WorldWideScience

Sample records for mdp-nod2 stimulation induces

  1. Inducing circular vection with tactile stimulation encircling the waist

    Tinga, A.M.; Jansen, C.; Smagt, M.J. van der; Nijboer, T.C.W.; Erp, J.B.F. van

    2018-01-01

    In general, moving sensory stimuli (visual and auditory) can induce illusory sensations of self-motion (i.e. vection) in the direction opposite of the sensory stimulation. The aim of the current study was to examine whether tactile stimulation encircling the waist could induce circular vection

  2. Diffuse Transcranial Electrical Stimulation (DTES)-induced ...

    Higher voltages were needed to induce convulsion in pretreated animals than in normal animals. It is therefore suggestive that DTES-induced hypermotility can be used as an animal model for testing drugs that can be of advantage in the management of non convulsive (petit mal) status epilepticus (SE), and DTES induced ...

  3. Electrical field stimulation-induced excitatory responses of ...

    effect of the endothelium on electrical field stimulation (EFS)-induced excitatory responses of pulmonary artery segments from pulmonary hypertensive rats. Methods: Pulmonary hypertension was induced in rats with a single dose of monocrotaline (60 mg/kg) and 21 days later, arterial rings were set up for isometric tension ...

  4. Radiation induced mitotic delay and stimulation of growth

    Feldmann, A.

    1974-01-01

    The mechanisms responsible for the radiation induced mitotic delay and stimulation of growth are discussed in connection with the results of studies in Lemna minor and Lepidium sativum. The action of temperature seems to be of major importance. As many authors suggest that various chemical agents and slight intoxications also affect mitosis in a way similar to that induced by ionizing radiation, the radiation induced stimulation has lost its specific character and approaches might be found for further investigations of this phenomenon. (MG) [de

  5. Illusory sensation of movement induced by repetitive transcranial magnetic stimulation

    Christensen, Mark Schram; Lundbye-Jensen, Jesper; Grey, Michael James

    2010-01-01

    Human movement sense relies on both somatosensory feedback and on knowledge of the motor commands used to produce the movement. We have induced a movement illusion using repetitive transcranial magnetic stimulation over primary motor cortex and dorsal premotor cortex in the absence of limb movement...... and its associated somatosensory feedback. Afferent and efferent neural signalling was abolished in the arm with ischemic nerve block, and in the leg with spinal nerve block. Movement sensation was assessed following trains of high-frequency repetitive transcranial magnetic stimulation applied over...... premotor cortex stimulation was less affected by sensory and motor deprivation than was primary motor cortex stimulation. We propose that repetitive transcranial magnetic stimulation over dorsal premotor cortex produces a corollary discharge that is perceived as movement....

  6. Peripheral nerve stimulator-induced electrostimulation at the P6 ...

    2012-12-03

    Dec 3, 2012 ... Original Research: Peripheral nerve stimulator-induced electrostimulation. 216. 2013;19(4). South Afr J Anaesth Analg. Introduction. Spinal anaesthesia is often associated with hypotension and bradycardia.1 Strategies to manage post-spinal hypotension include the use of vasopressors or fluids, or a ...

  7. Imaging of dopamine release induced by pharmacologic and nonpharmacologic stimulations

    Cho, Sang Soo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2007-04-15

    Technological advances in molecular imaging made it possible to image synaptic neurotransmitter concentration in living human brain. The dopaminergic system has been most intensively studied because of its importance in neurological as well as psychiatric disorders. This paper provides a brief overview of recent progress in imaging studies of dopamine release induced by pharmacologic and nonpharmacologic stimulations.

  8. Different protein of Echinococcus granulosus stimulates dendritic induced immune response.

    Wang, Yana; Wang, Qiang; Lv, Shiyu; Zhang, Shengxiang

    2015-06-01

    Cystic echinococcosis is a chronic infectious disease that results from a host/parasite interaction. Vaccination with ferritin derived from Echinococcus granulosus is a potential preventative treatment. To understand whether ferritin is capable of inducing a host immune response, we investigated the response of dendritic cells (DCs) to both recombinant ferritin protein and the hydatid fluid (HF) of E. granulosus. We evaluated the immunomodulatory potential of these antigens by performing, immunocytochemistry, electron microscopy and in vivo imaging of monocyte-derived murine DCs. During antigen stimulation of DCs, ferritin cause DCs maturation and induced higher levels of surface marker expression and activated T-cell proliferation and migration. On contrary, HF failed to induce surface marker expression and to stimulate T-cell proliferation. In response to HF, DCs produced interleukin-6 (IL-6), but no IL-12 and IL-10. DCs stimulated with ferritin produced high levels of cytokines. Overall, HF appears to induce host immunosuppression in order to ensure parasite survival via inhibits DC maturation and promotes Th2-dependent secretion of cytokines. Although ferritin also promoted DC maturation and cytokine release, it also activates CD4+T-cell proliferation, but regard of the mechanism of the Eg.ferritin induce host to eradicate E. granulosus were not clear.

  9. Spinal cord stimulation suppresses bradycardias and atrial tachyarrhythmias induced by mediastinal nerve stimulation in dogs.

    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.

  10. Granulocyte colony-stimulating factor induces in vitro lymphangiogenesis

    Lee, Ae Sin; Kim, Dal; Wagle, Susbin Raj; Lee, Jung Eun; Jung, Yu Jin; Kang, Kyung Pyo; Lee, Sik; Park, Sung Kwang; Kim, Won

    2013-01-01

    Highlights: •G-CSF induces tube formation, migration and proliferation of lymphatic cells. •G-CSF increases phosphorylation of MAPK and Akt in lymphatic endothelial cells. •MAPK and Akt pathways are linked to G-CSF-induced in vitro lymphangiogenesis. •G-CSF increases sprouting of a lymphatic ring. •G-CSF produces peritoneal lymphangiogenesis. -- Abstract: Granulocyte-colony stimulating factor (G-CSF) is reported to induce differentiation in cells of the monocyte lineage and angiogenesis in vascular endothelial cells, but its effects on lymphangiogenesis is uncertain. Here we examined the effects and the mechanisms of G-CSF-induced lymphangiogenesis using human lymphatic endothelial cells (hLECs). Our results showed that G-CSF induced capillary-like tube formation, migration and proliferation of hLECs in a dose- and time-dependent manner and enhanced sprouting of thoracic duct. G-CSF increased phosphorylation of Akt and ERK1/2 in hLECs. Supporting the observations, specific inhibitors of phosphatidylinositol 3′-kinase and MAPK suppressed the G-CSF-induced in vitro lymphangiogenesis and sprouting. Intraperitoneal administration of G-CSF to mice also stimulated peritoneal lymphangiogenesis. These findings suggest that G-CSF is a lymphangiogenic factor

  11. Electrical stimulation induces propagated colonic contractions in an experimental model.

    Aellen, S; Wiesel, P H; Gardaz, J-P; Schlageter, V; Bertschi, M; Virag, N; Givel, J-C

    2009-02-01

    Direct colonic electrical stimulation may prove to be a treatment option for specific motility disorders such as chronic constipation. The aim of this study was to provoke colonic contractions using electrical stimulation delivered from a battery-operated device. Electrodes were inserted into the caecal seromuscular layer of eight anaesthetized pigs. Contractions were induced by a neurostimulator (Medtronic 3625). Caecal motility was measured simultaneously by video image analysis, manometry and a technique assessing colonic transit. Caecal contractions were generated using 8-10 V amplitude, 1000 micros pulse width, 120 Hz frequency for 10-30 s, with an intensity of 7-15 mA. The maximal contraction strength was observed after 20-25 s. Electrical stimulation was followed by a relaxation phase of 1.5-2 min during which contractions propagated orally and aborally over at least 10 cm. Spontaneous and stimulated caecal motility values were significantly different for both intraluminal pressure (mean(s.d.) 332(124) and 463(187) mmHg respectively; P < 0.001, 42 experiments) and movement of contents (1.6(0.9) and 3.9(2.8) mm; P < 0.001, 40 experiments). Electrical stimulation modulated caecal motility, and provoked localized and propagated colonic contractions.

  12. Effects of contraction mode and stimulation frequency on electrical stimulation-induced skeletal muscle hypertrophy.

    Ashida, Yuki; Himori, Koichi; Tatebayashi, Daisuke; Yamada, Ryotaro; Ogasawara, Riki; Yamada, Takashi

    2018-02-01

    We compared the skeletal muscle hypertrophy resulting from isometric (Iso) or eccentric (Ecc) electrical stimulation (ES) training with different stimulation frequencies. Male Wistar rats were assigned to the Iso and Ecc groups. These were divided into three further subgroups that were stimulated at 10 Hz (Iso-10 and Ecc-10), 30 Hz (Iso-30 and Ecc-30), or 100 Hz (Iso-100 and Ecc-100). In experiment 1, the left plantarflexor muscles were stimulated every other day for 3 wk. In experiment 2, mammalian target of rapamycin complex 1 (mTORC1) signaling was investigated 6 h after one bout of ES. The contralateral right muscle served as a control (non-ES). Ecc contractions comprised forced dorsiflexion combined with ES. The peak torque and torque-time integral during ES were higher in the Ecc group than that in the Iso group in all stimulation frequencies examined. The gastrocnemius muscle weight normalized to body weight in ES side was increased compared with the non-ES side by 6, 7, and 17% in the Ecc-30, Iso-100, and Ecc-100 groups, respectively, with a greater gain in Ecc-100 than the Ecc-30 and Iso-100 groups. The p70S6K (Thr389) phosphorylation level was higher in the Ecc-30 and -100 than in the Iso-30 and -100 groups, respectively. The peak torque and torque-time integral were highly correlated with the magnitude of increase in muscle mass and the phosphorylation of p70S6K. These data suggest that ES-induced muscle hypertrophy and mTORC1 activity are determined by loading intensity and volume during muscle contraction independent of the contraction mode. NEW & NOTEWORTHY Eccentric contraction and high-frequency stimulation (HFS) are regarded as an effective way to increase muscle mass by electrical stimulation (ES) training. However, little is known about whether muscle hypertrophy is affected by contraction mode and stimulation frequency in ES training. Here, we provide the evidence that muscle hypertrophy and mammalian target of rapamycin complex 1 activity are

  13. MRI-induced heating of deep brain stimulation leads

    Mohsin, Syed A; Sheikh, Noor M; Saeed, Usman

    2008-01-01

    The radiofrequency (RF) field used in magnetic resonance imaging is scattered by medical implants. The scattered field of a deep brain stimulation lead can be very intense near the electrodes stimulating the brain. The effect is more pronounced if the lead behaves as a resonant antenna. In this paper, we examine the resonant length effect. We also use the finite element method to compute the near field for (i) the lead immersed in inhomogeneous tissue (fat, muscle, and brain tissues) and (ii) the lead connected to an implantable pulse generator. Electric field, specific absorption rate and induced temperature rise distributions have been obtained in the brain tissue surrounding the electrodes. The worst-case scenario has been evaluated by neglecting the effect of blood perfusion. The computed values are in good agreement with in vitro measurements made in the laboratory.

  14. Stimulation of respiration in rat thymocytes induced by ionizing radiation

    Gudz, T.I.; Pandelova, I.G.; Novgorodov, S.A.

    1994-01-01

    The effect of X irradiation on the respiration of rat thymocytes was studied. An increase in the rate of O 2 uptake was observed 1 h after cells were irradiated with doses of 6-10 Gy. The radiation-induced increase in respiration could be blocked by oligomycin, an inhibitor of mitochondrial ATP synthase, suggesting control by increased cytoplasmic ATP turnover. The stimulation of respiration was not associated with changes in the activity of mitochondrial electron transfer enzymes or permeability of the inner membrane. Several inhibitors of processes which used ATP were screened for their effects on the basal respiration rate and on the radiation response. In irradiated thymocytes, an enhancement of inhibition of respiration by ouabain, La 3+ and cycloheximide was observed. These results indicate that the radiation-induced stimulation of respiration is due to changes in ion homeostasis and protein synthesis. The effect of X irradiation was shown to be independent of the redox status of nonprotein thiols and was not associated with detectable changes in some products of lipid peroxidation. The radiation-induced decrease in activity of superoxide dismutase suggests free radical involvement in deleterious effects of radiation. 43 refs., 2 figs., 3 tabs

  15. Mapping the follicle-stimulating hormone-induced signalling networks

    Pauline eGloaguen

    2011-10-01

    Full Text Available Follicle-stimulating hormone (FSH is a central regulator of male and female reproductive function. Over the last decade, there has been a growing perception of the complexity associated with FSH-induced cellular signalling. It is now clear that the canonical Gs/cAMP/PKA pathway is not the sole mechanism that must be considered in FSH biological actions. In parallel, consistent with the emerging concept of biased agonism, several examples of ligand-mediated selective signalling pathway activation by gonadotropin receptors have been reported. In this context, it is important to gain an integrative view of the signalling pathways induced by FSH and how they interconnect to form a network. In this review, we propose a first attempt at building topological maps of various pathways known to be involved in the FSH-induced signalling network. We discuss the multiple facets of FSH-induced signalling and how they converge to the hormone integrated biological response. Despite of their incompleteness, these maps of the FSH-induced signalling network represent a first step towards gaining a system-level comprehension of this hormone’s actions, which may ultimately facilitate the discovery of novel regulatory processes and therapeutic strategies for infertilities and non-steroidal contraception.

  16. Comparison of the shock artifacts induced by tripolar and bipolar electrical stimulation techniques.

    Wee, A S; Jiles, K; Brennan, R

    2001-01-01

    Tripolar and bipolar electrical stimulation procedures were performed on the upper limbs of eight subjects. The mid-forearm was stimulated electrically (tripolar or bipolar) by surface electrodes, and the induced stimulus shock artifacts were recorded simultaneously from the wrist and elbow. During tripolar stimulation, two types of stimulating configurations were utilized: with the center electrode designated as the cathode and the two outermost electrodes connected to a common anode, and vice versa. During bipolar stimulation, the center electrode served as one pole of the stimulator, and one of the two outermost electrodes of the tripolar stimulator was disconnected. The stimulus intensity was kept constant in all stimulating procedures. Artifacts were reduced significantly during tripolar compared to bipolar stimulation, if the outermost electrodes of the tripolar stimulator (which were facing the recording electrodes) were also oriented toward the recording sites during bipolar stimulation and had the same stimulus polarity. Artifacts were slightly reduced in amplitude from tripolar stimulation, if the center electrode were oriented toward the recording sites during bipolar stimulation and had the same stimulus polarity as previously used during tripolar stimulation.

  17. Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

    Thanos Manos

    2018-04-01

    Full Text Available In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce

  18. Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization.

    Manos, Thanos; Zeitler, Magteld; Tass, Peter A

    2018-01-01

    In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long

  19. Anti-kindling induced by two-stage coordinated reset stimulation with weak onset intensity

    Magteld eZeitler

    2016-05-01

    Full Text Available Abnormal neuronal synchrony plays an important role in a number of brain diseases. To specifically counteract abnormal neuronal synchrony by desynchronization, Coordinated Reset (CR stimulation, a spatiotemporally patterned stimulation technique, was designed with computational means. In neuronal networks with spike timing–dependent plasticity CR stimulation causes a decrease of synaptic weights and finally anti-kindling, i.e. unlearning of abnormally strong synaptic connectivity and abnormal neuronal synchrony. Long-lasting desynchronizing aftereffects of CR stimulation have been verified in pre-clinical and clinical proof of concept studies. In general, for different neuromodulation approaches, both invasive and non-invasive, it is desirable to enable effective stimulation at reduced stimulation intensities, thereby avoiding side effects. For the first time, we here present a two-stage CR stimulation protocol, where two qualitatively different types of CR stimulation are delivered one after another, and the first stage comes at a particularly weak stimulation intensity. Numerical simulations show that a two-stage CR stimulation can induce the same degree of anti-kindling as a single-stage CR stimulation with intermediate stimulation intensity. This stimulation approach might be clinically beneficial in patients suffering from brain diseases characterized by abnormal neuronal synchrony where a first treatment stage should be performed at particularly weak stimulation intensities in order to avoid side effects. This might, e.g., be relevant in the context of acoustic CR stimulation in tinnitus patients with hyperacusis or in the case of electrical deep brain CR stimulation with sub-optimally positioned leads or side effects caused by stimulation of the target itself. We discuss how to apply our method in first in man and proof of concept studies.

  20. Colony-stimulating factors for chemotherapy-induced febrile neutropenia.

    Mhaskar, Rahul; Clark, Otavio Augusto Camara; Lyman, Gary; Engel Ayer Botrel, Tobias; Morganti Paladini, Luciano; Djulbegovic, Benjamin

    2014-10-30

    Febrile neutropenia is a frequent adverse event experienced by people with cancer who are undergoing chemotherapy, and is a potentially life-threatening situation. The current treatment is supportive care plus antibiotics. Colony-stimulating factors (CSFs), such as granulocyte-CSF (G-CSF) and granulocyte-macrophage CSF (GM-CSF), are cytokines that stimulate and accelerate the production of one or more cell lines in the bone marrow. Clinical trials have addressed the question of whether the addition of a CSF to antibiotics could improve outcomes in individuals diagnosed with febrile neutropenia. However, the results of these trials are conflicting. To evaluate the safety and efficacy of adding G-CSF or GM-CSF to standard treatment (antibiotics) when treating chemotherapy-induced febrile neutropenia in individuals diagnosed with cancer. We conducted the search in March 2014 and covered the major electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and SCI. We contacted experts in hematology and oncology and also scanned the citations from the relevant articles. We searched for randomized controlled trials (RCTs) that compared CSF plus antibiotics versus antibiotics alone for the treatment of chemotherapy-induced febrile neutropenia in adults and children. We used the standard methodological procedures expected by The Cochrane Collaboration. We performed meta-analysis of the selected studies using Review Manager 5 software. Fourteen RCTs (15 comparisons) including a total of 1553 participants addressing the role of CSF plus antibiotics in febrile neutropenia were included. Overall mortality was not improved by the use of CSF plus antibiotics versus antibiotics alone (hazard ratio (HR) 0.74 (95% confidence interval (CI) 0.47 to 1.16) P = 0.19; 13 RCTs; 1335 participants; low quality evidence). A similar finding was seen for infection-related mortality (HR 0.75 (95% CI 0.47 to 1.20) P = 0.23; 10 RCTs; 897

  1. Right-sided vagus nerve stimulation inhibits induced spinal cord seizures.

    Tubbs, R Shane; Salter, E George; Killingsworth, Cheryl; Rollins, Dennis L; Smith, William M; Ideker, Raymond E; Wellons, John C; Blount, Jeffrey P; Oakes, W Jerry

    2007-01-01

    We have previously shown that left-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. To test our hypothesis that right-sided vagus nerve stimulation will also abort seizure activity, we have initiated seizures in the spinal cord and then performed right-sided vagus nerve stimulation in an animal model. Four pigs were anesthetized and placed in the lateral position and a small laminectomy performed in the lumbar region. Topical penicillin, a known epileptogenic drug to the cerebral cortex and spinal cord, was next applied to the dorsal surface of the exposed cord. With the exception of the control animal, once seizure activity was discernible via motor convulsion or increased electrical activity, the right vagus nerve previously isolated in the neck was stimulated. Following multiple stimulations of the vagus nerve and with seizure activity confirmed, the cord was transected in the midthoracic region and vagus nerve stimulation performed. Right-sided vagus nerve stimulation resulted in cessation of spinal cord seizure activity in all animals. Transection of the spinal cord superior to the site of seizure induction resulted in the ineffectiveness of vagus nerve stimulation in causing cessation of seizure activity in all study animals. As with left-sided vagus nerve stimulation, right-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. Additionally, the effects of right-sided vagus nerve stimulation on induced spinal cord seizures involve descending spinal pathways. These data may aid in the development of alternative mechanisms for electrical stimulation for patients with medically intractable seizures and add to our knowledge regarding the mechanism for seizure cessation following peripheral nerve stimulation.

  2. FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors

    Cheng, Jung-Chien; Chang, Hsun-Ming; Qiu, Xin; Fang, Lanlan; Leung, Peter C.K., E-mail: peter.leung@ubc.ca

    2014-01-10

    Highlights: •Activin A stimulates cell proliferation in KGN human granulosa cell tumor-derived cell line. •Cyclin D2 mediates activin A-induced KGN cell proliferation. •FOXL2 induces follistatin expression in KGN cells. •FOXL2-induced follistatin attenuates activin A-stimulated KGN cell proliferation. -- Abstract: Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C > G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation.

  3. Synergistic nonuniform shortening of atrial refractory period induced by autonomic stimulation.

    Takei, M; Furukawa, Y; Narita, M; Ren, L M; Karasawa, Y; Murakami, M; Chiba, S

    1991-12-01

    We investigated the nonuniform effects of autonomic nerve stimulation of the effective refractory period (ERP) of the right atrium in the anesthetized dog. Stimulation of the discrete intracardiac sympathetic nerves to the sinoatrial (SA) nodal region uniformly shortened ERPs at three sites in the right atrium after administration of atropine. Right ansa subclavia (RS) stimulation similarly shortened ERPs in the absence of atropine. Stimulation of the discrete intracardiac parasympathetic nerves to the SA nodal region (SAP stimulation) shortened ERPs of the right atrium in a nonuniform manner. Simultaneous RS and SAP stimulation additively shortened ERPs at each site and decreased sinus rate much more than SAP stimulation alone. Shortening of ERP induced by SAP stimulation was greater than that induced by RS stimulation at similar absolute changes in heart rate. These results suggest that simultaneous activation of sympathetic and parasympathetic nerves nonuniformly shortens the ERP in the right atrium as the algebraic sum of the individual responses to each stimulation. However, parasympathetics exert the principal neural control over atrial ERP.

  4. Effect of transcutaneous electrical nerve stimulation induced parotid stimulation on salivary flow

    Sreenivasulu Pattipati

    2013-01-01

    Full Text Available Aims and Objectives: The main objective of this study was to evaluate the duration of stimulation over the parotid salivary flow following the use of transcutaneous electric nerve stimulation (TENS in different age groups. Materials and Methods: The study was carried out in three different age groups. Under group A individuals from 21 to 35 years of age, group B 36-50 years and group C above 51 years were considered. In each group 30 subjects were taken of whom 15 were males and 15 were females. The placement of pads was approximated bilaterally over the parotid glands. The working parameters of TENS unit were fixed at 50 Hz and the unit was in normal mode. Results: Subjects belonging to group B were showing statistically significant increases in the duration of stimulated parotid salivary flow following the use of TENS. Conclusion: TENS can be considered as a non-pharmacological alternative to improve salivation for longer period in xerostomia patients.

  5. Difference in quick phases induced by horizontal and vertical vestibular stimulations: role of the otolithic input.

    Pettorossi, V E; Errico, P; Ferraresi, A

    1997-01-01

    Quick phases (QPs) induced by horizontal and vertical sinusoidal vestibular stimulations were studied in rabbits, cats, and humans. In all the animals, large and frequent horizontal QPs were observed following yaw stimulation in prone position. By contrast, QPs were almost absent during roll stimulation in rabbits, and they were small and oblique during pitch stimulation in cats and humans. As a result of these differences, the range of gaze displacement induced by vestibular stimulations was greater in the horizontal plane than in the vertical one. We also found that the trajectory of the QPs in rabbits was kept horizontal even when the yaw rotation was off vertical axis of +/- 45 degrees in the sagittal plane. Moreover, in the rabbit, the rare horizontal QPs induced by roll stimulation did not change their orientation at various pitch angles of roll stimulation axis. The QPs were also analyzed following roll stimulation of the rabbit in supine position. In this condition, in which the otolithic receptors were activated in the opposite way compared to prone position, large vertical QPs were elicited. We concluded that these results provide evidence that the otolithic signal plays a role in controlling occurrence and trajectory orientation of the QPs.

  6. Long-lasting desynchronization in rat hippocampal slice induced by coordinated reset stimulation

    Tass, P. A.; Barnikol, U. B.; Silchenko, A. N.; Hauptmann, C.; Speckmann, E.-J.

    2009-01-01

    In computational models it has been shown that appropriate stimulation protocols may reshape the connectivity pattern of neural or oscillator networks with synaptic plasticity in a way that the network learns or unlearns strong synchronization. The underlying mechanism is that a network is shifted from one attractor to another, so that long-lasting stimulation effects are caused which persist after the cessation of stimulation. Here we study long-lasting effects of multisite electrical stimulation in a rat hippocampal slice rendered epileptic by magnesium withdrawal. We show that desynchronizing coordinated reset stimulation causes a long-lasting desynchronization between hippocampal neuronal populations together with a widespread decrease in the amplitude of the epileptiform activity. In contrast, periodic stimulation induces a long-lasting increase in both synchronization and amplitude.

  7. Electrical Stimulation of the Ventral Tegmental Area Induces Reanimation from General Anesthesia

    Solt, Ken; Van Dort, Christa J.; Chemali, Jessica J.; Taylor, Norman E.; Kenny, Jonathan D.; Brown, Emery N.

    2014-01-01

    BACKGROUND Methylphenidate or a D1 dopamine receptor agonist induce reanimation (active emergence) from general anesthesia. We tested whether electrical stimulation of dopaminergic nuclei also induces reanimation from general anesthesia. METHODS In adult rats, a bipolar insulated stainless steel electrode was placed in the ventral tegmental area (VTA, n = 5) or substantia nigra (SN, n = 5). After a minimum 7-day recovery period, the isoflurane dose sufficient to maintain loss of righting was established. Electrical stimulation was initiated and increased in intensity every 3 min to a maximum of 120μA. If stimulation restored the righting reflex, an additional experiment was performed at least 3 days later during continuous propofol anesthesia. Histological analysis was conducted to identify the location of the electrode tip. In separate experiments, stimulation was performed in the prone position during general anesthesia with isoflurane or propofol, and the electroencephalogram was recorded. RESULTS To maintain loss of righting, the dose of isoflurane was 0.9% ± 0.1 vol%, and the target plasma dose of propofol was 4.4 μg/ml ± 1.1 μg/ml (mean ± SD). In all rats with VTA electrodes, electrical stimulation induced a graded arousal response including righting that increased with current intensity. VTA stimulation induced a shift in electroencephalogram peak power from δ (anesthesia with isoflurane or propofol. These results are consistent with the hypothesis that dopamine release by VTA, but not SN, neurons induces reanimation from general anesthesia. PMID:24398816

  8. [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

    Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

    2014-01-01

    A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

  9. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    Taub, Mary, E-mail: biochtau@buffalo.edu

    2016-03-11

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10{sup −5} M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  10. Cancer drug troglitazone stimulates the growth and response of renal cells to hypoxia inducible factors

    Taub, Mary

    2016-01-01

    Troglitazone has been used to suppress the growth of a number of tumors through apoptosis and autophagy. However, previous in vitro studies have employed very high concentrations of troglitazone (≥10"−"5 M) in order to elicit growth inhibitory effects. In this report, when employing lower concentrations of troglitazone in defined medium, troglitazone was observed to stimulate the growth of primary renal proximal tubule (RPT) cells. Rosiglitazone, like troglitazone, is a thiazolidinedione (TZD) that is known to activate Peroxisome Proliferator Activated Receptor Υ (PPARΥ). Notably, rosiglitazone also stimulates RPT cell growth, as does Υ-linolenic acids, another PPARΥ agonist. The PPARΥ antagonist GW9662 inhibited the growth stimulatory effect of troglitazone. In addition, troglitazone stimulated transcription by a PPAR Response Element/Luciferase construct. These results are consistent with the involvement of PPARΥ as a mediator of the growth stimulatory effect of troglitazone. In a number of tumor cells, the expression of hypoxia inducible factor (HIF) is increased, promoting the expression of HIF inducible genes, and vascularization. Troglitazone was observed to stimulate transcription by a HIF/luciferase construct. These observations indicate that troglitazone not only promotes growth, also the survival of RPT cells under conditions of hypoxia. - Highlights: • Troglitazone and rosiglitazone stimulate renal proximal tubule cell growth. • Troglitazone and linolenic acid stimulate growth via PPARϒ. • Linolenic acid stimulates growth in the presence of fatty acid free serum albumin. • Rosiglitazone stimulates transcription by a HRE luciferase construct.

  11. Stimulation of mitochondrial respiration induced by laser irradiation in the presence of rhodamine dyes

    Krasnikov, B.F.; Zorov, D.B.

