlation between stimulant use and histrionic personality disorder (P personality disorders (P histrionic, and narcissistic personality disorders (P personality disorders (P personality disorders, and narcotic and stimulants consumption (P personality disorder and narcotics (P personality disorders and types of used drugs were in accordance with the previous studies results. It is necessary to design appropriate treatment plans for medical treatment of those with personality disorders.

  1. Morning administration of oral methamphetamine dose-dependently disrupts nighttime sleep in recreational stimulant users.

    Science.gov (United States)

    Herrmann, Evan S; Johnson, Patrick S; Bruner, Natalie R; Vandrey, Ryan; Johnson, Matthew W

    2017-09-01

    Use of amphetamine-type stimulants (e.g., methamphetamine) is associated with acute sleep disruptions. No prior reports have characterized the acute effects of methamphetamine on sleep using polysomnography, the gold standard for objective sleep monitoring. Recreational stimulant users (n=19) completed a baseline assessment, which included questionnaires assessing demographic and substance use characteristics, and the Pittsburgh Sleep Quality Index (PSQI), which assesses sleep quality over the past month. Participants were administered 0mg (placebo), 20mg, or 40mg oral methamphetamine at 08:15h on study days, using a double-blind, randomized, within-subjects design. Sleep was monitored using polysomnography from 22:20 that evening until 06:15 the following morning. PSQI scores indicated more than half of participants reported poor sleep quality at baseline. Methamphetamine dose-dependently increased sleep latency, and decreased total sleep time, sleep efficiency, time in NREM 2 sleep, number of REM periods, and total time in REM sleep. Sleep under placebo conditions was consistent with what would be expected from healthy adults. Morning oral administration of methamphetamine produces robust disruptions in nighttime sleep. Future research should examine relations between stimulant use and sleep disruption in naturalistic settings, with regard to both stimulant abuse and licit prescription use. Copyright © 2017. Published by Elsevier B.V.

  2. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

    Science.gov (United States)

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-12-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.

  3. Neuregulin 1 Promotes Glutathione-Dependent Neuronal Cobalamin Metabolism by Stimulating Cysteine Uptake

    Directory of Open Access Journals (Sweden)

    Yiting Zhang

    2016-01-01

    Full Text Available Neuregulin 1 (NRG-1 is a key neurotrophic factor involved in energy homeostasis and CNS development, and impaired NRG-1 signaling is associated with neurological disorders. Cobalamin (Cbl, also known as vitamin B12, is an essential micronutrient which mammals must acquire through diet, and neurologic dysfunction is a primary clinical manifestation of Cbl deficiency. Here we show that NRG-1 stimulates synthesis of the two bioactive Cbl species adenosylcobalamin (AdoCbl and methylcobalamin (MeCbl in human neuroblastoma cells by both promoting conversion of inactive to active Cbl species and increasing neuronal Cbl uptake. Formation of active Cbls is glutathione- (GSH- dependent and the NRG-1-initiated increase is dependent upon its stimulation of cysteine uptake by excitatory amino acid transporter 3 (EAAT3, leading to increased GSH. The stimulatory effect of NRG-1 on cellular Cbl uptake is associated with increased expression of megalin, which is known to facilitate Cbl transport in ileum and kidney. MeCbl is a required cofactor for methionine synthase (MS and we demonstrate the ability of NRG-1 to increase MS activity, and affect levels of methionine methylation cycle metabolites. Our results identify novel neuroprotective roles of NRG-1 including stimulating antioxidant synthesis and promoting active Cbl formation.

  4. Yokukansan and Yokukansankachimpihange Ameliorate Aggressive Behaviors in Rats with Cholinergic Degeneration in the Nucleus Basalis of Meynert

    Directory of Open Access Journals (Sweden)

    Masahiro Tabuchi

    2017-04-01

    Full Text Available Yokukansan (YKS and yokukansankachimpihange (YKSCH are traditional Japanese Kampo medicines. The latter comprises YKS along with the medicinal herbs Citrus unshiu peel and Pinellia tuber. Both of these Kampo medicines are indicated for the treatment of night crying and irritability in children and for neurosis and insomnia in adults. In recent clinical trials, YKS exhibited ameliorative effects on the behavioral and psychological symptoms of dementia, such as aggressiveness, excitement, and irritability. In the present study, we aimed to clarify the involvement of cholinergic degeneration in the nucleus basalis of Meynert (NBM in the development of aggressiveness in rats. Subsequently, using this animal model, the effects of YKS and YKSCH on aggressiveness were compared and the mechanisms underlying these effects were investigated. L-Glutamic acid (Glu was injected into the right NBM of rats to induce deterioration of cholinergic neurons. On day 8 after Glu injection, aggressive behaviors were evaluated using resident–intruder tests. After the evaluation, YKS or YKSCH was administered to rats with aggressive behaviors daily for 7 days. In some groups, the 5-HT1A receptor antagonist WAY-100635 was coadministered with YKS or YKSCH over the same period. In other groups, locomotor activity was measured on days 12–14 after Glu injection. On day 15, immunohistochemistry was then performed to examine choline acetyltransferase (ChAT activities in the NBM. Aggressive behaviors had developed on day 8 after Glu injection and were maintained until day 15. YKS and YKSCH significantly ameliorated the aggressive behaviors. These suppressive effects were entirely abolished following coadministration of WAY-100635. Finally, the number of ChAT-positive cells in the right NBM was significantly reduced on day 15 after Glu injection, and treatment with YKS or YKSCH did not ameliorate these reduced cell numbers. Our results show that unilateral Glu injections

  5. Shared Neural Mechanisms for the Evaluation of Intense Sensory Stimulation and Economic Reward, Dependent on Stimulation-Seeking Behavior.

    Science.gov (United States)

    Norbury, Agnes; Valton, Vincent; Rees, Geraint; Roiser, Jonathan P; Husain, Masud

    2016-09-28

    Why are some people strongly motivated by intense sensory experiences? Here we investigated how people encode the value of an intense sensory experience compared with economic reward, and how this varies according to stimulation-seeking preference. Specifically, we used a novel behavioral task in combination with computational modeling to derive the value individuals assigned to the opportunity to experience an intense tactile stimulus (mild electric shock). We then examined functional imaging data recorded during task performance to see how the opportunity to experience the sensory stimulus was encoded in stimulation-seekers versus stimulation-avoiders. We found that for individuals who positively sought out this kind of sensory stimulation, there was common encoding of anticipated economic and sensory rewards in the ventromedial prefrontal cortex. Conversely, there was robust encoding of the modeled probability of receiving such stimulation in the insula only in stimulation-avoidant individuals. Finally, we found preliminary evidence that sensory prediction error signals may be positively signed for stimulation-seekers, but negatively signed for stimulation-avoiders, in the posterior cingulate cortex. These findings may help explain why high intensity sensory experiences are appetitive for some individuals, but not for others, and may have relevance for the increased vulnerability for some psychopathologies, but perhaps increased resilience for others, in high sensation-seeking individuals. People vary in their preference for intense sensory experiences. Here, we investigated how different individuals evaluate the prospect of an unusual sensory experience (electric shock), compared with the opportunity to gain a more traditional reward (money). We found that in a subset of individuals who sought out such unusual sensory stimulation, anticipation of the sensory outcome was encoded in the same way as that of monetary gain, in the ventromedial prefrontal cortex

  6. In situ hybridization of nucleus basalis neurons shows increased β-amyloid mRNA in Alzheimer disease

    International Nuclear Information System (INIS)

    Cohen, M.L.; Golde, T.E.; Usiak, M.F.; Younkin, L.H.; Younkin, S.G.

    1988-01-01

    To determine which cells within the brain produce β-amyloid mRNA and to assess expression of the β-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that β-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more β-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the β-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease

  7. Cognitive functions in a patient with Parkinson-dementia syndrome undergoing deep brain stimulation.

    Science.gov (United States)

    Freund, Hans-Joachim; Kuhn, Jens; Lenartz, Doris; Mai, Jürgen K; Schnell, Thomas; Klosterkoetter, Joachim; Sturm, Volker

    2009-06-01

    Dementia represents one of the most challenging health problems. Despite intense research, available therapies have thus far only achieved modest results. Deep brain stimulation (DBS) is an effective treatment option for some movement disorders and is under study for psychiatric applications. Recently, diencephalic DBS revealed selective effects on memory functions, another facet of subcortical DBS. To report a new DBS strategy for the modification of cognitive functions in a patient with severe Parkinson-dementia syndrome. Prospective study with double-blinded sham stimulation period. Departments of Stereotaxy and Functional Neurosurgery and Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany. A 71-year-old man with slowly progressive Parkinson-dementia syndrome. Intervention We inserted 2 electrodes into the nucleus basalis of Meynert in addition to electrodes in the subthalamic nucleus. Main Outcome Measure Improvement of cognitive functions. Turning on the subthalamic nucleus electrodes improved motor symptoms but left cognitive performance almost unchanged. Turning on electrical stimulation of the nucleus basalis of Meynert resulted in markedly improved cognitive functions. The improvement in attention, concentration, alertness, drive, and spontaneity resulted in the patient's renewed enjoyment of former interests and enhanced social communication. Such a broad effect on cognition is consistent with ample experimental evidence revealing that the nucleus basalis of Meynert provides cholinergic innervation to the cortical mantle, complemented by glutaminergic and gamma-aminobutyric acid-transmitting projections from the basal forebrain. These projections provide background tuning facilitating cortical operations. Furthermore, nucleus basalis of Meynert stimulation paired with sensory stimuli can accomplish persistent reorganization of specific processing modules. The improvements in cognitive and behavioral performance in our patient are likely

  8. Intensity dependent waiting time for strong electron trapping events in speckle stimulated raman scatter

    Energy Technology Data Exchange (ETDEWEB)

    Rose, Harvey [Los Alamos National Laboratory; Daughton, W [Los Alamos National Laboratory; Yin, L [Los Alamos National Laboratory

    2009-01-01

    The onset of Stimulated Raman scatter from an intense laser speckle is the simplest experimentally realizable laser-plasma-interaction environment. Despite this data and recent 3D particle simulations, the controlling mechanism at the onset of backscatter in the kinetic regime when strong electron trapping in the daughter Langmuir wave is a dominant nonlinearity is not understood. This paper explores the consequences of assuming that onset is controlled by large thermal fluctuations. A super exponential dependence of mean reflectivity on speckle intensity in the onset regime is predicted.

  9. Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder.

    Science.gov (United States)

    Meunier, David; Ersche, Karen D; Craig, Kevin J; Fornito, Alex; Merlo-Pich, Emilio; Fineberg, Naomi A; Shabbir, Shaila S; Robbins, Trevor W; Bullmore, Edward T

    2012-01-16

    There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. In vivo optogenetic stimulation of neocortical excitatory neurons drives brain-state-dependent inhibition.

    Science.gov (United States)

    Mateo, Celine; Avermann, Michael; Gentet, Luc J; Zhang, Feng; Deisseroth, Karl; Petersen, Carl C H

    2011-10-11

    Synaptic interactions between excitatory and inhibitory neocortical neurons are important for mammalian sensory perception. Synaptic transmission between identified neurons within neocortical microcircuits has mainly been studied in brain slice preparations in vitro. Here, we investigate brain-state-dependent neocortical synaptic interactions in vivo by combining the specificity of optogenetic stimulation with the precision of whole-cell recordings from postsynaptic excitatory glutamatergic neurons and GFP-labeled inhibitory GABAergic neurons targeted through two-photon microscopy. Channelrhodopsin-2 (ChR2) stimulation of excitatory layer 2/3 barrel cortex neurons evoked larger and faster depolarizing postsynaptic potentials and more synaptically driven action potentials in fast-spiking (FS) GABAergic neurons compared to both non-fast-spiking (NFS) GABAergic neurons and postsynaptic excitatory pyramidal neurons located within the same neocortical microcircuit. The number of action potentials evoked in ChR2-expressing neurons showed low trial-to-trial variability, but postsynaptic responses varied strongly with near-linear dependence upon spontaneously driven changes in prestimulus membrane potential. Postsynaptic responses in excitatory neurons had reversal potentials, which were hyperpolarized relative to action potential threshold and were therefore inhibitory. Reversal potentials measured in postsynaptic GABAergic neurons were close to action potential threshold. Postsynaptic inhibitory neurons preferentially fired synaptically driven action potentials from spontaneously depolarized network states, with stronger state-dependent modulation in NFS GABAergic neurons compared to FS GABAergic neurons. Inhibitory neurons appear to dominate neocortical microcircuit function, receiving stronger local excitatory synaptic input and firing more action potentials compared to excitatory neurons. In mouse layer 2/3 barrel cortex, we propose that strong state-dependent

  11. Mechanical stimulation induces formin-dependent assembly of a perinuclear actin rim.

    Science.gov (United States)

    Shao, Xiaowei; Li, Qingsen; Mogilner, Alex; Bershadsky, Alexander D; Shivashankar, G V

    2015-05-19

    Cells constantly sense and respond to mechanical signals by reorganizing their actin cytoskeleton. Although a number of studies have explored the effects of mechanical stimuli on actin dynamics, the immediate response of actin after force application has not been studied. We designed a method to monitor the spatiotemporal reorganization of actin after cell stimulation by local force application. We found that force could induce transient actin accumulation in the perinuclear region within ∼ 2 min. This actin reorganization was triggered by an intracellular Ca(2+) burst induced by force application. Treatment with the calcium ionophore A23187 recapitulated the force-induced perinuclear actin remodeling. Blocking of actin polymerization abolished this process. Overexpression of Klarsicht, ANC-1, Syne Homology (KASH) domain to displace nesprins from the nuclear envelope did not abolish Ca(2+)-dependent perinuclear actin assembly. However, the endoplasmic reticulum- and nuclear membrane-associated inverted formin-2 (INF2), a potent actin polymerization activator (mutations of which are associated with several genetic diseases), was found to be important for perinuclear actin assembly. The perinuclear actin rim structure colocalized with INF2 on stimulation, and INF2 depletion resulted in attenuation of the rim formation. Our study suggests that cells can respond rapidly to external force by remodeling perinuclear actin in a unique Ca(2+)- and INF2-dependent manner.

  12. Influence of host origin on host choice of the parasitoid Dinarmus basalis: does upbringing influence choices later in life?

    Science.gov (United States)

    Sankara, F; Dabiré, L C B; Ilboudo, Z; Dugravot, S; Cortesero, A M; Sanon, A

    2014-02-26

    The aim of this study was to investigate the influence of volatile compounds from four secondary host plants on the ability of Dinarmus basalis Rond. (Hymenoptera: Pteromalidae) to locate, recognize, and parasitize its host, 4(th)instar larvae or pupae of Callosobruchus maculatus F. (Coleoptera: Chrysomelidae). To examine this, strains of D. basalis were transferred from cow-pea seeds (Vigna unguiculata (L.) Walp. (Fabales: Fabaceae)) to pigeon pea (Cajanus cajan (L.) Millsp.) and two varieties of Bambara groundnut (Vigna subterranea (L.) Verdc.) seeds. The ability of D. basalis females to recognize the volatile compounds emanating from their complex host plant was tested by using a Y-tube olfactometer and a three-dimensional device. The results suggest that when females have a choice between pure air and the air emanating from their complex host of origin, they are attracted to the air tainted by the volatile compounds they have become accustomed to. They spent significantly more time (p pea seed hosts were offered a choice between cowpea and pigeon pea seeds, all containing 4(th)instar larvae, the familiar odor of pigeon pea seeds were most attractive. When females from Bambara groundnut (white and striped) seed hosts were offered a choice between cowpea and pigeon pea seeds, all containing 4(th)instar larvae, they were significantly attracted to the odour of cowpea seeds. In the three-dimensional system, the females from the four strains did not appear to have any preference for a given type of seed containing 4(th)instar larvae or pupae. The parasitism rate remained high on all four types of seeds used. These results show that the use of D. basalis as a biological control agent is possible in host changing situations where C. maculatus starts to attack other legumes. The results of this study also provide information supporting the behavioral plasticity of D. basalis. Understanding the mechanisms involved in the adaptive phenomena of biological control agents

  13. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans.

    Science.gov (United States)

    Batsikadze, G; Moliadze, V; Paulus, W; Kuo, M-F; Nitsche, M A

    2013-04-01

    Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm(2) has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI

  14. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    International Nuclear Information System (INIS)

    Raufman, Jean-Pierre; Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng

    2011-01-01

    Highlights: ► Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. ► Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. ► Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers – this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre-treatment with anti-MMP1 antibody. This study contributes to understanding

  15. Muscarinic receptor agonists stimulate matrix metalloproteinase 1-dependent invasion of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Raufman, Jean-Pierre, E-mail: jraufman@medicine.umaryland.edu [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States); Cheng, Kunrong; Saxena, Neeraj; Chahdi, Ahmed; Belo, Angelica; Khurana, Sandeep; Xie, Guofeng [Division of Gastroenterology and Hepatology, University of Maryland School of Medicine, Baltimore, MD (United States)

    2011-11-18

    Highlights: Black-Right-Pointing-Pointer Muscarinic receptor agonists stimulated robust human colon cancer cell invasion. Black-Right-Pointing-Pointer Anti-matrix metalloproteinase1 antibody pre-treatment blocks cell invasion. Black-Right-Pointing-Pointer Bile acids stimulate MMP1 expression, cell migration and MMP1-dependent invasion. -- Abstract: Mammalian matrix metalloproteinases (MMPs) which degrade extracellular matrix facilitate colon cancer cell invasion into the bloodstream and extra-colonic tissues; in particular, MMP1 expression correlates strongly with advanced colon cancer stage, hematogenous metastasis and poor prognosis. Likewise, muscarinic receptor signaling plays an important role in colon cancer; muscarinic receptors are over-expressed in colon cancer compared to normal colon epithelial cells. Muscarinic receptor activation stimulates proliferation, migration and invasion of human colon cancer cells. In mouse intestinal neoplasia models genetic ablation of muscarinic receptors attenuates carcinogenesis. In the present work, we sought to link these observations by showing that MMP1 expression and activation plays a mechanistic role in muscarinic receptor agonist-induced colon cancer cell invasion. We show that acetylcholine, which robustly increases MMP1 expression, stimulates invasion of HT29 and H508 human colon cancer cells into human umbilical vein endothelial cell monolayers - this was abolished by pre-incubation with atropine, a non-selective muscarinic receptor inhibitor, and by pre-incubation with anti-MMP1 neutralizing antibody. Similar results were obtained using a Matrigel chamber assay and deoxycholyltaurine (DCT), an amidated dihydroxy bile acid associated with colon neoplasia in animal models and humans, and previously shown to interact functionally with muscarinic receptors. DCT treatment of human colon cancer cells resulted in time-dependent, 10-fold increased MMP1 expression, and DCT-induced cell invasion was also blocked by pre

  16. Nicotine stimulates nerve growth factor in lung fibroblasts through an NFκB-dependent mechanism.

    Directory of Open Access Journals (Sweden)

    Cherry Wongtrakool

    Full Text Available Airway hyperresponsiveness (AHR is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF secretion into the environment.Primary lung fibroblasts isolated from wild type and α7 nicotinic acetylcholine receptor (α7 nAChR deficient mice were treated with nicotine (50 µg/ml in vitro for 72 hours. NGF levels were measured in culture media and in bronchoalveolar lavage (BAL fluid from asthmatic, smoking and non-smoking subjects by ELISA. The role of the NFκB pathway in nicotine-induced NGF expression was investigated by measuring NFκB nuclear translocation, transcriptional activity, chromatin immunoprecipitation assays, and si-p65 NFκB knockdown. The ability of nicotine to stimulate a fibroblast-mediated, contractile ASM cell phenotype was confirmed by examining expression of contractile proteins in ASM cells cultured with fibroblast-conditioned media or BAL fluid.NGF levels were elevated in the bronchoalveolar lavage fluid of nicotine-exposed mice, current smokers, and asthmatic children. Nicotine increased NGF secretion in lung fibroblasts in vitro in a dose-dependent manner and stimulated NFκB nuclear translocation, p65 binding to the NGF promoter, and NFκB transcriptional activity. These responses were attenuated in α7 nAChR deficient fibroblasts and in wild type fibroblasts following NFκB inhibition. Nicotine-treated, fibroblast-conditioned media increased expression of contractile proteins in ASM cells.Nicotine stimulates NGF release by lung fibroblasts through α7 nAChR and NFκB dependent pathways. These novel findings

  17. Differentiation-Dependent Motility-Responses of Developing Neural Progenitors to Optogenetic Stimulation

    Directory of Open Access Journals (Sweden)

    Tímea Köhidi

    2017-12-01

    Full Text Available During neural tissue genesis, neural stem/progenitor cells are exposed to bioelectric stimuli well before synaptogenesis and neural circuit formation. Fluctuations in the electrochemical potential in the vicinity of developing cells influence the genesis, migration and maturation of neuronal precursors. The complexity of the in vivo environment and the coexistence of various progenitor populations hinder the understanding of the significance of ionic/bioelectric stimuli in the early phases of neuronal differentiation. Using optogenetic stimulation, we investigated the in vitro motility responses of radial glia-like neural stem/progenitor populations to ionic stimuli. Radial glia-like neural stem cells were isolated from CAGloxpStoploxpChR2(H134-eYFP transgenic mouse embryos. After transfection with Cre-recombinase, ChR2(channelrhodopsin-2-expressing and non-expressing cells were separated by eYFP fluorescence. Expression of light-gated ion channels were checked by patch clamp and fluorescence intensity assays. Neurogenesis by ChR2-expressing and non-expressing cells was induced by withdrawal of EGF from the medium. Cells in different (stem cell, migrating progenitor and maturing precursor stages of development were illuminated with laser light (λ = 488 nm; 1.3 mW/mm2; 300 ms in every 5 min for 12 h. The displacement of the cells was analyzed on images taken at the end of each light pulse. Results demonstrated that the migratory activity decreased with the advancement of neuronal differentiation regardless of stimulation. Light-sensitive cells, however, responded on a differentiation-dependent way. In non-differentiated ChR2-expressing stem cell populations, the motility did not change significantly in response to light-stimulation. The displacement activity of migrating progenitors was enhanced, while the motility of differentiating neuronal precursors was markedly reduced by illumination.

  18. Immune complexes stimulate CCR7-dependent dendritic cell migration to lymph nodes

    Science.gov (United States)

    Clatworthy, Menna R.; Aronin, Caren E. Petrie; Mathews, Rebeccah J.; Morgan, Nicole; Smith, Kenneth G.C.; Germain, Ronald N.

    2014-01-01

    Antibodies are critical for defence against a variety of microbes but may also be pathogenic in some autoimmune diseases. Many effector functions of antibody are mediated by Fcγ receptors (FcγRs), which are found on most immune cells, including dendritic cells (DCs). DCs are important antigen presenting cells and play a central role in inducing antigen-specific tolerance or immunity1,2. Following antigen acquisition in peripheral tissues, DCs migrate to draining lymph nodes via lymphatics to present antigen to T cells. In this study we demonstrate that FcγR engagement by IgG immune complexes (IC) stimulates DC migration from peripheral tissues to the paracortex of draining lymph nodes. In vitro, IC-stimulated murine and human DCs showed enhanced directional migration in a CCL19 gradient and increased CCR7 expression. Using intravital two-photon microscopy, we observed that local administration of IC resulted in dermal DC mobilisation. We confirmed that dermal DC migration to lymph nodes was CCR7-dependent and increased in the absence of the inhibitory receptor, FcγRIIb. These observations have relevance to autoimmunity, because autoantibody-containing serum from mice and humans with SLE also increased dermal DC migration to lymph nodes in vivo, suggesting that this process may occur in lupus, potentially driving the inappropriate localisation of autoantigen-bearing DCs. PMID:25384086

  19. A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion.

    Science.gov (United States)

    Shigeto, Makoto; Cha, Chae Young; Rorsman, Patrik; Kaku, Kohei

    2017-04-01

    Glucagon-like peptide-1 (GLP-1) is an endogenous glucose-lowering hormone and GLP-1 receptor agonists are currently being used as antidiabetic drugs clinically. The canonical signalling pathway (including cAMP, Epac2, protein kinase A (PKA) and K ATP channels) is almost universally accepted as the main mechanism of GLP-1-stimulated insulin secretion. This belief is based on in vitro studies that used nanomolar (1-100 nM) concentrations of GLP-1. Recently, it was found that the physiological concentrations (1-10 pM) of GLP-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [Ca 2+ ] in isolated β cells/pancreatic islets. These responses were unaffected by PKA inhibitors and occurred without detectable increases in intracellular cAMP and PKA activity. These PKA-independent actions of GLP-1 depend on protein kinase C (PKC), involve activation of the standard GLP-1 receptor (GLP1R) and culminate in activation of phospholipase C (PLC), leading to an elevation of diacylglycerol (DAG), increased L-type Ca 2+ and TRPM4/TRPM5 channel activities. Here, we review these recent data and contrast them against the effects of nanomolar concentrations of GLP-1. The differential intracellular signalling activated by low and high concentrations of GLP-1 could provide a clue to explain how GLP-1 exerts different function in the central nervous system and peripheral organs.

  20. Predicting stimulation-dependent enhancer-promoter interactions from ChIP-Seq time course data.

    Science.gov (United States)

    Dzida, Tomasz; Iqbal, Mudassar; Charapitsa, Iryna; Reid, George; Stunnenberg, Henk; Matarese, Filomena; Grote, Korbinian; Honkela, Antti; Rattray, Magnus

    2017-01-01

    We have developed a machine learning approach to predict stimulation-dependent enhancer-promoter interactions using evidence from changes in genomic protein occupancy over time. The occupancy of estrogen receptor alpha (ERα), RNA polymerase (Pol II) and histone marks H2AZ and H3K4me3 were measured over time using ChIP-Seq experiments in MCF7 cells stimulated with estrogen. A Bayesian classifier was developed which uses the correlation of temporal binding patterns at enhancers and promoters and genomic proximity as features to predict interactions. This method was trained using experimentally determined interactions from the same system and was shown to achieve much higher precision than predictions based on the genomic proximity of nearest ERα binding. We use the method to identify a genome-wide confident set of ERα target genes and their regulatory enhancers genome-wide. Validation with publicly available GRO-Seq data demonstrates that our predicted targets are much more likely to show early nascent transcription than predictions based on genomic ERα binding proximity alone.

  1. Predicting stimulation-dependent enhancer-promoter interactions from ChIP-Seq time course data

    Directory of Open Access Journals (Sweden)

    Tomasz Dzida

    2017-09-01

    Full Text Available We have developed a machine learning approach to predict stimulation-dependent enhancer-promoter interactions using evidence from changes in genomic protein occupancy over time. The occupancy of estrogen receptor alpha (ERα, RNA polymerase (Pol II and histone marks H2AZ and H3K4me3 were measured over time using ChIP-Seq experiments in MCF7 cells stimulated with estrogen. A Bayesian classifier was developed which uses the correlation of temporal binding patterns at enhancers and promoters and genomic proximity as features to predict interactions. This method was trained using experimentally determined interactions from the same system and was shown to achieve much higher precision than predictions based on the genomic proximity of nearest ERα binding. We use the method to identify a genome-wide confident set of ERα target genes and their regulatory enhancers genome-wide. Validation with publicly available GRO-Seq data demonstrates that our predicted targets are much more likely to show early nascent transcription than predictions based on genomic ERα binding proximity alone.

  2. Dose-dependent platelet stimulation and inhibition induced by anti-PIA1 IgG

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, T.; Davis, J.M.; Schwartz, K.A. (Michigan State Univ., East Lansing (USA))

    1990-07-01

    The PIA1 antibody produces several clinically distinct and severe thrombocytopenias. Investigations have demonstrated divergent effects on platelet function; prior reports demonstrated inhibition, while a conflicting publication showed platelet activation. We have resolved this conflict using anti-PIA1 IgG produced by a patient with posttransfusion purpura. Relatively low concentrations stimulated platelet aggregation and release of adenosine triphosphate (ATP) whereas high concentrations inhibited platelet function, producing a thrombasthenia-like state. The number of molecules of platelet-associated IgG necessary to initiate aggregation and ATP release (2,086 +/- 556) or produce maximum aggregation (23,420 +/- 3,706) or complete inhibition (63,582 +/- 2654) were measured with a quantitative radiometric assay for bound anti-PIA1. Preincubation of platelets with high concentrations of PIA1 antibody inhibited platelet aggregation with 10 mumol/L adenosine diphosphate and blocked 125I-labeled fibrinogen platelet binding. Platelet activation with nonfibrinogen dependent agonist, 1 U/ml thrombin, was not inhibited by this high concentration of PIA1 IgG. In conclusion, anti-PIAI IgG produces (1) stimulation of platelet aggregation and ATP release that is initiated with 2000 molecules IgG per platelet and is associated with an increase of 125I-fibrinogen binding; (2) conversely, inhibition of platelet aggregation is observed with maximum antibody binding, 63,000 molecules IgG per platelet, and is mediated via a blockade of fibrinogen binding.

  3. Frequency-Dependent Multi-Well Cardiotoxicity Screening Enabled by Optogenetic Stimulation

    Directory of Open Access Journals (Sweden)

    Susanne Rehnelt

    2017-12-01

    Full Text Available Side effects on cardiac ion channels causing lethal arrhythmias are one major reason for drug withdrawals from the market. Field potential (FP recording from cardiomyocytes, is a well-suited tool to assess such cardiotoxic effects of drug candidates in preclinical drug development, but it is currently limited to the spontaneous beating of the cardiomyocytes and manual analysis. Herein, we present a novel optogenetic cardiotoxicity screening system suited for the parallel automated frequency-dependent analysis of drug effects on FP recorded from human-induced pluripotent stem cell-derived cardiomyocytes. For the expression of the light-sensitive cation channel Channelrhodopsin-2, we optimised protocols using virus transduction or transient mRNA transfection. Optical stimulation was performed with a new light-emitting diode lid for a 96-well FP recording system. This enabled reliable pacing at physiologically relevant heart rates and robust recording of FP. Thereby we detected rate-dependent effects of drugs on Na+, Ca2+ and K+ channel function indicated by FP prolongation, FP shortening and the slowing of the FP downstroke component, as well as generation of afterdepolarisations. Taken together, we present a scalable approach for preclinical frequency-dependent screening of drug effects on cardiac electrophysiology. Importantly, we show that the recording and analysis can be fully automated and the technology is readily available using commercial products.

  4. NAD+-dependent HDAC inhibitor stimulates Monascus pigment production but inhibit citrinin.

    Science.gov (United States)

    Hu, Yan; Zhou, Youxiang; Mao, Zejing; Li, Huihui; Chen, Fusheng; Shao, Yanchun

    2017-08-23

    Monascus species are edible fungi due to the production of food colorant and other beneficial compounds. Hence, it has been an attractive thesis to improve their productivities. Increasing numbers of investigations revealed that regulating the activities of histone deacetylases can significantly perturb secondary metabolites (SM) production at a global level. In this study, dihydrocoumarin (DHC, an inhibitor of the Sirtuin family of NAD + -dependent deacetylases) was used to treat Monascus ruber for evaluating its effects on organism growth and SM production. The results revealed that the variation trends of colonial sizes, biomass and mycotoxin were in a dose-dependent manner. Generally, they decreased with the increased DHC concentrations in the designed range. But the variation trend of pigment was different. Comparison of SM profile, three new peaks occurred to the mycelia extractions from DHC-treated strain corresponding to molecular weights 402, 416 and 444, respectively. These three compounds were identified as Monasfluol B, Monascus azaphilone C and acetyl-monasfluol B (a new Monascus chemical pigment structure). In short, DHC can stimulate M. ruber strain to produce more pigment-like polyketides but inhibition of mycotoxin (citrinin).

  5. Amplitude-dependency of response of SI cortex to flutter stimulation

    Directory of Open Access Journals (Sweden)

    Whitsel Barry L

    2005-06-01

    Full Text Available Abstract Background It is established that increasing the amplitude of a flutter stimulus increases its perceived intensity. Although many studies have examined this phenomenon with regard to the responding afferent population, the way in which the intensity of a stimulus is coded in primary somatosensory cortex (SI remains unclear. Results Optical intrinsic signal (OIS imaging was used to study the evoked responses in SI of anesthetized squirrel monkeys by 25 Hz sinusoidal vertical skin displacement stimulation. Stimuli were 10 sec duration with a 50 sec inter-stimulus interval. Stimulus amplitude ranged from 50 to 400 microns and different amplitudes were interleaved. Control levels of activity were measured in the absence of stimulation, and used to compare with activation levels evoked by the different stimulus amplitudes. Stimulation of a discrete skin site on the forelimb evoked a prominent increase in absorbance within the forelimb representational region in cytoarchitectonic areas 3b and 1 of the contralateral hemisphere. An increase in stimulus amplitude led to a proportional increase in the magnitude of the absorbance increase in this region of areas 3b and 1 while surrounding cortex underwent a decrease in absorbance. Correlation maps revealed that as stimulus amplitude is increased, the spatial extent of the activated region in SI remains relatively constant, and the activity within this region increases progressively. Additionally, as stimulus amplitude is increased to suprathreshold levels, activity in the surround of the activated SI territory decreases, suggesting an increase in inhibition of neuronal activity within these regions. Conclusion Increasing the amplitude of a flutter stimulus leads to a proportional increase in absorbance within the forelimb representational region of SI. This most likely reflects an increase in the firing rate of neurons in this region of SI. The relatively constant spatial extent of this stimulus

  6. Gravity dependence of the effect of optokinetic stimulation on the subjective visual vertical.

    Science.gov (United States)

    Ward, Bryan K; Bockisch, Christopher J; Caramia, Nicoletta; Bertolini, Giovanni; Tarnutzer, Alexander Andrea

    2017-05-01

    Accurate and precise estimates of direction of gravity are essential for spatial orientation. According to Bayesian theory, multisensory vestibular, visual, and proprioceptive input is centrally integrated in a weighted fashion based on the reliability of the component sensory signals. For otolithic input, a decreasing signal-to-noise ratio was demonstrated with increasing roll angle. We hypothesized that the weights of vestibular (otolithic) and extravestibular (visual/proprioceptive) sensors are roll-angle dependent and predicted an increased weight of extravestibular cues with increasing roll angle, potentially following the Bayesian hypothesis. To probe this concept, the subjective visual vertical (SVV) was assessed in different roll positions (≤ ± 120°, steps = 30°, n = 10) with/without presenting an optokinetic stimulus (velocity = ± 60°/s). The optokinetic stimulus biased the SVV toward the direction of stimulus rotation for roll angles ≥ ± 30° ( P gravity with optokinetic stimulation. Visual input was weighted more when vestibular input became less reliable, i.e., at larger roll-tilt angles. However, according to Bayesian theory, the variability of combined cues is always lower than the variability of each source cue. If the observed increase in variability, although nonsignificant, is true, either it must depend on an additional source of variability, added after SVV computation, or it would conflict with the Bayesian hypothesis. NEW & NOTEWORTHY Applying a rotating optokinetic stimulus while recording the subjective visual vertical in different whole body roll angles, we noted the optokinetic-induced bias to correlate with the roll angle. These findings allow the hypothesis that the established optimal weighting of single-sensory cues depending on their reliability to estimate direction of gravity could be extended to a bias caused by visual self-motion stimuli. Copyright © 2017 the American Physiological Society.

  7. Phosphatidylserine-stimulated production of N-acyl-phosphatidylethanolamines by Ca2+-dependent N-acyltransferase.

    Science.gov (United States)

    Hussain, Zahir; Uyama, Toru; Kawai, Katsuhisa; Binte Mustafiz, Smriti Sultana; Tsuboi, Kazuhito; Araki, Nobukazu; Ueda, Natsuo

    2018-05-01

    N-acyl-phosphatidylethanolamine (NAPE) is known to be a precursor for various bioactive N-acylethanolamines including the endocannabinoid anandamide. NAPE is produced in mammals through the transfer of an acyl chain from certain glycerophospholipids to phosphatidylethanolamine (PE) by Ca 2+ -dependent or -independent N-acyltransferases. The ε isoform of mouse cytosolic phospholipase A 2 (cPLA 2 ε) was recently identified as a Ca 2+ -dependent N-acyltransferase (Ca-NAT). In the present study, we first showed that two isoforms of human cPLA 2 ε function as Ca-NAT. We next purified both mouse recombinant cPLA 2 ε and its two human orthologues to examine their catalytic properties. The enzyme absolutely required Ca 2+ for its activity and the activity was enhanced by phosphatidylserine (PS). PS enhanced the activity 25-fold in the presence of 1 mM CaCl 2 and lowered the EC 50 value of Ca 2+ >8-fold. Using a PS probe, we showed that cPLA 2 ε largely co-localizes with PS in plasma membrane and organelles involved in the endocytic pathway, further supporting the interaction of cPLA 2 ε with PS in living cells. Finally, we found that the Ca 2+ -ionophore ionomycin increased [ 14 C]NAPE levels >10-fold in [ 14 C]ethanolamine-labeled cPLA 2 ε-expressing cells while phospholipase A/acyltransferase-1, acting as a Ca 2+ -independent N-acyltransferase, was insensitive to ionomycin for full activity. In conclusion, PS potently stimulated the Ca 2+ -dependent activity and human cPLA 2 ε isoforms also functioned as Ca-NAT. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Modulation of risky choices in recently abstinent dependent cocaine users: a transcranial direct-current stimulation (tDCS study

    Directory of Open Access Journals (Sweden)

    Alessandra eGorini

    2014-08-01

    Full Text Available Previous neurobiological and neuropsychological investigations have shown that risk-taking behaviors and addictions share many structural and functional aspects. In particular, both are characterised by an irresistible need to obtain immediate rewards as well as by specific alterations in brain circuits responsible for such behaviors.In this study, we used a transcranial direct-current stimulation (tDCS over the dorsolateral prefrontal cortex (DLPFC of two samples of subjects (18 dependent cocaine users and 18 control subjects to investigate the effects of left and right cortical excitability on two risk tasks: the Balloon Analog Risk Task (BART and the Game of Dice Task (GDT. All subjects randomly received a left anodal/right cathodal stimulation (LAn+, a right anodal/left cathodal stimulation (RAn+, and a sham (placebo stimulation each run at least 48 hours apart. Participants were asked to perform the BART and the GDT immediately before and after each stimulation.Our results reveal that the activation of the DLPFC (left and right results in a reduction of risky behaviors at the BART task both in controls subjects and cocaine dependent users. The effect of dTCS on GDT, instead, is more complex. Cocaine users increased safe behavior after right DLPFC anodal stimulation, while risk-taking behavior increased after left DLPFC anodal stimulation. Control subjects’ performance were only affected by the anodal stimulation of the right DLPFC, resulting in an increase of safe bets. These results support the hypothesis that excessive risk propensity in dependent cocaine users, might be due to a hypoactivation of the right DLPFC, as well as to an unbalance interhemispheres interaction. In conclusion, since risky decision-making seems to be, at least in part, responsible for maintenance and relapse of addiction, we argue that a neuromodulation-based approach could represent a valuable adjunct in the clinical treatment of addiction.

  9. An interferometer experiment to explore the aspect angle dependence of stimulated electromagnetic emission spectra

    Directory of Open Access Journals (Sweden)

    Isham

    2005-01-01

    Full Text Available When the Earth's ionosphere is irradiated by a radiofrequency (RF electromagnetic wave of sufficiently high power density and tuned to match a natural E- or F-region plasma frequency, ionospheric magnetoionic wave modes may be excited and may generate RF electromagnetic sideband waves via nonlinear interactions. These secondary emissions, which may then escape from the ionosphere, have been termed stimulated electromagnetic emission or SEE. The frequency spectra of this radiation has been studied extensively, and a number of characteristic spectral features have been identified and in some cases related to particular plasma processes. The separation in frequency between the RF pump and the harmonics of the local electron gyrofrequency is critical in determining the amount of anomalous absorption suffered by the pump wave and the spectral properties of the stimulated sidebands. The pump can excite electrostatic waves which do not propagate away but can in some cases be observed via radio-wave scattering from the electron density fluctuations associated with them. These enhanced density fluctuations are created by processes commonly referred to as upper-hybrid and Langmuir turbulence. Langmuir turbulence has been the subject of 930-MHz scattering observations with antenna scanning through several pre-selected angles between the geographic and geomagnetic zenith directions, and a preference for pointing angles between the Spitze angle and geomagnetic field-aligned was identified. Other phenomena, such as the generation of enhanced electron temperatures and artificial aurora, have more recently been shown to have special behavior at similar angles, near but apparently not quite at field-aligned. In view of this evidence for angular structure in several pump-induced effects, in light of the rich variety of SEE phenomena strongly dependent on the geomagnetic field via the frequency interval between the pump and the gyrofrequency harmonics, and in

  10. Global perception depends on coherent work of bilateral visual cortices: transcranial magnetic stimulation (TMS) studies.

    Science.gov (United States)

    Zhang, Xin; Han, ShiHui

    2007-08-01

    Previous research suggests that the right and left hemispheres dominate global and local perception of hierarchical patterns, respectively. The current work examined whether global perception of hierarchical stimuli requires coherent work of bilateral visual cortices using transcranial magnetic stimulation (TMS). Subjects discriminated global or local properties of compound letters in Experiment 1. Reaction times were recorded when single-pulse real TMS or sham TMS was delivered over the left or right visual cortex. While a global precedence effect (i.e., faster responses to global than local targets and stronger global-to-local interference than the reverse) was observed, TMS decreased global-to-local interference whereas increased local-to-global interference. Experiment 2 ruled out the possibility that the effects observed in Experiment 1 resulted from perceptual learning. Experiment 3 used compound shapes and observed TMS effect similar to that in Experiment 1. Moreover, TMS also slowed global RTs whereas speeded up local RTs in Experiment 3. Finally, the TMS effects observed in Experiments 1 and 3 did not differ between the conditions when TMS was applied over the left and right hemispheres. The results support a coherence hypothesis that global perception of compound stimuli depends upon the coherent work of bilateral visual cortices.

  11. Topical Histamine Stimulates Repigmentation of Nonsegmental Vitiligo by a Receptor-Dependent Mechanism.

    Science.gov (United States)

    Liu, Jun; Xu, Yan; Lin, Tzu-Kai; Lv, Chengzhi; Elias, Peter M; Man, Mao-Qiang

    2017-01-01

    Though vitiligo is a common depigmentary disorder, it still represents a substantial therapeutic challenge. Therapeutic options are limited in part due to its uncertain etiology. Because recent studies suggest that histamine stimulates melanogenesis in vitro, we determined here whether topical histamine stimulates repigmentation in patients with stable, nonsegmental vitiligo. A total of 23 otherwise normal volunteers with vitiligo, including 14 males and 9 females aged 6-59 years (mean age 29.2 ± 2.8), were enrolled in this study. 1% histamine in distilled water was applied to the lesions twice daily for 5 weeks, while comparable lesions, treated with distilled water alone, served as the controls. The melanin index was measured on the uninvolved and lesional skin sites before and after 5 weeks of treatments using the melanin/erythema probe connected to a Courage-Khazaka MPA5 (Cologne, Germany). Changes in epidermal permeability barrier were also assessed at the same time point. To determine whether histamine-induced repigmentation is receptor-dependent, both ears of C57BL/6J mice were treated topically with 5% cimetidine, a histamine type 2 receptor (H2r) antagonist, twice daily for 10 days. One hour after each cimetidine application, the right ear was treated topically with 10% histamine, while vehicle alone was applied to the left ear. Changes in melanin index were measured 24 h after the last application of histamine and vehicle as described in the human study. In patients with vitiligo treated with vehicle alone for 5 weeks, the melanin index remained unchanged, while topical histamine treatment increased the melanin index by 38% (p 60% reduction in lesion surface area. Moreover, topical histamine accelerated permeability barrier recovery. No adverse events were observed following histamine applications. In mice, topical histamine significantly increased the melanin index, while topical co-applications of the H2r antagonist (cimetidine) prevented the expected

  12. Neuromuscular electrical stimulation efficacy in acute stroke feeding tube-dependent dysphagia during inpatient rehabilitation.

    Science.gov (United States)

    Kushner, David S; Peters, Kenneth; Eroglu, Stacy Thomashaw; Perless-Carroll, Melissa; Johnson-Greene, Douglas

    2013-06-01

    The aim of this study was to compare the efficacy of neuromuscular electrical stimulation (NMES) in addition to traditional dysphagia therapy (TDT) including progressive resistance training (PRT) with that of TDT/PRT alone during inpatient rehabilitation for treatment of feeding tube-dependent dysphagia in patients who have had an acute stroke. This study is an inpatient rehabilitation case-control study involving 92 patients who have had an acute stroke with initial Functional Oral Intake Scale (FOIS) scores of 3 or lower and profound to severe feeding tube-dependent dysphagia. Sixty-five patients, the NMES group, received NMES with TDT/PRT, and 27 patients, the case-control group, received only TDT/PRT. Treatment occurred in hourly sessions daily for a mean ± SD of 18 ± 3 days. χ(2) Analyses/t tests revealed no significant statistical differences between the groups for age (t = -0.85; P = 0.40), sex (χ(2) = 0.05; P = 0.94), and stroke location (χ(2) = 4.2; P = 0.24). A Mann-Whitney U test revealed a statistically significant difference between the groups for the initial FOIS score (z = -2.4; P = 0.015), with the NMES group having worse initial scores with a mean rank of 42.64 and the case-control TDT/PRT group having a mean rank of 55.8. The main outcome measure was the comparison of the FOIS scores after treatment. The mean ± SD FOIS score after NMES with TDT/PRT treatment was 5.1 ± 1.8 compared with 3.3 ± 2.2 in the case-control TDT/PRT group. The mean gain for the NMES group was 4.4 points; and for the case-control group, 2.4 points. Significant improvement in swallowing performance was found for the NMES group compared with the TDT/PRT group (z = 3.64; P rehabilitation in reducing feeding tube-dependent dysphagia in patients who have had an acute stroke.

  13. Sex differences in disinhibition and its relationship to physical abuse in a sample of stimulant-dependent patients.

    Science.gov (United States)

    Winhusen, Theresa; Lewis, Daniel

    2013-04-01

    Research suggests that impulsivity is a vulnerability factor for developing stimulant dependence, that women develop dependence more quickly than men, and that physical abuse can increase impulsivity and may have greater adverse health consequences in women. This study sought to tie these findings together by evaluating: (1) sex differences in disinhibition prior to lifetime initiation of stimulant abuse and (2) the relationship between physical abuse and disinhibition in stimulant-dependent patients. The Frontal Systems Behavior Scale (FrSBe) is a reliable and valid self-report assessment of three neurobehavioral domains associated with frontal systems functioning (Apathy, Disinhibition, and Executive Dysfunction, summed for a Total), that assesses pre-morbid functioning and has a specific cutoff for defining clinically significant abnormalities. Six sites evaluating 12-step facilitation for stimulant abusers obtained the FrSBe from 118 methamphetamine- and/or cocaine-dependent participants. Lifetime physical abuse was measured by the Addiction Severity Index (ASI). The proportion reporting clinically significant disinhibition was significantly higher in women (64.9%) than in men (45.0%, p=0.04), with no significant difference on the other FrSBe scales. Physical abuse in women, but not men, was associated with worse functioning, with physically abused, relative to non-abused, women having a significantly greater proportion with clinically significant disinhibition (pabuse and that physical abuse in women is associated with greater disinhibition. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Conglutinin exhibits a complement-dependent enhancement of the respiratory burst of phagocytes stimulated by E. coli

    DEFF Research Database (Denmark)

    Friis, P; Svehag, S E; Andersen, Ove

    1991-01-01

    . Conglutinin enhances, in a dose-dependent manner, the respiratory burst of spleen cells stimulated with serum-opsonized Escherichia coli. The enhancement was only demonstrable in the presence of a functional complement system. The conglutinin-mediated enhancement of the respiratory burst was inhibited...

  15. Stimulation of gluconeogenesis by intravenous lipids in preterm infants: response depends on fatty acid profile

    NARCIS (Netherlands)

    van Kempen, Anne A. M. W.; van der Crabben, Saskia N.; Ackermans, Mariëtte T.; Endert, Erik; Kok, Joke H.; Sauerwein, Hans P.

    2006-01-01

    In preterm infants, both hypo- and hyperglycemia are a frequent problem. Intravenous lipids can affect glucose metabolism by stimulation of gluconeogenesis by providing glycerol, which is a gluconeogenic precursor, and/or free fatty acids (FFA), which are stimulants of the rate of gluconeogenesis.

  16. [Effect of tanshinone IIA on the change of calcium current induced by beta-amyloid protein 25-35 in neurons of nucleus basalis of Meynert].

    Science.gov (United States)

    Zhu, Shujuan; Qian, Yihua; Shi, Lili; Yang, Weina; Feng, Xinzheng; Li, Cuiqin; Liu, Yong

    2010-08-01

    To explore the effect of tanshinone IIA (TanIIA) on calcium current induced by beta-amyloid protein 25-35 (Abeta25-35) in neurons of nucleus basalis of Meynert (nbM). Cell acute dissociated technique and the whole-cell recording model of patch-clamp technique of single-cell were used. The voltage-dependent calcium current in neurons of nbM was recorded in SD rats first. Then the effect of TanIIA on the voltage-dependent calcium current in the neurons was assayed. The change of calcium current induced by Abeta25-35 as well as the effect of TanIIA on the change of calcium current induced by Abeta25-35 in neurons of nbM were analyzed. Extracellular fluid containing different concentrations of TanIIA was irrigated, respectively. The peak current did not change obviously. There was no difference in current density between the TanIIA group and the control group at 0 mV (P>0.05). Extracellular fluid containing 200 nmol/L Abeta25-35 was irrigated after the normal calcium current recorded under whole patch clamp, and the peak current changed obviously. There was distinct difference in the current density between the Abeta group and the control group at 0 mV (Pcalcium current was recorded under whole patch clamp, respectively, and the peak current did not change. There was no difference in current density between the TanIIA +Abeta group and the control group at 0 mV (P>0.05). In vitro, TanIIA could inhibit the calcium current amplification induced by Abeta25-35 in neurons of nbM. TanIIA may protect neurons against the toxicity of Abeta and decrease the inward flow of Ca(2+).

  17. beta-amyloid((1-42))-induced cholinergic lesions in rat nucleus basalis bidirectionally modulate serotonergic innervation of the basal forebrain and cerebral cortex

    NARCIS (Netherlands)

    Harkany, T; O'Mahony, S; Kelly, JP; Konya, C; Borostyankoi, ZA; Gorcs, TJ; Zarandi, M; Penke, B; Leonard, BE; Luiten, PGM; Keijser, Jan N.

    Ample experimental evidence suggests that beta -amyloid (A beta), when injected into the rat magnocellular nucleus basalis (MBN), impels excitotoxic injury of cholinergic projection neurons. Whereas learning and memory dysfunction is a hallmark of A beta -induced cholinergic deficits, anxiety, or

  18. Neuroprotection Against NMDA Induced Cell Death in Rat Nucleus Basalis by Ca2+ Antagonist Nimodipine, Influence of Aging and Developmental Drug Treatment

    NARCIS (Netherlands)

    Luiten, P.G.M.; Douma, B.R.K.; Zee, E.A. van der; Nyakas, C.

    In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic

  19. Quality of life outcome after subthalamic stimulation in Parkinson's disease depends on age.

    Science.gov (United States)

    Dafsari, Haidar S; Reker, Paul; Stalinski, Lisa; Silverdale, Monty; Rizos, Alexandra; Ashkan, Keyoumars; Barbe, Michael T; Fink, Gereon R; Evans, Julian; Steffen, Julia; Samuel, Michael; Dembek, Till A; Visser-Vandewalle, Veerle; Antonini, Angelo; Ray-Chaudhuri, K; Martinez-Martin, Pablo; Timmermann, Lars

    2018-01-01

    The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age. In this prospective, open-label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow-up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (≤59, 60-69, ≥70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size. The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups ≤59, 60 to 69, and ≥70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged ≤59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged ≥70 years. Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. © 2017 International

  20. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    International Nuclear Information System (INIS)

    Akter, Jesmin; Takatori, Atsushi; Islam, Md. Sazzadul; Nakazawa, Atsuko; Ozaki, Toshinori; Nagase, Hiroki; Nakagawara, Akira

    2014-01-01

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas

  1. Intracellular fragment of NLRR3 (NLRR3-ICD) stimulates ATRA-dependent neuroblastoma differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Akter, Jesmin [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Takatori, Atsushi, E-mail: atakatori@chiba-cc.jp [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Islam, Md. Sazzadul [Laboratory of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakazawa, Atsuko [Department of Pathology, National Center for Child Health and Development, Tokyo (Japan); Ozaki, Toshinori, E-mail: tozaki@chiba-cc.jp [Laboratory of DNA Damage Signaling, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nagase, Hiroki [Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba 260-8717 (Japan); Nakagawara, Akira [Saga Medical Centre, 840-8571 (Japan)

    2014-10-10

    Highlights: • NLRR3 is a membrane protein highly expressed in favorable neuroblastoma. • NLRR3-ICD was produced through proteolytic processing by secretases. • NLRR3-ICD was induced to be translocated into cell nucleus following ATRA exposure. • NLRR3-ICD plays a pivotal role in ATRA-mediated neuroblastoma differentiation. - Abstract: We have previously identified neuronal leucine-rich repeat protein-3 (NLRR3) gene which is preferentially expressed in favorable human neuroblastomas as compared with unfavorable ones. In this study, we have found for the first time that NLRR3 is proteolytically processed by secretases and its intracellular domain (NLRR3-ICD) is then released to translocate into cell nucleus during ATRA-mediated neuroblastoma differentiation. According to our present observations, NLRR3-ICD was induced to accumulate in cell nucleus of neuroblastoma SH-SY5Y cells following ATRA treatment. Since the proteolytic cleavage of NLRR3 was blocked by α- or γ-secretase inhibitor, it is likely that NLRR3-ICD is produced through the secretase-mediated processing of NLRR3. Intriguingly, forced expression of NLRR3-ICD in neuroblastoma SK-N-BE cells significantly suppressed their proliferation as examined by a live-cell imaging system and colony formation assay. Similar results were also obtained in neuroblastoma TGW cells. Furthermore, overexpression of NLRR3-ICD stimulated ATRA-dependent neurite elongation in SK-N-BE cells. Together, our present results strongly suggest that NLRR3-ICD produced by the secretase-mediated proteolytic processing of NLRR3 plays a crucial role in ATRA-mediated neuronal differentiation, and provide a clue to develop a novel therapeutic strategy against aggressive neuroblastomas.

  2. Perceived Intensity and Discrimination Ability for Lingual Electrotactile Stimulation Depends on Location and Orientation of Electrodes

    Directory of Open Access Journals (Sweden)

    Leslie M. Stone-Roy

    2017-04-01

    Full Text Available Malfunctioning sensory systems can severely impact quality of life and repair is not always possible. One solution, called sensory substitution, is to use another sensory system to bring lost information to the brain. This approach often involves the use of bioengineered devices that electrically stimulate somatosensory fibers. Interestingly, the tongue is an ideal location for electrotactile stimulation due to its dense innervation, moisture, and protected environment. Success with transmitting visual and vestibular information through the tongue indicates promise for future applications. However, sensitivity and discrimination ability varies between individuals and across the tongue surface complicating efforts to produce reliable and consistent sensations. The goals of the present study were to investigate these differences more precisely to better understand the mechanosensory innervation of the tongue so that future electrotactile devices can be designed more effectively. Specifically, we tested whether stimulation of certain regions of the tongue consistently result in better perception, whether the spacing of stimulating electrodes affects perceived intensity, and whether the orientation of electrodes affects perceived intensity and discrimination. To test these hypotheses, we built a custom tongue stimulation device, recruited 25 participants, and collected perceived intensity and discrimination data. We then subjected the data to thorough statistical analyses. Consistent with previous studies, we found that stimulation of the anterior medial tongue region was perceived as more intense than stimulation of lateral and posterior regions. This region also had the best discrimination ability for electrodes. Dividing the stimulated tongue area into 16 distinct regions allowed us to compare perception ability between anterior and posterior regions, medial and lateral regions, and the left and right sides of the tongue. Stimulation of the most

  3. Subthalamic deep brain stimulation modulates small fiber-dependent sensory thresholds in Parkinson's disease.

    Science.gov (United States)

    Ciampi de Andrade, Daniel; Lefaucheur, Jean-Pascal; Galhardoni, Ricardo; Ferreira, Karine S L; Brandão Paiva, Anderson Rodrigues; Bor-Seng-Shu, Edson; Alvarenga, Luciana; Myczkowski, Martin L; Marcolin, Marco Antonio; de Siqueira, Silvia R D T; Fonoff, Erich; Barbosa, Egberto Reis; Teixeira, Manoel Jacobsen

    2012-05-01

    The effects of deep brain stimulation of the subthalamic nucleus on nonmotor symptoms of Parkinson's disease (PD) rarely have been investigated. Among these, sensory disturbances, including chronic pain (CP), are frequent in these patients. The aim of this study was to evaluate the changes induced by deep brain stimulation in the perception of sensory stimuli, either noxious or innocuous, mediated by small or large nerve fibers. Sensory detection and pain thresholds were assessed in 25 PD patients all in the off-medication condition with the stimulator turned on or off (on- and off-stimulation conditions, respectively). The relationship between the changes induced by surgery on quantitative sensory testing, spontaneous CP, and motor abilities were studied. Quantitative sensory test results obtained in PD patients were compared with those of age-matched healthy subjects. Chronic pain was present in 72% of patients before vs 36% after surgery (P=.019). Compared with healthy subjects, PD patients had an increased sensitivity to innocuous thermal stimuli and mechanical pain, but a reduced sensitivity to innocuous mechanical stimuli. In addition, they had an increased pain rating when painful thermal stimuli were applied, particularly in the off-stimulation condition. In the on-stimulation condition, there was an increased sensitivity to innocuous thermal stimuli but a reduced sensitivity to mechanical or thermal pain. Pain provoked by thermal stimuli was reduced when the stimulator was turned on. Motor improvement positively correlated with changes in warm detection and heat pain thresholds. Subthalamic nucleus deep brain stimulation contributes to relieve pain associated with PD and specifically modulates small fiber-mediated sensations. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Cortical axons, isolated in channels, display activity-dependent signal modulation as a result of targeted stimulation

    Directory of Open Access Journals (Sweden)

    Marta K. Lewandowska

    2016-03-01

    Full Text Available Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 Hz up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells’ signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for many different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations.

  5. Is effect of transcranial direct current stimulation on visuomotor coordination dependent on task difficulty?

    Directory of Open Access Journals (Sweden)

    Yong Hyun Kwon

    2015-01-01

    Full Text Available Transcranial direct current stimulation (tDCS, an emerging technique for non-invasive brain stimulation, is increasingly used to induce changes in cortical excitability and modulate motor behavior, especially for upper limbs. The purpose of this study was to investigate the effects of tDCS of the primary motor cortex on visuomotor coordination based on three levels of task difficulty in healthy subjects. Thirty-eight healthy participants underwent real tDCS or sham tDCS. Using a single-blind, sham-controlled crossover design, tDCS was applied to the primary motor cortex. For real tDCS conditions, tDCS intensity was 1 mA while stimulation was applied for 15 minutes. For the sham tDCS, electrodes were placed in the same position, but the stimulator was turned off after 5 seconds. Visuomotor tracking task, consisting of three levels (levels 1, 2, 3 of difficulty with higher level indicating greater difficulty, was performed before and after tDCS application. At level 2, real tDCS of the primary motor cortex improved the accurate index compared to the sham tDCS. However, at levels 1 and 3, the accurate index was not significantly increased after real tDCS compared to the sham tDCS. These findings suggest that tasks of moderate difficulty may improve visuomotor coordination in healthy subjects when tDCS is applied compared with easier or more difficult tasks.

  6. Diacylglycerol-stimulated endocytosis of transferrin in trypanosomatids is dependent on tyrosine kinase activity.

    Directory of Open Access Journals (Sweden)

    Sandesh Subramanya

    2010-01-01

    Full Text Available Small molecule regulation of cell function is an understudied area of trypanosomatid biology. In Trypanosoma brucei diacylglycerol (DAG stimulates endocytosis of transferrin (Tf. However, it is not known whether other trypanosomatidae respond similarly to the lipid. Further, the biochemical pathways involved in DAG signaling to the endocytic system in T. brucei are unknown, as the parasite genome does not encode canonical DAG receptors (e.g. C1-domains. We established that DAG stimulates endocytosis of Tf in Leishmania major, and we evaluated possible effector enzymes in the pathway with multiple approaches. First, a heterologously expressed glycosylphosphatidylinositol phospholipase C (GPI-PLC activated endocytosis of Tf 300% in L. major. Second, exogenous phorbol ester and DAGs promoted Tf endocytosis in L. major. In search of possible effectors of DAG signaling, we discovered a novel C1-like domain (i.e. C1_5 in trypanosomatids, and we identified protein Tyr kinases (PTKs linked with C1_5 domains in T. brucei, T. cruzi, and L. major. Consequently, we hypothesized that trypanosome PTKs might be effector enzymes for DAG signaling. General uptake of Tf was reduced by inhibitors of either Ser/Thr or Tyr kinases. However, DAG-stimulated endocytosis of Tf was blocked only by an inhibitor of PTKs, in both T. brucei and L. major. We conclude that (i DAG activates Tf endocytosis in L. major, and that (ii PTKs are effectors of DAG-stimulated endocytosis of Tf in trypanosomatids. DAG-stimulated endocytosis of Tf may be a T. brucei adaptation to compete effectively with host cells for vertebrate Tf in blood, since DAG does not enhance endocytosis of Tf in human cells.

  7. T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers.

    Directory of Open Access Journals (Sweden)

    Wai-Ping Fung-Leung

    Full Text Available Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers.

  8. A randomized trial of concurrent smoking-cessation and substance use disorder treatment in stimulant-dependent smokers.

    Science.gov (United States)

    Winhusen, Theresa M; Brigham, Gregory S; Kropp, Frankie; Lindblad, Robert; Gardin, John G; Penn, Pat; Hodgkins, Candace; Kelly, Thomas M; Douaihy, Antoine; McCann, Michael; Love, Lee D; DeGravelles, Eliot; Bachrach, Ken; Sonne, Susan C; Hiott, Bob; Haynes, Louise; Sharma, Gaurav; Lewis, Daniel F; VanVeldhuisen, Paul; Theobald, Jeff; Ghitza, Udi

    2014-04-01

    To evaluate the impact of concurrent treatments for substance use disorder and nicotine-dependence for stimulant-dependent patients. A randomized, 10-week trial with follow-up at 3 and 6 months after smoking quit date conducted at 12 substance use disorder treatment programs between February 2010 and July 2012. Adults meeting DSM-IV-TR criteria for cocaine and/or methamphetamine dependence and interested in quitting smoking were randomized to treatment as usual (n = 271) or treatment as usual with smoking-cessation treatment (n = 267). All participants received treatment as usual for substance use disorder treatment. Participants assigned to treatment as usual with concurrent smoking-cessation treatment received weekly individual smoking cessation counseling and extended-release bupropion (300 mg/d) during weeks 1-10. During post-quit treatment (weeks 4-10), participants assigned to treatment as usual with smoking-cessation treatment received a nicotine inhaler and contingency management for smoking abstinence. Weekly proportion of stimulant-abstinent participants during the treatment phase, as assessed by urine drug screens and self-report, was the primary outcome. Secondary measures included other substance/nicotine use outcomes and treatment attendance. There were no significant treatment effects on stimulant-use outcomes, as measured by the primary outcome and stimulant-free days, on drug-abstinence, or on attendance. Participants assigned to treatment as usual with smoking-cessation treatment, relative to those assigned to treatment as usual, had significantly better outcomes for drug-free days at 6-month follow-up (χ(2)(1) = 4.09, P P substance use disorder treatment will not worsen, and may enhance, abstinence from nonnicotine substance use. ClinicalTrials.gov identifier: NCT01077024. © Copyright 2013 Physicians Postgraduate Press, Inc.