    1996-01-01

    The effect of micromolar concentration of rhodamine 123 (methylrhodamine) and ethyl and amyl esters of unsubstituted rhodamine on oxygen consumption by rat liver mitochondria was studied under irradiation by an argon laser (488 and 514 nm). Irradiation of mitochondria in the presence of rhodamine stimulates their respiration. Light-induced stimulation of respiration is not inhibited by free radical scavenger ionol and by inhibitor of the permeability transition pore cyclosporine A. Stimulation of respiration by moderate doses of radiation is reversed in the dark. Increase in radiation dose resulted in only partial reversal of stimulated respiration in the dark. Rhodamine efficacy in stimulation of mitochondrial respiration depends on its structure (amyl > ethyl > methylrhodamine). 22 refs.; 4 figs

  12. Transcranial direct-current stimulation induced in stroke patients with aphasia: a prospective experimental cohort study

    Santos,Michele Devido; Gagliardi,Rubens José; Mac-Kay,Ana Paula Machado Goyano; Boggio,Paulo Sergio; Lianza,Roberta; Fregni,Felipe

    2013-01-01

    CONTEXT AND OBJECTIVE: Previous animal and human studies have shown that transcranial direct current stimulation can induce significant and lasting neuroplasticity and may improve language recovery in patients with aphasia. The objective of the study was to describe a cohort of patients with aphasia after stroke who were treated with transcranial direct current stimulation. DESIGN AND SETTING: Prospective cohort study developed in a public university hospital. METHODS: Nineteen patients with ...

  13. Chromium-induced accumulation of peroxide content, stimulation of ...

    Chromium (Cr)-induced oxidative damage and changes in contents of chlorophyll, protein, peroxide and malondialdehyde (MDA) and activities of enzymatic antioxidants were investigated in 4-day-old green gram (Vigna radiata L. cv. Wilczek) seedlings. Cr increased the contents of peroxide and MDA but decreased the ...

  14. Modulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation

    Hoeger, S.; Bergstraesser, C.; Selhorst, J.; Fontana, J.; Birck, R.; Waldherr, R.; Beck, G.; Sticht, C.; Seelen, M. A.; van Son, W. J.; Leuvenink, H.; Ploeg, R.; Schnuelle, P.; Yard, B. A.

    Because the vagus nerve is implicated in control of inflammation, we investigated if brain death (BD) causes impairment of the parasympathetic nervous system, thereby contributing to inflammation. BD was induced in rats. Anaesthetised ventilated rats (NBD) served as control. Heart rate variability

  15. Enhanced accuracy in novel mirror drawing after repetitive transcranial magnetic stimulation-induced proprioceptive deafferentation

    Balslev, Daniela; Christensen, Lars O.D.; Lee, Ji-hang

    2004-01-01

    a performance benefit. In this study, we tested whether deafferentation induced by repetitive transcranial magnetic stimulation (rTMS) can improve mirror tracing skills in normal subjects. Hand trajectory error during novel mirror drawing was compared across two groups of subjects that received either 1 Hz r......TMS over the somatosensory cortex contralateral to the hand or sham stimulation. Mirror tracing was more accurate after rTMS than after sham stimulation. Using a position-matching task, we confirmed that rTMS reduced proprioceptive acuity and that this reduction was largest when the coil was placed...

  16. Electrical Stimulation Promotes Cardiac Differentiation of Human Induced Pluripotent Stem Cells

    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.

  17. Interhemispheric Inhibition Induced by Transcranial Magnetic Stimulation Over Primary Sensory Cortex.

    Iwata, Yasuyuki; Jono, Yasutomo; Mizusawa, Hiroki; Kinoshita, Atsushi; Hiraoka, Koichi

    2016-01-01

    The present study investigated whether the long-interval interhemispheric inhibition (LIHI) is induced by the transcranial magnetic stimulation over the primary sensory area (S1-TMS) without activation of the conditioning side of the primary motor area (M1) contributing to the contralateral motor evoked potential (MEP), whether the S1-TMS-induced LIHI is dependent on the status of the S1 modulated by the tactile input, and whether the pathways mediating the LIHI are different from those mediating the M1-TMS-induced LIHI. In order to give the TMS over the S1 without eliciting the MEP, the intensity of the S1-TMS was adjusted to be the sub-motor-threshold level and the trials with the MEP response elicited by the S1-TMS were discarded online. The LIHI was induced by the S1-TMS given 40 ms before the test TMS in the participants with the attenuation of the tactile perception of the digit stimulation (TPDS) induced by the S1-TMS, indicating that the LIHI is induced by the S1-TMS without activation of the conditioning side of the M1 contributing to the contralateral MEP in the participants in which the pathways mediating the TPDS is sensitive to the S1-TMS. The S1-TMS-induced LIHI was positively correlated with the attenuation of the TPDS induced by the S1-TMS, indicating that the S1-TMS-induced LIHI is dependent on the effect of the S1-TMS on the pathways mediating the TPDS at the S1. In another experiment, the effect of the digit stimulation given before the conditioning TMS on the S1- or M1-TMS-induced LIHI was examined. The digit stimulation produces tactile input to the S1 causing change in the status of the S1. The S1-TMS-induced LIHI was enhanced when the S1-TMS was given in the period in which the tactile afferent volley produced by the digit stimulation just arrived at the S1, while the LIHI induced by above-motor-threshold TMS over the contralateral M1 was not enhanced by the tactile input. Thus, the S1-TMS-induced LIHI is dependent on the status of the S1

  18. Adrenaline rush: the role of adrenergic receptors in stimulant-induced behaviors.

    Schmidt, Karl T; Weinshenker, David

    2014-04-01

    Psychostimulants, such as cocaine and amphetamines, act primarily through the monoamine neurotransmitters dopamine (DA), norepinephrine, and serotonin. Although stimulant addiction research has largely focused on DA, medication development efforts targeting the dopaminergic system have thus far been unsuccessful, leading to alternative strategies aimed at abating stimulant abuse. Noradrenergic compounds have shown promise in altering the behavioral effects of stimulants in rodents, nonhuman primates, and humans. In this review, we discuss the contribution of each adrenergic receptor (AR) subtype (α1, α2, and β) to five stimulant-induced behaviors relevant to addiction: locomotor activity, conditioned place preference, anxiety, discrimination, and self-administration. AR manipulation has diverse effects on these behaviors; each subtype profoundly influences outcomes in some paradigms but is inconsequential in others. The functional neuroanatomy and intracellular signaling mechanisms underlying the impact of AR activation/blockade on these behaviors remain largely unknown, presenting a new frontier for research on psychostimulant-AR interactions.

  19. Peripheral optogenetic stimulation induces whisker movement and sensory perception in head-fixed mice.

    Park, Sunmee; Bandi, Akhil; Lee, Christian R; Margolis, David J

    2016-06-08

    We discovered that optical stimulation of the mystacial pad in Emx1-Cre;Ai27D transgenic mice induces whisker movements due to activation of ChR2 expressed in muscles controlling retraction and protraction. Using high-speed videography in anesthetized mice, we characterize the amplitude of whisker protractions evoked by varying the intensity, duration, and frequency of optogenetic stimulation. Recordings from primary somatosensory cortex (S1) in anesthetized mice indicated that optogenetic whisker pad stimulation evokes robust yet longer latency responses than mechanical whisker stimulation. In head-fixed mice trained to report optogenetic whisker pad stimulation, psychometric curves showed similar dependence on stimulus duration as evoked whisker movements and S1 activity. Furthermore, optogenetic stimulation of S1 in expert mice was sufficient to substitute for peripheral stimulation. We conclude that whisker protractions evoked by optogenetic activation of whisker pad muscles results in cortical activity and sensory perception, consistent with the coding of evoked whisker movements by reafferent sensory input.

  20. Hyposmotic stimulation-induced nitric oxide production in outer hair cells of the guinea pig cochlea.

    Takeda-Nakazawa, Hiroko; Harada, Narinobu; Shen, Jing; Kubo, Nobuo; Zenner, Hans-Peter; Yamashita, Toshio

    2007-08-01

    Nitric oxide (NO) production during hyposmotic stimulation in outer hair cells (OHCs) of the guinea pig cochlea was investigated using the NO sensitive dye DAF-2. Simultaneous measurement of the cell length and NO production showed rapid hyposmotic-induced cell swelling to precede NO production in OHCs. Hyposmotic stimulation failed to induce NO production in the Ca2+-free solution. L-NG-nitroarginine methyl ester (L-NAME), a non-specific NO synthase inhibitor and gadolinium, a stretch-activated channel blocker inhibited the hyposmotic stimulation-induced NO production whereas suramin, a P2 receptor antagonist did not. S-nitroso-N-acetylpenicillamine (SNAP), a NO donor inhibited the hyposmotic stimulation-induced increase in the intracellular Ca2+ concentrations ([Ca2+]i) while L-NAME enhanced it. 1H-[1,2,4]oxadiazole[4,3a]quinoxalin-1-one, an inhibitor of guanylate cyclase and KT5823, an inhibitor of cGMP-dependent protein kinase (PKG) mimicked effects of L-NAME on the Ca2+ response. Transient receptor potential vanilloid 4 (TRPV4), an osmo- and mechanosensitive channel was expressed in the OHCs by means of immunohistochemistry. 4alpha-phorbol 12,13-didecanoate, a TRPV4 synthetic activator, induced NO production in OHCs. These results suggest that hyposmotic stimulation can induce NO production by the [Ca2+]i increase, which is presumably mediated by the activation of TRPV4 in OHCs. NO conversely inhibits the Ca2+ response via the NO-cGMP-PKG pathway by a feedback mechanism.

  1. Using non-invasive brain stimulation to augment motor training-induced plasticity

    Pascual-Leone Alvaro

    2009-03-01

    Full Text Available Abstract Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS and transcranial direct current stimulation (tDCS. These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.

  2. An investigation into the induced electric fields from transcranial magnetic stimulation

    Hadimani, Ravi; Lee, Erik; Duffy, Walter; Waris, Mohammed; Siddiqui, Waquar; Islam, Faisal; Rajamani, Mahesh; Nathan, Ryan; Jiles, David; David C Jiles Team; Walter Duffy Collaboration

    Transcranial magnetic stimulation (TMS) is a promising tool for noninvasive brain stimulation that has been approved by the FDA for the treatment of major depressive disorder. To stimulate the brain, TMS uses large, transient pulses of magnetic field to induce an electric field in the head. This transient magnetic field is large enough to cause the depolarization of cortical neurons and initiate a synaptic signal transmission. For this study, 50 unique head models were created from MRI images. Previous simulation studies have primarily used a single head model, and thus give a limited image of the induced electric field from TMS. This study uses finite element analysis simulations on 50 unique, heterogeneous head models to better investigate the relationship between TMS and the electric field induced in brain tissues. Results showed a significant variation in the strength of the induced electric field in the brain, which can be reasonably predicted by the distance from the TMS coil to the stimulated brain. Further, it was seen that some models had high electric field intensities in over five times as much brain volume as other models.

  3. Stimulation of cell proliferation by histamine H2 receptors in dimethylhdrazine-induced adenocarcinomata.

    Tutton, P J; Barkla, D H

    1978-03-01

    Cell proliferation in dimethylhydrazine-induced colonic carcinomata was stimulated by histamine and by the histamine H2 receptor agonist dimaprit and inhibited by the histamine H2 receptor antagonists Metiamide and Cimetidine but not by the histamine H1 receptor antagonist Mepyramine. In contrast histamine had no effect on colonic crypt cell proliferation in normal or dimethylhydrazine-treated rats.

  4. Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates

    Opitz, Alexander; Falchier, Arnaud; Yan, Chao-Gan

    2016-01-01

    Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reac...

  5. Variability and Reliability of Paired-Pulse Depression and Cortical Oscillation Induced by Median Nerve Stimulation.

    Onishi, Hideaki; Otsuru, Naofumi; Kojima, Sho; Miyaguchi, Shota; Saito, Kei; Inukai, Yasuto; Yamashiro, Koya; Sato, Daisuke; Tamaki, Hiroyuki; Shirozu, Hiroshi; Kameyama, Shigeki

    2018-05-08

    Paired-pulse depression (PPD) has been widely used to investigate the functional profiles of somatosensory cortical inhibition. However, PPD induced by somatosensory stimulation is variable, and the reasons for between- and within-subject PPD variability remains unclear. Therefore, the purpose of this study was to clarify the factors influencing PPD variability induced by somatosensory stimulation. The study participants were 19 healthy volunteers. First, we investigated the relationship between the PPD ratio of each component (N20m, P35m, and P60m) of the somatosensory magnetic field, and the alpha, beta, and gamma band changes in power [event-related desynchronization (ERD) and event-related synchronization (ERS)] induced by median nerve stimulation. Second, because brain-derived neurotrophic factor (BDNF) gene polymorphisms reportedly influence the PPD ratio, we assessed whether BDNF genotype influences PPD ratio variability. Finally, we evaluated the test-retest reliability of PPD and the alpha, beta, and gamma ERD/ERS induced by somatosensory stimulation. Significant positive correlations were observed between the P60m_PPD ratio and beta power change, and the P60m_PPD ratio was significantly smaller for the beta ERD group than for the beta ERS group. P35m_PPD was found to be robust and highly reproducible; however, P60m_PPD reproducibility was poor. In addition, the ICC values for alpha, beta, and gamma ERD/ERS were 0.680, 0.760, and 0.552 respectively. These results suggest that the variability of PPD for the P60m deflection may be influenced by the ERD/ERS magnitude, which is induced by median nerve stimulation.

  6. Noninvasive brain stimulation can induce paradoxical facilitation . Are these neuroenhancements transferable and meaningful to security services?

    Jean eLevasseur-Moreau

    2013-08-01

    Full Text Available For ages, we have been looking for ways to enhance our physical and cognitive capacities in order to augment our security. One potential way to achieve this goal may be to externally stimulate the brain. Methods of noninvasive brain stimulation (NIBS, such as repetitive transcranial magnetic stimulation and transcranial electrical stimulation, have been recently developed to modulate brain activity. Both techniques are relatively safe and can transiently modify motor and cognitive functions outlasting the stimulation period. The purpose of this paper is to review data suggesting that NIBS can enhance motor and cognitive performance in healthy volunteers. We frame these findings in the context of whether they may serve security purposes. Specifically, we review studies reporting that NIBS induces paradoxical facilitation in motor (precision, speed, strength, acceleration endurance, and execution of daily motor task and cognitive functions (attention, impulsive behaviour, risk-taking, working memory, planning, and deceptive capacities. Although transferability and meaningfulness of these NIBS-induced paradoxical facilitations into real life situations are not clear yet, NIBS may contribute at improving training of motor and cognitive functions relevant for military, civil and forensic security services. This is an enthusiastic perspective that also calls for fair and open debates on the ethics of using NIBS in healthy individuals to enhance normal functions.

  7. Localized Induced Current Stimulation to Neuronal Culture Using Soft Magnetic Material

    Saito, Atsushi; Saito, Aki; Moriguchi, Hiroyuki; Kotani, Kiyoshi; Jimbo, Yasuhiko

    To establish precisely focused magnetic stimulation, we developed a Mu-meal based low-frequency localized induced current (LIC) stimulation system with micro-fabricated dual cell-culture chamber. The dual cell-culture chamber was arranged in a concentric circle manner. Between the inner and outer chambers, 4 or 8 connecting micro-channels were fabricated using polydimethylsiloxane (PDMS). Rat cortical neurons were separately cultured in outer and inner chambers. Through the micro-channels, functional synaptic connections were formed. Mu-metal that has very high magnetic permeability was aligned along the outer circle, which allowed us of LIC stimulation to the cells in the outer chamber. Applying low-frequency magnetic fields to the Mu-metal, induced currents were generated and the electrical activity of the cells in the outer chamber was modified depending on the stimulation intensity. Following the modified activity in the outer circles, the cells in the inner chamber also showed slightly depressed activity patterns. These results suggested that our system would be promising for localized stimulation of neuronal networks and highly regulation of network activities.

  8. Electrical stimulation induces calcium-dependent release of NGF from cultured Schwann cells.

    Huang, Jinghui; Ye, Zhengxu; Hu, Xueyu; Lu, Lei; Luo, Zhuojing

    2010-04-01

    Production of nerve growth factor (NGF) from Schwann cells (SCs) progressively declines in the distal stump, if axonal regeneration is staggered across the suture site after peripheral nerve injuries. This may be an important factor limiting the outcome of nerve injury repair. Thus far, extensive efforts are devoted to modulating NGF production in cultured SCs, but little has been achieved. In the present in vitro study, electrical stimulation (ES) was attempted to stimulate cultured SCs to release NGF. Our data showed that ES was capable of enhancing NGF release from cultured SCs. An electrical field (1 Hz, 5 V/cm) caused a 4.1-fold increase in NGF release from cultured SCs. The ES-induced NGF release is calcium dependent. Depletion of extracellular or/and intracellular calcium partially/ completely abolished the ES-induced NGF release. Further pharmacological interventions showed that ES induces calcium influx through T-type voltage-gated calcium channels and mobilizes calcium from 1, 4, 5-trisphosphate-sensitive stores and caffeine/ryanodine-sensitive stores, both of which contributed to the enhanced NGF release induced by ES. In addition, a calcium-triggered exocytosis mechanism was involved in the ES-induced NGF release from cultured SCs. These findings show the feasibility of using ES in stimulating SCs to release NGF, which holds great potential in promoting nerve regeneration by enhancing survival and outgrowth of damaged nerves, and is of great significance in nerve injury repair and neuronal tissue engineering.

  9. Transcranial direct-current stimulation induced in stroke patients with aphasia: a prospective experimental cohort study

    Michele Devido Santos

    Full Text Available CONTEXT AND OBJECTIVE: Previous animal and human studies have shown that transcranial direct current stimulation can induce significant and lasting neuroplasticity and may improve language recovery in patients with aphasia. The objective of the study was to describe a cohort of patients with aphasia after stroke who were treated with transcranial direct current stimulation. DESIGN AND SETTING: Prospective cohort study developed in a public university hospital. METHODS: Nineteen patients with chronic aphasia received 10 transcranial direct current stimulation sessions lasting 20 minutes each on consecutive days, using a current of 2 mA. The anode was positioned over the supraorbital area and the cathode over the contralateral motor cortex. The following variables were analyzed before and after the 10 neuromodulation sessions: oral language comprehension, copying, dictation, reading, writing, naming and verbal fluency. RESULTS: There were no adverse effects in the study. We found statistically significant differences from before to after stimulation in relation to simple sentence comprehension (P = 0.034, naming (P = 0.041 and verbal fluency for names of animals (P = 0.038. Improved scores for performing these three tasks were seen after stimulation. CONCLUSIONS: We observed that excitability of the primary motor cortex through transcranial direct current stimulation was associated with effects on different aspects of language. This can contribute towards future testing in randomized controlled trials.

  10. Transcranial direct-current stimulation induced in stroke patients with aphasia: a prospective experimental cohort study.

    Santos, Michele Devido; Gagliardi, Rubens José; Mac-Kay, Ana Paula Machado Goyano; Boggio, Paulo Sergio; Lianza, Roberta; Fregni, Felipe

    2013-01-01

    Previous animal and human studies have shown that transcranial direct current stimulation can induce significant and lasting neuroplasticity and may improve language recovery in patients with aphasia. The objective of the study was to describe a cohort of patients with aphasia after stroke who were treated with transcranial direct current stimulation. Prospective cohort study developed in a public university hospital. Nineteen patients with chronic aphasia received 10 transcranial direct current stimulation sessions lasting 20 minutes each on consecutive days, using a current of 2 mA. The anode was positioned over the supraorbital area and the cathode over the contralateral motor cortex. The following variables were analyzed before and after the 10 neuromodulation sessions: oral language comprehension, copying, dictation, reading, writing, naming and verbal fluency. There were no adverse effects in the study. We found statistically significant differences from before to after stimulation in relation to simple sentence comprehension (P = 0.034), naming (P = 0.041) and verbal fluency for names of animals (P = 0.038). Improved scores for performing these three tasks were seen after stimulation. We observed that excitability of the primary motor cortex through transcranial direct current stimulation was associated with effects on different aspects of language. This can contribute towards future testing in randomized controlled trials.

  11. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation.

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam; Ardell, Jeffrey L

    2016-11-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. Copyright © 2016 the American Physiological Society.

  12. Adenosine Receptor Stimulation Improves Glucocorticoid-Induced Osteoporosis in a Rat Model

    Gabriele Pizzino

    2017-09-01

    Full Text Available Glucocorticoid-induced osteoporosis (GIO is a secondary cause of bone loss. Bisphosphonates approved for GIO, might induce jaw osteonecrosis; thus additional therapeutics are required. Adenosine receptor agonists are positive regulators of bone remodeling, thus the efficacy of adenosine receptor stimulation for treating GIO was tested. In a preventive study GIO was induced in Sprague-Dawley rats by methylprednisolone (MP for 60 days. Animals were randomly assigned to receive polydeoxyribonucleotide (PDRN, an adenosine A2 receptor agonist, or PDRN and DMPX (3,7-dimethyl-1-propargylxanthine, an A2 antagonist, or vehicle (0.9% NaCl. Another set of animals was used for a treatment study, following the 60 days of MP-induction rats were randomized to receive (for additional 60 days PDRN, or PDRN and DMPX (an adenosine A2 receptor antagonist, or zoledronate (as control for gold standard treatment, or vehicle. Control animals were administered with vehicle for either 60 or 120 days. Femurs were analyzed after treatments for histology, imaging, and breaking strength analysis. MP treatment induced severe bone loss, the concomitant use of PDRN prevented the developing of osteoporosis. In rats treated for 120 days, PDRN restored bone architecture and bone strength; increased b-ALP, osteocalcin, osteoprotegerin and stimulated the Wnt canonical and non-canonical pathway. Zoledronate reduced bone resorption and ameliorated the histological features, without significant effects on bone formation. Our results suggest that adenosine receptor stimulation might be useful for preventing and treating GIO.

  13. Fast multigrid-based computation of the induced electric field for transcranial magnetic stimulation

    Laakso, Ilkka; Hirata, Akimasa

    2012-12-01

    In transcranial magnetic stimulation (TMS), the distribution of the induced electric field, and the affected brain areas, depends on the position of the stimulation coil and the individual geometry of the head and brain. The distribution of the induced electric field in realistic anatomies can be modelled using computational methods. However, existing computational methods for accurately determining the induced electric field in realistic anatomical models have suffered from long computation times, typically in the range of tens of minutes or longer. This paper presents a matrix-free implementation of the finite-element method with a geometric multigrid method that can potentially reduce the computation time to several seconds or less even when using an ordinary computer. The performance of the method is studied by computing the induced electric field in two anatomically realistic models. An idealized two-loop coil is used as the stimulating coil. Multiple computational grid resolutions ranging from 2 to 0.25 mm are used. The results show that, for macroscopic modelling of the electric field in an anatomically realistic model, computational grid resolutions of 1 mm or 2 mm appear to provide good numerical accuracy compared to higher resolutions. The multigrid iteration typically converges in less than ten iterations independent of the grid resolution. Even without parallelization, each iteration takes about 1.0 s or 0.1 s for the 1 and 2 mm resolutions, respectively. This suggests that calculating the electric field with sufficient accuracy in real time is feasible.

  14. Questiomycin A stimulates sorafenib-induced cell death via suppression of glucose-regulated protein 78.

    Machihara, Kayo; Tanaka, Hidenori; Hayashi, Yoshihiro; Murakami, Ichiro; Namba, Takushi

    2017-10-07

    Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat owing to the lack of effective chemotherapeutic methods. Sorafenib, the first-line and only available treatment for HCC, extends patient overall survival by several months, with a response rate below 10%. Thus, the identification of an agent that enhances the anticancer effect of sorafenib is critical for the development of therapeutic options for HCC. Endoplasmic reticulum (ER) stress response is one of the methods of sorafenib-induced cell death. Here we report that questiomycin A suppresses expression of GRP78, a cell-protective ER chaperone protein. Analysis of the molecular mechanisms of questiomycin A revealed that this compound stimulated GRP78 protein degradation in an ER stress response-independent manner. Cotreatment with sorafenib and questiomycin A suppressed GRP78 protein expression, which is essential for the stimulation of sorafenib-induced cell death. Moreover, our in vivo study demonstrated that the coadministration of sorafenib and questiomycin A suppressed tumor formation in HCC-induced xenograft models. These results suggest that cotreatment with sorafenib and questiomycin A is a novel therapeutic strategy for HCC by enhancing sorafenib-dependent ER stress-induced cell death, and downregulation of GRP78 is a new target for the stimulation of the therapeutic effects of sorafenib in HCC. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. [Phrenic nerve stimulation protects against mechanical ventilation-induced diaphragmatic dysfunction through myogenic regulatory factors].

    An, G H; Chen, M; Zhan, W F; Hu, B; Zhang, H X

    2018-02-12

    Objective: To explore the protective effect of electrical stimulation of phrenic nerve on diaphragmatic function during mechanical ventilation. Methods: Forty healthy adult SD rats were randomly divided into 5 groups: blank control group (BC), spontaneous breathing group (SB), electrical stimulation group (ES), mechanical ventilation group (MV), and electrical stimulation and mechanical ventilation group (MS). The rats in each group were treated for 18 h except for the BC group. After treatment, the diaphragm muscle tissue was obtained and the diaphragm contractility including peak-to-peak value(Vpp) and maximum rate of contraction(+ dT/dt max) were measured. Expression of MyoD and myogenin were detected. Results: Except for the ES and the MS groups, there was a significant difference for peak-to-peak value (Vpp) between each 2 groups ( P mechanical ventilation induced diaphragmatic function damage, and therefore plays a protective effect on the diaphragm.

  16. Painful tonic heat stimulation induces GABA accumulation in the prefrontal cortex in man

    Kupers, Ron; Danielsen, Else R; Kehlet, Henrik

    2009-01-01

    Relatively little is known on pain-induced neurotransmitter release in the human cerebral cortex. We used proton magnetic resonance spectroscopy (1H-MRS) during tonic painful heat stimulation to test the hypothesis of increases in both glutamate and GABA, two neurotransmitters with a key role...... that GABA is released in the human cerebral cortex during painful stimulation. The results are in line with animal findings on the role of GABA in pain processing and with studies in humans showing analgesic efficacy of GABA-related drugs in clinical pain conditions....... in pain processing. Using a 3T MR scanner, we acquired spectra from the rostral anterior cingulate cortex (rACC) in 13 healthy right-handed subjects at rest and during painful heat stimulation. The painful stimulus consisted of a suprathreshold painful tonic heat pulse, which was delivered to the right...

  17. Investigation of assumptions underlying current safety guidelines on EM-induced nerve stimulation

    Neufeld, Esra; Vogiatzis Oikonomidis, Ioannis; Iacono, Maria Ida; Angelone, Leonardo M.; Kainz, Wolfgang; Kuster, Niels

    2016-06-01

    An intricate network of a variety of nerves is embedded within the complex anatomy of the human body. Although nerves are shielded from unwanted excitation, they can still be stimulated by external electromagnetic sources that induce strongly non-uniform field distributions. Current exposure safety standards designed to limit unwanted nerve stimulation are based on a series of explicit and implicit assumptions and simplifications. This paper demonstrates the applicability of functionalized anatomical phantoms with integrated coupled electromagnetic and neuronal dynamics solvers for investigating the impact of magnetic resonance exposure on nerve excitation within the full complexity of the human anatomy. The impact of neuronal dynamics models, temperature and local hot-spots, nerve trajectory and potential smoothing, anatomical inhomogeneity, and pulse duration on nerve stimulation was evaluated. As a result, multiple assumptions underlying current safety standards are questioned. It is demonstrated that coupled EM-neuronal dynamics modeling involving realistic anatomies is valuable to establish conservative safety criteria.