  9. Temperature-dependent stimulated emission cross section and concentration quenching in highly doped Nd3+:YAG crystals

    International Nuclear Information System (INIS)

    Dong, Jun; Rapaport, A.; Bass, M.; Szipocs, F.; Ueda, Ken-ichi

    2005-01-01

    Measurements are reported of the spectroscopic properties (absorption and emission spectra, stimulated emission cross section, and radiative lifetime) of Nd:YAG crystals doped with 1, 2 and 3 at% Nd 3+ in the temperature range between 70 and 300 K. The stimulated emission cross sections for these crystals were determined using the Fuechtbauer-Ladenburg (F-L) formula at each different temperature. The absorption spectra at room temperature were used to calculate the 4 F 3/2 → 4 I 11/2 stimulated-emission cross section and the 4 F 3/2 radiative lifetime according to Judd-Ofelt theory. As the temperature decreases the emission cross section increases, while the emission lifetime remains constant for all the samples. The temperature dependences of the stimulated emission cross sections for the differently doped crystals are in good agreement with earlier predictions. The concentration quenching effect in highly doped Nd:YAG was also addressed. Although there is concentration quenching in the highly doped Nd:YAG crystals, they are still promising efficient laser materials for high-power microchip solid-state lasers. (copyright 2005 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

  10. Nutritional State-Dependent Ghrelin Activation of Vasopressin Neurons via Retrograde Trans-Neuronal–Glial Stimulation of Excitatory GABA Circuits

    Science.gov (United States)

    Haam, Juhee; Halmos, Katalin C.; Di, Shi

    2014-01-01

    Behavioral and physiological coupling between energy balance and fluid homeostasis is critical for survival. The orexigenic hormone ghrelin has been shown to stimulate the secretion of the osmoregulatory hormone vasopressin (VP), linking nutritional status to the control of blood osmolality, although the mechanism of this systemic crosstalk is unknown. Here, we show using electrophysiological recordings and calcium imaging in rat brain slices that ghrelin stimulates VP neurons in the hypothalamic paraventricular nucleus (PVN) in a nutritional state-dependent manner by activating an excitatory GABAergic synaptic input via a retrograde neuronal–glial circuit. In slices from fasted rats, ghrelin activation of a postsynaptic ghrelin receptor, the growth hormone secretagogue receptor type 1a (GHS-R1a), in VP neurons caused the dendritic release of VP, which stimulated astrocytes to release the gliotransmitter adenosine triphosphate (ATP). ATP activation of P2X receptors excited presynaptic GABA neurons to increase GABA release, which was excitatory to the VP neurons. This trans-neuronal–glial retrograde circuit activated by ghrelin provides an alternative means of stimulation of VP release and represents a novel mechanism of neuronal control by local neuronal–glial circuits. It also provides a potential cellular mechanism for the physiological integration of energy and fluid homeostasis. PMID:24790191

  11. Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon.

    Science.gov (United States)

    Tang, Lieqi; Peng, Minzhi; Liu, Li; Chang, Wenhan; Binder, Henry J; Cheng, Sam X

    2015-05-15

    Colonic bicarbonate (HCO3(-)) secretion is a well-established physiological process that is closely linked to overall fluid and electrolyte movement in the mammalian colon. These present studies show that extracellular calcium-sensing receptor (CaSR), a fundamental mechanism for sensing and regulating ionic and nutrient compositions of extracellular milieu in the small and large intestine, regulates HCO3(-) secretion. Basal and induced HCO3(-) secretory responses to CaSR agonists were determined by pH stat techniques used in conjunction with short-circuit current measurements in mucosa from rat distal colon mounted in Ussing chambers. R568, a specific CaSR activator, stimulated lumen Cl(-)- and short-chain fatty acid (SCFA)-dependent HCO3(-) secretion but inhibited cyclic nucleotide-activated HCO3(-) secretion. Consequently, at physiological conditions (either at basal or during lumen acid challenge) when electroneutral Cl(-)/HCO3(-) and SCFA/HCO3(-) exchangers dominate, CaSR stimulates HCO3(-) secretion; in contrast, in experimental conditions that stimulate fluid and HCO3(-) secretion, e.g., when forskolin activates electrogenic cystic fibrosis transmembrane conductance regulator-mediated HCO3(-) conductance, CaSR activation inhibits HCO3(-) secretion. Corresponding changes in JHCO3 (μeq·h(-1)·cm(-2), absence vs. presence of R568) were 0.18 ± 0.03 vs. 0.31 ± 0.08 under basal nonstimulated conditions and 1.85 ± 0.23 vs. 0.45 ± 0.06 under forskolin-stimulated conditions. Similarly, activation of CaSR by R568 stimulated Cl(-)- and SCFA-dependent HCO3(-) secretion and inhibited cAMP-dependent HCO3(-) secretion in colon mucosa of wild-type mice; such effects were abolished in CaSR-null mice. These results suggest a new paradigm for regulation of intestinal ion transport in which HCO3(-) secretion may be fine-tuned by CaSR in accordance with nutrient availability and state of digestion and absorption. The ability of CaSR agonists to inhibit secretagogue

  12. Personality Disorders, Narcotics, and Stimulants; Relationship in Iranian Male Substance Dependents Population

    OpenAIRE

    Noorbakhsh, Simasadat; Zeinodini, Zahra; Khanjani, Zeynab; Poorsharifi, Hamid; Rajezi Esfahani, Sepideh

    2015-01-01

    Background: Individuals with certain personality disorders, especially the antisocial and borderline personality disorders, are more prone to substance use disorders. Objectives: Regarding the importance of substance use disorders, this study aimed to explore the association between personality disorders and types of used drugs (narcotics and stimulants) in Iranian male substance users. Patients and Methods: The current study was a correlation study. We evaluated 285 male substance users and ...

  13. Subcellular Optogenetic Stimulation for Activity-Dependent Myelination of Axons in a Novel Microfluidic Compartmentalized Platform.

    Science.gov (United States)

    Lee, Hae Ung; Nag, Sudip; Blasiak, Agata; Jin, Yan; Thakor, Nitish; Yang, In Hong

    2016-10-19

    Myelination is governed by neuron-glia communication, which in turn is modulated by neural activity. The exact mechanisms remain elusive. We developed a novel in vitro optogenetic stimulation platform that facilitates subcellular activity induction in hundreds of neurons simultaneously. The light isolation was achieved by creating a biocompatible, light-absorbent, black microfluidic device integrated with a programmable, high-power LED array. The system was applied to a compartmentalized culture of primary neurons whose distal axons were interacting with oligodendrocyte precursor cells. Neural activity was induced along whole neurons or was constrained to cell bodies with proximal axons or distal axons only. All three modes of stimulation promoted oligodendrocyte differentiation and the myelination of axons as evidenced by a decrease in the number of oligodendrocyte precursor cells followed by increases in the number of mature oligodendrocytes and myelin sheath fragments. These results demonstrated the potential of our novel optogenetic stimulation system for the global and focal induction of neural activity in vitro for studying axon myelination.

  14. Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes

    DEFF Research Database (Denmark)

    Petersen, Rasmus Koefoed; Madsen, Lise; Pedersen, Lone Møller

    2008-01-01

    AMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho......-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of c......AMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response....

  15. Sperm production and mating potential of males after a cold shock on pupae of the parasitoid wasp Dinarmus basalis (Hymenoptera: Pteromalidae).

    Science.gov (United States)

    Lacoume, Sandrine; Bressac, Christophe; Chevrier, Claude

    2007-10-01

    For ectothermic species, temperature is a key environmental factor influencing several aspects of their physiology and ecology, acting particularly on reproduction. To measure the consequences of a severe thermal stress during development on male reproduction, a cold shock (1h at -18 degrees C) was tested on Dinarmus basalis pupae. D. basalis (Hymenoptera: Pteromalidae) is a parasitoid wasp in which sperm management in both male and female is of prime importance. After a cold shock, developmental success was reduced, with a quarter of cold-shocked males not emerging correctly. The stress effects were estimated at the level of sperm stock in seminal vesicles of males at different ages and on the ability of 2-day-old males to access females in single and multiple mating and in male-male competition. Cold-shocked males had a reduced sperm stock compared to control males and this difference persisted with age. The rate of sperm production was similar in both groups. The consequences of a cold shock on male reproductive ability were perceptible in multiple mating and male-male competition but not in single mating. Cold-shocked males were at a disadvantage, inseminating fewer females and copulating less frequently. Finally, male pupae of D. basalis were able to withstand severe temperature stresses and their reproductive functions were partially preserved.

  16. Conglutinin exhibits a complement-dependent enhancement of the respiratory burst of phagocytes stimulated by E. coli

    DEFF Research Database (Denmark)

    Friis, P; Svehag, S E; Andersen, Ove

    1991-01-01

    . Conglutinin enhances, in a dose-dependent manner, the respiratory burst of spleen cells stimulated with serum-opsonized Escherichia coli. The enhancement was only demonstrable in the presence of a functional complement system. The conglutinin-mediated enhancement of the respiratory burst was inhibited......Conglutinin is a mammalian C-type lectin which shows anti-bacterial activity when tested in vivo and in vitro. This study concerns the effect of conglutinin on the respiratory burst of murine spleen cells, using a chemiluminescence assay for measurement of generated reactive oxygen metabolites...

  17. The beta-cell response to glucagon and mixed meal stimulation in non-insulin dependent diabetes

    DEFF Research Database (Denmark)

    Gjessing, H J; Damsgaard, E M; Matzen, L E

    1988-01-01

    The aim of this study was to evaluate the correlations of the C-peptide and insulin responses after stimulation with glucagon intravenously as well as the 24-h urinary excretion of C-peptide to the C-peptide response to a standard mixed meal in 30 patients with non-insulin dependent diabetes...... mellitus (NIDDM). Fasting plasma C-peptide as well as the C-peptide and insulin responses to glucagon, showed similar but only modest correlations with the C-peptide response to the meal. Urinary C-peptide showed no correlation with the C-peptide response to the meal, but correlated modestly with fasting...... plasma C-peptide (r = 0.55, p less than 0.01). The C-peptide and insulin responses after meal stimulation correlated modestly inversely with HbA1. In conclusion, measurement of C-peptide in fasting state, as well as measurements of C-peptide and insulin after glucagon stimulation, only modestly predict...

  18. Does Childhood Use of Stimulant Medication as a Treatment for ADHD Affect the Likelihood of Future Drug Abuse and Dependence? A Literature Review

    Science.gov (United States)

    Golden, Shawn M.

    2009-01-01

    This article describes the disparate research findings regarding the effects of stimulant medication in subsequent substance abuse and dependence. A minimum of 4 to 5% of children in the United States will be diagnosed with ADHD; thus it is important for parents to be informed when making decisions about the use of stimulant medication to treat…

  19. CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

    Science.gov (United States)

    Zheng, Hongzhi; Fu, Jingqi; Xue, Peng; Zhao, Rui; Dong, Jian; Liu, Dianxin; Yamamoto, Masayuki; Tong, Qingchun; Teng, Weiping; Qu, Weidong; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo

    2015-04-01

    The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.

  20. Fornix deep brain stimulation circuit effect is dependent on major excitatory transmission via the nucleus accumbens.

    Science.gov (United States)

    Ross, Erika K; Kim, Joo Pyung; Settell, Megan L; Han, Seong Rok; Blaha, Charles D; Min, Hoon-Ki; Lee, Kendall H

    2016-03-01

    Deep brain stimulation (DBS) is a circuit-based treatment shown to relieve symptoms from multiple neurologic and neuropsychiatric disorders. In order to treat the memory deficit associated with Alzheimer's disease (AD), several clinical trials have tested the efficacy of DBS near the fornix. Early results from these studies indicated that patients who received fornix DBS experienced an improvement in memory and quality of life, yet the mechanisms behind this effect remain controversial. It is known that transmission between the medial limbic and corticolimbic circuits plays an integral role in declarative memory, and dysfunction at the circuit level results in various forms of dementia, including AD. Here, we aimed to determine the potential underlying mechanism of fornix DBS by examining the functional circuitry and brain structures engaged by fornix DBS. A multimodal approach was employed to examine global and local temporal changes that occur in an anesthetized swine model of fornix DBS. Changes in global functional activity were measured by functional MRI (fMRI), and local neurochemical changes were monitored by fast scan cyclic voltammetry (FSCV) during electrical stimulation of the fornix. Additionally, intracranial microinfusions into the nucleus accumbens (NAc) were performed to investigate the global activity changes that occur with dopamine and glutamate receptor-specific antagonism. Hemodynamic responses in both medial limbic and corticolimbic circuits measured by fMRI were induced by fornix DBS. Additionally, fornix DBS resulted in increases in dopamine oxidation current (corresponding to dopamine efflux) monitored by FSCV in the NAc. Finally, fornix DBS-evoked hemodynamic responses in the amygdala and hippocampus decreased following dopamine and glutamate receptor antagonism in the NAc. The present findings suggest that fornix DBS modulates dopamine release on presynaptic dopaminergic terminals in the NAc, involving excitatory glutamatergic input, and

  1. Blood oxygenation level dependent signal and neuronal adaptation to optogenetic and sensory stimulation in somatosensory cortex in awake animals.

    Science.gov (United States)

    Aksenov, Daniil P; Li, Limin; Miller, Michael J; Wyrwicz, Alice M

    2016-11-01

    The adaptation of neuronal responses to stimulation, in which a peak transient response is followed by a sustained plateau, has been well-studied. The blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal has also been shown to exhibit adaptation on a longer time scale. However, some regions such as the visual and auditory cortices exhibit significant BOLD adaptation, whereas other such as the whisker barrel cortex may not adapt. In the sensory cortex a combination of thalamic inputs and intracortical activity drives hemodynamic changes, although the relative contributions of these components are not entirely understood. The aim of this study is to assess the role of thalamic inputs vs. intracortical processing in shaping BOLD adaptation during stimulation in the somatosensory cortex. Using simultaneous fMRI and electrophysiology in awake rabbits, we measured BOLD, local field potentials (LFPs), single- and multi-unit activity in the cortex during whisker and optogenetic stimulation. This design allowed us to compare BOLD and haemodynamic responses during activation of the normal thalamocortical sensory pathway (i.e., both inputs and intracortical activity) vs. the direct optical activation of intracortical circuitry alone. Our findings show that whereas LFP and multi-unit (MUA) responses adapted, neither optogenetic nor sensory stimulation produced significant BOLD adaptation. We observed for both paradigms a variety of excitatory and inhibitory single unit responses. We conclude that sensory feed-forward thalamic inputs are not primarily responsible for shaping BOLD adaptation to stimuli; but the single-unit results point to a role in this behaviour for specific excitatory and inhibitory neuronal sub-populations, which may not correlate with aggregate neuronal activity. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  2. ROCK inhibition stimulates SOX9/Smad3-dependent COL2A1 expression in inner meniscus cells.

    Science.gov (United States)

    Furumatsu, Takayuki; Maehara, Ami; Ozaki, Toshifumi

    2016-07-01

    Proper functioning of the meniscus depends on the composition and organization of its fibrocartilaginous extracellular matrix. We previously demonstrated that the avascular inner meniscus has a more chondrocytic phenotype compared with the outer meniscus. Inhibition of the Rho family GTPase ROCK, the major regulator of the actin cytoskeleton, stimulates the chondrogenic transcription factor Sry-type HMG box (SOX) 9-dependent α1(II) collagen (COL2A1) expression in inner meniscus cells. However, the crosstalk between ROCK inhibition, SOX9, and other transcription modulators on COL2A1 upregulation remains unclear in meniscus cells. The aim of this study was to investigate the role of SOX9-related transcriptional complex on COL2A1 expression under the inhibition of ROCK in human meniscus cells. Human inner and outer meniscus cells were prepared from macroscopically intact lateral menisci. Cells were cultured in the presence or absence of ROCK inhibitor (ROCKi, Y27632). Gene expression, collagen synthesis, and nuclear translocation of SOX9 and Smad2/3 were analyzed. Treatment of ROCKi increased the ratio of type I/II collagen double positive cells derived from the inner meniscus. In real-time PCR analyses, expression of SOX9 and COL2A1 genes was stimulated by ROCKi treatment in inner meniscus cells. ROCKi treatment also induced nuclear translocation of SOX9 and phosphorylated Smad2/3 in immunohistological analyses. Complex formation between SOX9 and Smad3 was increased by ROCKi treatment in inner meniscus cells. Chromatin immunoprecipitation analyses revealed that association between SOX9/Smad3 transcriptional complex with the COL2A1 enhancer region was increased by ROCKi treatment. This study demonstrated that ROCK inhibition stimulated SOX9/Smad3-dependent COL2A1 expression through the immediate nuclear translocation of Smad3 in inner meniscus cells. Our results suggest that ROCK inhibition can stimulates type II collagen synthesis through the cooperative activation

  3. 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase-Dependent Stimulation of Renal Klotho Expression by Spironolactone

    Directory of Open Access Journals (Sweden)

    Ioana Alesutan

    2013-11-01

    Full Text Available Background: Klotho, a transmembrane protein, protease and hormone mainly expressed in kidney, is required for the suppression of 1,25(OH2D3-generating 25-hydroxyvitamin D3 1-alpha-hydroxylase (Cyp27b1 by FGF23. Conversely, 1,25(OH2D3 stimulates, by activating the vitamin D3 receptor (Vdr, the expression of klotho, thus establishing a negative feedback loop. Klotho protects against renal and vascular injury. Klotho deficiency accelerates aging and early death, effects at least partially due to excessive formation of 1,25(OH2D3 and subsequent hyperphosphatemia. Klotho expression is inhibited by aldosterone. The present study explored the interaction of aldosterone and DOCA as well as the moderately selective mineralocorticoid receptor antagonist spironolactone on klotho expression. Methods: mRNA levels were determined utilizing quantitative RT-PCR in human embryonic kidney cells (HEK293 or in renal tissues from mice without or with prior mineralocorticoid (aldosterone or DOCA and/or spironolactone treatment. In HEK293 cells, protein levels were determined by western blotting. The experiments in HEK293 cells were performed without or with silencing of CYP27B1, of vitamin D3 receptor (VDR or of mineralocorticoid receptor (NR3C2. Results: In HEK293 cells aldosterone and in mice DOCA significantly decreased KLOTHO gene expression, effects opposed by spironolactone treatment. Spironolactone treatment alone significantly increased KLOTHO and CYP27B1 transcript levels in HEK293 cells (24 hours and mice (8 hours or 5 days. Moreover, spironolactone significantly increased klotho and CYP27B1 protein levels in HEK293 cells (48 hours. Reduced NR3C2 expression following silencing did not significantly affect KLOTHO and CYP27B1 transcript levels in presence or absence of spironolactone. Silencing of CYP27B1 and VDR significantly blunted the stimulating effect of spironolactone on KLOTHO mRNA levels in HEK293 cells. Conclusion: Besides blocking the effects of

  4. Chronic cadmium exposure stimulates SDF-1 expression in an ERα dependent manner.

    Directory of Open Access Journals (Sweden)

    Esmeralda Ponce

    Full Text Available Cadmium is an omnipotent environmental contaminant associated with the development of breast cancer. Studies suggest that cadmium functions as an endocrine disruptor, mimicking the actions of estrogen in breast cancer cells and activating the receptor to promote cell growth. Although acute cadmium exposure is known to promote estrogen receptor-mediated gene expression associated with growth, the consequence of chronic cadmium exposure is unclear. Since heavy metals are known to bioaccumulate, it is necessary to understand the effects of prolonged cadmium exposure. This study aims to investigate the effects of chronic cadmium exposure on breast cancer progression. A MCF7 breast cancer cell line chronically exposed to 10(-7 M CdCl2 serves as our model system. Data suggest that prolonged cadmium exposures result in the development of more aggressive cancer phenotypes - increased cell growth, migration and invasion. The results from this study show for the first time that chronic cadmium exposure stimulates the expression of SDF-1 by altering the molecular interactions between ERα, c-jun and c-fos. This study provides a mechanistic link between chronic cadmium exposure and ERα and demonstrates that prolonged, low-level cadmium exposure contributes to breast cancer progression.

  5. Substrate dependence of electron-stimulated O - yields from dissociative electron attachment to physisorbed O2

    Science.gov (United States)

    Huels, M. A.; Parenteau, L.; Sanche, L.

    1994-03-01

    We present measurements of O- electron stimulated desorption yields obtained under identical experimental conditions from 0.15 monolayers (ML) of O2 deposited onto disordered substrates consisting of 4 ML of either Kr, Xe, C2H6, C2H4, N2O, CH3Cl, or H2O, all condensed on Pt (polycrystalline). The resulting O- yield functions, for incident electron energies below 20 eV, are compared to that obtained from the O2/Kr solid; this allows us to assess the order of magnitude effects of the local substrate environment on dissociative electron attachment (DEA) via the 2Πu and gas phase forbidden 2Σ+g,u resonances of O-2. We note that, in addition to electron energy losses in the substrate prior to DEA to O2 and post-dissociation interactions of the O- with the substrate molecules, charge or energy transfer from the O-2 transient anion to a substrate molecule, and capture of the incident electron into a dissociative anion resonance of the substrate molecule may contribute to a reduced O- yield from the physisorbed O2. In the case of O2 deposited on amorphous ice, we find that the O- signal from DEA to O2 is completely absent for electron energies below 14 eV; we attribute this to a complete quenching of the dissociative O-2(2Πu, 2Σ+) resonances by the adjacent water molecules.

  6. 5-Lipoxygenase-Dependent Recruitment of Neutrophils and Macrophages by Eotaxin-Stimulated Murine Eosinophils

    Directory of Open Access Journals (Sweden)

    Ricardo Alves Luz

    2014-01-01

    Full Text Available The roles of eosinophils in antimicrobial defense remain incompletely understood. In ovalbumin-sensitized mice, eosinophils are selectively recruited to the peritoneal cavity by antigen, eotaxin, or leukotriene(LTB4, a 5-lipoxygenase (5-LO metabolite. 5-LO blockade prevents responses to both antigen and eotaxin. We examined responses to eotaxin in the absence of sensitization and their dependence on 5-LO. BALB/c or PAS mice and their mutants (5-LO-deficient ALOX; eosinophil-deficient GATA-1 were injected i.p. with eotaxin, eosinophils, or both, and leukocyte accumulation was quantified up to 24 h. Significant recruitment of eosinophils by eotaxin in BALB/c, up to 24 h, was accompanied by much larger numbers of recruited neutrophils and monocytes/macrophages. These effects were abolished by eotaxin neutralization and 5-LO-activating protein inhibitor MK886. In ALOX (but not PAS mice, eotaxin recruitment was abolished for eosinophils and halved for neutrophils. In GATA-1 mutants, eotaxin recruited neither neutrophils nor macrophages. Transfer of eosinophils cultured from bone-marrow of BALB/c donors, or from ALOX donors, into GATA-1 mutant recipients, i.p., restored eotaxin recruitment of neutrophils and showed that the critical step dependent on 5-LO is the initial recruitment of eosinophils by eotaxin, not the secondary neutrophil accumulation. Eosinophil-dependent recruitment of neutrophils in naive BALB/c mice was associated with increased binding of bacteria.

  7. Histaminergic modulation of cholinergic release from the nucleus basalis magnocellularis into insular cortex during taste aversive memory formation.

    Directory of Open Access Journals (Sweden)

    Liliana Purón-Sierra

    Full Text Available The ability of acetylcholine (ACh to alter specific functional properties of the cortex endows the cholinergic system with an important modulatory role in memory formation. For example, an increase in ACh release occurs during novel stimulus processing, indicating that ACh activity is critical during early stages of memory processing. During novel taste presentation, there is an increase in ACh release in the insular cortex (IC, a major structure for taste memory recognition. There is extensive evidence implicating the cholinergic efferents of the nucleus basalis magnocellularis (NBM in cortical activity changes during learning processes, and new evidence suggests that the histaminergic system may interact with the cholinergic system in important ways. However, there is little information as to whether changes in cholinergic activity in the IC are modulated during taste memory formation. Therefore, in the present study, we evaluated the influence of two histamine receptor subtypes, H1 in the NBM and H3 in the IC, on ACh release in the IC during conditioned taste aversion (CTA. Injection of the H3 receptor agonist R-α-methylhistamine (RAMH into the IC or of the H1 receptor antagonist pyrilamine into the NBM during CTA training impaired subsequent CTA memory, and simultaneously resulted in a reduction of ACh release in the IC. This study demonstrated that basal and cortical cholinergic pathways are finely tuned by histaminergic activity during CTA, since dual actions of histamine receptor subtypes on ACh modulation release each have a significant impact during taste memory formation.

  8. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation.

    Science.gov (United States)

    Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M; Bonds, Jacqueline A; Horikawa, Yousuke T; Saldana, Michelle; Dalton, Nancy D; Head, Brian P; Patel, Piyush M; Roth, David M; Patel, Hemal H

    2010-11-01

    Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH(2)-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to

  9. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on δ-opioid receptor stimulation

    Science.gov (United States)

    Panneerselvam, Mathivadhani; Tsutsumi, Yasuo M.; Bonds, Jacqueline A.; Horikawa, Yousuke T.; Saldana, Michelle; Dalton, Nancy D.; Head, Brian P.; Patel, Piyush M.; Roth, David M.

    2010-01-01

    Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (δ-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, κ-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IκBα, while simultaneously decreasing the expression of c-Jun NH2-terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the δ-opioid receptor to

  10. Rhinovirus attenuates non-typeable Hemophilus influenzae-stimulated IL-8 responses via TLR2-dependent degradation of IRAK-1.

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    Benjamin L Unger

    Full Text Available Bacterial infections following rhinovirus (RV, a common cold virus, are well documented, but pathogenic mechanisms are poorly understood. We developed animal and cell culture models to examine the effects of RV on subsequent infection with non-typeable Hemophilus influenzae (NTHi. We focused on NTHI-induced neutrophil chemoattractants expression that is essential for bacterial clearance. Mice infected with RV1B were superinfected with NTHi and lung bacterial density, chemokines and neutrophil counts determined. Human bronchial epithelial cells (BEAS-2B or mouse alveolar macrophages (MH-S were infected with RV and challenged with NHTi, TLR2 or TLR5 agonists. Chemokine levels were measured by ELISA and expression of IRAK-1, a component of MyD88-dependent TLR signaling, assessed by immunoblotting. While sham-infected mice cleared all NTHi from the lungs, RV-infected mice showed bacteria up to 72 h post-infection. However, animals in RV/NTHi cleared bacteria by day 7. Delayed bacterial clearance in RV/NTHi animals was associated with suppressed chemokine levels and neutrophil recruitment. RV-infected BEAS-2B and MH-S cells showed attenuated chemokine production after challenge with either NTHi or TLR agonists. Attenuated chemokine responses were associated with IRAK-1 protein degradation. Inhibition of RV-induced IRAK-1 degradation restored NTHi-stimulated IL-8 expression. Knockdown of TLR2, but not other MyD88-dependent TLRs, also restored IRAK-1, suggesting that TLR2 is required for RV-induced IRAK-1 degradation.In conclusion, we demonstrate for the first time that RV infection delays bacterial clearance in vivo and suppresses NTHi-stimulated chemokine responses via degradation of IRAK-1. Based on these observations, we speculate that modulation of TLR-dependent innate immune responses by RV may predispose the host to secondary bacterial infection, particularly in patients with underlying chronic respiratory disorders.

  11. Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase–Dependent Pathway That Is Impaired With Obesity

    Science.gov (United States)

    Steinberg, Gregory R.; Watt, Matthew J.; Ernst, Matthias; Birnbaum, Morris J.; Kemp, Bruce E.; Jørgensen, Sebastian Beck

    2009-01-01

    OBJECTIVE Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gp130-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. RESEARCH DESIGN AND METHODS Mice were injected intraperitoneally with saline or CNTF, and blood glucose was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKα2 kinase-dead, gp130ΔSTAT, and lean and obese ob/ob and high-fat–fed mice. The effect of C2-ceramide on glucose uptake and gp130 signaling was also examined. RESULTS CNTF reduced blood glucose and increased glucose uptake in isolated muscles in a time- and dose-dependent manner with maximal effects after 30 min with 100 ng/ml. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (KD) and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt phosphorylation were substantially reduced in obesity (high-fat diet and ob/ob) despite normal induction of gp130/AMPK signaling—effects also observed when treating myotubes with C2-ceramide. CONCLUSIONS CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway that does not require AMPK. CNTF-stimulated glucose uptake is impaired in obesity-induced insulin resistance and by ceramide. PMID:19136654

  12. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway.

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    Asiri R Wijenayaka

    Full Text Available Sclerostin is a product of mature osteocytes embedded in mineralised bone and is a negative regulator of bone mass and osteoblast differentiation. While evidence suggests that sclerostin has an anti-anabolic role, the possibility also exists that sclerostin has catabolic activity. To test this we treated human primary pre-osteocyte cultures, cells we have found are exquisitely sensitive to sclerostin, or mouse osteocyte-like MLO-Y4 cells, with recombinant human sclerostin (rhSCL and measured effects on pro-catabolic gene expression. Sclerostin dose-dependently up-regulated the expression of receptor activator of nuclear factor kappa B (RANKL mRNA and down-regulated that of osteoprotegerin (OPG mRNA, causing an increase in the RANK:OPG mRNA ratio. To examine the effects of rhSCL on resulting osteoclastic activity, MLO-Y4 cells plated onto a bone-like substrate were primed with rhSCL for 3 days and then either mouse splenocytes or human peripheral blood mononuclear cells (PBMC were added. This resulted in cultures with elevated osteoclastic resorption (approximately 7-fold compared to untreated co-cultures. The increased resorption was abolished by co-addition of recombinant OPG. In co-cultures of MLO-Y4 cells with PBMC, SCL also increased the number and size of the TRAP-positive multinucleated cells formed. Importantly, rhSCL had no effect on TRAP-positive cell formation from monocultures of either splenocytes or PBMC. Further, rhSCL did not induce apoptosis of MLO-Y4 cells, as determined by caspase activity assays, demonstrating that the osteoclastic response was not driven by dying osteocytes. Together, these results suggest that sclerostin may have a catabolic action through promotion of osteoclast formation and activity by osteocytes, in a RANKL-dependent manner.

  13. Ultraviolet-B component of sunlight stimulates photosynthesis and flavonoid accumulation in variegated Plectranthus coleoides leaves depending on background light.

    Science.gov (United States)

    Vidović, Marija; Morina, Filis; Milić, Sonja; Zechmann, Bernd; Albert, Andreas; Winkler, Jana Barbro; Veljović Jovanović, Sonja

    2015-05-01

    We used variegated Plectranthus coleoides as a model plant with the aim of clarifying whether the effects of realistic ultraviolet-B (UV-B) doses on phenolic metabolism in leaves are mediated by photosynthesis. Plants were exposed to UV-B radiation (0.90 W m(-2) ) combined with two photosynthetically active radiation (PAR) intensities [395 and 1350 μmol m(-2)  s(-1) , low light (LL) and high light (HL)] for 9 d in sun simulators. Our study indicates that UV-B component of sunlight stimulates CO2 assimilation and stomatal conductance, depending on background light. UV-B-specific induction of apigenin and cyanidin glycosides was observed in both green and white tissues. However, all the other phenolic subclasses were up to four times more abundant in green leaf tissue. Caffeic and rosmarinic acids, catechin and epicatechin, which are endogenous peroxidase substrates, were depleted at HL in green tissue. This was correlated with increased peroxidase and ascorbate peroxidase activities and increased ascorbate content. The UV-B supplement to HL attenuated antioxidative metabolism and partly recovered the phenolic pool indicating stimulation of the phenylpropanoid pathway. In summary, we propose that ortho-dihydroxy phenolics are involved in antioxidative defence in chlorophyllous tissue upon light excess, while apigenin and cyanidin in white tissue have preferentially UV-screening function. © 2014 John Wiley & Sons Ltd.

  14. Stimulation of hair follicle stem cell proliferation through an IL-1 dependent activation of γδT-cells

    Science.gov (United States)

    Dutta, Abhik; Pincha, Neha; Rana, Isha; Ghosh, Subhasri; Witherden, Deborah; Kandyba, Eve; MacLeod, Amanda; Kobielak, Krzysztof; Havran, Wendy L

    2017-01-01

    The cutaneous wound-healing program is a product of a complex interplay among diverse cell types within the skin. One fundamental process that is mediated by these reciprocal interactions is the mobilization of local stem cell pools to promote tissue regeneration and repair. Using the ablation of epidermal caspase-8 as a model of wound healing in Mus musculus, we analyzed the signaling components responsible for epithelial stem cell proliferation. We found that IL-1α and IL-7 secreted from keratinocytes work in tandem to expand the activated population of resident epidermal γδT-cells. A downstream effect of activated γδT-cells is the preferential proliferation of hair follicle stem cells. By contrast, IL-1α-dependent stimulation of dermal fibroblasts optimally stimulates epidermal stem cell proliferation. These findings provide new mechanistic insights into the regulation and function of epidermal cell–immune cell interactions and into how components that are classically associated with inflammation can differentially influence distinct stem cell niches within a tissue. PMID:29199946

  15. In vitro temperature dependent activation of T-lymphocytes in Common wall lizards (Podarcis muralis in response to PHA stimulation

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    Roberto Sacchi

    2014-12-01

    Full Text Available Ecological immunology attempts to explain the variability of immune response among individuals by invoking costs and trade-offs, which may optimize the immune defence against pathogens. In ectotherms body temperature is correlated to that of the surrounding environment, so that their entire physiology, including immune functions, is influenced by the environmental temperature. We used in vitro phytohaemoagglutinin (PHA stimulation in order to assess the effects of temperature on cell mediated adaptive response in male and female Common wall lizards (Podarcis muralis. Cell cultures were prepared from blood samples, inoculated with PHA and incubated at 22°C, 25°C, 32°C, and 38°C for three days. PHA stimulation caused proliferation of T-lymphocytes, but the effect depended on the incubation temperature. Lymphocyte proliferation was significantly impaired at both 22°C and 38°C compared to 32°C, which represented the highest levels of activation. Furthermore, lymphocyte activation was more variable in males while females were less immune suppressed than males at low temperatures. Differences between sexes suggest a possible influence of steroid hormones.

  16. Neurophysiological mechanisms of formation of non-chemical dependence through self-stimulation of positive emotiogenic areas of rats’ brains

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    O. G. Berchenko

    2016-05-01

    Full Text Available The aim of our research was to study the limbic-neocortical mechanisms of addictive behaviour in rats formed throughthe arousal of intense emotions on the model of self-stimulation reaction of the brain. We carried out investigations by conducting a chronic experiment on 15 nonlinear laboratory male rats weighing 250 to 320 grams, at the ages of 5 to 6 months. As a model of receiving positive emotions we used the behaviour of animals held in a Skinner box which was formed through self stimulation of the positive emotional zones of the posterior ventrolateral hypothalamus. We registered the frequency of self-stimulation reactions of the ventrolateral hypothalamus daily for 4 days and on the 7th day after its ccessation (state of deprivation. We performed visual and spectral analysis of the electrical activity of the brain using "Neuron-spektr.net" software. We assessed the absolute spectral density of the power of rhythm signals of the following frequency bands: delta (0.5–4.0 Hz, theta (4.0–7.0 Hz, alpha (8.0–12.0 Hz and low frequency beta (14.0–20.0 Hz. The formation of behaviour dependent on receiving intense emotions as a result of self-stimulation of the positive zones of the ventrolateral hypothalamus is caused by the initial high level of need for positive emotional reinforcement and further growth in the implementation of desire and is associated with activation of emotional memory mechanisms, changes in electrogenesis in the hippocampus and the reticular formation in the form of decrease in the spectral power of rhythms of alpha and beta bands and increased spectral power of biopotentials of the delta range in the hippocampus and theta range in the reticular formation with severe manifestations of seizure and paroxysmal activity components and increased activity of the sympatho-adrenal system. The syndrome of withdrawal fromthe receiving of positive emotions in some rats with implementation of a programme of a phobic character

  17. Thermal dependence of time-resolved blue light stimulated luminescence in α-Al2O3:C

    DEFF Research Database (Denmark)

    Pagonis, Vasilis; Ankjærgaard, Christina; Jain, Mayank

    2013-01-01

    -dependent phosphorescence signal, the delayed-OSL described previously for this material. The temperature dependent luminescence lifetimes obtained from analysis of the optical stimulation period are identical to those obtained from the corresponding relaxation period. However, the values of these luminescence lifetimes...

  18. IL-1β stimulates COX-2 dependent PGE₂ synthesis and CGRP release in rat trigeminal ganglia cells.

    Science.gov (United States)

    Neeb, Lars; Hellen, Peter; Boehnke, Carsten; Hoffmann, Jan; Schuh-Hofer, Sigrid; Dirnagl, Ulrich; Reuter, Uwe

    2011-03-04

    Pro-inflammatory cytokines like Interleukin-1 beta (IL-1β) have been implicated in the pathophysiology of migraine and inflammatory pain. The trigeminal ganglion and calcitonin gene-related peptide (CGRP) are crucial components in the pathophysiology of primary headaches. 5-HT1B/D receptor agonists, which reduce CGRP release, and cyclooxygenase (COX) inhibitors can abort trigeminally mediated pain. However, the cellular source of COX and the interplay between COX and CGRP within the trigeminal ganglion have not been clearly identified. 1. We used primary cultured rat trigeminal ganglia cells to assess whether IL-1β can induce the expression of COX-2 and which cells express COX-2. Stimulation with IL-1β caused a dose and time dependent induction of COX-2 but not COX-1 mRNA. Immunohistochemistry revealed expression of COX-2 protein in neuronal and glial cells. 2. Functional significance was demonstrated by prostaglandin E2 (PGE(2)) release 4 hours after stimulation with IL-1β, which could be aborted by a selective COX-2 (parecoxib) and a non-selective COX-inhibitor (indomethacin). 3. Induction of CGRP release, indicating functional neuronal activation, was seen 1 hour after PGE(2) and 24 hours after IL-1β stimulation. Immunohistochemistry showed trigeminal neurons as the source of CGRP. IL-1β induced CGRP release was blocked by parecoxib and indomethacin, but the 5-HT1B/D receptor agonist sumatriptan had no effect. We identified a COX-2 dependent pathway of cytokine induced CGRP release in trigeminal ganglia neurons that is not affected by 5-HT1B/D receptor activation. Activation of neuronal and glial cells in the trigeminal ganglion by IL-β leads to an elevated expression of COX-2 in these cells. Newly synthesized PGE(2) (by COX-2) in turn activates trigeminal neurons to release CGRP. These findings support a glia-neuron interaction in the trigeminal ganglion and demonstrate a sequential link between COX-2 and CGRP. The results could help to explain the

  19. Contact- and Protein Transfer-Dependent Stimulation of Assembly of the Gliding Motility Machinery in Myxococcus xanthus.

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    Beata Jakobczak

    2015-07-01

    Full Text Available Bacteria engage in contact-dependent activities to coordinate cellular activities that aid their survival. Cells of Myxococcus xanthus move over surfaces by means of type IV pili and gliding motility. Upon direct contact, cells physically exchange outer membrane (OM lipoproteins, and this transfer can rescue motility in mutants lacking lipoproteins required for motility. The mechanism of gliding motility and its stimulation by transferred OM lipoproteins remain poorly characterized. We investigated the function of CglC, GltB, GltA and GltC, all of which are required for gliding. We demonstrate that CglC is an OM lipoprotein, GltB and GltA are integral OM β-barrel proteins, and GltC is a soluble periplasmic protein. GltB and GltA are mutually stabilizing, and both are required to stabilize GltC, whereas CglC accumulate independently of GltB, GltA and GltC. Consistently, purified GltB, GltA and GltC proteins interact in all pair-wise combinations. Using active fluorescently-tagged fusion proteins, we demonstrate that GltB, GltA and GltC are integral components of the gliding motility complex. Incorporation of GltB and GltA into this complex depends on CglC and GltC as well as on the cytoplasmic AglZ protein and the inner membrane protein AglQ, both of which are components of the gliding motility complex. Conversely, incorporation of AglZ and AglQ into the gliding motility complex depends on CglC, GltB, GltA and GltC. Remarkably, physical transfer of the OM lipoprotein CglC to a ΔcglC recipient stimulates assembly of the gliding motility complex in the recipient likely by facilitating the OM integration of GltB and GltA. These data provide evidence that the gliding motility complex in M. xanthus includes OM proteins and suggest that this complex extends from the cytoplasm across the cell envelope to the OM. These data add assembly of gliding motility complexes in M. xanthus to the growing list of contact-dependent activities in bacteria.

  20. Influence de Boscia senegalensis (Pers Lam. Ex Poir. (Capparaceae sur les capacités de dispersion de Dinarmus basalis Rond. (Hymenoptera- Pteromalidae dans les systèmes de stockage traditionnels de niébé

    Directory of Open Access Journals (Sweden)

    Doumma, A.

    2006-01-01

    Full Text Available Impact of Boscia senegalensis (Pers Lam. Ex Poir. (Capparaceae on the Dispersion Capacities of Dinarmus basalis Rond. (Hymenoptera- Pteromalidae in Traditional Storage System. In this study, the impact of Boscia senegalensis (Pers Lam. Ex Poir. (Capparaceae on dispersion capacities of Dinarmus basalis Rond (Hymenoptera-Pteromalidae, a solitary ectoparasitoïd of the development stages of bruchid pests of cowpea (Vigna unguiculata (L. Walp, within a traditional storage system is analysed. The results point out that, whatever the position of the treated patch, females of D. basalis are able to move between seeds of cowpea and some of them are able to localize and parasitize their hosts. In a non choice situation, the rates of parasitism observed were less important than the ones obtained when the patchs were not treated with B. senegalensis. Nevertheless in situation of choice, females seem to avoid the patch treated with the insecticidal plant B. senegalensis.

  1. Sunlight Triggers Cutaneous Lupus through a Colony Stimulating Factor-1 (CSF-1) Dependent Mechanism in MRL-Faslpr mice

    Science.gov (United States)

    Menke, Julia; Hsu, Mei-Yu; Byrne, Katelyn T.; Lucas, Julie A.; Rabacal, Whitney A.; Croker, Byron P.; Zong, Xiao-Hua; Stanley, E. Richard; Kelley, Vicki R.

    2008-01-01

    Sunlight (UVB) triggers cutaneous (CLE) and systemic lupus through an unknown mechanism. We tested the hypothesis that UVB triggers CLE through a CSF-1-dependent, macrophage (Mø) -mediated mechanism in MRL-Faslpr mice. By constructing mutant MRL-Faslpr strains expressing varying levels of CSF-1 (high, intermediate, none), and use of an ex-vivo gene transfer to deliver CSF-1 intra-dermally, we determined that CSF-1 induces CLE in lupus-susceptible, MRL-Faslpr mice, but not in lupus-resistant, BALB/c mice. Notably, UVB incites an increase in Mø, apoptosis in the skin and CLE in MRL-Faslpr, but not in CSF-1-deficient MRL-Faslpr mice. Furthermore, UVB did not induce CLE in BALB/c mice. Probing further, UVB stimulates CSF-1 expression by keratinocytes leading to recruitment and activation of Mø that, in turn, release mediators, which induce apoptosis in keratinocytes. Thus, sunlight triggers a CSF-1-dependent, Mø-mediated destructive inflammation in the skin leading to CLE in lupus-susceptible MRL-Faslpr, but not lupus-resistant BALB/c mice. Taken together, we envision CSF-1 as the “match” and lupus-susceptibility as the “tinder” leading to CLE. PMID:18981160

  2. Modulation of spinal inhibitory reflexes depends on the frequency of transcutaneous electrical nerve stimulation in spastic stroke survivors.

    Science.gov (United States)

    Koyama, Soichiro; Tanabe, Shigeo; Takeda, Kazuya; Sakurai, Hiroaki; Kanada, Yoshikiyo

    2016-03-01

    Neurophysiological studies in healthy subjects suggest that increased spinal inhibitory reflexes from the tibialis anterior (TA) muscle to the soleus (SOL) muscle might contribute to decreased spasticity. While 50 Hz is an effective frequency for transcutaneous electrical nerve stimulation (TENS) in healthy subjects, in stroke survivors, the effects of TENS on spinal reflex circuits and its appropriate frequency are not well known. We examined the effects of different frequencies of TENS on spinal inhibitory reflexes from the TA to SOL muscle in stroke survivors. Twenty chronic stroke survivors with ankle plantar flexor spasticity received 50-, 100-, or 200-Hz TENS over the deep peroneal nerve (DPN) of the affected lower limb for 30 min. Before and immediately after TENS, reciprocal Ia inhibition (RI) and presynaptic inhibition of the SOL alpha motor neuron (D1 inhibition) were assessed by adjusting the unconditioned H-reflex amplitude. Furthermore, during TENS, the time courses of spinal excitability and spinal inhibitory reflexes were assessed via the H-reflex, RI, and D1 inhibition. None of the TENS protocols affected mean RI, whereas D1 inhibition improved significantly following 200-Hz TENS. In a time-series comparison during TENS, repeated stimulation did not produce significant changes in the H-reflex, RI, or D1 inhibition regardless of frequency. These results suggest that the frequency-dependent effect of TENS on spinal reflexes only becomes apparent when RI and D1 inhibition are measured by adjusting the amplitude of the unconditioned H-reflex. However, 200-Hz TENS led to plasticity of synaptic transmission from the antagonist to spastic muscles in stroke survivors.

  3. The ethanol-induced stimulation of rat duodenal mucosal bicarbonate secretion in vivo is critically dependent on luminal Cl-.

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    Anna Sommansson

    Full Text Available Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ∼30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of 51Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v. did not change the secretory response to ethanol, while removing Cl- from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v. but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl- and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.

  4. NADPH Oxidase-Dependent Reactive Oxygen Species Stimulate β-Cell Regeneration Through Differentiation of Endocrine Progenitors in Murine Pancreas.

    Science.gov (United States)

    Liang, Juan; Wu, Shang Ying; Zhang, Dan; Wang, Lin; Leung, Kwan Keung; Leung, Po Sing

    2016-03-10

    Reactive oxygen species (ROS) act as second messengers for redox modification of transcription factors essential for differentiation. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a major source of ROS, has been shown to regulate differentiation of various progenitor cells, while its role in pancreatic endocrine cell differentiation is unclear. This study was aimed at this knowledge gap. Our results showed that ROS levels were dynamically changed during pancreas development concomitant with endocrine cell differentiation induced by modest exogenous ROS in rudiment cultures. NOX4, but not NOX2, the member of NADPH oxidase, was expressed persistently in endocrine lineage and showed high activity in critical pancreas development phase. Inhibition of NADPH oxidase activity impeded the differentiation of endocrine progenitors in vitro, and exogenous ROS reversed this effect. Studies performed in streptozotocin (STZ)-injected neonatal rats showed that diphenyleneiodonium (DPI) obstructed β-cell regeneration through the suppression of neurogenin 3 (NGN3) expression, but not Ki67-labeling β-cells, indicating that ROS stimulation promoted differentiation beyond proliferation of β-cells. Inhibition of NADPH oxidase also reduced expression of SRY (sex-determining region Y)-box 9 (SOX9), a transcriptional regulator of Ngn3, in endocrine precursor cells, both in vivo and in vitro. Overexpression of SOX9 attenuated the reduction of NGN3 induced by suppression of NADPH oxidase. This is the first study to demonstrate NADPH oxidase, especially NOX4-dependent ROS that promotes pancreatic progenitor cell differentiation into endocrine cells both in vitro and in vivo, probably through the regulation of SOX9. We provide evidence that NADPH oxidase-dependent ROS-mediated signaling is necessary for endocrine cell differentiation, which provides a potential strategy for efficient generation of insulin-producing cells in clinical application.

  5. Differential intensity-dependent effects of magnetic stimulation on the longest neurites and shorter dendrites in neuroscreen-1 cells

    Science.gov (United States)

    Lin, Ching-Yi; Huang, Whitney J.; Li, Kevin; Swanson, Roy; Cheung, Brian; Lin, Vernon W.; Lee, Yu-Shang

    2015-04-01

    Objective. Magnetic stimulation (MS) is a potential treatment for neuropsychiatric disorders. This study investigates whether MS-regulated neuronal activity can translate to specific changes in neuronal arborization and thus regulate synaptic activity and function. Approach. To test our hypotheses, we examined the effects of MS on neurite growth of neuroscreen-1 (NS-1) cells over the pulse frequencies of 1, 5 and 10 Hz at field intensities controlled via machine output (MO). Cells were treated with either 30% or 40% MO. Due to the nature of circular MS coils, the center region of the gridded coverslip (zone 1) received minimal (∼5%) electromagnetic current density while the remaining area (zone 2) received maximal (∼95%) current density. Plated NS-1 cells were exposed to MS twice per day for three days and then evaluated for length and number of neurites and expression of brain-derived neurotrophic factor (BDNF). Main results. We show that MS dramatically affects the growth of the longest neurites (axon-like) but does not significantly affect the growth of shorter neurites (dendrite-like). Also, MS-induced changes in the longest neurite growth were most evident in zone 1, but not in zone 2. MS effects were intensity-dependent and were most evident in bolstering longest neurite outgrowth, best seen in the 10 Hz MS group. Furthermore, we found that MS-increased BDNF expression and secretion was also frequency-dependent. Taken together, our results show that MS exerts distinct effects when different frequencies and intensities are applied to the neuritic compartments (longest neurite versus shorter dendrite(s)) of NS-1 cells. Significance. These findings support the concept that MS increases BDNF expression and signaling, which sculpts longest neurite arborization and connectivity by which neuronal activity is regulated. Understanding the mechanisms underlying MS is crucial for efficiently incorporating its use into potential therapeutic strategies.

  6. The role of Ca2+-dependent K+- channels at the rat corticostriatal synapses revealed by paired pulse stimulation.

    Science.gov (United States)

    Robles Gómez, Angel A; Vega, Ana V; Gónzalez-Sandoval, Carolina; Barral, Jaime

    2018-02-01

    Potassium channels play an important role in modulating synaptic activity both at presynaptic and postsynaptic levels. We have shown before that presynaptically located K V and K IR channels modulate the strength of corticostriatal synapses in rat brain, but the role of other types of potassium channels at these synapses remains largely unknown. Here, we show that calcium-dependent potassium channels BK-type but not SK-type channels are located presynaptically in corticostriatal synapses. We stimulated cortical neurons in rat brain slices and recorded postsynaptic excitatory potentials (EPSP) in medium spiny neurons (MSN) in dorsal neostriatum. By using a paired pulse protocol, we induced synaptic facilitation before applying either BK- or SK-specific toxins. Thus, we found that blockage of BK Ca with iberiotoxin (10 nM) reduces synaptic facilitation and increases the amplitude of the EPSP, while exposure to SK-blocker apamin (100 nM) has no effect. Additionally, we induced train action potentials on striatal MSN by current injection before and after the exposure to K Ca toxins. We found that the action potential becomes broader when the MSN is exposed to iberiotoxin, although it has no impact on frequency. In contrast, exposure to apamin results in loss of afterhyperpolarization phase and an increase of spike frequency. Therefore, we concluded that postsynaptic SK channels are involved in afterhyperpolarization and modulation of spike frequency while the BK channels are involved on the late repolarization phase of the action potential. Altogether, our results show that calcium-dependent potassium channels modulate both input towards and output from the striatum. © 2017 Wiley Periodicals, Inc.

  7. Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator-stimulated phosphoprotein serine-phosphorylation.

    Science.gov (United States)

    Banday, Anees A; Lokhandwala, Mustafa F

    2018-02-09

    Reactive oxygen species induce vascular dysfunction and hypertension by directly interacting with nitric oxide (NO) which leads to NO inactivation. In addition to a decrease in NO bioavailability, there is evidence that oxidative stress can also modulate NO signaling during hypertension. Here, we investigated the effect of oxidative stress on NO signaling molecules cGMP-dependent protein kinase (PKG) and vasodilator-stimulated phosphoprotein (VASP) which are known to mediate vasodilatory actions of NO. Male Sprague Dawley (SD) rats were provided with tap water (control), 30 mM L-buthionine sulfoximine (BSO, a pro-oxidant), 1 mM tempol (T, an antioxidant) and BSO + T for 3 wks. BSO-treated rats exhibited high blood pressure and oxidative stress. Incubation of mesenteric arterial rings with NO donors caused concentration-dependent relaxation in control rats. However, the response to NO donors was significantly lower in BSO-treated rats with a marked decrease in pD2. In control rats, NO donors activated mesenteric PKG, increased VASP phosphorylation and its interaction with transient receptor potential channels 4 (TRPC4) and inhibited store-operated Ca 2+ influx. NO failed to activate these signaling molecules in mesenteric arteries from BSO-treated rats. Supplementation of BSO-treated rats with tempol reduced oxidative stress and blood pressure and normalized the NO signaling. These data suggest that oxidative stress can reduce NO-mediated PKG activation and VASP-TRPC4 interaction which leads to failure of NO to reduce Ca 2+ influx in smooth muscle cells. The increase in intracellular Ca 2+ contributes to sustained vasoconstriction and subsequent hypertension. Antioxidant supplementation decreases oxidative stress, normalizes NO signaling and reduces blood pressure.

  8. HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF-β/Smad signaling

    International Nuclear Information System (INIS)

    András, Ibolya E.; Toborek, Michal

    2014-01-01

    Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Aβ) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood–brain barrier (BBB). Treatment with HIV-1 and/or Aβ resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-β/Smad effectively attenuated HIV-1-induced Aβ accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Aβ involves the dynamin-dependent EEA1 and TGF-β/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. - Highlights: • HIV-1 induces nuclear accumulation of amyloid beta (Aβ) in brain endothelial cells. • EEA-1 and TGF-Β/Smad act in concert to regulate nuclear entry of Aβ. • Dynamin appropriates the EEA-1 and TGF-Β/Smad signaling. • Dynamin serves as a master regulator of HIV-1-induced nuclear accumulation of Aβ

  9. Assessment of glycosylation-dependent cell adhesion molecule 1 as a correlate of allergen-stimulated lymph node activation

    International Nuclear Information System (INIS)

    Betts, Catherine J.; Moggs, Jonathan G.; Caddick, Helen T.; Cumberbatch, Marie; Orphanides, George; Dearman, Rebecca J.; Ryan, Cindy A.; Hulette, Ben C.; Frank Gerberick, G.; Kimber, Ian

    2003-01-01

    Early changes in gene expression have been identified by cDNA microarray technology. Analysis of draining auricular lymph node tissue sampled at 48 h following exposure to the potent contact allergen 2,4-dinitrofluorobenzene (DNFB) provided examples of up- and down-regulated genes, including onzin and guanylate binding protein 2, and glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1), respectively. Allergen-induced changes in these three genes were confirmed in dose-response and kinetic analyses using Northern blotting and/or reverse transcription-polymerase chain reaction techniques. The results confirmed that these genes are robust and relatively sensitive markers of early changes provoked in the lymph node by contact allergen. Upon further investigation, it was found that altered expression of the adhesion molecule GlyCAM-1 was not restricted to treatment with DNFB. Topical sensitization of mice to a chemically unrelated contact allergen, oxazolone, was also associated with a decrease in the expression of mRNA for GlyCAM-1. Supplementary experiments revealed that changes in expression of this gene are independent of the stimulation by chemical allergens of proliferative responses by draining lymph node cells. Taken together these data indicate that the expression of GlyCAM-1 is down-regulated rapidly following epicutaneous treatment of mice with chemical allergens, but that this reduction is associated primarily with changes in lymph node cell number, or some other aspect of lymph node activation, rather than proliferation

  10. The pedunculopontine tegmental nucleus and the nucleus basalis magnocellularis: Do both have a role in sustained attention?

    Directory of Open Access Journals (Sweden)

    Latimer Mary P

    2008-01-01

    Full Text Available Abstract Background It is well established that nucleus basalis magnocellularis (NbM lesions impair performance on tests of sustained attention. Previous work from this laboratory has also demonstrated that pedunculopontine tegmental nucleus (PPTg lesioned rats make more omissions on a test of sustained attention, suggesting that it might also play a role in mediating this function. However, the results of the PPTg study were open to alternative interpretation. We aimed to resolve this by conducting a detailed analysis of the effects of damage to each brain region in the same sustained attention task used in our previous work. Rats were trained in the task before surgery and post-surgical testing examined performance in response to unpredictable light signals of 1500 ms and 4000 ms duration. Data for PPTg lesioned rats were compared to control rats, and rats with 192 IgG saporin infusions centred on the NbM. In addition to operant data, video data of rats' performance during the task were also analysed. Results Both lesion groups omitted trials relative to controls but the effect was milder and transient in NbM rats. The number of omitted trials decreased in all groups when tested using the 4000 ms signal compared to the 1500 ms signal. This confirmed previous findings for PPTg lesioned rats. Detailed analysis revealed that the increase in omissions in PPTg rats was not a consequence of motor impairment. The video data (taken on selected days showed reduced lever orientation in PPTg lesioned rats, coupled with an increase in unconditioned behaviours such as rearing and sniffing. In contrast NbM rats showed evidence of inadequate lever pressing. Conclusion The question addressed here is whether the PPTg and NbM both have a role in sustained attention. Rats bearing lesions of either structure showed deficits in the test used. However, we conclude that the most parsimonious explanation for the deficit observed in PPTg rats is inadequate response

  11. Angiotensin II inhibits insulin-stimulated GLUT4 translocation and Akt activation through tyrosine nitration-dependent mechanisms.

    Directory of Open Access Journals (Sweden)

    Alfredo Csibi

    Full Text Available Angiotensin II (Ang II plays a major role in the pathogenesis of insulin resistance and diabetes by inhibiting insulin's metabolic and potentiating its trophic effects. Whereas the precise mechanisms involved remain ill-defined, they appear to be associated with and dependent upon increased oxidative stress. We found Ang II to block insulin-dependent GLUT4 translocation in L6 myotubes in an NO- and O(2(*--dependent fashion suggesting the involvement of peroxynitrite. This hypothesis was confirmed by the ability of Ang II to induce tyrosine nitration of the MAP kinases ERK1/2 and of protein kinase B/Akt (Akt. Tyrosine nitration of ERK1/2 was required for their phosphorylation on Thr and Tyr and their subsequent activation, whereas it completely inhibited Akt phosphorylation on Ser(473 and Thr(308 as well as its activity. The inhibitory effect of nitration on Akt activity was confirmed by the ability of SIN-1 to completely block GSK3alpha phosphorylation in vitro. Inhibition of nitric oxide synthase and NAD(PHoxidase and scavenging of free radicals with myricetin restored insulin-stimulated Akt phosphorylation and GLUT4 translocation in the presence of Ang II. Similar restoration was obtained by inhibiting the ERK activating kinase MEK, indicating that these kinases regulate Akt activation. We found a conserved nitration site of ERK1/2 to be located in their kinase domain on Tyr(156/139, close to their active site Asp(166/149, in agreement with a permissive function of nitration for their activation. Taken together, our data show that Ang II inhibits insulin-mediated GLUT4 translocation in this skeletal muscle model through at least two pathways: first through the transient activation of ERK1/2 which inhibit IRS-1/2 and second through a direct inhibitory nitration of Akt. These observations indicate that not only oxidative but also nitrative stress play a key role in the pathogenesis of insulin resistance. They underline the role of protein

  12. Pulse Width-Dependent Effects of Intestinal Electrical Stimulation for Obesity: Role of Gastrointestinal Motility and Hormones.

    Science.gov (United States)

    Li, Shiying; Chen, Jiande D Z

    2017-01-01

    The goals of this experiment were to study therapeutic potential of intestinal electrical stimulation (IES) for obesity, its mechanisms involving gastrointestinal motility and hormones, and role of pulse width in diet-induced obese rats. In a 4-week study, rats equipped with one pair of electrodes at the duodenum were assigned to receive either a sham or IES of varied pulse widths in a sequential way. Food intake was measured daily and body weight measured weekly. Blood samples were collected for the measurement of glucagon-like peptide-1 (GLP-1). Solid gastric emptying (GE) and small bowel transit (SIT) tests were performed at the end of the experiment. The results of the study were as follows: (1) Daily food intake, not affected by IES of 0.3 ms, was pulse width-dependently reduced by 1.9 g with 1 ms and by 5.7 g with 3 ms. Accordingly, body weight was pulse width-dependently reduced by 2.4 g with 1 ms and by 12.8 g with 3 ms compared to a gain of 5.6 g in sham. (2) GLP-1 level was elevated by both 0.3 and 3 ms at 15 min, but was elevated only with 3 ms at 60 min. (3) GE was delayed to 52.3 % by IES of 3 ms but not 0.3 ms, compared to that at 64.4 % with sham IES. (4) Compared to the geometric center of 7.0 with sham IES, SIT was accelerated by 3 ms to 7.8 but not by 0.3 ms. IES pulse width-dependently reduces food intake and body weight, attributed to the delay of gastric emptying and the acceleration of small bowel transit, as well as the enhancement of GLP-1 secretion.

  13. LM-OSL signals from some insulators: an analysis of the dependency of the detrapping probability on stimulation light intensity

    DEFF Research Database (Denmark)

    Bulur, E.; Bøtter-Jensen, L.; Murray, A.S.

    2001-01-01

    Optically stimulated luminescence (OSL) signals from various insulators including quartz, Al2O3 : C, BeO and NaCl have been studied using the linear modulation OSL (LM-OSL) technique. LM-OSL is based on the linear increase of the stimulation light power from zero to a maximum during the measurement...... is not always correct. The initial decay rates of the blue (similar to 470 nm) light stimulated constant power OSL decay curves were examined to test the relation between the detrapping rates and the stimulation light intensity. In SiO2, Al2O3 : C and BeO a linear relation between the detrapping rates....... The resultant OSL curve initially increases and then decays after reaching a maximum, The analysis of LM-OSL data usually assumes a linear relationship between the detrapping rate and the stimulation light intensity. However, experiments carried out using various insulators have shown that this assumption...

  14. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Jeongyeon; Ryoo, Sungwoo, E-mail: ryoosw08@kangwon.ac.kr

    2013-06-07

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner.

  15. Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production

    International Nuclear Information System (INIS)

    Yoon, Jeongyeon; Ryoo, Sungwoo

    2013-01-01

    Highlights: •Arginase inhibition suppressed proliferation of IL-1β-stimulated VSMCs in dose-dependent manner. •NO production from IL-1β-induced iNOS expression was augmented by arginase inhibition, reducing VSMC proliferation. •Incubation with cGMP analogues abolished IL-1β-dependent proliferation of VSMCs. -- Abstract: We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1β incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cGMP-dependent manner

  16. Protein kinase Cdelta stimulates proteasome-dependent degradation of C/EBPalpha during apoptosis induction of leukemic cells.