  18. Paradoxical action of fulvestrant in estradiol-induced regression of tamoxifen-stimulated breast cancer.

    Osipo, Clodia; Gajdos, Csaba; Liu, Hong; Chen, Bin; Jordan, V Craig

    2003-11-05

    Long-term tamoxifen treatment of breast cancer can result in tamoxifen-stimulated breast cancer, in which estrogen inhibits tumor growth after tamoxifen withdrawal. We investigated the molecular mechanism(s) of estradiol-induced tumor regression by using an in vivo model of tamoxifen-stimulated human breast cancer. Growth of parental estradiol-stimulated MCF-7E2 and long-term tamoxifen-stimulated MCF-7TAMLT xenografts in athymic mice was measured during treatment with vehicle, estradiol, estradiol plus tamoxifen, tamoxifen alone, estradiol plus fulvestrant, or fulvestrant alone. Apoptosis was detected by the terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Protein expression was assessed by western blot analysis. mRNA expression was assessed by real-time reverse transcription-polymerase chain reaction. All statistical tests were two-sided. MCF-7E2 tumor growth was stimulated by estradiol (cross-sectional area at week 13 = 1.06 cm2, 95% confidence interval [CI] = 0.82 to 1.30 cm2; Pestradiol-induced regression to 0.18 cm2 (95% CI = 0.15 to 0.21 cm2; P<.001), and tamoxifen or estradiol plus fulvestrant enhanced tumor growth to 1.00 cm2 (95% CI = 0.88 to 1.22 cm2). Estradiol increased the number of apoptotic cells in tumors by 23% (95% CI = 20% to 26%; P<.001) compared with all other treatments, decreased estrogen receptor alpha(ERalpha) protein expression, increased the expression of Fas mRNA and protein, decreased the expression of HER2/neu mRNA and protein and nuclear factor kappaB (NF-kappaB) protein but did not affect Fas ligand protein expression compared with control. Paradoxically, fulvestrant reversed this effect and stimulated MCF-7TAMLT tumor growth apparently through ERalpha-mediated regulation of Fas, HER2/neu, and NF-kappaB. Physiologic levels of estradiol induced regression of tamoxifen-stimulated breast cancer tumors, apparently by inducing the death receptor Fas and suppressing the antiapoptotic

  19. Comparison of the induced fields using different coil configurations during deep transcranial magnetic stimulation.

    Mai Lu

    Full Text Available Stimulation of deeper brain structures by transcranial magnetic stimulation (TMS plays a role in the study of reward and motivation mechanisms, which may be beneficial in the treatment of several neurological and psychiatric disorders. However, electric field distributions induced in the brain by deep transcranial magnetic stimulation (dTMS are still unknown. In this paper, the double cone coil, H-coil and Halo-circular assembly (HCA coil which have been proposed for dTMS have been numerically designed. The distributions of magnetic flux density, induced electric field in an anatomically based realistic head model by applying the dTMS coils were numerically calculated by the impedance method. Results were compared with that of standard figure-of-eight (Fo8 coil. Simulation results show that double cone, H- and HCA coils have significantly deep field penetration compared to the conventional Fo8 coil, at the expense of induced higher and wider spread electrical fields in superficial cortical regions. Double cone and HCA coils have better ability to stimulate deep brain subregions compared to that of the H-coil. In the mean time, both double cone and HCA coils increase risk for optical nerve excitation. Our results suggest although the dTMS coils offer new tool with potential for both research and clinical applications for psychiatric and neurological disorders associated with dysfunctions of deep brain regions, the selection of the most suitable coil settings for a specific clinical application should be based on a balanced evaluation between stimulation depth and focality.

  20. Pharmacological modulation of cortical excitability shifts induced by transcranial direct current stimulation in humans.

    Nitsche, M A; Fricke, K; Henschke, U; Schlitterlau, A; Liebetanz, D; Lang, N; Henning, S; Tergau, F; Paulus, W

    2003-11-15

    Transcranial direct current stimulation (tDCS) of the human motor cortex results in polarity-specific shifts of cortical excitability during and after stimulation. Anodal tDCS enhances and cathodal stimulation reduces excitability. Animal experiments have demonstrated that the effect of anodal tDCS is caused by neuronal depolarisation, while cathodal tDCS hyperpolarises cortical neurones. However, not much is known about the ion channels and receptors involved in these effects. Thus, the impact of the sodium channel blocker carbamazepine, the calcium channel blocker flunarizine and the NMDA receptor antagonist dextromethorphane on tDCS-elicited motor cortical excitability changes of healthy human subjects were tested. tDCS-protocols inducing excitability alterations (1) only during tDCS and (2) eliciting long-lasting after-effects were applied after drug administration. Carbamazepine selectively eliminated the excitability enhancement induced by anodal stimulation during and after tDCS. Flunarizine resulted in similar changes. Antagonising NMDA receptors did not alter current-generated excitability changes during a short stimulation, which elicits no after-effects, but prevented the induction of long-lasting after-effects independent of their direction. These results suggest that, like in other animals, cortical excitability shifts induced during tDCS in humans also depend on membrane polarisation, thus modulating the conductance of sodium and calcium channels. Moreover, they suggest that the after-effects may be NMDA receptor dependent. Since NMDA receptors are involved in neuroplastic changes, the results suggest a possible application of tDCS in the modulation or induction of these processes in a clinical setting. The selective elimination of tDCS-driven excitability enhancements by carbamazepine proposes a role for this drug in focussing the effects of cathodal tDCS, which may have important future clinical applications.

  1. Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.

    Stavreva, Diana A; Wiench, Malgorzata; John, Sam; Conway-Campbell, Becky L; McKenna, Mervyn A; Pooley, John R; Johnson, Thomas A; Voss, Ty C; Lightman, Stafford L; Hager, Gordon L

    2009-09-01

    Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.

  2. Femoral perfusion after pulsed electromagnetic field stimulation in a steroid-induced osteonecrosis model.

    Ikegami, Akira; Ueshima, Keiichiro; Saito, Masazumi; Ikoma, Kazuya; Fujioka, Mikihiro; Hayashi, Shigeki; Ishida, Masashi; Fujiwara, Hiroyoshi; Mazda, Osam; Kubo, Toshikazu

    2015-07-01

    This study was designed to evaluate femoral perfusion after pulsed electromagnetic field (PEMF) stimulation in a steroid-induced osteonecrosis rabbit model by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Steroid-induced osteonecrosis was produced by single intramuscular injection of methylprednisolone in 15 rabbits. Eight rabbits underwent PEMF stimulation (PEMF group) and seven did not (control group). DCE-MRI was performed before PEMF stimulation, immediately before steroid administration, and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. Enhancement ratio (ER), initial slope (IS), and area under the curve (AUC) were analyzed. ER, IS, and AUC in the control group significantly decreased after steroid administration compared with before administration (P<0.05). In PEMF group, IS significantly decreased; however, ER and AUC showed no significant differences after steroid administration compared with before. ER and IS in PEMF group were higher than in control group until 10th day, and AUC was higher until 5th day after steroid administration (P<0.05). PEMF stimulation restrains the decrease in blood flow after steroid administration. © 2015 Wiley Periodicals, Inc.

  3. Non-invasive brain stimulation of motor cortex induces embodiment when integrated with virtual reality feedback.

    Bassolino, M; Franza, M; Bello Ruiz, J; Pinardi, M; Schmidlin, T; Stephan, M A; Solcà, M; Serino, A; Blanke, O

    2018-04-01

    Previous evidence highlighted the multisensory-motor origin of embodiment - that is, the experience of having a body and of being in control of it - and the possibility of experimentally manipulating it. For instance, an illusory feeling of embodiment towards a fake hand can be triggered by providing synchronous visuo-tactile stimulation to the hand of participants and to a fake hand or by asking participants to move their hand and observe a fake hand moving accordingly (rubber hand illusion). Here, we tested whether it is possible to manipulate embodiment not through stimulation of the participant's hand, but by directly tapping into the brain's hand representation via non-invasive brain stimulation. To this aim, we combined transcranial magnetic stimulation (TMS), to activate the hand corticospinal representation, with virtual reality (VR), to provide matching (as contrasted to non-matching) visual feedback, mimicking involuntary hand movements evoked by TMS. We show that the illusory embodiment occurred when TMS pulses were temporally matched with VR feedback, but not when TMS was administered outside primary motor cortex, (over the vertex) or when stimulating motor cortex at a lower intensity (that did not activate peripheral muscles). Behavioural (questionnaires) and neurophysiological (motor-evoked-potentials, TMS-evoked-movements) measures further indicated that embodiment was not explained by stimulation per se, but depended on the temporal coherence between TMS-induced activation of hand corticospinal representation and the virtual bodily feedback. This reveals that non-invasive brain stimulation may replace the application of external tactile hand cues and motor components related to volition, planning and anticipation. © 2018 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  4. Rats with decreased brain cholecystokinin levels show increased responsiveness to peripheral electrical stimulation-induced analgesia.

    Zhang, L X; Li, X L; Wang, L; Han, J S

    1997-01-16

    Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be endogenous opiate antagonist.

  5. Local mechanical stimulation induces components of the pathogen defense response in parsley

    Gus-Mayer, Sabine; Naton, Beatrix; Hahlbrock, Klaus; Schmelzer, Elmon

    1998-01-01

    Cell suspension cultures of parsley (Petroselinum crispum) have previously been used as a suitable system for studies of the nonhost resistance response to Phytophthora sojae. In this study, we replaced the penetrating fungus by local mechanical stimulation by using a needle of the same diameter as a fungal hypha, by local application of a structurally defined fungus-derived elicitor, or by a combination of the two stimuli. Similar to the fungal infection hypha, the local mechanical stimulus alone induced the translocation of cytoplasm and nucleus to the site of stimulation, the generation of intracellular reactive oxygen intermediates (ROI), and the expression of some, but not all, elicitor-responsive genes. When the elicitor was applied locally to the cell surface without mechanical stimulation, intracellular ROI also accumulated rapidly, but morphological changes were not detected. A combination of the mechanical stimulus with simultaneous application of low doses of elicitor closely simulated early reactions to fungal infection, including cytoplasmic aggregation, nuclear migration, and ROI accumulation. By contrast, cytoplasmic rearrangements were impaired at high elicitor concentrations. Neither papilla formation nor hypersensitive cell death occurred under the conditions tested. These results suggest that mechanical stimulation by the invading fungus is responsible for the observed intracellular rearrangements and may trigger some of the previously demonstrated changes in the activity of elicitor-responsive genes, whereas chemical stimulation is required for additional biochemical processes. As yet unidentified signals may be involved in papilla formation and hypersensitive cell death. PMID:9653198

  6. Chronological changes in astrocytes induced by chronic electrical sensorimotor cortex stimulation in rats.

    Morishita, Takashi; Yamashita, Akiko; Katayama, Yoichi; Oshima, Hideki; Nishizaki, Yuji; Shijo, Katsunori; Fukaya, Chikashi; Yamamoto, Takamitsu

    2011-01-01

    Motor cortex stimulation (MCS) is a treatment option for various disorders such as medically refractory pain, poststroke hemiplegia, and movement disorders. However, the exact mechanisms underlying its effects remain unknown. In this study, the effects of long-term chronic MCS were investigated by observing changes in astrocytes. A quadripolar stimulation electrode was implanted on the dura over the sensorimotor cortex of adult rats, and the cortex was continuously stimulated for 3 hours, 1 week, 4 weeks, and 8 weeks. Immunohistochemical staining of microglia (ionized calcium-binding adaptor molecule 1 [Iba1] staining) and astrocytes (glial fibrillary acidic protein [GFAP] staining), and neuronal degeneration histochemistry (Fluoro-Jade B staining) were carried out to investigate the morphological changes following long-term chronic MCS. Iba1 staining and Fluoro-Jade B staining showed no evidence of Iba1-positive microglial changes or neurodegeneration. Following continuous MCS, GFAP-positive astrocytes were enlarged and their number increased in the cortex and the thalamus of the stimulated hemisphere. These findings indicate that chronic electrical stimulation can continuously activate astrocytes and result in morphological and quantitative changes. These changes may be involved in the mechanisms underlying the neuroplasticity effect induced by MCS.

  7. Caloric stimulation with near infrared radiation does not induce paradoxical nystagmus.

    Walther, L E; Asenov, D R; Di Martino, E

    2011-04-01

    Near infrared radiation can be used for warm stimulation in caloric irrigation of the equilibrium organ. Aim of this study was to determine whether near infrared radiation offers effective stimulation of the vestibular organ, whether it is well tolerated by the patients and especially whether it is a viable alternative to warm air stimulation in patients with defects of the tympanic membrane and radical mastoid cavities. Patients with perforations of the tympanic membrane (n = 15) and with radical mastoid cavities (n = 13) were tested both with near infrared radiation and warm dry air. A caloric-induced nystagmus could be seen equally effectively and rapidly in all patients. Contrary to stimulation with warm dry air, no paradoxical nystagmus was observed following caloric irrigation with a warm stimulus (near infrared radiation). Results of a questionnaire showed excellent patient acceptance of near infrared stimulation with no arousal effects or unpleasant feeling. In conclusion, near infrared radiation proved to be an alternative method of caloric irrigation to warm dry air in patients with tympanic membrane defects and radical mastoid cavities. Near infrared radiation is pleasant, quick, contact free, sterile and quiet. With this method an effective caloric warm stimulus is available. If near infrared radiation is used for caloric stimulus no evaporative heat loss occurs.

  8. Adaptation to Cortical Noise Induced by Transcranial Magnetic Stimulation to the Occipital Lobe

    David Heslip

    2012-05-01

    Full Text Available Transcranial magnetic stimulation (TMS is increasingly used as a method to modify and study functional brain activity. However, results from various studies have produced conflicting theories on how TMS of cortical tissue influences ongoing visual processing. To investigate this issue, single pulse TMS was applied over left V1 in five healthy subjects during an orientation discrimination task (vertical vs. horizontal using a Gabor patch (2 c/deg, presented 6° in the right visual field. Stimulus contrast was set to each individual's threshold, measured in the absence of TMS. When TMS was applied over V1 performance decreased in all observers (by 1.2–8.7% compared to accuracy levels obtained during stimulation of a control site (Cz. Crucially, accuracy levels during V1 stimulation gradually improved across blocks of 200 trials in some subjects, whereas performance remained stable during control site stimulation. In contrast, this pattern of recovery was not found in an analogous backward masking paradigm, using a brief visual noise mask instead of a TMS pulse. These results show that that the magnitude of TMS disruption can dissipate with repeated stimulation. This suggests that future studies using this technique should minimise the length of TMS exposure within each session to maximise its effectiveness. Our results show that the visual system can adapt dynamically to increased internal noise levels, minimising the impact of TMS induced cortical activity on sensory judgments.

  9. Vagal stimulation targets select populations of intrinsic cardiac neurons to control neurally induced atrial fibrillation

    Salavatian, Siamak; Beaumont, Eric; Longpré, Jean-Philippe; Armour, J. Andrew; Vinet, Alain; Jacquemet, Vincent; Shivkumar, Kalyanam

    2016-01-01

    Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)-sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P < 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory. PMID:27591222

  10. Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin.

    Chyczewska, E; Chyczewski, L; Bańkowski, E; Sułkowski, S; Nikliński, J

    1993-01-01

    It was found that the BCG vaccine injected subcutaneously to the rats enhances the process of lung fibrosis induced by bleomycin. Pretreatment of rats with this vaccine results in accumulation of activated macrophages in lung interstitium and in the bronchoalveolar spaces. It may be suggested that the activated macrophages release various cytokines which may stimulate the proliferation of fibroblasts and biosynthesis of extracellular matrix components.

  11. Effect of Contour Shape of Nervous System Electromagnetic Stimulation Coils on the Induced Electrical Field Distribution

    Daskalov Ivan K

    2002-05-01

    Full Text Available Abstract Background Electromagnetic stimulation of the nervous system has the advantage of reduced discomfort in activating nerves. For brain structures stimulation, it has become a clinically accepted modality. Coil designs usually consider factors such as optimization of induced power, focussing, field shape etc. In this study we are attempting to find the effect of the coil contour shape on the electrical field distribution for magnetic stimulation. Method and results We use the maximum of the induced electric field stimulation in the region of interest as the optimization criterion. This choice required the application of the calculus of variation, with the contour perimeter taken as a pre-set condition. Four types of coils are studied and compared: circular, square, triangular and an 'optimally' shaped contour. The latter yields higher values of the induced electrical field in depths up to about 30 mm, but for depths around 100 mm, the circular shape has a slight advantage. The validity of the model results was checked by experimental measurements in a tank with saline solution, where differences of about 12% were found. In view the accuracy limitations of the computational and measurement methods used, such differences are considered acceptable. Conclusion We applied an optimization approach, using the calculus of variation, which allows to obtain a coil contour shape corresponding to a selected criterion. In this case, the optimal contour showed higher intensities for a longer line along the depth-axis. The method allows modifying the induced field structure and focussing the field to a selected zone or line.

  12. Relationship Between Non-invasive Brain Stimulation-induced Plasticity and Capacity for Motor Learning.

    López-Alonso, Virginia; Cheeran, Binith; Fernández-del-Olmo, Miguel

    2015-01-01

    Cortical plasticity plays a key role in motor learning (ML). Non-invasive brain stimulation (NIBS) paradigms have been used to modulate plasticity in the human motor cortex in order to facilitate ML. However, little is known about the relationship between NIBS-induced plasticity over M1 and ML capacity. NIBS-induced MEP changes are related to ML capacity. 56 subjects participated in three NIBS (paired associative stimulation, anodal transcranial direct current stimulation and intermittent theta-burst stimulation), and in three lab-based ML task (serial reaction time, visuomotor adaptation and sequential visual isometric pinch task) sessions. After clustering the patterns of response to the different NIBS protocols, we compared the ML variables between the different patterns found. We used regression analysis to explore further the relationship between ML capacity and summary measures of the MEPs change. We ran correlations with the "responders" group only. We found no differences in ML variables between clusters. Greater response to NIBS protocols may be predictive of poor performance within certain blocks of the VAT. "Responders" to AtDCS and to iTBS showed significantly faster reaction times than "non-responders." However, the physiological significance of these results is uncertain. MEP changes induced in M1 by PAS, AtDCS and iTBS appear to have little, if any, association with the ML capacity tested with the SRTT, the VAT and the SVIPT. However, cortical excitability changes induced in M1 by AtDCS and iTBS may be related to reaction time and retention of newly acquired skills in certain motor learning tasks. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Regularity increases middle latency evoked and late induced beta brain response following proprioceptive stimulation

    Arnfred, Sidse M.; Hansen, Lars Kai; Parnas, Josef

    2008-01-01

    as an indication of increased readiness. This is achieved through detailed analysis of both evoked and induced responses in the time-frequency domain. Electroencephalography in a 64 channels montage was recorded in four-teen healthy subjects. Two paradigms were explored: A Regular alternation between hand......). After initial exploration of the AvVVT and Induced collapsed files of all subjects using two-way factor analyses (Non-Negative Matrix Factorization), further data decomposition was performed in restricted windows of interest (WOI). Main effects of side of stimulation, onset or offset, regularity...

  14. Multimodal responses induced by cortical stimulation of the parietal lobe: a stereo-electroencephalography study.

    Balestrini, Simona; Francione, Stefano; Mai, Roberto; Castana, Laura; Casaceli, Giuseppe; Marino, Daniela; Provinciali, Leandro; Cardinale, Francesco; Tassi, Laura

    2015-09-01

    The functional complexity of the parietal lobe still represents a challenge for neurophysiological and functional neuroimaging studies. While the somatosensory functions of the anterior parietal cortex are well established, the posterior parietal cortex has a relevant role in processing the sensory information, including visuo-spatial perception, visual attention, visuo-motor transformations and other complex and not completely understood functions. We retrospectively analysed all the clinical manifestations induced by intracerebral bipolar electrical stimulation in 172 patients suffering from drug-resistant focal epilepsy (mean age 25.6, standard deviation 11.6; 44% females and 56% males) with at least one electrode stereotactically implanted in the parietal cortex. A total of 1186 electrical stimulations were included in the analysis, of which 88 were subsequently excluded because of eliciting pathological electric activity or inducing ictal symptomatology. In the dominant parietal lobe, clinical responses were observed for 56 (25%) of the low-frequency stimulations and for 76 (50%) of the high-frequency stimulations. In the non-dominant parietal lobe, 111 (27%) low-frequency and 176 (55%) high-frequency stimulations were associated with a clinical response. Body scheme alteration was the only clinical effect showing a lateralization, as they were evoked only in the non-dominant hemisphere. The occurrence of somatosensory sensations, motor symptoms, dysarthria and multimodal responses were significantly associated with stimulation of the postcentral gyrus (odds ratio: 5.83, P < 0.001; odds ratio: 8.77, P < 0.001; odds ratio: 5.44, P = 0.011; odds ratio: 8.33, P = 0.006; respectively). Stimulation of the intraparietal sulcus was associated with the occurrence of sensory illusions or hallucinations (odds ratio: 8.68, P < 0.001) and eyeball/eyelid movements or sensations (odds ratio: 4.35, P = 0.047). To our knowledge, this is the only currently available complete

  15. Differential inhibitory effect on human nociceptive skin senses induced by local stimulation of thin cutaneous fibers.

    Nilsson, H J; Schouenborg, J

    1999-03-01

    It is known that stimulation of thin cutaneous nerve fibers can induce long lasting analgesia through both supraspinal and segmental mechanisms, the latter often exhibiting restricted receptive fields. On this basis, we recently developed a new method, termed cutaneous field stimulation (CFS), for localized stimulation of A delta and C fibers in the superficial part of the skin. In the present study, we have evaluated the effects of CFS on non-nociceptive and nociceptive skin senses. We compared the effects of CFS with those of conventional transcutaneous electrical nerve stimulation (TENS), known to preferentially activate coarse myelinated fibers. A battery of sensory tests were made on the right volar forearm of 20 healthy subjects. CFS (16 electrodes, 4 Hz per electrode, 1 ms, up to 0.8 mA) and TENS (100 Hz, 0.2 ms, up to 26 mA) applied either on the right volar forearm (homotopically), or on the lower right leg (heterotopically) were used as conditioning stimulation for 25 min. The tactile threshold was not affected by either homo- or heterotopical CFS or TENS. The mean thresholds for detecting warming or cooling of the skin were increased by 0.4-0.9 degrees C after homo- but not heterotopical CFS and TENS. Regarding nociceptive skin senses, homo- but not heterotopical CFS, markedly reduced CO2-laser evoked A delta- and C fiber mediated heat pain to 75 and 48% of control, respectively, and mechanically evoked pain to 73% of control. Fabric evoked prickle, was not affected by CFS. Neither homo- nor heterotopical TENS induced any marked analgesic effects. It is concluded that different qualities of nociception can be differentially controlled by CFS.

  16. Transcranial Stimulation of the Dorsolateral Prefrontal Cortex Prevents Stress-Induced Working Memory Deficits.

    Bogdanov, Mario; Schwabe, Lars

    2016-01-27

    Stress is known to impair working memory performance. This disruptive effect of stress on working memory has been linked to a decrease in the activity of the dorsolateral prefrontal cortex (dlPFC). In the present experiment, we tested whether transcranial direct current stimulation (tDCS) of the dlPFC can prevent stress-induced working memory impairments. We tested 120 healthy participants in a 2 d, sham-controlled, double-blind between-subjects design. Participants completed a test of their individual baseline working memory capacity on day 1. On day 2, participants were exposed to either a stressor or a control manipulation before they performed a visuospatial and a verbal working memory task. While participants completed the tasks, anodal, cathodal, or sham tDCS was applied over the right dlPFC. Stress impaired working memory performance in both tasks, albeit to a lesser extent in the verbal compared with the visuospatial working memory task. This stress-induced working memory impairment was prevented by anodal, but not sham or cathodal, stimulation of the dlPFC. Compared with sham or cathodal stimulation, anodal tDCS led to significantly better working memory performance in both tasks after stress. Our findings indicate a causal role of the dlPFC in working memory impairments after acute stress and point to anodal tDCS as a promising tool to reduce cognitive deficits related to working memory in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder. Working memory deficits are prominent in stress-related mental disorders, such as depression, schizophrenia, or post-traumatic stress disorder. Similar working memory impairments have been observed in healthy individuals exposed to acute stress. So far, attempts to prevent such stress-induced working memory deficits focused mainly on pharmacological interventions. Here, we tested the idea that transcranial direct current stimulation of the dorsolateral prefrontal

  17. Spontaneous and stimulated emission induced by an electron, electron bunch, and electron beam in a plasma

    Kuzelev, M V; Rukhadze, A A

    2008-01-01

    Two fundamental mechanisms - the Cherenkov effect and anomalous Doppler effect - underlying the emission by an electron during its superluminal motion in medium are considered. Cherenkov emission induced by a single electron and a small electron bunch is spontaneous. In the course of spontaneous Cherenkov emission, the translational motion of an electron is slowed down and the radiation energy grows linearly with time. As the number of radiating electrons increases, Cherenkov emission becomes stimulated. Stimulated Cherenkov emission represents a resonance beam instability. This emission process is accompanied by longitudinal electron bunching in the beam or by the breaking of an electron bunch into smaller bunches, in which case the radiation energy grows exponentially with time. In terms of the longitudinal size L e of the electron bunch there is a transition region λ e 0 -1 between the spontaneous and stimulated Cherenkov effects, where λ is the average radiation wavelength, and δ 0 is the dimensionless (in units of the radiation frequency) growth rate of the Cherenkov beam instability. The range to the left of this region is dominated by spontaneous emission, whereas the range to the right of this region is dominated by stimulated emission. In contrast to the Vavilov-Cherenkov effect, the anomalous Doppler effect should always (even for a single electron) be considered as stimulated, because it can only be explained by accounting for the reverse action of the radiation field on the moving electron. During stimulated emission in conditions where anomalous Doppler effect shows itself, an electron is slowed down and spins up; in this case, the radiation energy grows exponentially with time. (reviews of topical problems)

  18. The H2O2 scavenger ebselen decreases ethanol-induced locomotor stimulation in mice.

    Ledesma, Juan Carlos; Font, Laura; Aragon, Carlos M G

    2012-07-01

    In the brain, the enzyme catalase by reacting with H(2)O(2) forms Compound I (catalase-H(2)O(2) system), which is the main system of central ethanol metabolism to acetaldehyde. Previous research has demonstrated that acetaldehyde derived from central-ethanol metabolism mediates some of the psychopharmacological effects produced by ethanol. Manipulations that modulate central catalase activity or sequester acetaldehyde after ethanol administration modify the stimulant effects induced by ethanol in mice. However, the role of H(2)O(2) in the behavioral effects caused by ethanol has not been clearly addressed. The present study investigated the effects of ebselen, an H(2)O(2) scavenger, on ethanol-induced locomotion. Swiss RjOrl mice were pre-treated with ebselen (0-50mg/kg) intraperitoneally (IP) prior to administration of ethanol (0-3.75g/kg; IP). In another experiment, animals were pre-treated with ebselen (0 or 25mg/kg; IP) before caffeine (15mg/kg; IP), amphetamine (2mg/kg; IP) or cocaine (10mg/kg; IP) administration. Following these treatments, animals were placed in an open field to measure their locomotor activity. Additionally, we evaluated the effect of ebselen on the H(2)O(2)-mediated inactivation of brain catalase activity by 3-amino-1,2,4-triazole (AT). Ebselen selectively prevented ethanol-induced locomotor stimulation without altering the baseline activity or the locomotor stimulating effects caused by caffeine, amphetamine and cocaine. Ebselen reduced the ability of AT to inhibit brain catalase activity. Taken together, these data suggest that a decline in H(2)O(2) levels might result in a reduction of the ethanol locomotor-stimulating effects, indicating a possible role for H(2)O(2) in some of the psychopharmacological effects produced by ethanol. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  19. Stimulation Induced Electrographic Seizures in Deep Brain Stimulation of the Anterior Nucleus of the Thalamus Do Not Preclude a Subsequent Favorable Treatment Response.

    Nora, Tommi; Heinonen, Hanna; Tenhunen, Mirja; Rainesalo, Sirpa; Järvenpää, Soila; Lehtimäki, Kai; Peltola, Jukka

    2018-01-01

    Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a method of neuromodulation used for refractory focal epilepsy. We report a patient suffering from drug-resistant epilepsy who developed novel visual symptoms and atypical seizures with the onset of ANT-DBS therapy. Rechallenge under video electroencephalography recording confirmed that lowering the stimulation voltage alleviated these symptoms. Subsequent stimulation with the initial voltage value did not cause the recurrence of either the visual symptoms or the new seizure type, and appeared to alleviate the patient's seizures in long-term follow-up. We therefore hypothesize that the occurrence of stimulation induced seizures at the onset of DBS therapy should not be considered as a failure in the DBS therapy, and the possibility of a subsequent favorable response to the treatment still exists.