    Directory of Open Access Journals (Sweden)

    Meng Zhao

    Full Text Available BACKGROUND: The precise regulation and maintenance of balance between cell proliferation, differentiation and death in metazoan are critical for tissue homeostasis. CCAAT/enhancer-binding protein alpha (C/EBPalpha has been implicated as a key regulator of differentiation and proliferation in various cell types. Here we investigated the potential dynamic change and role of C/EBPalpha protein during apoptosis induction. METHODOLOGY/PRINCIPAL FINDINGS: Upon onset of apoptosis induced by various kinds of inducers such as NSC606985, etoposide and others, C/EBPalpha expression presented a profound down-regulation in leukemic cell lines and primary cells via induction of protein degradation and inhibition of transcription, as assessed respectively by cycloheximide inhibition test, real-time quantitative RT-PCR and luciferase reporter assay. Applying chemical inhibition, forced expression of dominant negative mutant and catalytic fragment (CF of protein kinase Cdelta (PKCdelta, which was proteolytically activated during apoptosis induction tested, we showed that the active PKCdelta protein contributed to the increased degradation of C/EBPalpha protein. Three specific proteasome inhibitors antagonized C/EBPalpha degradation during apoptosis induction. More importantly, ectopic expression of PKCdelta-CF stimulated the ubiquitination of C/EBPalpha protein, while the chemical inhibition of PKCdelta action significantly inhibited the enhanced ubiquitination of C/EBPalpha protein under NSC606985 treatment. Additionally, silencing of C/EBPalpha expression by small interfering RNAs enhanced, while inducible expression of C/EBPalpha inhibited NSC606985/etoposide-induced apoptosis in leukemic cells. CONCLUSIONS/SIGNIFICANCE: These observations indicate that the activation of PKCdelta upon apoptosis results in the increased proteasome-dependent degradation of C/EBPalpha, which partially contributes to PKCdelta-mediated apoptosis.

  17. Arterial Levels of Oxygen Stimulate Intimal Hyperplasia in Human Saphenous Veins via a ROS-Dependent Mechanism

    Science.gov (United States)

    Joddar, Binata; Firstenberg, Michael S.; Reen, Rashmeet K.; Varadharaj, Saradhadevi; Khan, Mahmood; Childers, Rachel C.; Zweier, Jay L.; Gooch, Keith J.

    2015-01-01

    Saphenous veins used as arterial grafts are exposed to arterial levels of oxygen partial pressure (pO2), which are much greater than what they experience in their native environment. The object of this study is to determine the impact of exposing human saphenous veins to arterial pO2. Saphenous veins and left internal mammary arteries from consenting patients undergoing coronary artery bypass grafting were cultured ex vivo for 2 weeks in the presence of arterial or venous pO2 using an established organ culture model. Saphenous veins cultured with arterial pO2 developed intimal hyperplasia as evidenced by 2.8-fold greater intimal area and 5.8-fold increase in cell proliferation compared to those freshly isolated. Saphenous veins cultured at venous pO2 or internal mammary arteries cultured at arterial pO2 did not develop intimal hyperplasia. Intimal hyperplasia was accompanied by two markers of elevated reactive oxygen species (ROS): increased dihydroethidium associated fluorescence (4-fold, ppO2 is suggested by the observation that chronic exposure to tiron, a ROS scavenger, during the two-week culture period, blocked intimal hyperplasia. Electron paramagnetic resonance based oximetry revealed that the pO2 in the wall of the vessel tracked that of the atmosphere with a ~30 mmHg offset, thus the cells in the vessel wall were directly exposed to variations in pO2. Monolayer cultures of smooth muscle cells isolated from saphenous veins exhibited increased proliferation when exposed to arterial pO2 relative to those cultured at venous pO2. This increased proliferation was blocked by tiron. Taken together, these data suggest that exposure of human SV to arterial pO2 stimulates IH via a ROS-dependent pathway. PMID:25799140

  18. Kisspeptin stimulates growth hormone release by utilizing Neuropeptide Y pathways and is dependent on the presence of ghrelin

    Science.gov (United States)

    Although kisspeptin is the primary stimulator of gonadotropin releasing hormone secretion and therefore the hypothalamic-pituitary gonadal axis, new findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Central delivery of kisspep...

  19. No effects of slow oscillatory transcranial direct current stimulation (tDCS) on sleep-dependent memory consolidation in healthy elderly subjects.

    Science.gov (United States)

    Eggert, Torsten; Dorn, Hans; Sauter, Cornelia; Nitsche, Michael A; Bajbouj, Malek; Danker-Hopfe, Heidi

    2013-11-01

    Studies in young healthy volunteers provided evidence of a beneficial impact of an anodal time-varied transcranial direct current stimulation (tDCS) during early slow wave rich sleep on declarative memory but not on procedural memory. The present study investigated whether sleep-dependent memory consolidation can also be affected by slow oscillating tDCS in a population of elderly subjects. 26 subjects (69.1 years ± 7.7 years) received bi-frontal anodal stimulation (max. current density: 0.331 mA/cm(2)) during early NREM sleep in a double-blind placebo-controlled randomized crossover study. Stimulation effects on offline consolidation were tested by using a declarative and a procedural memory task. Furthermore, sleep stages were scored, EEG power was analyzed and spindle densities were assessed. Independently from stimulation condition, performance in both memory tasks significantly decreased overnight. Stimulation revealed no significant effect on sleep-dependent memory consolidation. Verum tDCS was accompanied by significantly more time awake and significantly less NREM stage 3 sleep during five 1-min stimulation free intervals. The results of the present study are in line with other studies showing that offline consolidation during sleep varies with age and is less pronounced in the elderly than in young or middle-aged subjects. Contrary to an almost identical positive study in young adults, slow oscillatory tDCS applied to the elderly failed to show a beneficial effect on memory consolidation in the present study. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Immunoglobulin production induced in vitro by glucocorticoid hormones: T cell-dependent stimulation of immunoglobulin production without B cell proliferation in cultures of human peripheral blood lymphocytes

    International Nuclear Information System (INIS)

    Grayson, J.; Dooley, N.J.; Koski, I.R.; Blaese, R.M.

    1981-01-01

    The direct effects of steroid hormones on the production of immunoglobulins and DNA synthesis by human T and B lymphocytes was evaluated in cultures of peripheral blood mononuclear cells. As detected by a reverse hemolytic plaque assay, the addition of 0.1 mM to 10 nM hydrocortisone to lymphocytes in culture in the absence of other stimulants or mitogens, resulted in the dramatic induction of immunoglobulin production with responses comparable to those seen in similar cultures stimulated with pokeweed mitogen. Steroid-stimulated immunoglobulin production was first seen after 48 h and peaked at 8-10 d of culture. The production of IgG, IgA, and IgM was induced following incubation with steroid. Glucocorticoids, but not estrogens or androgens, were capable of mediating this effect, and only compounds with affinity for the glucocorticoid receptor were active. The induction of immunoglobulin production was dependent on both T cells and monocytes; cultures depleted of either cell type did not produce immunoglobulin when stimulated with glucocorticoid hormones. Proliferation of B cells or T cells could not be detected by [/sup 3/H]thymidine incorporation or total cell recovery from steroid-stimulated cultures, even though such cultures demonstrated marked increases in immunoglobulin production. The mechanism responsible for this functional maturation of B cells to become high rate immunoglobulin producing cells is as yet undefined, although it appears to involve more than merely steroid mediated inactivation of suppressor T cells

  1. BDNF mediated activity dependent maturation of visual Wulst following prenatal repetitive auditory stimulation at a critical developmental period in domestic chicks (Gallus domesticus).

    Science.gov (United States)

    Roy, Saborni; Sharma, Hanuman Prasad; Nag, Tapas C; Velpandian, Thirumurthy; Upadhyay, Ashish Datt; Mathur, Rashmi; Jain, Suman

    2014-10-01

    The developing visual circuitry attains its mature adult pattern through the process of activity-dependent refinement in which photic stimulation plays the major role. However, auditory stimulation can also facilitate the developing visual Wulst synaptic plasticity and postnatal perceptual behavior, though the underlying mechanism is unclear. We exposed the fertilized eggs of white Leghorn chickens during incubation to either species-specific calls or no sound for varying time periods depending on the functional development of the auditory and/or visual systems. The visual evoked potential (VEP) from the Wulst was recorded at embryonic days (E) 19, 20 and posthatch days (PH) 1-3, to assess functional maturation. A significant attenuation in latencies and higher amplitudes at PH1-3 in the stimulated groups that received exposure during visual system maturation, suggest beneficial effect of auditory inputs only during critical periods. Concomitant with this, there was a significant increase in the expression of BDNF and levels of neurotransmitters GABA, glutamate, norepinephrine and serotonin from E18 only in both hemispheres of the visual Wulst. A significant inter-hemispheric difference in expression was also found in all groups. These results suggest the role of BDNF in activity driven structural and functional maturation of the visual system following prenatal repetitive auditory stimulation. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Time-dependent Increase in the Network Response to the Stimulation of Neuronal Cell Cultures on Micro-electrode Arrays.

    Science.gov (United States)

    Gertz, Monica L; Baker, Zachary; Jose, Sharon; Peixoto, Nathalia

    2017-05-29

    Micro-electrode arrays (MEAs) can be used to investigate drug toxicity, design paradigms for next-generation personalized medicine, and study network dynamics in neuronal cultures. In contrast with more traditional methods, such as patch-clamping, which can only record activity from a single cell, MEAs can record simultaneously from multiple sites in a network, without requiring the arduous task of placing each electrode individually. Moreover, numerous control and stimulation configurations can be easily applied within the same experimental setup, allowing for a broad range of dynamics to be explored. One of the key dynamics of interest in these in vitro studies has been the extent to which cultured networks display properties indicative of learning. Mouse neuronal cells cultured on MEAs display an increase in response following training induced by electrical stimulation. This protocol demonstrates how to culture neuronal cells on MEAs; successfully record from over 95% of the plated dishes; establish a protocol to train the networks to respond to patterns of stimulation; and sort, plot, and interpret the results from such experiments. The use of a proprietary system for stimulating and recording neuronal cultures is demonstrated. Software packages are also used to sort neuronal units. A custom-designed graphical user interface is used to visualize post-stimulus time histograms, inter-burst intervals, and burst duration, as well as to compare the cellular response to stimulation before and after a training protocol. Finally, representative results and future directions of this research effort are discussed.

  3. Inhibition of cAMP-Dependent PKA Activates β2-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 via Raf-1/MEK/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes.

    Science.gov (United States)

    Pabbidi, M R; Ji, X; Maxwell, J T; Mignery, G A; Samarel, A M; Lipsius, S L

    2016-01-01

    We previously reported in atrial myocytes that inhibition of cAMP-dependent protein kinase (PKA) by laminin (LMN)-integrin signaling activates β2-adrenergic receptor (β2-AR) stimulation of cytosolic phospholipase A2 (cPLA2). The present study sought to determine the signaling mechanisms by which inhibition of PKA activates β2-AR stimulation of cPLA2. We therefore determined the effects of zinterol (0.1 μM; zint-β2-AR) to stimulate ICa,L in atrial myocytes in the absence (+PKA) and presence (-PKA) of the PKA inhibitor (1 μM) KT5720 and compared these results with atrial myocytes attached to laminin (+LMN). Inhibition of Raf-1 (10 μM GW5074), phospholipase C (PLC; 0.5 μM edelfosine), PKC (4 μM chelerythrine) or IP3 receptor (IP3R) signaling (2 μM 2-APB) significantly inhibited zint-β2-AR stimulation of ICa,L in-PKA but not +PKA myocytes. Western blots showed that zint-β2-AR stimulation increased ERK1/2 phosphorylation in-PKA compared to +PKA myocytes. Adenoviral (Adv) expression of dominant negative (dn) -PKCα, dn-Raf-1 or an IP3 affinity trap, each inhibited zint-β2-AR stimulation of ICa,L in + LMN myocytes compared to control +LMN myocytes infected with Adv-βgal. In +LMN myocytes, zint-β2-AR stimulation of ICa,L was enhanced by adenoviral overexpression of wild-type cPLA2 and inhibited by double dn-cPLA2S505A/S515A mutant compared to control +LMN myocytes infected with Adv-βgal. In-PKA myocytes depletion of intracellular Ca2+ stores by 5 μM thapsigargin failed to inhibit zint-β2-AR stimulation of ICa,L via cPLA2. However, disruption of caveolae formation by 10 mM methyl-β-cyclodextrin inhibited zint-β2-AR stimulation of ICa,L in-PKA myocytes significantly more than in +PKA myocytes. We conclude that inhibition of PKA removes inhibition of Raf-1 and thereby allows β2-AR stimulation to act via PKCα/Raf-1/MEK/ERK1/2 and IP3-mediated Ca2+ signaling to stimulate cPLA2 signaling within caveolae. These findings may be relevant to the remodeling of

  4. The nucleus basalis (Ch4) in the alcoholic Wernicke-Korsakoff syndrome: reduced cell number in both amnesic and non-amnesic patients.

    Science.gov (United States)

    Cullen, K M; Halliday, G M; Caine, D; Kril, J J

    1997-09-01

    The cholinergic nucleus basalis (Ch4) is an exclusive site of neurofibrillary degeneration in alcoholic patients with Wernicke's encephalopathy. To test the hypothesis that the loss of Ch4 neurons contributes to the memory disorder, Korsakoff's psychosis, commonly seen in Wernicke's encephalopathy. Magnocellular basal forebrain neurons were quantified in alcoholic patients with Wernicke's encephalopathy, both with and without Korsakoff's psychosis, and neurologically asymptomatic alcoholic and non-alcoholic controls. Because amnesic and non-amnesic patients with Wernicke's encephalopathy share common periventricular lesions, both thiamine deficient groups as well as alcoholic patients with no neurological complications were included to determine the lesion specific to memory impairment. Ch4 cell number did not differ significantly between alcoholic and non-alcoholic controls and there was no correlation between cell number and lifetime alcohol intake. However, Ch4 cell number in all groups was significantly correlated with the volume of its major projection target, the cerebral cortex. Ch4 cell number in the non-amnesic Wernicke's encephalopathy group was significantly below controls (24%), with cell number in patients with Korsakoff's psychosis 21% below controls. There was considerable overlap in cell number between groups. On discriminant analysis, there was significantly greater cell loss in three non-amnesic patients with Wernicke's encephalopathy than in some patients with Korsakoff's psychosis. The nonamnesic patient with the greatest cell loss was impaired on attentional tasks. Whereas neurons in the nucleus basalis are at risk in thiamine deficient alcoholic patients, cell loss is minor and does not account for the profound memory disorder.

  5. Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

    DEFF Research Database (Denmark)

    Brosbøl-Ravnborg, A; Hvas, C L; Agnholt, J

    2008-01-01

    and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor......., nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD...... patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1 beta and tumour necrosis...

  6. Toll-like receptor-induced granulocyte-macrophage colony-stimulating factor secretion is impaired in Crohn's disease by nucleotide oligomerization domain 2-dependent and -independent pathways

    DEFF Research Database (Denmark)

    Ravnborg, Anne Brosbøl-; Hvas, Christian Lodberg; Agnholt, Jørgen

    2009-01-01

    and display an impaired NOD2-dependent down-regulation of TNF-alpha secretion. The defect in GM-CSF secretion suggests a hitherto unknown role of NOD2 in the pathogenesis of CD and is consistent with the hypothesis that impaired GM-CSF secretion in part constitutes a NOD2-dependent disease risk factor......., nucleotide oligomerization domain 2) are associated with Crohn's disease (CD). We investigated the impact of NOD2 polymorphisms on cytokine secretion and proliferation of peripheral blood mononuclear cells (PBMCs) in response to Toll-like receptor (TLR) and NOD2 ligands. Based on NOD2 SNP analyses, 41 CD...... patients and 12 healthy controls were studied. PBMCs were stimulated with NOD2 and TLR ligands. After 18 h culture supernatants were measured using multiplex assays for the presence of human cytokines granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1beta and tumour necrosis...

  7. The spectral features of EEG responses to transcranial magnetic stimulation of the primary motor cortex depend on the amplitude of the motor evoked potentials.

    Science.gov (United States)

    Fecchio, Matteo; Pigorini, Andrea; Comanducci, Angela; Sarasso, Simone; Casarotto, Silvia; Premoli, Isabella; Derchi, Chiara-Camilla; Mazza, Alice; Russo, Simone; Resta, Federico; Ferrarelli, Fabio; Mariotti, Maurizio; Ziemann, Ulf; Massimini, Marcello; Rosanova, Mario

    2017-01-01

    Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event-related desynchronization (ERD-peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

  8. Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner

    OpenAIRE

    Hirbe, Angela C.; Uluçkan, Özge; Morgan, Elizabeth A.; Eagleton, Mark C.; Prior, Julie L.; Piwnica-Worms, David; Trinkaus, Kathryn; Apicelli, Anthony; Weilbaecher, Katherine

    2007-01-01

    Inhibition of osteoclast (OC) activity has been associated with decreased tumor growth in bone in animal models. Increased recognition of factors that promote osteoclastic bone resorption in cancer patients led us to investigate whether increased OC activation could enhance tumor growth in bone. Granulocyte colony-stimulating factor (G-CSF) is used to treat chemotherapy-induced neutropenia, but is also associated with increased markers of OC activity and decreased bone mineral density (BMD). ...

  9. Transcranial direct current stimulation facilitates cognitive multi-task performance differentially depending on anode location and subtask.

    Directory of Open Access Journals (Sweden)

    Melissa eScheldrup

    2014-09-01

    Full Text Available There is a need to facilitate acquisition of real world cognitive multi-tasks that require long periods of training (e.g., air traffic control, intelligence analysis, medicine. Non-invasive brain stimulation – specifically transcranial Direct Current Stimulation (tDCS – has promise as a method to speed multi-task training. We hypothesized that during acquisition of the complex multi-task Space Fortress, subtasks that require focused attention on ship control would benefit from tDCS aimed at the dorsal attention network while subtasks that require redirection of attention would benefit from tDCS aimed at the right hemisphere ventral attention network. We compared effects of 30 min prefrontal and parietal stimulation to right and left hemispheres on subtask performance during the first 45 min of training. The strongest effects both overall and for ship flying (control and velocity subtasks were seen with a right parietal (C4 to left shoulder montage, shown by modeling to induce an electric field that includes nodes in both dorsal and ventral attention networks. This is consistent with the re-orienting hypothesis that the ventral attention network is activated along with the dorsal attention network if a new, task-relevant event occurs while visuospatial attention is focused (Corbetta et al., 2008. No effects were seen with anodes over sites that stimulated only dorsal (C3 or only ventral (F10 attention networks. The speed subtask (update memory for symbols benefited from an F9 anode over left prefrontal cortex. These results argue for development of tDCS as a training aid in real world settings where multi-tasking is critical.

  10. EphB4 Tyrosine Kinase Stimulation Inhibits Growth of MDA-MB-231 Breast Cancer Cells in a Dose and Time Dependent Manner

    Directory of Open Access Journals (Sweden)

    Farnaz Barneh

    2013-01-01

    Full Text Available Background. EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc. Methods. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence. Results. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel. Conclusion. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.

  11. Impact of commonly used transplant immunosuppressive drugs on human NK cell function is dependent upon stimulation condition.

    Directory of Open Access Journals (Sweden)

    Aislin C Meehan

    Full Text Available Lung transplantation is a recognised treatment for patients with end stage pulmonary disease. Transplant recipients receive life-long administration of immunosuppressive drugs that target T cell mediated graft rejection. However little is known of the impact on NK cells, which have the potential to be alloreactive in response to HLA-mismatched ligands on the lung allograft and in doing so, may impact negatively on allograft survival. NK cells from 20 healthy controls were assessed in response to Cyclosporine A, Mycophenolic acid (MPA; active form of Mycophenolate mofetil and Prednisolone at a range of concentrations. The impact of these clinically used immunosuppressive drugs on cytotoxicity (measured by CD107a expression, IFN-γ production and CFSE proliferation was assessed in response to various stimuli including MHC class-I negative cell lines, IL-2/IL-12 cytokines and PMA/Ionomycin. Treatment with MPA and Prednisolone revealed significantly reduced CD107a expression in response to cell line stimulation. In comparison, addition of MPA and Cyclosporine A displayed reduced CD107a expression and IFN-γ production following PMA/Ionomycin stimulation. Diminished proliferation was observed in response to treatment with each drug. Additional functional inhibitors (LY294002, PD98059, Rottlerin, Rapamycin were used to elucidate intracellular pathways of NK cell activation in response to stimulation with K562 or PMA-I. CD107a expression was significantly decreased with the addition of PD98059 following K562 stimulation. Similarly, CD107a expression significantly decreased following PMA-I stimulation with the addition of LY294002, PD98059 and Rottlerin. Ten lung transplant patients, not receiving immunosuppressive drugs pre-transplant, were assessed for longitudinal changes post-transplant in relation to the administration of immunosuppressive drugs. Individual patient dynamics revealed different longitudinal patterns of NK cell function post

  12. Thyroid hormone stimulated glucose uptake in human mononuclear blood cells from normal persons and from patients with non-insulin-dependent diabetes mellitus

    DEFF Research Database (Denmark)

    Kvetny, J; Matzen, L

    1989-01-01

    of stimulation of cells from control subjects and patients with NIDDM revealed an identical oxygen consumption, whereas the thyroid hormone-induced glucose uptake was significantly increased in cells from patients with NIDDM. T4 (5 mumol/l) stimulation in controls: 1.34 +/- 0.23 mmol.l-1 (mg DNA)-1.h-1, in NIDDM...... an increased thyroid hormone induced glucose uptake, indicating increased thyroid hormone sensitivity. This observation contrasts the well known insulin insensitivity, suggesting separate mechanisms for glucose uptake elicited by insulin and thyroid hormones....... by physiological and supraphysiological concentrations of T3 and T4 in a dose-dependent manner (50-5000 nmol/l), whereas rT3 and T2 had no stimulatory effect. The effect of T3 and T4 was independent of new protein synthesis in that it was not blocked by tunicamycin (1 mg/l) and tiothepa (75 mg/l). Examination...

  13. Guanine nucleotide-dependent, pertussis toxin-insensitive, stimulation of inositol phosphate formation by carbachol in a membrane preparation from astrocytoma cells

    International Nuclear Information System (INIS)

    Hepler, J.R.; Harden, T.K.

    1986-01-01

    Formation of the inositol phosphates (InsP), InsP 3 , InsP 2 , and InsP 1 was increased in a concentration dependent manner (K/sub 0.5/ ∼ 5 μM) by GTPΣS in washed membranes prepared from 3 H-inositol-prelabelled 1321N1 human astrocytoma cells. Both GTPγS and GppNHp stimulated InsP formation by 2-3 fold over control; GTP and GDP were much less efficacious and GMP had no effect. Although the muscarinic cholinergic receptor agonist carbachol had no effect in the absence of guanine nucleotide, in the presence of 10 μM GTPγS, carbachol stimulated (K/sub 0.5/ ∼ 10 μ M) the formation of InsP above the level achieved with GTPγS alone. The effect of carbachol was completely blocked by atropine. The order of potency for a series of nucleotides for stimulation of InsP formation in the presence of 500 μM carbachol was GTPγS > GppNHp > GTP = GDP. Pertussis toxin, at concentrations that fully ADP-ribosylate and functionally inactivate G/sub i/, had no effect on InsP formation in the presence of GTPγS or GTPγS plus carbachol. Histamine and bradykinin also stimulated InsP formation in the presence of GTPγS in washed membranes from 1321N1 cells. These data are consistent with the idea that a guanine nucleotide regulatory protein that is not G/sub i/ is involved in receptor-mediated stimulation of InsP formation in 1321N1 human astrocytoma cells

  14. Differential IFN-gamma stimulation of HLA-A gene expression through CRM-1-dependent nuclear RNA export.

    Science.gov (United States)

    Browne, Sarah K; Roesser, James R; Zhu, Sheng Zu; Ginder, Gordon D

    2006-12-15

    IFNs regulate most MHC class I genes by stimulating transcription initiation. As shown previously, IFN-gamma controls HLA-A expression primarily at the posttranscriptional level. We have defined two 8-base sequences in a 39-nucleotide region in the 3'-transcribed region of the HLA-A gene that are required for the posttranscriptional response to IFN-gamma. Stimulation of HLA-A expression by IFN-gamma requires nuclear export of HLA-A mRNA by chromosome maintenance region 1 (CRM-1). Treatment of cells with leptomycin B, a specific inhibitor of CRM-1, completely inhibited IFN-gamma induction of HLA-A. Expression of a truncated, dominant-negative form of the nucleoporin NUP214/CAN, DeltaCAN, that specifically interacts with CRM-1, also prevented IFN-gamma stimulation of HLA-A, providing confirmation of the role of CRM-1. Increased expression of HLA-A induced by IFN-gamma also requires protein methylation, as shown by the fact that treatment of SK-N-MC cells or HeLa cells with the PRMT1 inhibitor 5'-methyl-5'-thioadenosine abolished the cellular response to IFN-gamma. In contrast with HLA-A, IFN-gamma-induced expression of the HLA class Ib gene, HLA-E, was not affected by either 5'-methyl-5'-thioadenosine or leptomycin B. These results provide proof of principle that it is possible to differentially modulate the IFN-gamma-induced expression of the HLA-E and HLA-A genes, whose products often mediate opposing effects on cellular immunity to tumor cells, pathogens, and autoantigens.

  15. The chaperone ClpX stimulates expression of Staphylococcus aureus protein A by rot dependent and independent pathways

    DEFF Research Database (Denmark)

    Jelsbak, Lotte; Ingmer, Hanne; Valihrach, Lukás

    2010-01-01

    at pinpointing the role of ClpX in Rot synthesis revealed that ClpX is required for translation of Rot. Interestingly, translation of the spa mRNA was, like the rot mRNA, enhanced by ClpX. These data demonstrate that ClpX performs dual roles in regulating Protein A expression, as ClpX stimulates transcription...... of spa by enhancing translation of Rot, and that ClpX additionally is required for full translation of the spa mRNA. The current findings emphasize that ClpX has a central role in fine-tuning virulence regulation in S. aureus....

  16. In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion.

    Science.gov (United States)

    de Souza Armini, Rubia; Bernabé, Cristian Setúbal; Rosa, Caroline Azevedo; Siller, Carlos Antônio; Schimitel, Fagna Giacomin; Tufik, Sérgio; Klein, Donald Franklin; Schenberg, Luiz Carlos

    2015-03-01

    Panic disorder patients are exquisitely and specifically sensitive to hypercapnia. The demonstration that carbon dioxide provokes panic in fear-unresponsive amygdala-calcified Urbach-Wiethe patients emphasizes that panic is not fear nor does it require the activation of the amygdala. This is consonant with increasing evidence suggesting that panic is mediated caudally at midbrain's dorsal periaqueductal gray matter (DPAG). Another startling feature of the apparently spontaneous clinical panic is the counterintuitive lack of increments in corticotropin, cortisol and prolactin, generally considered 'stress hormones'. Here we show that the stress hormones are not changed during DPAG-evoked panic when escape is prevented by stimulating the rat in a small compartment. Neither did the corticotropin increase when physical exertion was statistically adjusted to the same degree as non-stimulated controls, as measured by lactate plasma levels. Conversely, neuroendocrine responses to foot-shocks were independent from muscular effort. Data are consonant with DPAG mediation of panic attacks. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct.

    Science.gov (United States)

    Gonzalez, Alexis A; Liu, Liu; Lara, Lucienne S; Bourgeois, Camille R T; Ibaceta-Gonzalez, Cristobal; Salinas-Parra, Nicolas; Gogulamudi, Venkateswara R; Seth, Dale M; Prieto, Minolfa C

    2015-11-15

    In contrast to the negative feedback of angiotensin II (ANG II) on juxtaglomerular renin, ANG II stimulates renin in the principal cells of the collecting duct (CD) in rats and mice via ANG II type 1 (AT1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT1R activation through protein kinase C (PKC), but the exact mechanisms are unknown. We hypothesize that ANG II stimulates CD renin synthesis through AT1R via PKC and the subsequent activation of cAMP/PKA/CREB pathway. In M-1 cells, ANG II increased cAMP, renin mRNA (3.5-fold), prorenin, and renin proteins, as well as renin activity in culture media (2-fold). These effects were prevented by PKC inhibition with calphostin C, PKC-α dominant negative, and by PKA inhibition. Forskolin-induced increases in cAMP and renin expression were prevented by calphostin C. PKC inhibition and Ca2+ depletion impaired ANG II-mediated CREB phosphorylation and upregulation of renin. Adenylate cyclase 6 (AC) siRNA remarkably attenuated the ANG II-dependent upregulation of renin mRNA. Physiological activation of AC with vasopressin increased renin expression in M-1 cells. The results suggest that the ANG II-dependent upregulation of renin in the CD depends on PKC-α, which allows the augmentation of cAMP production and activation of PKA/CREB pathway via AC6. This study defines the intracellular signaling pathway involved in the ANG II-mediated stimulation of renin in the CD. This is a novel mechanism responsible for the regulation of local renin-angiotensin system in the distal nephron. Copyright © 2015 the American Physiological Society.

  18. Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells

    International Nuclear Information System (INIS)

    Chung, Byung-Hee; Kim, Jong-Dai; Kim, Chun-Ki; Kim, Jung Huan; Won, Moo-Ho; Lee, Han-Soo; Dong, Mi-Sook; Ha, Kwon-Soo; Kwon, Young-Geun; Kim, Young-Myeong

    2008-01-01

    We investigated the molecular effect and signal pathway of icariin, a major flavonoid of Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated in vitro endothelial cell proliferation, migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy

  19. Stimulation of hERG1 channel activity promotes a calcium-dependent degradation of cyclin E2, but not cyclin E1, in breast cancer cells.

    Science.gov (United States)

    Perez-Neut, Mathew; Shum, Andrew; Cuevas, Bruce D; Miller, Richard; Gentile, Saverio

    2015-01-30

    Cyclin E2 gene amplification, but not cyclin E1, has been recently defined as marker for poor prognosis in breast cancer, and appears to play a major role in proliferation and therapeutic resistance in several breast cancer cells. Our laboratory has previously reported that stimulation of the hERG1 potassium channel with selective activators led to down-regulation of cyclin E2 in breast cancer cells. In this work, we demonstrate that stimulation of hERG1 promotes an ubiquitin-proteasome-dependent degradation of cyclin E2 in multiple breast cancer cell lines representing Luminal A, HER2+ and Trastuzumab-resistant breast cancer cells. In addition we have also reveal that hERG1 stimulation induces an increase in intracellular calcium that is required for cyclin E2 degradation. This novel function for hERG1 activity was specific for cyclin E2, as cyclins A, B, D E1 were unaltered by the treatment. Our results reveal a novel mechanism by which hERG1 activation impacts the tumor marker cyclin E2 that is independent of cyclin E1, and suggest a potential therapeutic use for hERG1 channel activators.

  20. Protein kinase A stimulates Kv7.1 surface expression by regulating Nedd4-2-dependent endocytic trafficking

    DEFF Research Database (Denmark)

    Andersen, Martin Nybo; Hefting, Louise Leth; Steffensen, Annette Buur

    2015-01-01

    The potassium channel Kv7.1 plays critical physiological roles in both heart and epithelial tissues. In heart, Kv7.1 and the accessory subunit KCNE1 forms the IKs current, which is enhanced by PKA mediated phosphorylation. The observed current increase requires both phosphorylation of Kv7.......1 and the presence of KCNE1. However, PKA also stimulates Kv7.1 currents in epithelial tissues, such as colon, where the channel does not co-assemble with KCNE1. Here, we demonstrate that PKA activity significantly impacts the subcellular localization of Kv7.1 in Madin Darby Canine Kidney cells. While PKA inhibition...... reduced the fraction of channels at the cell surface, PKA activation increased it. We show that PKA inhibition lead to intracellular accumulation of Kv7.1 in late endosomes/lysosomes. By mass spectroscopy we identified eight phosphorylated residues on Kv7.1, however, none appeared to play a role...

  1. Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent.

    Science.gov (United States)

    Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus

    2014-01-01

    Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Integrin-mediated transactivation of P2X7R via hemichannel-dependent ATP release stimulates astrocyte migration.

    Science.gov (United States)

    Alvarez, Alvaro; Lagos-Cabré, Raúl; Kong, Milene; Cárdenas, Areli; Burgos-Bravo, Francesca; Schneider, Pascal; Quest, Andrew F G; Leyton, Lisette

    2016-09-01

    Our previous reports indicate that ligand-induced αVβ3 integrin and Syndecan-4 engagement increases focal adhesion formation and migration of astrocytes. Additionally, ligated integrins trigger ATP release through unknown mechanisms, activating P2X7 receptors (P2X7R), and the uptake of Ca(2+) to promote cell adhesion. However, whether the activation of P2X7R and ATP release are required for astrocyte migration and whether αVβ3 integrin and Syndecan-4 receptors communicate with P2X7R via ATP remains unknown. Here, cells were stimulated with Thy-1, a reported αVβ3 integrin and Syndecan-4 ligand. Results obtained indicate that ATP was released by Thy-1 upon integrin engagement and required the participation of phosphatidylinositol-3-kinase (PI3K), phospholipase-C gamma (PLCγ) and inositol trisphosphate (IP3) receptors (IP3R). IP3R activation leads to increased intracellular Ca(2+), hemichannel (Connexin-43 and Pannexin-1) opening, and ATP release. Moreover, silencing of the P2X7R or addition of hemichannel blockers precluded Thy-1-induced astrocyte migration. Finally, Thy-1 lacking the integrin-binding site did not stimulate ATP release, whereas Thy-1 mutated in the Syndecan-4-binding domain increased ATP release, albeit to a lesser extent and with delayed kinetics compared to wild-type Thy-1. Thus, hemichannels activated downstream of an αVβ3 integrin-PI3K-PLCγ-IP3R pathway are responsible for Thy-1-induced, hemichannel-mediated and Syndecan-4-modulated ATP release that transactivates P2X7Rs to induce Ca(2+) entry. These findings uncover a hitherto unrecognized role for hemichannels in the regulation of astrocyte migration via P2X7R transactivation induced by integrin-mediated ATP release. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Disassembly of the actin network inhibits insulin-dependent stimulation of glucose transport and prevents recruitment of glucose transporters to the plasma membrane.

    Science.gov (United States)

    Tsakiridis, T; Vranic, M; Klip, A

    1994-11-25

    In muscle and fat tissues, insulin stimulates glucose transport through the translocation of glucose transporter proteins from an intracellular storage pool to the plasma membrane. The mechanism of this translocation is unknown. We have examined the possible role of the actin microfilament network in the stimulation of glucose transport by insulin and on the distribution of glucose transporters, in differentiated L6 rat skeletal muscle cells. Insulin (10(-7) M for 30 min) caused a major reorganization of the actin network of differentiated L6 myotubes. Cytochalasin D, a widely used inhibitor of actin filament formation, caused a dose- and time-dependent disassembly of the actin network, which was associated with an 80% inhibition of the insulin stimulation of glucose transport, without affecting the basal rate of glucose uptake. L6 myotubes express three glucose transporter isoforms, named GLUT1, GLUT3, and GLUT4. Disassembly of the actin network by cytochalasin D did not affect the number of basal glucose transporters in the plasma membrane but reduced the content of all three glucose transporters in intracellular membranes and prevented their appearance at the plasma membrane response to insulin. The inhibitory effect of cytochalasin D treatment on the insulin stimulation of glucose transport occurred downstream of tyrosine phosphorylation of the insulin receptor substrate-1 and of binding of phosphatidylinositol 3-kinase to the insulin receptor substrate-1. Using immunoprecipitation of intact membranes, we detected specific association of the actin-binding protein spectrin with GLUT4 glucose transporter-containing vesicles. We conclude that an intact actin network is required for the correct intracellular localization of glucose transporters, as well as for their incorporation into the plasma membrane in response to insulin. A direct interaction may exist between the actin network and the glucose transporter vesicles which may be mediated through a spectrin

  4. Prostaglandin E2 modulates F-actin stress fiber in FSS-stimulated MC3T3-E1 cells in a PKA-dependent manner.

    Science.gov (United States)

    Gong, Xiaoyuan; Yang, Weidong; Wang, Liyun; Duncan, Randall L; Pan, Jun

    2014-01-01

    The effect of prostaglandin E2 (PGE2) on bone mass has been well-established in vivo. Previous studies have showed that PGE2 increases differentiation, proliferation, and regulates cell morphology through F-actin stress fiber in statically cultured osteoblasts. However, the effect of PGE2 on osteoblasts in the presence of fluid shear stress (FSS), which could better uncover the anabolic effect of PGE2 in vivo, has yet to be examined. Here, we hypothesized that PGE2 modulates F-actin stress fiber in FSS-stimulated MC3T3-E1 osteoblastic cells through protein kinase A (PKA) pathway. Furthermore, this PGE2-induced F-actin remodeling was associated with the recovery of cellular mechanosensitivity. Our data showed that treatment with 10 nM dmPGE2 for 15 min significantly suppressed the F-actin stress fiber intensity in FSS-stimulated cells in a PKA-dependent manner. In addition, dmPGE2 treatment enhanced the cells' calcium peak magnitude and the percentage of responding cells in the second FSS stimulation, though these effects were abolished and attenuated by co-treatment with phalloidin. Our results demonstrated that 10 nM dmPGE2 was able to accelerate the 'reset' process of F-actin stress fiber to its pre-stimulated level partially through PKA pathway, and thus promoted the recovery of cellular mechanosensitivity. Our finding provided a novel cellular mechanism by which PGE2 increased bone formation as shown in vivo, suggesting that PGE2 could be a potential target for treatments of bone formation-related diseases.

  5. RKIP phosphorylation–dependent ERK1 activation stimulates adipogenic lipid accumulation in 3T3-L1 preadipocytes overexpressing LC3

    Energy Technology Data Exchange (ETDEWEB)

    Hahm, Jong Ryeal [Department of Internal Medicine, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of); Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of); Ahmed, Mahmoud [Department of Biochemistry and Convergence Medical Science, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of); Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of); Kim, Deok Ryong, E-mail: drkim@gnu.ac.kr [Department of Biochemistry and Convergence Medical Science, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of); Institute of Health Sciences, Gyeongsang National University School of Medicine, JinJu, 527-27 (Korea, Republic of)

    2016-09-09

    3T3-L1 preadipocytes undergo adipogenesis in response to treatment with dexamethaxone, 1-methyl-3-isobutylxanthine, and insulin (DMI) through activation of several adipogenic transcription factors. Many autophagy-related proteins are also highly activated in the earlier stages of adipogenesis, and the LC3 conjugation system is required for formation of lipid droplets. Here, we investigated the effect of overexpression of green fluorescent protein (GFP)-LC3 fusion protein on adipogenesis. Overexpression of GFP-LC3 in 3T3-L1 preadipocytes using poly-L-lysine-assisted adenoviral GFP-LC3 transduction was sufficient to produce intracellular lipid droplets. Indeed, GFP-LC3 overexpression stimulated expression of some adipogenic transcription factors (e.g., C/EBPα or β, PPARγ, SREBP2). In particular, SREBP2 was highly activated in preadipocytes transfected with adenoviral GFP-LC3. Also, phosphorylation of Raf kinase inhibitory protein (RKIP) at serine 153, consequently stimulating extracellular-signal regulated kinase (ERK)1 activity, was significantly increased during adipogenesis induced by either poly-L-lysine-assisted adenoviral GFP-LC3 transduction or culture in the presence of dexamethasone, 1-methyl-3-isobutylxanthine, and insulin. Furthermore, RKIP knockdown promoted ERK1 and PPARγ activation, and significantly increased the intracellular accumulation of triacylglycerides in DMI-induced adipogenesis. In conclusion, GFP-LC3 overexpression in 3T3-L1 preadipocytes stimulates adipocyte differentiation via direct modulation of RKIP-dependent ERK1 activity. - Highlights: • Overexpression of GFP-LC3 in 3T3-L1 cells produces intracellular lipid droplets. • SREBP2 is highly activated in preadipocytes transfected with adenoviral GFP-LC3. • RKIP phosphorylation at serine 153 is significantly increased during adipogenesis. • RKIP knockdown promotes ERK1 and PPARγ activation during adipogenesis. • RKIP-dependent ERK1 activation increases triacylglycerides in

  6. Novel regulation of equlibrative nucleoside transporter 1 (ENT1) by receptor-stimulated Ca2+-dependent calmodulin binding

    Science.gov (United States)

    Bicket, Alex; Mehrabi, Pedram; Naydenova, Zlatina; Wong, Victoria; Donaldson, Logan; Stagljar, Igor

    2016-01-01

    Equilibrative nucleoside transporters (ENTs) facilitate the flux of nucleosides, such as adenosine, and nucleoside analog (NA) drugs across cell membranes. A correlation between adenosine flux and calcium-dependent signaling has been previously reported; however, the mechanistic basis of these observations is not known. Here we report the identification of the calcium signaling transducer calmodulin (CaM) as an ENT1-interacting protein, via a conserved classic 1-5-10 motif in ENT1. Calcium-dependent human ENT1-CaM protein interactions were confirmed in human cell lines (HEK293, RT4, U-87 MG) using biochemical assays (HEK293) and the functional assays (HEK293, RT4), which confirmed modified nucleoside uptake that occurred in the presence of pharmacological manipulations of calcium levels and CaM function. Nucleoside and NA drug uptake was significantly decreased (∼12% and ∼39%, respectively) by chelating calcium (EGTA, 50 μM; BAPTA-AM, 25 μM), whereas increasing intracellular calcium (thapsigargin, 1.5 μM) led to increased nucleoside uptake (∼26%). Activation of N-methyl-d-aspartate (NMDA) receptors (in U-87 MG) by glutamate (1 mM) and glycine (100 μM) significantly increased nucleoside uptake (∼38%) except in the presence of the NMDA receptor antagonist, MK-801 (50 μM), or CaM antagonist, W7 (50 μM). These data support the existence of a previously unidentified novel receptor-dependent regulatory mechanism, whereby intracellular calcium modulates nucleoside and NA drug uptake via CaM-dependent interaction of ENT1. These findings suggest that ENT1 is regulated via receptor-dependent calcium-linked pathways resulting in an alteration of purine flux, which may modulate purinergic signaling and influence NA drug efficacy. PMID:27009875

  7. Discounting of money and sex: effects of commodity and temporal position in stimulant-dependent men and women.

    Science.gov (United States)

    Jarmolowicz, David P; Landes, Reid D; Christensen, Darren R; Jones, Bryan A; Jackson, Lisa; Yi, Richard; Bickel, Warren K

    2014-11-01

    Research on delay discounting has contributed to the understanding of numerous addiction-related phenomena. For example, studies have shown that substance dependent individuals discount their addictive substances (e.g., cocaine) more rapidly than they do other commodities (e.g., money). Recent research has shown that substance dependent individuals discount delayed sex more rapidly than delayed money, and their discounting rates for delayed sex were higher than those of non-addicted individuals. The particular reason that delay discounting rates for sex are higher than those for money, however, are unclear. Do individuals discount delayed sex rapidly because immediate sex is particularly appealing or because delayed sex does not retain its value? Moreover, do the same factors influence men and women's choices? The current study examined delay discounting in four conditions (money now versus money later; sex now versus sex later; money now, versus sex later; sex now versus money later) in cocaine dependent men and women. The procedures used isolated the role of the immediate versus delayed commodity. For men, the higher rates of delay discounting for sex were because delayed sex did not retain its value, whereas both the immediate and delayed commodity influenced the female participants' decisions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Stimulation of dihydroxyacetone and glycerol kinase activity in Streptococcus faecalis by phosphoenolpyruvate-dependent phosphorylation catalyzed by enzyme I and HPr of the phosphotransferase systems

    International Nuclear Information System (INIS)

    Deutscher, J.; Sauerwald, H.

    1986-01-01

    Recently a report was given of the phosphoenolpyruvate (PEP)-dependent phosphorylation of a 55-kilodalton protein of Streptococus faecalis catalyzed by enzyme I and histidine-containing protein (HPr) of the phosphotransferase system. The purified 55-kilodalton protein was found to exhibit dihydroxyacetone kinase activity. Glycerol was six times more slowly phosphorylated than dihydroxyacetone. The K/sub m/s were found to 0.7 mM for ATP, 0.45 mM for dihydroxyacetone, and 0.9 MM for glycerol. PEP-dependent phosphorylation of dihydroxyacetone kinase stimulated phosphorylation of both substrates about 10-fold. Fructose 1,6-diphosphate at concentrations higher than 2 mM inhibited the activity of phosphorylated and unphosphorylated dihydroxyacetone kinase in a noncompetitive manner. The rate of PEP-dependent phosphorylation of dihydroxyacetone kinase was about 200-fold slower than the phosphorylation rate of III proteins (also called enzyme III or factor III), which so far have been considered the only phosphoryl acceptors of histidyl-phosphorylated HPr. P-Dihydroxyacetone kinase was found to be able to transfer its phosphoryl group in a backward reaction to HPr. Following [ 32 P]PEP-dependent phosphorylation and tryptic digestion of dihydroxyacetone kinase, the authors isolated a labeled peptide composed of 37 amino acids, as determined by amino acid analysis. The single histidyl residue of this peptide most likely carries the phosphoryl group in phosphorylated dihydroxyacetone kinase

  9. Stimulation of dihydroxyacetone and glycerol kinase activity in Streptococcus faecalis by phosphoenolpyruvate-dependent phosphorylation catalyzed by enzyme I and HPr of the phosphotransferase systems

    Energy Technology Data Exchange (ETDEWEB)

    Deutscher, J.; Sauerwald, H.

    1986-06-01

    Recently a report was given of the phosphoenolpyruvate (PEP)-dependent phosphorylation of a 55-kilodalton protein of Streptococus faecalis catalyzed by enzyme I and histidine-containing protein (HPr) of the phosphotransferase system. The purified 55-kilodalton protein was found to exhibit dihydroxyacetone kinase activity. Glycerol was six times more slowly phosphorylated than dihydroxyacetone. The K/sub m/s were found to 0.7 mM for ATP, 0.45 mM for dihydroxyacetone, and 0.9 MM for glycerol. PEP-dependent phosphorylation of dihydroxyacetone kinase stimulated phosphorylation of both substrates about 10-fold. Fructose 1,6-diphosphate at concentrations higher than 2 mM inhibited the activity of phosphorylated and unphosphorylated dihydroxyacetone kinase in a noncompetitive manner. The rate of PEP-dependent phosphorylation of dihydroxyacetone kinase was about 200-fold slower than the phosphorylation rate of III proteins (also called enzyme III or factor III), which so far have been considered the only phosphoryl acceptors of histidyl-phosphorylated HPr. P-Dihydroxyacetone kinase was found to be able to transfer its phosphoryl group in a backward reaction to HPr. Following (/sup 32/P)PEP-dependent phosphorylation and tryptic digestion of dihydroxyacetone kinase, the authors isolated a labeled peptide composed of 37 amino acids, as determined by amino acid analysis. The single histidyl residue of this peptide most likely carries the phosphoryl group in phosphorylated dihydroxyacetone kinase.

  10. Cord blood-derived macrophage-lineage cells rapidly stimulate osteoblastic maturation in mesenchymal stem cells in a glycoprotein-130 dependent manner.

    Directory of Open Access Journals (Sweden)

    Tania J Fernandes

    Full Text Available In bone, depletion of osteoclasts reduces bone formation in vivo, as does osteal macrophage depletion. How osteoclasts and macrophages promote the action of bone forming osteoblasts is, however, unclear. Since recruitment and differentiation of multi-potential stromal cells/mesenchymal stem cells (MSC generates new active osteoblasts, we investigated whether human osteoclasts and macrophages (generated from cord blood-derived hematopoietic progenitors induce osteoblastic maturation in adipose tissue-derived MSC. When treated with an osteogenic stimulus (ascorbate, dexamethasone and β-glycerophosphate these MSC form matrix-mineralising, alkaline phosphatase-expressing osteoblastic cells. Cord blood-derived progenitors were treated with macrophage colony stimulating factor (M-CSF to form immature proliferating macrophages, or with M-CSF plus receptor activator of NFκB ligand (RANKL to form osteoclasts; culture medium was conditioned for 3 days by these cells to study their production of osteoblastic factors. Both osteoclast- and macrophage-conditioned medium (CM greatly enhanced MSC osteoblastic differentiation in both the presence and absence of osteogenic medium, evident by increased alkaline phosphatase levels within 4 days and increased mineralisation within 14 days. These CM effects were completely ablated by antibodies blocking gp130 or oncostatin M (OSM, and OSM was detectable in both CM. Recombinant OSM very potently stimulated osteoblastic maturation of these MSC and enhanced bone morphogenetic protein-2 (BMP-2 actions on MSC. To determine the influence of macrophage activation on this OSM-dependent activity, CM was collected from macrophage populations treated with M-CSF plus IL-4 (to induce alternative activation or with GM-CSF, IFNγ and LPS to cause classical activation. CM from IL-4 treated macrophages stimulated osteoblastic maturation in MSC, while CM from classically-activated macrophages did not. Thus, macrophage-lineage cells

  11. Nitric Oxide Synthase 1 Modulates Basal and β-Adrenergic-Stimulated Contractility by Rapid and Reversible Redox-Dependent S-Nitrosylation of the Heart.

    Directory of Open Access Journals (Sweden)

    Alejandra Z Vielma

    Full Text Available S-nitrosylation of several Ca2+ regulating proteins in response to β-adrenergic stimulation was recently described in the heart; however the specific nitric oxide synthase (NOS isoform and signaling pathways responsible for this modification have not been elucidated. NOS-1 activity increases inotropism, therefore, we tested whether β-adrenergic stimulation induces NOS-1-dependent S-nitrosylation of total proteins, the ryanodine receptor (RyR2, SERCA2 and the L-Type Ca2+ channel (LTCC. In the isolated rat heart, isoproterenol (10 nM, 3-min increased S-nitrosylation of total cardiac proteins (+46±14% and RyR2 (+146±77%, without affecting S-nitrosylation of SERCA2 and LTCC. Selective NOS-1 blockade with S-methyl-L-thiocitrulline (SMTC and Nω-propyl-l-arginine decreased basal contractility and relaxation (-25-30% and basal S-nitrosylation of total proteins (-25-60%, RyR2, SERCA2 and LTCC (-60-75%. NOS-1 inhibition reduced (-25-40% the inotropic response and protein S-nitrosylation induced by isoproterenol, particularly that of RyR2 (-85±7%. Tempol, a superoxide scavenger, mimicked the effects of NOS-1 inhibition on inotropism and protein S-nitrosylation; whereas selective NOS-3 inhibitor L-N5-(1-Iminoethylornithine had no effect. Inhibition of NOS-1 did not affect phospholamban phosphorylation, but reduced its oligomerization. Attenuation of contractility was abolished by PKA blockade and unaffected by guanylate cyclase inhibition. Additionally, in isolated mouse cardiomyocytes, NOS-1 inhibition or removal reduced the Ca2+-transient amplitude and sarcomere shortening induced by isoproterenol or by direct PKA activation. We conclude that 1 normal cardiac performance requires basal NOS-1 activity and S-nitrosylation of the calcium-cycling machinery; 2 β-adrenergic stimulation induces rapid and reversible NOS-1 dependent, PKA and ROS-dependent, S-nitrosylation of RyR2 and other proteins, accounting for about one third of its inotropic effect.

  12. Prostanoid formation in primary astroglial cell cultures: Ca(2+)-dependency and stimulation by A 23187, melittin and phospholipases A(2) and C.

    Science.gov (United States)

    Keller, M; Seregi, A; Hertting, G; Jackisch, R

    1987-01-01

    Prostaglandin (PG) and thromboxane B(2) (TXB(2)) biosynthesis was studied in cultured astrocytes from neonatal rat brain hemispheres. After two weeks of cultivation, prostanoids were formed with the spectrum: PGD(2) > TXB(2) > PGF(2?) > PGE(2), as measured by specific radioimmunoassays. Under basal conditions PGD(2) biosynthesis (9.55 ng/mg protein/15 min) was in the same order of magnitude as the sum of the other prostanoids. The formation of prostanoids was stimulated in a concentration dependent manner (up to 6-10 fold) by the calcium ionophore A 23187 (0.01-10 ?M) as well as by melittin (0.01-5 ?g/ml), phospholipase A(2) (10-40 U/ml) and phospholipase C (0.01-1 U/ml). Basal and evoked PG and TXB(2) biosynthesis depended on the availability of Ca(2+), as demonstrated in Ca(2+) free incubation medium containing Na(2)EDTA (1 ?M), or with verapamil (100 ?M) and 3,4,5-trimethoxybenzoic acid-8-(diethylamino)-octylester-HCl (TMB-8, 1-100 ?M). Indomethacin (10 ?M), mepacrine (100 ?M) and p-bromophenacylbromide (50 ? M) inhibited basal and evoked PG formation. Thin-layer chromatography (TLC) detection after incubation of the cells with [(3)H]arachidonic acid (1 ?Ci/ml, for 60 min) confirmed the results obtained by radioimmunoassay. Incubation of [(3)H]arachidonic acid labelled cells with inonophore or phospholipases, followed by lipid extraction and TLC, showed that A 23187 liberated [(3)H]arachidonic acid predominantly from phosphatidylethanolamine, whereas phospholipase A(2) and C reduced mainly the labelling of the phosphatidyl-inositol/-choline fraction. Potassium depolarization of the cells did not enhance prostanoid formation. Similarly, drugs with affinity to ?- or ?-adrenoceptors, or to dopamine-, 5-hydroxytryptamine-, muscarine-, histamine-, glutamate-, aspartate-, GABA, adenosine- and opioid-receptors failed to stimulate prostanoid biosynthesis. Also compounds like angiotensin, bradykinin and thrombin were ineffective in this respect. In conclusion, our

  13. Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion

    Directory of Open Access Journals (Sweden)

    Kathrin eHoppenrath

    2016-03-01

    Full Text Available Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV fast-spiking interneurons (FSIs, evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs of FSIs start to grow around postnatal day 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo – in vitro whole-cell patch clamp recordings from pre-labelled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28 and older animals (PD40-62. Slices of verum iTBS-treated rats further showed higher rates of spontaneous EPSCs. Based on these and previous findings we conclude that FSIs are particularly sensitive to theta-burst stimulation during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

  14. Is the efficacy of sacral nerve stimulation for faecal incontinence dependent on the number of active electrode poles achieved during permanent lead insertion?

    Science.gov (United States)

    Duelund-Jakobsen, J; Lundby, L; Lehur, P-A; Wyart, V; Laurberg, S; Buntzen, S

    2016-11-01

    Sacral nerve stimulation (SNS) is effective for faecal incontinence (FI). Little is known about the relationship between the implantation technique and the functional outcome. This study aimed to explore the relationship between the numbers of active electrode poles (AEP) achieved during permanent lead placement and subsequent function, therapeutic amplitude and the need for extra appointments between scheduled follow-up visits. One hundred and eighty-six patients with FI who underwent permanent implantation between May 2009 and March 2015 with a tined (barbed) lead (3093/3080, Medtronic) using the straight stylet were registered on the European two-centre SNS prospective database (SNSPD). Correlation between the number of AEP, function, stimulation amplitude and the need for extra visits was analysed. The numbers of patients having an intra-operative motor response on stimulation of one, two, three and four poles were 18 (9.7%), 75 (40.3%), 61 (32.8%) and 32 (17.2%). The Wexner incontinence score was significantly reduced from 15 (±2.8) at baseline to 9.2 (±4.8) at the latest follow-up after a mean 878 ± 561 days (SD; P  0.05). Patients with four-AEP had a reduced therapeutic amplitude up to 289 (±146) days of follow-up (P < 0.03). The number of AEP did not influence the need for extra follow-up visits (P < 0.223). The functional outcome and number of extra visits after SNS for FI did not depend on the number of AEP achieved. The therapeutic amplitude was reduced during the first postoperative year if four AEP were achieved during lead placement. Colorectal Disease © 2016 The Association of Coloproctology of Great Britain and Ireland.

  15. Orexin-A stimulates the expression of GLUT4 in a glucose dependent manner in the liver of orange-spotted grouper (Epinephelus coioides).

    Science.gov (United States)

    Zhang, Cong; Sun, Caiyun; Wang, Bin; Yan, Peipei; Wu, Amin; Yang, Guokun; Li, Wensheng

    2016-09-01

    Orexins are hypothalamic neuropeptides involved in the central regulation of feeding behavior, sleep-wake cycle and other physiological functions. Orexin-A can regulate energy metabolism and increase glucose uptake, suggesting a role in glucose metabolism. In this study, we investigated the effects of orexin-A on GLUT4 mRNA and protein levels and the intracellular signaling mechanisms mediating orexin-A activity in the hepatocytes of grouper. Our results demonstrate that intraperitoneal injection of orexin-A increased the expression of GLUT4 in the liver, and this effect was significantly enhanced by co-injection of glucose. Treatment of primary cultured hepatocytes with either orexin-A or glucose alone had no effect on the expression of GLUT4, while co-treatment with orexin-A and glucose significantly increased the expression of GLUT4. This stimulatory effect was partially blocked by inhibitors to ERK1/2, JNK or p38 MAPK and was further blocked by an orexin receptor antagonist, which indicates that orexin-A could stimulate the expression of GLUT4 in a glucose dependent manner in primary hepatocytes via ERK1/2, JNK and p38 signaling. Our results suggest that orexin-A could play a pivotal role in stimulating glucose utilization in grouper, for a long-term goal, which might be useful in reducing costs in the aquaculture industry. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Energy dependence measurement of small-type optically stimulated luminescence (OSL) dosimeter by means of characteristic X-rays induced with general diagnostic X-ray equipment.

    Science.gov (United States)

    Takegami, Kazuki; Hayashi, Hiroaki; Okino, Hiroki; Kimoto, Natsumi; Maehata, Itsumi; Kanazawa, Yuki; Okazaki, Tohru; Hashizume, Takuya; Kobayashi, Ikuo

    2016-01-01

    For X-ray inspections by way of general X-ray equipment, it is important to measure an entrance-skin dose. Recently, a small optically stimulated luminescence (OSL) dosimeter was made commercially available by Landauer, Inc. The dosimeter does not interfere with the medical images; therefore, it is expected to be a convenient detector for measuring personal exposure doses. In an actual clinical situation, it is assumed that X-rays of different energies will be detected by a dosimeter. For evaluation of the exposure dose measured by a dosimeter, it is necessary to know the energy dependence of the dosimeter. Our aim in this study was to measure the energy dependence of the OSL dosimeter experimentally in the diagnostic X-ray region. Metal samples weighing several grams were irradiated and, in this way, characteristic X-rays having energies ranging from 8 to 85 keV were generated. Using these mono-energetic X-rays, the dosimeter was irradiated. Simultaneously, the fluence of the X-rays was determined with a CdTe detector. The energy-dependent efficiency of the dosimeter was derived from the measured value of the dosimeter and the fluence. Moreover, the energy-dependent efficiency was calculated by Monte-Carlo simulation. The efficiency obtained in the experiment was in good agreement with that of the simulation. In conclusion, our proposed method, in which characteristic X-rays are used, is valuable for measurement of the energy dependence of a small OSL dosimeter in the diagnostic X-ray region.

  17. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease.

    Science.gov (United States)

    Thomas, Karen E; Sapone, Anna; Fasano, Alessio; Vogel, Stefanie N

    2006-02-15

    Recent studies have demonstrated the importance of TLR signaling in intestinal homeostasis. Celiac disease (CD) is an autoimmune enteropathy triggered in susceptible individuals by the ingestion of gliadin-containing grains. In this study, we sought to test the hypothesis that gliadin initiates this response by stimulating the innate immune response to increase intestinal permeability and by up-regulating macrophage proinflammatory gene expression and cytokine production. To this end, intestinal permeability and the release of zonulin (an endogenous mediator of gut permeability) in vitro, as well as proinflammatory gene expression and cytokine release by primary murine macrophage cultures, were measured. Gliadin and its peptide derivatives, 33-mer and p31-43, were found to be potent inducers of both a zonulin-dependent increase in intestinal permeability and macrophage proinflammatory gene expression and cytokine secretion. Gliadin-induced zonulin release, increased intestinal permeability, and cytokine production were dependent on myeloid differentiation factor 88 (MyD88), a key adapter molecule in the TLR/IL-1R signaling pathways, but were neither TLR2- nor TLR4-dependent. Our data support the following model for the innate immune response to gliadin in the initiation of CD. Gliadin interaction with the intestinal epithelium increases intestinal permeability through the MyD88-dependent release of zonulin that, in turn, enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa. There, the interaction of gliadin with macrophages elicits a MyD88-dependent proinflammatory cytokine milieu that facilitates the interaction of T cells with APCs, leading ultimately to the Ag-specific adaptive immune response seen in patients with CD.

  18. Cholinergic Transactivation of the EGFR in HaCaT Keratinocytes Stimulates a Flotillin-1 Dependent MAPK-Mediated Transcriptional Response

    Directory of Open Access Journals (Sweden)

    Sina Kühne

    2015-03-01

    Full Text Available Acetylcholine and its receptors regulate numerous cellular processes in keratinocytes and other non-neuronal cells. Muscarinic acetylcholine receptors are capable of transactivating the epidermal growth factor receptor (EGFR and, downstream thereof, the mitogen-activated protein kinase (MAPK cascade, which in turn regulates transcription of genes involved in cell proliferation and migration. We here show that cholinergic stimulation of human HaCaT keratinocytes results in increased transcription of matrix metalloproteinase MMP-3 as well as several ligands of the epidermal growth factor family. Since both metalloproteinases and the said ligands are involved in the transactivation of the EGFR, this transcriptional upregulation may provide a positive feed-forward loop for EGFR/MAPK activation. We here also show that the cholinergic EGFR and MAPK activation and the upregulation of MMP-3 and EGF-like ligands are dependent on the expression of flotillin-1 which we have previously shown to be a regulator of MAPK signaling.

  19. NOX5-L can stimulate proliferation and apoptosis depending on its levels and cellular context, determining cancer cell susceptibility to cisplatin

    Science.gov (United States)

    Kwon, Eun-Soo; Lim, Jae Cheong; Park, Sung Sup; Kwon, Ki-Sun

    2015-01-01

    The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death—a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner. PMID:26513170

  20. Methoxychlor and triclosan stimulates ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an estrogen receptor-dependent pathway.

    Science.gov (United States)

    Kim, Joo-Young; Yi, Bo-Rim; Go, Ryeo-Eun; Hwang, Kyung-A; Nam, Ki-Hoan; Choi, Kyung-Chul

    2014-05-01

    Methoxychlor and triclosan are emergent or suspected endocrine-disrupting chemicals (EDCs). Methoxychlor [MXC; 1,1,1-trichlor-2,2-bis (4-methoxyphenyl) ethane] is an organochlorine pesticide that has been primarily used since dichlorodiphenyltrichloroethane (DDT) was banned. In addition, triclosan (TCS) is used as a common component of soaps, deodorants, toothpastes, and other hygiene products at concentrations up to 0.3%. In the present study, the potential impact of MXC and TCS on ovarian cancer cell growth and underlying mechanism(s) was examined following their treatments in BG-1 ovarian cancer cells. As results, MXC and TCS induced BG-1 cell growth via regulating cyclin D1, p21 and Bax genes related with cell cycle and apoptosis. A methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay confirmed that the proliferation of BG-1 ovarian cancer cells was stimulated by MXC (10(-6), 10(-7), 10(-8), and 10(-9)M) or TCS (10(-6), 10(-7), 10(-8), and 10(-9)M). Treatment of BG-1 cells with MXC or TCS resulted in the upregulation of cyclin D1 and downregulation of p21 and Bax transcriptions. In addition, the protein level of cyclin D1 was increased by MXC or TCS while p21 and Bax protein levels appeared to be reduced in these cells. Furthermore, MXC- or TCS-induced alterations of these genes were reversed in the presence of ICI 182,780 (10(-7)M), suggesting that the changes in these gene expressions may be regulated by an ER-dependent signaling pathway. In conclusion, the results of our investigation indicate that two potential EDCs, MXC and TCS, may stimulate ovarian cancer growth by regulating cell cycle- and apoptosis-related genes via an ER-dependent pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Comparaison de quelques caractéristiques biologiques entre Dinarmus basalis Rond. (Hymenoptera: Pteromalidae élevé soit sur son hôte habituel Callosobruchus maculatus F. (Coleoptera: Bruchidae soit sur Acanthoscelides macrophthalmus Schaef. ou Bruchidius lineatopygus Pic. identifiés comme hôtes de substitution

    Directory of Open Access Journals (Sweden)

    Nuto, Y.

    2006-01-01

    Full Text Available Comparison of some Biological Characteristics between Dinarmus basalis Rond. (Hymenoptera: Pteromalidae Reared either on his Habitual Host Callosobruchus maculatus F. (Coleoptera: Bruchidae or on Acanthoscelides macrophthalmus Schaef. and Bruchidius lineatopygus Pic. Identified as Substitution Hosts. In this study, we have measured some biological parameters of Dinarmus basalis Rond. (Hymenoptera: Pteromalidae when this parasitoid grows on three hosts: Callosobruchus maculatus F. (usual host, Acanthoscelides macrophthalma Schaef. and Bruchidius lineatopygus Pic. (substitution hosts. The results of this comparative study in no choice situation show that, life duration and development duration of this parasitoid are identical in laboratory conditions. By contrast, the female fecundity, the sexual rate and the parasitism rate of D. basalis are different according to the hosts presented. Although such differences appear to be small between C. maculatus and A. macrophthalmus. In presence of these two species, the number of eggs laid by the female of D. basalis is respectively 61 ± 5.24 and 54 ± 5.60, the sexual rate 37.63 ± 2.13% and 41.73 ± 3.69% and the parasitism rate 85.46 ± 2.61% and 76.48 ± 5.90%. This indicates that these two Bruchids can be used as hosts to D. basalis for a mass production. In presence of B. lineatopygus, the fecundity and the parasitism rate of D. basalis female are very low and the sexual rate more favourable of the males. This situation is unfavourable for a parasitoid production. When D. basalis females are placed in choice situation with equal number of the hosts nowely C. maculatus and A. macrophthalmus, the parasitism rate obtained, is higher for C. maculatus that of A. macrophthalmus. This parasitism rate remains high for C. maculatus even when the other host A. macrophthalmus is twice the number of C. maculatus. Thus the parasitoid seems to have a preference for his natural host. However, A. macrophthalmus can

  2. Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve- and Catecholamine-Dependent Mechanisms

    Directory of Open Access Journals (Sweden)

    Albino Villegas-Bastida

    2014-01-01

    Full Text Available Electrical vagus nerve (VN stimulation during sepsis attenuates tumor necrosis factor (TNF production through the cholinergic anti-inflammatory pathway, which depends on the integrity of the VN and catecholamine production. To characterize the effect of electroacupuncture at ST36 (EA-ST36 on serum TNF, IL-6, nitrite, and HMGB1 levels and survival rates, based on VN integrity and catecholamine production, a sepsis model was induced in rats using cecal ligation and puncture (CLP. The septic rats were subsequently treated with EA-ST36 (CLP+ST36, and serum samples were collected and analyzed for cytokines levels. The serum TNF, IL-6, nitrite, and HMGB1 levels in the CLP+ST36 group were significantly lower compared with the group without treatment, the survival rates were significantly higher (P<0.05, and the acute organ injury induced by CLP was mitigated by EA-ST36; however, when subdiaphragmatic vagotomy was performed, the serum levels of TNF in the CLP+ST36 group did not show a significant difference compared with the group without electrostimulation, and, similarly, no significant difference in serum TNF levels was found under the pharmacological blockade of catecholamines. These results suggest that in rats with CLP sepsis models EA-ST36 reduces serum TNF levels through VN- and atecholamine-dependent mechanisms.

  3. Induction of retinal-dependent calcium influx in human melanocytes by UVA or UVB radiation contributes to the stimulation of melanosome transfer.

    Science.gov (United States)

    Hu, Qing-Mei; Yi, Wen-Juan; Su, Meng-Yun; Jiang, Shan; Xu, Shi-Zheng; Lei, Tie-Chi

    2017-12-01

    The transfer of melanosomes from melanocytes to neighbouring keratinocytes is critical to protect the skin from the deleterious effects of ultraviolet A (UVA) and ultraviolet B (UVB) irradiation; however, the initial factor(s) that stimulates melanosome transfer remains unclear. In this study, we investigated the induction of retinal-dependent calcium (Ca 2+ ) influx in melanocytes (MCs) by UVA or UVB irradiation and the effect of transient receptor potential cation channel subfamily M member 1 (TRPM1) (melastatin1)-related Ca 2+ influx on melanosome transfer. Primary human epidermal MCs were exposed to physiological doses of UVB or UVA light and loaded with a calcium indicator Fluo-4 dye. The change of intracellular calcium of MCs was monitored using a two-photon confocal fluorescence microscopy. MCs were co-cultured with human epidermal keratinocytes (KCs) in the absence or presence of voriconazole (a TRPM1 blocker) or calcium chelators. MCs were also transfected with TRPM1 siRNA for silencing the expression of TRPM1 gene. The melanosome transfer in the co-cultured cells was quantitatively analysed using flow cytometry and was further confirmed by immunofluorescent double-staining. The protein levels and distributions of TRPM1, OPN3 and OPN5 in MCs were measured by Western blotting or immunofluorescent staining. The retinal-dependent Ca 2+ influx of UVA-exposed melanocytes differed greatly from that of UVB-exposed melanocytes in the timing-phase. The protein expression of TRPM1 in mono- and co-cultured MCs was dose-dependently up-regulated by UVA and UVB. TRPM1 siRNA-mediated knockdown and the blockage of TRPM1 channel using a putative antagonist (voriconazole) significantly inhibited melanosome transfer in co-cultures following UVA or UVB exposure. The distinct time-phases of Ca 2+ influx in MCs induced by UVA or UVB contribute to the consecutive stimulation of melanosome transfer, thereby providing a potent photoprotection against harmful UV radiation. © 2017

  4. Inhibition of Calpain Prevents N-Methyl-D-aspartate-Induced Degeneration of the Nucleus Basalis and Associated Behavioral Dysfunction

    NARCIS (Netherlands)

    Nimmrich, Volker; Szabo, Robert; Nyakas, Csaba; Granic, Ivica; Reymann, Klaus G.; Schroeder, Ulrich H.; Gross, Gerhard; Schoemaker, Hans; Wicke, Karsten; Moeller, Achim; Luiten, Paul

    2008-01-01

    N-Methyl-D-aspartate( NMDA) receptor-mediated excitotoxicity is thought to underlie a variety of neurological disorders, and inhibition of either the NMDA receptor itself, or molecules of the intracellular cascade, may attenuate neurodegeneration in these diseases. Calpain, a calcium-dependent

  5. Intermittent Theta-Burst Transcranial Magnetic Stimulation Alters Electrical Properties of Fast-Spiking Neocortical Interneurons in an Age-Dependent Fashion.

    Science.gov (United States)

    Hoppenrath, Kathrin; Härtig, Wolfgang; Funke, Klaus

    2016-01-01

    Modulation of human cortical excitability by repetitive transcranial magnetic stimulation (rTMS) appears to be in part related to changed activity of inhibitory systems. Our own studies showed that intermittent theta-burst stimulation (iTBS) applied via rTMS to rat cortex primarily affects the parvalbumin-expressing (PV) fast-spiking interneurons (FSIs), evident via a strongly reduced PV expression. We further found the iTBS effect on PV to be age-dependent since no reduction in PV could be induced before the perineuronal nets (PNNs) of FSIs start to grow around postnatal day (PD) 30. To elucidate possible iTBS-induced changes in the electrical properties of FSIs and cortical network activity during cortical critical period, we performed ex vivo-in vitro whole-cell patch clamp recordings from pre-labeled FSIs in the current study. FSIs of verum iTBS-treated rats displayed a higher excitability than sham-treated controls at PD29-38, evident as higher rates of induced action potential firing at low current injections (100-200 pA) and a more depolarized resting membrane potential. This effect was absent in younger (PD26-28) and older animals (PD40-62). Slices of verum iTBS-treated rats further showed higher rates of spontaneous excitatory postsynaptic currents (sEPSCs). Based on these and previous findings we conclude that FSIs are particularly sensitive to TBS during early cortical development, when FSIs show an activity-driven step of maturation which is paralleled by intense growth of the PNNs and subsequent closure of the cortical critical period. Although to be proven further, rTMS may be a possible early intervention to compensate for hypo-activity related mal-development of cortical neuronal circuits.

  6. Kaempferol stimulates large conductance Ca2+-activated K+ (BKCa) channels in human umbilical vein endothelial cells via a cAMP/PKA-dependent pathway

    Science.gov (United States)

    Xu, Y C; Leung, G P H; Wong, P Y D; Vanhoutte, P M; Man, R Y K

    2008-01-01

    Background and purpose: Kaempferol has been shown to possess a vasodilator effect but its mechanism of action remains unclear. In this study, experiments were carried out to study the effect of kaempferol on K+ channels in endothelial cells. Experimental approach: K+ channel activities in human umbilical vein endothelial cells (HUVECs) were studied by conventional whole cell and cell-attached patch-clamp electrophysiology. Key results: Kaempferol stimulated an outward-rectifying current in HUVECs in a dose-dependent manner with an EC50 value of 2.5±0.02 μM. This kaempferol-induced current was abolished by large conductance Ca2+-activated K+ (BKCa) channel blockers, such as iberiotoxin (IbTX) and charybdotoxin (ChTX), whereas the small conductance Ca2+-activated K+ (SKCa) channel blocker, apamin, and the voltage-dependent K+ (KV) channel blocker, 4-aminopyridine, had no effect. Cell-attached patches demonstrated that kaempferol increased the open probability of BkCa channels in HUVECs. Clamping intracellular Ca2+ did not prevent kaempferol-induced increases in outward current. In addition, the kaempferol-induced current was diminished by the adenylyl cyclase inhibitor SQ22536, the cAMP antagonist Rp-8-Br-cAMP and the PKA inhibitor KT5720, but was not affected by the guanylyl cyclase inhibitor ODQ, the cGMP antagonist Rp-8-Br-cGMP and the PKG inhibitor KT5823. The activation of BKCa channels by kaempferol caused membrane hyperpolarization of HUVECs. Conclusion and implications: These results demonstrate that kaempferol activates the opening of BKCa channels in HUVECs via a cAMP/PKA-dependent pathway, resulting in membrane hyperpolarization. This mechanism may partly account for the vasodilator effects of kaempferol. PMID:18493242

  7. Mycobacterium tuberculosis UvrB Is a Robust DNA-Stimulated ATPase That Also Possesses Structure-Specific ATP-Dependent DNA Helicase Activity.

    Science.gov (United States)

    Thakur, Manoj; Kumar, Mohan B J; Muniyappa, K

    2016-10-18

    Much is known about the Escherichia coli nucleotide excision repair (NER) pathway; however, very little is understood about the proteins involved and the molecular mechanism of NER in mycobacteria. In this study, we show that Mycobacterium tuberculosis UvrB (MtUvrB), which exists in solution as a monomer, binds to DNA in a structure-dependent manner. A systematic examination of MtUvrB substrate specificity reveals that it associates preferentially with single-stranded DNA, duplexes with 3' or 5' overhangs, and linear duplex DNA with splayed arms. Whereas E. coli UvrB (EcUvrB) binds weakly to undamaged DNA and has no ATPase activity, MtUvrB possesses intrinsic ATPase activity that is greatly stimulated by both single- and double-stranded DNA. Strikingly, we found that MtUvrB, but not EcUvrB, possesses the DNA unwinding activity characteristic of an ATP-dependent DNA helicase. The helicase activity of MtUvrB proceeds in the 3' to 5' direction and is strongly modulated by a nontranslocating 5' single-stranded tail, indicating that in addition to the translocating strand it also interacts with the 5' end of the substrate. The fraction of DNA unwound by MtUvrB decreases significantly as the length of the duplex increases: it fails to unwind duplexes longer than 70 bp. These results, on one hand, reveal significant mechanistic differences between MtUvrB and EcUvrB and, on the other, support an alternative role for UvrB in the processing of key DNA replication intermediates. Altogether, our findings provide insights into the catalytic functions of UvrB and lay the foundation for further understanding of the NER pathway in M. tuberculosis.

  8. CFTR-mediated anion secretion across intestinal epithelium-like Caco-2 monolayer under PTH stimulation is dependent on intermediate conductance K+ channels.

    Science.gov (United States)

    Jantarajit, Walailak; Lertsuwan, Kornkamon; Teerapornpuntakit, Jarinthorn; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

    2017-07-01

    Parathyroid hormone (PTH), a pleiotropic hormone that maintains mineral homeostasis, is also essential for controlling pH balance and ion transport across renal and intestinal epithelia. Optimization of luminal pH is important for absorption of trace elements, e.g., calcium and phosphorus. We have previously demonstrated that PTH rapidly stimulated electrogenic [Formula: see text] secretion in intestinal epithelial-like Caco-2 monolayers, but the underlying cellular mechanism, contributions of other ions, particularly Cl - and K + , and long-lasting responses are not completely understood. Herein, PTH and forskolin were confirmed to induce anion secretion, which peaked within 1-3 min (early phase), followed by an abrupt decay and plateau that lasted for 60 min (late phase). In both early and late phases, apical membrane capacitance was increased with a decrease in basolateral capacitance after PTH or forskolin exposure. PTH also induced a transient increase in apical conductance with a long-lasting decrease in basolateral conductance. Anion secretion in both phases was reduced under [Formula: see text]-free and/or Cl - -free conditions or after exposure to carbonic anhydrase inhibitor (acetazolamide), CFTR inhibitor (CFTRinh-172), Na + /H + exchanger (NHE)-3 inhibitor (tenapanor), or K + channel inhibitors (BaCl 2 , clotrimazole, and TRAM-34; basolateral side), the latter of which suggested that PTH action was dependent on basolateral K + recycling. Furthermore, early- and late-phase responses to PTH were diminished by inhibitors of PI3K (wortmannin and LY-294002) and PKA (PKI 14-22). In conclusion, PTH requires NHE3 and basolateral K + channels to induce [Formula: see text] and Cl - secretion, thus explaining how PTH regulated luminal pH balance and pH-dependent absorption of trace minerals. Copyright © 2017 the American Physiological Society.

  9. Stimulation of Na+-alanine cotransport activates a voltage-dependent conductance in single proximal tubule cells isolated from frog kidney

    Science.gov (United States)

    Robson, L; Hunter, M

    1999-01-01

    The swelling induced by Na+-alanine cotransport in proximal tubule cells of the frog kidney is followed by regulatory volume decrease (RVD). This RVD is inhibited by gadolinium (Gd3+), an inhibitor of stretch-activated channels, but is independent of extracellular Ca2+. In this study, the whole cell patch clamp technique was utilized to examine the effect of Na+-alanine cotransport on two previously identified volume- and Gd3+-sensitive conductances. One conductance is voltage dependent and anion selective (GVD) whilst the other is voltage independent and cation selective (GVI). Addition of 5 mM L-alanine to the bathing solution increased the whole cell conductance and gave a positive (depolarizing) shift in the reversal potential (Vrev, equivalent to the membrane potential in current-clamped cells) consistent with activation of Na+-alanine cotransport. Vrev shifted from -36 ± 4·9 to +12·9 ± 4·2 mV (n= 15). In the presence of alanine, the total whole cell conductance had several components including the cotransporter conductance and GVD and GVI. These conductances were separated using Gd3+, which inhibits both GVD and GVI, and the time dependency of GVD. Of these two volume-sensitive conductances, L-alanine elicited a specific increase in GVD, whereas GVI was unaffected. The L-alanine-induced activation of GVD was significantly reduced when cells were incubated in a hypertonic bathing solution. In summary, in single proximal tubule cells isolated from frog kidney, on stimulation of Na+-alanine cotransport GVD is activated, while GVI is unaffected. Taken with other evidence, this suggests that GVD is activated by cell swelling, consequent upon alanine entry, and may play a role as an anion efflux pathway during alanine-induced volume regulation. PMID:10226159

  10. Environmental enrichment and brain repair: harnessing the therapeutic effects of cognitive stimulation and physical activity to enhance experience-dependent plasticity.

    Science.gov (United States)

    Hannan, A J

    2014-02-01

    Environmental enrichment (EE) increases levels of novelty and complexity, inducing enhanced sensory, cognitive and motor stimulation. In wild-type rodents, EE has been found to have a range of effects, such as enhancing experience-dependent cellular plasticity and cognitive performance, relative to standard-housed controls. Whilst environmental enrichment is of course a relative term, dependent on the nature of control environmental conditions, epidemiological studies suggest that EE has direct clinical relevance to a range of neurological and psychiatric disorders. EE has been demonstrated to induce beneficial effects in animal models of a wide variety of brain disorders. The first evidence of beneficial effects of EE in a genetically targeted animal model was generated using Huntington's disease transgenic mice. Subsequent studies found that EE was also therapeutic in mouse models of Alzheimer's disease, consistent with epidemiological studies of relevant environmental modifiers. EE has also been found to ameliorate behavioural, cellular and molecular deficits in animal models of various neurological and psychiatric disorders, including Parkinson's disease, stroke, traumatic brain injury, epilepsy, multiple sclerosis, depression, schizophrenia and autism spectrum disorders. This review will focus on the effects of EE observed in animal models of neurodegenerative brain diseases, at molecular, cellular and behavioural levels. The proposal that EE may act synergistically with other approaches, such as drug and cell therapies, to facilitate brain repair will be discussed. I will also discuss the therapeutic potential of 'enviromimetics', drugs which mimic or enhance the therapeutic effects of cognitive activity and physical exercise, for both neuroprotection and brain repair. © 2013 British Neuropathological Society.

  11. Effects of modafinil and R-modafinil on brain stimulation reward thresholds: implications for their use in the treatment of psychostimulant dependence.

    Science.gov (United States)

    Burrows, Brian T; Watterson, Lucas R; Johnson, Meagan A; Olive, M Foster

    2015-12-01

    Modafinil and its enantiomer R-modafinil are approved for the treatment of various sleep disorders, and may also be efficacious in the treatment of psychostimulant abuse. However, the ability of modafinil and R-modafinil to alter brain reward function has not yet been assessed. This study assessed the effects of modafinil and R-modafinil on brain reward function using the intracranial self-stimulation (ICSS) paradigm. Male Sprague-Dawley rats were trained to respond for ICSS using current-intensity threshold determination procedures. Changes in ICSS thresholds were then assessed following administration of modafinil and R-modafinil (50, 100, and 150 mg/kg), or cocaine (2.5 - 20 mg/kg) as a positive control. ICSS thresholds were reduced by modafinil at the 150 mg/kg dose, as well as by cocaine at the 10 and 20 mg/kg doses. R-modafinil only produced non-significant trends towards reducing ICSS thresholds. Modafinil and R-modafinil have limited effects on brain reward function in otherwise drug-naïve subjects. Additional assessments of these effects in the context of psychostimulant dependence are needed.

  12. Stimulation of apical sodium-dependent bile acid transporter expands the bile acid pool and generates bile acids with positive feedback properties.

    Science.gov (United States)

    Rudling, Mats; Bonde, Ylva

    2015-01-01

    Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as α- and β-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans. 2015 S. Karger AG, Basel.

  13. Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver

    NARCIS (Netherlands)

    Beuers, U.; Bilzer, M.; Chittattu, A.; Kullak-Ublick, G. A.; Keppler, D.; Paumgartner, G.; Dombrowski, F.

    2001-01-01

    Ursodeoxycholic acid (UDCA) exerts anticholestatic effects by undefined mechanisms. Previous work suggested that UDCA stimulates biliary exocytosis via Ca(++)- and protein kinase C (PKC)-dependent mechanisms. Therefore, the effect of taurine-conjugated UDCA (TUDCA) was studied in the experimental

  14. Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease.

    Science.gov (United States)

    Viaña, John Noel M; Bittlinger, Merlin; Gilbert, Frederic

    2017-01-01

    Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

  15. Incremental cost effectiveness of pharmacist-managed erythropoiesis-stimulating agent clinics for non-dialysis-dependent chronic kidney disease patients.

    Science.gov (United States)

    Aspinall, Sherrie L; Smith, Kenneth J; Good, Chester B; Zhao, Xinhua; Stone, Roslyn A; Tonnu-Mihara, Ivy Q; Cunningham, Francesca E

    2013-12-01

    Pharmacists successfully manage patients with anemia and chronic kidney disease (CKD), but the cost effectiveness of these programs is unknown. To compare the cost effectiveness of pharmacist-managed erythropoiesis-stimulating agent (ESA) clinics with that of usual care in patients with non-dialysis-dependent (NDD)-CKD. A Markov model was used to estimate the incremental cost effectiveness of pharmacist-managed ESA clinics compared with usual care in outpatient veterans receiving ESAs for NDD-CKD in 2009. The analysis was conducted from a US Veterans Health Administration perspective with a 5-year time horizon, and the year of valuation for cost results was 2012. The effect of parameter uncertainty was explored in one-way and probabilistic sensitivity analyses. In the deterministic base case analysis, costs and effectiveness per patient over 5 years were US$13,412 and 2.096 quality-adjusted life-years (QALYs) in the pharmacist-managed ESA clinics and US$16,173 and 2.093 QALYs in usual care; ESA clinics dominated usual care. In one-way sensitivity analyses, ESA clinics no longer dominated if their patients' probability of being in the target hemoglobin range fell to 52 % (base case 71 %) or if the mean cost/patient/month of epoetin or darbepoetin in ESA clinics increased to approximately US$382 (base case US$226) or US$477 (base case US$268), respectively. When all parameters were varied simultaneously in a probabilistic sensitivity analysis, ESA clinics were favored ≥80 % of the time at willingness-to-pay thresholds of US$0-$100,000 per QALY gained. Pharmacist-managed ESA clinics were less costly and more effective than usual care in patients receiving ESAs for anemia and NDD-CKD. Results were robust to variation and support the use of pharmacist-managed ESA clinics.

  16. NF-kappaB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses.

    Directory of Open Access Journals (Sweden)

    Rui Zhou

    2009-12-01

    Full Text Available Cryptosporidium parvum is a protozoan parasite that infects the gastrointestinal epithelium and causes diarrheal disease worldwide. Innate epithelial immune responses are key mediators of the host's defense to C. parvum. MicroRNAs (miRNAs regulate gene expression at the posttranscriptional level and are involved in regulation of both innate and adaptive immune responses. Using an in vitro model of human cryptosporidiosis, we analyzed C. parvum-induced miRNA expression in biliary epithelial cells (i.e., cholangiocytes. Our results demonstrated differential alterations in the mature miRNA expression profile in cholangiocytes following C. parvum infection or lipopolysaccharide stimulation. Database analysis of C. parvum-upregulated miRNAs revealed potential NF-kappaB binding sites in the promoter elements of a subset of miRNA genes. We demonstrated that mir-125b-1, mir-21, mir-30b, and mir-23b-27b-24-1 cluster genes were transactivated through promoter binding of the NF-kappaB p65 subunit following C. parvum infection. In contrast, C. parvum transactivated mir-30c and mir-16 genes in cholangiocytes in a p65-independent manner. Importantly, functional inhibition of selected p65-dependent miRNAs in cholangiocytes increased C. parvum burden. Thus, we have identified a panel of miRNAs regulated through promoter binding of the NF-kappaB p65 subunit in human cholangiocytes in response to C. parvum infection, a process that may be relevant to the regulation of epithelial anti-microbial defense in general.

  17. OK-432-stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF-κB phosphorylation, in vitro.

    Science.gov (United States)

    Olsnes, Carla; Bredholt, Therese; Olofsson, Jan; Aarstad, Hans J

    2013-04-01

    Interaction between the immune system and cancer cells allows for the use of biological response modifiers, like OK-432, in cancer therapy. We have studied the involvement of monocytes (MOs) in the immune response to OK-432 by examining MCP-1, MIP-1α and MIP-1β secretion, in vitro. OK-432-induced IL-6/TNF-α secretion has previously been shown to depend on mitogen-activated protein kinases (MAPKs) ERK1/2 and p38, and we therefore investigated the role of these MAPKs in OK-432-induced chemokine secretion. Here we demonstrate that pharmacological MEK1/2 kinase inhibition generally impaired chemokine secretion from MOs, whereas p38 MAPK inhibition in particular reduced MIP-1α production. Furthermore, simultaneous inhibition of MEK1/2 and Syk kinase was seen to have an additive impact on reduced MCP-1, MIP-1α and MIP-1β secretion. Based on single cell flow cytometry analyses, OK-432, lipoteichoic acid (LTA) and lipopolysaccharide (LPS) were seen to induce p38 MAPK and NF-κB phosphorylation in MOs with different time kinetics. LTA and LPS have been shown to induce ERK1/2 phosphorylation, whereas the levels of phosphorylated ERK1/2 remained constant following OK-432 treatment at the time points tested. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, and we demonstrate increased TLR2 cell surface levels on the MO population, most profoundly following stimulation with LTA and OK-432. Together these results indicate that modulation of MEK1/2 and p38 MAPK signalling could affect the response to OK-432 treatment, having the potential to improve its therapeutic potential within cancer and lymphangioma treatment. © 2012 The Authors APMIS © 2012 APMIS.

  18. Urokinase-type plasminogen activator (uPA) stimulates triglyceride synthesis in Huh7 hepatoma cells via p38-dependent upregulation of DGAT2.

    Science.gov (United States)

    Paland, Nicole; Gamliel-Lazarovich, Aviva; Coleman, Raymond; Fuhrman, Bianca

    2014-11-01

    The liver is the central organ of fatty acid and triglyceride metabolism. Oxidation and synthesis of fatty acids and triglycerides is under the control of peroxisome-proliferator-activated receptors (PPAR) α. Impairment of these receptors' function contributes to the accumulation of triglycerides in the liver resulting in non-alcoholic fatty liver disease. Urokinase-type plasminogen activator (uPA) was shown to regulate gene expression in the liver involving PPARγ transcriptional activity. In this study we questioned whether uPA modulates triglyceride metabolism in the liver, and investigated the mechanisms involved in the observed processes. Huh7 hepatoma cells were incubated with increasing concentrations of uPA for 24 h uPA dose-dependently increased the cellular triglyceride mass, and this effect resulted from increased de novo triglyceride synthesis mediated by the enzyme diglyceride acyltransferase 2 (DGAT2). Also, the amount of free fatty acids was highly up regulated by uPA through activation of the transcription factor SREBP-1. Chemical activation of PPARα further increased uPA-stimulated triglyceride synthesis, whereas inhibition of p38, an upstream activator of PPARα, completely abolished the stimulatory effect of uPA on both triglyceride synthesis and DGAT2 upregulation. The effect of uPA on triglyceride synthesis in Huh7 cells was mediated via binding to its receptor, the uPAR. In vivo studies in uPAR(-/-) mice demonstrated that no lipid droplets were observed in their livers compared to C57BL/6 mice and the triglyceride levels were significantly lower. This study presents a new biological function of the uPA/uPAR system in the metabolism of triglycerides and might present a new target for an early therapeutic intervention for NAFLD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Relative contribution of glycogenolysis and gluconeogenesis to basal, glucagon- and nerve stimulation-dependent glucose output in the perfused liver from fed and fasted rats

    NARCIS (Netherlands)

    Beuers, U.; JUNGERMANN, K.

    1990-01-01

    The relative contribution to basal, glucagon- and nerve stimulation-enhanced glucose output of glycogenolysis (glucose output in the presence of the gluconeogenic inhibitor mercaptopicolinate) and gluconeogenesis (difference in glucose output in the absence and presence of the inhibitor) was

  20. Mode-dependent effect of high-frequency electrical stimulation of the anterior thalamic nucleus on amygdala-kindled seizures in rats.

    Science.gov (United States)

    Zhang, Q; Wu, Z C; Yu, J-T; Yu, N N; Zhong, X L; Tan, L

    2012-08-16

    Deep brain stimulation (DBS) is an emerging treatment of epilepsy. Anterior nucleus of the thalamus (ANT) is considered to be an attractive target due to its close connection to the limbic structures and wide regions of neocortex. The present study aimed to investigate the effects of high frequency stimulation (HFS) targeting the ANT on amygdala-kindled seizures in Wistar rats in two different stimulation modes i.e. pre-treatment and post-treatment stimulations, mimicking the scheduled and responsive stimulations in clinical use respectively. When fully-kindled seizures were achieved by daily amygdala kindling (1 s train of 1 ms pulses at 60 Hz), HFS (15 min train of 100 μs pulses at 150 Hz and 450-800 μA) was applied in two modes for 10 days. Bilateral post-treatment with HFS reduced the incidence of generalized seizures and the mean behavioral seizure stage and shortened average afterdischarge duration (ADD) and generalized seizure duration (GSD), while bilateral pre-treatment with HFS resulted in a similar but much weaker inhibition of seizures. On the other hand, we also found the two stimulation modes both increased the afterdischarge threshold (ADT) and the differences of current intensity between ADT and generalized seizure threshold (GST) i.e. Δ(GST-ADT). However, Δ(GST-ADT) increased by at least 20 μA in bilateral post-treatment group, while less in bilateral pre-treatment group. Additionally, unilateral post-treatment with HFS failed to inhibit seizures. Our data show that anti-epileptic effect of bilateral post-treatment with HFS of ANT is much stronger than that of bilateral pre-treatment HFS, indicating bilateral responsive stimulation might be more appropriate for clinical anti-epileptic treatment of ANT HFS. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells

    Science.gov (United States)

    Massey, Katherine J.; Li, Quanwen; Rossi, Noreen F.; Keezer, Susan M.; Mattingly, Raymond R.

    2015-01-01

    How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser938 were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K·mg protein−1·min−1 and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser938 is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na-K pump in opossum kidney cells. PMID:26582472

  2. Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells.

    Science.gov (United States)

    Massey, Katherine J; Li, Quanwen; Rossi, Noreen F; Keezer, Susan M; Mattingly, Raymond R; Yingst, Douglas R

    2016-02-01

    How angiotensin (ANG) II acutely stimulates the Na-K pump in proximal tubules is only partially understood, limiting insight into how ANG II increases blood pressure. First, we tested whether ANG II increases the number of pumps in plasma membranes of native rat proximal tubules under conditions of rapid activation. We found that exposure to 100 pM ANG II for 2 min, which was previously shown to increase affinity of the Na-K pump for Na and stimulate activity threefold, increased the amount of the Na-K pump in plasma membranes of native tubules by 33%. Second, we tested whether previously observed increases in phosphorylation of the Na-K pump at Ser(938) were part of the stimulatory mechanism. These experiments were carried out in opossum kidney cells, cultured proximal tubules stably coexpressing the ANG type 1 (AT1) receptor, and either wild-type or a S938A mutant of rat kidney Na-K pump under conditions found by others to stimulate activity. We found that 10 min of incubation in 10 pM ANG II stimulated activity of wild-type pumps from 2.3 to 3.5 nmol K · mg protein(-1) · min(-1) and increased the amount of the pump in the plasma membrane by 80% but had no effect on cells expressing the S938A mutant. We conclude that acute stimulation of Na-K pump activity in native rat proximal tubules includes increased trafficking to the plasma membrane and that phosphorylation at Ser(938) is part of the mechanism by which ANG II directly stimulates activity and trafficking of the rat kidney Na-K pump in opossum kidney cells.

  3. The stimulatory effect of albumin on luteinizing hormone-stimulated Leydig cell steroid production depends on its fatty acid content and correlates with conformational changes

    NARCIS (Netherlands)

    R. Melsert (R.); O.J.M. Bos (O. J M); R.F. van der Linden (R.); M.J.E. Fischer (M. J E); S.M. Wilting (Saskia); L.H.M. Janssen (Lambert); J.W. Hoogerbrugge (Jos); F.F.G. Rommerts (Focko)

    1991-01-01

    markdownabstract__Abstract__ The effects of purified albumin species and albumin fragments (0.2–1% w/v) on short-term (4 h) steroid secretion by immature rat Leydig cells, in the presence of a maximally stimulating dose of luteinizing hormone (LH), were investigated. Human albumin and the peptic

  4. Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism

    DEFF Research Database (Denmark)

    Olsen, Hervør L; Nørby, Peder L; Høy, Marianne

    2003-01-01

    was likewise inhibited by ACA, AACOCF(3), and cPLA(2)alpha antisense oligonucleotide treatment. In pancreatic islets NNC77-0074 stimulated PLA(2) activity. We propose that cPLA(2)alpha plays an important role in the regulation of NNC77-0074-evoked exocytosis in insulin secreting beta-cells....

  5. Age-dependent effects of acute methylphenidate on amygdala reactivity in stimulant treatment-naive patients with Attention Deficit/Hyperactivity Disorder

    NARCIS (Netherlands)

    Bottelier, Marco A.; Schrantee, Anouk; Ferguson, Bart; Tamminga, Hyke G. H.; Bouziane, Cheima; Kooij, J. J. Sandra; de Ruiter, Michiel B.; Reneman, Liesbeth

    2017-01-01

    In the present study, we investigate whether methylphenidate (MPH) affects emotional processing and whether this effect is modulated by age. We measured amygdala reactivity with functional Magnetic Resonance Imaging (fMRI) during processing of angry and fearful facial expressions in male stimulant

  6. Cerebral blood flow modulation by Basal forebrain or whisker stimulation can occur independently of large cytosolic Ca2+ signaling in astrocytes.

    Science.gov (United States)

    Takata, Norio; Nagai, Terumi; Ozawa, Katsuya; Oe, Yuki; Mikoshiba, Katsuhiko; Hirase, Hajime

    2013-01-01

    We report that a brief electrical stimulation of the nucleus basalis of Meynert (NBM), the primary source of cholinergic projection to the cerebral cortex, induces a biphasic cerebral cortical blood flow (CBF) response in the somatosensory cortex of C57BL/6J mice. This CBF response, measured by laser Doppler flowmetry, was attenuated by the muscarinic type acetylcholine receptor antagonist atropine, suggesting a possible involvement of astrocytes in this type of CBF modulation. However, we find that IP3R2 knockout mice, which lack cytosolic Ca2+ surges in astrocytes, show similar CBF changes. Moreover, whisker stimulation resulted in similar degrees of CBF increase in IP3R2 knockout mice and the background strain C57BL/6J. Our results show that neural activity-driven CBF modulation could occur without large cytosolic increases of Ca2+ in astrocytes.

  7. Wnt6, Wnt10a and Wnt10b inhibit adipogenesis and stimulate osteoblastogenesis through a β-catenin-dependent mechanism

    OpenAIRE

    Cawthorn, William P.; Bree, Adam J.; Yao, Yao; Du, Baowen; Hemati, Nahid; Martinez-Santibañez, Gabriel; MacDougald, Ormond A.

    2011-01-01

    Wnt10b is an established regulator of mesenchymal stem cell (MSC) fate that inhibits adipogenesis and stimulates osteoblastogenesis, thereby impacting bone mass in vivo. However, downstream mechanisms through which Wnt10b exerts these effects are poorly understood. Moreover, whether other endogenous Wnt ligands also modulate MSC fate remains to be fully addressed. In this study, we identify Wnt6 and Wnt10a as additional Wnt family members that, like Wnt10b, are downregulated during developmen...

  8. Host cytokine responses induced after overnight stimulation with novel M. tuberculosis infection phase-dependent antigens show promise as diagnostic candidates for TB disease.

    Directory of Open Access Journals (Sweden)

    Paulin N Essone

    Full Text Available BACKGROUND: We previously identified Mycobacterium tuberculosis (M.tb antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated culture supernatants. METHODS: We recruited 15 culture confirmed TB cases and 15 non-TB cases from a high-TB endemic community in Cape Town, South Africa into a pilot case-control study from an on-going larger study. Blood samples collected from study participants were stimulated with 4 M.tb antigens that were previously identified as promising (ESAT6/CFP10 (early secreted, Rv2029c (latency, Rv2032 (latency and Rv2389c (rpf in a 7-day or overnight culture assay. Supernatants were also collected form the standard QuantiFERON In Tube (QFT-IT test. The levels of 26 host markers were evaluated in the three culture supernatants using the Luminex platform. RESULTS: The unstimulated levels of CRP, Serum amyloid P (SAP and serum amyloid A (SAA and ESAT-6/CFP-10 specific IP-10 and SAA were amongst the best discriminatory markers in all 3 assays, ascertaining TB with AUC of 72-84%. Four-marker models accurately classified up to 92%, 100% and 100% of study participants in the overnight, 7-day and Quantiferon culture supernatants, respectively, after leave-one-out cross validation. CONCLUSION: Unstimulated and antigen-specific levels of CRP, SAA, IP-10, MMP-2 and sCD40L hold promise as diagnostic candidates for TB disease in short-term stimulation assays. Larger studies are required to validate these findings but the data suggest that antigen-specific cytokine production and in particular mutimarker biosignatures might contribute to future diagnostic strategies.

  9. Host cytokine responses induced after overnight stimulation with novel M. tuberculosis infection phase-dependent antigens show promise as diagnostic candidates for TB disease.

    Science.gov (United States)

    Essone, Paulin N; Chegou, Novel N; Loxton, Andre G; Stanley, Kim; Kriel, Magdalena; van der Spuy, Gian; Franken, Kees L; Ottenhoff, Tom H; Walzl, Gerhard

    2014-01-01

    We previously identified Mycobacterium tuberculosis (M.tb) antigen-induced host markers that showed promise as TB diagnostic candidates in 7-day whole blood culture supernatants. The aim of the present study was to evaluate the utility of these markers further, and cross-compare results with short-term antigen stimulated and unstimulated culture supernatants. We recruited 15 culture confirmed TB cases and 15 non-TB cases from a high-TB endemic community in Cape Town, South Africa into a pilot case-control study from an on-going larger study. Blood samples collected from study participants were stimulated with 4 M.tb antigens that were previously identified as promising (ESAT6/CFP10 (early secreted), Rv2029c (latency), Rv2032 (latency) and Rv2389c (rpf)) in a 7-day or overnight culture assay. Supernatants were also collected form the standard QuantiFERON In Tube (QFT-IT) test. The levels of 26 host markers were evaluated in the three culture supernatants using the Luminex platform. The unstimulated levels of CRP, Serum amyloid P (SAP) and serum amyloid A (SAA) and ESAT-6/CFP-10 specific IP-10 and SAA were amongst the best discriminatory markers in all 3 assays, ascertaining TB with AUC of 72-84%. Four-marker models accurately classified up to 92%, 100% and 100% of study participants in the overnight, 7-day and Quantiferon culture supernatants, respectively, after leave-one-out cross validation. Unstimulated and antigen-specific levels of CRP, SAA, IP-10, MMP-2 and sCD40L hold promise as diagnostic candidates for TB disease in short-term stimulation assays. Larger studies are required to validate these findings but the data suggest that antigen-specific cytokine production and in particular mutimarker biosignatures might contribute to future diagnostic strategies.

  10. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway

    DEFF Research Database (Denmark)

    Kolkova, K; Novitskaya, V; Pedersen, N

    2000-01-01

    , inhibitors of the nonreceptor tyrosine kinase p59(fyn), PLC, PKC and MEK and an activator of PKC, phorbol-12-myristate-13-acetate (PMA). MEK2 transfection rescued cells treated with all inhibitors. The same was found for PMA treatment, except when cells concomitantly were treated with the MEK inhibitor....... Arachidonic acid rescued cells treated with antibodies to the FGF receptor or the PLC inhibitor, but not cells in which the activity of PKC, p59(fyn), FAK, Ras, or MEK was inhibited. Interaction of NCAM with a synthetic NCAM peptide ligand, known to induce neurite outgrowth, was shown to stimulate...

  11. Rat L6 myotubes as an in vitro model system to study GLUT4-dependent glucose uptake stimulated by inositol derivatives

    OpenAIRE

    Yap, Angeline; Nishiumi, Shin; Yoshida, Ken-ichi; Ashida, Hitoshi

    2007-01-01

    Some of inositol derivatives have been reported to help the action of insulin stimulating glucose uptake in skeletal muscle cells. Rat L6 myotubes were employed in an attempt to develop an in vitro model system for investigation of the possible insulin-like effect of eight inositol derivatives, namely allo-inositol, d-chiro-inositol l-chiro-inositol, epi-inositol, muco-inositol, myo-inositol, scyllo-inositol and d-pinitol. At a higher concentration of 1 mM seven inositol derivatives other tha...

  12. Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor.

    Science.gov (United States)

    Leibinger, Marco; Müller, Adrienne; Andreadaki, Anastasia; Hauk, Thomas G; Kirsch, Matthias; Fischer, Dietmar

    2009-11-11

    After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.

  13. Monitoring the distributed impact wave on a concrete slab due to the traffic based on polarization dependence on stimulated Brillouin scattering

    International Nuclear Information System (INIS)

    Bao Xiaoyi; Zhang Chunshu; Li Wenhai; Eisa, M; El-Gamal, S; Benmokrane, B

    2008-01-01

    For the first time to our knowledge, distributed impact waves due to the highway traffic on concrete slabs reinforced with FRP bars are monitored in real time using stimulated Brillouin scattering. The impact wave is caused by the traffic passing on the highway pavement at high speed (>100 km h −1 ), which induced pressure on the concrete slabs, and in turn created a local birefringence change, leading to variation of the local state of polarization change (SOP). The pump and probe waves of the stimulated Brillouin scattering 'see' the SOP change and react with a decrease of the Brillouin gain or loss signal, when the pump and probe waves have the same input polarization state. The frequency difference between the pump and probe waves are locked at the static-strain-related Brillouin frequency. Optical fiber was embedded throughout the concrete pavement continuously reinforced with FRP bars in Highway 40 East, Montréal, Quebec to detect impact waves caused by cars and trucks passing on these pavements at a sampling rate of 10 kHz. A spatial resolution of 2 m was used over a sensing length of 300 m

  14. Human interleukin 1β stimulates islet insulin release by a mechanism not dependent on changes in phospholipase C and protein kinase C activities or Ca2+ handling

    International Nuclear Information System (INIS)

    Welsh, N.; Nilsson, T.; Hallberg, A.; Arkhammar, P.; Berggren, P.-O.; Sandler, S.

    1989-01-01

    Isolated islets from adult rats or obese hyperglycemic (ob/ob) mice were incubated with human recombinant interleukin 1β in order to study whether the acute effects of the cytokine on islet insulin release are associated with changes in islet phospholipase C activity, Ca 2+ handling or protein phosphorylation. The cytokine stimulated insulin release both at low and high glucose concentrations during one hour incubations. In shortterm incubations ( 2+ concentration at rest nor that observed subsequent to stimulation with a high concentration of glucose. Furthermore, the endogenous protein kinase C activity, as visualized by immunoprecipitation of a 32 P-labelled substrate for this enzyme, was not altered by interleukin 1β. Separation of 32 P-labelled proteins by means of 2-dimensional gel electrophoresis failed to reveal any specific effects of the cytokine on the total protein phosphorylation activity. These results suggest that the stimulatory effects on insulin release exerted by interleukin 1β are not caused by acute activation of phospholipase C and protein kinase C or by an alternation of islet Ca 2+ handling of the B-cells. (author)

  15. Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

    Science.gov (United States)

    Ohta, Mitsuhiro; Fujinami, Aya; Kobayashi, Norihiro; Amano, Akiko; Ishigami, Akihito; Tokuda, Harukuni; Suzuki, Nobutaka; Ito, Fumitake; Mori, Taisuke; Sawada, Morio; Iwasa, Koichi; Kitawaki, Jo; Ohnishi, Katsunori; Tsujikawa, Muneo; Obayashi, Hiroshi

    2015-07-01

    4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Structure-dependent photo- and infrared-stimulated luminescence of Eu2+ and Sm3+ in CaS:Eu, Sm

    International Nuclear Information System (INIS)

    Wu Jianping; Newman, David; Viney, Ian V.F.

    2002-01-01

    In this paper, delayed photoluminescence (DPL) and infrared-stimulated luminescence (ISL) spectra of Eu 2+ and Sm 3+ in CaS:Eu, Sm have been investigated. It is found that Eu 2+ and Sm 3+ show different characteristic luminescence in DPL. The explanation is based on the fact that Eu 2+ ideally have the same local environment in the lattice position while Sm 3+ have a more complicated local environment due to charge compensation. By studying ISL spectroscopy of CaS:Eu, Sm, different ISL behaviour has also been found. Since defects are formed in CaS:Eu, Sm by replacing divalent calcium with trivalent samarium in the lattice position, the ISL in CaS : Eu, Sm is thought to be contributed by combination of Sm 3+ itself and defects formed in charge compensation. (author)

  17. Neural cell adhesion molecule-stimulated neurite outgrowth depends on activation of protein kinase C and the Ras-mitogen-activated protein kinase pathway

    DEFF Research Database (Denmark)

    Kolkova, K; Novitskaya, V; Pedersen, N

    2000-01-01

    transfected with expression plasmids encoding constitutively active forms of Ras, Raf, MAP kinase kinases MEK1 and 2, dominant negative forms of Ras and Raf, and the FAK-related nonkinase. Alternatively, PC12-E2 cells were submitted to treatment with antibodies to the fibroblast growth factor (FGF) receptor......, inhibitors of the nonreceptor tyrosine kinase p59(fyn), PLC, PKC and MEK and an activator of PKC, phorbol-12-myristate-13-acetate (PMA). MEK2 transfection rescued cells treated with all inhibitors. The same was found for PMA treatment, except when cells concomitantly were treated with the MEK inhibitor....... Arachidonic acid rescued cells treated with antibodies to the FGF receptor or the PLC inhibitor, but not cells in which the activity of PKC, p59(fyn), FAK, Ras, or MEK was inhibited. Interaction of NCAM with a synthetic NCAM peptide ligand, known to induce neurite outgrowth, was shown to stimulate...

  18. Glucose-Dependent Insulin Secretion in Pancreatic β-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors.

    Directory of Open Access Journals (Sweden)

    Paola Llanos

    Full Text Available Glucose-stimulated insulin secretion (GSIS from pancreatic β-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]. Glucose uptake into β-cells promotes Ca2+ influx and reactive oxygen species (ROS generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR channels. Therefore, we explored here if RyR-mediated Ca2+ release contributes to GSIS in β-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated β-cells. Conventional PCR assays and immunostaining confirmed that β-cells express RyR2, the cardiac RyR isoform. Extended incubation of β-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC, which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated β-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose to β-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS.

  19. Recombinant TSH stimulated remnant ablation therapy in thyroid cancer: the success rate depends on the definition of ablation success--an observational study.

    Directory of Open Access Journals (Sweden)

    Anouk N A van der Horst-Schrivers

    Full Text Available Patients with differentiated thyroid cancer (DTC are treated with (near-total thyroidectomy followed by remnant ablation. Optimal radioiodine-131 (131I uptake is achieved by withholding thyroid hormone (THW, pretreatment with recombinant human Thyrotropin Stimulating Hormone (rhTSH is an alternative. Six randomized trials have been published comparing THW and rhTSH, however comparison is difficult because an uniform definition of ablation success is lacking. Using a strict definition, we performed an observational study aiming to determine the efficacy of rhTSH as preparation for remnant ablation.Adult DTC patients with, tumor stage T1b to T3, Nx, N0 and N1, M0 were included in a prospective multicenter observational study with a fully sequential design, using a stopping rule. All patients received remnant ablation with 131I using rhTSH. Ablation success was defined as no visible uptake in the original thyroid bed on a rhTSH stimulated 150 MBq 131I whole body scan (WBS 9 months after remnant ablation, or no visible uptake in the original thyroid bed on a post therapeutic WBS when a second high dose was necessary.After interim analysis of the first 8 patients, the failure rate was estimated to be 69% (90% confidence interval (CI 20-86% and the inclusion of new patients had to be stopped. Final analysis resulted in an ablation success in 11 out of 17 patients (65%, 95% CI 38-86%.According to this study, the efficacy of rhTSH in the preparation of 131I ablation therapy is inferior, when using a strict definition of ablation success. The current lack of agreement as to the definition of successful remnant ablation, makes comparison between different ablation strategies difficult. Our results point to the need for an international consensus on the definition of ablation success, not only in routine patient's care but also for scientific reasons.Dutch Trial Registration NTR2395.

  20. Prevention of Tracheal High-Dose Tolerance Induction by Granulocyte-Macrophage Colony Stimulating Factor- Dependent Restoration of Antigen-Presenting Cell Function

    Directory of Open Access Journals (Sweden)

    Kanna Haneda

    2000-01-01

    Full Text Available The intrusion of airborne allergens into airways elicits eosinophilic inflammation, as represented by bronchial asthma. It has been shown that excessive amounts of allergen in murine trachea lead to an unexpected evasion of deleterious eosinophilic inflammation by inducing T cell tolerance. In the present study, the mechanisms of tracheal high-dose tolerance are examined with regard to accessory cell functions and the effects of pro-inflammatory cytokines on tolerance. Antigen-induced tracheal eosinophilia was suppressed on instillation of high doses of antigen into the trachea, while concurrent instillation of granulocyte-macrophage colony stimulating factor (GM-CSF with the antigen restored the diminished responses. The restoration of eosinophilic infiltration by GM-CSF occurred in parallel with an increase in interleukin (IL-4 production by CD4+ T cells from the mediastinal lymph nodes. This was found to reflect the empowerment of antigen-presenting cells by GM-CSF, because the impaired ability of Ia+ cells from the tolerant mice to stimulate IL-4-producing T cells is restored by GM-CSF administration. The prevention of tolerance by up-regulating accessory cell functions is a feature unique to GM-CSF, because another pro-inflammatory cytokine, IL-iβ, failed to empower antigen-presenting cells. Thus, besides the induction of transforming growth factor-β-secreting CD4+ T cells, high-dose tolerance in the trachea includes an impairment of the accessory cell functions that support IL-4 production from T cells, which was reversed by GM-CSF. This report is the first demonstration that GM-CSF breaks the T cell tolerance of IL-4-producing T helper cells.

  1. Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe.

    Science.gov (United States)

    Foradori, Chad D; Whitlock, Brian K; Daniel, Jay A; Zimmerman, Arthur D; Jones, Melaney A; Read, Casey C; Steele, Barbara P; Smith, Jeremy T; Clarke, Iain J; Elsasser, Theodore H; Keisler, Duane H; Sartin, James L

    2017-10-01

    Although kisspeptin is the primary stimulator of gonadotropin-releasing hormone secretion and therefore the hypothalamic-pituitary-gonadal axis, recent findings suggest kisspeptin can also regulate additional neuroendocrine processes including release of growth hormone (GH). Here we show that central delivery of kisspeptin causes a robust rise in plasma GH in fasted but not fed sheep. Kisspeptin-induced GH secretion was similar in animals fasted for 24 hours and those fasted for 72 hours, suggesting that the factors involved in kisspeptin-induced GH secretion are responsive to loss of food availability and not the result of severe negative energy balance. Pretreatment with the neuropeptide Y (NPY) Y1 receptor antagonist, BIBO 3304, blocked the effects of kisspeptin-induced GH release, implicating NPY as an intermediary. Kisspeptin treatment induced c-Fos in NPY and GH-releasing hormone (GHRH) cells of the arcuate nucleus. The same kisspeptin treatment resulted in a reduction in c-Fos in somatostatin (SS) cells in the periventricular nucleus. Finally, blockade of systemic ghrelin release or antagonism of the ghrelin receptor eliminated or reduced the ability of kisspeptin to induce GH release, suggesting the presence of ghrelin is required for kisspeptin-induced GH release in fasted animals. Our findings support the hypothesis that during short-term fasting, systemic ghrelin concentrations and NPY expression in the arcuate nucleus rise. This permits kisspeptin activation of NPY cells. In turn, NPY stimulates GHRH cells and inhibits SS cells, resulting in GH release. We propose a mechanism by which kisspeptin conveys reproductive and hormone status onto the somatotropic axis, resulting in alterations in GH release. Copyright © 2017 Endocrine Society.

  2. On the nanotoxicity of PAMAM dendrimers: Superfect® stimulates the EGFR-ERK1/2 signal transduction pathway via an oxidative stress-dependent mechanism in HEK 293 cells.

    Science.gov (United States)

    Akhtar, Saghir; Chandrasekhar, Bindu; Attur, Sreeja; Yousif, Mariam H M; Benter, Ibrahim F

    2013-05-01

    Polyamidoamine (PAMAM) dendrimers are cationic branch-like macromolecules that may serve as drug delivery systems for gene-based therapies such as RNA interference. For their safe use in the clinic, they should ideally only enhance drug delivery to target tissues and exhibit no adverse effects. However, little is known about their toxicological profiles in terms of their interactions with cellular signal transduction pathways such as the epidermal growth factor receptor (EGFR). The EGFR is an important signaling cascade that regulates cell growth, differentiation, migration, survival and apoptosis. Here, we investigated the impact of naked, unmodified Superfect (SF), a commercially available generation 6 PAMAM dendrimer, on the epidermal growth factor receptor (EGFR) tyrosine kinase-extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway in human embryonic kidney (HEK 293) cells. At concentrations routinely used for transfection, SF exhibited time and dose-dependent stimulation of EGFR and ERK1/2 phosphorylation whereas AG1478, a selective EGFR tyrosine kinase antagonist, inhibited EGFR-ERK1/2 signaling. SF-induced phosphorylation of EGFR for 1h was partly reversible upon removal of the dendrimer and examination of cells 24 later. Co-treatment of SF with epidermal growth factor (EGF) ligand resulted in greater EGFR stimulation than either agent alone implying that the stimulatory effects of SF and the ligand are synergistic. Dendrimer-induced stimulation of EGFR-ERK1/2 signaling could be attenuated by the antioxidants apocynin, catalase and tempol implying that an oxidative stress dependent mechanism was involved. These results show for the first time that PAMAM dendrimers, aside from their ability to improve drug delivery, can modulate the important EGFR-ERK1/2 cellular signal transduction pathway - a novel finding that may have a bearing on their safe application as drug delivery systems. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. Daidzein stimulates osteogenesis facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via estrogen receptor-dependent MEK/ERK and PI3K/Akt activation.

    Science.gov (United States)

    Jin, Xin; Sun, Jing; Yu, Bo; Wang, Yue; Sun, Wei Jia; Yang, Jing; Huang, Su Hui; Xie, Wen Li

    2017-06-01

    Daidzein, a natural soy isoflavone, has a structure similar to estradiol and exhibiting bone-sparing effects against osteoporosis. However, the molecular mechanisms of osteogenesis remain unclear. We hypothesized that daidzein stimulates osteogenesis through estrogen receptor (ER)-dependent signal pathways. To test this hypothesis, we investigated the effects of daidzein compared with 17β-estradiol on proliferation, differentiation, and cisplatin-induced apoptosis in human osteoblast-like MG-63 cells containing 2 ER isoforms. The results showed that daidzein stimulated cell proliferation by altering cell cycle distribution, promoted cell differentiation by increasing the alkaline phosphatase activity and collagen content, and reduced cell apoptosis associated by up-regulating the expression of Bcl-xL. The above actions of daidzein were prevented by cotreatment with the ER antagonist ICI 182780. Using small interfering RNA technology, we further demonstrated that the effects of daidzein on alkaline phosphatase activity, collagen content, and cell apoptosis are mediated by both ERα and ERβ, whereas the effects on cell proliferation are primarily mediated by ERα. However, the effects of 17β-estradiol on osteoblastic proliferation and survival are mediated by both ER isotypes, and the effects on osteoblastic differentiation are primarily mediated by ERα. The use of specific inhibitors indicated that activation of the mitogen-activated protein kinase kinase/extracellular regulated kinase (MEK/ERK) and phosphoinositide 3-kinase/protein kinase B or PKB (PI3K/Akt) signaling pathway at least partially accounts for these effects of daidzein. Taken together, the results indicate that daidzein stimulates osteogenesis through facilitating proliferation, differentiation, and antiapoptosis in human osteoblast-like MG-63 cells via activation of MEK/ERK and PI3K/Akt in an ER-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Chronic electroconvulsive stimulation but not chronic restraint stress modulates mRNA expression of voltage-dependent potassium channels Kv7.2 and Kv11.1 in the rat piriform cortex

    DEFF Research Database (Denmark)

    Hjæresen, Marie-Louise; Hageman, Ida; Wörtwein, Gitta

    2008-01-01

    The mechanisms by which stress and electroconvulsive therapy exert opposite effects on the course of major depression are not known. Potential candidates might include the voltage-dependent potassium channels. Potassium channels play an important role in maintaining the resting membrane potential...... and controlling neuronal excitability. To explore this hypothesis, we examined the effects of one or several electroconvulsive stimulations and chronic restraint stress (6 h/day for 21 days) on the expression of voltage-dependent potassium channel Kv7.2, Kv11.1, and Kv11.3 mRNA in the rat brain using in situ...... hybridization. Repeated, but not acute, electroconvulsive stimulation increased Kv7.2 and Kv11.1 mRNA levels in the piriform cortex. In contrast, restraint stress had no significant effect on mRNA expression of Kv7.2, Kv11.1, or Kv11.3 in any of the brain regions examined. Thus, it appears that the investigated...

  5. Phosphorylated intermediate of (Ca2+ + K+)-stimulated Mg2+-dependent transport ATPase in endoplasmic reticulum from rat pancreatic acinar cells

    International Nuclear Information System (INIS)

    Imamura, K.; Schulz, I.

    1985-01-01

    Formation and decomposition of the phosphorylated intermediate of endoplasmic reticulum (Ca 2+ + Mg 2+ )-ATPase from pancreatic acinar cells have been studied using lithium dodecyl sulfate- and tetradecyltrimethylammonium bromide-polyacrylamide gel electrophoresis. Incorporation of 32 P from [gamma- 32 P]ATP is Ca 2+ -dependent (approximate Km for free [Ca 2+ ] = 2-3 x 10(-8) mol/liter). Formation of the 100-kDa phosphoprotein is rapid, reaching maximal 32 P incorporation within 1 s at room temperature. At 4 degrees C, phosphorylation is slower and dephosphorylation is drastically decreased. For dephosphorylation, Mg 2+ and monovalent cations such as K + or Na + are necessary. Vanadate inhibits both 32 P incorporation and 32 P liberation dose dependently (Km = 3 x 10(-6) mol/liter), whereas mitochondrial inhibitors and ouabain have no effect. The phosphoprotein is stable at pH 2 and destabilizes with increasing pH being completely decomposed at pH 9. Reduction of 32 P incorporation in the presence of high concentrations of cold ATP and hydroxylamine suggests formation of acylphosphate present in the ATPase intermediate. The characteristics of Ca 2+ , cation, and pH dependencies of the ATPase activity are similar to those previously described for MgATP-dependent Ca 2+ transport into rough endoplasmic reticulum from pancreatic acinar cells. The data suggest that the 100-kDa phosphoprotein as described in this study is the intermediate of this Ca2+ transport ATPase

  6. Augmented norepinephrine-stimulated Ca2+ entry via voltage-dependent Ca2+ channels in spontaneously hypertensive rats (SHR): effects of captopril treatment

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Dobešová, Zdenka; Paulis, L.; Kuneš, Jaroslav

    2006-01-01

    Roč. 22, č. 13 (2006), s. 58-58 ISSN 1000-4718. [International Congress of Pathophysiology /5./. 28.06.2006-01.07.2006, Beijing] R&D Projects: GA MZd(CZ) NR7786 Keywords : Ca2+ entry * voltage-dependent Ca2+ channels * hypertensive rat Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  7. Effects of captopril treatment on augmented norepinephrine-stimulated calcium entry through voltage-dependent calcium channels in spontaneously hypertensive rats

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Paulis, Ĺudovít; Dobešová, Zdenka; Kuneš, Jaroslav

    2006-01-01

    Roč. 24, č. S4 (2006), S338-S338 ISSN 0263-6352. [European Meeting on Hypertension /16./. 12.06.2006-15.06.2006, Madrid] R&D Projects: GA MZd(CZ) NR7786 Keywords : voltage-dependent calcium channel * hypertension * captopril * norepinephrine Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  8. Expression of cGMP-dependent protein kinase I and phosphorylation of its substrate, vasodilator-stimulated phosphoprotein, in human endothelial cells of different origin

    NARCIS (Netherlands)

    Draijer, R.; Vaandrager, A.B.; Nolte, C.; Jonge, H.R. de; Walter, U.; Hinsbergh, V.W.M. van

    1995-01-01

    Previous studies demonstrated that the thrombin-induced permeability of endothelial cell monolayers is reduced by the elevation of cGMP. In the present study, the presence of cGMP-dependent protein kinase (cGMP-PK) immunoreactivity and activity in various types of human endothelial cells (ECs) and

  9. Effects of pulsed electromagnetic field (PEMF) stimulation on bone tissue like formation are dependent on the maturation stages of the osteoblasts.

    Science.gov (United States)

    Diniz, Pericles; Shomura, Kenji; Soejima, Kazuhisa; Ito, Gakuji

    2002-07-01

    The effects of pulsed electromagnetic field (PEMF, 15 Hz pulse burst, 7 mT peak) stimulation on bone tissue-like formation on osteoblasts (MC3T3-E1 cell line) in different stages of maturation were assessed to determine whether the PEMF stimulatory effect on bone tissue-like formation was associated with the increase in the number of cells and/or with the enhancement of the cellular differentiation. The cellular proliferation (DNA content), differentiation (alkaline phosphatase activity), and bone tissue-like formation (area of mineralized matrix) were determined at different time points. PEMF treatment of osteoblasts in the active proliferation stage accelerated cellular proliferation, enhanced cellular differentiation, and increased bone tissue-like formation. PEMF treatment of osteoblasts in the differentiation stage enhanced cellular differentiation and increased bone tissue-like formation. PEMF treatment of osteoblasts in the mineralization stage decreased bone tissue-like formation. In conclusion, PEMF had a stimulatory effect on the osteoblasts in the early stages of culture, which increased bone tissue-like formation. This stimulatory effect was most likely associated with enhancement of the cellular differentiation, but not with the increase in the number of cells. Copyright 2002 Wiley-Liss, Inc.

  10. AS160 associates with the Na+,K+-ATPase and mediates the adenosine monophosphate-stimulated protein kinase-dependent regulation of sodium pump surface expression.

    Science.gov (United States)

    Alves, Daiane S; Farr, Glen A; Seo-Mayer, Patricia; Caplan, Michael J

    2010-12-01

    The Na(+),K(+)-ATPase is the major active transport protein found in the plasma membranes of most epithelial cell types. The regulation of Na(+),K(+)-ATPase activity involves a variety of mechanisms, including regulated endocytosis and recycling. Our efforts to identify novel Na(+),K(+)-ATPase binding partners revealed a direct association between the Na(+),K(+)-ATPase and AS160, a Rab-GTPase-activating protein. In COS cells, coexpression of AS160 and Na(+),K(+)-ATPase led to the intracellular retention of the sodium pump. We find that AS160 interacts with the large cytoplasmic NP domain of the α-subunit of the Na(+),K(+)-ATPase. Inhibition of the activity of the adenosine monophosphate-stimulated protein kinase (AMPK) in Madin-Darby canine kidney cells through treatment with Compound C induces Na(+),K(+)-ATPase endocytosis. This effect of Compound C is prevented through the short hairpin RNA-mediated knockdown of AS160, demonstrating that AMPK and AS160 participate in a common pathway to modulate the cell surface expression of the Na(+),K(+)-ATPase.