  20. Stimulation Induced Electrographic Seizures in Deep Brain Stimulation of the Anterior Nucleus of the Thalamus Do Not Preclude a Subsequent Favorable Treatment Response

    Tommi Nora

    2018-02-01

    Full Text Available Deep brain stimulation (DBS of the anterior nucleus of the thalamus (ANT is a method of neuromodulation used for refractory focal epilepsy. We report a patient suffering from drug-resistant epilepsy who developed novel visual symptoms and atypical seizures with the onset of ANT-DBS therapy. Rechallenge under video electroencephalography recording confirmed that lowering the stimulation voltage alleviated these symptoms. Subsequent stimulation with the initial voltage value did not cause the recurrence of either the visual symptoms or the new seizure type, and appeared to alleviate the patient’s seizures in long-term follow-up. We therefore hypothesize that the occurrence of stimulation induced seizures at the onset of DBS therapy should not be considered as a failure in the DBS therapy, and the possibility of a subsequent favorable response to the treatment still exists.

  1. Ganglionated plexi stimulation induces pulmonary vein triggers and promotes atrial arrhythmogenecity: In silico modeling study.

    Minki Hwang

    Full Text Available The role of the autonomic nervous system (ANS on atrial fibrillation (AF is difficult to demonstrate in the intact human left atrium (LA due to technical limitations of the current electrophysiological mapping technique. We examined the effects of the ANS on the initiation and maintenance of AF by employing a realistic in silico human left atrium (LA model integrated with a model of ganglionated plexi (GPs.We incorporated the morphology of the GP and parasympathetic nerves in a three-dimensional (3D realistic LA model. For the model of ionic currents, we used a human atrial model. GPs were stimulated by increasing the IK[ACh], and sympathetic nerve stimulation was conducted through a homogeneous increase in the ICa-L. ANS-induced wave-dynamics changes were evaluated in a model that integrated a patient's LA geometry, and we repeated simulation studies using LA geometries from 10 different patients.The two-dimensional model of pulmonary vein (PV cells exhibited late phase 3 early afterdepolarization-like activity under 0.05μM acetylcholine (ACh stimulation. In the 3D simulation model, PV tachycardia was induced, which degenerated to AF via GP (0.05μM ACh and sympathetic (7.0×ICa-L stimulations. Under sustained AF, local reentries were observed at the LA-PV junction. We also observed that GP stimulation reduced the complex fractionated atrial electrogram (CFAE-cycle length (CL, p<0.01 and the life span of phase singularities (p<0.01. GP stimulation also increased the overlap area of the GP and CFAE areas (CFAE-CL≤120ms, p<0.01. When 3 patterns of virtual ablations were applied to the 3D AF models, circumferential PV isolation including the GP was the most effective in terminating AF.Cardiac ANS stimulations demonstrated triggered activity, automaticity, and local reentries at the LA-PV junction, as well as co-localized GP and CFAE areas in the 3D in silico GP model of the LA.

  2. Proteinase-activated receptor 4 stimulation-induced epithelial-mesenchymal transition in alveolar epithelial cells

    Araki Hiromasa

    2007-04-01

    Full Text Available Abstract Background Proteinase-activated receptors (PARs; PAR1–4 that can be activated by serine proteinases such as thrombin and neutrophil catepsin G are known to contribute to the pathogenesis of various pulmonary diseases including fibrosis. Among these PARs, especially PAR4, a newly identified subtype, is highly expressed in the lung. Here, we examined whether PAR4 stimulation plays a role in the formation of fibrotic response in the lung, through alveolar epithelial-mesenchymal transition (EMT which contributes to the increase in myofibroblast population. Methods EMT was assessed by measuring the changes in each specific cell markers, E-cadherin for epithelial cell, α-smooth muscle actin (α-SMA for myofibroblast, using primary cultured mouse alveolar epithelial cells and human lung carcinoma-derived alveolar epithelial cell line (A549 cells. Results Stimulation of PAR with thrombin (1 U/ml or a synthetic PAR4 agonist peptide (AYPGKF-NH2, 100 μM for 72 h induced morphological changes from cobblestone-like structure to elongated shape in primary cultured alveolar epithelial cells and A549 cells. In immunocytochemical analyses of these cells, such PAR4 stimulation decreased E-cadherin-like immunoreactivity and increased α-SMA-like immunoreactivity, as observed with a typical EMT-inducer, tumor growth factor-β (TGF-β. Western blot analyses of PAR4-stimulated A549 cells also showed similar changes in expression of these EMT-related marker proteins. Such PAR4-mediated changes were attenuated by inhibitors of epidermal growth factor receptor (EGFR kinase and Src. PAR4-mediated morphological changes in primary cultured alveolar epithelial cells were reduced in the presence of these inhibitors. PAR4 stimulation increased tyrosine phosphorylated EGFR or tyrosine phosphorylated Src level in A549 cells, and the former response being inhibited by Src inhibitor. Conclusion PAR4 stimulation of alveolar epithelial cells induced epithelial

  3. Induced absorption and stimulated emission in a driven two-level atom

    Mavroyannis, C.

    1992-01-01

    We have considered the induced processes that occur in a driven two-level atom, where a laser photon is absorbed and emitted by the ground and by the excited states of the atom, respectively. In the low-intensity limit of the laser field, the induced spectra arising when a laser photon is absorbed by the ground state of the atom consist of two peaks describing induced absorption and stimulated-emission processes, respectively, where the former prevails over the latter. Asymmetry of the spectral lines occurs at off-resonance and its extent depends on the detuning of the laser field. The physical. process where a laser photon is emitted by the excited state is the reverse of that arising from the absorption of a laser photon by the ground state of the atom. The former differs from the latter in that the emission of a laser photon by the excited state occurs in the low frequency regime and that the stimulated-emission process prevails over that of the induced absorption. In this case, amplification of ultrashort pulses is likely to occur without the need of population inversion between the optical transitions. The computed spectra are graphically presented and discussed. (author)

  4. Diosgenin induces apoptosis in IGF-1-stimulated human thyrocytes through two caspase-dependent pathways

    Mu, Shumin; Tian, Xingsong; Ruan, Yongwei; Liu, Yuantao; Bian, Dezhi; Ma, Chunyan; Yu, Chunxiao; Feng, Mei; Wang, Furong; Gao, Ling; Zhao, Jia-jun

    2012-01-01

    Highlights: ► Diosgenin induces apoptosis in IGF-1-treated thyrocytes through two caspase pathways. ► Diosgenin inhibits FLIP and activates caspase-8 in FAS related-pathway. ► Diosgenin increases ROS, regulates the ratio of Bax/Bcl-2 in mitochondrial pathway. -- Abstract: Insulin-like growth factor-1 (IGF-1) is a growth factor of the thyroid that has been shown in our previous study to possess proliferative and antiapoptotic effects in FRTL-5 cell lines through the upregulation of cyclin D and Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). Diosgenin, a natural steroid sapogenin from plants, has been shown to induce apoptosis in many cell lines, with the exception of thyroid cells. In this report, we investigated the apoptotic effect and mechanism of diosgenin in IGF-1-stimulated primary human thyrocytes. Primary human thyrocytes were preincubated with or without IGF-1 for 24 h and subsequently exposed to varying concentrations of diosgenin for different times. We found that diosgenin induced apoptosis in human thyrocytes pretreated with IGF-1 in a dose-dependent manner through the activation of caspase cascades. Moreover, diosgenin inhibited FLIP and activated caspase-8 in the FAS-related apoptotic pathway. Diosgenin increased the production of ROS, regulated the balance of Bax and Bcl-2 and cleaved caspase-9 in the mitochondrial apoptotic pathway. These results indicate that diosgenin induces apoptosis in IGF-1-stimulated primary human thyrocytes through two caspase-dependent pathways.

  5. THMC Modeling of EGS Reservoirs -- Continuum through Discontinuum Representations. Capturing Reservoir Stimulation, Evolution and Induced Seismicity

    Elsworth, Derek [Pennsylvania State Univ., State College, PA (United States); Izadi, Ghazal [Pennsylvania State Univ., State College, PA (United States); Gan, Quan [Pennsylvania State Univ., State College, PA (United States); Fang, Yi [Pennsylvania State Univ., State College, PA (United States); Taron, Josh [US Geological Survey, Menlo Park, CA (United States); Sonnenthal, Eric [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2015-07-28

    This work has investigated the roles of effective stress induced by changes in fluid pressure, temperature and chemistry in contributing to the evolution of permeability and induced seismicity in geothermal reservoirs. This work has developed continuum models [1] to represent the progress or seismicity during both stimulation [2] and production [3]. These methods have been used to resolve anomalous observations of induced seismicity at the Newberry Volcano demonstration project [4] through the application of modeling and experimentation. Later work then focuses on the occurrence of late stage seismicity induced by thermal stresses [5] including the codifying of the timing and severity of such responses [6]. Furthermore, mechanistic linkages between observed seismicity and the evolution of permeability have been developed using data from the Newberry project [7] and benchmarked against field injection experiments. Finally, discontinuum models [8] incorporating the roles of discrete fracture networks have been applied to represent stimulation and then thermal recovery for new arrangements of geothermal wells incorporating the development of flow manifolds [9] in order to increase thermal output and longevity in EGS systems.

  6. A new method to determine reflex latency induced by high rate stimulation of the nervous system

    Ilhan eKaracan

    2014-07-01

    Full Text Available High rate stimulations of the neuromuscular system, such as continuous whole body vibration, tonic vibration reflex and high frequency electrical stimulation, are used in the physiological research with an increasing interest. In these studies, the neuronal circuitries underlying the reflex responses remain unclear due to the problem of determining the exact reflex latencies. We present a novel cumulated average method to determine the reflex latency during high rate stimulation of the nervous system which was proven to be significantly more accurate than the classical method. The classical method, cumulant density analysis, reveals the relationship between the two synchronously recorded signals as a function of the lag between the signals. The comparison of new method with the classical technique and their relative accuracy was tested using a computer simulation. In the simulated signals the EMG response latency was constructed to be exactly 40 ms. The new method accurately indicated the value of the simulated reflex latency (40 ms. However, the classical method showed that the lag time between the simulated triggers and the simulated signals was 49 ms. Simulation results illustrated that the cumulated average method is a reliable and more accurate method compared with the classical method. We therefore suggest that the new cumulated average method is able to determine the high rate stimulation induced reflex latencies more accurately than the classical method.

  7. GABAergic modulation of DC stimulation-induced motor cortex excitability shifts in humans.

    Nitsche, Michael A; Liebetanz, David; Schlitterlau, Anett; Henschke, Undine; Fricke, Kristina; Frommann, Kai; Lang, Nicolas; Henning, Stefan; Paulus, Walter; Tergau, Frithjof

    2004-05-01

    Weak transcranial DC stimulation (tDCS) of the human motor cortex results in excitability shifts during and after the end of stimulation, which are most probably localized intracortically. Anodal stimulation enhances excitability, whereas cathodal stimulation reduces it. Although the after-effects of tDCS are NMDA receptor-dependent, nothing is known about the involvement of additional receptors. Here we show that pharmacological strengthening of GABAergic inhibition modulates selectively the after-effects elicited by anodal tDCS. Administration of the GABA(A) receptor agonist lorazepam resulted in a delayed, but then enhanced and prolonged anodal tDCS-induced excitability elevation. The initial absence of an excitability enhancement under lorazepam is most probably caused by a loss of the anodal tDCS-generated intracortical diminution of inhibition and enhancement of facilitation, which occurs without pharmacological intervention. The reasons for the late-occurring excitability enhancement remain unclear. Because intracortical inhibition and facilitation are not changed in this phase compared with pre-tDCS values, excitability changes originating from remote cortical or subcortical areas could be involved.

  8. Increased rate of repair of ultraviolet-induced DNA strand breaks in mitogen stimulated lymphocytes

    Hamlet, S.M.; Lavin, M.F.; Jennings, P.A. (Queensland Univ., St. Lucia (Australia). Dept. of Biochemistry; Queensland Univ., St. Lucia (Australia). Dept. of Veterinary Pathology; Queensland Univ. St. Lucia (Australia). Dept. of Public Health)

    1982-05-01

    Previous results have shown that phytohaemagglutinin-stimulated bovine lymphocytes exhibit a peak of ultraviolet-induced DNA repair synthesis 3 to 4 days after addition of mitogen. The level of repair synthesis was approximately tenfold higher than that in unstimulated lymphocytes. These studies have been extended to examine the rate of repair of strand breaks in U.V.-irradiated bovine lymphocytes. The extent of breakage of DNA was shown to be the same in mitogen-stimulated and unstimulated lymphocytes from two breeds of cattle, when determined by sedimentation of nucleoids on sucrose gradients. However, in mitogen-stimulated cells the time taken to repair DNA strand breaks was 6 hours compared with 12 hours in stationary phase lymphocytes after a U.V. dose of 5 J/m/sup 2/. These results suggest that the increased rate of repair of strand breaks is due to the induction of enzymes involved at the post-incision stage of DNA repair. Thus the increased level of repair synthesis observed in earlier work correlates with an increased rate of repair of DNA strand breaks in phytohaemagglutinin-stimulated bovine lymphocytes.

  9. Increased rate of repair of ultraviolet-induced DNA strand breaks in mitogen stimulated lymphocytes

    Hamlet, S.M.; Lavin, M.F.; Jennings, P.A.; Queensland Univ., St. Lucia; Queensland Univ. St. Lucia

    1982-01-01

    Previous results have shown that phytohaemagglutinin-stimulated bovine lymphocytes exhibit a peak of ultraviolet-induced DNA repair synthesis 3 to 4 days after addition of mitogen. The level of repair synthesis was approximately tenfold higher than that in unstimulated lymphocytes. These studies have been extended to examine the rate of repair of strand breaks in U.V.-irradiated bovine lymphocytes. The extent of breakage of DNA was shown to be the same in mitogen-stimulated and unstimulated lymphocytes from two breeds of cattle, when determined by sedimentation of nucleoids on sucrose gradients. However, in mitogen-stimulated cells the time taken to repair DNA strand breaks was 6 hours compared with 12 hours in stationary phase lymphocytes after a U.V. dose of 5 J/m 2 . These results suggest that the increased rate of repair of strand breaks is due to the induction of enzymes involved at the post-incision stage of DNA repair. Thus the increased level of repair synthesis observed in earlier work correlates with an increased rate of repair of DNA strand breaks in phytohaemagglutinin-stimulated bovine lymphocytes. (author)

  10. Vasomotor response to cold stimulation in human capsaicin-induced hyperalgesic area.

    Pud, Dorit; Andersen, Ole Kaeseler; Arendt-Nielsen, Lars; Eisenberg, Elon; Yarnitsky, David

    2005-07-01

    Cooling the skin induces sympathetically driven vasoconstriction, with some vasoparalytic dilatation at the lowest temperatures. Neurogenic inflammation, on the other hand, entails vasodilatation. In this study we investigated the balance between vasoconstriction and vasodilatation in an area of experimentally induced secondary hyperalgesia (2 degrees HA), in response to low-temperature stimulations. Fourteen healthy volunteers were exposed to three 30-s long cold stimuli (20, 10, and 0 degrees C) applied, at three adjacent sites, before (baseline) and 8 min after intradermal injection of 50 microg capsaicin to the volar forearm. The cold stimuli were applied distally to the injection site within the 2 degrees HA. Blood flux (BF) and skin temperatures were measured at four different regions (proximally, and distally to the capsaicin injection and at the 0, 10, and 20 degrees C thermode sites) all within the 2 degrees HA. The vascular measurements were conducted five times. Results showed a marked increase in BF after baseline cold stimulation (Peffect (elevated BF) was found following the capsaicin injection compared with baseline for all regions (Pcooled area was dilated by 450+/-5.1%; The vasoconstrictive effect for the 10 and 20 degrees C did not overcome the capsaicin vasodilatation, but did reduce it, with dilatation of 364+/-7.0% and 329+/-7.3%, respectively. For 0 degrees C, a dilatation of 407+/-6.5% was seen. It is concluded that in this experimental model, and potentially in the equivalent clinical syndromes, vasodilatation induced by the inflammation is only slightly reduced by cold stimulation such that it is still dominant, despite some cold-induced vasoconstriction.

  11. Basic calcium phosphate crystal-induced Egr-1 expression stimulates mitogenesis in human fibroblasts

    Zeng, Xiao R.; Sun Yubo; Wenger, Leonor; Cheung, Herman S.

    2005-01-01

    Previously, we have reported that basic calcium phosphate (BCP) crystals stimulate mitogenesis and synthesis of matrix metalloproteinases in cultured human foreskin and synovial fibroblasts. However, the detailed mechanisms involved are still unclear. In the present study, using RT-PCR and Egr-1 promoter analysis we showed that BCP crystals could stimulate early growth response gene Egr-1 transcription through a PKCα-dependent p44/p42 MAPK pathway. Using a retrovirus gene expression system (Clontech) to overexpress Egr-1 in human fibroblast BJ-1 cells resulted in promotion of mitogenesis measured either by MTT cell proliferation analysis or by direct cell counting. The results demonstrate that Egr-1 may play a key role in mediating BCP crystal-induced synovial fibroblast mitogenesis

  12. A Novel Transcranial Magnetic Stimulator Inducing Near Rectangular Pulses with Controllable Pulse Width (cTMS)

    Jalinous, Reza; Lisanby, Sarah H.

    2013-01-01

    A novel transcranial magnetic stimulation (TMS) device with controllable pulse width (PW) and near rectangular pulse shape (cTMS) is described. The cTMS device uses an insulated gate bipolar transistor (IGBT) with appropriate snubbers to switch coil currents up to 7 kA, enabling PW control from 5 μs to over 100 μs. The near-rectangular induced electric field pulses use 22–34% less energy and generate 67–72% less coil heating compared to matched conventional cosine pulses. CTMS is used to stimulate rhesus monkey motor cortex in vivo with PWs of 20 to 100 μs, demonstrating the expected decrease of threshold pulse amplitude with increasing PW. The technological solutions used in the cTMS prototype can expand functionality, and reduce power consumption and coil heating in TMS, enhancing its research and therapeutic applications. PMID:18232369

  13. Repetitive transcranial magnetic stimulation induces oscillatory power changes in chronic tinnitus

    Martin eSchecklmann

    2015-10-01

    Full Text Available Chronic tinnitus is associated with neuroplastic changes in auditory and non-auditory cortical areas. About ten years ago, repetitive transcranial magnetic stimulation (rTMS of auditory and prefrontal cortex was introduced as potential treatment for tinnitus. The resulting changes in tinnitus loudness are interpreted in the context of rTMS induced activity changes (neuroplasticity. Here, we investigate the effect of single rTMS sessions on oscillatory power to probe the capacity of rTMS to interfere with tinnitus-specific cortical plasticity. We measured 20 patients with bilateral chronic tinnitus and 20 healthy controls comparable for age, sex, handedness, and hearing level with a 63-channel EEG system. Educational level, intelligence, depressivity and hyperacusis were controlled for by analysis of covariance. Different rTMS protocols were tested: Left and right temporal and left and right prefrontal cortices were each stimulated with 200 pulses at 1Hz and with an intensity of 60% stimulator output. Stimulation of central parietal cortex with 6-fold reduced intensity (inverted passive-cooled coil served as sham condition. Before and after each rTMS protocol five minutes of resting state EEG were recorded. The order of rTMS protocols was randomized over two sessions with one week interval in between.Analyses on electrode level showed that people with and without tinnitus differed in their response to left temporal and right frontal stimulation. In tinnitus patients left temporal rTMS decreased frontal theta and delta and increased beta2 power, whereas right frontal rTMS decreased right temporal beta3 and gamma power. No changes or increases were observed in the control group. Only non-systematic changes in tinnitus loudness were induced by single sessions of rTMS.This is the first study to show tinnitus-related alterations of neuroplasticity that were specific to stimulation site and oscillatory frequency. The observed effects can be interpreted

  14. Repetitive transcranial magnetic stimulation induces oscillatory power changes in chronic tinnitus

    Schecklmann, Martin; Lehner, Astrid; Gollmitzer, Judith; Schmidt, Eldrid; Schlee, Winfried; Langguth, Berthold

    2015-01-01

    Chronic tinnitus is associated with neuroplastic changes in auditory and non-auditory cortical areas. About 10 years ago, repetitive transcranial magnetic stimulation (rTMS) of auditory and prefrontal cortex was introduced as potential treatment for tinnitus. The resulting changes in tinnitus loudness are interpreted in the context of rTMS induced activity changes (neuroplasticity). Here, we investigate the effect of single rTMS sessions on oscillatory power to probe the capacity of rTMS to interfere with tinnitus-specific cortical plasticity. We measured 20 patients with bilateral chronic tinnitus and 20 healthy controls comparable for age, sex, handedness, and hearing level with a 63-channel electroencephalography (EEG) system. Educational level, intelligence, depressivity and hyperacusis were controlled for by analysis of covariance. Different rTMS protocols were tested: Left and right temporal and left and right prefrontal cortices were each stimulated with 200 pulses at 1 Hz and with an intensity of 60% stimulator output. Stimulation of central parietal cortex with 6-fold reduced intensity (inverted passive-cooled coil) served as sham condition. Before and after each rTMS protocol 5 min of resting state EEG were recorded. The order of rTMS protocols was randomized over two sessions with 1 week interval in between. Analyses on electrode level showed that people with and without tinnitus differed in their response to left temporal and right frontal stimulation. In tinnitus patients left temporal rTMS decreased frontal theta and delta and increased beta2 power, whereas right frontal rTMS decreased right temporal beta3 and gamma power. No changes or increases were observed in the control group. Only non-systematic changes in tinnitus loudness were induced by single sessions of rTMS. This is the first study to show tinnitus-related alterations of neuroplasticity that were specific to stimulation site and oscillatory frequency. The observed effects can be

  15. Gamma-radiation-induced chromosal aberration in human lymphocytes: dose-rate effects in stimulated and non-stimulated cells

    Liniecki, J.; Bajerska, A.; Wyszynska, K.; Cisowska, B.

    1977-01-01

    Stimulated and non-stimulated human peripheral blood lymphocytes were irradiated acutely and chronically, over 24 h. Dose-effect relationships for dicentric chromosomes were established and various models were fitted to the data. At prolonged irradiations, the yield decreased in basic agreement with the linear-quadratic model of aberration induction. Dose-protraction experiments on PHA + and PHA - lymphocytes, irradiated under various conditions of oxygenation and suspension (culture medium, whole blood) showed that the rejoining time increased from about 3 h in non-stimulated cells to about 10 h after PHA stimulation, and that this retarded rejoining was most likely due to blastic transformation itself and not to other conditions of irradiation

  16. Gamma radiation induced chromosal aberration in human lymphocytes: dose-rate effects in stimulated and non-stimulated cells

    Liniecki, J; Bajerska, A; Wyszynska, K [School of Medicine, Lodz (Poland). Div. of Nuclear Medicine and Radiobiology. Medical Research Center; Cisowska, B [Copernicus Municipal Hospital, Lodz (Poland). Oncology Center. Radiotherapy Dept.

    1977-05-01

    Stimulated and non-stimulated human peripheral blood lymphocytes were irradiated acutely and chronically, over 24 h. Dose-effect relationships for dicentric chromosomes were established and various models were fitted to the data. At prolonged irradiations, the yield decreased in basic agreement with the linear-quadratic model of aberration induction. Dose-protraction experiments on PHA/sup +/ and PHA/sup -/ lymphocytes, irradiated under various conditions of oxygenation and suspension (culture medium, whole blood) showed that the rejoining time increased from about 3 h in non-stimulated cells to about 10 h after PHA stimulation, and that this retarded rejoining was most likely due to blastic transformation itself and not to other conditions of irradiation.

  17. Mast Cell Proteases 6 and 7 Stimulate Angiogenesis by Inducing Endothelial Cells to Release Angiogenic Factors.

    Devandir Antonio de Souza Junior

    Full Text Available Mast cell proteases are thought to be involved with tumor progression and neo-vascularization. However, their exact role is still unclear. The present study was undertaken to further elucidate the function of specific subtypes of recombinant mouse mast cell proteases (rmMCP-6 and 7 in neo-vascularization. SVEC4-10 cells were cultured on Geltrex® with either rmMCP-6 or 7 and tube formation was analyzed by fluorescence microscopy and scanning electron microscopy. Additionally, the capacity of these proteases to induce the release of angiogenic factors and pro and anti-angiogenic proteins was analyzed. Both rmMCP-6 and 7 were able to stimulate tube formation. Scanning electron microscopy showed that incubation with the proteases induced SVEC4-10 cells to invade the gel matrix. However, the expression and activity of metalloproteases were not altered by incubation with the mast cell proteases. Furthermore, rmMCP-6 and rmMCP-7 were able to induce the differential release of angiogenic factors from the SVEC4-10 cells. rmMCP-7 was more efficient in stimulating tube formation and release of angiogenic factors than rmMCP-6. These results suggest that the subtypes of proteases released by mast cells may influence endothelial cells during in vivo neo-vascularization.

  18. Slow-oscillatory transcranial direct current stimulation can induce bidirectional shifts in motor cortical excitability in awake humans

    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...... slow oscillations during sleep and theta oscillations during wakefulness. To embed this new type of stimulation into the existing tDCS literature, we aimed to characterize the after effects of slowly oscillating stimulation (so-tDCS) on M1(HAND) excitability and to compare them to those of c-tDCS. Here...

  19. What is the optimal anodal electrode position for inducing corticomotor excitability changes in transcranial direct current stimulation?

    Lee, Minji; Kim, Yun-Hee; Im, Chang-Hwan; Kim, Jung-Hoon; Park, Chang-hyun; Chang, Won Hyuk; Lee, Ahee

    2015-01-01

    Transcranial direct current stimulation (tDCS) non-invasively modulates brain function by inducing neuronal excitability. The conventional hot spot for inducing the highest current density in the hand motor area may not be the optimal site for effective stimulation. In this study, we investigated the influence of the center position of the anodal electrode on changes in motor cortical excitability. We considered three tDCS conditions in 16 healthy subjects: (i) real stimulation with the anodal electrode located at the conventional hand motor hot spot determined by motor evoked potentials (MEPs); (ii) real stimulation with the anodal electrode located at the point with the highest current density in the hand motor area as determined by electric current simulation; and (iii) sham stimulation. Motor cortical excitability as measured by MEP amplitude increased after both real stimulation conditions, but not after sham stimulation. Stimulation using the simulation-derived anodal electrode position, which was found to be posterior to the MEP hot spot for all subjects, induced higher motor cortical excitability. Individual positioning of the anodal electrode, based on the consideration of anatomical differences between subjects, appears to be important for maximizing the effects of tDCS. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Individual differences in learning correlate with modulation of brain activity induced by transcranial direct current stimulation

    Falcone, Brian; Wada, Atsushi; Parasuraman, Raja

    2018-01-01

    Transcranial direct current stimulation (tDCS) has been shown to enhance cognitive performance on a variety of tasks. It is hypothesized that tDCS enhances performance by affecting task related cortical excitability changes in networks underlying or connected to the site of stimulation facilitating long term potentiation. However, many recent studies have called into question the reliability and efficacy of tDCS to induce modulatory changes in brain activity. In this study, our goal is to investigate the individual differences in tDCS induced modulatory effects on brain activity related to the degree of enhancement in performance, providing insight into this lack of reliability. In accomplishing this goal, we used functional magnetic resonance imaging (fMRI) concurrently with tDCS stimulation (1 mA, 30 minutes duration) using a visual search task simulating real world conditions. The experiment consisted of three fMRI sessions: pre-training (no performance feedback), training (performance feedback which included response accuracy and target location and either real tDCS or sham stimulation given), and post-training (no performance feedback). The right posterior parietal cortex was selected as the site of anodal tDCS based on its known role in visual search and spatial attention processing. Our results identified a region in the right precentral gyrus, known to be involved with visual spatial attention and orienting, that showed tDCS induced task related changes in cortical excitability that were associated with individual differences in improved performance. This same region showed greater activity during the training session for target feedback of incorrect (target-error feedback) over correct trials for the tDCS stim over sham group indicating greater attention to target features during training feedback when trials were incorrect. These results give important insight into the nature of neural excitability induced by tDCS as it relates to variability in

  1. LIF is a contraction-induced myokine stimulating human myocyte proliferation

    Broholm, Christa; Laye, Matthew J; Brandt, Claus

    2011-01-01

    in skeletal muscle, but LIF was not detectable in plasma of the subjects. However, electrically stimulated cultured human myotubes produced and secreted LIF, suggesting that LIF is a myokine with local effects. The well-established exercise-induced signaling molecules PI3K, Akt and mTor contributed...... to the regulation of LIF in cultured human myotubes as chemical inhibition of PI3K and mTor and siRNA knockdown of Akt1 were independently sufficient to down regulate LIF. Human myoblast proliferation was increased by recombinant exogenous LIF and decreased by siRNA knockdown of the endogenous LIF receptor. Finally...