  11. Infection-stimulated anemia results primarily from interferon gamma-dependent, signal transducer and activator of transcription 1-independent red cell loss.

    Science.gov (United States)

    Wang, Zheng; Zhang, Dong-Xia; Zhao, Qi

    2015-04-05

    Although the onset of anemia during infectious disease is commonly correlated with production of inflammatory cytokines, the mechanisms by which cytokines induce anemia are poorly defined. This study focused on the mechanism research. Different types of mice were infected perorally with Toxoplasma gondii strain ME49. At the indicated times, samples from each mouse were harvested, processed, and analyzed individually. Blood samples were analyzed using a Coulter Counter and red blood cell (RBC) survival was measured by biotinylation. Levels of tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), and inducible protein 10 (IP-10) mRNA in liver tissue were measured by real-time polymerase chain reaction. T. gondii-infected mice exhibited anemia due to a decrease in both erythropoiesis and survival time of RBC in the circulation (P anemia was associated with fecal occult, supporting previous literature that hemorrhage is a consequence of T. gondii infection in mice. Infection-induced anemia was abolished in interferon gamma (IFNγ) and IFNγ receptor deficient mice (P anemia resulting solely from increased loss of circulating RBC. Infection-stimulated decrease in erythropoiesis and losses of RBC have distinct mechanistic bases. These results show that during T. gondii infection, IFNγ is responsible for an anemia that results from both a decrease in erythropoiesis and a STAT1 independent loss of circulating RBC.

  12. Human IL6 stimulates bovine satellite cell proliferation through a Signal transducer and activator of transcription 3 (STAT3)-dependent mechanism.

    Science.gov (United States)

    Brandt, A M; Kania, J M; Reinholt, B M; Johnson, S E

    2018-01-01

    Bovine satellite cell (bSC) myogenesis and skeletal muscle hypertrophy occur through the orchestrated actions of multiple autocrine and paracrine growth factors. Intimate to the bSC niche is IL6, a dual-purpose cytokine with proinflammatory and mitogenic properties. The objective of the experiment was to examine the effects of IL6 on proliferation and differentiation of bSC in vitro. Treatment of primary bSC cultures with recombinant bovine IL6 (bIL6) failed to alter myogenesis owing to the absence of intracellular signal transduction. The cytokine was able to stimulate phosphorylation of signal transducer and activator of transcription 3 tyrosine 705 (STAT3 Y705 ) in Madin-Darby bovine kidney (MDBK) epithelial cells, thus demonstrating bioactivity. Media supplemented with recombinant human IL6 (hIL6) caused phosphorylation of STAT3 Y705 in bSC and increased (P bSC proliferation. Morphologic and biochemical measures of bSC differentiation remained unchanged (P > 0.05) following treatment for 48 h with hIL6. These results support a role for hIL6 as a bSC mitogen in vitro. The inability of bIL6 to initiate an intracellular signal in bSC requires further investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The positive effects of high-frequency right dorsolateral prefrontal cortex repetitive transcranial magnetic stimulation on memory, correlated with increases in brain metabolites detected by proton magnetic resonance spectroscopy in recently detoxified alcohol-dependent patients

    Directory of Open Access Journals (Sweden)

    Qiao J

    2016-09-01

    Full Text Available Jun Qiao,1,2 Guixing Jin,1,2 Licun Lei,3 Lan Wang,1,2 Yaqiang Du,3 Xueyi Wang1,2 1Institute of Mental Health, The First Hospital of Hebei Medical University, 2Brain Ageing and Cognitive Neuroscience Laboratory, Hebei Medical University, 3Department of Radiology, The First Hospital of Hebei Medical University, Hebei, People’s Republic of China Objective: To explore the effect of right dorsolateral prefrontal cortex (DLPFC repetitive transcranial magnetic stimulation (rTMS on memory, and its correlation with levels of hippocampal brain metabolites detected by proton magnetic resonance spectroscopy (1H-MRS in recently detoxified alcohol-dependent patients. Materials and methods: In this randomized, double-blind sham-controlled trial, alcohol-dependent patients were enrolled and randomized into two groups: the experimental group (rTMS, 10 Hz, on right DLPFC, 20 sessions and the control group (sham stimulation. Memory function was assessed using Hopkins Verbal Learning Test-Revised (HVLT-R and Brief Visuospatial Memory Test-Revised (BVMT-R before and after treatment. 1H-MRS was used to detect the levels of N-acetyl aspartic acid (NAA, choline (Cho, and creatine (Cr in bilateral hippocampi before and after treatment. Results: Thirty-eight patients (18 in the experimental group and 20 in the control group were included in the analyses. The experimental group showed significantly greater changes in HVLT-R, BVMT-R, NAA/Cr, and Cho/Cr after rTMS from baseline than the control group. The percentage change in BVMT-R and HVLT-R correlated with the percentage change in NAA/Cr and Cho/Cr in the right brain. Conclusion: High-frequency right DLPFC rTMS was associated with improvement in memory dysfunction, which is correlated with levels of hippocampal brain metabolites detected by 1H-MRS in recently detoxified alcohol-dependent patients. Keywords: alcohol dependence, memory, repetitive transcranial magnetic stimulation, MR spectroscopy

  14. The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor- and DNA-dependent kinase phosphorylation

    International Nuclear Information System (INIS)

    Dittmann, Klaus; Mayer, Claus; Wanner, Gabriele; Kehlbach, Rainer; Rodemann, H. Peter

    2007-01-01

    Background and purpose: Purpose of the study was to elucidate the underlying molecular mechanism of the radioprotector O-phospho-tyrosine (P-Tyr). Methods: Molecular effects of P-Tyr at the level of EGFR responses were investigated in vitro with bronchial carcinoma cell line A549. Nuclear EGFR transport and DNA-PK activation were quantified after Western blotting. Residual DNA-damages were quantified by help of γH 2 AX focus assay. Results: As determined by dose-response curves, treatment of cells with P-Tyr for 16 h before irradiation results in radioprotection. Simultaneous treatment with EGFR blocking antibody Cetuximab abolished P-Tyr associated radioprotection. At the molecular level P-Tyr mediated a general phosphorylation of EGFR and a pronounced phosphorylation of nuclear EGFR at residue Thr No. 654, also observed after treatment with ionizing radiation. This phosphorylation was associated with nuclear EGFR accumulation. Moreover, P-Tyr-triggered EGFR nuclear accumulation was associated with phosphorylation of DNA-PK at Thr 2609. This activated form of DNA-PK was not DNA associated, but after radiation, DNA binding increased, particularly after P-Tyr pre-treatment. These molecular effects of P-Tyr resulted in a reduction of residual DNA-damage after irradiation. Conclusions: Radioprotection by P-Tyr is mediated through its stimulation of nuclear EGFR transport and concurrent, but DNA-damage independent, activation of DNA-PK. Thus, subsequent irradiation results in increased binding of DNA-PK to DNA, improved DNA-repair and increased cell survival

  15. Convulxin induces platelet activation by a tyrosine-kinase-dependent pathway and stimulates tyrosine phosphorylation of platelet proteins, including PLC gamma 2, independently of integrin alpha IIb beta 3.

    Science.gov (United States)

    Francischetti, I M; Ghazaleh, F A; Reis, R A; Carlini, C R; Guimarães, J A

    1998-05-15

    1Convulxin (Cvx) is a well-characterized platelet aggregating glycoprotein isolated from Crotalus durissus terrificus and C. d. cascavella venoms. In the present report we show that Cvx induces tyrosine phosphorylation of human platelet proteins, including phospholipase C-gamma 2 (PLC gamma 2), and also stimulates [3H]arachidonic acid ([3H]AA) mobilization, pleckstrin phosphorylation, and an increase in the cytosolic Ca2+ concentration ([Ca2+]in) due to both Ca2+ entry and internal Ca2+ mobilization. Staurosporine, a potent protein kinase inhibitor, and genistein, a specific inhibitor of protein tyrosine kinases (PTK), were used to evaluate the role of protein tyrosine phosphorylation (PTP) in the signal transduction evoked by Cvx. Staurosporine and genistein inhibited in a dose-dependent manner platelet aggregation induced by Cvx. Both inhibitors significantly blocked to near basal levels breakdown of phosphatidylinositol 4,5-bisphosphate from [myo-2-3H]inositol-labeled platelets and the production of [3H]AA metabolites from [3H]AA-labeled platelets after challenge with Cvx. Cvx provokes an increase in [Ca2+]in in Fura-2-loaded platelets that was abolished by concentrations of staurosporine which also inhibited Cvx-induced platelet aggregation. In addition, Cvx stimulates a rapid increase in tyrosine phosphorylation of human platelets proteins with molecular masses of 40, 72/74, 78/80, 105, 120, and 145 kDa, followed by dephosphorylation. Furthermore, Cvx stimulates a rapid tyrosyl phosphorylation of a 145-kDa molecular mass protein that was identified as PLC gamma 2. PTP induced by Cvx was not inhibited when platelets were stimulated in the presence of indomethacin, apyrase, EDTA, or RGDS peptide. These results indicate that PTP is chronologically proximal to Cvx binding to platelets, and is independent of aggregation or fibrinogen binding to the integrin alpha IIb beta 3. On the other hand, the dephosphorylation step is inhibited by RGDS peptide or EDTA

  16. Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

    Science.gov (United States)

    Phumsatitpong, Chayarndorn; Moenter, Suzanne M

    2018-01-01

    Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

  17. Brain Stimulation Therapies

    Science.gov (United States)

    ... Magnetic Seizure Therapy Deep Brain Stimulation Additional Resources Brain Stimulation Therapies Overview Brain stimulation therapies can play ... for a shorter recovery time than ECT Deep Brain Stimulation Deep brain stimulation (DBS) was first developed ...

  18. Dual Stimulus-Dependent Effect of Oenothera paradoxa Extract on the Respiratory Burst in Human Leukocytes: Suppressing for Escherichia coli and Phorbol Myristate Acetate and Stimulating for Formyl-Methionyl-Leucyl-Phenylalanine

    Directory of Open Access Journals (Sweden)

    Izabela Burzynska-Pedziwiatr

    2014-01-01

    Full Text Available Although a growing body of evidence suggests that plant polyphenols can modulate human immune responses, their simultaneous action on monocyte and neutrophil oxidative burst is currently poorly understood. Based on the hypothesis that various polyphenols contained in plant extracts might affect the oxidative burst of phagocytes, we evaluated the effects of ethanolic O. paradoxa extract polyphenols on monocyte and neutrophil oxidative burst in vitro activated by different stimuli, including opsonized bacteria E. coli, phorbol 12-myristate 13-acetate (PMA, and formyl-methionyl-leucyl-phenylalanine (fMLP. Samples were analyzed by the dihydrorhodamine flow cytometry assay. Our results showed that the extract repressed significantly and dose-dependently reactive oxygen species production in both cell types stimulated with E. coli and PMA (P < 0.05 and its inhibitory efficiency was stimulus- and cell-type-dependent. Interestingly, there was significant stimulatory effect of the extract on bursting phagocytes induced by fMLP (P < 0.05. Additionally, several flavonoids and phenolic compounds as well as penta-galloyl-β-(D-glucose (PGG, the representative of hydrolyzable tannins, were identified in the 60% extract by high-performance liquid chromatography (HPLC coupled to electrospray ionization in negative ion mode. In summary, the ethanolic O. paradoxa extract, rich in flavonoids and phenolic compounds, exhibits dual stimulus-dependent effect on the respiratory burst in human leukocytes; hence, it might affect immune responses in humans.

  19. Lipidated dengue-2 envelope protein domain III independently stimulates long-lasting neutralizing antibodies and reduces the risk of antibody-dependent enhancement.

    Directory of Open Access Journals (Sweden)

    Chen-Yi Chiang

    Full Text Available BACKGROUND: Dengue virus is a mosquito-transmitted virus that can cause self-limiting dengue fever, severe life-threatening dengue hemorrhagic fever and dengue shock syndrome. The existence of four serotypes of dengue virus has complicated the development of an effective and safe dengue vaccine. Recently, a clinical phase 2b trial of Sanofi Pasteur's CYD tetravalent dengue vaccine revealed that the vaccine did not confer full protection against dengue-2 virus. New approaches to dengue vaccine development are urgently needed. Our approach represents a promising method of dengue vaccine development and may even complement the deficiencies of the CYD tetravalent dengue vaccine. METHODOLOGY/PRINCIPAL FINDINGS: Two important components of a vaccine, the immunogen and immunopotentiator, were combined into a single construct to generate a new generation of vaccines. We selected dengue-2 envelope protein domain III (D2ED III as the immunogen and expressed this protein in lipidated form in Escherichia coli, yielding an immunogen with intrinsic immunopotentiation activity. The formulation containing lipidated D2ED III (LD2ED III in the absence of exogenous adjuvant elicited higher D2ED III-specific antibody responses than those obtained from its nonlipidated counterpart, D2ED III, and dengue-2 virus. In addition, the avidity and neutralizing capacity of the antibodies induced by LD2ED III were higher than those elicited by D2ED III and dengue-2 virus. Importantly, we showed that after lipidation, the subunit candidate LD2ED III exhibited increased immunogenicity while reducing the potential risk of antibody-dependent enhancement of infection in mice. CONCLUSIONS/SIGNIFICANCE: Our study suggests that the lipidated subunit vaccine approach could be applied to other serotypes of dengue virus and other pathogens.

  20. SRC1 promotes Th17 differentiation by overriding Foxp3 suppression to stimulate RORγt activity in a PKC-θ-dependent manner.

    Science.gov (United States)

    Sen, Subha; Wang, Fei; Zhang, Jing; He, Zhiheng; Ma, Jian; Gwack, Yousang; Xu, Jianming; Sun, Zuoming

    2018-01-16

    Th17 cells are major players in multiple autoimmune diseases and are developmentally contingent on reciprocal functionality between the transcription factor Retineic acid receptor-related orphan nuclear receptor gamma (RORγt) and Forkhead box protein P3 (Foxp3). Here we deciphered a previously unappreciated role of Steroid receptor coactivator 1 (SRC1) in defining the lineage decision for the development of Th17 versus induced T-regulatory (iTreg) cells. We demonstrate that SRC1 functions as a critical coactivator for RORγt in vivo to promote the functional dominance of RORγt over Foxp3 and thus establishing an unopposed Th17 differentiation program. In the absence of SRC1, T cell polarization resulted in decreased IL-17 + and increased Foxp3 + cells during both in vitro differentiation and in vivo development of experimental autoimmune encephalomyelitis. Mechanistically, T cell receptor (TCR) signaling molecule protein kinase C theta (PKC-θ)-mediated phosphorylation of SRC1 is important for inducing enhanced RORγt-SRC1 interaction, stable DNA binding, and resultant IL-17A transcription. Furthermore, phospho-SRC1-mediated recruitment of CARM1 induced prominent asymmetric dimethylation of H3R17 while preventing repressive H3K9 trimethylation and hence further modifying the IL-17 locus for optimal transcription. Moreover, binding of phospho-SRC1 to RORγt displaced bound Foxp3, leading to prompt degradation of the dissociated Foxp3 via a ubiquitin-proteosomal pathway and hence reversing the inhibitory action of Foxp3 on RORγt activity. Thus, SRC1 acts as a crucial molecular mediator to integrate positive PKC-θ-dependent TCR signals to induce peak RORγt activity and establish phenotypic dominance of Th17 over the iTreg pathway.

  1. Early embryonic renal tubules of wild-type and polycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembrane conductance regulator/Na(+),K(+),2Cl(-) Co-transporter-dependent cystic dilation.

    Science.gov (United States)

    Magenheimer, Brenda S; St John, Patricia L; Isom, Kathryn S; Abrahamson, Dale R; De Lisle, Robert C; Wallace, Darren P; Maser, Robin L; Grantham, Jared J; Calvet, James P

    2006-12-01

    Metanephric organ culture has been used to determine whether embryonic kidney tubules can be stimulated by cAMP to form cysts. Under basal culture conditions, wild-type kidneys from embryonic day 13.5 to 15.5 mice grow in size and continue ureteric bud branching and tubule formation over a 4- to 5-d period. Treatment of these kidneys with 8-Br-cAMP or the cAMP agonist forskolin induced the formation of dilated tubules within 1 h, which enlarged over several days and resulted in dramatically expanded cyst-like structures of proximal tubule and collecting duct origin. Tubule dilation was reversible upon withdrawal of 8-Br-cAMP and was inhibited by the cAMP-dependent protein kinase inhibitor H89 and the cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor CFTR(inh)172. For further testing of the role of CFTR, metanephric cultures were prepared from mice with a targeted mutation of the Cftr gene. In contrast to kidneys from wild-type mice, those from Cftr -/- mice showed no evidence of tubular dilation in response to 8-Br-cAMP, indicating that CFTR Cl(-) channels are functional in embryonic kidneys and are required for cAMP-driven tubule expansion. A requirement for transepithelial Cl(-) transport was demonstrated by inhibiting the basolateral Na(+),K(+),2Cl(-) co-transporter with bumetanide, which effectively blocked all cAMP-stimulated tubular dilation. For determination of whether cystic dilation occurs to a greater extent in PKD kidneys in response to cAMP, Pkd1(m1Bei) -/- embryonic kidneys were treated with 8-Br-cAMP and were found to form rapidly CFTR- and Na(+),K(+),2Cl(-) co-transporter-dependent cysts that were three- to six-fold larger than those of wild-type kidneys. These results suggest that cAMP can stimulate fluid secretion early in renal tubule development during the time when renal cysts first appear in PKD kidneys and that PKD-deficient renal tubules are predisposed to abnormally increased cyst expansion in response to elevated levels

  2. AhR-dependent secretion of PDGF-BB by human classically activated macrophages exposed to DEP extracts stimulates lung fibroblast proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Jaguin, Marie [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France); Fardel, Olivier [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France); Pôle Biologie, Centre Hospitalier Universitaire (CHU) Rennes, 2 rue Henri Le Guilloux, 35033 Rennes Cedex (France); Lecureur, Valérie, E-mail: valerie.lecureur@univ-rennes1.fr [UMR INSERM U1085, Institut de Recherche sur la Santé, l' Environnement et le Travail (IRSET), Université de Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes Cedex (France)

    2015-06-15

    Lung diseases are aggravated by exposure to diesel exhaust particles (DEPs) found in air pollution. Macrophages are thought to play a crucial role in lung immune response to these pollutants, even if the mechanisms involved remain incompletely characterized. In the present study, we demonstrated that classically and alternative human macrophages (MΦ) exhibited increased secretion of PDGF-B in response to DEP extract (DEPe). This occurred via aryl hydrocarbon receptor (AhR)-activation because DEPe-induced PDGF-B overexpression was abrogated after AhR expression knock-down by RNA interference, in both M1 and M2 polarizing MΦ. In addition, TCDD and benzo(a)pyrene, two potent AhR ligands, also significantly increased mRNA expression of PDGF-B in M1 MΦ, whereas some weak ligands of AhR did not. We next evaluated the impact of conditioned media (CM) from MΦ culture exposed to DEPe or of recombinant PDGF-B onto lung fibroblast proliferation. The tyrosine kinase inhibitor, AG-1295, prevents phosphorylations of PDGF-Rβ, AKT and ERK1/2 and the proliferation of MRC-5 fibroblasts induced by recombinant PDGF-B and by CM from M1 polarizing MΦ, strongly suggesting that the PDGF-BB secreted by DEPe-exposed MΦ is sufficient to activate the PDGF-Rβ pathway of human lung fibroblasts. In conclusion, we demonstrated that human MΦ, whatever their polarization status, secrete PDGF-B in response to DEPe and that PDGF-B is a target gene of AhR. Therefore, induction of PDGF-B by DEP may participate in the deleterious effects towards human health triggered by such environmental urban contaminants. - Highlights: • PDGF-B expression and secretion are increased by DEPe exposure in human M1 and M2 MΦ. • DEPe-induced PDGF-B expression is aryl-hydrocarbon-dependent. • DEPe-exposed M1 MΦ secrete sufficient PDGF-B to increase lung fibroblast proliferation.

  3. Anti-Inflammatory Action of an Antimicrobial Model Peptide That Suppresses the TRIF-Dependent Signaling Pathway via Inhibition of Toll-Like Receptor 4 Endocytosis in Lipopolysaccharide-Stimulated Macrophages.

    Directory of Open Access Journals (Sweden)

    Do-Wan Shim

    Full Text Available Antimicrobial peptides (AMPs, also called host defense peptides, particularly those with amphipathic helical structures, are emerging as target molecules for therapeutic development due to their immunomodulatory properties. Although the antimicrobial activity of AMPs is known to be exerted primarily by permeation of the bacterial membrane, the mechanism underlying its anti-inflammatory activity remains to be elucidated. We report potent anti-inflammatory activity of WALK11.3, an antimicrobial model peptide with an amphipathic helical conformation, in lipopolysaccharide (LPS-stimulated RAW264.7 cells. This peptide inhibited the expression of inflammatory mediators, including nitric oxide, COX-2, IL-1β, IL-6, INF-β, and TNF-α. Although WALK11.3 did not exert a major effect on all downstream signaling in the MyD88-dependent pathway, toll-like receptor 4 (TLR4- mediated pro-inflammatory signals were markedly attenuated in the TRIF-dependent pathway due to inhibition of the phosphorylation of STAT1 by attenuation of IRF3 phosphorylation. WALK11.3 specifically inhibited the endocytosis of TLR4, which is essential for triggering TRIF-mediated signaling in macrophage cells. Hence, we suggest that specific interference with TLR4 endocytosis could be one of the major modes of the anti-inflammatory action of AMPs. Our designed WALK11 peptides, which possess both antimicrobial and anti-inflammatory activities, may be promising molecules for the development of therapies for infectious inflammation.

  4. Soluble CD40 ligand stimulates CD40-dependent activation of the β2 integrin Mac-1 and protein kinase C zeda (PKCζ in neutrophils: implications for neutrophil-platelet interactions and neutrophil oxidative burst.

    Directory of Open Access Journals (Sweden)

    Rong Jin

    Full Text Available Recent work has revealed an essential involvement of soluble CD40L (sCD40L in inflammation and vascular disease. Activated platelets are the major source of sCD40L, which has been implicated in platelet and leukocyte activation, although its exact functional impact on leukocyte-platelet interactions and the underlying mechanisms remain undefined. We aimed to determine the impact and the mechanisms of sCD40L on neutrophils. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte recruitment to the sites of injury. Our data show that CD40L contributes to neutrophil firm adhesion to and transmigration across activated surface-adherent platelets, possibly through two potential mechanisms. One involves the direct interaction of ligand-receptor (CD40L-CD40, i.e., platelet surface CD40L interaction with neutrophil CD40; another involves an indirect mechanism, i.e. soluble CD40L stimulates activation of the leukocyte-specific β2 integrin Mac-1 in neutrophils and thereby further promotes neutrophil adhesion and migration. Activation of the integrin Mac-1 is known to be critical for mediating neutrophil adhesion and migration. sCD40L activated Mac-1 in neutrophils and enhanced neutrophil-platelet interactions in wild-type neutrophils, but failed to elicit such responses in CD40-deficient neutrophils. Furthermore, our data show that the protein kinase C zeta (PKCζ is critically required for sCD40L-induced Mac-1 activation and neutrophil adhesive function. sCD40L strongly stimulated the focal clustering of Mac-1 (CD11b and the colocalization of Mac-1 with PKCζ in wild-type neutrophils, but had minimal effect in CD40-deficient neutrophils. Blocking PKCζ completely inhibited sCD40L-induced neutrophil firm adhesion. Moreover, sCD40L strongly stimulates neutrophil oxidative burst via CD40-dependent activation of PI3K/NF-KB, but independent of Mac-1 and PKCζ. These findings may contribute to a better

  5. Histamine H3 receptor activation selectively inhibits dopamine D1 receptor-dependent [3H]GABA release from depolarization-stimulated slices of rat substantia nigra pars reticulata

    International Nuclear Information System (INIS)

    Aceves, J.; Young, J.M.; Arias-Montano, J.A.; Floran, B.; Garcia, M.

    1997-01-01

    The release of [ 3 H]GABA from slices of rat substantia nigra pars reticulata induced by increasing extracellular K + from 6 to 15 mM in the presence of 10 μM sulpiride was inhibited by 73±3% by 1 μM SCH 23390, consistent with a large component of release dependent upon D 1 receptor activation. The histamine H 3 receptor-selective agonist immepip (1 μM) and the non-selective agonist histamine (100 μM) inhibited [ 3 H]GABA release by 78±2 and 80±2%, respectively. The inhibition by both agonists was reversed by the H 3 receptor antagonist thioperamide (1 μM). However, in the presence of 1 μM SCH 23390 depolarization-induced release of [ 3 H]GABA was not significantly decreased by 1 μM immepip. In rats depleted of dopamine by pretreatment with reserpine, immepip no longer inhibited control release of [ 3 H]GABA, but in the presence of 1 μM SKF 38393, which produced a 7±1-fold stimulation of release, immepip reduced the release to a level not statistically different from that in the presence of immepip alone. Immepip (1 μM) also inhibited the depolarization-induced release of [ 3 H]dopamine from substantia nigra pars reticulata slices, by 38±3%.The evidence is consistent with the proposition that activation of histamine H 3 receptors leads to the selective inhibition of the component of depolarization-induced [ 3 H]GABA release in substantia nigra pars reticulata slices which is dependent upon D 1 receptor activation. This appears to be largely an action at the terminals of the striatonigral GABA projection neurons, which may be enhanced by a partial inhibition of dendritic [ 3 H]dopamine release. (Copyright (c) 1997 Elsevier Science B.V., Amsterdam. All rights reserved.)

  6. 13-hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR-BI and stimulates apoA-I-dependent cholesterol efflux in RAW264.7 macrophages

    Directory of Open Access Journals (Sweden)

    Kämmerer Ines

    2011-11-01

    Full Text Available Abstract Background Synthetic activators of peroxisome proliferator-activated receptors (PPARs stimulate cholesterol removal from macrophages through PPAR-dependent up-regulation of liver × receptor α (LXRα and subsequent induction of cholesterol exporters such as ATP-binding cassette transporter A1 (ABCA1 and scavenger receptor class B type 1 (SR-BI. The present study aimed to test the hypothesis that the hydroxylated derivative of linoleic acid (LA, 13-HODE, which is a natural PPAR agonist, has similar effects in RAW264.7 macrophages. Methods RAW264.7 macrophages were treated without (control or with LA or 13-HODE in the presence and absence of PPARα or PPARγ antagonists and determined protein levels of LXRα, ABCA1, ABCG1, SR-BI, PPARα and PPARγ and apolipoprotein A-I mediated lipid efflux. Results Treatment of RAW264.7 cells with 13-HODE increased PPAR-transactivation activity and protein concentrations of LXRα, ABCA1, ABCG1 and SR-BI when compared to control treatment (P Conclusion 13-HODE induces cholesterol efflux from macrophages via the PPAR-LXRα-ABCA1/SR-BI-pathway.

  7. Dopamine D1/D5, but not D2/D3, receptor dependency of synaptic plasticity at hippocampal mossy fiber synapses that is enabled by patterned afferent stimulation, or spatial learning

    Directory of Open Access Journals (Sweden)

    Hardy Hagena

    2016-09-01

    Full Text Available Although the mossy fiber (MF synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24h synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH-CA1 and perforant path (PP-dentate gyrus (DG synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP and long-term depression (LTD. These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of these receptors in persistent (>24h forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data

  8. Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

    Science.gov (United States)

    Hagena, Hardy; Manahan-Vaughan, Denise

    2016-01-01

    Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an

  9. Initial activation state, stimulation intensity and timing of stimulation interact in producing behavioral effects of TMS

    OpenAIRE

    Silvanto, Juha; Bona, Silvia; Cattaneo, Zaira

    2017-01-01

    Behavioral effects of transcranial magnetic stimulation (TMS) have been shown to depend on various factors, such as neural activation state, stimulation intensity, and timing of stimulation. Here we examined whether these factors interact, by applying TMS at either sub- or suprathreshold intensity (relative to phosphene threshold, PT) and at different time points during a state-dependent TMS paradigm. The state manipulation involved a behavioral task in which a visual prime (color grating) wa...

  10. Variations in Cellular Responses of Mouse T Cells to Adenosine-5′-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage

    Directory of Open Access Journals (Sweden)

    Hanaa Safya

    2018-02-01

    Full Text Available A previous report has shown that regulatory T cells (Treg were markedly more sensitive to adenosine-5′-triphosphate (ATP than conventional T cells (Tconv. Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlow Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44low to effector/memory CD45RBlowCD44high stage. Maximum levels of upregulation are reached on recently activated CD69+ naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+ CD45RBhighCD44low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS. In contrast, naive CD45RBhighCD44low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlow Tconvs, CD45RBlowFoxp3+ Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the

  11. Variations in Cellular Responses of Mouse T Cells to Adenosine-5′-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage

    Science.gov (United States)

    Safya, Hanaa; Mellouk, Amine; Legrand, Julie; Le Gall, Sylvain M.; Benbijja, Mohcine; Kanellopoulos-Langevin, Colette; Kanellopoulos, Jean M.; Bobé, Pierre

    2018-01-01

    A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5′-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlow Tconvs, but not CD45RBhigh Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlow Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44low to effector/memory CD45RBlowCD44high stage. Maximum levels of upregulation are reached on recently activated CD69+ naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+ CD45RBhighCD44low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RBhighCD44low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlow Tconvs, CD45RBlowFoxp3+ Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different

  12. Variations in Cellular Responses of Mouse T Cells to Adenosine-5'-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage.

    Science.gov (United States)

    Safya, Hanaa; Mellouk, Amine; Legrand, Julie; Le Gall, Sylvain M; Benbijja, Mohcine; Kanellopoulos-Langevin, Colette; Kanellopoulos, Jean M; Bobé, Pierre

    2018-01-01

    A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RB low Tconvs, but not CD45RB high Tconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RB low Tconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RB high CD44 low to effector/memory CD45RB low CD44 high stage. Maximum levels of upregulation are reached on recently activated CD69 + naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69 + CD45RB high CD44 low Tconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RB high CD44 low Tconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RB low Tconvs, CD45RB low Foxp3 + Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary

  13. Stimulated Superconductivity at Strong Coupling

    Energy Technology Data Exchange (ETDEWEB)

    Bao, Ning; Dong, Xi; Silverstein, Eva; Torroba, Gonzalo; /Stanford U., ITP /Stanford U., Phys. Dept. /SLAC

    2011-08-12

    Stimulating a system with time dependent sources can enhance instabilities, thus increasing the critical temperature at which the system transitions to interesting low-temperature phases such as superconductivity or superfluidity. After reviewing this phenomenon in non-equilibrium BCS theory (and its marginal fermi liquid generalization) we analyze the effect in holographic superconductors. We exhibit a simple regime in which the transition temperature increases parametrically as we increase the frequency of the time-dependent source.

  14. Anal sphincter responses after perianal electrical stimulation

    DEFF Research Database (Denmark)

    Pedersen, Ejnar; Klemar, B; Schrøder, H D

    1982-01-01

    not fatigued by repeated stimulation, were most dependent on placement of stimulating and recording electrodes, and always had a higher threshold than the third response. The third response was constantly present in normal subjects. It had the longest EMG response and the latency decreased with increasing...

  15. Anti-inflammatory action of 2-carbomethoxy-2,3-epoxy-3-prenyl-1,4-naphthoquinone (CMEP-NQ) suppresses both the MyD88-dependent and TRIF-dependent pathways of TLR4 signaling in LPS-stimulated RAW264.7 cells.

    Science.gov (United States)

    Ju Woo, Hyun; Jun, Do Youn; Lee, Ji Young; Park, Hae Sun; Woo, Mi Hee; Park, Sook Jahr; Kim, Sang Chan; Yang, Chae Ha; Kim, Young Ho

    2017-06-09

    The roots of Rubia cordifolia L. have been widely used as a traditional herbal medicine in Northeast Asia for treating inflammatory diseases. To elucidate the anti-inflammatory mechanism of 2-carbomethoxy-2,3-epoxy-3- prenyl-1,4-naphthoquinone (CMEP-NQ), purified from the roots of R. cordifolia L. as the major anti-inflammatory component, in LPS-treated RAW264.7 murine macrophage cells. Anti-inflammatory activity of CMEP-NQ was investigated in LPS-treated RAW264.7 cells by measuring the levels of NO, PGE 2 , and cytokines (IL1β, IL-6, TNF-α) in the culture supernatants and the TLR4-mediated intracellular events including association of MyD88 with IRAK1, activation of IRAK1, TAK1, MAPKs, NF-κB/AP-1, and IRF3, and generation of ROS. Pretreatment of RAW264.7 cells with CMEP-NQ reduced LPS-induced production of NO and PGE 2 by suppressing iNOS and COX-2 gene expression. CMEP-NQ also reduced the secretion of IL-1β, IL-6, and TNF-α by down-regulating mRNA levels. Under these conditions, TLR4-mediated MyD88-dependent events were inhibited by CMEP-NQ, including the association of MyD88 with IRAK1, phosphorylation of IRAK1, TAK1, and MAPKs (ERK, JNK and p38 MAPK), and activation of NF-κB and AP-1. As TRIF-dependent events of TLR4 signaling, phosphorylation of IRF3 and induction of iNOS protein expression were also inhibited by CMEP-NQ. However, the binding of FITC-conjugated LPS to cell surface TLR4 was not affected by CMEP-NQ. Following LPS stimulation, intracellular ROS production was first detected by DCFH-DA staining at 1h; then it continuously increased until 16h. Although CMEP-NQ failed to exhibit DPPH radical- or ABTS radical-scavenging activity in vitro, LPS-induced ROS production in RAW264.7 cells was more efficiently blocked by CMEP-NQ than by NAC. These results demonstrate that the suppressive effect of CMEP-NQ on LPS-induced inflammatory responses in RAW264.7 cells was mainly exerted via its inhibition of TLR4-mediated proximal events, such as MyD88

  16. Temperature-dependent luminescence and temperature-stimulated NIR-to-VIS up-conversion in Nd3+-doped La2O3-Na2O-ZnO-TeO2 glasses

    Science.gov (United States)

    Sobczyk, Marcin

    2013-04-01

    Telluride glasses of the composition xNd2O3-(7-x)La2O3-3Na2O-25ZnO-65TeO2, where (0≤x≤7) were prepared by the melt quench technique. Some physical and optical properties of the glasses were evaluated. The thermal behavior i.e. glass transition and crystallization temperatures were studied by using TGA-DTA technique. Optical properties of Nd3+-doped telluride glasses were investigated between 298 and 700 K. Basing on the obtained values of J-O parameter values (×10-20 cm2: Ω2=4.49±0.84, Ω4=5.03±0.61, Ω6=4.31±0.73), the radiative transition probabilities (AT), radiative lifetimes (τR), fluorescence branching ratios (β) and emission cross-sections (σem) were calculated for the 4F3/2→4IJ/2 (where J=9, 11 and 13) transitions of Nd3+ ions. The τR value of the 4F3/2 level amount to 164 μs and is slightly higher than the measured decay time of 162 μs. With the increasing of Nd2O3 concentration from 0.5 to 7.0 mol% the experimental lifetime of the fluorescent level decreases from 162 to 5.6 μs. The estimated quantum efficiency amount to 100%, based on a comparison of τR and the experimental decay time of a slightly doped Nd3+ telluride glass. An analysis of the non-radiative decay was based on the cross-relaxation mechanisms. The 4F3/2→4I9/2 and 4F5/2→4I9/2 transitions were analyzed with respect to the fluorescence intensity ratio (FIR) and were found to be temperature dependent. Infrared-to-visible up-conversion emissions with a maximum at 603.0 and 635.3 nm were observed at high temperatures using the 804 nm excitation and are due to the 4G5/2→4I9/2 and 4G5/2→4I11/2 transitions of Nd3+ ions, respectively. The near quadratic dependence of fluorescence on excitation laser power confirms that two photons contribute to up-conversion of the orange emissions. The temperature-stimulated up-conversion excitation processes have been analyzed in detail. The optical results indicate that the investigated glasses are potentially applicable as a 1063 nm

  17. Mechanisms of deep brain stimulation

    Science.gov (United States)

    Cheng, Jennifer J.; Eskandar, Emad N.

    2015-01-01

    Deep brain stimulation (DBS) is widely used for the treatment of movement disorders including Parkinson's disease, essential tremor, and dystonia and, to a lesser extent, certain treatment-resistant neuropsychiatric disorders including obsessive-compulsive disorder. Rather than a single unifying mechanism, DBS likely acts via several, nonexclusive mechanisms including local and network-wide electrical and neurochemical effects of stimulation, modulation of oscillatory activity, synaptic plasticity, and, potentially, neuroprotection and neurogenesis. These different mechanisms vary in importance depending on the condition being treated and the target being stimulated. Here we review each of these in turn and illustrate how an understanding of these mechanisms is inspiring next-generation approaches to DBS. PMID:26510756

  18. Pre-therapeutic blood dosimetry in patients with differentiated thyroid carcinoma using 124-iodine. Predicted blood doses correlate with changes in blood cell counts after radioiodine therapy and depend on modes of TSH stimulation and number of preceding radioiodine therapies

    International Nuclear Information System (INIS)

    Hartung-Knemeyer, V.; Nagarajah, J.; Jentzen, W.; Ruhlmann, M.; Freudenberg, L.S.; Stahl, A.R.; Bockisch, A.; Rosenbaum-Krumme, S.J.

    2012-01-01

    Pre-therapeutic blood dosimetry prior to a high-dose radioiodine therapy (RAIT) is recommended and a blood dose of 2 Gy is considered to be safe. In this study, changes in the blood cell count after radioiodine therapy of high risk differentiated thyroid carcinoma (DTC) were analyzed and compared with the results of the pre-therapeutic blood dosimetry using 124 I. Moreover, the influence of different modes of TSH stimulation and the number of preceding radioiodine therapies on the blood dose were assessed. 198 patients with locally advanced or metastasized DTC received a pre-therapeutic blood dosimetry using 124 I. To analyze the influence of the modes of TSH stimulation and the number of preceding RAITs on blood dose subgroups were built as follows: patients with endogenous TSH stimulation versus patients with exogenous TSH stimulation and patients with no preceding RAIT versus patients with at least one preceding RAIT. In 124/198 patients subsequent RAIT was performed. In 73/124 patients, hemograms were performed from day 2 to 12 month after RAIT. There was no high-grade bone marrow toxicity (id est (i.e.) ≥grade 3) in patients receiving less than 2 Gy blood dose-independent of the therapeutic history. Within the first month after radioiodine therapy, there was an overall decrease in the white blood cell and platelet counts. The erythrocyte count was essentially stable. There was a correlation between cell count decrease and predicted blood doses (Spearman's correlation coefficient >-0.6 each) for the white cell line and the platelets. With regard to the subgroups, the blood dose per administered 131 I activity (BDpA) was significantly higher in patients with endogenous TSH stimulation (median 0.08 Gy/GBq) than in patients with exogenous TSH stimulation (0.06 Gy/GBq) and in patients with no previous RAIT (0.08 Gy/GBq) compared to patients who had previously undergone at least one RAIT (0.07 Gy/GBq). The range of BDpA among DTC patients is rather wide. Our

  19. Stimulation of phagocytosis by sulforaphane

    Energy Technology Data Exchange (ETDEWEB)

    Suganuma, Hiroyuki, E-mail: hsuganu1@jhmi.edu [Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205 (United States); Fahey, Jed W., E-mail: jfahey@jhmi.edu [Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205 (United States); Bryan, Kelley E., E-mail: kbryanm1@jhmi.edu [Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205 (United States); Healy, Zachary R., E-mail: zhealy1@jhmi.edu [Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205 (United States); Talalay, Paul, E-mail: ptalalay@jhmi.edu [Lewis B. and Dorothy Cullman Cancer Chemoprotection Center, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205 (United States)

    2011-02-04

    Research highlights: {yields} Sulforaphane stimulates the phagocytosis of RAW 264.7 macrophages under conditions of serum deprivation. {yields} This effect does not require Nrf2-dependent induction of phase 2 genes. {yields} Inactivation of macrophage migration inhibitory factor (MIF) by sulforaphane may be involved in stimulation of phagocytosis by sulforaphane. -- Abstract: Sulforaphane, a major isothiocyanate derived from cruciferous vegetables, protects living systems against electrophile toxicity, oxidative stress, inflammation, and radiation. A major protective mechanism is the induction of a network of endogenous cytoprotective (phase 2) genes that are regulated by transcription factor Nrf2. To obtain a more detailed understanding of the anti-inflammatory and immunomodulatory effects of sulforaphane, we evaluated its effect on the phagocytosis activity of RAW 264.7 murine macrophage-like cells by measuring the uptake of 2-{mu}m diameter polystyrene beads. Sulforaphane raised the phagocytosis activity of RAW 264.7 cells but only in the absence or presence of low concentrations (1%) of fetal bovine serum. Higher serum concentrations depressed phagocytosis and abolished its stimulation by sulforaphane. This stimulation did not depend on the induction of Nrf2-regulated genes since it occurred in peritoneal macrophages of nrf2{sup -/-} mice. Moreover, a potent triterpenoid inducer of Nrf2-dependent genes did not stimulate phagocytosis, whereas sulforaphane and another isothiocyanate (benzyl isothiocyanate) had comparable inducer potencies. It has been shown recently that sulforaphane is a potent and direct inactivator of macrophage migration inhibitory factor (MIF), an inflammatory cytokine. Moreover, the addition of recombinant MIF to RAW 264.7 cells attenuated phagocytosis, but sulforaphane-inactivated MIF did not affect phagocytosis. The inactivation of MIF may therefore be involved in the phagocytosis-enhancing activity of sulforaphane.

  20. Feldspar, Infrared Stimulated Luminescence

    DEFF Research Database (Denmark)

    Jain, Mayank

    2014-01-01

    This entry primarily concerns the characteristics and the origins of infrared-stimulated luminescence in feldspars.......This entry primarily concerns the characteristics and the origins of infrared-stimulated luminescence in feldspars....

  1. Growth hormone stimulation test

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003377.htm Growth hormone stimulation test To use the sharing features on this page, please enable JavaScript. The growth hormone (GH) stimulation test measures the ability of the ...

  2. Spinal cord stimulation

    Science.gov (United States)

    ... 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 ...

  3. Stimulation of a Cd-binding protein, and inhibition of the vitamin D-dependent calcium-binding protein, by zinc or cadmium in organ-cultured embryonic chick duodenum

    International Nuclear Information System (INIS)

    Corradino, R.A.; Fullmer, C.S.

    1980-01-01

    Embryonic chick duodenum maintained in organ culture responds to 1 α,25-dihydroxy vitamin D 3 in the culture medium by de novo synthesis of a specific calcium-binding protein (CaBP). The addition of Cd 2+ (3-5 x 10 -5 M) or Zn 2+ (10 -5 -10 -4 M) to the medium inhibited CaBP, but stimulated biosynthesis of a Cd-binding protein (CdBP). CdBP in duodenal homogenate supernatants was assessed in two ways: first, by its 109 Cd-binding activity ( 109 CdBA) using a competitive ion exchange procedure; and, second, by the extent of [ 35 S]-cystine incorporation into a specific peak or band after gel filtration or analytical polyacrylamide disc gel electrophoresis, respectively. Regardless of whether cadmium- or zinc-stimulated, the 35 S-labeled CdBP - the only protein significantly labeled under the conditions employed - migrated identically upon gel filtration and electrophoresis, and comigrated with purified chick liver Cd-metallothionein. Neither actinomycin D nor α-amanitin, in concentrations sufficient to severely inhibit CaBP, significantly reduced CdBP production. However, cycloheximide did inhibit either Cd 2+ - or Zn 2+ -stimulated CdBP by about 50% at an inhibitor concentration which abolished CaBP. The inhibitor studies, coupled with the observations of extensive incorporation of [ 35 S]cystine into CdBP, suggest that the metals stimulated biosynthesis by a mechanism operating at the translational level. The organ-cultured duodenum seems well suited for studies of the regulation of CdBP biosynthesis especially since it responds predictably to the steroid hormone, 1α,25-dihydroxy vitamin D 3 , in the induction of another specific protein, CaBP, at the transcriptional level. The biosynthesis of CaBP thus may serve as a convenient control in studies of CdBP production under various experimental conditions

  4. Anal sphincter responses after perianal electrical stimulation

    DEFF Research Database (Denmark)

    Pedersen, Ejnar; Klemar, B; Schrøder, H D

    1982-01-01

    not fatigued by repeated stimulation, were most dependent on placement of stimulating and recording electrodes, and always had a higher threshold than the third response. The third response was constantly present in normal subjects. It had the longest EMG response and the latency decreased with increasing......By perianal electrical stimulation and EMG recording from the external anal sphincter three responses were found with latencies of 2-8, 13-18 and 30-60 ms, respectively. The two first responses were recorded in most cases. They were characterised by constant latency and uniform pattern, were...

  5. "Slinky" coils for neuromagnetic stimulation.

    Science.gov (United States)

    Zimmermann, K P; Simpson, R K

    1996-04-01

    Future advances in neuromagnetic stimulation depend significantly on the design of coils with improved focality. Although in the absence of internal current sources, no true focusing of magnetically induced currents is possible, improvements in the focality of current concentrations passing through an area of biologic tissue are achievable through variations of the shape, orientation and size of neuromagnetic stimulating coils. The "butterfly" and the "4-leaf" coils are two examples of planar designs which achieve improved focality through centralization of the maximum coil current and peripheral distribution of the return currents. We introduce the "slinky" coil design as a 3-dimensional generalization of the principle of peripheral distribution of return currents and demonstrate its advantages over planar designs.

  6. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults

    DEFF Research Database (Denmark)

    Laursen, Torben; Jørgensen, Jens Otto Lunde; Møller, Jens

    1994-01-01

    Abstract OBJECTIVE: The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH-deficient patients as part of a GH dose......-response study. PATIENTS: Eight GH-deficient adults, who received stable T4 substitution due to central hypothyroidism; two patients, who were euthyroid without T4 supplementation were studied separately. DESIGN: All patients were initially studied after at least 4 weeks without GH followed by 3 consecutive 4......-week periods in fixed order during which they received daily doses of 1, 2 and 4 IU of GH/m2 body surface area. The patients were hospitalized for 24 hours at the end of each period. MEASUREMENTS: Circulating total and free concentrations of T4 and T3, total rT3 and TSH were measured once at the end...

  7. Optically stimulated luminesence dosimeter

    International Nuclear Information System (INIS)

    Liu Qiujiang; Zhu Lei; Zhu Lei; Chinese Academy of Sciences, Beijing; Chen Zhaoyang; Fan Yanwei; Ba Weizhen; Cong Xiuyun; Tang Xinqiang; Guo Qi; Lu Wu

    2007-01-01

    In this paper, the principle and makeup of optically stimulated luminescence dosimeter is described, and a measurement for radiation is carried, some actual problem is discussed. The dosimeter has high sensitive and can be reseted in-flight by stimulated light. (authors)

  8. [Transcranial magnetic stimulation].

    Science.gov (United States)

    Tormos, J M; Catalá, M D; Pascual-Leone, A

    Transcranial magnetic stimulation (TMS) permits stimulation of the cerebral cortex in humans without requiring open access to the brain and is one of the newest tools available in neuroscience. There are two main types of application: single-pulse TMS and repetitive TMS. The magnetic stimulator is composed of a series of capacitors that store the voltage necessary to generate a stimulus of the sufficient intensity of generate an electric field in the stimulation coil. The safety of TMS is supported by the considerable experience derived from studies involving electrical stimulation of the cortex in animals and humans, and also specific studies on the safety of TMS in humans. In this article we review historical and technical aspects of TMS, describe its adverse effects and how to avoid them, summarize the applications of TMS in the investigation of different cerebral functions, and discuss the possibility of using TMS for the treatment of neuropsychiatric disorders.

  9. Stimulating at the right time: phase-specific deep brain stimulation.

    Science.gov (United States)

    Cagnan, Hayriye; Pedrosa, David; Little, Simon; Pogosyan, Alek; Cheeran, Binith; Aziz, Tipu; Green, Alexander; Fitzgerald, James; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Hariz, Marwan; Friston, Karl J; Denison, Timothy; Brown, Peter

    2017-01-01

    SEE MOLL AND ENGEL DOI101093/AWW308 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Brain regions dynamically engage and disengage with one another to execute everyday actions from movement to decision making. Pathologies such as Parkinson's disease and tremor emerge when brain regions controlling movement cannot readily decouple, compromising motor function. Here, we propose a novel stimulation strategy that selectively regulates neural synchrony through phase-specific stimulation. We demonstrate for the first time the therapeutic potential of such a stimulation strategy for the treatment of patients with pathological tremor. Symptom suppression is achieved by delivering stimulation to the ventrolateral thalamus, timed according to the patient's tremor rhythm. Sustained locking of deep brain stimulation to a particular phase of tremor afforded clinically significant tremor relief (up to 87% tremor suppression) in selected patients with essential tremor despite delivering less than half the energy of conventional high frequency stimulation. Phase-specific stimulation efficacy depended on the resonant characteristics of the underlying tremor network. Selective regulation of neural synchrony through phase-locked stimulation has the potential to both increase the efficiency of therapy and to minimize stimulation-induced side effects. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

  10. Modulation of Specific Sensory Cortical Areas by Segregated Basal Forebrain Cholinergic Neurons Demonstrated by Neuronal Tracing and Optogenetic Stimulation in Mice.

    Science.gov (United States)

    Chaves-Coira, Irene; Barros-Zulaica, Natali; Rodrigo-Angulo, Margarita; Núñez, Ángel

    2016-01-01

    Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF) projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-Gold (FlGo) and Fast Blue (FB) fluorescent retrograde tracers were deposited into the primary somatosensory (S1) and primary auditory (A1) cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB) projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B) nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP) under the control of the choline-acetyl transferase promoter (ChAT). Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  11. Modulation of specific sensory cortical areas by segregated basal forebrain cholinergic neurons demonstrated by neuronal tracing and optogenetic stimulation in mice

    Directory of Open Access Journals (Sweden)

    Irene eChaves-Coira

    2016-04-01

    Full Text Available Neocortical cholinergic activity plays a fundamental role in sensory processing and cognitive functions. Previous results have suggested a refined anatomical and functional topographical organization of basal forebrain (BF projections that may control cortical sensory processing in a specific manner. We have used retrograde anatomical procedures to demonstrate the existence of specific neuronal groups in the BF involved in the control of specific sensory cortices. Fluoro-gold and Fast Blue fluorescent retrograde tracers were deposited into the primary somatosensory (S1 and primary auditory (A1 cortices in mice. Our results revealed that the BF is a heterogeneous area in which neurons projecting to different cortical areas are segregated into different neuronal groups. Most of the neurons located in the horizontal limb of the diagonal band of Broca (HDB projected to the S1 cortex, indicating that this area is specialized in the sensory processing of tactile stimuli. However, the nucleus basalis magnocellularis (B nucleus shows a similar number of cells projecting to the S1 as to the A1 cortices. In addition, we analyzed the cholinergic effects on the S1 and A1 cortical sensory responses by optogenetic stimulation of the BF neurons in urethane-anesthetized transgenic mice. We used transgenic mice expressing the light-activated cation channel, channelrhodopsin-2, tagged with a fluorescent protein (ChR2-YFP under the control of the choline-acetyl transferase promoter (ChAT. Cortical evoked potentials were induced by whisker deflections or by auditory clicks. According to the anatomical results, optogenetic HDB stimulation induced more extensive facilitation of tactile evoked potentials in S1 than auditory evoked potentials in A1, while optogenetic stimulation of the B nucleus facilitated either tactile or auditory evoked potentials equally. Consequently, our results suggest that cholinergic projections to the cortex are organized into segregated

  12. Rewiring neural interactions by micro-stimulation

    Directory of Open Access Journals (Sweden)

    James M Rebesco

    2010-08-01

    Full Text Available Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain-machine interface applications.

  13. Early experiences with tachycardia-triggered vagus nerve stimulation using the AspireSR stimulator.

    Science.gov (United States)

    El Tahry, Riëm; Hirsch, Martin; Van Rijckevorsel, Kenou; Santos, Susana Ferrao; de Tourtchaninoff, Marianne; Rooijakkers, Herbert; Coenen, Volker; Schulze-Bonhage, Andreas

    2016-06-01

    Many epilepsy patients treated with vagus nerve stimulation additionally use an "on-demand" function, triggering an extra stimulation to terminate a seizure or diminish its severity. Nevertheless, a substantial number of patients are not able to actively trigger stimulations by use of a magnet, due to the absence of an aura or inability for voluntary actions in the early phase of a seizure. To address this need, a novel implantable pulse generator, the AspireSR VNS system, was developed to provide automated ictal stimulation triggered by a seizure-detecting algorithm. We report our experience with three patients in assessing the functionality of ictal stimulation, illustrating the detection system in practice. Detection of ictal tachycardia and variable additional detections of physiological tachycardia depended on the individual seizure-detecting algorithm settings.

  14. Stimulant-induced trichotillomania.

    Science.gov (United States)

    Hamalian, Gareen; Citrome, Leslie

    2010-01-01

    A prior report described the presentation of cocaine-induced trichotillomania, which resolved with the cessation of cocaine use. Here the authors describe the case of stimulant-induced trichotillomania that resolved with the discontinuation of stimulants and initiation of olanzapine. To the authors' knowledge this is the first reported adult case of stimulant-induced trichotillomania. The case is of a patient with a previous diagnosis of attention deficit hyperactivity disorder whose symptoms of trichotillomania coincide with abuse of amphetamine and with the resolution of symptoms in the absence of amphetamine use. Given the increase in exposure of prescription amphetamines among adults, further study into the association between stimulants and adverse events such as trichotillomania is needed.

  15. Vagus Nerve Stimulation

    Science.gov (United States)

    ... you do certain activities such as public speaking, singing or exercising, or when you're eating if ... of life. Research is still mixed on the benefits of vagus nerve stimulation for the treatment of ...

  16. Multipolar intrafascicular stimulation

    NARCIS (Netherlands)

    Meier, Jan H.; Meier, J.H.; Rutten, Wim

    1992-01-01

    The suppressing effect of two intrafascicular anodes on the neural recruitment elicited by one intrafascicular cathode has been studied. Recruitment curves are calculated with a nerve stimulation model and are compared to experimental curves for the peroneal nerve of rat.

  17. Modeling and time-dependent dynamics of processes of stimulated depolymerization, auto-repairing, degradation and radiation curing of DNA macromolecules and biopolymers at separated and combined actions of ionizing irradiation

    Science.gov (United States)

    Vysotskii, Vladimir I.; Pinchuk, Anatoliy O.; Kornilova, Alla A.; Samoylenko, Igor I.

    2001-12-01

    The time-dependent dynamics of the formation, relaxation and auto-repairing of double breaks of DNA macromolecules at the combined radiation action and non-radiation processes of degradation (e.g. by free radicals) were considered. The auto-repairing of DNA double breaks is connected with the peculiarities of long-range interaction of nucleotide charges, atoms and molecules in the intracellular milieu. The properties of intracellular liquid and the characteristics of force interaction between the end-pairs of nucleotides in the area of DNA break in response to radiation are changed. Each kind of radiation is characterized by a certain effectiveness of the double DNA break formation but simultaneously one creates the conditions for their liquidation. On the basis of the analysis and correlation of these processes the time-dependent theory for DNA degradation was created, including hormesis phenomenon, radiation antagonism, the validity of anomaly influence of low and large doses at sharp and chronic radiation and other effects. The qualitative and quantitative correspondences of the theory and experimental results of radiation biology were obtained.

  18. Nonlinear electrodynamics in microwave-stimulated superconductivity

    International Nuclear Information System (INIS)

    Mooij, J.E.; Klapwijk, T.M.

    1983-01-01

    In practical experiments on microwave-stimulated superconductivity the current source character of the microwave coupling leads to a strong dependence of the field strength on the value of the gap. Various consequences are pointed out, in particular, for a quantitative comparison between critical current and gap or order-parameter enhancement

  19. Progesterone stimulates pancreatic cell proliferation in vivo

    NARCIS (Netherlands)

    Nieuwenhuizen, AG; Schuiling, GA; Liem, SMS; Moes, H; Koiter, TR; Uilenbroek, JTJ

    Treatment of cyclic and pregnant rats with progesterone stimulates cell proliferation within the islets of Langerhans. It was investigated whether this effect of progesterone depends on sex and/or the presence of the gonads or the presence of oestradiol, For this purpose, Silastic tubes containing

  20. Effect of electrical stimulation on blood flow velocity and vessel size

    Directory of Open Access Journals (Sweden)

    Jin Hee-Kyung

    2017-03-01

    Full Text Available Interferential current electrical stimulation alters blood flow velocity and vessel size. We aimed to investigate the changes in the autonomic nervous system depending on electrical stimulation parameters.

  1. Dose-dependent effects of luteinizing hormone and follicle ...

    African Journals Online (AJOL)

    Dose-dependent effects of luteinizing hormone and follicle stimulating hormone on in vitro maturation, apoptosis, secretion function and expression of follicle stimulating hormone receptor and luteinizing hormone receptor of sheep oocytes.

  2. Mechanism of adrenergic stimulation of hepatic ketogenesis.

    Science.gov (United States)

    Kosugi, K; Harano, Y; Nakano, T; Suzuki, M; Kashiwagi, A; Shigeta, Y

    1983-11-01

    The effects of alpha- and beta-adrenergic stimulation on ketogenesis were examined in freshly isolated rat hepatocytes in order to determine which alpha- or beta-adrenergic stimulation is involved in the enhancement of ketogenesis. In the presence of 0.3 mmol/L (U-14C)-palmitate, epinephrine, norepinephrine, and phenylephrine at 500 ng/mL increased ketogenesis by 25% (16.0 +/- 0.17 v 12.8 +/- 0.13 nmol/mg protein per hour), 20% (15.3 +/- 0.28) and 20% (15.4 +/- 0.36), respectively. However, isoproterenol even at 1 microgram/mL did not stimulate ketogenesis. Phentolamine (5 micrograms/mL) almost completely abolished the effect of epinephrine on ketogenesis (13.7 +/- 0.30 v 16.0 +/- 0.17) but propranolol did not inhibit the stimulation by epinephrine (15.6 +/- 0.38 v 16.0 +/- 0.17). Trifluoperazine (10 mumol/L), presumably an inhibitor of calcium-dependent protein kinase, abolished the effect of epinephrine (13.6 +/- 0.22 v 16.0 +/- 0.17). These results indicate that catecholamines increase ketogenesis predominantly through the alpha-adrenergic system independent of cyclic AMP, and calcium-dependent protein kinase is thought to be involved in the activation of ketogenesis. On the other hand, glucagon stimulated ketogenesis with an increase of cyclic AMP, which was not inhibited by alpha- and beta-adrenergic antagonists. Alpha-adrenergic stimulation increased hepatic glycogenolysis much more at much lower concentrations when compared with ketogenesis. Stimulation of ketogenesis by catecholamines seemed to be less sensitive and responsive compared with hepatic glycogenolysis.

  3. Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent.

    Science.gov (United States)

    Manevski, Nenad; Troberg, Johanna; Svaluto-Moreolo, Paolo; Dziedzic, Klaudyna; Yli-Kauhaluoma, Jari; Finel, Moshe

    2013-01-01

    Human UDP-glucuronosyltransferases (UGTs) are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA) significantly enhances in vitro activities of UGTs, a limiting factor in in vitro-in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2-4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction's K(m), increasing its V(max), or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions' K(m) are concerned. In the cases of V(max) values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to V(max) increases. Additionally, the BSA effects may be UGT subfamily dependent since K(m) decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large V(max) increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs.

  4. Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent.

    Directory of Open Access Journals (Sweden)

    Nenad Manevski

    Full Text Available Human UDP-glucuronosyltransferases (UGTs are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA significantly enhances in vitro activities of UGTs, a limiting factor in in vitro-in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2-4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction's K(m, increasing its V(max, or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions' K(m are concerned. In the cases of V(max values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to V(max increases. Additionally, the BSA effects may be UGT subfamily dependent since K(m decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large V(max increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs.

  5. Internal jugular vein: Peripheral vein adrenocorticotropic hormone ratio in patients with adrenocorticotropic hormone-dependent Cushing′s syndrome: Ratio calculated from one adrenocorticotropic hormone sample each from right and left internal jugular vein during corticotrophin releasing hormone stimulation test

    Directory of Open Access Journals (Sweden)

    Sachin Chittawar

    2013-01-01

    Full Text Available Background: Demonstration of central: Peripheral adrenocorticotropic hormone (ACTH gradient is important for diagnosis of Cushing′s disease. Aim: The aim was to assess the utility of internal jugular vein (IJV: Peripheral vein ACTH ratio for diagnosis of Cushing′s disease. Materials and Methods: Patients with ACTH-dependent Cushing′s syndrome (CS patients were the subjects for this study. One blood sample each was collected from right and left IJV following intravenous hCRH at 3 and 5 min, respectively. A simultaneous peripheral vein sample was also collected with each IJV sample for calculation of IJV: Peripheral vein ACTH ratio. IJV sample collection was done under ultrasound guidance. ACTH was assayed using electrochemiluminescence immunoassay (ECLIA. Results: Thirty-two patients participated in this study. The IJV: Peripheral vein ACTH ratio ranged from 1.07 to 6.99 ( n = 32. It was more than 1.6 in 23 patients. Cushing′s disease could be confirmed in 20 of the 23 cases with IJV: Peripheral vein ratio more than 1.6. Four patients with Cushing′s disease and 2 patients with ectopic ACTH syndrome had IJV: Peripheral vein ACTH ratio less than 1.6. Six cases with unknown ACTH source were excluded for calculation of sensitivity and specificity of the test. Conclusion: IJV: Peripheral vein ACTH ratio calculated from a single sample from each IJV obtained after hCRH had 83% sensitivity and 100% specificity for diagnosis of CD.

  6. Alanine administration does not stimulate gluconeogenesis in preterm infants

    NARCIS (Netherlands)

    van Kempen, Anne A. M. W.; Romijn, Johannes A.; Ruiter, An F. C.; Endert, Erik; Weverling, Gerrit Jan; Kok, Johanna H.; Sauerwein, Hans P.

    2003-01-01

    Gluconeogenesis partially depends on sufficient precursor supply, and plasma alanine concentrations are generally low in preterm infants. Stimulation of gluconeogenesis may contribute to the prevention of hypoglycemia, an important clinical problem in these infants. In this study we evaluated the

  7. Beryllium-stimulated apoptosis in macrophage cell lines.

    Science.gov (United States)

    Sawyer, R T; Fadok, V A; Kittle, L A; Maier, L A; Newman, L S

    2000-08-21

    In vitro stimulation of bronchoalveolar lavage cells from patients with chronic beryllium disease (CBD) induces the production of TNF-alpha. We tested the hypothesis that beryllium (Be)-stimulated TNF-alpha might induce apoptosis in mouse and human macrophage cell lines. These cell lines were selected because they produce a range of Be-stimulated TNF-alpha. The mouse macrophage cell line H36.12j produces high levels of Be-stimulated TNF-alpha. The mouse macrophage cell line P388D.1 produces low, constitutive, levels of TNF-alpha and does not up-regulate Be-stimulated TNF-alpha production. The DEOHS-1 human CBD macrophage cell line does not produce constitutive or Be-stimulated TNF-alpha. Apoptosis was determined by microscopic observation of propidium iodide stained fragmented nuclei in unstimulated and BeSO(4)-stimulated macrophage cell lines. BeSO(4) induced apoptosis in all macrophage cell lines tested. Beryllium-stimulated apoptosis was dose-responsive and maximal after 24 h of exposure to 100 microM BeSO(4). In contrast, unstimulated and Al(2)(SO(4))(3)-stimulated macrophage cell lines did not undergo apoptosis. The general caspase inhibitor BD-fmk inhibited Be-stimulated macrophage cell line apoptosis at concentrations above 50 microM. Our data show that Be-stimulated macrophage cell line apoptosis was caspase-dependent and not solely dependent on Be-stimulated TNF-alpha levels. We speculate that the release of Be-antigen from apoptotic macrophages may serve to re-introduce Be material back into the lung microenvironment, make it available for uptake by new macrophages, and thereby amplify Be-stimulated cytokine production, promoting ongoing inflammation and granuloma maintenance in CBD.

  8. The Underlying Mechanism of Preventing Facial Nerve Stimulation by Triphasic Pulse Stimulation in Cochlear Implant Users Assessed With Objective Measure.

    Science.gov (United States)

    Bahmer, Andreas; Baumann, Uwe

    2016-10-01

    Triphasic pulse stimulation prevents from facial nerve stimulation (FNS) because of a different electromyographic input-output function compared with biphasic pulse stimulation. FNS is sometimes observed in cochlear implant users as an unwanted side effect of electrical stimulation of the auditory nerve. The common stimulation applied in current cochlear implant consists of biphasic pulse patterns. Two common clinical remedies to prevent unpleasant FNS caused by activation of certain electrodes are to expand their pulse phase duration or simply deactivate them. Unfortunately, in some patients these methods do not provide sufficient FNS prevention. In these patients triphasic pulse can prevent from FNS. The underlying mechanism is yet unclear. Electromyographic (EMG) recordings of muscles innervated by the facial nerve (musculi orbicularis ori and oculi) were applied to quantitatively assess the effects on FNS. Triphasic and biphasic fitting maps were compared in four subjects with severe FNS. Based on the recordings, a model is presented which intends to explain the beneficial effects of triphasic pulse application. Triphasic stimulation provided by fitting of an OPUS 2 speech processor device. For three patients, EMG was successfully recorded depending on stimulation level up to uncomfortable and intolerable FNS stimulation as upper boarder. The obtained EMG recordings demonstrated high individual variability. However, a difference between the input-output function for biphasic and triphasic pulse stimulation was visually observable. Compared with standard biphasic stimulation, triphasic pulses require higher stimulation levels to elicit an equal amount of FNS, as reflected by EMG amplitudes. In addition, we assume a steeper slope of the input-output function for biphasic pulse stimulation compared with triphasic pulse stimulation. Triphasic pulse stimulation prevents from FNS because of a smaller gradient of EMG input-output function compared with biphasic pulse

  9. New York Canyon Stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Raemy, Bernard

    2012-06-21

    The New York Canyon Stimulation Project was to demonstrate the commercial application of Enhanced Geothermal System techniques in Buena Vista Valley area of Pershing County, Nevada. From October 2009 to early 2012, TGP Development Company aggressively implemented Phase I of Pre-Stimulation and Site/Wellbore readiness. This included: geological studies; water studies and analyses and procurement of initial permits for drilling. Oversubscription of water rights and lack of water needed for implementation of EGS were identified and remained primary obstacles. Despite extended efforts to find alternative solutions, the water supply circumstances could not be overcome and led TGP to determine a "No Go" decision and initiate project termination in April 2012.

  10. Prostaglandins stimulate renin secretion and renin mRNA in mouse renal juxtaglomerular cells

    DEFF Research Database (Denmark)

    Jensen, B L; Schmid, C; Kurtz, A

    1996-01-01

    identified PGI2 and PGE2 as stimulators of renin secretion; the effects were dose and time dependent. PGE2 also increased renin mRNA accumulation time and dose dependent. PGE2 and PGI2 activated adenylate cyclase concentration dependent in granular cells. PGE2 stimulations of renin secretion and renin m...

  11. stimulated BV2 Microglial

    African Journals Online (AJOL)

    2012-03-26

    Mar 26, 2012 ... (PGE2) as well as their regulatory genes such as inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-. 2), in LPS-stimulated ... mediated NF-κB activity. Keywords: Myelophycus caespitosus, Nitric oxide, Prostaglandin E2, Nuclear factor-κB. ..... induced by hypoxia and endotoxin. J Immunol. 2000 ...

  12. Brain stimulation in migraine.

    Science.gov (United States)

    Brighina, Filippo; Cosentino, Giuseppe; Fierro, Brigida

    2013-01-01

    Migraine is a very prevalent disease with great individual disability and socioeconomic burden. Despite intensive research effort in recent years, the etiopathogenesis of the disease remains to be elucidated. Recently, much importance has been given to mechanisms underlying the cortical excitability that has been suggested to be dysfunctional in migraine. In recent years, noninvasive brain stimulation techniques based on magnetic fields (transcranial magnetic stimulation, TMS) and on direct electrical currents (transcranial direct current stimulation, tDCS) have been shown to be safe and effective tools to explore the issue of cortical excitability, activation, and plasticity in migraine. Moreover, TMS, repetitive TMS (rTMS), and tDCS, thanks to their ability to interfere with and/or modulate cortical activity inducing plastic, persistent effects, have been also explored as potential therapeutic approaches, opening an interesting perspective for noninvasive neurostimulation for both symptomatic and preventive treatment of migraine and other types of headache. In this chapter we critically review evidence regarding the role of noninvasive brain stimulation in the pathophysiology and treatment of migraine, delineating the advantages and limits of these techniques together with potential development and future application. © 2013 Elsevier B.V. All rights reserved.

  13. Deep brain stimulation: how does it work?

    Science.gov (United States)

    Agnesi, Filippo; Johnson, Matthew D; Vitek, Jerrold L

    2013-01-01

    Chronic deep brain stimulation (DBS) has become a widely accepted surgical treatment for medication-refractory movement disorders and is under evaluation for a variety of neurological disorders. In order to create opportunities to improve treatment efficacy, streamline parameter selection, and foster new potential applications, it is important to have a clear and comprehensive understanding of how DBS works. Although early hypothesis proposed that high-frequency electrical stimulation inhibited neuronal activity proximal to the active electrode, recent studies have suggested that the output of the stimulated nuclei is paradoxically activated by DBS. Such regular, time-locked output is thought to override the transmission of pathological bursting and oscillatory activity through the stimulated nuclei, as well as inducing synaptic plasticity and network reorganization. This chapter reviews electrophysiological experiments, biochemical analyses, computer modeling and imaging studies positing that, although general principles exist, the therapeutic mechanism(s) of action depend both on the site of stimulation and on the disorder being treated. © 2013 Elsevier B.V. All rights reserved.

  14. Low temperature stimulates alpha-melanophore-stimulating hormone secretion and inhibits background adaptation in Xenopus laevis.

    NARCIS (Netherlands)

    Tonosaki, Y; Cruijsen, P.M.; Nishiyama, K; Yaginuma, H; Roubos, E.W.

    2004-01-01

    It is well-known that alpha-melanophore-stimulating hormone (alpha-MSH) release from the amphibian pars intermedia (PI) depends on the light condition of the animal's background, permitting the animal to adapt the colour of its skin to background light intensity. In the present study, we carried out

  15. A novel dual-wavelength laser stimulator to elicit transient and tonic nociceptive stimulation.

    Science.gov (United States)

    Dong, Xiaoxi; Liu, Tianjun; Wang, Han; Yang, Jichun; Chen, Zhuying; Hu, Yong; Li, Yingxin

    2017-07-01

    This study aimed to develop a new laser stimulator to elicit both transient and sustained heat stimulation with a dual-wavelength laser system as a tool for the investigation of both transient and tonic experimental models of pain. The laser stimulator used a 980-nm pulsed laser to generate transient heat stimulation and a 1940-nm continuous-wave (CW) laser to provide sustained heat stimulation. The laser with 980-nm wavelength can elicit transient pain with less thermal injury, while the 1940-nm CW laser can effectively stimulate both superficial and deep nociceptors to elicit tonic pain. A proportional integral-derivative (PID) temperature feedback control system was implemented to ensure constancy of temperature during heat stimulation. The performance of this stimulator was evaluated by in vitro and in vivo animal experiments. In vitro experiments on totally 120 specimens fresh pig skin included transient heat stimulation by 980-nm laser (1.5 J, 10 ms), sustained heat stimulation by 1940-nm laser (50-55 °C temperature control mode or 1.5 W, 5 min continuous power supply), and the combination of transient/sustained heat stimulation by dual lasers (1.5 J, 10 ms, 980-nm pulse laser, and 1940-nm laser with 50-55 °C temperature control mode). Hemoglobin brushing and wind-cooling methods were tested to find better stimulation model. A classic tail-flick latency (TFL) experiment with 20 Wistar rats was used to evaluate the in vivo efficacy of transient and tonic pain stimulation with 15 J, 100 ms 980-nm single laser pulse, and 1.5 W constant 1940-nm laser power. Ideal stimulation parameters to generate transient pain were found to be a 26.6 °C peak temperature rise and 0.67 s pain duration. In our model of tonic pain, 5 min of tonic stimulation produced a temperature change of 53.7 ± 1.3 °C with 1.6 ± 0.2% variation. When the transient and tonic stimulation protocols were combined, no significant difference was observed depending on the order

  16. Dorsal column stimulator applications

    OpenAIRE

    Yampolsky, Claudio; Hem, Santiago; Bendersky, Damián

    2012-01-01

    Background: Spinal cord stimulation (SCS) has been used to treat neuropathic pain since 1967. Following that, technological progress, among other advances, helped SCS become an effective tool to reduce pain. Methods: This article is a non-systematic review of the mechanism of action, indications, results, programming parameters, complications, and cost-effectiveness of SCS. Results: In spite of the existence of several studies that try to prove the mechanism of action of SCS, it still remains...

  17. Grating stimulated echo

    International Nuclear Information System (INIS)

    Dubetsky, B.; Berman, P.R.; Sleator, T.

    1992-01-01

    A theory of a grating simulated echo (GTE) is developed. The GSE involves the sequential excitation of atoms by two counterpropagating traveling waves, a standing wave, and a third traveling wave. It is shown that the echo signal is very sensitive to small changes in atomic velocity, much more sensitive than the normal stimulated echo. Use of the GSE as a collisional probe or accelerometer is discussed

  18. KCl stimulation increases norepinephrine transporter function in PC12 cells.

    Science.gov (United States)

    Mandela, Prashant; Ordway, Gregory A

    2006-09-01

    The norepinephrine transporter (NET) plays a pivotal role in terminating noradrenergic signaling and conserving norepinephrine (NE) through the process of re-uptake. Recent evidence suggests a close association between NE release and regulation of NET function. The present study evaluated the relationship between release and uptake, and the cellular mechanisms that govern these processes. KCl stimulation of PC12 cells robustly increased [3H]NE uptake via the NET and simultaneously increased [3H]NE release. KCl-stimulated increases in uptake and release were dependent on Ca2+. Treatment of cells with phorbol-12-myristate-13-acetate (PMA) or okadaic acid decreased [3H]NE uptake but did not block KCl-stimulated increases in [3H]NE uptake. In contrast, PMA increased [3H]NE release and augmented KCl-stimulated release, while okadaic acid had no effects on release. Inhibition of Ca2+-activated signaling cascades with KN93 (a Ca2+ calmodulin-dependent kinase inhibitor), or ML7 and ML9 (myosin light chain kinase inhibitors), reduced [3H]NE uptake and blocked KCl-stimulated increases in uptake. In contrast, KN93, ML7 and ML9 had no effect on KCl-stimulated [3H]NE release. KCl-stimulated increases in [3H]NE uptake were independent of transporter trafficking to the plasma membrane. While increases in both NE release and uptake mediated by KCl stimulation require Ca2+, different intracellular mechanisms mediate these two events.

  19. Low intensity transcranial electric stimulation

    DEFF Research Database (Denmark)

    Antal, A.; Alekseichuk, I.; Bikson, M.

    2017-01-01

    Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears...

  20. Physiological aspects of paired stimulation

    NARCIS (Netherlands)

    Meijler, F.L.; Durrer, D.

    1965-01-01

    In this paper some physiological and clinical aspects of paired stimulation are discussed. I) The augmenting effect of paired stimulation on rnyocardial contractility is due to potentiation (increase in speed of restitution) and fusion of two contractions. 2) While using paired stimulation the

  1. Pancreatic exocrine responses to parasympathetic stimulation in anaesthetized pigs.

    Science.gov (United States)

    Halfacree, Z J; Read, P A; Edwards, A V

    2001-03-23

    Pancreatic exocrine responses to stimulation of the peripheral ends of the vagus nerves intermittently have been investigated in anaesthetized pigs and compared with the effects of continuous stimulation at corresponding frequencies. At relatively low frequencies Hz in bursts or 2 Hz continuously) both the flow of pancreatic juice and the output of protein therein were potentiated by stimulating in bursts. Thus stimulation at 20 Hz in bursts produced a significantly greater flow of pancreatic juice than stimulation at 2 Hz continuously (10.9+/-0.9 compared to 4.8+/-0.7 microl min(-1) (g gland)-1 , respectively; PHz (144+/-23 microg min(-1) (g gland)-1) far exceeded that produced during continuous stimulation at 2 Hz (49+/-9 microg min(-1) (g gland)-1; PHz) and substantially reduced the output of protein during intermittent stimulation (to 27+/-7 ng min(-1) (g gland)-1; PHz in bursts). These results show that a variety of pancreatic exocrine responses can be enhanced by stimulating the parasympathetic innervation in bursts. They are also consistent with the contention that the secretion of protein from the gland, in response to parasympathetic stimulation, is dependent mainly on activation of muscarinic receptors. They confirm that the flow of pancreatic juice is due mainly to the release of VIP and show that, in the absence of atropine, this is restricted by muscarinic inhibition which may be presynaptic as elsewhere.

  2. Dependent Classes

    DEFF Research Database (Denmark)

    Gasiunas, Vaidas; Mezini, Mira; Ostermann, Klaus

    2007-01-01

    of dependent classes and a machine-checked type soundness proof in Isabelle/HOL [29], the first of this kind for a language with virtual classes and path-dependent types. [29] T.Nipkow, L.C. Poulson, and M. Wenzel. Isabelle/HOL -- A Proof Assistant for Higher-Order Logic, volume 2283 of LNCS, Springer, 2002......Virtual classes allow nested classes to be refined in subclasses. In this way nested classes can be seen as dependent abstractions of the objects of the enclosing classes. Expressing dependency via nesting, however, has two limitations: Abstractions that depend on more than one object cannot...... be modeled and a class must know all classes that depend on its objects. This paper presents dependent classes, a generalization of virtual classes that expresses similar semantics by parameterization rather than by nesting. This increases expressivity of class variations as well as the flexibility...

  3. Non-invasive neural stimulation

    Science.gov (United States)

    Tyler, William J.; Sanguinetti, Joseph L.; Fini, Maria; Hool, Nicholas

    2017-05-01

    Neurotechnologies for non-invasively interfacing with neural circuits have been evolving from those capable of sensing neural activity to those capable of restoring and enhancing human brain function. Generally referred to as non-invasive neural stimulation (NINS) methods, these neuromodulation approaches rely on electrical, magnetic, photonic, and acoustic or ultrasonic energy to influence nervous system activity, brain function, and behavior. Evidence that has been surmounting for decades shows that advanced neural engineering of NINS technologies will indeed transform the way humans treat diseases, interact with information, communicate, and learn. The physics underlying the ability of various NINS methods to modulate nervous system activity can be quite different from one another depending on the energy modality used as we briefly discuss. For members of commercial and defense industry sectors that have not traditionally engaged in neuroscience research and development, the science, engineering and technology required to advance NINS methods beyond the state-of-the-art presents tremendous opportunities. Within the past few years alone there have been large increases in global investments made by federal agencies, foundations, private investors and multinational corporations to develop advanced applications of NINS technologies. Driven by these efforts NINS methods and devices have recently been introduced to mass markets via the consumer electronics industry. Further, NINS continues to be explored in a growing number of defense applications focused on enhancing human dimensions. The present paper provides a brief introduction to the field of non-invasive neural stimulation by highlighting some of the more common methods in use or under current development today.

  4. Lubiprostone stimulates small intestinal mucin release

    Directory of Open Access Journals (Sweden)

    De Lisle Robert C

    2012-11-01

    Full Text Available Abstract Background Lubiprostone is a synthetic bicyclic fatty acid derivative of prostaglandin E1 (PGE1 used for chronic constipation. The best known action of lubiprostone is simulation of Cl- dependent fluid secretion. In a mouse model of the genetic disease cystic fibrosis, we previously showed that in vivo administration of lubiprostone resulted in greater mucus accumulation in the small intestine. The aim of this study was to directly test whether lubiprostone stimulates intestinal mucin release. Methods Mucin release was measured by mounting segments (4-5 cm of mouse proximal-mid small intestine in an organ bath, allowing access to the perfusate (luminal and the bath (serosal solutions. Nifedipine (10-6 M and indomethacin (10-5 M were included in all solutions to inhibit smooth muscle activity and endogenous prostaglandin production, respectively. The tissue was equilibrated under flow for 30 min, using the perfusate collected during the final 10 min of the equilibration period to measure unstimulated release rate. Stimulus was then added to either the perfusate or the bath and the perfusate was collected for another 30 min to measure the stimulated mucin release rate. Mucin in perfusates was quantified by periodic acid-Schiff's base dot-blot assay, using purified pig gastric mucin as a standard. Results When applied luminally at 1 μM lubiprostone was ineffective at stimulating mucin release. When added to the serosal solution, 1 μM lubiprostone stimulated mucin release to ~300% of the unstimulated rate. As a positive control, serosal 1 μM prostaglandin E2 increased mucin release to ~400% of the unstimulated rate. Conclusions These results support the idea that lubiprostone has prostaglandin-like actions on the intestine, which includes stimulation of mucin release. Stimulation of mucin release by lubiprostone may be protective in gastrointestinal conditions where loss of mucus is believed to contribute to pathogenesis. Thus, in

  5. Motile Responses of Cochlear Outer Hair Cells Stimulated with an Alternating Electrical Field

    OpenAIRE

    Kitani, Rei; Kakehata, Seiji; Kalinec, Federico

    2011-01-01

    The goal of the present study was to evaluate and characterize the motile responses of guinea pig OHCs, stimulated at frequencies varying from 50 Hz to 4 kHz, using high-definition, high-speed video recording and fully automatic image analysis software. Cells stimulated in continuous, burst and sweeping modes with an external alternating electrical field showed robust fast and slow motility, which were dependent on frequency, mode and intensity of stimulation. In response to continuous stimul...

  6. Spinal Cord Stimulation

    DEFF Research Database (Denmark)

    Meier, Kaare

    2014-01-01

    Spinal cord stimulation (SCS) is a surgical treatment for chronic neuropathic pain that is refractory to other treatment. Originally described by Shealy et al. in 1967(1), it is used to treat a range of conditions such as complex regional pain syndrome (CRPS I)(2), angina pectoris(3), radicular...... pain after failed back surgery syndrome (FBSS)(4), pain due to peripheral nerve injury, stump pain(5), peripheral vascular disease(6) and diabetic neuropathy(7,8); whereas phantom pain(9), postherpetic neuralgia(10), chronic visceral pain(11), and pain after partial spinal cord injury(12) remain more...

  7. Theory of feedback controlled brain stimulations for Parkinson's disease

    Science.gov (United States)

    Sanzeni, A.; Celani, A.; Tiana, G.; Vergassola, M.

    2016-01-01

    Limb tremor and other debilitating symptoms caused by the neurodegenerative Parkinson's disease are currently treated by administering drugs and by fixed-frequency deep brain stimulation. The latter interferes directly with the brain dynamics by delivering electrical impulses to neurons in the subthalamic nucleus. While deep brain stimulation has shown therapeutic benefits in many instances, its mechanism is still unclear. Since its understanding could lead to improved protocols of stimulation and feedback control, we have studied a mathematical model of the many-body neural network dynamics controlling the dynamics of the basal ganglia. On the basis of the results obtained from the model, we propose a new procedure of active stimulation, that depends on the feedback of the network and that respects the constraints imposed by existing technology. We show by numerical simulations that the new protocol outperforms the standard ones for deep brain stimulation and we suggest future experiments that could further improve the feedback procedure.

  8. Dependency Parsing

    CERN Document Server

    Kubler, Sandra; Nivre, Joakim

    2009-01-01

    Dependency-based methods for syntactic parsing have become increasingly popular in natural language processing in recent years. This book gives a thorough introduction to the methods that are most widely used today. After an introduction to dependency grammar and dependency parsing, followed by a formal characterization of the dependency parsing problem, the book surveys the three major classes of parsing models that are in current use: transition-based, graph-based, and grammar-based models. It continues with a chapter on evaluation and one on the comparison of different methods, and it close

  9. Ipsilateral masking between acoustic and electric stimulations.

    Science.gov (United States)

    Lin, Payton; Turner, Christopher W; Gantz, Bruce J; Djalilian, Hamid R; Zeng, Fan-Gang

    2011-08-01

    Residual acoustic hearing can be preserved in the same ear following cochlear implantation with minimally traumatic surgical techniques and short-electrode arrays. The combined electric-acoustic stimulation significantly improves cochlear implant performance, particularly speech recognition in noise. The present study measures simultaneous masking by electric pulses on acoustic pure tones, or vice versa, to investigate electric-acoustic interactions and their underlying psychophysical mechanisms. Six subjects, with acoustic hearing preserved at low frequencies in their implanted ear, participated in the study. One subject had a fully inserted 24 mm Nucleus Freedom array and five subjects had Iowa/Nucleus hybrid implants that were only 10 mm in length. Electric masking data of the long-electrode subject showed that stimulation from the most apical electrodes produced threshold elevations over 10 dB for 500, 625, and 750 Hz probe tones, but no elevation for 125 and 250 Hz tones. On the contrary, electric stimulation did not produce any electric masking in the short-electrode subjects. In the acoustic masking experiment, 125-750 Hz pure tones were used to acoustically mask electric stimulation. The acoustic masking results showed that, independent of pure tone frequency, both long- and short-electrode subjects showed threshold elevations at apical and basal electrodes. The present results can be interpreted in terms of underlying physiological mechanisms related to either place-dependent peripheral masking or place-independent central masking.

  10. Optically stimulated luminescence

    International Nuclear Information System (INIS)

    Espinosa, G.; Bogard, J.S.

    2007-01-01

    Full text: The use of Optically Stimulated Luminescence (OSL) for radiation dosimetry has become increasingly popular in recent years. The OSL method is based on luminescence emitted from semiconductor materials stimulated with specific wavelengths of light, after being exposed to ionizing radiation. The OSL intensity is a function of the radiation dose absorbed by the material. This work complements previous studies by the authors of the thermoluminescence (TL) response by SiO 2 commercial optical fiber exposed to ionizing radiation and provides preliminary results describing some of the material's OSL properties. Linear OSL response to beta radiation dose, along with a consistent shape of the photon emission curve with time, were observed using a green/blue OSL excitation laser. The reproducibility of OSL response after repeated irradiations and the change in intensity with time were also examined. The search and characterization of materials that exhibit this OSL response, in parallel with the continued development of OSL methodology and instrumentation, is an important scientific and commercial issue. (Author)

  11. Preliminary evaluation of a model of stimulant use, oxidative damage and executive dysfunction.

    Science.gov (United States)

    Winhusen, Theresa; Walker, Jessica; Brigham, Gregory; Lewis, Daniel; Somoza, Eugene; Theobald, Jeff; Somoza, Veronika

    2013-07-01

    Illicit stimulant use increases oxidative stress and oxidative stress has been found to be associated with deficits in memory, attention and problem-solving. To test a model of the association among oxidative DNA damage, a severe form of oxidative stress, and stimulant use, executive function and stimulant-use outcomes. Six sites evaluating 12-step facilitation for stimulant abusers obtained peripheral blood samples from methamphetamine-dependent (n = 45) and cocaine-dependent (n = 120) participants. The blood samples were submitted to a comet assay to assess oxidative DNA damage. Executive Dysfunction was assessed with the Frontal Systems Behavior Scale (FrSBe), which is a reliable and valid self-report assessment of executive dysfunction, disinhibition and apathy. Stimulant-use measures included self-reported stimulant use and stimulant urine drug screens (UDS). While more recent cocaine use (executive dysfunction and stimulant use outcomes for cocaine-dependent patients. Support for the model was found for methamphetamine-dependent patients, with oxidative DNA damage significantly greater in methamphetamine-dependent patients with executive dysfunction (W = 2.2, p executive dysfunction being a significant mediator of oxidative DNA damage and stimulant use during active treatment (ab = 0.089, p executive dysfunction, which in turn increases vulnerability to future stimulant use.

  12. A distributed current stimulator ASIC for high density neural stimulation.

    Science.gov (United States)

    Jeong Hoan Park; Chaebin Kim; Seung-Hee Ahn; Tae Mok Gwon; Joonsoo Jeong; Sang Beom Jun; Sung June Kim

    2016-08-01

    This paper presents a novel distributed neural stimulator scheme. Instead of a single stimulator ASIC in the package, multiple ASICs are embedded at each electrode site for stimulation with a high density electrode array. This distributed architecture enables the simplification of wiring between electrodes and stimulator ASIC that otherwise could become too complex as the number of electrode increases. The individual ASIC chip is designed to have a shared data bus that independently controls multiple stimulating channels. Therefore, the number of metal lines is determined by the distributed ASICs, not by the channel number. The function of current steering is also implemented within each ASIC in order to increase the effective number of channels via pseudo channel stimulation. Therefore, the chip area can be used more efficiently. The designed chip was fabricated with area of 0.3 mm2 using 0.18 μm BCDMOS process, and the bench-top test was also conducted to validate chip performance.

  13. Transcranial brain stimulation: closing the loop between brain and stimulation

    DEFF Research Database (Denmark)

    Karabanov, Anke; Thielscher, Axel; Siebner, Hartwig Roman

    2016-01-01

    PURPOSE OF REVIEW: To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. RECENT FINDINGS: Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain...... transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to ‘standardize’ the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait......-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified...

  14. Testosterone Suppression of CRH-stimulated Cortisol in Men

    OpenAIRE

    Rubinow, David R.; Roca, Catherine A.; Schmidt, Peter J.; Danaceau, Merry A.; Putnam, Karen; Cizza, Giovanni; Chrousos, George; Nieman, Lynnette

    2005-01-01

    Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in ten men (ages 18–45) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower ...

  15. [Affective dependency].

    Science.gov (United States)

    Scantamburlo, G; Pitchot, W; Ansseau, M

    2013-01-01

    Affective dependency is characterized by emotional distress (insecure attachment) and dependency to another person with a low self-esteem and reassurance need. The paper proposes a reflection on the definition of emotional dependency and the confusion caused by various denominations. Overprotective and authoritarian parenting, cultural and socio-environmental factors may contribute to the development of dependent personality. Psychological epigenetic factors, such as early socio-emotional trauma could on neuronal circuits in prefronto-limbic regions that are essential for emotional behaviour.We also focus on the interrelations between dependent personality, domestic violence and addictions. The objective for the clinician is to propose a restoration of self-esteem and therapeutic strategies focused on autonomy.

  16. Distributed stimulation increases force elicited with functional electrical stimulation

    Science.gov (United States)

    Buckmire, Alie J.; Lockwood, Danielle R.; Doane, Cynthia J.; Fuglevand, Andrew J.

    2018-04-01

    Objective. The maximum muscle forces that can be evoked using functional electrical stimulation (FES) are relatively modest. The reason for this weakness is not fully understood but could be partly related to the widespread distribution of motor nerve branches within muscle. As such, a single stimulating electrode (as is conventionally used) may be incapable of activating the entire array of motor axons supplying a muscle. Therefore, the objective of this study was to determine whether stimulating a muscle with more than one source of current could boost force above that achievable with a single source. Approach. We compared the maximum isometric forces that could be evoked in the anterior deltoid of anesthetized monkeys using one or two intramuscular electrodes. We also evaluated whether temporally interleaved stimulation between two electrodes might reduce fatigue during prolonged activity compared to synchronized stimulation through two electrodes. Main results. We found that dual electrode stimulation consistently produced greater force (~50% greater on average) than maximal stimulation with single electrodes. No differences, however, were found in the fatigue responses using interleaved versus synchronized stimulation. Significance. It seems reasonable to consider using multi-electrode stimulation to augment the force-generating capacity of muscles and thereby increase the utility of FES systems.

  17. Brain stimulation for intractable epilepsy: Anterior thalamus and responsive stimulation

    Directory of Open Access Journals (Sweden)

    Vibhor Krishna

    2014-01-01

    Full Text Available Despite medications, resective surgery, and vagal nerve stimulation, some patients with epilepsy continue to have seizures. In these patients, other approaches are urgently needed. The biological basis of stimulation of anterior thalamic nucleus and epileptogenic focus is presented. Results from two large randomized controlled trials Stimulation of Anterior Nucleus of Thalamus for Epilepsy (SANTE and Neuropace pivotal trial are discussed. Neuromodulation provides effective treatment for a select group of refractory epilepsy patients. Future investigations into the mechanism underlying ′response′ to brain stimulation are desired.

  18. Vagus Nerve Stimulation.

    Science.gov (United States)

    Ekmekçi, Hakan; Kaptan, Hülagu

    2017-06-15

    The vagus nerve stimulation (VNS) is an approach mainly used in cases of intractable epilepsy despite all the efforts. Also, its benefits have been shown in severe cases of depression resistant to typical treatment. The aim of this study was to present current knowledge of vagus nerve stimulation. A new value has emerged just at this stage: VNS aiming the ideal treatment with new hopes. It is based on the placement of a programmable generator on the chest wall. Electric signals from the generator are transmitted to the left vagus nerve through the connection cable. Control on the cerebral bioelectrical activity can be achieved by way of these signal sent from there in an effort for controlling the epileptic discharges. The rate of satisfactory and permanent treatment in epilepsy with monotherapy is around 50%. This rate will increase by one-quarters (25%) with polytherapy. However, there is a patient group roughly constituting one-thirds of this population, and this group remains unresponsive or refractory to all the therapies and combined regimes. The more the number of drugs used, the more chaos and side effects are observed. The anti-epileptic drugs (AEDs) used will have side effects on both the brain and the systemic organs. Cerebral resection surgery can be required in some patients. The most commonly encountered epilepsy type is the partial one, and the possibility of benefiting from invasive procedures is limited in most patients of this type. Selective amygdala-hippocampus surgery is a rising value in complex partial seizures. Therefore, as epilepsy surgery can be performed in very limited numbers and rather developed centres, success can also be achieved in limited numbers of patients. The common ground for all the surgical procedures is the target of preservation of memory, learning, speaking, temper and executive functions as well as obtaining a good control on seizures. However, the action mechanism of VNS is still not exactly known. On the other hand

  19. Engagement sensitive visual stimulation

    Directory of Open Access Journals (Sweden)

    Deepesh Kumar

    2016-06-01

    Full Text Available Stroke is one of leading cause of death and disability worldwide. Early detection during golden hour and treatment of individual neurological dysfunction in stroke using easy-to-access biomarkers based on a simple-to-use, cost-effective, clinically-valid screening tool can bring a paradigm shift in healthcare, both urban and rural. In our research we have designed a quantitative automatic home-based oculomotor assessment tool that can play an important complementary role in prognosis of neurological disorders like stroke for the neurologist. Once the patient has been screened for stroke, the next step is to design proper rehabilitation platform to alleviate the disability. In addition to the screening platform, in our research, we work in designing virtual reality based rehabilitation exercise platform that has the potential to deliver visual stimulation and in turn contribute to improving one’s performance.

  20. Effect of Parkinson's Disease in Transcranial Magnetic Stimulation Treatment

    Science.gov (United States)

    Syeda, Farheen; Magsood, Hamzah; Lee, Erik; El-Gendy, Ahmed; Jiles, David; Hadimani, Ravi

    Transcranial Magnetic Stimulation is a non-invasive clinical therapy used to treat depression and migraine, and shows further promise as treatment for Parkinson's disease, Alzheimer's disease, and other neurological disorders. However, it is yet unclear as to how anatomical differences may affect stimulation from this treatment. We use finite element analysis to model and analyze the results of Transcranial Magnetic Stimulation in various head models. A number of heterogeneous head models have been developed using MRI data of real patients, including healthy individuals as well as patients of Parkinson's disease. Simulations of Transcranial Magnetic Stimulation performed on 22 anatomically different models highlight the differences in induced stimulation. A standard Figure of 8 coil is used with frequency 2.5 kHz, placed 5 mm above the head. We compare cortical stimulation, volume of brain tissue stimulated, specificity, and maximum E-field induced in the brain for models ranging from ages 20 to 60. Results show that stimulation varies drastically between patients of the same age and health status depending upon brain-scalp distance, which is not necessarily a linear progression with age.

  1. Stimulated coherent transition radiation

    International Nuclear Information System (INIS)

    Hung-chi Lihn.

    1996-03-01

    Coherent radiation emitted from a relativistic electron bunch consists of wavelengths longer than or comparable to the bunch length. The intensity of this radiation out-numbers that of its incoherent counterpart, which extends to wavelengths shorter than the bunch length, by a factor equal to the number of electrons in the bunch. In typical accelerators, this factor is about 8 to 11 orders of magnitude. The spectrum of the coherent radiation is determined by the Fourier transform of the electron bunch distribution and, therefore, contains information of the bunch distribution. Coherent transition radiation emitted from subpicosecond electron bunches at the Stanford SUNSHINE facility is observed in the far-infrared regime through a room-temperature pyroelectric bolometer and characterized through the electron bunch-length study. To measure the bunch length, a new frequency-resolved subpicosecond bunch-length measuring system is developed. This system uses a far-infrared Michelson interferometer to measure the spectrum of coherent transition radiation through optical autocorrelation with resolution far better than existing time-resolved methods. Hence, the radiation spectrum and the bunch length are deduced from the autocorrelation measurement. To study the stimulation of coherent transition radiation, a special cavity named BRAICER is invented. Far-infrared light pulses of coherent transition radiation emitted from electron bunches are delayed and circulated in the cavity to coincide with subsequent incoming electron bunches. This coincidence of light pulses with electron bunches enables the light to do work on electrons, and thus stimulates more radiated energy. The possibilities of extending the bunch-length measuring system to measure the three-dimensional bunch distribution and making the BRAICER cavity a broadband, high-intensity, coherent, far-infrared light source are also discussed

  2. Motor stimulation with interferential currents.

    Science.gov (United States)

    DE Domenico, G G; Strauss, G R

    1985-01-01

    The stimulation of motor nerves to produce muscle contraction in normally innervated muscles is a long established part of orthodox physiotherapy. Recently however, a revival of interest in the area has occurred, particularly in the U.S.A. Recent research has indicated that such stimulation can improve muscle strength, reduce muscle spasm and modulate spasticity, in addition to the more usual re-educative role of electrical stimulation. The concept of functional electrical stimulation (F.E.S.) seems destined to become an integral part of many programmes for the neurologically handicapped patient. This paper describes the technique of motor stimulation using interferential currents. The stimulating parameters and electrode placement are considered, along with a detailed explanation of the pre-modulated system of electrode arrangement. Copyright © 1985 Australian Physiotherapy Association. Published by . All rights reserved.

  3. Tissue damage thresholds during therapeutic electrical stimulation

    Science.gov (United States)

    Cogan, Stuart F.; Ludwig, Kip A.; Welle, Cristin G.; Takmakov, Pavel

    2016-04-01

    Objective. Recent initiatives in bioelectronic modulation of the nervous system by the NIH (SPARC), DARPA (ElectRx, SUBNETS) and the GlaxoSmithKline Bioelectronic Medicines effort are ushering in a new era of therapeutic electrical stimulation. These novel therapies are prompting a re-evaluation of established electrical thresholds for stimulation-induced tissue damage. Approach. In this review, we explore what is known and unknown in published literature regarding tissue damage from electrical stimulation. Main results. For macroelectrodes, the potential for tissue damage is often assessed by comparing the intensity of stimulation, characterized by the charge density and charge per phase of a stimulus pulse, with a damage threshold identified through histological evidence from in vivo experiments as described by the Shannon equation. While the Shannon equation has proved useful in assessing the likely occurrence of tissue damage, the analysis is limited by the experimental parameters of the original studies. Tissue damage is influenced by factors not explicitly incorporated into the Shannon equation, including pulse frequency, duty cycle, current density, and electrode size. Microelectrodes in particular do not follow the charge per phase and charge density co-dependence reflected in the Shannon equation. The relevance of these factors to tissue damage is framed in the context of available reports from modeling and in vivo studies. Significance. It is apparent that emerging applications, especially with microelectrodes, will require clinical charge densities that exceed traditional damage thresholds. Experimental data show that stimulation at higher charge densities can be achieved without causing tissue damage, suggesting that safety parameters for microelectrodes might be distinct from those defined for macroelectrodes. However, these increased charge densities may need to be justified by bench, non-clinical or clinical testing to provide evidence of device

  4. Deep brain stimulation surgery for alcohol addiction.

    Science.gov (United States)

    Voges, Juergen; Müller, Ulf; Bogerts, Bernhard; Münte, Thomas; Heinze, Hans-Jochen

    2013-01-01

    The consequences of chronic alcohol dependence cause important health and economic burdens worldwide. Relapse rates after standard treatment (medication and psychotherapy) are high. There is evidence from in vivo investigations and from studies in patients that the brain's reward system is critically involved in the development and maintenance of addictive behavior, suggesting that modification of this system could significantly improve the prognosis of addictive patients. Motivated by an accidental observation, we used the nucleus accumbens (NAc), which has a central position in the dopaminergic reward system for deep brain stimulation (DBS) of alcohol addiction. We report our first experiences with NAc DBS for alcohol dependence and review the literature addressing the mechanisms leading to addiction. Five patients were treated off-label with bilateral NAc DBS for severe alcohol addiction (average follow-up 38 months). All patients experienced significant and ongoing improvement of craving. Two patients remained completely abstinent for more than 4 years. NAc stimulation was tolerated without permanent side effects. Simultaneous recording of local field potentials from the target area and surface electroencephalography while patients performed neuropsychological tasks gave a hint on the pivotal role of the NAc in processing alcohol-related cues. To our knowledge, the data presented here reflect the first attempt to treat alcohol-addicted patients with NAc DBS. Electrical NAc stimulation probably counterbalances the effect of drug-related stimuli triggering involuntarily drug-seeking behavior. Meanwhile, two prospective clinical studies using randomized, double-blind, and crossover stimulation protocols for DBS are underway to corroborate these preliminary results. Published by Elsevier Inc.

  5. Temporal evolution of stimulated Brillouin backscatter

    International Nuclear Information System (INIS)

    Hinkel, D.E.; Williams, E.A.; Berger, R.L.

    1994-01-01

    A qualitative understanding of the time dependence of stimulated Brillouin scattering (SBS) provides estimates of the amount of temporal growth that occurs in current inertial confinement fusion and short laser pulse interaction experiments when the growth is limited by the length of the experiment or by motion of the ''hot spots'' of the laser intensity pattern induced by beam smoothing. In the weak coupling limit, the instantaneous growth rate depends upon the plasma initial conditions early in time, is proportional to t -1/2 later in time, and asymptotically approaches the absolute growth rate (in the absence of damping). When the instability is strongly coupled, the growth rate depends upon the plasma initial conditions early in time but is proportional to t -1/3 later in time. When the growth rate drops to a value comparable to that of the ion acoustic frequency, the instability becomes effectively weakly coupled. The effects of damping are also discussed

  6. Olfactory host location in beetle bruchid parasitoid Dinarmus basalis ...

    African Journals Online (AJOL)

    Rond.) was investigated in bioassays by measuring response to stimuli associated with one of its hosts, the larvae of beetle bruchid, Bruchidius atrolineatus (Pic.) infesting Vigna unguiculata (L. Walp.) seeds. Orientation of parasitoid females was ...

  7. Adrenergic influence on pentagastrin and bethanechol stimulated gastric acid secretion in dogs with gastric fistula

    DEFF Research Database (Denmark)

    Hovendal, C; Bech, K; Gottrup, F

    1984-01-01

    The purpose of this study was to elucidate the effect of alpha-, beta- and dopaminergic receptor stimulation and blockade on pentagastrin and bethanechol stimulated gastric acid secretion in conscious dogs with gastric fistula. Gastric acid secretion was found to be subject to a dose related....... The inhibitory effect of isoprenaline on pentagastrin stimulated acid secretion showed the characteristics of competitive type and on bethanechol stimulated acid secretion of non competitive type. An increasing and dose-dependent stimulation of bethanechol stimulated gastric acid secretion was found for dopamine...... 1, 5 and 10 micrograms/kg/min. Dopamine (40 micrograms/kg/min.) exerted an inhibitory effect on pentagastrin and bethanechol stimulated gastric acid secretion mediated, via the beta 1-receptors. The stimulatory effect of low doses of dopamine during bethanechol stimulation could not be defined...

  8. Timing-dependent actions of NGF required for cell differentiation.

    Directory of Open Access Journals (Sweden)

    Jaehoon Chung

    Full Text Available BACKGROUND: Continuous NGF stimulation induces PC12 cell differentiation. However, why continuous NGF stimulation is required for differentiation is unclear. In this study, we investigated the underlying mechanisms of the timing-dependent requirement of NGF action for cell differentiation. METHODOLOGY/PRINCIPAL FINDINGS: To address the timing-dependency of the NGF action, we performed a discontinuous stimulation assay consisting of a first transient stimulation followed by an interval and then a second sustained stimulation and quantified the neurite extension level. Consequently, we observed a timing-dependent action of NGF on cell differentiation, and discontinuous NGF stimulation similarly induced differentiation. The first stimulation did not induce neurite extension, whereas the second stimulation induced fast neurite extension; therefore, the first stimulation is likely required as a prerequisite condition. These observations indicate that the action of NGF can be divided into two processes: an initial stimulation-driven latent process and a second stimulation-driven extension process. The latent process appears to require the activities of ERK and transcription, but not PI3K, whereas the extension-process requires the activities of ERK and PI3K, but not transcription. We also found that during the first stimulation, the activity of NGF can be replaced by PACAP, but not by insulin, EGF, bFGF or forskolin; during the second stimulation, however, the activity of NGF cannot be replaced by any of these stimulants. These findings allowed us to identify potential genes specifically involved in the latent process, rather than in other processes, using a microarray. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that NGF induces the differentiation of PC12 cells via mechanically distinct processes: an ERK-driven and transcription-dependent latent process, and an ERK- and PI3K-driven and transcription-independent extension process.

  9. Molecular Mechanisms of Glucose-Stimulated GLP-1 Secretion From Perfused Rat Small Intestine

    DEFF Research Database (Denmark)

    Kuhre, Rune E.; Frost, Charlotte R.; Svendsen, Berit

    2015-01-01

    /v) stimulated the secretion dose dependently, but vascular glucose was without significant effect at 5, 10, 15, and 25 mmol/L. GLP-1 stimulation by luminal glucose (20%) secretion was blocked by the voltage-gated Ca channel inhibitor, nifedipine, or by hyperpolarization with diazoxide. Luminal administration...... not stimulate a response. Luminal glucose-stimulated GLP-1 secretion was also sensitive to luminal GLUT2 inhibition (phloretin), but in contrast to SGLT1 inhibition, phloretin did not eliminate the response, and luminal glucose (20%) stimulated larger GLP-1 responses than luminal α-MGP in matched concentrations...

  10. Stimulating Language: Insights from TMS

    Science.gov (United States)

    Devlin, Joseph T.; Watkins, Kate E.

    2007-01-01

    Fifteen years ago, Pascual-Leone and colleagues used transcranial magnetic stimulation (TMS) to investigate speech production in pre-surgical epilepsy patients and in doing so, introduced a novel tool into language research. TMS can be used to non-invasively stimulate a specific cortical region and transiently disrupt information processing. These…

  11. Atomic oxygen stimulated outgassing

    Science.gov (United States)

    Linton, Roger C.; Reynolds, John M.

    1991-01-01

    The passive Long Duration Exposure Facility (LDEF) Experiment A0034, Atomic Oxygen Simulated Outgassing, consisted of two identical one-sixth tray modules, exposing selected thermal control coatings to atomic oxygen and the combined space environment on the leading edge and, for reference, to the relative wake environment on the trailing edge. Optical mirrors were included adjacent to the thermal coatings for deposition of outgassing products. Ultraviolet grade windows and metal covers were provided for additional assessment of the effects of the various environmental factors. Preliminary results indicate that orbital atomic oxygen is both a degrading and a optically restorative factor in the thermo-optical properties of selected thermal coatings. There is evidence of more severe optical degradation on collector mirrors adjacent to coatings that were exposed to the RAM-impinging atomic oxygen. This evidence of atomic oxygen stimulated outgassing is discussed in relation to alternative factors that could affect degradation. The general effects of the space environment on the experiment hardware as well as the specimens are discussed.

  12. Cranial electrotherapy stimulation and transcranial pulsed current stimulation: a computer based high-resolution modeling study.

    Science.gov (United States)

    Datta, Abhishek; Dmochowski, Jacek P; Guleyupoglu, Berkan; Bikson, Marom; Fregni, Felipe

    2013-01-15

    The field of non-invasive brain stimulation has developed significantly over the last two decades. Though two techniques of noninvasive brain stimulation--transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)--are becoming established tools for research in neuroscience and for some clinical applications, related techniques that also show some promising clinical results have not been developed at the same pace. One of these related techniques is cranial electrotherapy stimulation (CES), a class of transcranial pulsed current stimulation (tPCS). In order to understand further the mechanisms of CES, we aimed to model CES using a magnetic resonance imaging (MRI)-derived finite element head model including cortical and also subcortical structures. Cortical electric field (current density) peak intensities and distributions were analyzed. We evaluated different electrode configurations of CES including in-ear and over-ear montages. Our results confirm that significant amounts of current pass the skull and reach cortical and subcortical structures. In addition, depending on the montage, induced currents at subcortical areas, such as midbrain, pons, thalamus and hypothalamus are of similar magnitude than that of cortical areas. Incremental variations of electrode position on the head surface also influence which cortical regions are modulated. The high-resolution modeling predictions suggest that details of electrode montage influence current flow through superficial and deep structures. Finally we present laptop based methods for tPCS dose design using dominant frequency and spherical models. These modeling predictions and tools are the first step to advance rational and optimized use of tPCS and CES. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Stimulation of acid formation in permeable gastric glands by valinomycin

    International Nuclear Information System (INIS)

    Hersey, S.J.; Steiner, L.

    1988-01-01

    Isolated gastric glands made permeable with digitonin treatment were employed to study the ionic requirements of acid formation. Acid formation was monitored by the accumulation of a novel weak base probe, [ 14 C]benzylamine. ATP-dependent acid formation was found to require K + in a concentration-dependent manner, with an apparent K 0.5 = 7 mM. The anion dependence of acid formation gave a selectivity sequence of Cl = I > Br 3 > SO 4 = isethionate, with isethionate being ∼50% as effective as Cl. The dependence of acid formation on [Cl] gave an apparent K 0.5 = 6 mM. Addition of the K + ionophore, valinomycin, to resting glands (cimetidine pretreatment) resulted in a two- to threefold increase in ATP-dependent acid formation. In contrast, stimulated (forskolin pretreated) glands showed a greater accumulation of benzylamine with ATP but significantly less valinomycin stimulation. The valinomycin stimulation required both K + and Cl - and was inhibited by omeprazole and Sch 28080. The results and interpreted to indicate that major events in the transition from a resting to a stimulated state include changes in both K + and anion permeability of the secretory membrane of parietal cells

  14. Ontological dependency

    NARCIS (Netherlands)

    Stamper, R.K.

    1996-01-01

    Successful ontological analysis depends upon having the right underlying theory. The work described here, exploring how to understand organisations as systems of social norms found that the familiar objectivist position did not work, eventually replacing it with a radically subjectivist ontology

  15. Mechanisms of Dorsal Root Ganglion Stimulation in Pain Suppression: A Computational Modeling Analysis.

    Science.gov (United States)

    Kent, Alexander R; Min, Xiaoyi; Hogan, Quinn H; Kramer, Jeffery M

    2018-04-01

    The mechanisms of dorsal root ganglion (DRG) stimulation for chronic pain remain unclear. The objective of this work was to explore the neurophysiological effects of DRG stimulation using computational modeling. Electrical fields produced during DRG stimulation were calculated with finite element models, and were coupled to a validated biophysical model of a C-type primary sensory neuron. Intrinsic neuronal activity was introduced as a 4 Hz afferent signal or somatic ectopic firing. The transmembrane potential was measured along the neuron to determine the effect of stimulation on intrinsic activity across stimulation parameters, cell location/orientation, and membrane properties. The model was validated by showing close correspondence in action potential (AP) characteristics and firing patterns when compared to experimental measurements. Subsequently, the model output demonstrated that T-junction filtering was amplified with DRG stimulation, thereby blocking afferent signaling, with cathodic stimulation at amplitudes of 2.8-5.5 × stimulation threshold and frequencies above 2 Hz. This amplified filtering was dependent on the presence of calcium and calcium-dependent small-conductance potassium channels, which produced a hyperpolarization offset in the soma, stem, and T-junction with repeated somatic APs during stimulation. Additionally, DRG stimulation suppressed somatic ectopic activity by hyperpolarizing the soma with cathodic or anodic stimulation at amplitudes of 3-11 × threshold and frequencies above 2 Hz. These effects were dependent on the stem axon being relatively close to and oriented toward a stimulating contact. These results align with the working hypotheses on the mechanisms of DRG stimulation, and indicate the importance of stimulation amplitude, polarity, and cell location/orientation on neuronal responses. © 2018 International Neuromodulation Society.

  16. Vagal nerve stimulation therapy: what is being stimulated?

    Directory of Open Access Journals (Sweden)

    Guy Kember

    Full Text Available Vagal nerve stimulation in cardiac therapy involves delivering electrical current to the vagal sympathetic complex in patients experiencing heart failure. The therapy has shown promise but the mechanisms by which any benefit accrues is not understood. In this paper we model the response to increased levels of stimulation of individual components of the vagal sympathetic complex as a differential activation of each component in the control of heart rate. The model provides insight beyond what is available in the animal experiment in as much as allowing the simultaneous assessment of neuronal activity throughout the cardiac neural axis. The results indicate that there is sensitivity of the neural network to low level subthreshold stimulation. This leads us to propose that the chronic effects of vagal nerve stimulation therapy lie within the indirect pathways that target intrinsic cardiac local circuit neurons because they have the capacity for plasticity.

  17. Using Transcranial Direct Current Stimulation to Enhance Creative Cognition: Interactions between Task, Polarity, and Stimulation Site

    Directory of Open Access Journals (Sweden)

    Adam B. Weinberger

    2017-05-01

    Full Text Available Creative cognition is frequently described as involving two primary processes, idea generation and idea selection. A growing body of research has used transcranial direct current stimulation (tDCS to examine the neural mechanisms implicated in each of these processes. This literature has yielded a diverse set of findings that vary depending on the location and type (anodal, cathodal, or both of electrical stimulation employed, as well as the task’s reliance on idea generation or idea selection. As a result, understanding the interactions between stimulation site, polarity and task demands is required to evaluate the potential of tDCS to enhance creative performance. Here, we review tDCS designs that have elicited reliable and dissociable enhancements for creative cognition. Cathodal stimulation over the left inferior frontotemporal cortex has been associated with improvements on tasks that rely primarily on idea generation, whereas anodal tDCS over left dorsolateral prefrontal cortex (DLPFC and frontopolar cortex has been shown to augment performance on tasks that impose high demands on creative idea selection. These results highlight the functional selectivity of tDCS for different components of creative thinking and confirm the dissociable contributions of left dorsal and inferior lateral frontotemporal cortex for different creativity tasks. We discuss promising avenues for future research that can advance our understanding of the effectiveness of tDCS as a method to enhance creative cognition.

  18. Electrical stimulation in exercise training

    Science.gov (United States)

    Kroll, Walter

    1994-01-01

    Electrical stimulation has a long history of use in medicine dating back to 46 A.D. when the Roman physician Largus found the electrical discharge of torpedo fishes useful in the treatment of pain produced by headache and gout. A rival Greek physician, Dioscorides, discounted the value of the torpedo fish for headache relief but did recommend its use in the treatment of hemorrhoids. In 1745, the Leyden jar and various sized electrostatic generators were used to treat angina pectoris, epilepsy, hemiplegia, kidney stones, and sciatica. Benjamin Franklin used an electrical device to treat successfully a young woman suffering from convulsive fits. In the late 1800's battery powered hydroelectric baths were used to treat chronic inflammation of the uterus while electrified athletic supporters were advertised for the treatment of male problems. Fortunately, such an amusing early history of the simple beginnings of electrical stimulation did not prevent eventual development of a variety of useful therapeutic and rehabilitative applications of electrical stimulation. Over the centuries electrical stimulation has survived as a modality in the treatment of various medical disorders with its primary application being in the rehabilitation area. Recently, a surge of new interest in electrical stimulation has been kindled by the work of a Russian sport scientist who reported remarkable muscle strength and endurance improvements in elite athletes. Yakov Kots reported his research on electric stimulation and strength improvements in 1977 at a Canadian-Soviet Exchange Symposium held at Concordia University in Montreal. Since then an explosion of new studies has been seen in both sport science and in medicine. Based upon the reported works of Kots and the present surge of new investigations, one could be misled as to the origin of electrical stimulation as a technique to increase muscle strength. As a matter of fact, electric stimulation has been used as a technique to improve

  19. Role of Akt substrate of 160 kDa in insulin-stimulated and contraction-stimulated glucose transport

    DEFF Research Database (Denmark)

    Cartee, Gregory D; Wojtaszewski, Jørgen F P

    2007-01-01

    160 phosphorylation in skeletal muscle. Available data from skeletal muscle support the concepts developed in adipocytes with regard to the role AS160 plays in the regulation of insulin-stimulated glucose transport. In vivo exercise, in vitro contractions, or in situ contractions can also stimulate AS......Insulin and exercise, the most important physiological stimuli to increase glucose transport in skeletal muscle, trigger a redistribution of GLUT4 glucose transporter proteins from the cell interior to the cell surface, thereby increasing glucose transport capacity. The most distal insulin...... signaling protein that has been linked to GLUT4 translocation, Akt substrate of 160 kDa (AS160), becomes phosphorylated in insulin-stimulated 3T3-L1 adipocytes; this is important for insulin-stimulated GLUT4 translocation and glucose transport. Insulin also induces a rapid and dose-dependent increase in AS...

  20. Recombinant human granulocyte-macrophage colony-stimulating factor stimulates in vitro mature human neutrophil and eosinophil function, surface receptor expression, and survival.

    OpenAIRE

    Lopez, A F; Williamson, D J; Gamble, J R; Begley, C G; Harlan, J M; Klebanoff, S J; Waltersdorph, A; Wong, G; Clark, S C; Vadas, M A

    1986-01-01

    A purified recombinant human granulocyte-macrophage colony stimulating factor (rH GM-CSF) was a powerful stimulator of mature human eosinophils and neutrophils. The purified rH GM-CSF enhanced the cytotoxic activity of neutrophils and eosinophils against antibody-coated targets, stimulated phagocytosis of serum-opsonized yeast by both cell types in a dose-dependent manner, and stimulated neutrophil-mediated iodination in the presence of zymosan. In addition, rH GM-CSF enhanced N-formylmethion...

  1. Emdogain stimulates matrix degradation by osteoblasts.

    Science.gov (United States)

    Goda, S; Inoue, H; Kaneshita, Y; Nagano, Y; Ikeo, T; Ikeo, Y T; Iida, J; Domae, N

    2008-08-01

    Emdogain has been used clinically for periodontal regeneration, although the underlying molecular mechanisms are not clear at present. In this study, we hypothesized that Emdogain stimulated degradation of type I collagen via osteoblasts. We showed that Emdogain enhanced cell-mediated degradation of type I collagen in an MMP-dependent manner. Although MG-63 cells spontaneously produced a zymogen form of MMP-1, treatment with Emdogain significantly induced the generation of the active form of this enzyme. We demonstrated that MMP-3 was produced from MG63 cells in response to Emdogain in a MEK1/2-dependent manner. Concomitantly, blocking of MEK1/2 activation by U0126 significantly inhibited the generation of the active form of MMP-1 without affecting the total production of this collagenase. These results suggest that Emdogain facilitates tissue regeneration through the activation of the collagenase, MMP-1, that degrades matrix proteins in bone tissue microenvironments.

  2. Modulation of hippocampal activity with fornix Deep Brain Stimulation.

    Science.gov (United States)

    Stypulkowski, Paul H; Stanslaski, Scott R; Giftakis, Jonathon E

    Deep Brain Stimulation (DBS) within the Papez circuit is under investigation as a treatment for epilepsy and Alzheimer's disease. We previously reported the effects of stimulation at nodes within this network (anterior thalamic nucleus and hippocampus) on hippocampal activity in a large animal model, using a chronic implantable, clinical-grade system that permits concurrent stimulation and recording. In this study we extended earlier work to compare the effects of fornix DBS on evoked potentials (EPs) and local field potential (LFP) activity within the hippocampus, and to assess closed-loop stimulation. Unilateral fornix and hippocampal DBS leads were implanted in three ovine subjects using image-guided, frameless stereotaxy. Chronic, awake recordings of EPs and LFPs in response to fornix and hippocampal stimulation were collected with the implanted device and analyzed off-line. Stimulation of the fornix produced robust, short latency hippocampal EPs. High frequency fornix stimulation generated parameter-dependent effects. At low amplitudes, short lasting inhibition of LFP activity occurred. Above a specific amplitude threshold, DBS elicited pronounced bursts of theta activity, followed by a marked state shift in hippocampal activity. These effects persisted for minutes post-DBS and were reflected as changes in LFP spectral content and phase-amplitude coupling. Real-time modulation of hippocampal activity via the implanted device was demonstrated using LFPs as the control signal for closed-loop stimulation. The current results expand earlier findings and demonstrate target-specific effects produced by DBS within this neural circuit. These changes in network activity may provide insights into stimulation targets and parameter selection for clinical investigations. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  3. Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs.

    Science.gov (United States)

    Cardinal, René; Pagé, Pierre; Vermeulen, Michel; Bouchard, Caroline; Ardell, Jeffrey L; Foreman, Robert D; Armour, J Andrew

    2006-11-01

    Spinal cord stimulation (SCS) applied to the dorsal aspect of the cranial thoracic cord imparts cardioprotection under conditions of neuronally dependent cardiac stress. This study investigated whether neuronally induced atrial arrhythmias can be modulated by SCS. In 16 anesthetized dogs with intact stellate ganglia and in five with bilateral stellectomy, trains of five electrical stimuli were delivered during the atrial refractory period to right- or left-sided mediastinal nerves for up to 20 s before and after SCS (20 min). Recordings were obtained from 191 biatrial epicardial sites. Before SCS (11 animals), mediastinal nerve stimulation initiated bradycardia alone (12 nerve sites), bradycardia followed by tachyarrhythmia/fibrillation (50 sites), as well as tachyarrhythmia/fibrillation without a preceding bradycardia (21 sites). After SCS, the number of responsive sites inducing bradycardia was reduced by 25% (62 to 47 sites), and the cycle length prolongation in residual bradycardias was reduced. The number of responsive sites inducing tachyarrhythmia was reduced by 60% (71 to 29 sites). Once elicited, residual tachyarrhythmias arose from similar epicardial foci, displaying similar dynamics (cycle length) as in control states. In the absence of SCS, bradycardias and tachyarrhythmias induced by repeat nerve stimulation were reproducible (five additional animals). After bilateral stellectomy, SCS no longer influenced neuronal induction of bradycardia and atrial tachyarrhythmias. These data indicate that SCS obtunds the induction of atrial arrhythmias resulting from excessive activation of intrinsic cardiac neurons and that such protective effects depend on the integrity of nerves coursing via the subclavian ansae and stellate ganglia.

  4. Noninvasive Stimulation of the Human Brain

    DEFF Research Database (Denmark)

    Di Lazzaro, Vincenzo; Rothwell, John; Capogna, Marco

    2017-01-01

    Noninvasive brain stimulation methods, such as transcranial electric stimulation and transcranial magnetic stimulation are widely used tools for both basic research and clinical applications. However, the cortical circuits underlying their effects are poorly defined. Here we review the current...

  5. Enteral feeding without pancreatic stimulation

    DEFF Research Database (Denmark)

    Kaushik, Neeraj; Pietraszewski, Marie; Holst, Jens Juul

    2005-01-01

    .5 g protein/kg ideal body weight/d. Plasma gut peptide responses were monitored in 15 subjects. RESULTS: In comparison with basal fasting trypsin secretion rates (mean = 134 [standard error = 22] U/h), duodenal feeding with the polymeric and elemental formulae stimulated trypsin secretion (mean = 408...... in enteral feeding without pancreatic stimulation, with particular reference to trypsin, because the avoidance of trypsin stimulation may optimize enteral feeding in acute pancreatitis. METHODS: The pancreatic secretory responses to feeding were studied in 36 healthy volunteers by standard double...... [standard error = 51] U/h; P standard error = 34] U/h) and mid-distal jejunal (mean = 119 [standard error = 16] U/h) did not. Stimulation was associated with an increase in plasma cholecystokinin, whereas distal jejunal feeding resulted in an increase...

  6. Demultiplexer circuit for neural stimulation

    Science.gov (United States)

    Wessendorf, Kurt O; Okandan, Murat; Pearson, Sean

    2012-10-09

    A demultiplexer circuit is disclosed which can be used with a conventional neural stimulator to extend the number of electrodes which can be activated. The demultiplexer circuit, which is formed on a semiconductor substrate containing a power supply that provides all the dc electrical power for operation of the circuit, includes digital latches that receive and store addressing information from the neural stimulator one bit at a time. This addressing information is used to program one or more 1:2.sup.N demultiplexers in the demultiplexer circuit which then route neural stimulation signals from the neural stimulator to an electrode array which is connected to the outputs of the 1:2.sup.N demultiplexer. The demultiplexer circuit allows the number of individual electrodes in the electrode array to be increased by a factor of 2.sup.N with N generally being in a range of 2-4.

  7. Growth hormone stimulation test (image)

    Science.gov (United States)

    ... stimulation test is usually performed to identify if hGH (human growth hormone) is deficient. The test is ... amino acid arginine in a vein to raise hGH levels. The test measures the ability of the ...

  8. Intermittent stimulation delays adaptation to electrocutaneous sensory feedback

    NARCIS (Netherlands)

    Buma, D.G.; Buma, Dorindo G.; Buitenweg, Jan R.; Veltink, Petrus H.