  2. Striatal dopamine release induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex: effect of aging

    Bang, Seong Ae; Cho, Sang Soo; Yoon, Eun Jin; Kim, Ji Sun; Lee, Byung Chul; Kim, Yu Kyeong; Kim, Sang Eun

    2007-01-01

    We previously demonstrated dopamine (DA) release in the bilateral striatal regions following prefrontal repetitive transcranial magnetic stimulation (rTMS) in young subjects. Several lines of evidence support substantial age-related changes in human dopaminergic neurotransmission. One possible explanation is alteration of cortico striatal neural connection with aging. Therefore, we investigated how frontal activation by rTMS influences striatal DA release in the elderly with SPECT measurements of striatal binding of [123I]iodobenzamide (lBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy elderly male subjects (age, 64 3 y) were studied with brain [123I]IBZM SPECT under three conditions (resting, sham stimulation, and active rTMS over left dorsolateral prefrontal cortex (DLPFC)), while receiving a bolus plus constant infusion of [123I]IBZM. rTMS session consisted of three blocks. In each block, 15 trains of 2 sec duration were delivered with 10 Hz stimulation frequency and 100% motor threshold. Striatal V3', calculated as (striatal - occipital)/occipital radioactivity, was measured under equilibrium condition at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over left DLPFC induced no significant change in V3' in the right striatum compared with baseline condition (0.91 0.25 vs. 0.96 0.25, P = NS). Interestingly, left striatal V3' showed a significant increase after rTMS over left DLPFC compared with sham condition (1.09 0.33 vs. 0.93 0.27, P < 0.05; 17.0 11.1% increase). These results are discrepant from previous ones from young subjects, who showed frontal rTMS-induced reduction of striatal V3', indicating rTMS-induced striatal DA release. We found no significant striatal DA release induced by rTMS over DLPFC in healthy elderly subjects using in vivo binding competition techniques. These results may support an altered cortico striatal circuit in normal aging

  3. Striatal dopamine release induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex: effect of aging

    Bang, Seong Ae; Cho, Sang Soo; Yoon, Eun Jin; Kim, Ji Sun; Lee, Byung Chul; Kim, Yu Kyeong; Kim, Sang Eun [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2007-07-01

    We previously demonstrated dopamine (DA) release in the bilateral striatal regions following prefrontal repetitive transcranial magnetic stimulation (rTMS) in young subjects. Several lines of evidence support substantial age-related changes in human dopaminergic neurotransmission. One possible explanation is alteration of cortico striatal neural connection with aging. Therefore, we investigated how frontal activation by rTMS influences striatal DA release in the elderly with SPECT measurements of striatal binding of [123I]iodobenzamide (lBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy elderly male subjects (age, 64 3 y) were studied with brain [123I]IBZM SPECT under three conditions (resting, sham stimulation, and active rTMS over left dorsolateral prefrontal cortex (DLPFC)), while receiving a bolus plus constant infusion of [123I]IBZM. rTMS session consisted of three blocks. In each block, 15 trains of 2 sec duration were delivered with 10 Hz stimulation frequency and 100% motor threshold. Striatal V3', calculated as (striatal - occipital)/occipital radioactivity, was measured under equilibrium condition at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over left DLPFC induced no significant change in V3' in the right striatum compared with baseline condition (0.91 0.25 vs. 0.96 0.25, P = NS). Interestingly, left striatal V3' showed a significant increase after rTMS over left DLPFC compared with sham condition (1.09 0.33 vs. 0.93 0.27, P < 0.05; 17.0 11.1% increase). These results are discrepant from previous ones from young subjects, who showed frontal rTMS-induced reduction of striatal V3', indicating rTMS-induced striatal DA release. We found no significant striatal DA release induced by rTMS over DLPFC in healthy elderly subjects using in vivo binding competition techniques. These results may support an altered cortico striatal circuit in normal aging.

  4. Collision-induced stimulated photon echoes in ‘strong’ magnetic field

    Reshetov, V. A.

    2018-05-01

    Collision-induced stimulated photon echoes formed in a gaseous medium on the transition with the angular momentum change Ja=0 → Jb=1 under the action of ‘strong’ longitudinal magnetic field, when the echo pulse becomes unpolarized, are considered with an account of elastic depolarizing collisions. In the case of narrow spectral line the explicit expressions for the echo polarization density matrix and the degree of polarization are obtained. In the case of broad spectral line the results of the numeric calculations reproduce qualitatively the curve obtained in the experiments with ytterbium vapor.

  5. Effects of vibratory stimulation-induced kinesthetic illusions on the neural activities of patients with stroke.

    Kodama, Takayuki; Nakano, Hideki; Ohsugi, Hironori; Murata, Shin

    2016-01-01

    [Purpose] This study evaluated the influence of vibratory stimulation-induced kinesthetic illusion on brain function after stroke. [Subjects] Twelve healthy individuals and 13 stroke patients without motor or sensory loss participated. [Methods] Electroencephalograms were taken at rest and during vibratory stimulation. As a neurophysiological index of brain function, we measured the μ-rhythm, which is present mainly in the kinesthetic cortex and is attenuated by movement or motor imagery and compared the data using source localization analyses in the Standardized Low Resolution Brain Electromagnetic Tomography (sLORETA) program. [Results] At rest, μ-rhythms appeared in the sensorimotor and supplementary motor cortices in both healthy controls and stroke patients. Under vibratory stimulation, no μ-rhythm appeared in the sensorimotor cortex of either group. Moreover, in the supplementary motor area, which stores the motor imagery required for kinesthetic illusions, the μ-rhythms of patients were significantly stronger than those of the controls, although the μ-rhythms of both groups were reduced. Thus, differences in neural activity in the supplementary motor area were apparent between the subject groups. [Conclusion] Kinesthetic illusions do occur in patients with motor deficits due to stroke. The neural basis of the supplementary motor area in stroke patients may be functionally different from that found in healthy controls.

  6. Acoustic stimulation can induce a selective neural network response mediated by piezoelectric nanoparticles

    Rojas, Camilo; Tedesco, Mariateresa; Massobrio, Paolo; Marino, Attilio; Ciofani, Gianni; Martinoia, Sergio; Raiteri, Roberto

    2018-06-01

    Objective. We aim to develop a novel non-invasive or minimally invasive method for neural stimulation to be applied in the study and treatment of brain (dys)functions and neurological disorders. Approach. We investigate the electrophysiological response of in vitro neuronal networks when subjected to low-intensity pulsed acoustic stimulation, mediated by piezoelectric nanoparticles adsorbed on the neuronal membrane. Main results. We show that the presence of piezoelectric barium titanate nanoparticles induces, in a reproducible way, an increase in network activity when excited by stationary ultrasound waves in the MHz regime. Such a response can be fully recovered when switching the ultrasound pulse off, depending on the generated pressure field amplitude, whilst it is insensitive to the duration of the ultrasound pulse in the range 0.5 s–1.5 s. We demonstrate that the presence of piezoelectric nanoparticles is necessary, and when applying the same acoustic stimulation to neuronal cultures without nanoparticles or with non-piezoelectric nanoparticles with the same size distribution, no network response is observed. Significance. We believe that our results open up an extremely interesting approach when coupled with suitable functionalization strategies of the nanoparticles in order to address specific neurons and/or brain areas and applied in vivo, thus enabling remote, non-invasive, and highly selective modulation of the activity of neuronal subpopulations of the central nervous system of mammalians.

  7. UV induced photoluminescence and thermally stimulated luminescence of ThO2:Tb3+ phosphor

    Godbole, S.V.; Nagpal, J.S.; Page, A.G.

    2000-01-01

    Thorium oxide doped with trivalent terbium ions offers itself as a novel phosphor with its photo- and thermally-stimulated luminescence (PL and TSL) characteristics showing a marked change on sustained exposure to 254 and 365 nm ultraviolet (UV) radiation. The reduction in luminescence intensity of Tb 3+ ions, on irradiation with 254 nm photons and subsequent restoration on exposure to 365 nm, has been correlated with the complimentary behaviour in UV-induced TSL. These changes are, in turn, ascribed to inter-configurational (f-d) transitions and e-h formation and recombination processes. UV radiation induced TSL output increases linearly with incident UV radiant energy at a constant radiation flux; however, for a fixed exposure, TSL output increases with increase in radiant flux

  8. The moving rubber hand illusion revisited: comparing movements and visuotactile stimulation to induce illusory ownership.

    Kalckert, Andreas; Ehrsson, H Henrik

    2014-05-01

    The rubber hand illusion is a perceptual illusion in which a model hand is experienced as part of one's own body. In the present study we directly compared the classical illusion, based on visuotactile stimulation, with a rubber hand illusion based on active and passive movements. We examined the question of which combinations of sensory and motor cues are the most potent in inducing the illusion by subjective ratings and an objective measure (proprioceptive drift). In particular, we were interested in whether the combination of afferent and efferent signals in active movements results in the same illusion as in the purely passive modes. Our results show that the illusion is equally strong in all three cases. This demonstrates that different combinations of sensory input can lead to a very similar phenomenological experience and indicates that the illusion can be induced by any combination of multisensory information. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  9. Chronic Enhancement of Serotonin Facilitates Excitatory Transcranial Direct Current Stimulation-Induced Neuroplasticity.

    Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang; Nitsche, Michael A

    2016-04-01

    Serotonin affects memory formation via modulating long-term potentiation (LTP) and depression (LTD). Accordingly, acute selective serotonin reuptake inhibitor (SSRI) administration enhanced LTP-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. However, it usually takes some time for SSRI to reduce clinical symptoms such as anxiety, negative mood, and related symptoms of depression and anxiety disorders. This might be related to an at least partially different effect of chronic serotonergic enhancement on plasticity, as compared with single-dose medication. Here we explored the impact of chronic application of the SSRI citalopram (CIT) on plasticity induced by tDCS in healthy humans in a partially double-blinded, placebo (PLC)-controlled, randomized crossover study. Furthermore, we explored the dependency of plasticity induction from the glutamatergic system via N-methyl-D-aspartate receptor antagonism. Twelve healthy subjects received PLC medication, combined with anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took CIT (20 mg/day) consecutively for 35 days. During this period, four additional interventions were performed (CIT and PLC medication with anodal/cathodal tDCS, CIT and dextromethorphan (150 mg) with anodal/cathodal tDCS). Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic application of CIT increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h, and converted cathodal tDCS-induced LTD-like plasticity into facilitation. These effects were abolished by dextromethorphan. Chronic serotonergic enhancement results in a strengthening of LTP-like glutamatergic plasticity, which might partially explain the therapeutic impact of SSRIs in depression and other neuropsychiatric diseases.

  10. Diosgenin induces apoptosis in IGF-1-stimulated human thyrocytes through two caspase-dependent pathways

    Mu, Shumin [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Hospital Affiliated to Shandong Traditional Chinese Medicine University, Jinan 250011 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Tian, Xingsong; Ruan, Yongwei [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Liu, Yuantao [The Second Hospital of Shandong University, Jinan 250033 (China); Bian, Dezhi [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Jining Medical College, Jining 272013 (China); Ma, Chunyan [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Yu, Chunxiao [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Feng, Mei [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Wang, Furong [Shandong University of Traditional Chinese Medicine, Jinan 250011 (China); Gao, Ling [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China); Zhao, Jia-jun, E-mail: jjzhao@medmail.com.cn [Provincial Hospital Affiliated to Shandong University, Jinan 250021 (China); Institute of Endocrinology, Shandong Academy of Clinical Medicine, Jinan 250021 (China)

    2012-02-10

    Highlights: Black-Right-Pointing-Pointer Diosgenin induces apoptosis in IGF-1-treated thyrocytes through two caspase pathways. Black-Right-Pointing-Pointer Diosgenin inhibits FLIP and activates caspase-8 in FAS related-pathway. Black-Right-Pointing-Pointer Diosgenin increases ROS, regulates the ratio of Bax/Bcl-2 in mitochondrial pathway. -- Abstract: Insulin-like growth factor-1 (IGF-1) is a growth factor of the thyroid that has been shown in our previous study to possess proliferative and antiapoptotic effects in FRTL-5 cell lines through the upregulation of cyclin D and Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). Diosgenin, a natural steroid sapogenin from plants, has been shown to induce apoptosis in many cell lines, with the exception of thyroid cells. In this report, we investigated the apoptotic effect and mechanism of diosgenin in IGF-1-stimulated primary human thyrocytes. Primary human thyrocytes were preincubated with or without IGF-1 for 24 h and subsequently exposed to varying concentrations of diosgenin for different times. We found that diosgenin induced apoptosis in human thyrocytes pretreated with IGF-1 in a dose-dependent manner through the activation of caspase cascades. Moreover, diosgenin inhibited FLIP and activated caspase-8 in the FAS-related apoptotic pathway. Diosgenin increased the production of ROS, regulated the balance of Bax and Bcl-2 and cleaved caspase-9 in the mitochondrial apoptotic pathway. These results indicate that diosgenin induces apoptosis in IGF-1-stimulated primary human thyrocytes through two caspase-dependent pathways.

  11. Electro-tactile stimulation of the posterior neck induces body anteropulsion during upright stance.

    De Nunzio, A M; Yavuz, U S; Martinez-Valdes, E; Farina, D; Falla, D

    2018-05-01

    Sensory information conveyed along afferent fibers from muscle and joint proprioceptors play an important role in the control of posture and gait in humans. In particular, proprioceptive information from the neck is fundamental in supplying the central nervous system with information about the orientation and movement of the head relative to the rest of the body. The previous studies have confirmed that proprioceptive afferences originating from the neck region, evoked via muscle vibration, lead to strong body-orienting effects during static conditions (e.g., leaning of the body forwards or backwards, depending on location of vibration). However, it is not yet certain in humans, whether the somatosensory receptors located in the deep skin (cutaneous mechanoreceptors) have a substantive contribution to postural control, as vibratory stimulation encompasses the receptive field of all the somatosensory receptors from the skin to the muscles. The aim of this study was to investigate the postural effect of cutaneous mechanoreceptor afferences using electro-tactile stimulation applied to the neck. Ten healthy volunteers (8M, 2F) were evaluated. The average position of their centre of foot pressure (CoP) was acquired before, during, and after a subtle electro-tactile stimulation over their posterior neck (mean ± SD = 5.1 ± 2.3 mA at 100 Hz-140% of the perception threshold) during upright stance with their eyes closed. The electro-tactile stimulation led to a body-orienting effect with the subjects consistently leaning forward. An average shift of the CoP of 12.1 ± 11.9 mm (mean ± SD) was reported, which significantly (p < 0.05) differed from its average position under a control condition (no stimulation). These results indicate that cutaneous mechanoreceptive inflow from the neck is integrated to control stance. The findings are relevant for the exploitation of electro-tactile stimulation for rehabilitation interventions where induced

  12. Developing a dynamic virtual stimulation protocol to induce linear egomotion during orthostatic posture control test

    Paulo José Guimarães Da-Silva

    Full Text Available Abstract Introduction In this work, the effect of a dynamic visual stimulation (DS protocol was used to induce egomotion, the center of pressure (COP displacement response. Methods DS was developed concerning the scenario structure (chessboard-pattern floor and furniture and luminance. To move the scenario in a discrete forward (or backward direction, the furniture is expanded (or reduced and the black and white background is reversed during floor translation while the luminance is increased (or reduced by steps of 2 cd/m2. This protocol was evaluated using COP signals from 29 healthy volunteers: standing on a force platform observing the virtual scene (1.72 × 1.16 m projected 1 m ahead (visual incidence angle: θl = 81.4° and θv = 60.2°, which moves with constant velocity (2 m/s during 250 ms. A set of 100 DS was applied in random order, interspersed by a 10 s of static scene. Results The Tukey post-hoc test (p < 0.001 indicated egomotion in the same direction of DS. COP displacement increased over stimulation (8.4 ± 1.7 to 22.6 ±5.3 mm, as well as time to recover stability (4.1 ± 0.4 to 7.2 ± 0.6 s. The peak of egomotion during DSF occurred 200 ms after DSB (Wilcoxon, p = 0.002. Conclusion The dynamic configuration of this protocol establishes virtual flow effects of linear egomotion dependent on the direction of the dynamic visual stimulation. This finding indicates the potential application of the proposed virtual dynamic stimulation protocol to investigate the cortical visual evoked response in postural control studies.

  13. Differential Effects of HRAS Mutation on LTP-Like Activity Induced by Different Protocols of Repetitive Transcranial Magnetic Stimulation.

    Dileone, Michele; Ranieri, Federico; Florio, Lucia; Capone, Fioravante; Musumeci, Gabriella; Leoni, Chiara; Mordillo-Mateos, Laura; Tartaglia, Marco; Zampino, Giuseppe; Di Lazzaro, Vincenzo

    2016-01-01

    Costello syndrome (CS) is a rare congenital disorder due to a G12S amino acid substitution in HRAS protoncogene. Previous studies have shown that Paired Associative Stimulation (PAS), a repetitive brain stimulation protocol inducing motor cortex plasticity by coupling peripheral nerve stimulation with brain stimulation, leads to an extremely pronounced motor cortex excitability increase in CS patients. Intermittent Theta Burst Stimulation (iTBS) represents a protocol able to induce motor cortex plasticity by trains of stimuli at 50 Hz. In healthy subjects PAS and iTBS produce similar after-effects in motor cortex excitability. Experimental models showed that HRAS-dependent signalling pathways differently affect LTP induced by different patterns of repetitive synaptic stimulation. We aimed to compare iTBS-induced after-effects on motor cortex excitability with those produced by PAS in CS patients and to observe whether HRAS mutation differentially affects two different forms of neuromodulation protocols. We evaluated in vivo after-effects induced by PAS and iTBS applied over the right motor cortex in 4 CS patients and in 21 healthy age-matched controls. Our findings confirmed HRAS-dependent extremely pronounced PAS-induced after-effects and showed for the first time that iTBS induces no change in MEP amplitude in CS patients whereas both protocols lead to an increase of about 50% in controls. CS patients are characterized by an impairment of iTBS-related LTP-like phenomena besides enhanced PAS-induced after-effects, suggesting that HRAS-dependent signalling pathways have a differential influence on PAS- and iTBS-induced plasticity in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Repeatability and reliability of muscle relaxation properties induced by motor cortical stimulation.

    Molenaar, Joery P; Voermans, Nicol C; de Jong, Lysanne A; Stegeman, Dick F; Doorduin, Jonne; van Engelen, Baziel G

    2018-03-15

    Impaired muscle relaxation is a feature of many neuromuscular disorders. However, there are few tests available to quantify muscle relaxation. Transcranial magnetic stimulation (TMS) of the motor cortex can induce muscle relaxation by abruptly inhibiting corticospinal drive. The aim of our study is to investigate if repeatability and reliability of TMS-induced relaxation is greater than voluntary relaxation. Furthermore, effects of sex, cooling and fatigue on muscle relaxation properties were studied. Muscle relaxation of deep finger flexors was assessed in twenty-five healthy subjects (14 M and 11 F, aged 39.1{plus minus}12.7 and 45.3{plus minus}8.7 years old, respectively) using handgrip dynamometry. All outcome measures showed greater repeatability and reliability in TMS-induced relaxation compared to voluntary relaxation. The within-subject coefficient of variability of normalized peak relaxation rate was lower in TMS-induced relaxation than in voluntary relaxation (3.0 vs 19.7% in men, and 6.1 vs 14.3% in women). The repeatability coefficient was lower (1.3 vs 6.1 s -1 in men and 2.3 vs 3.1 s -1 in women), and the intraclass correlation coefficient was higher (0.95 vs 0.53 in men and 0.78 vs 0.69 in women), for TMS-induced relaxation compared to voluntary relaxation. TMS enabled to demonstrate slowing effects of sex, muscle cooling, and muscle fatigue on relaxation properties that voluntary relaxation could not. In conclusion, repeatability and reliability of TMS-induced muscle relaxation was greater compared to voluntary muscle relaxation. TMS-induced muscle relaxation has the potential to be used in clinical practice for diagnostic purposes and therapy effect monitoring in patients with impaired muscle relaxation.

  15. DA-6034-induced mucin secretion via Ca2+-dependent pathways through P2Y receptor stimulation.

    Lee, Hun; Kim, Eung Kweon; Kim, Ji Yeon; Yang, Yu-Mi; Shin, Dong Min; Kang, Kyung Koo; Kim, Tae-im

    2014-09-11

    We evaluated whether DA-6034 is involved in mucin secretion via P2Y receptor activation and/or intracellular Ca2+ concentration ([Ca2+]i) change. Also, we investigated the effect of P2Y receptor inhibitors or Ca2+ chelators on the DA-6034-induced mucin secretion and [Ca2+]i increases. Effects of DA-6034 on mucin expression in primary, cultured, conjunctival epithelial cells was studied using RT-PCR, Western blot analysis, and periodic acid-schiff (PAS) staining. To evaluate thin film layer thickness generated by mucin and fluid secretion, cells were incubated in DA-6034 with/without P2Y antagonists or extracellular/intracellular Ca2+ chelators, and were imaged with confocal microscope using Texas Red-dextran dye. In addition, DA-6034-induced Ca2+-dependent Cl- channels opening was evaluated using perforated patch clamp. Fluo-4/AM was used to measure changes in [Ca2+]i induced by DA-6034 in Ca2+-free or Ca2+-containing buffered condition, as well as P2Y antagonists. DA-6034 induced the expression of mucin genes, production of mucin protein, and increase of number of mucin-secreting cells. P2Y antagonists inhibited DA-6034-induced mucin and fluid secretion, which was also affected by extracellular/intracellular Ca2+ chelators. DA-6034 stimulated Cl- channel opening and [Ca2+]i elevation. Further, [Ca2+]i increases induced by DA-6034 were lacking in either P2Y antagonists or Ca2+-free buffered condition, and diminished when endoplasmic reticulum Ca2+ was depleted by cyclopiazonic acid in Ca2+-free buffered condition. This study demonstrated that DA-6034 has a potential to induce mucin secretion via Ca2+-dependent pathways through P2Y receptors in multilayer, cultured, human conjunctival epithelial cells. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

  16. The electric field induced by transcranial magnetic stimulation: A comparison between analytic and fem solutions

    Porzig Konstantin

    2014-01-01

    Full Text Available The induced electric field profiles in a homogeneous isotropic sphere, were calculated and compared between an analytic and a finite-element method in the framework of transcranial magnetic stimulation (TMS. This model can also be applied for concentric spheres in the framework of magnetic induction tomography (MIT, non destructive testing (NDT or to calculate the lead field in magnetoencephalography (MEG. The calculations were performed using Eaton’s method as well as the finite-element program Comsol Multiphysics 4.2a (COMSOL Inc., Burlington, USA. A circular- and a figure-of-8 coil were used to operate as the sources of excitation. In our study the spherical volume conductor represents the human head consisting of grey matter. In order to quantify the differences between both methods an intense parameter study was performed. A comparison between both methods show a higher conformity than reported in previous studies. Regarding Eaton’s method, the influence of the maximum order of approximation L and the number of elements per winding K was investigated. The maximum relative difference was approximately 0.3% for L = 20 and K > 16. Furthermore the relative efficiency of the algorithm was calculated to save computational time. With the presented results it is possible to use Eaton’s method efficiently to compute the induced electric field profiles very quickly for example while searching for specific coil arrangements around the humans head, as in the case of deep brain transcranial magnetic stimulation (dTMS.

  17. Ca2+ Entry is Required for Mechanical Stimulation-induced ATP Release from Astrocyte

    Lee, Jaekwang; Chun, Ye-Eun; Han, Kyung-Seok; Lee, Jungmoo; Woo, Dong Ho

    2015-01-01

    Astrocytes and neurons are inseparable partners in the brain. Neurotransmitters released from neurons activate corresponding G protein-coupled receptors (GPCR) expressed in astrocytes, resulting in release of gliotransmitters such as glutamate, D-serine, and ATP. These gliotransmitters in turn influence neuronal excitability and synaptic activities. Among these gliotransmitters, ATP regulates the level of network excitability and is critically involved in sleep homeostasis and astrocytic Ca2+ oscillations. ATP is known to be released from astrocytes by Ca2+-dependent manner. However, the precise source of Ca2+, whether it is Ca2+ entry from outside of cell or from the intracellular store, is still not clear yet. Here, we performed sniffer patch to detect ATP release from astrocyte by using various stimulation. We found that ATP was not released from astrocyte when Ca2+ was released from intracellular stores by activation of Gαq-coupled GPCR including PAR1, P2YR, and B2R. More importantly, mechanical stimulation (MS)-induced ATP release from astrocyte was eliminated when external Ca2+ was omitted. Our results suggest that Ca2+ entry, but not release from intracellular Ca2+ store, is critical for MS-induced ATP release from astrocyte. PMID:25792866

  18. Repeated Microneedle Stimulation Induces Enhanced Hair Growth in a Murine Model.

    Kim, Yoon Seob; Jeong, Kwan Ho; Kim, Jung Eun; Woo, Young Jun; Kim, Beom Joon; Kang, Hoon

    2016-10-01

    Microneedle is a method that creates transdermal microchannels across the stratum corneum barrier layer of skin. No previous study showed a therapeutic effect of microneedle itself on hair growth by wounding. The aim of this study is to investigate the effect of repeated microwound formed by microneedle on hair growth and hair growth-related genes in a murine model. A disk microneedle roller was applied to each group of mice five times a week for three weeks. First, to identify the optimal length and cycle, microneedles of lengths of 0.15 mm, 0.25 mm, 0.5 mm, and 1 mm and cycles of 3, 6, 10, and 13 cycles were applied. Second, the effect of hair growth and hair-growth-related genes such as Wnt3a, β-catenin, vascular endothelial growth factor (VEGF), and Wnt10b was observed using optimized microneedle. Outcomes were observed using visual inspection, real-time polymerase chain reaction, and immunohistochemistry. We found that the optimal length and cycle of microneedle treatment on hair growth was 0.25 mm/10 cycles and 0.5 mm/10 cycles. Repeated microneedle stimulation promoted hair growth, and it also induced the enhanced expression of Wnt3a, β-catenin, VEGF, and Wnt10b. Our study provides evidence that microneedle stimulation can induce hair growth via activation of the Wnt/β-catenin pathway and VEGF. Combined with the drug delivery effect, we believe that microneedle stimulation could lead to new approaches for alopecia.

  19. The water avoidance stress induces bladder pain due to a prolonged alpha1A adrenoceptor stimulation.

    Matos, Rita; Serrão, Paula; Rodriguez, Larissa; Birder, Lori Ann; Cruz, Francisco; Charrua, Ana

    2017-08-01

    Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) remains an elusive disease with the cause for the pain unclear. BPS/IC patients present increased sympathetic activity and high levels of urinary noradrenaline. At the experimental level, it has been shown that chronic adrenergic stimulation produces pain and bladder changes through an alpha 1A adrenoceptor mediated mechanism. Water avoidance stress (WAS) in rodents reproduces signs of nociception and bladder changes seen in BPS/IC patients. In this study, we explore the possible role of alpha 1A adrenoceptor in bladder pain and morphological changes. WAS was induced in a group of female Wistar rats. A separate WAS group received 0.2 mg/kg day silodosin (WAS + S). Lower abdominal pain was determined by performing sensitivity to Von Frey filaments. Bladder reflex activity was determined by cystometry in anaesthetised animals. Urine was collected for noradrenaline quantification by HPLC. Bladders were harvested and stained with Haematoxylin-eosin (to analyse urothelial morphology and to determine the disruption of surface umbrella cells) or with Toluidine Blue 0.1% to analyse mast cell infiltration. WAS increased urinary noradrenaline level and bladder frequency and decreased mechanical pain threshold, which was reversed by silodosin. WAS induced lymphocytic and mast cells infiltration in the mucosa and mild urothelial disruption, which was absent in WAS + S group. Alpha 1A adrenoceptor stimulation has an important role in the appearance of bladder pain in rats. Since BPS/IC patients present high levels of noradrenaline, alpha 1A stimulation may be an additional trigger for bladder dysfunction presented by these patients. Further studies will determine the clinical relevance of this finding in the treatment of BPS/IC patients.