    Electrotactile displays deliver information to the user by means of electrocutaneous stimulation. If such displays are used in prostheses, the functionality depends on long term stability of this information channel. The perceived sensation, however, decays within 15 min due to central adaptation if

  9. Nonlinear joint angle control for artificially stimulated muscle

    NARCIS (Netherlands)

    Veltink, Petrus H.; Chizeck, Howard J.; Crago, Patrick E.; El-Bialy, Ahmed

    1992-01-01

    Designs of both open- and closed-loop controllers of electrically stimulated muscle that explicitly depend on a nonlinear mathematical model of muscle input-output properties are presented and evaluated. The muscle model consists of three factors: a muscle activation dynamics factor, an angle-torque

  10. Pharyngeal Electrical Stimulation for Treatment of Dysphagia in Subacute Stroke

    DEFF Research Database (Denmark)

    Bath, Philip M W; Scutt, Polly; Love, Jo

    2016-01-01

    BACKGROUND AND PURPOSE: Dysphagia is common after stroke, associated with increased death and dependency, and treatment options are limited. Pharyngeal electric stimulation (PES) is a novel treatment for poststroke dysphagia that has shown promise in 3 pilot randomized controlled trials. METHODS:...

  11. 3D numerical modeling of shale gas stimulation and seisimicity

    NARCIS (Netherlands)

    Shahid, A.S.; Wassing, B.B.T.; Verga, F.; Fokker, P.A.

    2013-01-01

    The economic production from shale gas reservoir depends on the success of hydraulic stimulation, which is aimed at the creation of a permeable complex fracture network. This is achieved by the reactivation of a natural fracture network; however, the reactivation may be accompanied by unwanted

  12. Economics of nuclear gas stimulation

    International Nuclear Information System (INIS)

    Frank, G.W.; Coffer, H.F.; Luetkehans, G.R.

    1970-01-01

    Nuclear stimulation of the Mesaverde Formation in the Piceance Basin appears to be the only available method that can release the contained gas economically. In the Rulison Field alone estimates show six to eight trillion cubic feet of gas may be made available by nuclear means, and possibly one hundred trillion cubic feet could be released in the Piceance Basin. Several problems remain to be solved before this tremendous gas reserve can be tapped. Among these are (1) rates of production following nuclear stimulation; (2) costs of nuclear stimulation; (3) radioactivity of the chimney gas; and (4) development of the ideal type of device to carry out the stimulations. Each of these problems is discussed in detail with possible solutions suggested. First and foremost is the rate at which gas can be delivered following nuclear stimulation. Calculations have been made for expected production behavior following a 5-kiloton device and a 40-kiloton device with different permeabilities. These are shown, along with conventional production history. The calculations show that rates of production will be sufficient if costs can be controlled. Costs of nuclear stimulation must be drastically reduced for a commercial process. Project Rulison will cost approximately $3.7 million, excluding lease costs, preliminary tests, and well costs. At such prices, nothing can possibly be commercial; however, these costs can come down in a logical step-wise fashion. Radiation contamination of the gas remains a problem. Three possible solutions to this problem are included. (author)

  13. Biomarkers and Stimulation Algorithms for Adaptive Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Kimberly B. Hoang

    2017-10-01

    Full Text Available The goal of this review is to describe in what ways feedback or adaptive stimulation may be delivered and adjusted based on relevant biomarkers. Specific treatment mechanisms underlying therapeutic brain stimulation remain unclear, in spite of the demonstrated efficacy in a number of nervous system diseases. Brain stimulation appears to exert widespread influence over specific neural networks that are relevant to specific disease entities. In awake patients, activation or suppression of these neural networks can be assessed by either symptom alleviation (i.e., tremor, rigidity, seizures or physiological criteria, which may be predictive of expected symptomatic treatment. Secondary verification of network activation through specific biomarkers that are linked to symptomatic disease improvement may be useful for several reasons. For example, these biomarkers could aid optimal intraoperative localization, possibly improve efficacy or efficiency (i.e., reduced power needs, and provide long-term adaptive automatic adjustment of stimulation parameters. Possible biomarkers for use in portable or implanted devices span from ongoing physiological brain activity, evoked local field potentials (LFPs, and intermittent pathological activity, to wearable devices, biochemical, blood flow, optical, or magnetic resonance imaging (MRI changes, temperature changes, or optogenetic signals. First, however, potential biomarkers must be correlated directly with symptom or disease treatment and network activation. Although numerous biomarkers are under consideration for a variety of stimulation indications the feasibility of these approaches has yet to be fully determined. Particularly, there are critical questions whether the use of adaptive systems can improve efficacy over continuous stimulation, facilitate adjustment of stimulation interventions and improve our understanding of the role of abnormal network function in disease mechanisms.

  14. [Dependency syndrome].

    Science.gov (United States)

    Vuorisalo, Sailaritta

    2013-01-01

    The most common causes of lower limb edema include cardiac insufficiency, venous insufficiency, insufficiency of lymph flow, and side effects of drugs. It can also be due to dependency syndrome, in which the edema and skin changes can only be explained by a passive calf muscle pump and the resulting venous hypertension. Underlying the drop foot is always immobilization for one reason or other. The patient must be given an explanation about the situation, activated to move if possible, and in any case guided to the use of support stockings and postural therapy.

  15. Vertex Stimulation as a Control Site for Transcranial Magnetic Stimulation: A Concurrent TMS/fMRI Study.

    Science.gov (United States)

    Jung, JeYoung; Bungert, Andreas; Bowtell, Richard; Jackson, Stephen R

    2016-01-01

    A common control condition for transcranial magnetic stimulation (TMS) studies is to apply stimulation at the vertex. An assumption of vertex stimulation is that it has relatively little influence over on-going brain processes involved in most experimental tasks, however there has been little attempt to measure neural changes linked to vertex TMS. Here we directly test this assumption by using a concurrent TMS/fMRI paradigm in which we investigate fMRI blood-oxygenation-level-dependent (BOLD) signal changes across the whole brain linked to vertex stimulation. Thirty-two healthy participants to part in this study. Twenty-one were stimulated at the vertex, at 120% of resting motor threshold (RMT), with short bursts of 1 Hz TMS, while functional magnetic resonance imaging (fMRI) BOLD images were acquired. As a control condition, we delivered TMS pulses over the left primary motor cortex using identical parameters to 11 other participants. Vertex stimulation did not evoke increased BOLD activation at the stimulated site. By contrast we observed widespread BOLD deactivations across the brain, including regions within the default mode network (DMN). To examine the effects of vertex stimulation a functional connectivity analysis was conducted. The results demonstrated that stimulating the vertex with suprathreshold TMS reduced neural activity in brain regions related to the DMN but did not influence the functional connectivity of this network. Our findings provide brain imaging evidence in support of the use of vertex simulation as a control condition in TMS but confirm that vertex TMS induces regional widespread decreases in BOLD activation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Experimental Study of the Course of Threshold Current, Voltage and Electrode Impedance During Stepwise Stimulation From the Skin Surface to the Human Cortex

    NARCIS (Netherlands)

    Szelenyi, Andrea; Journee, Henricus Louis; Herrlich, Simon; Galistu, Gianni M.; van den Berg, Joris; van Dijk, J. Marc C.

    Background: Transcranial electric stimulation as used during intraoperative neurostimulation is dependent on electrode and skull impedances. Objective: Threshold currents, voltages and electrode impedances were evaluated with electrical stimulation at 8 successive layers between the skin and the

  17. Deep Brain Stimulation for Parkinson's Disease

    Science.gov (United States)

    ... Home » Disorders » All Disorders Deep Brain Stimulation for Parkinson's Disease Information Page Deep Brain Stimulation for Parkinson's Disease Information Page What research is being done? The ...

  18. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans

    DEFF Research Database (Denmark)

    Kuhre, Rune Ehrenreich; Gribble, Fiona M; Hartmann, Bolette

    2014-01-01

    was metabolized and stimulated GLP-1 secretion dose-dependently (EC50 = 0.155 mM) by ATP-sensitive potassium channel closure and cell depolarization. Because fructose elicits GLP-1 secretion without simultaneous release of glucagonotropic GIP, the pathways underlying fructose-stimulated GLP-1 release might...... be useful targets for type 2 diabetes mellitus and obesity drug development....

  19. Sodium-potassium pump assessment by submaximal electrical nerve stimulation.

    Science.gov (United States)

    Hageman, Steven; Kovalchuk, Maria O; Sleutjes, Boudewijn T H M; van Schelven, Leonard J; van den Berg, Leonard H; Franssen, Hessel

    2018-04-01

    Sodium-potassium pump dysfunction in peripheral nerve is usually assessed by determining axonal hyperpolarization following maximal voluntary contraction (MVC) or maximal electrical nerve stimulation. As MVC may be unreliable and maximal electrical stimulation too painful, we assessed if hyperpolarization can also be induced by submaximal electrical nerve stimulation. In 8 healthy volunteers different submaximal electrical stimulus trains were given to the median nerve at the wrist, followed by 5 min assessment of thresholds for compound muscle action potentials of 20%, 40% or 60% of maximal. Threshold increase after submaximal electrical nerve stimulation was most prominent after an 8 Hz train of at least 5 min duration evoking submaximal CMAPs of 60%. It induced minimal discomfort and was not painful. Threshold increase after MVC was not significantly higher than this stimulus train. Submaximal electrical stimulation evokes activity dependent hyperpolarization in healthy test subjects without causing significant discomfort. Sodium-potassium pump function may be assessed using submaximal electrical stimulation. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  20. Stimulant use disorders: characteristics and comorbidity in an Australian population sample.

    Science.gov (United States)

    Sara, Grant; Burgess, Philip; Harris, Meredith; Malhi, Gin S; Whiteford, Harvey; Hall, Wayne

    2012-12-01

    To describe the correlates of stimulant use disorders (abuse, dependence) in an Australian population sample, to compare the characteristics of stimulant users with and without stimulant use disorders and to describe the patterns of service use and help-seeking in people with stimulant use disorders. Data were drawn from the 2007 National Survey of Mental Health and Wellbeing, which sampled 8841 residents of private dwellings in Australia in 2007. Lifetime DSM-IV substance use and mental disorder diagnoses were obtained from interviews conducted by lay interviewers, using the Composite International Diagnostic Interview (CIDI). Socio-demographic, socio-economic and clinical correlates of stimulant use disorders were identified using binary logistic regression models. Stimulant users with and without stimulant use disorders were compared to non-stimulant users via multinomial logistic regression models. Compared to Australians without stimulant use disorder, people with stimulant use disorders were younger, more likely to be male, of non-heterosexual orientation and born in Australia, but were not more socially disadvantaged. Lifetime comorbidity rates were high: 79% of persons with stimulant use disorders had a lifetime alcohol use disorder, 73% a lifetime cannabis use disorder, and more than one third a lifetime mood or anxiety disorder. Stimulant use disorders were associated with a family history of substance use, affective disorders and psychosis. One in five people with lifetime stimulant use disorders had been imprisoned, homeless or hospitalised for substance or mental health problems, and 13% reported at least one symptom of psychosis. Nearly half had sought help for substance or mental health problems, primarily from General Practitioners (GPs), psychologists or psychiatrists. Stimulant use disorders in a representative population sample are associated with significant comorbidity and harm. Many persons with stimulant use disorders had sought care and

  1. Ovarian stimulation, endometrium and implantation

    Directory of Open Access Journals (Sweden)

    mandana Beigi Boroujeni

    2011-03-01

    Full Text Available In the Paper article, the collection of the studies related to the effect of ovarian stimulation on endometrium of uterus and implantation have been investigated. History: Monash group used ovarian stimulation method for the first time in infertility treatment and also, they could increase the pregnancy rate using this method. However, the percentage of successful embryonic implantation has been decreased by this method due to imbalance of hormones and the effect of these hormonal changes on endometrium. Materials and Methods: Studies done by researchers have shown that ovarian stimulation causes undesirable changes in endometrium which in turn such alterations lead to inadequate attachment of embryo to endometrium and finally decrease the percentage of embryonic implantation. Conclusion: Based on several researches and the importance of using the ovarian stimulation method in treatment of infertility, also due to undesirable effects that ovarian stimulation has on endometrium during embryonic implantation it is inevitable that more investigations should be done for improvement of treatment methods in infertility clinics.

  2. Evoked Electromyographically Controlled Electrical Stimulation

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Hayashibe

    2016-07-01

    Full Text Available Time-variant muscle responses under electrical stimulation (ES are often problematic for all the applications of neuroprosthetic muscle control. This situation limits the range of ES usage in relevant areas, mainly due to muscle fatigue and also to changes in stimulation electrode contact conditions, especially in transcutaneous ES. Surface electrodes are still the most widely used in noninvasive applications.Electrical field variations caused by changes in the stimulation contact condition markedly affect the resulting total muscle activation levels. Fatigue phenomena under functional electrical stimulation (FES are also well known source of time-varying characteristics coming from muscle response under ES. Therefore it is essential to monitor the actual muscle state and assess the expected muscle response by ES so as to improve the current ES system in favour of adaptive muscle-response-aware FES control. To deal with this issue, we have been studying a novel control technique using evoked electromyography (eEMG signals to compensate for these muscle time-variances under ES for stable neuroprosthetic muscle control. In this perspective article, I overview the background of this topic and highlight important points to be aware of when using ES to induce the desired muscle activation regardless of the time-variance. I also demonstrate how to deal with the common critical problem of ES to move toward robust neuroprosthetic muscle control with the Evoked Electromyographically Controlled Electrical Stimulation paradigm.

  3. The Electrical Stimulation Modifies the Cerebral Function

    Science.gov (United States)

    Rocha, Luisa Lilia; López-Meraz, María Leonor; Cuéllar-Herrera, Manola; Neri-Bazán., Leticia

    2002-08-01

    Electrical stimulation has been used for therapeuthic purposes. In this review, we present the clinical and scientific bases for using electrical stimulation as a treatment for pharmacological refractory epilepsy. We also describe results in receptors of inhibitory neurotransmitters obtained in rat brain with or without epilepsy, undergoing brain stimulation. Brain electrical stimulation may improve our understanding of brain function and neuroplasticity.

  4. Comparison of mild stimulation and conventional stimulation in ART outcome.

    Science.gov (United States)

    Karimzadeh, Mohammad Ali; Ahmadi, Shahnaz; Oskouian, Homa; Rahmani, Elham

    2010-04-01

    To provide a treatment for particular condition that is the most effective treatment with the least risk and cost for the patient we compared the efficacy of using clomiphene 100 mg + delayed low dose gonadotropin + flexible GnRH antagonist administration for ovarian stimulation protocol and GnRH agonist + gonadotropin for stimulation protocol in IVF outcome. Clinical outcome of 243 women with regularly menstruation who were candidate for IVF. They had undergone stimulation with GnRH agonist and gonadotropin (group A) or clomiphene citrate, gonadotropin and GnRH antagonist (group B). Main outcome was ongoing pregnancy. There were no significant difference in mean age, cause of infertility, basal FSH, BMI, duration of infertility, endometrial thickness on the day HCG administration in two groups. The number of recovered oocytes, obtained embryos, transferred embryos, peak of estradiol on the day HCG administration and OHSS were significantly higher in group A. Significantly more patients in control group had embryos for cryopreservation. There were no significant difference in clinical pregnancy rate and ongoing pregnancy rate between two groups. Clomiphene + delayed low dose gonadotropin + flexible GnRH - antagonist stimulation is an acceptable alternative protocol for IVF in patients with regularly menstruation.

  5. Repetitive transcranial magnetic stimulation reduces cigarette consumption in schizophrenia patients.

    Science.gov (United States)

    Prikryl, Radovan; Ustohal, Libor; Kucerova, Hana Prikrylova; Kasparek, Tomas; Jarkovsky, Jiri; Hublova, Veronika; Vrzalova, Michaela; Ceskova, Eva

    2014-03-03

    High-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) seemed to decrease tobacco consumption and craving in nicotine-dependent people without psychiatric disorder or otherwise healthy people. Even if the prevalence of cigarette smoking in schizophrenia patients is high and estimated to be between 45% and 88%, this technique has not been systematically studied in this indication in schizophrenia yet. The aim of this study was to test the ability of high-frequency (10Hz) rTMS over the left DLPFC to decrease cigarette consumption in schizophrenia patients. The study included 35 male schizophrenia patients on stable antipsychotic medication. The patients were divided into two groups: the first (18 patients) were actively stimulated and the second (17 patients) underwent sham (placebo) stimulation. The sham rTMS was administered using a purpose-built sham coil that was identical in appearance to the real coil and made the same noise but did not deliver a substantial stimulus. The rTMS was administered at the stimulation parameters: location (left dorsolateral prefrontal cortex: DLPFC), intensity of magnetic stimulation in % of motor threshold (110%), stimulation frequency (10Hz), number of trains (20), single train duration (10s), inter-train interval (30s), and total number of stimulation sessions (21). In each stimulation session, 2000TMSpulses were given, with a total of 42,000pulses per treatment course. Patients noted the number of cigarettes smoked in the 7days before treatment, during the whole stimulation treatment (21days), and again for a 7-day period after treatment. Cigarette consumption was statistically significantly lower in the actively stimulated patients than in the sham rTMS group as early as the first week of stimulation. No statistically relevant correlations were found in the changes of ongoing negative or depressive schizophrenia symptoms and the number of cigarettes smoked. High

  6. Enteral feeding without pancreatic stimulation

    DEFF Research Database (Denmark)

    Kaushik, Neeraj; Pietraszewski, Marie; Holst, Jens Juul

    2005-01-01

    OBJECTIVE: All forms of commonly practiced enteral feeding techniques stimulate pancreatic secretion, and only intravenous feeding avoids it. In this study, we explored the possibility of more distal enteral infusions of tube feeds to see whether activation of the ileal brake mechanism can result...... in plasma glucagon-like peptide-1 and peptide YY concentrations. CONCLUSIONS: Our results suggest that enteral feeding can be given without stimulating pancreatic trypsin secretion provided it is delivered into the mid-distal jejunum. The mechanism may involve activation of the ileal brake mechanism....

  7. Thermally stimulated properties of amber

    International Nuclear Information System (INIS)

    Bowlt, C.

    1983-01-01

    Thermoelectrets yielded thermally stimulated currents but radioelectrets could not be produced even following exposures of 16000 R of ionising radiation. It is concluded that the thermally stimulated currents are due to the depolarisation of dipoles, with activation energy of 1.4 +- 0.1 eV, rather than to discharge of trapped charge carriers. Amber exhibits thermal luminescence following exposure to light of lambda < 500 nm but not to ionising radiation after exposures up to 5500 R, indicating localised impurity/trap/recombination complexes in the specimen surface, with a trap depth of 1.5 +- 0.1 eV. (author)

  8. Noninvasive Transcranial Brain Stimulation and Pain

    OpenAIRE

    Rosen, Allyson C.; Ramkumar, Mukund; Nguyen, Tam; Hoeft, Fumiko

    2009-01-01

    Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are two noninvasive brain stimulation techniques that can modulate activity in specific regions of the cortex. At this point, their use in brain stimulation is primarily investigational; however, there is clear evidence that these tools can reduce pain and modify neurophysiologic correlates of the pain experience. TMS has also been used to predict response to surgically implanted stimulation for the tre...

  9. Dynamic impedance model of the skin-electrode interface for transcutaneous electrical stimulation.

    Directory of Open Access Journals (Sweden)

    José Luis Vargas Luna

    Full Text Available Transcutaneous electrical stimulation can depolarize nerve or muscle cells applying impulses through electrodes attached on the skin. For these applications, the electrode-skin impedance is an important factor which influences effectiveness. Various models describe the interface using constant or current-depending resistive-capacitive equivalent circuit. Here, we develop a dynamic impedance model valid for a wide range stimulation intensities. The model considers electroporation and charge-dependent effects to describe the impedance variation, which allows to describe high-charge pulses. The parameters were adjusted based on rectangular, biphasic stimulation pulses generated by a stimulator, providing optionally current or voltage-controlled impulses, and applied through electrodes of different sizes. Both control methods deliver a different electrical field to the tissue, which is constant throughout the impulse duration for current-controlled mode or have a very current peak for voltage-controlled. The results show a predominant dependence in the current intensity in the case of both stimulation techniques that allows to keep a simple model. A verification simulation using the proposed dynamic model shows coefficient of determination of around 0.99 in both stimulation types. The presented method for fitting electrode-skin impedance can be simple extended to other stimulation waveforms and electrode configuration. Therefore, it can be embedded in optimization algorithms for designing electrical stimulation applications even for pulses with high charges and high current spikes.

  10. Simulation of morphologically structured photo-thermal neural stimulation

    Science.gov (United States)

    Weissler, Y.; Farah, N.; Shoham, S.

    2017-10-01

    Objective. Rational design of next-generation techniques for photo-thermal excitation requires the development of tools capable of modeling the effects of spatially- and temporally-dependent temperature distribution on cellular neuronal structures. Approach. We present a new computer simulation tool for predicting the effects of arbitrary spatiotemporally-structured photo-thermal stimulation on 3D, morphologically realistic neurons. The new simulation tool is based on interfacing two generic platforms, NEURON and MATLAB and is therefore suited for capturing different kinds of stimuli and neural models. Main results. Simulation results are validated using photo-absorber induced neuro-thermal stimulation (PAINTS) empirical results, and advanced features are explored. Significance. The new simulation tool could have an important role in understanding and investigating complex optical stimulation at the single-cell and network levels.

  11. Dependency Traits Among Parents of Drug Abusers

    Science.gov (United States)

    Tennant, Forest S., Jr.

    1976-01-01

    Studies question whether there is a significant association between parents' dependency traits and drug habits in their offspring. Reported here is a survey of 1,091 young males. The reported occurrence of parents' alcohol consumption, smoking, use of stimulants and sedatives, and overeating were compared among abusers and non-users of hashish,…

  12. Dosimetry of typical transcranial magnetic stimulation devices

    Science.gov (United States)

    Lu, Mai; Ueno, Shoogo

    2010-05-01

    The therapeutic staff using transcranial magnetic stimulation (TMS) devices could be exposed to magnetic pulses. In this paper, dependence of induced currents in real human man model on different coil shapes, distance between the coil and man model as well as the rotation of the coil in space have been investigated by employing impedance method. It was found that the figure-of-eight coil has less leakage magnetic field and low current density induced in the body compared with the round coil. The TMS power supply cables play an important role in the induced current density in human body. The induced current density in TMS operator decreased as the coil rotates from parallel position to perpendicular position. Our present study shows that TMS operator should stand at least 110 cm apart from the coil.

  13. Nanoparticles: a challenging vehicle for neural stimulation

    Directory of Open Access Journals (Sweden)

    Elisabetta eColombo

    2016-03-01

    Full Text Available Neurostimulation represents a powerful and well-established tool for the treatment of several diseases affecting the central nervous system. Although effective in reducing the symptoms or the progression of brain disorders, the poor accessibility of the deepest areas of the brain currently hampers the possibility of a more specific and controlled therapeutic stimulation, depending on invasive surgical approaches and long-term stability and biocompatibility issues. The massive research of the last decades on nanomaterials and nanoscale devices favored the development of new tools to address the limitations of the available neurostimulation approaches. This mini-review focuses on the employment of nanoparticles for the modulation of the electrophysiological activity of neuronal networks and the related transduction mechanisms underlying the nanostructure-neuron interfaces.

  14. Stimulant use disorders in people with psychosis: a meta-analysis of rate and factors affecting variation.

    Science.gov (United States)

    Sara, Grant E; Large, Matthew M; Matheson, Sandra L; Burgess, Philip M; Malhi, Gin S; Whiteford, Harvey A; Hall, Wayne D

    2015-02-01

    Stimulant abuse and dependence often complicate the care of people with psychotic disorders. This study systematically reviews the prevalence estimates reported for stimulant abuse and dependence in people with psychotic disorders, and examines personal, clinical, regional and methodological factors which explain variation in these rates. PsychINFO, EMBASE and MEDLINE (1946-2013) were searched systematically for studies reporting on stimulant drug use disorders in representative samples of people with psychotic disorders. Random effects models estimated the pooled rate of a stimulant use disorder, defined to include stimulant abuse and stimulant dependence. Study characteristics associated with heterogeneity in rates of stimulant use disorder were examined by subgroup analyses for categorical variables, by meta-regression for continuous independent variables and by multiple meta-regression. Sixty-four studies provided 68 estimates of lifetime or recent stimulant use disorders in 22,500 people with psychosis. The pooled rate of stimulant use disorder was 8.9% (95% CI 7.4%, 10.5%). Higher rates of stimulant use disorders were reported in studies of affective psychosis, studies from inpatient settings, studies from the USA and Australia, and studies with higher rates of cannabis disorder; in multiple meta-regression analysis these factors explained 68% of between-study variance. Rates of stimulant use disorder were stable over time, and unrelated to age, sex, stage of psychosis, type of stimulant drug or study methodology factors. Reported rates of stimulant use disorder in people with psychosis are much higher than in the general population but vary widely and are associated with regional, service setting and clinical differences between studies. It is likely that stimulants contribute to the overall burden of psychosis, and that social and environmental factors combine with drug and illness-related factors to influence stimulant use in psychosis. © The Royal

  15. Optimizing performance by stimulating conflict

    NARCIS (Netherlands)

    van de Vliert, E.; de Dreu, C.K.W.

    1994-01-01

    To enhance the quality of group decision making, to promote affective acceptance of decisions by all participants involved, or to increase joint outcomes, a principal party or a third party may stimulate social conflict. We argue that when conflict focuses on identity issues, when tension level is

  16. Stimulated emission during axial channeling

    International Nuclear Information System (INIS)

    Ternov, I.M.; Khalilov, V.R.; Kholomai, B.V.

    1985-01-01

    A quantum-mechanical analysis shows that it would be possible to achieve stimulated emission in an axisymmetric focusing electric field by a mechanism based on the nonuniform spacing of levels in the electron energy spectrum and on recoil effects during the emission and absorption of photons by the electrons

  17. Optimizing performance by conflict stimulation

    NARCIS (Netherlands)

    Van de Vliert, E; De Dreu, C K W

    To enhance the quality of group decision making, to promote affective acceptance of decisions by all participants involved, or to increase joint outcomes, a principal party or a third party may stimulate social conflict. We argue that when conflict focuses on identity issues, when tension level is

  18. Transcranial magnetic stimulation in schizophrenia.

    Science.gov (United States)

    Zaman, Rashid; Thind, Dilraj; Kocmur, Marga

    2008-11-01

    Transcranial magnetic stimulation (TMS) is a non-invasive and painless way of stimulating the neural tissue (cerebral cortex, spinal roots, and cranial and peripheral nerves). The first attempts at stimulating the neural tissue date back to 1896 by d'Arsonval; however, it was successfully carried out by Barker and colleagues in Sheffield, UK, in 1985. It soon became a useful tool in neuroscience for neurophysiologists and neurologists and psychiatrists. The original single-pulse TMS, largely used as an investigative tool, was further refined and developed in the early 1990s into what is known as repetitive TMS (rTMS), having a frequency range of 1-60 Hz. The stimulation by both TMS and rTMS of various cortical regions displayed alteration of movement, mood, and behavior, leading researchers to investigate a number of psychiatric and neuropsychiatric disorders, as well as to explore its therapeutic potential. There is now a large amount of literature on the use of TMS/rTMS in depression; however, its use in schizophrenia, both as an investigative and certainly as a therapeutic tool is relatively recent with a limited but increasing number of publications. In this article, we will outline the principles of TMS/rTMS and critically review their use in schizophrenia both as investigative and potential therapeutic tools.

  19. Thermally stimulated luminescence and photoluminescence ...

    Indian Academy of Sciences (India)

    2012-01-13

    Jan 13, 2012 ... Peltier cooled photo-multiplier tube as detector (Jain et al. 2008). The acquisition and analysis of the data were carried out by F-900 software supplied by Edinburgh Analytical. Instruments, UK. Thermally stimulated luminescence (TSL) glow curves were recorded using home-built unit between. 300 and ...

  20. Ovarian stimulation and embryo quality

    NARCIS (Netherlands)

    Baart, Esther; Macklon, Nick S.; Fauser, Bart J. C. M.

    To Study the effects of different ovarian stimulation approaches on oocyte and embryo quality, it is imperative to assess embryo quality with a reliable and objective method. Embryos rated as high quality by standardized morphological assessment are associated with higher implantation and pregnancy

  1. Breast Cancer Stimulation of Osteolysis

    Science.gov (United States)

    2000-09-01

    number seen in osteoporosis . M- increase osteoclast activity. Paracrine stimulation of osteo-clas aciviy my bea pi ay mchansm y wich CSF also promotes the...effects on gies, including periodontitis and orthopedic implant loos- kidney and bone metabolism. Paracrine actions of ening. Antibody blockade of

  2. Orientation selective deep brain stimulation

    Science.gov (United States)

    Lehto, Lauri J.; Slopsema, Julia P.; Johnson, Matthew D.; Shatillo, Artem; Teplitzky, Benjamin A.; Utecht, Lynn; Adriany, Gregor; Mangia, Silvia; Sierra, Alejandra; Low, Walter C.; Gröhn, Olli; Michaeli, Shalom

    2017-02-01

    Objective. Target selectivity of deep brain stimulation (DBS) therapy is critical, as the precise locus and pattern of the stimulation dictates the degree to which desired treatment responses are achieved and adverse side effects are avoided. There is a clear clinical need to improve DBS technology beyond currently available stimulation steering and shaping approaches. We introduce orientation selective neural stimulation as a concept to increase the specificity of target selection in DBS. Approach. This concept, which involves orienting the electric field along an axonal pathway, was tested in the corpus callosum of the rat brain by freely controlling the direction of the electric field on a plane using a three-electrode bundle, and monitoring the response of the neurons using functional magnetic resonance imaging (fMRI). Computational models were developed to further analyze axonal excitability for varied electric field orientation. Main results. Our results demonstrated that the strongest fMRI response was observed when the electric field was oriented parallel to the axons, while almost no response was detected with the perpendicular orientation of the electric field relative to the primary fiber tract. These results were confirmed by computational models of the experimental paradigm quantifying the activation of radially distributed axons while varying the primary direction of the electric field. Significance. The described strategies identify a new course for selective neuromodulation paradigms in DBS based on axonal fiber orientation.

  3. Photoluminescence, thermally stimulated luminescence and ...

    Indian Academy of Sciences (India)

    an important role in the development of thermolumine- scent dosimeters (Vohra et al 1980; Shinde et al 1996) and offer a very fertile area for further studies to eluci- date the thermally stimulated reactions resulting in lumine- scence. Actinide doped alkaline-earth sulphates are of spe- cial interest due to an array of defect ...

  4. Thalamic stimulation in absence epilepsy

    NARCIS (Netherlands)

    Luttjohann, A.K.; Luijtelaar, E.L.J.M. van

    2013-01-01

    Purpose The site specific effects of two different types of electrical stimulation of the thalamus on electroencephalic epileptic activity as generated in the cortico-thalamo-cortical system were investigated in genetic epileptic WAG/Rij rats, a well characterized and validated absence

  5. Effects of lithium on stimulated metabolic parameters in dog thyroid slices

    International Nuclear Information System (INIS)

    Fen-Yu Tseng; Pasquali, D.; Field, J.B.

    1989-01-01

    Thyroid abnormalities may develop during chronic lithium therapy for affective disorders. Lithium, like iodide, inhibits TSH stimulation of adenylate cyclase and thyroid hormone release. The present study examined the effect of lithium on stimulation of intrathyroidal intermediary metabolism by several agonists, LiCl (5 mmol l) did not inhibit basal cAMP, glucose oxidation or 32 P incorporation into phospholipids in dog thyroid slices. Although LiCl inhibited TSH stimulation of cAMP, it did not abolish the hormone's effect on cAMP-dependent protein kinase. The stimulation of iodide organification, glucose oxidation or 32 P incorporation into phospholipids by TSH, carbachol and phorbol esters was not inhibited by lithium. This is in contrast to the effects of iodide, which inhibited stimulation of glucose oxidation and 32 P incorporation into phospholipids by various agonists. Thus, although both lithium and iodide inhibited TSH-stimulated cAMP formation, they act differently on intrahyriodal intermediary metabolism. (author)

  6. Glycogen depletion and resynthesis during 14 days of chronic low-frequency stimulation of rabbit muscle

    DEFF Research Database (Denmark)

    Prats, C; Bernal, C; Cadefau, J A

    2002-01-01

    Electro-stimulation alters muscle metabolism and the extent of this change depends on application intensity and duration. The effect of 14 days of chronic electro-stimulation on glycogen turnover and on the regulation of glycogen synthase in fast-twitch muscle was studied. The results showed...... that macro- and proglycogen degrade simultaneously during the first hour of stimulation. After 3 h, the muscle showed net synthesis, with an increase in the proglycogen fraction. The glycogen content peaked after 4 days of stimulation, macroglycogen being the predominant fraction at that time. Glycogen...... synthase was determined during electro-stimulation. The activity of this enzyme was measured at low UDPG concentration with either high or low Glu-6-P content. Western blots were performed against glycogen synthase over a range of stimulation periods. Activation of this enzyme was maximum before the net...

  7. The effect of static force on round window stimulation with the direct acoustic cochlea stimulator.

    Science.gov (United States)

    Maier, Hannes; Salcher, Rolf; Schwab, Burkard; Lenarz, Thomas

    2013-07-01

    The Direct Acoustic Cochlea Stimulator Partial Implant (DACS PI, Phonak Acoustic Implants SA, Switzerland) is intended to stimulate the cochlea by a conventional stapedotomy piston that is crimped onto the DACS PI artificial incus. An alternative approach to the round window (RW) is successfully done with other devices, having the advantage of being also independent of the existence of middle ear structure (e.g. ossicles). Here the possibility of stimulating the RW with the DACS actuator is investigated including the impact of static force on sound transmission to the cochlea. The maximum equivalent sound pressure output with RW stimulation was determined experimentally in fresh human temporal bones. Experiments were performed in analogy to the ASTM standard (F2504.24930-1) method for the output determination of implantable middle ear hearing devices (IMEHDs) in human cadaveric temporal bones (TBs). ASTM compliant temporal bones were stimulated with a prosthesis having a spherical tip (∅0.5 mm) attached to the actuator. The stimulation was performed perpendicular to the round window membrane (RWM) at varying position relative to the RW and the resulting static force on the RW membrane was determined. At each position the displacement output of the DACS PI actuator and the stapes footplate (SFP) vibration in response to actuator stimulation was measured with a Laser Doppler Velocimeter (LDV). By comparison of the achieved output at the stapes footplate in response to sound and transducer stimulation the equivalent sound pressure level at the tympanic membrane at 1Vrms input voltage was calculated assuming that the SFP displacement in both conditions is a measure of perceived loudness, as it is done in the ASTM standard. Ten TB preparations within the acceptance range of the ASTM standard were used for analysis. The actuator driven stapes footplate displacement amplitude as well as the resulting equivalent sound pressure level was highly dependent on the static

  8. A Novel In Vitro System for Comparative Analyses of Bone Cells and Bacteria under Electrical Stimulation

    Directory of Open Access Journals (Sweden)

    Thomas Josef Dauben

    2016-01-01

    Full Text Available Electrical stimulation is a promising approach to enhance bone regeneration while having potential to inhibit bacterial growth. To investigate effects of alternating electric field stimulation on both human osteoblasts and bacteria, a novel in vitro system was designed. Electric field distribution was simulated numerically and proved by experimental validation. Cells were stimulated on Ti6Al4V electrodes and in short distance to electrodes. Bacterial growth was enumerated in supernatant and on the electrode surface and biofilm formation was quantified. Electrical stimulation modulated gene expression of osteoblastic differentiation markers in a voltage-dependent manner, resulting in significantly enhanced osteocalcin mRNA synthesis rate on electrodes after stimulation with 1.4VRMS. While collagen type I synthesis increased when stimulated with 0.2VRMS, it decreased after stimulation with 1.4VRMS. Only slight and infrequent influence on bacterial growth was observed following stimulations with 0.2VRMS and 1.4VRMS after 48 and 72 h, respectively. In summary this novel test system is applicable for extended in vitro studies concerning definition of appropriate stimulation parameters for bone cell growth and differentiation, bacterial growth suppression, and investigation of general effects of electrical stimulation.

  9. Autonomous Optimization of Targeted Stimulation of Neuronal Networks.

    Science.gov (United States)

    Kumar, Sreedhar S; Wülfing, Jan; Okujeni, Samora; Boedecker, Joschka; Riedmiller, Martin; Egert, Ulrich

    2016-08-01

    Driven by clinical needs and progress in neurotechnology, targeted interaction with neuronal networks is of increasing importance. Yet, the dynamics of interaction between intrinsic ongoing activity in neuronal networks and their response to stimulation is unknown. Nonetheless, electrical stimulation of the brain is increasingly explored as a therapeutic strategy and as a means to artificially inject information into neural circuits. Strategies using regular or event-triggered fixed stimuli discount the influence of ongoing neuronal activity on the stimulation outcome and are therefore not optimal to induce specific responses reliably. Yet, without suitable mechanistic models, it is hardly possible to optimize such interactions, in particular when desired response features are network-dependent and are initially unknown. In this proof-of-principle study, we present an experimental paradigm using reinforcement-learning (RL) to optimize stimulus settings autonomously and evaluate the learned control strategy using phenomenological models. We asked how to (1) capture the interaction of ongoing network activity, electrical stimulation and evoked responses in a quantifiable 'state' to formulate a well-posed control problem, (2) find the optimal state for stimulation, and (3) evaluate the quality of the solution found. Electrical stimulation of generic neuronal networks grown from rat cortical tissue in vitro evoked bursts of action potentials (responses). We show that the dynamic interplay of their magnitudes and the probability to be intercepted by spontaneous events defines a trade-off scenario with a network-specific unique optimal latency maximizing stimulus efficacy. An RL controller was set to find this optimum autonomously. Across networks, stimulation efficacy increased in 90% of the sessions after learning and learned latencies strongly agreed with those predicted from open-loop experiments. Our results show that autonomous techniques can exploit quantitative

  10. Uncovering the mechanism(s) of deep brain stimulation

    Energy Technology Data Exchange (ETDEWEB)

    Li Gang; Yu Chao; Lin Ling; Lu, Stephen C-Y [Inspiring Technical Laboratory, College of Precision Instruments and Opto-Electronics Engineering, Tianjin University, Tianjin 300072 (China)

    2005-01-01

    Deep brain stimulators, often called 'pacemakers for the brain', are implantable devices which continuously deliver impulse stimulation to specific targeted nuclei of deep brain structure, namely deep brain stimulation (DBS). To date, deep brain stimulation (DBS) is the most effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been put forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS.

  11. Somatomedin-C stimulates glycogen synthesis in fetal rat hepatocytes

    International Nuclear Information System (INIS)

    Freemark, M.; D'Ercole, A.J.; Handwerger, S.

    1985-01-01

    The effects of somatomedin-C/insulin-like growth factor I (Sm-C) on glycogen metabolism in cultured hepatocytes from 20-day-old rat fetuses have been examined and compared with the effects of insulin. Sm-C (25-375 ng/ml; 3.25-50 nM) stimulated dose-dependent increases in [ 14 C]glucose incorporation into glycogen (14.4-72.9% and total cell glycogen content (10.6-34.3%. Maximal stimulation of glycogen synthesis by Sm-C occurred at 2-4 h of incubation. Insulin (10 nM to 10 microM) also stimulated [ 14 C]glucose incorporation but its potency was only 1/20th that of Sm-C. The time course of stimulation of glucose incorporation by insulin was identical to that of Sm-C, the dose-response curves of the two hormones were parallel, and the maximal effects of insulin were not enhanced by simultaneous exposure of cells to Sm-C. These findings suggest that Sm-C and insulin stimulate glycogenesis in fetal liver through similar or identical mechanisms. Since the potency of Sm-C was 20 times greater than that of insulin, the glycogenic action of insulin in fetal liver may be mediated through binding to a hepatic receptor which also binds Sm-C. In addition to having mitogenic effects on fetal tissues, Sm-C may have direct anabolic effects on fetal carbohydrate metabolism

  12. Brain transcranial direct current stimulation modulates motor excitability in mice.

    Science.gov (United States)

    Cambiaghi, Marco; Velikova, Svetla; Gonzalez-Rosa, Javier J; Cursi, Marco; Comi, Giancarlo; Leocani, Letizia

    2010-02-01

    Shortly after the application of weak transcranial direct current stimulation (tDCS) to the animal and human brain, changes in corticospinal excitability, which mainly depend on polarity, duration and current density of the stimulation protocol, have been reported. In humans, anodal tDCS has been reported to enhance motor-evoked potentials (MEPs) elicited by transcranial brain stimulation while cathodal tDCS has been shown to decrease them. Here we investigated the effects produced by tDCS on mice motor cortex. MEPs evoked by transcranial electric stimulation were recorded from forelimbs of 12 C57BL/6 mice, under sevofluorane anaesthesia, before and after (0, 5 and 10 min) anodal and cathodal tDCS (tDCS duration 10 min). With respect to sham condition stimulation (anaesthesia), MEP size was significantly increased immediately after anodal tDCS, and was reduced after cathodal tDCS (approximately 20% vs. sham). Both effects declined towards basal levels in the following 10 min. Although the site and mechanisms of action of tDCS need to be more clearly identified, the directionality of effects of tDCS on mice MEPs is consistent with previous findings in humans. The feasibility of tDCS in mice suggests the potential applicability of this technique to assess the potential therapeutic options of brain polarization in animal models of neurological and neuropsychiatric diseases.

  13. Uncovering the mechanism(s) of deep brain stimulation

    International Nuclear Information System (INIS)

    Li Gang; Yu Chao; Lin Ling; Lu, Stephen C-Y

    2005-01-01

    Deep brain stimulators, often called 'pacemakers for the brain', are implantable devices which continuously deliver impulse stimulation to specific targeted nuclei of deep brain structure, namely deep brain stimulation (DBS). To date, deep brain stimulation (DBS) is the most effective clinical technique for the treatment of several medically refractory movement disorders (e.g., Parkinson's disease, essential tremor, and dystonia). In addition, new clinical applications of DBS for other neurologic and psychiatric disorders (e.g., epilepsy and obsessive-compulsive disorder) have been put forward. Although DBS has been effective in the treatment of movement disorders and is rapidly being explored for the treatment of other neurologic disorders, the scientific understanding of its mechanisms of action remains unclear and continues to be debated in the scientific community. Optimization of DBS technology for present and future therapeutic applications will depend on identification of the therapeutic mechanism(s) of action. The goal of this review is to address our present knowledge of the effects of high-frequency stimulation within the central nervous system and comment on the functional implications of this knowledge for uncovering the mechanism(s) of DBS

  14. Dosimetry based on thermally and optically stimulated luminescence

    International Nuclear Information System (INIS)

    Agersnap Larsen, Niels

    1999-01-01

    Thermally Stimulated Luminescence (TL) and Optically Stimulated Luminescence (OSL) properties of quartz and α-Al 2 O 3 have been investigated. Anneling-induced OSL and TL sensitivity changes in quartz has been investigated by experiments and modelling. This study does not support a pre-dose effect to account for the observed annealing-induced sensitivity change. The experimental data indicates a more simple mechanism that involves alteration of the concentration of the defect centers. Results from modelling of removal or creation of defect centers comparing well with experimentally obtained data. Thermal quenching of luminescence for the main emission center, the F-center, in α-Al 2 O 3 :C has been investigated by analysing TL curves obtained at different heating rates. The thermal quenching dependence of luminescence is found to follow the classical Mott-Seitz expression. Basic investigations of OSL properties of αAl 2 O 3 :C, including: the thermal depth of the OSL traps, the temperature dependence of OSL, and the OSL stimulation spectra. Simultaneous measurements of TL and thermally stimulated conductivity (TSC) are presented for γ-irradiated αAl 2 O 3 :C. Activation energy analysis of the data reveals a superposition of several first-order TL and TSC peaks caused by release of charge carriers from a distribution of trapping states. Furthermore a description of an experimental method developed to determine the sign of the thermally released charge carriers has been presented. (au)

  15. Stimulating the Comfort of Textile Electrodes in Wearable Neuromuscular Electrical Stimulation

    OpenAIRE

    Hui Zhou; Yi Lu; Wanzhen Chen; Zhen Wu; Haiqing Zou; Ludovic Krundel; Guanglin Li

    2015-01-01

    Textile electrodes are becoming an attractive means in the facilitation of surface electrical stimulation. However, the stimulation comfort of textile electrodes and the mechanism behind stimulation discomfort is still unknown. In this study, a textile stimulation electrode was developed using conductive fabrics and then its impedance spectroscopy, stimulation thresholds, and stimulation comfort were quantitatively assessed and compared with those of a wet textile electrode and a hydrogel ele...

  16. Vagal stimulation in heart failure.

    Science.gov (United States)

    De Ferrari, Gaetano M

    2014-04-01

    Heart failure (HF) is accompanied by an autonomic imbalance that is almost always characterized by both increased sympathetic activity and withdrawal of vagal activity. Experimentally, vagal stimulation has been shown to exert profound antiarrhythmic activity and to improve cardiac function and survival in HF models. A open-label pilot clinical study in 32 patients with chronic HF has shown safety and tolerability of chronic vagal stimulation associated with subjective (improved quality of life and 6-min walk test) and objective improvements (reduced left ventricular systolic volumes and improved left ventricular ejection fraction). Three larger clinical studies, including a phase III trial are currently ongoing and will evaluate the clinical role of this new approach.

  17. Transcranial Magnetic Stimulation in Children

    OpenAIRE

    Garvey, Marjorie A.; Mall, Volker

    2008-01-01

    Developmental disabilities (e.g. attention deficit disorder; cerebral palsy) are frequently associated with deviations of the typical pattern of motor skill maturation. Neurophysiologic tools, such as transcranial magnetic stimulation (TMS), which probe motor cortex function, can potentially provide insights into both typical neuromotor maturation and the mechanisms underlying the motor skill deficits in children with developmental disabilities. These insights may set the stage for finding ef...

  18. Deep brain stimulation in psychiatry.

    Science.gov (United States)

    Mohr, Pavel

    2008-11-01

    Deep brain stimulation (DBS) is a reversible surgical procedure that involves stereotactic implantation of electrodes into the targeted brain regions, with a subcutaneously placed pulse generator powering the electrodes via one or two leads. The mechanism of action can be explained by the stimulation-induced modulation of impaired network activity. So far, the main use of DBS has been for neurological conditions, such as essential tremor, motor symptoms in Parkinson's disease, dystonia, epilepsy, and chronic pain. In psychiatry, case series and open studies indicate treatment efficacy of DBS in Gilles de la Tourette syndrome, treatment-resistant obsessive-compulsive disorder, and refractory major depression. Neuroimaging studies have confirmed the effects of DBS on the brain regions implicated in specific neuropsychiatric disorders. It is a well-tolerated method with relatively few serious side effects. Additional well-designed and appropriately powered controlled clinical trials are needed to conclusively establish the efficacy and safety of DBS and to identify the patient population(s) who may benefit most. Ongoing research with stimulation techniques may also significantly contribute to our understanding of major neuropsychiatric disorders.

  19. Performance Enhancement by Brain Stimulation

    Directory of Open Access Journals (Sweden)

    Parisa Gazerani

    2017-09-01

    Full Text Available Number of substances and strategies are available to increase performance in sport (Catlin and Murray, 1996. Since 2004, the World Anti-Doping Agency (WADA posts an updated list of substances and methods prohibited to athletes. Drugs (e.g., steroids, stimulants are a major part of this list; however, technologies and methods (e.g., gene doping are increasingly being identified and added (WADA, 2017. Among technologies and methods that might exert a potential effect on athletic performance, brain stimulation has recently been subjected to extensive discussion. Neuro-enhancement for doping purposes has been termed “neurodoping” in the literature (Davis, 2013; however, this concept needs further documentation before the term “neurodoping” can be used properly. Two major non-invasive techniques of brain stimulations are transcranial magnetic stimulation (TMS (Hallett, 2007; Rossi et al., 2009, and transcranial direct current stimulation (tDCS (Stagg and Nitsche, 2011. In TMS, an electric coil held over the head applies magnetic pulses to create currents in the brain. In tDCS, a low, continuous electrical current is delivered to the brain by using surface electrodes attached on the scalp. TMS and tDCS have been used in both research and clinic (Shin and Pelled, 2017 for example to examine alterations in cognitive function or motor skills or to assist in recovering motor function after a stroke (Gomez Palacio Schjetnan et al., 2013 or reducing fatigue in patients with multiple sclerosis (Saiote et al., 2014. In an opinion paper, it was proposed that use of emerging brain stimulation techniques might also enhance physical and mental performance in sports (Davis, 2013. The assumption was based on several reports. For example some studies have shown that TMS could shorten reaction times to visual, auditory and touch stimuli, reduce tremor, and enhance the acquisition of complex motor skills. Based on the current evidence, a recent review (Colzato

  20. Optical stimulated luminescence (OSL) dating

    International Nuclear Information System (INIS)

    Banerjee, D.

    1999-01-01

    Since the pioneering work by Huntley et al. (1985), optical dating is being increasingly recognised as an important technique for establishing a time frame of deposition of sediments (Aitken, 1998). Optical dating differs from thermoluminescence (TL) dating in that visible/infrared light from lasers or LEDs (light-emitting-diodes) is used as a means of stimulation, in contrast to thermal stimulation. It has several advantages over TL dating: (i) the resetting of the OSL (optically stimulated luminescence) clock is more effective than that of TL clock; for sediments transported under water or in other situations where the sediment grains have undergone inhomogeneous bleaching, this property ensures that ages based on optical dating are generally more reliable than TL ages, (ii) the optical dating technique is non-destructive, and multiple readouts of the optical signal is possible; this feature has resulted in the development of single-aliquot and single-grain protocols (Murray and Wintle, 1999; Banerjee et al. 1999), (iii) the sample is not heated as in TL; thus, spurious luminescence is avoided and there is a significant reduction in blackbody radiation. Dating of materials which change phase on heating is also practical, and finally, (iv) thermal quenching of luminescence is negligible, allowing accurate estimation of kinetic parameters using standard techniques and providing access to deep OSL traps. This characteristic may be helpful in extending the limits of optical dating beyond the last 150 ka from a global point of view

  1. Vagus Nerve Stimulation for Treating Epilepsy

    Science.gov (United States)

    ... and their FAMILIES VAGUS NERVE STIMULATION FOR TREATING EPILEPSY This information sheet is provided to help you ... how vagus nerve stimulation (VNS) may help treat epilepsy. The American Academy of Neurology (AAN) is the ...

  2. Follicle-stimulating hormone (FSH) blood test

    Science.gov (United States)

    ... ency/article/003710.htm Follicle-stimulating hormone (FSH) blood test To use the sharing features on this page, please enable JavaScript. The follicle stimulating hormone (FSH) blood test measures the level of FSH in blood. FSH ...

  3. Electrical Stimulation Promotes Cardiac Differentiation of Human Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Damián Hernández

    2016-01-01

    Full Text Available Background. Human induced pluripotent stem cells (iPSCs are an attractive source of cardiomyocytes for cardiac repair and regeneration. In this study, we aim to determine whether acute electrical stimulation of human iPSCs can promote their differentiation to cardiomyocytes. Methods. Human iPSCs were differentiated to cardiac cells by forming embryoid bodies (EBs for 5 days. EBs were then subjected to brief electrical stimulation and plated down for 14 days. Results. In iPS(Foreskin-2 cell line, brief electrical stimulation at 65 mV/mm or 200 mV/mm for 5 min significantly increased the percentage of beating EBs present by day 14 after plating. Acute electrical stimulation also significantly increased the cardiac gene expression of ACTC1, TNNT2, MYH7, and MYL7. However, the cardiogenic effect of electrical stimulation was not reproducible in another iPS cell line, CERA007c6. Beating EBs from control and electrically stimulated groups expressed various cardiac-specific transcription factors and contractile muscle markers. Beating EBs were also shown to cycle calcium and were responsive to the chronotropic agents, isoproterenol and carbamylcholine, in a concentration-dependent manner. Conclusions. Our results demonstrate that brief electrical stimulation can promote cardiac differentiation of human iPS cells. The cardiogenic effect of brief electrical stimulation is dependent on the cell line used.

  4. Low-frequency deep brain stimulation for Parkinson's disease: Great expectation or false hope?

    Science.gov (United States)

    di Biase, Lazzaro; Fasano, Alfonso

    2016-07-01

    The long-term efficacy of subthalamic deep brain stimulation for Parkinson's disease is not always retained, and many patients lose the improvement achieved during the "second honeymoon" following surgery. Deep brain stimulation is a versatile tool, as stimulation parameters may undergo a fine-tuning depending on clinical needs. Among them, frequency is the parameter that leads to more complex scenarios because there is no generalizable relationship between its modulation and the overall clinical response, which also depends on the specific considered sign. High-frequency stimulation (>100 Hz) has shown to be effective in improving most parkinsonian signs, particularly the levodopa-responsive ones. However, its effect on axial signs (such as balance, gait, speech, or swallowing) may not be sustained, minimal, or even detrimental. For these reasons, several studies have explored the effectiveness of low-frequency stimulation (generally 60 or 80 Hz). Methods, results, and especially interpretations of these studies are quite variable. Although the use of low-frequency stimulation certainly opens new avenues in the field of deep brain stimulation, after having gathered all the available evidence in patients with subthalamic implants, our conclusion is that it might be clinically useful mainly when it lessens the detrimental effects of high-frequency stimulation. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

  5. Shaping pseudoneglect with transcranial cerebellar direct current stimulation and music listening

    Directory of Open Access Journals (Sweden)

    Silvia ePicazio

    2015-03-01

    Full Text Available Non-invasive brain stimulation modulates cortical excitability depending on the initial activation state of the structure being stimulated. Combination of cognitive with neurophysiological stimulations has been successfully employed to modulate responses of specific brain regions. The present research combined a neurophysiological pre-conditioning with a cognitive conditioning stimulation to modulate behavior. We applied this new state-dependency approach to investigate the cerebellar role in musical and spatial information processing, given that a link between musical perception and visuo-spatial abilities and a clear cerebellar involvement in music perception and visuo-spatial tasks have been reported. Cathodal, anodal or sham transcranial cerebellar Direct Current Stimulation (tcDCS pre-conditioning was applied on the left cerebellar hemisphere followed by conditioning stimulation through music or white noise listening in a sample of healthy subjects performing a Line Bisection Task (LBT. The combination of the cathodal stimulation with music listening resulted in a marked attentional shift toward the right hemispace, compensating thus the natural leftward bias of the baseline condition (pseudoneglect. Conversely, the anodal or sham pre-conditioning stimulations combined with either music and white noise conditioning listening did not modulate spatial attention. The efficacy of the combined stimulation (cathodal pre-conditioning and music conditioning and the absence of any effect of the single stimulations provide a strong support to the state-dependency theory. They propose that tcDCS in combination with music listening could act as a rehabilitative tool to improve cognitive functions in the presence of neglect or other spatial disorders.

  6. Shaping pseudoneglect with transcranial cerebellar direct current stimulation and music listening.

    Science.gov (United States)

    Picazio, Silvia; Granata, Chiara; Caltagirone, Carlo; Petrosini, Laura; Oliveri, Massimiliano

    2015-01-01

    Non-invasive brain stimulation modulates cortical excitability depending on the initial activation state of the structure being stimulated. Combination of cognitive with neurophysiological stimulations has been successfully employed to modulate responses of specific brain regions. The present research combined a neurophysiological pre-conditioning with a cognitive conditioning stimulation to modulate behavior. We applied this new state-dependency approach to investigate the cerebellar role in musical and spatial information processing, given that a link between musical perception and visuo-spatial abilities and a clear cerebellar involvement in music perception and visuo-spatial tasks have been reported. Cathodal, anodal or sham transcranial cerebellar Direct Current Stimulation (tcDCS) pre-conditioning was applied on the left cerebellar hemisphere followed by conditioning stimulation through music or white noise listening in a sample of healthy subjects performing a Line Bisection Task (LBT). The combination of the cathodal stimulation with music listening resulted in a marked attentional shift toward the right hemispace, compensating thus the natural leftward bias of the baseline condition (pseudoneglect). Conversely, the anodal or sham pre-conditioning stimulations combined with either music and white noise conditioning listening did not modulate spatial attention. The efficacy of the combined stimulation (cathodal pre-conditioning and music conditioning) and the absence of any effect of the single stimulations provide a strong support to the state-dependency theory. They propose that tcDCS in combination with music listening could act as a rehabilitative tool to improve cognitive functions in the presence of neglect or other spatial disorders.

  7. Prenatal music stimulation facilitates the postnatal functional ...

    Indian Academy of Sciences (India)

    2014-01-27

    Jan 27, 2014 ... two main groups: 1. Control – incubated without any auditory stimulation and. 2. Sitar music stimulated – incubated with slow and fast sitar music. Therefore, the experimental paradigm as described by. Jain et al. (2004) for the sound stimulation was followed. Briefly, first sounds of low to mid frequencies, i.e. ...

  8. Modeling and Field Results from Seismic Stimulation

    International Nuclear Information System (INIS)

    Majer, E.; Pride, S.; Lo, W.; Daley, T.; Nakagawa, Seiji; Sposito, Garrison; Roberts, P.

    2006-01-01

    Modeling the effect of seismic stimulation employing Maxwell-Boltzmann theory shows that the important component of stimulation is mechanical rather than fluid pressure effects. Modeling using Biot theory (two phases) shows that the pressure effects diffuse too quickly to be of practical significance. Field data from actual stimulation will be shown to compare to theory

  9. Geothermal Reservoir Well Stimulation Program: technology transfer

    Energy Technology Data Exchange (ETDEWEB)

    1980-05-01

    Each of the following types of well stimulation techniques are summarized and explained: hydraulic fracturing; thermal; mechanical, jetting, and drainhole drilling; explosive and implosive; and injection methods. Current stimulation techniques, stimulation techniques for geothermal wells, areas of needed investigation, and engineering calculations for various techniques. (MHR)

  10. A Chip for an Implantable Neural Stimulator

    DEFF Research Database (Denmark)

    Gudnason, Gunnar; Bruun, Erik; Haugland, Morten

    2000-01-01

    This paper describes a chip for a multichannel neural stimulator for functional electrical stimulation (FES). The purpose of FES is to restore muscular control in disabled patients. The chip performs all the signal processing required in an implanted neural stimulator. The power and digital data...

  11. Stimulation of the sensory pudendal nerve increases bladder capacity in the rat.

    Science.gov (United States)

    Hokanson, James A; Langdale, Christopher L; Sridhar, Arun; Grill, Warren M

    2018-04-01

    Pudendal nerve stimulation is a promising treatment approach for lower urinary tract dysfunction, including symptoms of overactive bladder. Despite some promising clinical studies, there remain many unknowns as to how best to stimulate the pudendal nerve to maximize therapeutic efficacy. We quantified changes in bladder capacity and voiding efficiency during single-fill cystometry in response to electrical stimulation of the sensory branch of the pudendal nerve in urethane-anesthetized female Wistar rats. Increases in bladder capacity were dependent on both stimulation amplitude and rate. Stimulation that produced increases in bladder capacity also led to reductions in voiding efficiency. Also, there was a stimulation carryover effect, and increases in bladder capacity persisted during several nonstimulated trials following stimulated trials. Intravesically administered PGE 2 reduced bladder capacity, producing a model of overactive bladder (OAB), and sensory pudendal nerve stimulation again increased bladder capacity but also reduced voiding efficiency. This study serves as a basis for future studies that seek to maximize the therapeutic efficacy of sensory pudendal nerve stimulation for the symptoms of OAB.

  12. Effect of Electrical Stimulation on Blood Flow Velocity and Vessel Size

    Science.gov (United States)

    Jin, Hee-Kyung; Hwang, Tae-Yeon; Cho, Sung-Hyoun

    2017-01-01

    Abstract Interferential current electrical stimulation alters blood flow velocity and vessel size. We aimed to investigate the changes in the autonomic nervous system depending on electrical stimulation parameters. Forty-five healthy adult male and female subjects were studied. Bipolar adhesive pad electrodes were used to stimulate the autonomic nervous system at the thoracic vertebrae 1-4 levels for 20 min. Using Doppler ultrasonography, blood flow was measured to determine velocity and vessel size before, immediately after, and 30 min after electrical stimulation. Changes in blood flow velocity were significantly different immediately and 30 min after stimulation. The interaction between intervention periods and groups was significantly different between the exercise and pain stimulation groups immediately after stimulation (p<0.05). The vessel size was significantly different before and 30 min after stimulation (p<0.05). Imbalances in the sympathetic nervous system, which regulates balance throughout the body, may present with various symptoms. Therefore, in the clinical practice, the parameters of electrical stimulation should be selectively applied in accordance with various conditions and changes in form. PMID:28401194

  13. Effect of Electrical Stimulation on Blood Flow Velocity and Vessel Size.

    Science.gov (United States)

    Jin, Hee-Kyung; Hwang, Tae-Yeon; Cho, Sung-Hyoun

    2017-01-01

    Interferential current electrical stimulation alters blood flow velocity and vessel size. We aimed to investigate the changes in the autonomic nervous system depending on electrical stimulation parameters. Forty-five healthy adult male and female subjects were studied. Bipolar adhesive pad electrodes were used to stimulate the autonomic nervous system at the thoracic vertebrae 1-4 levels for 20 min. Using Doppler ultrasonography, blood flow was measured to determine velocity and vessel size before, immediately after, and 30 min after electrical stimulation. Changes in blood flow velocity were significantly different immediately and 30 min after stimulation. The interaction between intervention periods and groups was significantly different between the exercise and pain stimulation groups immediately after stimulation (p<0.05). The vessel size was significantly different before and 30 min after stimulation (p<0.05). Imbalances in the sympathetic nervous system, which regulates balance throughout the body, may present with various symptoms. Therefore, in the clinical practice, the parameters of electrical stimulation should be selectively applied in accordance with various conditions and changes in form.

  14. Stimulated-emission effects in particle creation near black holes

    Energy Technology Data Exchange (ETDEWEB)

    Wald, R.M.

    1976-06-15

    It has recently been shown that if a black hole is formed by gravitational collapse, spontaneous particle creation will occur and a thermal spectrum of all species of particles will be emitted to infinity if the quantum matter was initially in the vacuum state. In this paper we investigate the stimulated-emission effects which occur if particles are present initially. We show in general that for a Hermitian scalar field in an external potential or in curved, asymptotically flat spacetime, stimulated-emission effects can occur precisely in those modes for which there is spontaneous particle creation from the vacuum. For the case of a Schwarzschild black hole, this result appears paradoxical, since spontaneous emission occurs at late times but there is no classical analog of stimulated emission at late times. The resolution of this paradox is that in order to induce emission of particles which emerge at late times one must send in particles at early times, so that they reach the black hole very near the instant of its formation. However, enormous energy is required of these incoming particles in order to stimulate emission of particles which emerge at late times. Thus, for a Schwarzschild black hole, even if particles are initially present (with limited energy) they will induce emission only at early times; at late times one will see only the spontaneously emitted blackbody thermal radiation. For the case of a Kerr black hole stimulated emission can be induced by particles sent in at late times with the appropriate frequencies and angular dependence. If the number of incoming particles is large, this quantum stimulated emission just gives the classical superradiant scattering. (AIP)

  15. Stimulated-emission effects in particle creation near black holes

    International Nuclear Information System (INIS)

    Wald, R.M.