  20. Metal ion induced room temperature phase transformation and stimulated infrared spectroscopy on TiO{sub 2}-based surfaces

    Gole, James L. [Schools of Physics and Mechanical Engineering, Georgia Institute of Technology, 837 State Street, Atlanta, GA 30332-0430 (United States)], E-mail: jim.gole@physics.gatech.edu; Prokes, S.M. [Code 6876, NRL, Washington, DC 20375 (United States)], E-mail: prokes@estd.nrl.navy.mil; White, Mark G. [Dave C. Swalm School of Chemical Engineering, James Worth Bagley College of Engineering, Box 959, MS 39762 (United States)], E-mail: white@che.msstate.edu

    2008-11-30

    Raman and infrared spectroscopy are used to demonstrate (1) the high spin metal ion induced room temperature transformation of anatase to rutile TiO{sub 2} and (2) the phenomena of stimulated IR spectroscopy induced by simultaneous nitrogen doping and high spin metal ion seeding of a TiO{sub 2} nanocolloid lattice.

  1. Metal ion induced room temperature phase transformation and stimulated infrared spectroscopy on TiO2-based surfaces

    Gole, James L.; Prokes, S.M.; White, Mark G.

    2008-01-01

    Raman and infrared spectroscopy are used to demonstrate (1) the high spin metal ion induced room temperature transformation of anatase to rutile TiO 2 and (2) the phenomena of stimulated IR spectroscopy induced by simultaneous nitrogen doping and high spin metal ion seeding of a TiO 2 nanocolloid lattice

  2. The Alpha-Melanocyte Stimulating Hormone Induces Conversion of Effector T Cells into Treg Cells

    Andrew W. Taylor

    2011-01-01

    Full Text Available The neuropeptide alpha-melanocyte stimulating hormone (α-MSH has an important role in modulating immunity and homeostasis. The production of IFN-γ by effector T cells is suppressed by α-MSH, while TGF-β production is promoted in the same cells. Such α-MSH-treated T cells have immune regulatory activity and suppress hypersensitivity, autoimmune diseases, and graft rejection. Previous characterizations of the α-MSH-induced Treg cells showed that the cells are CD4+ T cells expressing the same levels of CD25 as effector T cells. Therefore, we further analyzed the α-MSH-induced Treg cells for expression of effector and regulatory T-cell markers. Also, we examined the potential for α-MSH-induced Treg cells to be from the effector T-cell population. We found that the α-MSH-induced Treg cells are CD25+  CD4+ T cells that share similar surface markers as effector T cells, except that they express on their surface LAP. Also, the α-MSH treatment augments FoxP3 message in the effector T cells, and α-MSH induction of regulatory activity was limited to the effector CD25+ T-cell population. Therefore, α-MSH converts effector T cells into Treg cells, which suppress immunity targeting specific antigens and tissues.

  3. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability.

    Liebetanz, David; Nitsche, Michael A; Tergau, Frithjof; Paulus, Walter

    2002-10-01

    Weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex. These plastic excitability changes are selectively controlled by the polarity, duration and current strength of stimulation. To reveal the underlying mechanisms of direct current (DC)-induced neuroplasticity, we combined tDCS of the motor cortex with the application of Na(+)-channel-blocking carbamazepine (CBZ) and the N-methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan (DMO). Monitored by transcranial magnetic stimulation (TMS), motor cortical excitability changes of up to 40% were achieved in the drug-free condition. Increase of cortical excitability could be selected by anodal stimulation, and decrease by cathodal stimulation. Both types of excitability change lasted several minutes after cessation of current stimulation. DMO suppressed the post-stimulation effects of both anodal and cathodal DC stimulation, strongly suggesting the involvement of NMDA receptors in both types of DC-induced neuroplasticity. In contrast, CBZ selectively eliminated anodal effects. Since CBZ stabilizes the membrane potential voltage-dependently, the results reveal that after-effects of anodal tDCS require a depolarization of membrane potentials. Similar to the induction of established types of short- or long-term neuroplasticity, a combination of glutamatergic and membrane mechanisms is necessary to induce the after-effects of tDCS. On the basis of these results, we suggest that polarity-driven alterations of resting membrane potentials represent the crucial mechanisms of the DC-induced after-effects, leading to both an alteration of spontaneous discharge rates and to a change in NMDA-receptor activation.

  4. Phencyclidine-induced social withdrawal results from deficient stimulation of cannabinoid CB₁ receptors: implications for schizophrenia.

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-08-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB₁-dependent manner, whereas pharmacological blockade of CB₁ receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB₁ receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB₁-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB₁ receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission.

  5. Assessing and inducing neuroplasticity with transcranial magnetic stimulation and robotics for motor function.

    O'Malley, Marcia K; Ro, Tony; Levin, Harvey S

    2006-12-01

    To describe 2 new ways of assessing and inducing neuroplasticity in the human brain--transcranial magnetic stimulation (TMS) and robotics--and to investigate and promote the recovery of motor function after brain damage. We identified recent articles and books directly bearing on TMS and robotics. Articles using these tools for purposes other than rehabilitation were excluded. From these studies, we emphasize the methodologic and technical details of these tools as applicable for assessing and inducing plasticity. Because both tools have only recently been used for rehabilitation, the majority of the articles selected for this review have been published only within the last 10 years. We used the PubMed and Compendex databases to find relevant peer-reviewed studies for this review. The studies were required to be relevant to rehabilitation and to use TMS or robotics methodologies. Guidelines were applied via independent extraction by multiple observers. Despite the limited amount of research using these procedures for assessing and inducing neuroplasticity, there is growing evidence that both TMS and robotics can be very effective, inexpensive, and convenient ways for assessing and inducing rehabilitation. Although TMS has primarily been used as an assessment tool for motor function, an increasing number of studies are using TMS as a tool to directly induce plasticity and improve motor function. Similarly, robotic devices have been used for rehabilitation because of their suitability for delivery of highly repeatable training. New directions in robotics-assisted rehabilitation are taking advantage of novel measurements that can be acquired via the devices, enabling unique methods of assessment of motor recovery. As refinements in technology and advances in our knowledge continue, TMS and robotics should play an increasing role in assessing and promoting the recovery of function. Ongoing and future studies combining TMS and robotics within the same populations may

  6. An in-situ stimulation experiment in crystalline rock - assessment of induced seismicity levels during stimulation and related hazard for nearby infrastructure

    Gischig, Valentin; Broccardo, Marco; Amann, Florian; Jalali, Mohammadreza; Esposito, Simona; Krietsch, Hannes; Doetsch, Joseph; Madonna, Claudio; Wiemer, Stefan; Loew, Simon; Giardini, Domenico

    2016-04-01

    A decameter in-situ stimulation experiment is currently being performed at the Grimsel Test Site in Switzerland by the Swiss Competence Center for Energy Research - Supply of Electricity (SCCER-SoE). The underground research laboratory lies in crystalline rock at a depth of 480 m, and exhibits well-documented geology that is presenting some analogies with the crystalline basement targeted for the exploitation of deep geothermal energy resources in Switzerland. The goal is to perform a series of stimulation experiments spanning from hydraulic fracturing to controlled fault-slip experiments in an experimental volume approximately 30 m in diameter. The experiments will contribute to a better understanding of hydro-mechanical phenomena and induced seismicity associated with high-pressure fluid injections. Comprehensive monitoring during stimulation will include observation of injection rate and pressure, pressure propagation in the reservoir, permeability enhancement, 3D dislocation along the faults, rock mass deformation near the fault zone, as well as micro-seismicity. The experimental volume is surrounded by other in-situ experiments (at 50 to 500 m distance) and by infrastructure of the local hydropower company (at ~100 m to several kilometres distance). Although it is generally agreed among stakeholders related to the experiments that levels of induced seismicity may be low given the small total injection volumes of less than 1 m3, detailed analysis of the potential impact of the stimulation on other experiments and surrounding infrastructure is essential to ensure operational safety. In this contribution, we present a procedure how induced seismic hazard can be estimated for an experimental situation that is untypical for injection-induced seismicity in terms of injection volumes, injection depths and proximity to affected objects. Both, deterministic and probabilistic methods are employed to estimate that maximum possible and the maximum expected induced

  7. Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

    Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2005-07-01

    Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25{+-}2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% {+-} 1.3% and 10.6% {+-} 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% {+-} 4.5% vs. 6.6% {+-} 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release.

  8. Dopamine release in human striatum induced by repetitive transcranial magnetic stimulation over dorsolateral prefrontal cortex

    Cho, Sang Soo; Yoon, Eun Jin; Kim, Yu Kyeong; Lee, Won Woo; Kim, Sang Eun

    2005-01-01

    Animal study suggests that prefrontal cortex plays an important Animal studies suggest that prefrontal cortex plays an important role in the modulation of dopamine (DA) release in subcortical areas. However, little is known about the relationship between DA release and prefrontal activation in human. We investigated whether repetitive transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex (DLPFC) influences DA release in human striatum with SPECT measurements of striatal binding of [123I)iodobenzamide (IBZM), a DA D2 receptor radioligand that is sensitive to endogenous DA. Five healthy male volunteers (age, 25±2 yr) were studied with brain [123I]IBZM SPECT under three conditions (resting, Sham stimulation, and active rTMS over left DLPFC), while receiving a bolus plus constant infusion of [123I]IBZM DLPFC was defined as a 6 cm anterior and 1cm lateral from the primary motor cortex. rTMS session consisted of three blocks, in each block, 15 trains of 2 see duration were delivered with 10 Hz stimulation frequency, 100% motor threshold, and between-train intervals of 10 sec. Striatal V3', calculated as (striatal - occipital) / occipital activity ratio, was measured under equilibrium condition, at baseline and after sham and active rTMS. Sham stimulation did not affect striatal V3'. rTMS over DLPFC induced reduction of V3' in the ipsilateral and contralateral striatum by 9.7% ± 1.3% and 10.6% ± 3.2%, respectively, compared with sham procedures (P < 0.01 and P < 0.01, respectively), indicating striatal DA release elicited by rTMS over DLPFC. V3' reduction in the ipsilateral caudate nucleus was greater than that in the contralateral caudate nucleus (9.9% ± 4.5% vs. 6.6% ± 3.1%, P < 0.05). These data demonstrate DA release in human striatum induced by rTMS over DLPFC, supporting that cortico-striatal fibers originating in prefrontal cortex are involved in local DA release

  9. Functional response of cerebral blood flow induced by somatosensory stimulation in rats with subarachnoid hemorrhage

    Li, Zhiguo; Huang, Qin; Liu, Peng; Li, Pengcheng; Ma, Lianting; Lu, Jinling

    2015-09-01

    Subarachnoid hemorrhage (SAH) is often accompanied by cerebral vasospasm (CVS), which is the phenomenon of narrowing of large cerebral arteries, and then can produce delayed ischemic neurological deficit (DIND) such as lateralized sensory dysfunction. CVS was regarded as a major contributor to DIND in patients with SAH. However, therapy for preventing vasospasm after SAH to improve the outcomes may not work all the time. It is important to find answers to the relationship between CVS and DIND after SAH. How local cerebral blood flow (CBF) is regulated during functional activation after SAH still remains poorly understood, whereas, the regulation of CBF may play an important role in weakening the impact of CVS on cortex function. Therefore, it is worthwhile to evaluate the functional response of CBF in the activated cortex in an SAH animal model. Most evaluation of the effect of SAH is presently carried out by neurological behavioral scales. The functional imaging of cortical activation during sensory stimulation may help to reflect the function of the somatosensory cortex more locally than the behavioral scales do. We investigated the functional response of CBF in the somatosensory cortex induced by an electrical stimulation to contralateral forepaw via laser speckle imaging in a rat SAH model. Nineteen Sprague-Dawley rats from two groups (control group, n=10 and SAH group, n=9) were studied. SAH was induced in rats by double injection of autologous blood into the cisterna magna after CSF aspiration. The same surgical procedure was applied in the control group without CSF aspiration or blood injection. Significant CVS was found in the SAH group. Meanwhile, we observed a delayed peak of CBF response in rats with SAH compared with those in the control group, whereas no significant difference was found in magnitude, duration, and areas under curve of relative CBF changes between the two groups. The results suggest that the regulation function of local CBF during

  10. Variable-temperature Microwave Impedance Microscope with Light Stimulation for Research on Photo-induced Phase Transitions

    2017-07-24

    SECURITY CLASSIFICATION OF: The DURIP program "Variable-temperature Microwave Impedance Microscope with Light Stimulation for Research on Photo... Stimulation for Research on Photo- induced Phase Transitions The views, opinions and/or findings contained in this report are those of the author(s) and should...reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions

  11. Characteristics of retinal reflectance changes induced by transcorneal electrical stimulation in cat eyes.

    Takeshi Morimoto

    Full Text Available Transcorneal electrical stimulation (TES activates retinal neurons leading to visual sensations. How the retinal cells are activated by TES has not been definitively determined. Investigating the reflectance changes of the retina is an established technique and has been used to determine the mechanism of retinal activation. The purpose of this study was to evaluate the reflectance changes elicited by TES in cat eyes. Eight eyes of Eight cats were studied under general anesthesia. Biphasic electrical pulses were delivered transcornealy. The fundus images observed with near-infrared light (800-880 nm were recorded every 25 ms for 26 s. To improve the signal-to-noise ratio, the images of 10 consecutive recordings were averaged. Two-dimensional topographic maps of the reflective changes were constructed by subtracting images before from those after the TES. The effects of different stimulus parameters, e.g., current intensity, pulse duration, frequency, and stimulus duration, on the reflective changes were studied. Our results showed that after TES, the reflective changes appeared on the retinal vessels and optic disc. The intensity of reflectance changes increased as the current intensity, pulse duration, and stimulation duration increased (P<0.05 for all. The maximum intensity of the reflective change was obtained when the stimulus frequency was 20 Hz. The time course of the reflectance changes was also altered by the stimulation parameters. The response started earlier and returned to the baseline later with higher current intensities, longer pulse durations, but the time of the peak of the response was not changed. These results showed that the reflective changes were due to the activation of retinal neurons by TES and might involve the vascular changes induced by an activation of the retinal neurons.

  12. The effect of transcranial direct current stimulation on experimentally induced heat pain.

    Aslaksen, Per M; Vasylenko, Olena; Fagerlund, Asbjørn J

    2014-06-01

    Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulatory technique that can affect human pain perception. Placebo effects are present in most treatments and could therefore also interact with treatment effects in tDCS. The present study investigated whether short-term tDCS reduced heat pain intensity, stress, blood pressure and increased heat pain thresholds in healthy volunteers when controlling for placebo effects. Seventy-five (37 females) participants were randomized into three groups: (1) active tDCS group receiving anodal tDCS (2 mA) for 7 min to the primary motor cortex (M1), (2) placebo group receiving the tDCS electrode montage but only active tDCS stimulation for 30 s and (3) natural history group that got no tDCS montage but the same pain stimulation as the active tDCS and the placebo group. Heat pain was induced by a PC-controlled thermode attached to the left forearm. Pain intensity was significantly lower in the active tDCS group when examining change scores (pretest-posttest) for the 47 °C condition. The placebo group displayed lower pain compared with the natural history group, displaying a significant placebo effect. In the 43 and 45 °C conditions, the effect of tDCS could not be separated from placebo effects. The results revealed no effects on pain thresholds. There was a tendency that active tDCS reduced stress and systolic blood pressure, however, not significant. In sum, tDCS had an analgesic effect on high-intensity pain, but the effect of tDCS could not be separated from placebo effects for medium and low pain.

  13. Polychlorinated biphenyl 126 stimulates basal and inducible aldosterone biosynthesis of human adrenocortical H295R cells

    Li, L.-A.; Wang, P.-W.; Chang, Louis W.

    2004-01-01

    To understand the effects of polychlorinated biphenyls (PCBs) on adrenal aldosterone biosynthesis, we have performed a systematical study to characterize the corresponding steroidogenic response of human adrenocortical cell line H295R to PCB126 exposure. We found that PCB126 at high concentrations stimulated basal and inducible aldosterone production. The aldosterone induction occurred concomitantly with activation of the CYP11B2 gene. Despite the fact that PCB126 acted in synergy with both potassium and angiotensin II (Ang II) in activation of aldosterone synthesis, PCB126 only modestly increased CYP11B2 mRNA expression in the presence of Ang II contrary to the synergistic transcriptional induction elicited by PCB126 and potassium. This implicated that PCB126 had differential interactions with the potassium and Ang II signaling systems in the regulation of aldosterone biosynthesis. In addition, high concentrations of PCB126 elevated transcriptional expression of the type I Ang II receptor (AT 1 ) and might thus sensitize the cellular Ang II responsiveness in both basal and inducible aldosterone biosynthesis. SF-1 was not involved in the PCB126-induced transcriptional regulation despite its importance in steroidogenic gene activation

  14. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi

    2000-01-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 μg/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  15. Does granulocyte colony-stimulating factor exacerbate radiation-induced acute lung injury in rats?

    Miura, Gouji; Awaya, Hitomi; Matsumoto, Tsuneo; Tanaka, Nobuyuki; Matsunaga, Naofumi [Yamaguchi Univ., Ube (Japan). School of Medicine

    2000-08-01

    Radiation pneumonitis (RP) frequently occurs as a complication of thoracic irradiation. However, the mechanism of RP is not well known. Activated neutrophils are a possible pathogenesis of RP. Neutrophil activation induced by granulocyte colony-stimulating factor (G-CSF) may exacerbate RP. We studied the effects of recombinant human G-CSF on acute lung injury induced by thoracic irradiation using rats. Animals were divided into three groups: sham irradiation with saline control, irradiation alone, and irradiation with G-CSF. Actual irradiation was given as a single fraction of 16 Gy delivered to the right hemithorax. G-CSF at a dose of 12 {mu}g/body was administered subcutaneously once a day from 14 to 18 days after actual irradiation. Lung injury was evaluated 21 days after irradiation by bronchoalveolar lavage (BAL) fluid findings and the lung wet/dry weight (W/D) ratio. Neutrophil and lymphocyte counts in BAL fluid and the W/D ratio were significantly increased in the irradiation alone and the irradiation with G-CSF groups compared with those of the sham irradiation+saline control group. However, there was no significant difference observed between the irradiation alone and irradiation with G-CSF groups. In conclusion, this study suggests that postradiation administration of G-CSF does not exacerbate acute lung injury induced by thoracic irradiation in rats. (author)

  16. Resuscitation therapy for traumatic brain injury-induced coma in rats: mechanisms of median nerve electrical stimulation

    Zhen Feng

    2015-01-01

    Full Text Available In this study, rats were put into traumatic brain injury-induced coma and treated with median nerve electrical stimulation. We explored the wake-promoting effect, and possible mechanisms, of median nerve electrical stimulation. Electrical stimulation upregulated the expression levels of orexin-A and its receptor OX1R in the rat prefrontal cortex. Orexin-A expression gradually increased with increasing stimulation, while OX1R expression reached a peak at 12 hours and then decreased. In addition, after the OX1R antagonist, SB334867, was injected into the brain of rats after traumatic brain injury, fewer rats were restored to consciousness, and orexin-A and OXIR expression in the prefrontal cortex was downregulated. Our findings indicate that median nerve electrical stimulation induced an up-regulation of orexin-A and OX1R expression in the prefrontal cortex of traumatic brain injury-induced coma rats, which may be a potential mechanism involved in the wake-promoting effects of median nerve electrical stimulation.

  17. Activation of the GABAB receptor prevents nicotine-induced locomotor stimulation in mice

    Carla eLobina

    2011-12-01

    Full Text Available Recent studies demonstrated that activation of the GABAB receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs, inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB receptor agonist, baclofen, and GABAB PAMs, CGP7930 and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p., CGP7930 (0, 25, and 50 mg/kg, i.g., or GS39783 (0, 25, and 50 mg/kg, i.g., then treated with nicotine (0 and 0.05 mg/kg, s.c., and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABAB PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABAB receptor may represent a potentially useful, anti-smoking therapeutic strategy.

  18. Enhancing the smoothness of joint motion induced by functional electrical stimulation using co-activation strategies

    Ruppel Mirjana

    2017-09-01

    Full Text Available The motor precision of today’s neuroprosthetic devices that use artificial generation of limb motion using Functional Electrical Stimulation (FES is generally low. We investigate the adoption of natural co-activation strategies as present in antagonistic muscle pairs aiming to improve motor precision produced by FES. In a test in which artificial knee-joint movements were generated, we could improve the smoothness of FES-induced motion by 513% when applying co-activation during the phases in which torque production is switched between muscles – compared to no co-activation. We further demonstrated how the co-activation level influences the joint stiffness in a pendulum test.

  19. Electron-stimulated purification of platinum nanostructures grown via focused electron beam induced deposition

    Brett B. Lewis

    2015-04-01

    Full Text Available Platinum–carbon nanostructures deposited via electron beam induced deposition from MeCpPt(IVMe3 are purified during a post-deposition electron exposure treatment in a localized oxygen ambient at room temperature. Time-dependent studies demonstrate that the process occurs from the top–down. Electron beam energy and current studies demonstrate that the process is controlled by a confluence of the electron energy loss and oxygen concentration. Furthermore, the experimental results are modeled as a 2nd order reaction which is dependent on both the electron energy loss density and the oxygen concentration. In addition to purification, the post-deposition electron stimulated oxygen purification process enhances the resolution of the EBID process due to the isotropic carbon removal from the as-deposited materials which produces high-fidelity shape retention.

  20. The role of electron-stimulated desorption in focused electron beam induced deposition

    van Dorp, Willem F.; Hansen, Thomas Willum; Wagner, Jakob Birkedal

    2013-01-01

    We present the results of our study about the deposition rate of focused electron beam induced processing (FEBIP) as a function of the substrate temperature with the substrate being an electron-transparent amorphous carbon membrane. When W(CO)6 is used as a precursor it is observed that the growt......, the majority desorbs from the surface rather than dissociates to contribute to the deposit. It is important to take this into account during FEBIP experiments, for instance when determining fundamental process parameters such as the activation energy for desorption....... experiments compared to literature values is consistent with earlier findings by other authors. The discrepancy is attributed to electron-stimulated desorption, which is known to occur during electron irradiation. The data suggest that, of the W(CO)6 molecules that are affected by the electron irradiation...

  1. Mathematical modeling of calcium waves induced by mechanical stimulation in keratinocytes.

    Yasuaki Kobayashi

    Full Text Available Recent studies have shown that the behavior of calcium in the epidermis is closely related to the conditions of the skin, especially the differentiation of the epidermal keratinocytes and the permeability barrier function, and therefore a correct understanding of the calcium dynamics is important in explaining epidermal homeostasis. Here we report on experimental observations of in vitro calcium waves in keratinocytes induced by mechanical stimulation, and present a mathematical model that can describe the experimentally observed wave behavior that includes finite-range wave propagation and a ring-shaped pattern. A mechanism of the ring formation hypothesized by our model may be related to similar calcium propagation patterns observed during the wound healing process in the epidermis. We discuss a possible extension of our model that may serve as a tool for investigating the mechanisms of various skin diseases.

  2. Elevated thyroid stimulating hormone in a neonate: Drug induced or disease?

    Sunil Kumar Kota

    2011-01-01

    Full Text Available Dyshormonogenesis is an uncommon cause of congenital hypothyroidism. The most common abnormality is absent or insufficient thyroid peroxidase enzyme. Maternal intake of antithyroid drug can also lead to elevated thyroid stimulating hormone (TSH in a neonate, albeit the scenario is temporary. We report one such interesting case where a clinically euthyroid neonate borne to a mother on antithyroid drug presents on 12 th day of life with reports of elevated TSH and increased tracer uptake in 99mTc thyroid scan. Disproportionately high TSH in comparison to low maternal antithyroid drug dosage and further elevation of TSH after stopping mother′s antithyroid drugs ruled out maternal antithyroid drug-induced congenital hypothyroidism in the baby. Early institution of therapy in these patients can prevent mental retardation and other features of hypothyroidism.

  3. Tail nerve electrical stimulation induces body weight-supported stepping in rats with spinal cord injury.

    Zhang, Shu-Xin; Huang, Fengfa; Gates, Mary; White, Jason; Holmberg, Eric G

    2010-03-30

    Walking or stepping has been considered the result from the activation of the central pattern generator (CPG). In most patients with spinal cord injury (SCI) the CPG is undamaged. To date, there are no noninvasive approaches for activating the CPG. Recently we developed a noninvasive technique, tail nerve electrical stimulation (TANES), which can induce positive hind limb movement of SCI rats. The purpose of this study is to introduce the novel technique and examine the effect of TANES on CPG activation. A 25 mm contusion injury was produced at spinal cord T10 of female, adult Long-Evans rats by using the NYU impactor device. Rats received TANES ( approximately 40 mA at 4 kHz) 7 weeks after injury. During TANES all injured rats demonstrated active body weight-supported stepping of hind limbs with left-right alternation and occasional front-hind coordination, resulting in significant, temporary increase in BBB scores (p<0.01). However, there is no response to TANES from rats with L2 transection, consistent with other reports that the CPG may be located at L1-2. S1 transection negatively implies the key role of TANES in CPG activation. The TANES not only renders paralyzed rats with a technique-induced ability to walk via activating CPG, but also is likely to be used for locomotor training. It has more beneficial effects for physical training over other training paradigms including treadmill training and invasive functional electrical stimulation. Therefore the TANES may have considerable potential for achieving improvement of functional recovery in animal models and a similar method may be suggested for human study. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  4. Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model.

    Haviv Levi

    Full Text Available The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known.The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG activity continuously recorded in behaving animals.Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion.SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications.

  5. Seeds of Brassicaceae weeds have an inherent or inducible response to the germination stimulant karrikinolide.

    Long, Rowena L; Stevens, Jason C; Griffiths, Erin M; Adamek, Markus; Gorecki, Marta J; Powles, Stephen B; Merritt, David J

    2011-10-01

    Karrikinolide (KAR(1)) is a smoke-derived chemical that can trigger seeds to germinate. A potential application for KAR(1) is for synchronizing the germination of weed seeds, thereby enhancing the efficiency of weed control efforts. Yet not all species germinate readily with KAR(1), and it is not known whether seemingly non-responsive species can be induced to respond. Here a major agronomic weed family, the Brassicaceae, is used to test the hypothesis that a stimulatory response to KAR(1) may be present in physiologically dormant seeds but may not be expressed under all circumstances. Seeds of eight Brassicaceae weed species (Brassica tournefortii, Raphanus raphanistrum, Sisymbrium orientale, S. erysimoides, Rapistrum rugosum, Lepidium africanum, Heliophila pusilla and Carrichtera annua) were tested for their response to 1 µm KAR(1) when freshly collected and following simulated and natural dormancy alleviation, which included wet-dry cycling, dry after-ripening, cold and warm stratification and a 2 year seed burial trial. Seven of the eight Brassicaceae species tested were stimulated to germinate with KAR(1) when the seeds were fresh, and the remaining species became responsive to KAR(1) following wet-dry cycling and dry after-ripening. Light influenced the germination response of seeds to KAR(1), with the majority of species germinating better in darkness. Germination with and without KAR(1) fluctuated seasonally throughout the seed burial trial. KAR(1) responses are more complex than simply stating whether a species is responsive or non-responsive; light and temperature conditions, dormancy state and seed lot all influence the sensitivity of seeds to KAR(1), and a response to KAR(1) can be induced. Three response types for generalizing KAR(1) responses are proposed, namely inherent, inducible and undetected. Given that responses to KAR(1) were either inherent or inducible in all 15 seed lots included in this study, the Brassicaceae may be an ideal target for

  6. Iron mediates N-methyl-D-aspartate receptor-dependent stimulation of calcium-induced pathways and hippocampal synaptic plasticity.