    1976-01-01

    It has recently been shown that if a black hole is formed by gravitational collapse, spontaneous particle creation will occur and a thermal spectrum of all species of particles will be emitted to infinity if the quantum matter was initially in the vacuum state. In this paper we investigate the stimulated-emission effects which occur if particles are present initially. We show in general that for a Hermitian scalar field in an external potential or in curved, asymptotically flat spacetime, stimulated-emission effects can occur precisely in those modes for which there is spontaneous particle creation from the vacuum. For the case of a Schwarzschild black hole, this result appears paradoxical, since spontaneous emission occurs at late times but there is no classical analog of stimulated emission at late times. The resolution of this paradox is that in order to induce emission of particles which emerge at late times one must send in particles at early times, so that they reach the black hole very near the instant of its formation. However, enormous energy is required of these incoming particles in order to stimulate emission of particles which emerge at late times. Thus, for a Schwarzschild black hole, even if particles are initially present (with limited energy) they will induce emission only at early times; at late times one will see only the spontaneously emitted blackbody thermal radiation. For the case of a Kerr black hole stimulated emission can be induced by particles sent in at late times with the appropriate frequencies and angular dependence. If the number of incoming particles is large, this quantum stimulated emission just gives the classical superradiant scattering

  16. Stimulant treatment for attention-deficit hyperactivity disorder and risk of developing substance use disorder

    NARCIS (Netherlands)

    Groenman, A.P.; Oosterlaan, J.; Rommelse, N.N.J.; Franke, B.; Greven, C.U.; Hoekstra, P.J.; Hartman, C.A.; Luman, M.; Roeyers, H.; Oades, R.D.; Sergeant, J.A.; Buitelaar, J.K.; Faraone, S.V.

    2013-01-01

    BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. AIMS: To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD

  17. Stimulant treatment for attention-deficit hyperactivity disorder and risk of developing substance use disorder

    NARCIS (Netherlands)

    Groenman, Annabeth P.; Oosterlaan, Jaap; Rommelse, Nanda N. J.; Franke, Barbara; Greven, Corina U.; Hoekstra, Pieter J.; Hartman, Catharina A.; Luman, Marjolein; Roeyers, Herbert; Oades, Robert D.; Sergeant, Joseph A.; Buitelaar, Jan K.; Faraone, Stephen V.

    Background Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. Aims To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD

  18. Stimulant treatment for attention-deficit hyperactivity disorder and risk of developing substance use disorder.

    NARCIS (Netherlands)

    Groenman, A.P.; Oosterlaan, J.; Rommelse, N.; Franke, B.; Greven, C.U.; Hoekstra, P.J.; Hartman, C.A.; Luman, M.; Roeyers, H.; Oades, R.D.; Sergeant, J.A.; Buitelaar, J.K.; Faraone, S.V.

    2013-01-01

    Background: Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence. Aims: To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD

  19. Chemical dependence - resources

    Science.gov (United States)

    Substance use - resources, Drug abuse - resources; Resources - chemical dependence ... organizations are a good resource for information on drug dependence: National Council on Alcoholism and Drug Dependence -- ncadd. ...

  20. Thermally stimulated scattering in plasmas

    DEFF Research Database (Denmark)

    Dysthe, K. B.; Mjølhus, E.; Pécseli, H. L.

    1985-01-01

    this experiment local heat conduction is of little importance and the dynamic evolution for the electron temperature is dominated by heating and energy exchange with the ion component. These features are incorporated in the analysis. The resulting set of equations gives a growth rate and characteristic scale size......A theory for stimulated scattering of a laser beam is formulated where the dominant nonlinearity is the ohmic heating of the plasma. The analysis is carried out with particular reference to experimental investigations of CO2 laser heating of linear discharge plasma. In the conditions characterizing...

  1. Optical stimulator for vision-based sensors

    DEFF Research Database (Denmark)

    Rössler, Dirk; Pedersen, David Arge Klevang; Benn, Mathias

    2014-01-01

    stimulator is used as a test bench to simulate high-precision navigation by different types of camera systems that are used onboard spacecraft, planetary rovers, and for spacecraft rendezvous and proximity maneuvers. Careful hardware design and preoperational calibration of the stimulator result in high......We have developed an optical stimulator system for vision-based sensors. The stimulator is an efficient tool for stimulating a camera during on-ground testing with scenes representative of spacecraft flights. Such scenes include starry sky, planetary objects, and other spacecraft. The optical...... precision and long-term stability. The system can be continuously used over several days. By facilitating a full camera including optics in the loop, the stimulator enables the more realistic simulation of flight maneuvers based on navigation cameras than pure computer simulations or camera stimulations...

  2. Wortmannin inhibits both insulin- and contraction-stimulated glucose uptake and transport in rat skeletal muscle

    DEFF Research Database (Denmark)

    Wojtaszewski, Jørgen; Hansen, B F; Ursø, Birgitte

    1996-01-01

    stimulation but was unaffected by contractions. In addition, the insulin-stimulated PI 3-kinase activity and muscle glucose uptake and transport in individual muscles were dose-dependently inhibited by wortmannin with one-half maximal inhibition values of approximately 10 nM and total inhibition at 1 micro......The role of phosphatidylinositol (PI) 3-kinase for insulin- and contraction-stimulated muscle glucose transport was investigated in rat skeletal muscle perfused with a cell-free perfusate. The insulin receptor substrate-1-associated PI 3-kinase activity was increased sixfold upon insulin......-stimulated glucose uptake but also decreased the contractility. In conclusion, inhibition of PI 3-kinase with wortmannin in skeletal muscle coincides with inhibition of insulin-stimulated glucose uptake and transport. Furthermore, in contrast to recent findings in incubated muscle, wortmannin also inhibited...

  3. Brain stimulation-induced neuroplasticity underlying therapeutic response in phantom sounds.

    Science.gov (United States)

    Poeppl, Timm B; Langguth, Berthold; Lehner, Astrid; Frodl, Thomas; Rupprecht, Rainer; Kreuzer, Peter M; Landgrebe, Michael; Schecklmann, Martin

    2018-01-01

    Noninvasive brain stimulation can modify phantom sounds for longer periods by modulating neural activity and putatively inducing regional neuroplastic changes. However, treatment response is limited and there are no good demographic or clinical predictors for treatment outcome. We used state-of-the-art voxel-based morphometry (VBM) to investigate whether transcranial magnetic stimulation-induced neuroplasticity determines therapeutic outcome. Sixty subjects chronically experiencing phantom sounds (i.e., tinnitus) received repetitive transcranial magnetic stimulation (rTMS) of left dorsolateral prefrontal and temporal cortex according to a protocol that has been shown to yield a significantly higher number of treatment responders than sham stimulation and previous stimulation protocols. Structural magnetic resonance imaging was performed before and after rTMS. In VBM whole-brain analyses (P neuroplastic capabilities. The latter in turn may depend on (differences in) their individual structural connectivity. Hum Brain Mapp 39:554-562, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  4. Blue light emitting diodes for optical stimulation of quartz in retrospective dosimetry and dating

    DEFF Research Database (Denmark)

    Bøtter-Jensen, L.; Duller, G.A.T.; Murray, A.S.

    1999-01-01

    Recently developed blue light emitting diodes (LEDs) for the optical stimulation of quartz for use in routine optically stimulated luminescence (OSL) dating and retrospective dosimetry have been tested. For similar power densities, it was found that the higher energy light provided by the blue LEDs...... (470 nm) gives order of magnitude greater rate of stimulation in quartz than that from conventional blue-green light filtered from a halogen lamp. A practical blue LED OSL configuration is described. From comparisons of OSL decay curves produced by green and blue light sources, and by examination...... of the dependence of the blue LED OSL on preheat temperature, it is deduced that there is no evidence that the blue LEDs stimulate deep traps in a different manner from broadband filtered light. It is concluded that blue LEDs offer a practical alternative to existing stimulation sources. They have the significant...

  5. Cortical deactivation induced by visual stimulation in human slow-wave sleep

    DEFF Research Database (Denmark)

    Born, Alfred Peter; Law, Ian; Lund, Torben E

    2002-01-01

    It has previously been demonstrated that sleeping and sedated young children respond with a paradoxical decrease in the blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal in the rostro-medial occipital visual cortex during visual stimulation...... visual stimulation in spontaneously sleeping adult volunteers. In five sleeping volunteers fMRI studies confirmed a robust signal decrease during stimulation in the rostro-medial occipital cortex. A similar relative decrease at the same location was found during visual stimulation...... and polysomnographically verified slow-wave sleep in a separate group of six subjects using H(2)(15)O PET measures of the regional cerebral blood flow (rCBF). This decrease was more rostro-dorsal compared to the relative rCBF increase along the calcarine sulcus found during visual stimulation in the awake state...

  6. Unilateral phrenic nerve stimulation for neurogenic hypoventilation in Arnold Chiari malformation

    Directory of Open Access Journals (Sweden)

    Nitin Garg

    2013-01-01

    Full Text Available Long- term ventilator dependence in patients with neurogenic hypoventilation is associated with significant morbidity and restricts mobility. Diaphragmatic pacing by phrenic nerve stimulation (PNS is a viable alternative. This is a case report of patient with Arnold-Chiari malformation with extensive syrinx who had neurogenic hypoventilation during sleep even after foramen magnum decompression and resolution of the syrinx. Unilateral PNS was done using spinal cord stimulator. With intermittent stimulation for 8 h while asleep, patient could be weaned off the ventilator completely. At 2 years follow- up, patient is ambulant and has returned to his routine activities. PNS is a good treatment tool in patients with neurogenic hypoventilation. Spinal cord stimulator can be used with optimal results. This is first such reported case of using spinal cord stimulator for PNS from India.

  7. Therapeutic electrical stimulation of injured peripheral nerve tissue using implantable thin-film wireless nerve stimulators.

    Science.gov (United States)

    MacEwan, Matthew R; Gamble, Paul; Stephen, Manu; Ray, Wilson Z

    2018-02-09

    OBJECTIVE Electrical stimulation of peripheral nerve tissue has been shown to accelerate axonal regeneration. Yet existing methods of applying electrical stimulation to injured peripheral nerves have presented significant barriers to clinical translation. In this study, the authors examined the use of a novel implantable wireless nerve stimulator capable of simultaneously delivering therapeutic electrical stimulation of injured peripheral nerve tissue and providing postoperative serial assessment of functional recovery. METHODS Flexible wireless stimulators were fabricated and implanted into Lewis rats. Thin-film implants were used to deliver brief electrical stimulation (1 hour, 20 Hz) to sciatic nerves after nerve crush or nerve transection-and-repair injuries. RESULTS Electrical stimulation of injured nerves via implanted wireless stimulators significantly improved functional recovery. Brief electrical stimulation was observed to increase the rate of functional recovery after both nerve crush and nerve transection-and-repair injuries. Wireless stimulators successfully facilitated therapeutic stimulation of peripheral nerve tissue and serial assessment of nerve recovery. CONCLUSIONS Implantable wireless stimulators can deliver therapeutic electrical stimulation to injured peripheral nerve tissue. Implantable wireless nerve stimulators might represent a novel means of facilitating therapeutic electrical stimulation in both intraoperative and postoperative settings.

  8. Testosterone suppression of CRH-stimulated cortisol in men.

    Science.gov (United States)

    Rubinow, David R; Roca, Catherine A; Schmidt, Peter J; Danaceau, Merry A; Putnam, Karen; Cizza, Giovanni; Chrousos, George; Nieman, Lynnette

    2005-10-01

    Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18-45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (pcortisol area under the curve was lower at a trend level (pcortisol : ACTH ratio, a measure of adrenal sensitivity, was lower during testosterone replacement (pcortisol. These data demonstrate that testosterone regulates CRH-stimulated HPA axis activity in men, with the divergent effects on ACTH and cortisol suggesting a peripheral (adrenal) locus for the suppressive effects on cortisol. Our results further demonstrate that the enhanced stimulated HPA axis activity previously described in young men compared with young women cannot be ascribed to an activational upregulation of the axis by testosterone.

  9. Transcranial focused ultrasound stimulation of human primary visual cortex

    Science.gov (United States)

    Lee, Wonhye; Kim, Hyun-Chul; Jung, Yujin; Chung, Yong An; Song, In-Uk; Lee, Jong-Hwan; Yoo, Seung-Schik

    2016-09-01

    Transcranial focused ultrasound (FUS) is making progress as a new non-invasive mode of regional brain stimulation. Current evidence of FUS-mediated neurostimulation for humans has been limited to the observation of subjective sensory manifestations and electrophysiological responses, thus warranting the identification of stimulated brain regions. Here, we report FUS sonication of the primary visual cortex (V1) in humans, resulting in elicited activation not only from the sonicated brain area, but also from the network of regions involved in visual and higher-order cognitive processes (as revealed by simultaneous acquisition of blood-oxygenation-level-dependent functional magnetic resonance imaging). Accompanying phosphene perception was also reported. The electroencephalo graphic (EEG) responses showed distinct peaks associated with the stimulation. None of the participants showed any adverse effects from the sonication based on neuroimaging and neurological examinations. Retrospective numerical simulation of the acoustic profile showed the presence of individual variability in terms of the location and intensity of the acoustic focus. With exquisite spatial selectivity and capability for depth penetration, FUS may confer a unique utility in providing non-invasive stimulation of region-specific brain circuits for neuroscientific and therapeutic applications.

  10. Photovoltaic Pixels for Neural Stimulation: Circuit Models and Performance.

    Science.gov (United States)

    Boinagrov, David; Lei, Xin; Goetz, Georges; Kamins, Theodore I; Mathieson, Keith; Galambos, Ludwig; Harris, James S; Palanker, Daniel

    2016-02-01

    Photovoltaic conversion of pulsed light into pulsed electric current enables optically-activated neural stimulation with miniature wireless implants. In photovoltaic retinal prostheses, patterns of near-infrared light projected from video goggles onto subretinal arrays of photovoltaic pixels are converted into patterns of current to stimulate the inner retinal neurons. We describe a model of these devices and evaluate the performance of photovoltaic circuits, including the electrode-electrolyte interface. Characteristics of the electrodes measured in saline with various voltages, pulse durations, and polarities were modeled as voltage-dependent capacitances and Faradaic resistances. The resulting mathematical model of the circuit yielded dynamics of the electric current generated by the photovoltaic pixels illuminated by pulsed light. Voltages measured in saline with a pipette electrode above the pixel closely matched results of the model. Using the circuit model, our pixel design was optimized for maximum charge injection under various lighting conditions and for different stimulation thresholds. To speed discharge of the electrodes between the pulses of light, a shunt resistor was introduced and optimized for high frequency stimulation.

  11. Braille line using electrical stimulation

    International Nuclear Information System (INIS)

    Puertas, A; Pures, P; Echenique, A M; Ensinck, J P Graffigna y G

    2007-01-01

    Conceived within the field of Rehabilitation Technologies for visually impaired persons, the present work aims at enabling the blind user to read written material by means of a tactile display. Once he is familiarized to operate this system, the user will be able to achieve greater performance in study, academic and job activities, thus achieving a rapid and easier social inclusion. The devise accepts any kind of text that is computer-loadable (documents, books, Internet information, and the like) which, through digital means, can be read as Braille text on the pad. This tactile display is composed of an electrodes platform that simulate, through stimulation the writing/reading Braille characters. In order to perceive said characters in similar way to the tactile feeling from paper material, the skin receptor of fingers are stimulated electrically so as to simulate the same pressure and depressions as those of the paper-based counterpart information. Once designed and developed, the display was tested with blind subjects, with relatively satisfactory results. As a continuing project, this prototype is currently being improved as regards

  12. Further investigations into pulsed optically stimulated luminescence from feldspars using blue and green light

    International Nuclear Information System (INIS)

    Ankjaergaard, C.; Jain, M.; Kalchgruber, R.; Lapp, T.; Klein, D.; McKeever, S.W.S.; Murray, A.S.; Morthekai, P.

    2009-01-01

    The purpose of this paper is to investigate characteristics of luminescence signals resulting from pulsed optical stimulation of feldspars and thereby to understand the underlying processes giving rise to the signal. Fourteen different feldspar specimens were investigated using time-resolved optically stimulated luminescence (TR-OSL), and these signals can be mathematically described as a sum of 4 exponential components (a, b, c, d). The slowest component, d, increases with the duration of the light pulse as expected from the exponential model. The stimulation temperature dependence experiment suggests that the TR-OSL signal decay is governed by the recombination process and not by the excited state lifetime. Furthermore data from the TR-OSL signal dependence on stimulation time and preheat temperature suggest that the recombination process may not be a sum of exponentials, although the model cannot be rejected definitively.

  13. Introducing transcranial magnetic stimulation (TMS) and its property of causal inference in investigating brain-function relationships

    NARCIS (Netherlands)

    Schutter, D.J.L.G.; Honk, E.J. van; Panksepp, J.

    2004-01-01

    Transcranial magnetic stimulation (TMS) is a method capable of transiently modulating neural excitability. Depending on the stimulation parameters information processing in the brain can be either enhanced or disrupted. This way the contribution of different brain areas involved in mental processes

  14. Sweet Taste Receptor Activation in the Gut Is of Limited Importance for Glucose-Stimulated GLP-1 and GIP Secretion

    DEFF Research Database (Denmark)

    Saltiel, Monika Yosifova; Kuhre, Rune Ehrenreich; Christiansen, Charlotte Bayer

    2017-01-01

    Glucose stimulates the secretion of the incretin hormones: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). It is debated whether the sweet taste receptor (STR) triggers this secretion. We investigated the role of STR activation for glucose-stimulated incretin...

  15. Slow-oscillatory transcranial direct current stimulation can induce bidirectional shifts in motor cortical excitability in awake humans

    DEFF Research Database (Denmark)

    Groppa, S; Bergmann, T O; Siems, C

    2010-01-01

    Constant transcranial direct stimulation (c-tDCS) of the primary motor hand area (M1(HAND)) can induce bidirectional shifts in motor cortical excitability depending on the polarity of tDCS. Recently, anodal slow oscillation stimulation at a frequency of 0.75 Hz has been shown to augment intrinsic...

  16. Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights

    Science.gov (United States)

    Williams, John C.; Entcheva, Emilia

    2015-01-01

    Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current—a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation

  17. The use of prescription stimulants to enhance academic performance among college students in health care programs.

    Science.gov (United States)

    Herman, Lawrence; Shtayermman, Oren; Aksnes, Brittany; Anzalone, Michelle; Cormerais, Andre; Liodice, Christina

    2011-01-01

    Prescription stimulant use as academic performance enhancers is increasingly widespread among college students. The purpose of this study was to evaluate the prevalence of prescription stimulant use among health care students attending a university in the northeastern United States. The study investigated the specific stimulants being used and the frequency of usage. It also examined the rates of nicotine, alcohol, and drug abuse versus dependence. A web-based survey was administered to medical and health profession students regarding prescription stimulant use for nonprescribed purposes. Tobacco, alcohol, and recreational drug use were also surveyed. Approximately 10.4% (32) of students surveyed have either used a stimulant or are currently using prescription stimulants illegally. The most common reason for stimulant use was to focus and concentrate during studying (93.5%). Of the 308 students, 45.2% were female, 83.9% were Caucasian, and amphetamine-dextroamphetamine was the most commonly abused stimulant (71.4%). Results from this study are consistent with previous research of undergraduate students regarding prescription stimulant use for nonprescribed purposes, specifically for academic performance enhancement. Data from the study support that alcohol abuse and dependence among students is a pertinent concern, suggesting that substance abuse in general must be addressed. Substance abuse and awareness programs combined with stress management programs in an overall substance-abuse reduction strategy, including the use of prescription stimulant use beyond the originally intended purpose, may be beneficial. Because of the lack of research focusing on graduate health care students, further investigations should use similar populations.

  18. Attention-deficit hyperactivity disorder (ADHD stimulant medications as cognitive enhancers

    Directory of Open Access Journals (Sweden)

    Claire Diane Advokat

    2013-05-01

    Full Text Available Recent increases in ADHD diagnoses, and the escalation of stimulant prescriptions, have raised concern about diversion and abuse of stimulants, as well as the ethics of using these drugs as ‘cognitive enhancers.’ Such concern appears misplaced in the face of substantial evidence that stimulant drugs do not improve the academic performance of ADHD-diagnosed students. Moreover, numerous studies have found little or no benefit of stimulants on neuropsychological tests of ADHD-diagnosed as well as normal, individuals. This paper examines the apparent paradox: why don’t drugs that improve ‘attention,’ produce better academic outcomes in ADHD-diagnosed students? We found that stimulant drugs significantly improved impairment of episodic memory in ADHD-diagnosed undergraduate students. Nevertheless, we also found consistent academic deficits between ADHD students and their nonADHD counterparts, regardless of whether or not they used stimulant medications. We reviewed the current literature on the behavioral effects of stimulants, to try to find an explanation for these conflicting phenomena. Across a variety of behavioral tasks, stimulants have been shown to reduce emotional reactions to frustration, improve the ability to detect errors, and increase effortful behavior. However, all of these effects would presumably enhance academic performance. On the other hand, the drugs were also found to promote ‘risky behavior’ and to increase susceptibility to environmental distraction. Such negative effects, including the use of drugs to promote wakefulness for last minute study, might explain the lack of academic benefit in the ‘real world,’ despite their cognitive potential. Like many drugs, stimulants influence behavior in multiple ways, depending on the environmental contingencies. Depending on the circumstances, stimulants may, or may not, enhance cognition.

  19. Low temperature stimulates alpha-melanophore-stimulating hormone secretion and inhibits background adaptation in Xenopus laevis.

    Science.gov (United States)

    Tonosaki, Y; Cruijsen, P M J M; Nishiyama, K; Yaginuma, H; Roubos, E W

    2004-11-01

    It is well-known that alpha-melanophore-stimulating hormone (alpha-MSH) release from the amphibian pars intermedia (PI) depends on the light condition of the animal's background, permitting the animal to adapt the colour of its skin to background light intensity. In the present study, we carried out nine experiments on the effect of low temperature on this skin adaptation process in the toad Xenopus laevis, using the skin melanophore index (MI) bioassay and a radioimmunoassay to measure skin colour adaptation and alpha-MSH secretion, respectively. We show that temperatures below 8 degrees C stimulate alpha-MSH secretion and skin darkening, with a maximum at 5 degrees C, independent of the illumination state of the background. No significant stimulatory effect of low temperature on the MI and alpha-MSH plasma contents was noted when the experiment was repeated with toads from which the neurointermediate lobe (NIL) had been surgically extirpated. This indicates that low temperature stimulates alpha-MSH release from melanotrope cells located in the PI. An in vitro superfusion study with the NIL demonstrated that low temperature does not act directly on the PI. A possible role of the central nervous system in cold-induced alpha-MSH release from the PI was tested by studying the hypothalamic expression of c-Fos (as an indicator for neuronal activity) and the coexistence of c-Fos with the regulators of melanotrope cell activity, neuropeptide Y (NPY) and thyrotrophin-releasing hormone (TRH), using double fluorescence immunocytochemistry. Upon lowering temperature from 22 degrees C to 5 degrees C, in white-adapted animals c-Fos expression decreased in NPY-producing suprachiasmatic-melanotrope-inhibiting neurones (SMIN) in the ventrolateral area of the suprachiasmatic nucleus (SC) but increased in TRH-containing neurones of the magnocellular nucleus. TRH is known to stimulate melanotrope alpha-MSH release. We conclude that temperatures around 5 degrees C inactivate the SMIN

  20. Referred pain and cutaneous responses from deep tissue electrical pain stimulation in the groin

    DEFF Research Database (Denmark)

    Aasvang, E K; Werner, M U; Kehlet, H

    2015-01-01

    outside the stimulation area was reported, with 90-100% having the same response on both days, depending on the location. Deep pain stimulation significantly increased the cutaneous HPT (P...>0.474, P≤0.040) at the two test days for the majority of test areas. CONCLUSION: Our results corroborate a systematic relationship between deep pain and changes in cutaneous nociception. The individual referred/projected pain patterns and cutaneous responses are variable, but reproducible...

  1. Magnetic-motor-root stimulation: review.

    Science.gov (United States)

    Matsumoto, Hideyuki; Hanajima, Ritsuko; Terao, Yasuo; Ugawa, Yoshikazu

    2013-06-01

    Magnetic stimulation can activate the human central and peripheral nervous systems non-invasively and virtually painlessly. Magnetic stimulation over the spinal enlargements can activate spinal nerves at the neuroforamina (magnetic-neuroforamina stimulation). This stimulation method provides us with information related to the latency of compound-muscle action potential (CMAP), which is usually interpreted as peripheral motor-conduction time (PMCT). However, this stimulation method has faced several problems in clinical applications. One is that supramaximal CMAPs were unobtainable. Another is that magnetic stimulation did not usually activate the spinal nerves in the spinal canal, i.e., the cauda equina, which prevented an evaluation of its conduction. For these reasons, magnetic-neuroforamina stimulation was rarely used to evaluate the conduction of peripheral nerves. It was mainly used to evaluate the conduction of the corticospinal tract using the parameter of central motor-conduction time (CMCT), which was calculated by subtracting PMCT from the latency of motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex. Recently, supramaximal stimulation has been achieved in magnetic-neuroforamina stimulation, and this has contributed to the measurement of both CMAP size and latency. The achievement of supramaximal stimulation is ascribed to the increase in magnetic-stimulator output and a novel coil, the magnetic augmented translumbosacral stimulation (MATS) coil. The most proximal part of the cauda equina can be reliably activated using the MATS coil (magnetic-conus stimulation), thus contributing to the measurement of cauda equina conduction time (CECT) and cortico-conus motor-conduction time (CCCT). These recent developments in magnetic-motor-root stimulation enable us to more precisely evaluate the conduction of the proximal part of peripheral nerves and that of the corticospinal tract for lower-limb muscles

  2. Noisy galvanic vestibular stimulation modulates the amplitude of EEG synchrony patterns.

    Directory of Open Access Journals (Sweden)

    Diana J Kim

    Full Text Available Noisy galvanic vestibular stimulation has been associated with numerous cognitive and behavioural effects, such as enhancement of visual memory in healthy individuals, improvement of visual deficits in stroke patients, as well as possibly improvement of motor function in Parkinson's disease; yet, the mechanism of action is unclear. Since Parkinson's and other neuropsychiatric diseases are characterized by maladaptive dynamics of brain rhythms, we investigated whether noisy galvanic vestibular stimulation was associated with measurable changes in EEG oscillatory rhythms within theta (4-7.5 Hz, low alpha (8-10 Hz, high alpha (10.5-12 Hz, beta (13-30 Hz and gamma (31-50 Hz bands. We recorded the EEG while simultaneously delivering noisy bilateral, bipolar stimulation at varying intensities of imperceptible currents - at 10, 26, 42, 58, 74 and 90% of sensory threshold - to ten neurologically healthy subjects. Using standard spectral analysis, we investigated the transient aftereffects of noisy stimulation on rhythms. Subsequently, using robust artifact rejection techniques and the Least Absolute Shrinkage Selection Operator regression and cross-validation, we assessed the combinations of channels and power spectral features within each EEG frequency band that were linearly related with stimulus intensity. We show that noisy galvanic vestibular stimulation predominantly leads to a mild suppression of gamma power in lateral regions immediately after stimulation, followed by delayed increase in beta and gamma power in frontal regions approximately 20-25 s after stimulation ceased. Ongoing changes in the power of each oscillatory band throughout frontal, central/parietal, occipital and bilateral electrodes predicted the intensity of galvanic vestibular stimulation in a stimulus-dependent manner, demonstrating linear effects of stimulation on brain rhythms. We propose that modulation of neural oscillations is a potential mechanism for the previously

  3. Deep brain stimulation suppresses pallidal low frequency activity in patients with phasic dystonic movements.

    Science.gov (United States)

    Barow, Ewgenia; Neumann, Wolf-Julian; Brücke, Christof; Huebl, Julius; Horn, Andreas; Brown, Peter; Krauss, Joachim K; Schneider, Gerd-Helge; Kühn, Andrea A

    2014-11-01

    Deep brain stimulation of the globus pallidus internus alleviates involuntary movements in patients with dystonia. However, the mechanism is still not entirely understood. One hypothesis is that deep brain stimulation suppresses abnormally enhanced synchronized oscillatory activity within the motor cortico-basal ganglia network. Here, we explore deep brain stimulation-induced modulation of pathological low frequency (4-12 Hz) pallidal activity that has been described in local field potential recordings in patients with dystonia. Therefore, local field potentials were recorded from 16 hemispheres in 12 patients undergoing deep brain stimulation for severe dystonia using a specially designed amplifier allowing simultaneous high frequency stimulation at therapeutic parameter settings and local field potential recordings. For coherence analysis electroencephalographic activity (EEG) over motor areas and electromyographic activity (EMG) from affected neck muscles were recorded before and immediately after cessation of high frequency stimulation. High frequency stimulation led to a significant reduction of mean power in the 4-12 Hz band by 24.8 ± 7.0% in patients with predominantly phasic dystonia. A significant decrease of coherence between cortical EEG and pallidal local field potential activity in the 4-12 Hz range was revealed for the time period of 30 s after switching off high frequency stimulation. Coherence between EMG activity and pallidal activity was mainly found in patients with phasic dystonic movements where it was suppressed after high frequency stimulation. Our findings suggest that high frequency stimulation may suppress pathologically enhanced low frequency activity in patients with phasic dystonia. These dystonic features are the quickest to respond to high frequency stimulation and may thus directly relate to modulation of pathological basal ganglia activity, whereas improvement in tonic features may depend on long-term plastic changes within the

  4. Socioeconomic evaluation of vagus stimulation

    DEFF Research Database (Denmark)

    Jennum, Poul; Sabers, Anne; Christensen, Jakob

    2016-01-01

    PURPOSE: We aimed to determine the health costs and social outcomes in terms of education, employment and income level after insertion of a vagus nerve stimulator (VNS) in patients with epilepsy. METHODS: This is a case-control study using Danish health care and socioeconomic register data....... The analysis of the effect involved a comparison of the health care costs, occupation and income status of VNS-treated epilepsy patients with those of a control group of epilepsy patients who had a VNS implanted during the 12 months before the index date (pre-period) and during the two years after the index...... implantation. VNS implantation was not associated with changes in occupational status (including employment and income). In fact, the number of people on disability pension increased during the period. CONCLUSIONS: VNS implantation in people with epilepsy is associated with reduced health care use...

  5. Multisensory stimulation in stroke rehabilitation

    Directory of Open Access Journals (Sweden)

    Barbro Birgitta Johansson

    2012-04-01

    Full Text Available The brain has a large capacity for automatic simultaneous processing and integration of sensory information. Combining information from different sensory modalities facilitates our ability to detect, discriminate, and recognize sensory stimuli, and learning is often optimal in a multisensory environment. Currently used multisensory stimulation methods in stroke rehabilitation include motor imagery, action observation, training with a mirror or in a virtual environment, or various kinds of music therapy. Several studies have shown positive effects been reported but to give general recommendation more studies are needed. Patient heterogeneity and the interactions of age, gender, genes and environment are discussed. Randomized controlled longitudinal trials starting earlier post stroke are needed. The advance in brain network science and neuroimaging enabling longitudinal studies of structural and functional networks are likely to have an important impact on patient selection for specific interventions in future stroke rehabilitation.

  6. Effect of anatomical variability in brain on transcranial magnetic stimulation treatment

    Science.gov (United States)

    Syeda, F.; Magsood, H.; Lee, E. G.; El-Gendy, A. A.; Jiles, D. C.; Hadimani, R. L.

    2017-05-01

    Transcranial Magnetic Stimulation is a non-invasive clinical therapy used to treat depression and migraine, and shows further promise as treatment for Parkinson's disease, Alzheimer's disease, and other neurological disorders. However, it is yet unclear as to how anatomical differences may affect stimulation from this treatment. We use finite element analysis to model and analyze the results of Transcranial Magnetic Stimulation in various head models. A number of heterogeneous head models have been developed using MRI data of real patients, including healthy individuals as well as patients of Parkinson's disease. Simulations of Transcranial Magnetic Stimulation performed on 22 anatomically different models highlight the differences in induced stimulation. A standard Figure of 8 coil is used with frequency 2.5 kHz, placed 5 mm above the head. We compare cortical stimulation, volume of brain tissue stimulated, specificity, and maximum E-field induced in the brain for models ranging from ages 20 to 60. Results show that stimulation varies drastically between patients of the same age and health status depending upon brain-scalp distance, which is not necessarily a linear progression with age.

  7. Coordinated reset stimulation in a large-scale model of the STN-GPe circuit

    Directory of Open Access Journals (Sweden)

    Martin eEbert

    2014-11-01

    Full Text Available Synchronization of populations of neurons is a hallmark of several brain diseases. Coordinated reset (CR stimulation is a model-based stimulation technique which specifically counteracts abnormal synchrony by desynchronization. Electrical CR stimulation, e.g. for the treatment of Parkinson’s disease (PD, is administered via depth electrodes. In order to get a deeper understanding of this technique, we extended the top-down approach of previous studies and constructed a large-scale computational model of the respective brain areas. Furthermore, we took into account the spatial anatomical properties of the simulated brain structures and incor- porated a detailed numerical representation of 2·104 simulated neurons. We simulated the subthalamic nucleus (STN and the globus pallidus externus (GPe. Connections within the STN were governed by spike-timing dependent plasticity (STDP. In this way, we modeled the physiological and pathological activity of the considered brain structures. In particular, we investigated how plasticity could be exploited and how the model could be shifted from strongly synchronized (pathological activity to strongly desynchronized (healthy activity of the neuronal populations via CR stimulation of the STN neurons. Furthermore, we investigated the impact of specific stimulation parameters especially the electrode position on the stimulation outcome. Our model provides a step forward towards a biophysically realistic model of the brain areas relevant to the emergence of pathological neuronal activity in PD. Furthermore, our model constitutes a test bench for the optimization of both stimulation parameters and novel electrode geometries for efficient CR stimulation.

  8. The effect of music and multimodal stimulation on responses of premature infants in neonatal intensive care.

    Science.gov (United States)

    Standley, J M

    1998-01-01

    To assess the benefits of lullaby singing and multimodal stimulation on premature infants in neonatal intensive care, 40 infants in a Level III Newborn Intermediate Care Unit were divided into control (n = 20) and experimental (n = 20) groups by pair matching on the basis of gender, birthweight, gestational age at birth and severity of medical complications. Participants met these project criteria: (a) corrected gestational age > 32 weeks; (b) age since birth > 10 days; and (c) weight > 1700 g. All participants had been referred for developmental stimulation by the medical staff. Experimental infants received reciprocal, multimodal (ATVV) stimulation paired with line singing of Brahms' Lullaby. Stimulation was provided for 15-30 minutes, one or two times per week from referral to discharge. Dependent variables were (a) days to discharge, (b) weight gain/day, and (c) experimental infants' tolerance for stimulation. Results showed that music and multimodal stimulation significantly benefited females' days to discharge and increased weight gain/day for both males and females. Both male and female infants' tolerance for stimulation showed marked and steady increase across the stimulation intervals with females' tolerance increasing more rapidly than males.

  9. Effect of Tactile Stimulation on Termination and Prevention of Apnea of Prematurity: A Systematic Review.

    Science.gov (United States)

    Cramer, Sophie J E; Dekker, Janneke; Dankelman, Jenny; Pauws, Steffen C; Hooper, Stuart B; Te Pas, Arjan B

    2018-01-01

    Apnea of prematurity (AOP) is one of the most common diagnoses in preterm infants. Severe and recurrent apneas are associated with cerebral injury and adverse neurodevelopmental outcome. Despite pharmacotherapy and respiratory support to prevent apneas, a proportion of infants continue to have apneas and often need tactile stimulation, mask, and bag ventilation and/or extra oxygen. The duration of the apnea and the concomitant hypoxia and bradycardia depends on the response time of the nurse. We systematically reviewed the literature with the aim of providing an overview of what is known about the effect of manual and mechanical tactile stimulation on AOP. Tactile stimulation, manual or mechanical, has been shown to shorten the duration of apnea, hypoxia, and or bradycardia or even prevent an apnea. Automated stimulation, using closed-loop pulsating or vibrating systems, has been shown to be effective in terminating apneas, but data are scarce. Several studies used continuous mechanical stimulation, with pulsating, vibrating, or oscillating stimuli, to prevent apneas, but the reported effect varied. More studies are needed to confirm whether automated stimulation using a closed loop is more effective than manual stimulation, how and where the automated stimulation should be performed and the potential side effects.

  10. Effects of Dual-Channel Functional Electrical Stimulation on Gait Performance in Patients with Hemiparesis

    Directory of Open Access Journals (Sweden)

    Shmuel Springer

    2012-01-01

    Full Text Available The study objective was to assess the effect of functional electrical stimulation (FES applied to the peroneal nerve and thigh muscles on gait performance in subjects with hemiparesis. Participants were 45 subjects (age 57.8 ± 14.8 years with hemiparesis (5.37 ± 5.43 years since diagnosis demonstrating a foot-drop and impaired knee control. Thigh stimulation was applied either to the quadriceps or hamstrings muscles, depending on the dysfunction most affecting gait. Gait was assessed during a two-minute walk test with/without stimulation and with peroneal stimulation alone. A second assessment was conducted after six weeks of daily use. The addition of thigh muscles stimulation to peroneal stimulation significantly enhanced gait velocity measures at the initial and second evaluation. Gait symmetry was enhanced by the dual-channel stimulation only at the initial evaluation, and single-limb stance percentage only at the second assessment. For example, after six weeks, the two-minute gait speed with peroneal stimulation and with the dual channel was 0.66 ± 0.30 m/sec and 0.70 ± 0.31 m/sec, respectively (. In conclusion, dual-channel FES may enhance gait performance in subjects with hemiparesis more than peroneal FES alone.

  11. Effect of Tactile Stimulation on Termination and Prevention of Apnea of Prematurity: A Systematic Review

    Directory of Open Access Journals (Sweden)

    Sophie J. E. Cramer

    2018-03-01

    Full Text Available Apnea of prematurity (AOP is one of the most common diagnoses in preterm infants. Severe and recurrent apneas are associated with cerebral injury and adverse neurodevelopmental outcome. Despite pharmacotherapy and respiratory support to prevent apneas, a proportion of infants continue to have apneas and often need tactile stimulation, mask, and bag ventilation and/or extra oxygen. The duration of the apnea and the concomitant hypoxia and bradycardia depends on the response time of the nurse. We systematically reviewed the literature with the aim of providing an overview of what is known about the effect of manual and mechanical tactile stimulation on AOP. Tactile stimulation, manual or mechanical, has been shown to shorten the duration of apnea, hypoxia, and or bradycardia or even prevent an apnea. Automated stimulation, using closed-loop pulsating or vibrating systems, has been shown to be effective in terminating apneas, but data are scarce. Several studies used continuous mechanical stimulation, with pulsating, vibrating, or oscillating stimuli, to prevent apneas, but the reported effect varied. More studies are needed to confirm whether automated stimulation using a closed loop is more effective than manual stimulation, how and where the automated stimulation should be performed and the potential side effects.

  12. Effect of Tactile Stimulation on Termination and Prevention of Apnea of Prematurity: A Systematic Review

    Science.gov (United States)

    Cramer, Sophie J. E.; Dekker, Janneke; Dankelman, Jenny; Pauws, Steffen C.; Hooper, Stuart B.; te Pas, Arjan B.

    2018-01-01

    Apnea of prematurity (AOP) is one of the most common diagnoses in preterm infants. Severe and recurrent apneas are associated with cerebral injury and adverse neurodevelopmental outcome. Despite pharmacotherapy and respiratory support to prevent apneas, a proportion of infants continue to have apneas and often need tactile stimulation, mask, and bag ventilation and/or extra oxygen. The duration of the apnea and the concomitant hypoxia and bradycardia depends on the response time of the nurse. We systematically reviewed the literature with the aim of providing an overview of what is known about the effect of manual and mechanical tactile stimulation on AOP. Tactile stimulation, manual or mechanical, has been shown to shorten the duration of apnea, hypoxia, and or bradycardia or even prevent an apnea. Automated stimulation, using closed-loop pulsating or vibrating systems, has been shown to be effective in terminating apneas, but data are scarce. Several studies used continuous mechanical stimulation, with pulsating, vibrating, or oscillating stimuli, to prevent apneas, but the reported effect varied. More studies are needed to confirm whether automated stimulation using a closed loop is more effective than manual stimulation, how and where the automated stimulation should be performed and the potential side effects. PMID:29552548

  13. Prescription Stimulant Medication Misuse: Where Are We and Where Do We Go from Here?

    Science.gov (United States)

    Weyandt, Lisa L.; Oster, Danielle R.; Marraccini, Marisa Ellen; Gudmundsdottir, Bergljot Gyda; Munro, Bailey A.; Rathkey, Emma S.; Mccallum, Alison

    2016-01-01

    Prescription stimulants, including methylphenidate (e.g., Ritalin) and amphetamine compounds (e.g., dextroamphetamine; Adderall), have been approved by the U.S. Food and Drug Administration for the treatment of attention deficit hyperactivity disorder (ADHD) and are classified by the United States Drug Enforcement Administration (DEA) as Schedule II medications due to their high potential for abuse and dependence (DEA, U.S. Department of Justice, 2015). Despite the potential health and judicial consequences, misuse of prescription stimulants, typically defined as taking stimulants without a valid prescription, or use of stimulants other than as prescribed, has become a serious problem in the United States and abroad, especially on college campuses. The purpose of the present paper is to review historical information concerning prescription stimulants and to summarize the literature with respect to misuse among adults, particularly college students, including risk factors, mediators and moderators, and motivations for prescription stimulant misuse. In addition, evidence is presented concerning the question of whether prescription stimulants truly enhance cognitive functioning in individuals with and without ADHD, and the ethical and professional implications of these findings are explored. Lastly, recommendations for addressing prescription stimulant misuse and suggestions for future research are advanced. PMID:27690507

  14. Is neural hyperpolarization by cathodal stimulation always detrimental at the behavioral level?

    Directory of Open Access Journals (Sweden)

    Cornelia ePirulli

    2014-06-01

    Full Text Available Cathodal transcranial direct current stimulation (c-tDCS is usually considered an inhibitory stimulation. From a physiological perspective, c-tDCS stimulation induces hyperpolarization at the neural level. However, from a behavioral perspective, c-tDCS application does not always result in performance deterioration. In this work, we investigated the role of several important stimulation parameters (i.e., timing, presence of pauses, duration and intensity in shaping the behavioral effects of c-tDCS over the primary visual cortex.In Experiment 1, we applied c-tDCS at two different times (before or during an orientation discrimination task. We also studied the effects of pauses during the stimulation. In Experiments 2 and 3, we compared different durations (9 minutes vs. 22 minutes and intensities (0.75 mA vs. 1.5 mA of stimulation.c-tDCS applied before task execution induced an improvement of performance, highlighting the importance of the activation state of the cortex. However, this result depended on the duration and intensity of stimulation.We suggest that the application of c-tDCS induces depression of cortical activity over a specific stimulated area; but to keep reactivity within given limits, the brain react in order to restore the equilibrium and this might result in increased sensitivity in visual performance. This is a further example of how the nervous system dynamically maintains a condition that permits adequate performance in different environments.

  15. Physical Variables in the Olfactory Stimulation Process

    Science.gov (United States)

    Tucker, Don

    1963-01-01

    Electrical recording from small twigs of nerve in a tortoise showed that olfactory, vomeronasal, and trigeminal receptors in the nose are responsive to various odorants. No one kind of receptor was most sensitive to all odorants. For controlled stimulation, odorant was caused to appear in a stream of gas already flowing through the nose. Of the parameters definable at the naris, temperature, relative humidity, and nature of inert gas had little effect on olfactory responses to amyl acetate, whereas odorant species, odorant concentration, and volume flow rate effectively determined the responses of all nasal chemoreceptors. An intrinsic variable of accessibility to the receptors, particularly olfactory, was demonstrated. Flow dependence of chemoreceptor responses is thought to reflect the necessity for delivery of odorant molecules to receptor sites. Since the olfactory receptors are relatively exposed, plateauing of the response with flow rate for slightly soluble odorants suggests an approach to concentration equilibrium in the overlying mucus with that in the air entering the naris. Accordingly, data for responses to amyl acetate were fitted with Beidler's (1954) taste equation for two kinds of sites being active. The requirement for finite aqueous solubility, if true, suggests substitution of aqueous solutions for gaseous solutions. A suitable medium was found and results conformed to expectations. Olfactory receptors were insensitive to variation of ionic strength, pH, and osmotic pressure. PMID:13994681

  16. Plasmon-enhanced optically stimulated luminescence

    International Nuclear Information System (INIS)

    Guidelli, E. J.; Baffa, O.; Ramos, A. P.

    2015-10-01

    Full text: Optically Stimulated Luminescence dosimeters (OSLD) have been largely used for personal, medical, and industrial radiation dosimetry. Developing highly sensitive and small-sized radiation detectors and dosimeters is essential for improving spatial resolution and consequently diagnosis quality and treatment efficacy in the case of applications in radiodiagnosis and radiation therapy, for instance. Conventional methods to improve the OSLD sensitivity consist of doping and co-doping the host materials with atoms of other elements, thereby increasing the amount of trapping and/or luminescent centers. Our group is researching on the use of the plasmon properties of noble metal nanoparticles to increase OSL intensity. Upon incidence of a light beam with appropriate resonant wavelengths, the oscillation of the free electrons at the nanoparticle surface originates the Localized Surface Plasmons (LSP) and the consequent plasmon resonance band. The interaction between the LSP and the surrounding luminescent material leads to new optical properties largely employed for enhancing several luminescent processes. Here we will show our results regarding the use of LSP to increase OSLD sensitivity. The interaction between the traps/luminescent centers and the plasmons depends on the distance between them, on the plasmon resonance band intensity and position, as well as on the surrounding medium. Therefore, the plasmon-enhanced luminescence is a promising tool to develop more sensitive and miniaturized OSLD. (Author)

  17. Plasmon-enhanced optically stimulated luminescence

    Energy Technology Data Exchange (ETDEWEB)

    Guidelli, E. J.; Baffa, O. [Universidade de Sao Paulo, Faculdade de Filosofia, Ciencias e Letras de Ribeirao Preto, Departamento de Fisica, Av. Bandeirantes 3900, 14040-901 Ribeirao Preto, Sao Paulo (Brazil); Ramos, A. P., E-mail: ederguidelli@gmail.com [Universidade de Sao Paulo, Faculdade de Filosofia, Ciencias e Letras de Ribeirao Preto, Departamento de Quimica, Av. Bandeirantes 3900, 14040-901 Ribeirao Preto, Sao Paulo (Brazil)

    2015-10-15

    Full text: Optically Stimulated Luminescence dosimeters (OSLD) have been largely used for personal, medical, and industrial radiation dosimetry. Developing highly sensitive and small-sized radiation detectors and dosimeters is essential for improving spatial resolution and consequently diagnosis quality and treatment efficacy in the case of applications in radiodiagnosis and radiation therapy, for instance. Conventional methods to improve the OSLD sensitivity consist of doping and co-doping the host materials with atoms of other elements, thereby increasing the amount of trapping and/or luminescent centers. Our group is researching on the use of the plasmon properties of noble metal nanoparticles to increase OSL intensity. Upon incidence of a light beam with appropriate resonant wavelengths, the oscillation of the free electrons at the nanoparticle surface originates the Localized Surface Plasmons (LSP) and the consequent plasmon resonance band. The interaction between the LSP and the surrounding luminescent material leads to new optical properties largely employed for enhancing several luminescent processes. Here we will show our results regarding the use of LSP to increase OSLD sensitivity. The interaction between the traps/luminescent centers and the plasmons depends on the distance between them, on the plasmon resonance band intensity and position, as well as on the surrounding medium. Therefore, the plasmon-enhanced luminescence is a promising tool to develop more sensitive and miniaturized OSLD. (Author)

  18. Noninvasive transcranial brain stimulation and pain.

    Science.gov (United States)

    Rosen, Allyson C; Ramkumar, Mukund; Nguyen, Tam; Hoeft, Fumiko

    2009-02-01

    Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are two noninvasive brain stimulation techniques that can modulate activity in specific regions of the cortex. At this point, their use in brain stimulation is primarily investigational; however, there is clear evidence that these tools can reduce pain and modify neurophysiologic correlates of the pain experience. TMS has also been used to predict response to surgically implanted stimulation for the treatment of chronic pain. Furthermore, TMS and tDCS can be applied with other techniques, such as event-related potentials and pharmacologic manipulation, to illuminate the underlying physiologic mechanisms of normal and pathological pain. This review presents a description and overview of the uses of two major brain stimulation techniques and a listing of useful references for further study.

  19. Mimicking muscle activity with electrical stimulation

    Science.gov (United States)

    Johnson, Lise A.; Fuglevand, Andrew J.

    2011-02-01

    Functional electrical stimulation is a rehabilitation technology that can restore some degree of motor function in individuals who have sustained a spinal cord injury or stroke. One way to identify the spatio-temporal patterns of muscle stimulation needed to elicit complex upper limb movements is to use electromyographic (EMG) activity recorded from able-bodied subjects as a template for electrical stimulation. However, this requires a transfer function to convert the recorded (or predicted) EMG signals into an appropriate pattern of electrical stimulation. Here we develop a generalized transfer function that maps EMG activity into a stimulation pattern that modulates muscle output by varying both the pulse frequency and the pulse amplitude. We show that the stimulation patterns produced by this transfer function mimic the active state measured by EMG insofar as they reproduce with good fidelity the complex patterns of joint torque and joint displacement.

  20. Viral evasion of DNA-stimulated innate immune responses.

    Science.gov (United States)

    Christensen, Maria H; Paludan, Søren R

    2017-01-01

    Cellular sensing of virus-derived nucleic acids is essential for early defenses against virus infections. In recent years, the discovery of DNA sensing proteins, including cyclic GMP-AMP synthase (cGAS) and gamma-interferon-inducible protein (IFI16), has led to understanding of how cells evoke strong innate immune responses against incoming pathogens carrying DNA genomes. The signaling stimulated by DNA sensors depends on the adaptor protein STING (stimulator of interferon genes), to enable expression of antiviral proteins, including type I interferon. To facilitate efficient infections, viruses have evolved a wide range of evasion strategies, targeting host DNA sensors, adaptor proteins and transcription factors. In this review, the current literature on virus-induced activation of the STING pathway is presented and we discuss recently identified viral evasion mechanisms targeting different steps in this antiviral pathway.

  1. Bio-robots automatic navigation with electrical reward stimulation.

    Science.gov (United States)

    Sun, Chao; Zhang, Xinlu; Zheng, Nenggan; Chen, Weidong; Zheng, Xiaoxiang

    2012-01-01

    Bio-robots that controlled by outer stimulation through brain computer interface (BCI) suffer from the dependence on realtime guidance of human operators. Current automatic navigation methods for bio-robots focus on the controlling rules to force animals to obey man-made commands, with animals' intelligence ignored. This paper proposes a new method to realize the automatic navigation for bio-robots with electrical micro-stimulation as real-time rewards. Due to the reward-seeking instinct and trial-and-error capability, bio-robot can be steered to keep walking along the right route with rewards and correct its direction spontaneously when rewards are deprived. In navigation experiments, rat-robots learn the controlling methods in short time. The results show that our method simplifies the controlling logic and realizes the automatic navigation for rat-robots successfully. Our work might have significant implication for the further development of bio-robots with hybrid intelligence.

  2. Effects of Deep Brain Stimulation on Autonomic Function

    Directory of Open Access Journals (Sweden)

    Adam Basiago

    2016-08-01

    Full Text Available Over the course of the development of deep brain stimulation (DBS into a well-established therapy for Parkinson’s disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target.

  3. Analysis of Facial Expression by Taste Stimulation

    Science.gov (United States)

    Tobitani, Kensuke; Kato, Kunihito; Yamamoto, Kazuhiko

    In this study, we focused on the basic taste stimulation for the analysis of real facial expressions. We considered that the expressions caused by taste stimulation were unaffected by individuality or emotion, that is, such expressions were involuntary. We analyzed the movement of facial muscles by taste stimulation and compared real expressions with artificial expressions. From the result, we identified an obvious difference between real and artificial expressions. Thus, our method would be a new approach for facial expression recognition.

  4. Sources and effects of electrode impedance during deep brain stimulation.

    Science.gov (United States)

    Butson, Christopher R; Maks, Christopher B; McIntyre, Cameron C

    2006-02-01

    Clinical impedance measurements for deep brain stimulation (DBS) electrodes in human patients are normally in the range 500-1500 Omega. DBS devices utilize voltage-controlled stimulation; therefore, the current delivered to the tissue is inversely proportional to the impedance. The goals of this study were to evaluate the effects of various electrical properties of the tissue medium and electrode-tissue interface on the impedance and to determine the impact of clinically relevant impedance variability on the volume of tissue activated (VTA) during DBS. Axisymmetric finite-element models (FEM) of the DBS system were constructed with explicit representation of encapsulation layers around the electrode and implanted pulse generator. Impedance was calculated by dividing the stimulation voltage by the integrated current density along the active electrode contact. The models utilized a Fourier FEM solver that accounted for the capacitive components of the electrode-tissue interface during voltage-controlled stimulation. The resulting time- and space-dependent voltage waveforms generated in the tissue medium were superimposed onto cable model axons to calculate the VTA. The primary determinants of electrode impedance were the thickness and conductivity of the encapsulation layer around the electrode contact and the conductivity of the bulk tissue medium. The difference in the VTA between our low (790 Omega) and high (1244 Omega) impedance models with typical DBS settings (-3 V, 90 mus, 130 Hz pulse train) was 121 mm3, representing a 52% volume reduction. Electrode impedance has a substantial effect on the VTA and accurate representation of electrode impedance should be an explicit component of computational models of voltage-controlled DBS. Impedance is often used to identify broken leads (for values > 2000 Omega) or short circuits in the hardware (for values impedance values also represent an important parameter in defining the spread of stimulation during DBS.

  5. Biophysical stimulation of bone fracture repair, regeneration and remodelling

    Directory of Open Access Journals (Sweden)

    Chao E. Y.S.

    2003-12-01

    Full Text Available Biophysical stimulation to enhance bone fracture repair and bone regenerate maturation to restore its structural strength must rely on both the biological and biomechanical principle according to the local tissue environment and the type of mechanical stress to be born by the skeletal joint system. This paper reviews the possible interactions between biophysical stimuli and cellular responses in healing bone fractures and proceeds to speculate the prospects and limitations of different experimental models in evaluating and optimising such non-invasive interventions. It is important to realize that bone fracture repair has several pathways with various combinations of bone formation mechanisms, but there may only be one bone remodeling principle regulated by the hypothesis proposed by Wolff. There are different mechanical and biophysical stimuli that could provide effective augmentation of fracture healing and bone regenerate maturation. The key requirements of establishing these positive interactions are to define the precise cellular response to the stimulation signal in an in vitro environment and to use well-established animal models to quantify and optimise the therapeutic regimen in a time-dependent manner. This can only be achieved through research collaboration among different disciplines using scientific methodologies. In addition, the specific forms of biophysical stimulation and its dose effect and application timing must be carefully determined and validated. Technological advances in achieving focalized stimulus delivery with adjustable signal type and intensity, in the ability to monitor healing callus mechanical property non-invasively, and in the establishment of a robust knowledgebase to develop effective and reliable treatment protocols are the essential pre-requisites to make biophysical stimulation acceptable in the main arena of health care. Finally, it is important to bear in mind that successful fracture repair or bone

  6. Geothermal Reservoir Well Stimulation Program: technology transfer

    Energy Technology Data Exchange (ETDEWEB)

    1980-05-01

    A literature search on reservoir and/or well stimulation techniques suitable for application in geothermal fields is presented. The literature on stimulation techniques in oil and gas field applications was also searched and evaluated as to its relevancy to geothermal operations. The equivalent low-temperature work documented in the open literature is cited, and an attempt is made to evaluate the relevance of this information as far as high-temperature stimulation work is concerned. Clays play an important role in any stimulation work. Therefore, special emphasis has been placed on clay behavior anticipated in geothermal operations. (MHR)

  7. Stimulant ADHD Medications -- Methylphenidate and Amphetamines

    Science.gov (United States)

    ... prescription stimulants? dextroamphetamine (Dexedrine ® ) dextroamphetamine/amphetamine combination product (Adderall ® ) methylphenidate (Ritalin ® , Concerta ® ). Popular slang terms for prescription ...

  8. Bacterial peptidoglycan stimulates adipocyte lipolysis via NOD1.

    Directory of Open Access Journals (Sweden)

    Wendy Chi

    Full Text Available Obesity is associated with inflammation that can drive metabolic defects such as hyperlipidemia and insulin resistance. Specific metabolites can contribute to inflammation, but nutrient intake and obesity are also associated with altered bacterial load in metabolic tissues (i.e. metabolic endotoxemia. These bacterial cues can contribute to obesity-induced inflammation. The specific bacterial components and host receptors that underpin altered metabolic responses are emerging. We previously showed that Nucleotide-binding oligomerization domain-containing protein 1 (NOD1 activation with bacterial peptidoglycan (PGN caused insulin resistance in mice. We now show that PGN induces cell-autonomous lipolysis in adipocytes via NOD1. Specific bacterial PGN motifs stimulated lipolysis in white adipose tissue (WAT explants from WT, but not NOD1⁻/⁻mice. NOD1-activating PGN stimulated mitogen activated protein kinases (MAPK,protein kinase A (PKA, and NF-κB in 3T3-L1 adipocytes. The NOD1-mediated lipolysis response was partially reduced by inhibition of ERK1/2 or PKA alone, but not c-Jun N-terminal kinase (JNK. NOD1-stimulated lipolysis was partially dependent on NF-κB and was completely suppressed by inhibiting ERK1/2 and PKA simultaneously or hormone sensitive lipase (HSL. Our results demonstrate that bacterial PGN stimulates lipolysis in adipocytes by engaging a stress kinase, PKA, NF-κB-dependent lipolytic program. Bacterial NOD1 activation is positioned as a component of metabolic endotoxemia that can contribute to hyperlipidemia, systemic inflammation and insulin resistance by acting directly on adipocytes.

  9. Early Maladaptive Schemas in Opiate and Stimulant Users

    Directory of Open Access Journals (Sweden)

    Zahra Karami

    2015-06-01

    Full Text Available Objectives: Early maladaptive schemas are valid representations of unpleasant childhood experiences that shape a person’s viewpoints of the world, and lead to clinical symptoms such as depression, personality disorders, and substance abuse. Given the importance of this matter, we conducted a research on early maladaptive schemas in substance-abusers, to allow more appropriate preventive measures to be taken with a better understanding of the issue. Methods: For this descriptive-comparative study, 115 patients (91 opiate users and 24 stimulant users visiting drug addiction treatment centers were selected through convenience sampling from persons who were admitted to substance abuse treatment centers (Methadone Maintenance therapy centers, addiction treatment camps and self-help groups and Narcotics Anonymous (NA of Yasuj. Data were collected using a Demographic Information Questionnaire and Young’s Schema Questionnaire-Short Form (SQ-SF. Data analysis was done with ANOVA and t-tests. Results: The results showed a significant difference (P<0.05 between users of opiates and stimulants in terms of vulnerability to harm or illness, enmeshment, subjugation, emotional inhibition, entitlement, insufficient self-control/self-discipline, emotional  deprivation, social isolation, defectiveness, failure/shame, and dependence. The average score of the stimulant-users was higher than that of opiate-users in all the schemas except for the dimensions of abandonment, mistrust, and unrelenting standards. Discussion: Stimulant users have more early maladaptive schemas and are at a greater risk of psychological vulnerability. Early maladaptive schemas can be used by clinicians and researchers as a psychopathology and treatment method for substance dependence disorder.

  10. Modulation of human time processing by subthalamic deep brain stimulation.

    Directory of Open Access Journals (Sweden)

    Lars Wojtecki

    Full Text Available Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS of the subthalamic nucleus (STN is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥ 130-Hz-STN-DBS compared to healthy controls. We found under(re-production of the 15-second interval and a significant enhancement of this under(re-production by 10-Hz-stimulation compared to no stimulation, ≥ 130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.

  11. A programmable optical stimulator for the Drosophila eye

    Directory of Open Access Journals (Sweden)

    Xinping Chen

    2017-10-01

    Full Text Available A programmable optical stimulator for Drosophila eyes is presented. The target application of the stimulator is to induce retinal degeneration in fly photoreceptor cells by exposing them to light in a controlled manner. The goal of this work is to obtain a reproducible system for studying age-related changes in susceptibility to environmental ocular stress. The stimulator uses light emitting diodes and an embedded computer to control illuminance, color (blue or red and duration in two independent chambers. Further, the stimulator is equipped with per-chamber light and temperature sensors and a fan to monitor light intensity and to control temperature. An ON/OFF temperature control implemented on the embedded computer keeps the temperature from reaching levels that will induce the heat shock stress response in the flies. A custom enclosure was fabricated to house the electronic components of the stimulator. The enclosure provides a light-impermeable environment that allows air flow and lets users easily load and unload fly vials. Characterization results show that the fabricated stimulator can produce light at illuminances ranging from 0 to 16000 lux and power density levels from 0 to 7.2 mW/cm2 for blue light. For red light the maximum illuminance is 8000 lux which corresponds to a power density of 3.54 mW/cm2. The fans and the ON/OFF temperature control are able to keep the temperature inside the chambers below 28.17 °C. Experiments with white-eye male flies were performed to assess the ability of the fabricated simulator to induce blue light-dependent retinal degeneration. Retinal degeneration is observed in flies exposed to 8 h of blue light at 7949 lux. Flies in a control experiment with no light exposure show no retinal degeneration. Flies exposed to red light for the similar duration and light intensity (8 h and 7994 lux do not show retinal degeneration either. Hence, the fabricated stimulator can be used to create environmental

  12. Cognitive stimulation in healthy older adults: a cognitive stimulation program using leisure activities compared to a conventional cognitive stimulation program.

    Science.gov (United States)

    Grimaud, Élisabeth; Taconnat, Laurence; Clarys, David

    2017-06-01

    The aim of this study was to compare two methods of cognitive stimulation for the cognitive functions. The first method used an usual approach, the second used leisure activities in order to assess their benefits on cognitive functions (speed of processing; working memory capacity and executive functions) and psychoaffective measures (memory span and self esteem). 67 participants over 60 years old took part in the experiment. They were divided into three groups: 1 group followed a program of conventional cognitive stimulation, 1 group a program of cognitive stimulation using leisure activities and 1 control group. The different measures have been evaluated before and after the training program. Results show that the cognitive stimulation program using leisure activities is as effective on memory span, updating and memory self-perception as the program using conventional cognitive stimulation, and more effective on self-esteem than the conventional program. There is no difference between the two stimulated groups and the control group on speed of processing. Neither of the two cognitive stimulation programs provides a benefit over shifting and inhibition. These results indicate that it seems to be possible to enhance working memory and to observe far transfer benefits over self-perception (self-esteem and memory self-perception) when using leisure activities as a tool for cognitive stimulation.

  13. Safety of multi-channel stimulation implants: a single blocking capacitor per channel is not sufficient after single-fault failure.

    Science.gov (United States)

    Nonclercq, Antoine; Lonys, Laurent; Vanhoestenberghe, Anne; Demosthenous, Andreas; Donaldson, Nick

    2012-04-01

    One reason given for placing capacitors in series with stimulation electrodes is that they prevent direct current flow and therefore tissue damage under fault conditions. We show that this is not true for multiplexed multi-channel stimulators with one capacitor per channel. A test bench of two