    Muñoz, Pablo; Humeres, Alexis; Elgueta, Claudio; Kirkwood, Alfredo; Hidalgo, Cecilia; Núñez, Marco T

    2011-04-15

    Iron deficiency hinders hippocampus-dependent learning processes and impairs cognitive performance, but current knowledge on the molecular mechanisms underlying the unique role of iron in neuronal function is sparse. Here, we investigated the participation of iron on calcium signal generation and ERK1/2 stimulation induced by the glutamate agonist N-methyl-D-aspartate (NMDA), and the effects of iron addition/chelation on hippocampal basal synaptic transmission and long-term potentiation (LTP). Addition of NMDA to primary hippocampal cultures elicited persistent calcium signals that required functional NMDA receptors and were independent of calcium influx through L-type calcium channels or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; NMDA also promoted ERK1/2 phosphorylation and nuclear translocation. Iron chelation with desferrioxamine or inhibition of ryanodine receptor (RyR)-mediated calcium release with ryanodine-reduced calcium signal duration and prevented NMDA-induced ERK1/2 activation. Iron addition to hippocampal neurons readily increased the intracellular labile iron pool and stimulated reactive oxygen species production; the antioxidant N-acetylcysteine or the hydroxyl radical trapper MCI-186 prevented these responses. Iron addition to primary hippocampal cultures kept in calcium-free medium elicited calcium signals and stimulated ERK1/2 phosphorylation; RyR inhibition abolished these effects. Iron chelation decreased basal synaptic transmission in hippocampal slices, inhibited iron-induced synaptic stimulation, and impaired sustained LTP in hippocampal CA1 neurons induced by strong stimulation. In contrast, iron addition facilitated sustained LTP induction after suboptimal tetanic stimulation. Together, these results suggest that hippocampal neurons require iron to generate RyR-mediated calcium signals after NMDA receptor stimulation, which in turn promotes ERK1/2 activation, an essential step of sustained LTP.

  7. Galvanic Tongue Stimulation Inhibits Five Basic Tastes Induced by Aqueous Electrolyte Solutions

    Kazuma Aoyama

    2017-12-01

    Full Text Available Galvanic tongue stimulation (GTS modulates taste sensation. However, the effect of GTS is contingent on the electrode polarity in the proximity of the tongue. If an anodal electrode is attached in the proximity of the tongue, an electrical or metallic taste is elicited. On the other hand, if only cathodal electrode is attached in the proximity of the tongue, the salty taste, which is induced by electrolyte materials, is inhibited. The mechanism of this taste inhibition is not adequately understood. In this study, we aim to demonstrate that the inhibition is cause by ions, which elicit taste and which migrate from the taste sensors on the tongue by GTS. We verified the inhibitory effect of GTS on all five basic tastes induced by electrolyte materials. This technology is effective for virtual reality systems and interfaces to support dietary restrictions. Our findings demonstrate that cathodal-GTS inhibits all the five basic tastes. The results also support our hypothesis that the effects of cathodal-GTS are caused by migrating tasting ions in the mouth.

  8. PLGA-based microcarriers induce mesenchymal stem cell chondrogenesis and stimulate cartilage repair in osteoarthritis.

    Morille, Marie; Toupet, Karine; Montero-Menei, Claudia N; Jorgensen, Christian; Noël, Danièle

    2016-05-01

    In the present study, we aimed at evaluating the ability of novel PLGA-P188-PLGA-based microspheres to induce the differentiation of mesenchymal stem/stromal cells (MSC) into chondrocytes. To this aim, we tested microspheres releasing TGFβ3 (PAM-T) in vitro and in situ, in a pathological osteoarthritic (OA) environment. We first evaluated the chondrogenic differentiation of human MSCs seeded onto PAM-T in vitro and confirmed the up-regulation of chondrogenic markers while the secretome of the cells was not changed by the 3D environment. We then injected human MSC seeded onto PAM-T in the knee joints of mice with collagenase-induced OA. After 6 weeks, histological analysis revealed that formation of a cartilage-like tissue occurred at the vicinity of PAM-T that was not observed when MSCs were seeded onto PAM. We also noticed that the endogenous articular cartilage was less degraded. The extent of cartilage protection was further analysed by confocal laser microscopy. When MSCs seeded onto PAM-T were injected early after OA induction, protection of cartilage against degradation was evidenced and this effect was associated to a higher survival of MSCs in presence of TGFβ3. This study points to the interest of using MSCs seeded onto PAM for cartilage repair and stimulation of endogenous cartilage regeneration. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. In vitro deposition of hydroxyapatite on cortical bone collagen stimulated by deformation-induced piezoelectricity.

    Noris-Suárez, Karem; Lira-Olivares, Joaquin; Ferreira, Ana Marina; Feijoo, José Luis; Suárez, Nery; Hernández, Maria C; Barrios, Esteban

    2007-03-01

    In the present work, we have studied the effect of the piezoelectricity of elastically deformed cortical bone collagen on surface using a biomimetic approach. The mineralization process induced as a consequence of the piezoelectricity effect was evaluated using scanning electron microscopy (SEM), thermally stimulated depolarization current (TSDC), and differential scanning calorimetry (DSC). SEM micrographs showed that mineralization occurred predominantly over the compressed side of bone collagen, due to the effect of piezoelectricity, when the sample was immersed in the simulated body fluid (SBF) in a cell-free system. The TSDC method was used to examine the complex collagen dielectric response. The dielectric spectra of deformed and undeformed collagen samples with different hydration levels were compared and correlated with the mineralization process followed by SEM. The dielectric measurements showed that the mineralization induced significant changes in the dielectric spectra of the deformed sample. DSC and TSDC results demonstrated a reduction of the collagen glass transition as the mineralization process advanced. The combined use of SEM, TSDC, and DSC showed that, even without osteoblasts present, the piezoelectric dipoles produced by deformed collagen can produce the precipitation of hydroxyapatite by electrochemical means, without a catalytic converter as occurs in classical biomimetic deposition.

  10. GABA(A) receptors mediate orexin-A induced stimulation of food intake.

    Kokare, Dadasaheb M; Patole, Angad M; Carta, Anna; Chopde, Chandrabhan T; Subhedar, Nishikant K

    2006-01-01

    Although the role of orexins in sleep/wake cycle and feeding behavior is well established, underlying mechanisms have not been fully understood. An attempt has been made to investigate the role of GABA(A) receptors and their benzodiazepine site on the orexin-A induced response to feeding. Different groups of rats were food deprived overnight and next day injected intracerebroventricularly (icv) with vehicle (artificial CSF; 5 microl/rat) or orexin-A (20-50 nM/rat) and the animals were given free access to food. Cumulative food intake was measured during light phase of light/dark cycle at 1-, 2-, 4- and 6-h post-injection time points. Orexin-A (30-50 nM/rat, icv) stimulated food intake at all the time points (P GABA(A) receptor agonists muscimol (25 ng/rat, icv) and diazepam (0.5 mg/kg, ip) at subeffective doses significantly potentiated the hyperphagic effect of orexin-A (30 nM/rat, icv). However, the effect was negated by the GABA(A) receptor antagonist bicuculline (1 mg/kg, ip). Interestingly, benzodiazepine receptor antagonist flumazenil (5 ng/rat, icv), augmented the orexin-A (30 nM/rat, icv) induced hyperphagia; the effect may be attributed to the intrinsic activity of the agent. The results suggest that the hyperphagic effect of orexin-A, at least in part, is mediated by enhanced GABA(A) receptor activity.

  11. Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response After Renal Denervation.

    de Jong, Mark R; Adiyaman, Ahmet; Gal, Pim; Smit, Jaap Jan J; Delnoy, Peter Paul H M; Heeg, Jan-Evert; van Hasselt, Boudewijn A A M; Lau, Elizabeth O Y; Persu, Alexandre; Staessen, Jan A; Ramdat Misier, Anand R; Steinberg, Jonathan S; Elvan, Arif

    2016-09-01

    Blood pressure (BP) response to renal denervation (RDN) is highly variable and its effectiveness debated. A procedural end point for RDN may improve consistency of response. The objective of the current analysis was to look for the association between renal nerve stimulation (RNS)-induced BP increase before and after RDN and changes in ambulatory BP monitoring (ABPM) after RDN. Fourteen patients with drug-resistant hypertension referred for RDN were included. RNS was performed under general anesthesia at 4 sites in the right and left renal arteries, both before and immediately after RDN. RNS-induced BP changes were monitored and correlated to changes in ambulatory BP at a follow-up of 3 to 6 months after RDN. RNS resulted in a systolic BP increase of 50±27 mm Hg before RDN and systolic BP increase of 13±16 mm Hg after RDN (Pefficacy of RDN and predict BP response to RDN. © 2016 American Heart Association, Inc.

  12. Adrenaline stimulates the proliferation and migration of mesenchymal stem cells towards the LPS-induced lung injury.

    Wu, Xiaodan; Wang, Zhiming; Qian, Mengjia; Wang, Lingyan; Bai, Chunxue; Wang, Xiangdong

    2014-08-01

    Bone marrow-derived mesenchymal stem cells (BMSCs) could modulate inflammation in experimental lung injury. On the other hand, adrenergic receptor agonists could increase DNA synthesis of stem cells. Therefore, we investigated the therapeutic role of adrenaline-stimulated BMSCs on lipopolysaccharide (LPS)-induced lung injury. BMSCs were cultured with adrenergic receptor agonists or antagonists. Suspensions of lung cells or sliced lung tissue from animals with or without LPS-induced injury were co-cultured with BMSCs. LPS-stimulated alveolar macrophages were co-cultured with BMSCs (with adrenaline stimulation or not) in Transwell for 6 hrs. A preliminary animal experiment was conducted to validate the findings in ex vivo study. We found that adrenaline at 10 μM enhanced proliferation of BMSCs through both α- and β-adrenergic receptors. Adrenaline promoted the migration of BMSCs towards LPS-injured lung cells or lung tissue. Adrenaline-stimulated BMSCs decreased the inflammation of LPS-stimulated macrophages, probably through the expression and secretion of several paracrine factors. Adrenaline reduced the extent of injury in LPS-injured rats. Our data indicate that adrenaline-stimulated BMSCs might contribute to the prevention from acute lung injury through the activation of adrenergic receptors, promotion of proliferation and migration towards injured lung, and modulation of inflammation. © 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  13. Antinociception induced by epidural motor cortex stimulation in naive conscious rats is mediated by the opioid system.

    Fonoff, Erich Talamoni; Dale, Camila Squarzoni; Pagano, Rosana Lima; Paccola, Carina Cicconi; Ballester, Gerson; Teixeira, Manoel Jacobsen; Giorgi, Renata

    2009-01-03

    Epidural motor cortex stimulation (MCS) has been used for treating patients with neuropathic pain resistant to other therapeutic approaches. Experimental evidence suggests that the motor cortex is also involved in the modulation of normal nociceptive response, but the underlying mechanisms of pain control have not been clarified yet. The aim of this study was to investigate the effects of epidural electrical MCS on the nociceptive threshold of naive rats. Electrodes were placed on epidural motor cortex, over the hind paw area, according to the functional mapping accomplished in this study. Nociceptive threshold and general activity were evaluated under 15-min electrical stimulating sessions. When rats were evaluated by the paw pressure test, MCS induced selective antinociception in the paw contralateral to the stimulated cortex, but no changes were noticed in the ipsilateral paw. When the nociceptive test was repeated 15 min after cessation of electrical stimulation, the nociceptive threshold returned to basal levels. On the other hand, no changes in the nociceptive threshold were observed in rats evaluated by the tail-flick test. Additionally, no behavioral or motor impairment were noticed in the course of stimulation session at the open-field test. Stimulation of posterior parietal or somatosensory cortices did not elicit any changes in the general activity or nociceptive response. Opioid receptors blockade by naloxone abolished the increase in nociceptive threshold induced by MCS. Data shown herein demonstrate that epidural electrical MCS elicits a substantial and selective antinociceptive effect, which is mediated by opioids.

  14. Metabolic costs of force generation for constant-frequency and catchlike-inducing electrical stimulation in human tibialis anterior muscle

    Ratkevicius, Aivaras; Quistorff, Bjørn

    2002-01-01

    -frequency trains, catchlike-inducing trains produced a faster force generation and were more effective in maintaining the force--time integral as well as peak force. However, ATP costs of force generation were similar for the catchlike-inducing and constant-frequency stimulation (6.7 plus/minus 1.1 and 6.6 plus......Metabolic costs of force generation were compared for constant-frequency and catchlike-inducing electrical stimulation. Repetitive catchlike-inducing trains consisted of 2 interpulse intervals (IPIs) at 12.5 ms, 1 IPI at 25 ms, and 5 IPIs at 50 ms. Constant-frequency trains consisted of 8 IPIs...... at 37.5 ms. One train was delivered to the peroneal nerve every 2.5 s for 36 times under ischemic conditions. Anaerobic adenosine triphosphate (ATP) turnover was determined using 31-phosphorus magnetic resonance spectroscopy (P-MRS) of the human tibialis anterior muscle. Compared with constant...

  15. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase

    Rajfer, R. A.; Kilic, A.; Neviaser, A. S.; Schulte, L. M.; Hlaing, S. M.; Landeros, J.; Ferrini, M. G.; Ebramzadeh, E.

    2017-01-01

    Objectives We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. Materials and Methods Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry. Results When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42. Conclusion This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression. Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:–97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2. PMID:28188129

  16. Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

    Jiao, Kun-Li; Li, Yi-Gang; Zhang, Peng-Pai; Chen, Ren-Hua; Yu, Yi

    2012-01-01

    Abstract The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression. PMID:22128836

  17. Dietary lipid and cholesterol induce ovarian dysfunction and abnormal LH response to stimulation in rabbits.

    Anne-Gaël Cordier

    Full Text Available BACKGROUND/AIM: Excess of fat intake is dramatically increasing in women of childbearing age and results in numerous health complications, including reproductive disorders. Using rabbit does as a biomedical model, the aim of this study was to evaluate onset of puberty, endocrine responses to stimulation and ovarian follicular maturation in females fed a high fat high cholesterol diet (HH diet from 10 weeks of age (i.e., 2 weeks before normal onset of puberty or a control diet (C diet. METHODOLOGY/PRINCIPAL FINDINGS: Three experiments were performed, each including 8 treated (HH group and 8 control (C group does. In experiment 1, the endocrine response to Gonadotropin releasing hormone (GnRH was evaluated at 13, 18 and 22 weeks of age. In experiment 2, the follicular population was counted in ovaries of adult females (18 weeks of age. In experiment 3, the LH response to mating and steroid profiles throughout gestation were evaluated at 18 weeks of age. Fetal growth was monitored by ultrasound and offspring birth weight was recorded. Data showed a significantly higher Luteinizing hormone (LH response after induction of ovulation at 13 weeks of age in the HH group. There was no difference at 18 weeks, but at 22 weeks, the LH response to GnRH was significantly reduced in the HH group. The number of atretic follicles was significantly increased and the number of antral follicles significantly reduced in HH does vs. controls. During gestation, the HH diet induced intra-uterine growth retardation (IUGR. CONCLUSION: The HH diet administered from before puberty onwards affected onset of puberty, follicular growth, hormonal responses to breeding and GnRH stimulation in relation to age and lead to fetal IUGR.

  18. K+-induced alterations in airway muscle responsiveness to electrical field stimulation

    Murlas, C.; Ehring, G.; Suszkiw, J.; Sperelakis, N.

    1986-01-01

    We investigated possible pre- and postsynaptic effects of K+-induced depolarization on ferret tracheal smooth muscle (TSM) responsiveness to cholinergic stimulation. To assess electromechanical activity, cell membrane potential (Em) and tension (Tm) were simultaneously recorded in buffer containing 6, 12, 18, or 24 mM K+ before and after electrical field stimulation (EFS) or exogenous acetylcholine (ACh). In 6 mM K+, Em was -58.1 +/- 1.0 mV (mean +/- SE). In 12 mM K+, Em was depolarized to -52.3 +/- 0.9 mV, basal Tm did not change, and both excitatory junctional potentials and contractile responses to EFS at short stimulus duration were larger than in 6 mM K+. No such potentiation occurred at a higher K+, although resting Em and Tm increased progressively above 12 mM K+. The sensitivity of ferret TSM to exogenous ACh appeared unaffected by K+. To determine whether the hyperresponsiveness in 12 mM K+ was due, in part, to augmented ACh release from intramural airway nerves, experiments were done using TSM preparations incubated with [3H]choline to measure [3H]ACh release at rest and during EFS. Although resting [3H]ACh release increased progressively in higher K+, release evoked by EFS was maximal in 12 mM K+ and declined in higher concentrations. We conclude that small elevations in the extracellular K+ concentration augment responsiveness of the airways, by increasing the release of ACh both at rest and during EFS from intramural cholinergic nerve terminals. Larger increases in K+ appear to be inhibitory, possibly due to voltage-dependent effects that occur both pre- and postsynaptically

  19. Preemptive, but not reactive, spinal cord stimulation mitigates transient ischemia-induced myocardial infarction via cardiac adrenergic neurons

    Southerland, E. M.; Milhorn, D. M.; Foreman, R. D.; Linderoth, B.; DeJongste, M. J. L.; Armour, J. A.; Subramanian, V.; Singh, M.; Singh, K.; Ardell, J. L.

    2007-01-01

    Our objective was to determine whether electrical neuromodulation using spinal cord stimulation ( SCS) mitigates transient ischemia-induced ventricular infarction and, if so, whether adrenergic neurons are involved in such cardioprotection. The hearts of anesthetized rabbits, subjected to 30 min of

  20. Associative stimulation of the supraorbital nerve fails to induce timing-specific plasticity in the human blink reflex

    Zeuner, Kirsten E; Knutzen, Arne; Al-Ali, Asmaa

    2010-01-01

    Associative high-frequency electrical stimulation (HFS) of the supraorbital nerve in five healthy individuals induced long-term potentiation (LTP)-like or depression (LTD)-like changes in the human blink reflex circuit according to the rules of spike timing-dependent plasticity (Mao and Evinger...

  1. Pharmacological Mechanisms of Cortical Enhancement Induced by the Repetitive Pairing of Visual/Cholinergic Stimulation.

    Jun-Il Kang

    Full Text Available Repetitive visual training paired with electrical activation of cholinergic projections to the primary visual cortex (V1 induces long-term enhancement of cortical processing in response to the visual training stimulus. To better determine the receptor subtypes mediating this effect the selective pharmacological blockade of V1 nicotinic (nAChR, M1 and M2 muscarinic (mAChR or GABAergic A (GABAAR receptors was performed during the training session and visual evoked potentials (VEPs were recorded before and after training. The training session consisted of the exposure of awake, adult rats to an orientation-specific 0.12 CPD grating paired with an electrical stimulation of the basal forebrain for a duration of 1 week for 10 minutes per day. Pharmacological agents were infused intracortically during this period. The post-training VEP amplitude was significantly increased compared to the pre-training values for the trained spatial frequency and to adjacent spatial frequencies up to 0.3 CPD, suggesting a long-term increase of V1 sensitivity. This increase was totally blocked by the nAChR antagonist as well as by an M2 mAChR subtype and GABAAR antagonist. Moreover, administration of the M2 mAChR antagonist also significantly decreased the amplitude of the control VEPs, suggesting a suppressive effect on cortical responsiveness. However, the M1 mAChR antagonist blocked the increase of the VEP amplitude only for the high spatial frequency (0.3 CPD, suggesting that M1 role was limited to the spread of the enhancement effect to a higher spatial frequency. More generally, all the drugs used did block the VEP increase at 0.3 CPD. Further, use of each of the aforementioned receptor antagonists blocked training-induced changes in gamma and beta band oscillations. These findings demonstrate that visual training coupled with cholinergic stimulation improved perceptual sensitivity by enhancing cortical responsiveness in V1. This enhancement is mainly mediated by n

  2. High frequency electrical stimulation concurrently induces central sensitization and ipsilateral inhibitory pain modulation.

    Vo, L; Drummond, P D

    2013-03-01

    In healthy humans, analgesia to blunt pressure develops in the ipsilateral forehead during various forms of limb pain. The aim of the current study was to determine whether this analgesic response is induced by ultraviolet B radiation (UVB), which evokes signs of peripheral sensitization, or by high-frequency electrical stimulation (HFS), which triggers signs of central sensitization. Before and after HFS and UVB conditioning, sensitivity to heat and to blunt and sharp stimuli was assessed at and adjacent to the treated site in the forearm. In addition, sensitivity to blunt pressure was measured bilaterally in the forehead. The effect of ipsilateral versus contralateral temple cooling on electrically evoked pain in the forearm was then examined, to determine whether HFS or UVB conditioning altered inhibitory pain modulation. UVB conditioning triggered signs of peripheral sensitization, whereas HFS conditioning triggered signs of central sensitization. Importantly, ipsilateral forehead analgesia developed after HFS but not UVB conditioning. In addition, decreases in electrically evoked pain at the HFS-treated site were greater during ipsilateral than contralateral temple cooling, whereas decreases at the UVB-treated site were similar during both procedures. HFS conditioning induced signs of central sensitization in the forearm and analgesia both in the ipsilateral forehead and the HFS-treated site. This ipsilateral analgesia was not due to peripheral sensitization or other non-specific effects, as it failed to develop after UVB conditioning. Thus, the supra-spinal mechanisms that evoke central sensitization might also trigger a hemilateral inhibitory pain modulation process. This inhibitory process could sharpen the boundaries of central sensitization or limit its spread. © 2012 European Federation of International Association for the Study of Pain Chapters.

  3. CD1 molecule expression on human monocytes induced by granulocyte-macrophage colony-stimulating factor.

    Kasinrerk, W; Baumruker, T; Majdic, O; Knapp, W; Stockinger, H

    1993-01-15

    In this paper we demonstrate that granulocyte-macrophage CSF (GM-CSF) specifically induces the expression of CD1 molecules, CD1a, CD1b and CD1c, upon human monocytes. CD1 molecules appeared upon monocytes on day 1 of stimulation with rGM-CSF, and expression was up-regulated until day 3. Monocytes cultured in the presence of LPS, FMLP, PMA, recombinant granulocyte-CSF, rIFN-gamma, rTNF-alpha, rIL-1 alpha, rIL-1 beta, and rIL-6 remained negative. The induction of CD1 molecules by rGM-CSF was restricted to monocytes, since no such effect was observed upon peripheral blood granulocytes, PBL, and the myeloid cell lines Monomac1, Monomac6, MV4/11, HL60, U937, THP1, KG1, and KG1A. CD1a mRNA was detectable in rGM-CSF-induced monocytes but not in those freshly isolated. SDS-PAGE and immunoblotting analyses of CD1a mAb VIT6 immunoprecipitate from lysate of rGM-CSF-activated monocytes revealed an appropriate CD1a polypeptide band of 49 kDa associated with beta 2-microglobulin. Expression of CD1 molecules on monocytes complements the distribution of these structures on accessory cells, and their specific induction by GM-CSF strengthens the suggestion that CD1 is a family of crucial structures required for interaction between accessory cells and T cells.

  4. Ps laser pulse induced stimulated Raman scattering of ammonium nitrate dissolved in water

    Kumar, V. Rakesh; Kiran, P. Prem

    2018-04-01

    An intense picosecond laser pulse focused into a liquid medium generates a shock wave in the focal region. This shock wave while propagating into the medium varies the pressure and temperature of the liquid locally leading to the appearance of novel phases which are manifested by the appearance of Raman peaks. We present the phase changes of ammonium nitrate (AN) dissolved in water by studying the forward and backward stimulated Raman Scattering (FSRS and BSRS) signals due to propagation of 30 ps laser pulse induced shockwaves. The dominant peak corresponding to the NO3- symmetric stretching mode is observed with a Raman shift of 1045 cm-1 which represents phase IV of AN with an orthogonal crystalline structure. Apart from this peak, the dominant mode of liquid phase of water with a Raman shift of 3400 cm-1 and an ice VII peak at a Raman shift of 3050 cm-1 confirming the pressure of 10 GPa is observed. The effect of the concentration and input energy on the appearance of the phases will be presented.

  5. The influence of sulcus width on simulated electric fields induced by transcranial magnetic stimulation

    Janssen, A M; Rampersad, S M; Stegeman, D F; Oostendorp, T F; Lucka, F; Lanfer, B; Aydin, Ü; Wolters, C H; Lew, S

    2013-01-01

    Volume conduction models can help in acquiring knowledge about the distribution of the electric field induced by transcranial magnetic stimulation. One aspect of a detailed model is an accurate description of the cortical surface geometry. Since its estimation is difficult, it is important to know how accurate the geometry has to be represented. Previous studies only looked at the differences caused by neglecting the complete boundary between cerebrospinal fluid (CSF) and grey matter (Thielscher et al 2011 NeuroImage 54 234–43, Bijsterbosch et al 2012 Med. Biol. Eng. Comput. 50 671–81), or by resizing the whole brain (Wagner et al 2008 Exp. Brain Res. 186 539–50). However, due to the high conductive properties of the CSF, it can be expected that alterations in sulcus width can already have a significant effect on the distribution of the electric field. To answer this question, the sulcus width of a highly realistic head model, based on T1-, T2- and diffusion-weighted magnetic resonance images, was altered systematically. This study shows that alterations in the sulcus width do not cause large differences in the majority of the electric field values. However, considerable overestimation of sulcus width produces an overestimation of the calculated field strength, also at locations distant from the target location. (paper)

  6. The influence of sulcus width on simulated electric fields induced by transcranial magnetic stimulation

    Janssen, A. M.; Rampersad, S. M.; Lucka, F.; Lanfer, B.; Lew, S.; Aydin, Ü.; Wolters, C. H.; Stegeman, D. F.; Oostendorp, T. F.

    2013-07-01

    Volume conduction models can help in acquiring knowledge about the distribution of the electric field induced by transcranial magnetic stimulation. One aspect of a detailed model is an accurate description of the cortical surface geometry. Since its estimation is difficult, it is important to know how accurate the geometry has to be represented. Previous studies only looked at the differences caused by neglecting the complete boundary between cerebrospinal fluid (CSF) and grey matter (Thielscher et al 2011 NeuroImage 54 234-43, Bijsterbosch et al 2012 Med. Biol. Eng. Comput. 50 671-81), or by resizing the whole brain (Wagner et al 2008 Exp. Brain Res. 186 539-50). However, due to the high conductive properties of the CSF, it can be expected that alterations in sulcus width can already have a significant effect on the distribution of the electric field. To answer this question, the sulcus width of a highly realistic head model, based on T1-, T2- and diffusion-weighted magnetic resonance images, was altered systematically. This study shows that alterations in the sulcus width do not cause large differences in the majority of the electric field values. However, considerable overestimation of sulcus width produces an overestimation of the calculated field strength, also at locations distant from the target location.

  7. Mild salinity stimulates a stress-induced morphogenic response in Arabidopsis thaliana roots.

    Zolla, Gaston; Heimer, Yair M; Barak, Simon

    2010-01-01

    Plant roots exhibit remarkable developmental plasticity in response to local soil conditions. It is shown here that mild salt stress stimulates a stress-induced morphogenic response (SIMR) in Arabidopsis thaliana roots characteristic of several other abiotic stresses: the proliferation of lateral roots (LRs) with a concomitant reduction in LR and primary root length. The LR proliferation component of the salt SIMR is dramatically enhanced by the transfer of seedlings from a low to a high NO3- medium, thereby compensating for the decreased LR length and maintaining overall LR surface area. Increased LR proliferation is specific to salt stress (osmotic stress alone has no stimulatory effect) and is due to the progression of more LR primordia from the pre-emergence to the emergence stage, in salt-stressed plants. In salt-stressed seedlings, greater numbers of LR primordia exhibit expression of a reporter gene driven by the auxin-sensitive DR5 promoter than in unstressed seedlings. Moreover, in the auxin transporter mutant aux1-7, the LR proliferation component of the salt SIMR is completely abrogated. The results suggest that salt stress promotes auxin accumulation in developing primordia thereby preventing their developmental arrest at the pre-emergence stage. Examination of ABA and ethylene mutants revealed that ABA synthesis and a factor involved in the ethylene signalling network also regulate the LR proliferation component of the salt SIMR.

  8. Macrophage colony stimulating factor (M-CSF) induces Fc receptor expression on macrophages

    Magee, D.M.; Wing, E.J.; Waheed, A.; Shadduck, R.K.

    1986-01-01

    M-CSF is a glycoprotein that stimulates bone marrow progenitor cells to proliferate and differentiate into macrophages (M theta). In addition, M-CSF can modulate the function of mature M theta. In this study, the authors determined the effect of M-CSF on expression of receptors for IgG (Fc receptors). Murine resident peritoneal M theta monolayers were incubated with either M-CSF, recombinant gamma interferon (IFN), or left untreated for 48 hrs. Expression of Fc receptors was assessed by microscopy using an antibody coated sheet erythrocytes (EA) rosette assay. The results indicated that M-CSF treated M theta had significantly higher numbers of bound EA (7.1 erythrocytes/M theta), than IFN M theta (4.4), or untreated M theta (2.5) (p 51 Cr labelled EA assay, CSF M theta (16,411 cpm), IFN M theta (10,887), untreated M theta (6897) (p < 0.001). Additionally, the maximal response was noted between 10 and 500 units M-CSF. Purified anti-M-CSF IgG, when included in the cultures, ablated the enhancement of EA binding, whereas normal rabbit IgG did not. These findings indicate that M-CSF is a potent inducer of Fc receptor expression on M theta and supports other data concerning the role of M-CSF as a biological response modifier

  9. Odorant cues linked to social immunity induce lateralized antenna stimulation in honey bees (Apis mellifera L.).

    McAfee, Alison; Collins, Troy F; Madilao, Lufiani L; Foster, Leonard J

    2017-04-07

    Hygienic behaviour (HB) is a social immunity trait in honey bees (Apis mellifera L.) whereby workers detect, uncap and remove unhealthy brood, improving disease resistance in the colony. This is clearly economically valuable; however, the molecular mechanism behind it is not well understood. The freeze-killed brood (FKB) assay is the conventional method of HB selection, so we compared odour profiles of FKB and live brood to find candidate HB-inducing odours. Surprisingly, we found that significantly more brood pheromone (β-ocimene) was released from FKB. β-ocimene abundance also positively correlated with HB, suggesting there could be a brood effect contributing to overall hygiene. Furthermore, we found that β-ocimene stimulated worker antennae in a dose-dependent manner, with the left antennae responding significantly stronger than right antennae in hygienic bees, but not in non-hygienic bees. Five other unidentifiable compounds were differentially emitted from FKB which could also be important for HB. We also compared odour profiles of Varroa-infested brood to healthy brood and found an overall interactive effect between developmental stage and infestation, but specific odours did not drive these differences. Overall, the data we present here is an important foundation on which to build our understanding the molecular mechanism behind this complex behaviour.

  10. Detuning-induced stimulated Raman adiabatic passage in dense two-level systems

    Deng, Li; Lin, Gongwei; Niu, Yueping; Gong, Shangqing

    2018-05-01

    We investigate the coherence generation in dense two-level systems under detuning-induced stimulated Raman adiabatic passage (D-STIRAP). In the dense two-level system, the near dipole-dipole (NDD) interaction should be taken into consideration. With the increase in the strength of the NDD interaction, it is found that a switchlike transition of the generated coherence from maximum value to zero appears. Meanwhile, the adiabatic condition of the D-STIRAP is destroyed in the presence of the NDD interaction. In order to avoid the sudden decrease in the generated coherence and maintain the maximum value, we can use stronger detuning pulse or pump pulse, between which increasing the intensity of the detuning pulse is of more efficiency. Except for taking advantage of such maximum coherence in the high density case into areas like enhancing the four-wave mixing process, we also point out that the phenomenon of the coherence transition can be applied as an optical switch.

  11. Stimulation of murine stem cell proliferation by circulating activities produced during the recovery of a radiation-induced hemopoietic injury

    Grande Azanedo, M.T.

    1988-01-01

    The proliferative activity of CFU-S, low in normal steady state, increases after treatment with different aggressors, i.e. radiation. This stimulation has been attributed in part to a local regulation system of stem cell proliferation, and at least in part to a humoral regulatory system. In the present work it has been investigated the role that circulating activities have in the CFU- S stimulation, by means of in vitro and in vivo incubation assays with diffusion chambers. The results show that bone marrow of mice irradiated with 5 Gy produces in vitro diffusible activities capable of stimulating the CFU-S proliferation. As well with this same dose circulating activities are also produced in vivo. In addition we have observed that these activities are only released during the periods of active hemopoietic regeneration that follow irradiation with moderate doses (1.5 and 5 Gy). In another set of experiments we saw that the stimulating activities are also detected in serum of mice irradiated with 5 Gy. These serum activities modify the proliferative state of very primitive precursors (12 d CFU-S). When the serum activities are added to long term bone marrow cultures the CFU-S) are also stimulated to proliferate. Finally, we observed that the radiation-induced serum activities stimulate the proliferation of bone marrow CFU-S when injected into normal mice, suggesting that such activities are involved in the regulation of CFU-S proliferation. (Author)

  12. Transcranial Random Noise Stimulation-induced plasticity is NMDA-receptor independent but sodium-channel blocker and benzodiazepines sensitive

    Leila eChaieb

    2015-04-01

    Full Text Available Background: Application of transcranial random noise stimulation (tRNS between 0.1 and 640 Hz of the primary motor cortex (M1 for 10 minutes induces a persistent excitability increase lasting for at least 60 minutes. However, the mechanism of tRNS-induced cortical excitability alterations is not yet fully understood. Objective: The main aim of this study was to get first efficacy data with regard to the possible neuronal effect of tRNS. Methods: Single-pulse transcranial magnetic stimulation (TMS was used to measure levels of cortical excitability before and after combined application of tRNS at an intensity of 1mA for 10mins stimulation duration and a pharmacological agent (or sham on 8 healthy male participants. Results: The sodium channel blocker carbamazepine showed a tendency towards inhibiting MEPs 5-60 mins poststimulation. The GABAA agonist lorazepam suppressed tRNS-induced cortical excitability increases at 0-20 and 60 min time points. The partial NMDA receptor agonist D-cycloserine, the NMDA receptor antagonist dextromethorphan and the D2/D3 receptor agonist ropinirole had no significant effects on the excitability increases seen with tRNS.Conclusions: In contrast to transcranial direct current stimulation (tDCS, aftereffects of tRNS are seem to be not NMDA receptor dependent and can be suppressed by benzodiazepines suggesting that tDCS and tRNS depend upon different mechanisms.

  13. Alkaloids from Prosopis juliflora leaves induce glial activation, cytotoxicity and stimulate NO production.

    Silva, A M M; Silva, A R; Pinheiro, A M; Freitas, S R V B; Silva, V D A; Souza, C S; Hughes, J B; El-Bachá, R S; Costa, M F D; Velozo, E S; Tardy, M; Costa, S L

    2007-04-01

    Prosopis juliflora is used for feeding cattle and humans. Intoxication with the plant has been reported, and is characterized by neuromuscular alterations and gliosis. Total alkaloidal extract (TAE) was obtained using acid/basic-modified extraction and was fractionated. TAE and seven alkaloidal fractions, at concentrations ranging 0.03-30 microg/ml, were tested for 24h on astrocyte primary cultures derived from the cortex of newborn Wistar rats. The MTT test and the measure of LDH activity on the culture medium, revealed that TAE and fractions F29/30, F31/33, F32 and F34/35 were cytotoxic to astrocytes. The EC(50) values for the most toxic compounds, TAE, F31/33 and F32 were 2.87 2.82 and 3.01 microg/ml, respectively. Morphological changes and glial cells activation were investigated through Rosenfeld's staining, by immunocytochemistry for the protein OX-42, specific of activated microglia, by immunocytochemistry and western immunoblot for GFAP, the marker of reactive and mature astrocytes, and by the production of nitric oxide (NO). We observed that astrocytes exposed to 3 microg/ml TAE, F29/30 or F31/33 developed compact cell body with many processes overexpressing GFAP. Treatment with 30 microg/ml TAE and fractions, induced cytotoxicity characterized by a strong cell body contraction, very thin and long processes and condensed chromatin. We also observed that when compared with the control (+/-1.34%), the proportion of OX-42 positive cells was increased in cultures treated with 30 microg/ml TAE or F29/30, F31/33, F32 and F34/35, with values raging from 7.27% to 28.74%. Moreover, incubation with 3 microg/ml F32, 30 microg/ml TAE, F29/30, F31/33 or F34/35 induced accumulation of nitrite in culture medium indicating induction of NO production. Taken together these results show that TAE and fractionated alkaloids from P. juliflora act directly on glial cells, inducing activation and/or cytotoxicity, stimulating NO production, and may have an impact on neuronal

  14. Seizure Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression.

    Cullen, Kathryn R; Jasberg, Suzanne; Nelson, Brent; Klimes-Dougan, Bonnie; Lim, Kelvin O; Croarkin, Paul E

    2016-09-01

    Deep transcranial magnetic stimulation (TMS) with an H-1 coil was recently approved by the U.S. Food and Drug Administration (U.S. FDA) for treatment-resistant depression (TRD) in adults. Studies assessing the safety and effectiveness of deep TMS in adolescent TRD are lacking. The purpose of this brief report is to provide a case history of an adolescent enrolled in an investigational deep TMS protocol. A case history is described of the first participant of a sham-controlled clinical trial who had a seizure in the course of deep TMS with parameter settings extrapolated from the adult studies that led to US FDA approval (H-1 coil, 120% target stimulation intensity, 18 Hz, 55 trains of 2-second duration, total 1980 pulses). The participant was a 17-year-old unmedicated female, with no significant medical history and no history of seizures or of drug or alcohol use. Brain magnetic resonance imaging showed no structural abnormalities. She initially received sham, which was well tolerated. During active treatment sessions, titration began at 85% of motor threshold (MT) and increased by 5% per day. Her weekly MT measurements were stable. On her first day of 120% MT (8th active treatment), during the 48th train, the participant had a generalized, tonic-clonic seizure that lasted 90 seconds and resolved spontaneously. She had an emergency medicine evaluation and was discharged home without anticonvulsant medications. There were no further seizures reported at a 6-month follow-up. We report a deep TMS-induced generalized tonic-clonic seizure in an adolescent with TRD participating in a clinical trial. Given the demonstrated benefits of deep TMS for adult TRD, research investigating its use in adolescents with TRD is an important area. However, in light of this experience, additional precautions for adolescents should be considered. We propose that further dose-finding investigations are needed to refine adolescent-specific parameters that may be safe and effective for

  15. The optimal timing of stimulation to induce long-lasting positive effects on episodic memory in physiological aging.

    Manenti, Rosa; Sandrini, Marco; Brambilla, Michela; Cotelli, Maria

    2016-09-15

    Episodic memory displays the largest degree of age-related decline. A noninvasive brain stimulation technique that can be used to modulate memory in physiological aging is transcranial Direct Current Stimulation (tDCS). However, an aspect that has not been adequately investigated in previous studies is the optimal timing of stimulation to induce long-lasting positive effects on episodic memory function. Our previous studies showed episodic memory enhancement in older adults when anodal tDCS was applied over the left lateral prefrontal cortex during encoding or after memory consolidation with or without a contextual reminder. Here we directly compared the two studies to explore which of the tDCS protocols would induce longer-lasting positive effects on episodic memory function in older adults. In addition, we aimed to determine whether subjective memory complaints would be related to the changes in memory performance (forgetting) induced by tDCS, a relevant issue in aging research since individuals with subjective memory complaints seem to be at higher risk of later memory decline. The results showed that anodal tDCS applied after consolidation with a contextual reminder induced longer-lasting positive effects on episodic memory, conceivably through reconsolidation, than anodal tDCS during encoding. Furthermore, we reported, providing new data, a moderate negative correlation between subjective memory complaints and forgetting when anodal tDCS was applied after consolidation with a contextual reminder. This study sheds light on the best-suited timing of stimulation to induce long-lasting positive effects on memory function and might help the clinicians to select the most effective tDCS protocol to prevent memory decline. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Opposite patterns of change in perception of imagined and physically induced pain over the course of repeated thermal stimulations.

    Gács, B; Szolcsányi, T; Csathó, Á

    2017-08-01

    Individuals frequently show habituation to repeated noxious heat. However, given the defensive function of human pain processing, it is reasonable to assume that individuals anticipate that they would become increasingly sensitive to repeated thermal pain stimuli. No previous studies have, however, been addressed to this assumption. Therefore, in the current study, we investigated how healthy human individuals imagine the intensity of repeated thermal pain stimulations, and compared this with the intensity ratings given after physically induced thermal pain trials. Healthy participants (N = 20) gave pain intensity ratings in two conditions: imagined and real thermal pain. In the real pain condition, thermal pain stimuli of two intensities (minimal and moderate pain) were delivered in four consecutive trials. The duration of the peak temperature was 20 s, and stimulation was always delivered to the same location. In each trial, participants rated the pain intensity twice, 5 and 15 s after the onset of the peak temperature. In the imagined pain condition, participants were subjected to a reference pain stimulus and then asked to imagine and rate the same sequence of stimulations as in the induced pain condition. Ratings of imagined pain and physically induced pain followed opposite courses over repeated stimulations: Ratings of imagined pain indicated sensitization, whereas ratings for physically induced pain indicated habituation. The findings were similar for minimal and moderate pain intensities. The findings suggest that, rather than habituating to pain, healthy individuals imagine that they would become increasingly sensitive to repeated thermal pain stimuli. This study identified opposite patterns of change in perception of imagined pain (sensitization) and physically induced pain (habituation). The findings show that individuals anticipate that they would become increasingly sensitive to repeated pain stimuli, which might also have clinical implications.

  17. Low-frequency electrical stimulation induces the proliferation and differentiation of peripheral blood stem cells into Schwann cells.

    Gu, Xudong; Fu, Jianming; Bai, Jing; Zhang, Chengwen; Wang, Jing; Pan, Wenping

    2015-02-01

    Functional recovery after peripheral nerve injury remains a tough problem at present. Specifically, a type of glial cell exists in peripheral nerves that promotes axonal growth and myelin formation and secretes various active substances, such as neurotrophic factors, extracellular matrix and adherence factors. These substances have important significance for the survival, growth and regeneration of nerve fibers. Numerous recent studies have shown that electrical stimulation can increase the number of myelinated nerve fibers. However, whether electrical stimulation acts on neurons or Schwann cells has not been verified in vivo. This study investigates low-frequency electrical stimulation-induced proliferation and differentiation of peripheral blood stem cells into Schwann cells and explores possible mechanisms. Peripheral blood stem cells from Sprague-Dawley rats were primarily cultured. Cells in passage 3 were divided into 4 groups: a low-frequency electrical stimulation group (20 Hz, 100 μs, 3 V), a low-frequency electrical stimulation+PD98059 (blocking the extracellular signal-regulated kinase [ERK] signaling pathway) group, a PD98059 group and a control group (no treatment). After induction, the cells were characterized. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliumbromide assay was employed to measure the absorbance values at 570 nm in the 4 groups. A Western blot assay was used to detect the expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4) in each group. No significant difference in cell viability was detected before induction. Peripheral blood stem cells from the 4 groups differentiated into Schwann cells. Phosphorylated ERK 1/2, cyclin D1 and CDK4 protein levels were highest in the low-frequency electrical stimulation group and lowest in the ERK blockage group. Phosphorylated ERK 1/2, cyclin D1 and CDK4 protein levels in the low-frequency electrical stimulation+ERK blockage group were lower than those in the low-frequency electrical

  18. The effect of left frontal transcranial direct-current stimulation on propranolol-induced fear memory acquisition and consolidation deficits.

    Nasehi, Mohammad; Khani-Abyaneh, Mozhgan; Ebrahimi-Ghiri, Mohaddeseh; Zarrindast, Mohammad-Reza

    2017-07-28

    Accumulating evidence supports the efficacy of transcranial direct current stimulation (tDCS) in modulating numerous cognitive functions. Despite the fact that tDCS has been used for the enhancement of memory and cognition, very few animal studies have addressed its impact on the modulation of fear memory. This study was designed to determine whether pre/post-training frontal tDCS application would alter fear memory acquisition and/or consolidation deficits induced by propranolol in NMRI mice. Results indicated that administration of β1-adrenoceptor blocker propranolol (0.1mg/kg) impaired fear memory retrieval. Pre/post-training application of anodal tDCS when propranolol was administered prior to training reversed contextual memory retrieval whereas only the anodal application prior to training could induce the same result in the auditory test. Meanwhile, anodal stimulation had no effect on fear memories by itself. Moreover, regardless of when cathode was applied and propranolol administered, their combination restored contextual memory retrieval, while only cathodal stimulation prior to training facilitated the contextual memory retrieval. Also, auditory memory retrieval was restored when cathodal stimulation and propranolol occurred prior to training but it was abolished when stimulation occurred after training and propranolol was administered prior to training. Collectively, our findings show that tDCS applied on the left frontal cortex of mice affects fear memory performance. This alteration seems to be task-dependent and varies depending on the nature and timing of the stimulation. In certain conditions, tDCS reverses the effect of propranolol. These results provide initial evidence to support the timely use of tDCS for the modulation of fear-related memories. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Inducible nitric oxide inhibitors block NMDA antagonist-stimulated motoric behaviors and medial prefrontal cortical glutamate efflux

    Hadley C Bergstrom

    2015-12-01

    Full Text Available Nitric oxide (NO plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS for studying the neurobehavioral effects of noncompetitive NMDA-antagonist stimulants such as dizocilpine (MK-801 and phencyclidine (PCP. This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS aminoguanidine (AG and (--epigallocatechin-3-gallate (EGCG in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG or vehicle prior to receiving NMDA antagonists MK-801, PCP or a conventional psychostimulant (cocaine and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated medial prefrontal cortical glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in green tea and chocolate may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia.

  20. Cycle-to-cycle control of swing phase of paraplegic gait induced by surface electrical stimulation

    Franken, H.M.; Franken, H.M.; Veltink, Petrus H.; Baardman, G.; Redmeijer, R.A.; Boom, H.B.K.

    1995-01-01

    Parameterised swing phase of gait in paraplegics was obtained using surface electrical stimulation of the hip flexors, hamstrings and quadriceps; the hip flexors were stimulated to obtain a desired hip angle range, the hamstrings to provide foot clearance in the forward swing, and the quadriceps to

  1. Fall in thyroid stimulating hormone (TSH) may be an early marker of ipilimumab-induced hypophysitis.

    De Sousa, Sunita M C; Sheriff, Nisa; Tran, Chau H; Menzies, Alexander M; Tsang, Venessa H M; Long, Georgina V; Tonks, Katherine T T

    2018-06-01

    Hypophysitis develops in up to 19% of melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte antigen-4 antibody. Early detection may avert life-threatening hypopituitarism. We aimed to assess the incidence of ipilimumab-induced hypophysitis (IH) at a quaternary melanoma referral centre, and to determine whether cortisol or thyroid stimulating hormone (TSH) monitoring could predict IH onset. We performed a retrospective cohort study of ipilimumab-treated patients at a quaternary melanoma referral centre in Australia. The inclusion criteria were patients with metastatic or unresectable melanoma treated with ipilimumab monotherapy, and cortisol and TSH measurements prior to ≥ 2 infusions. The main outcomes were IH incidence and TSH and cortisol patterns in patients who did and did not develop IH. Of 78 ipilimumab-treated patients, 46 met the study criteria and 9/46 (20%) developed IH at a median duration of 13.0 weeks (range 7.7-18.1) following ipilimumab initiation. All patients whose TSH fell ≥ 80% compared to baseline developed IH, and, in 5/9 patients with IH, TSH fell prior to cortisol fall and IH diagnosis. Pre-cycle-4 TSH was significantly lower in those who developed IH (0.31 vs. 1.73 mIU/L, P = 0.006). TSH fall was detected at a median time of 9.2 (range 7.7-16.4) weeks after commencing ipilimumab, and a median of 3.6 (range of - 1.4 to 9.7) weeks before IH diagnosis. There was no difference in TSH between the groups before cycles 1-3 or in cortisol before cycles 1-4. TSH fall ≥ 80% may be an early marker of IH. Serial TSH measurement during ipilimumab therapy may be an inexpensive tool to expedite IH diagnosis.

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

    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

  3. Transcranial magnetic stimulation-induced global propagation of transient phase resetting associated with directional information flow

    Masahiro eKawasaki

    2014-03-01

    Full Text Available Electroencephalogram (EEG phase synchronization analyses can reveal large-scale communication between distant brain areas. However, it is not possible to identify the directional information flow between distant areas using conventional phase synchronization analyses. In the present study, we applied transcranial magnetic stimulation (TMS to the occipital area in subjects who were resting with their eyes closed, and analyzed the spatial propagation of transient TMS-induced phase resetting by using the transfer entropy (TE, to quantify the causal and directional flow of information. The time-frequency EEG analysis indicated that the theta (5 Hz phase locking factor (PLF reached its highest value at the distant area (the motor area in this study, with a time lag that followed the peak of the transient PLF enhancements of the TMS-targeted area at the TMS onset. PPI (phase-preservation index analyses demonstrated significant phase resetting at the TMS-targeted area and distant area. Moreover, the TE from the TMS-targeted area to the distant area increased clearly during the delay that followed TMS onset. Interestingly, the time lags were almost coincident between the PLF and TE results (152 vs. 165 ms, which provides strong evidence that the emergence of the delayed PLF reflects the causal information flow. Such tendencies were observed only in the higher-intensity TMS condition, and not in the lower-intensity or sham TMS conditions. Thus, TMS may manipulate large-scale causal relationships between brain areas in an intensity-dependent manner. We demonstrated that single-pulse TMS modulated global phase dynamics and directional information flow among synchronized brain networks. Therefore, our results suggest that single-pulse TMS can manipulate both incoming and outgoing information in the TMS-targeted area associated with functional changes.

  4. High and low frequency stimulation of the subthalamic nucleus induce prolonged changes in subthalamic and globus pallidus neurons

    Hagar eLavian

    2013-12-01

    Full Text Available High frequency stimulation (HFS of the subthalamic nucleus (STN is widely used to treat the symptoms of Parkinson’s disease but the mechanism of this therapy is unclear. Using a rat brain slice preparation maintaining the connectivity between the STN and one of its target nuclei, the globus pallidus (GP, we investigated the effects of high and low frequency stimulation (HFS 100 Hz, LFS 10 Hz on activity of single neurons in the STN and GP. Both HFS and LFS caused changes in firing frequency and pattern of subthalamic and pallidal neurons. These changes were of synaptic origin, as they were abolished by glutamate and GABA antagonists. Both HFS and LFS also induced a long-lasting reduction in firing frequency in STN neurons possibly contending a direct causal link between HFS and the outcome DBS. In the GP both HFS and LFS induced either a long-lasting depression, or less frequently, a long-lasting excitation. Thus, in addition to the intrinsic activation of the stimulated neurons, long-lasting stimulation of the STN may trigger prolonged biochemical processes.

  5. Enhancing performance of a motor imagery based brain-computer interface by incorporating electrical stimulation-induced SSSEP

    Yi, Weibo; Qiu, Shuang; Wang, Kun; Qi, Hongzhi; Zhao, Xin; He, Feng; Zhou, Peng; Yang, Jiajia; Ming, Dong

    2017-04-01

    Objective. We proposed a novel simultaneous hybrid brain-computer interface (BCI) by incorporating electrical stimulation into a motor imagery (MI) based BCI system. The goal of this study was to enhance the overall performance of an MI-based BCI. In addition, the brain oscillatory pattern in the hybrid task was also investigated. Approach. 64-channel electroencephalographic (EEG) data were recorded during MI, selective attention (SA) and hybrid tasks in fourteen healthy subjects. In the hybrid task, subjects performed MI with electrical stimulation which was applied to bilateral median nerve on wrists simultaneously. Main results. The hybrid task clearly presented additional steady-state somatosensory evoked potential (SSSEP) induced by electrical stimulation with MI-induced event-related desynchronization (ERD). By combining ERD and SSSEP features, the performance in the hybrid task was significantly better than in both MI and SA tasks, achieving a ~14% improvement in total relative to the MI task alone and reaching ~89% in mean classification accuracy. On the contrary, there was no significant enhancement obtained in performance while separate ERD feature was utilized in the hybrid task. In terms of the hybrid task, the performance using combined feature was significantly better than using separate ERD or SSSEP feature. Significance. The results in this work validate the feasibility of our proposed approach to form a novel MI-SSSEP hybrid BCI outperforming a conventional MI-based BCI through combing MI with electrical stimulation.

  6. Stimulated Raman spectroscopy and nanoscopy of molecules using near field photon induced forces without resonant electronic enhancement gain

    Tamma, Venkata Ananth [CaSTL Center, Department of Chemistry, University of California, Irvine, California 92697 (United States); Huang, Fei; Kumar Wickramasinghe, H., E-mail: hkwick@uci.edu [Department of Electrical Engineering and Computer Science, 142 Engineering Tower, University of California, Irvine, California 92697 (United States); Nowak, Derek [Molecular Vista, Inc., 6840 Via Del Oro, San Jose, California 95119 (United States)

    2016-06-06

    We report on stimulated Raman spectroscopy and nanoscopy of molecules, excited without resonant electronic enhancement gain, and recorded using near field photon induced forces. Photon-induced interaction forces between the sharp metal coated silicon tip of an Atomic Force Microscope (AFM) and a sample resulting from stimulated Raman excitation were detected. We controlled the tip to sample spacing using the higher order flexural eigenmodes of the AFM cantilever, enabling the tip to come very close to the sample. As a result, the detection sensitivity was increased compared with previous work on Raman force microscopy. Raman vibrational spectra of azobenzene thiol and l-phenylalanine were measured and found to agree well with published results. Near-field force detection eliminates the need for far-field optical spectrometer detection. Recorded images show spatial resolution far below the optical diffraction limit. Further optimization and use of ultrafast pulsed lasers could push the detection sensitivity towards the single molecule limit.

  7. Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice

    Chan, Ming-Huan [Department of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan (China); Institute of Neuroscience, National Changchi University, Taipei, Taiwan (China); Chung, Shiang-Sheng [Department of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan (China); Department of Pharmacy, Yuli Veterans Hospital, Hualien, Taiwan (China); Stoker, Astrid K.; Markou, Athina [Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, CA (United States); Chen, Hwei-Hsien, E-mail: hwei@nhri.org.tw [Department of Pharmacology and Toxicology, Tzu Chi University, Hualien, Taiwan (China); Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Miaoli County, Taiwan (China)

    2012-12-01

    Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances, including motor incoordination and cognitive impairment. Toluene alters the function of a large number of receptors and ion channels. Blockade of N-methyl-D-aspartate (NMDA) receptors has been suggested to play a critical role in toluene-induced behavioral manifestations. The present study determined the effects of various toluene doses on motor coordination, recognition memory, body temperature, and intracranial self-stimulation (ICSS) thresholds in mice. Additionally, the effects of sarcosine on the behavioral and physiological effects induced by toluene were evaluated. Sarcosine may reverse toluene-induced behavioral manifestations by acting as an NMDA receptor co-agonist and by inhibiting the effects of the type I glycine transporter (GlyT1). Mice were treated with toluene alone or combined with sarcosine pretreatment and assessed for rotarod performance, object recognition memory, rectal temperature, and ICSS thresholds. Toluene dose-dependently induced motor incoordination, recognition memory impairment, and hypothermia and lowered ICSS thresholds. Sarcosine pretreatment reversed toluene-induced changes in rotarod performance, novel object recognition, and rectal temperature but not ICSS thresholds. These findings suggest that the sarcosine-induced potentiation of NMDA receptors may reverse motor incoordination, memory impairment, and hypothermia but not the enhancement of brain stimulation reward function associated with toluene exposure. Sarcosine may be a promising compound to prevent acute toluene intoxications by occupational or intentional exposure. -- Highlights: ► Toluene induces impairments in Rotarod test and novel object recognition test. ► Toluene lowers rectal temperature and ICSS thresholds in mice. ► Sarcosine reverses toluene-induced changes in motor, memory and body temperature. ► Sarcosine pretreatment does not affect toluene-induced

  8. Sarcosine attenuates toluene-induced motor incoordination, memory impairment, and hypothermia but not brain stimulation reward enhancement in mice

    Chan, Ming-Huan; Chung, Shiang-Sheng; Stoker, Astrid K.; Markou, Athina; Chen, Hwei-Hsien

    2012-01-01

    Toluene, a widely used and commonly abused organic solvent, produces various behavioral disturbances, including motor incoordination and cognitive impairment. Toluene alters the function of a large number of receptors and ion channels. Blockade of N-methyl-D-aspartate (NMDA) receptors has been suggested to play a critical role in toluene-induced behavioral manifestations. The present study determined the effects of various toluene doses on motor coordination, recognition memory, body temperature, and intracranial self-stimulation (ICSS) thresholds in mice. Additionally, the effects of sarcosine on the behavioral and physiological effects induced by toluene were evaluated. Sarcosine may reverse toluene-induced behavioral manifestations by acting as an NMDA receptor co-agonist and by inhibiting the effects of the type I glycine transporter (GlyT1). Mice were treated with toluene alone or combined with sarcosine pretreatment and assessed for rotarod performance, object recognition memory, rectal temperature, and ICSS thresholds. Toluene dose-dependently induced motor incoordination, recognition memory impairment, and hypothermia and lowered ICSS thresholds. Sarcosine pretreatment reversed toluene-induced changes in rotarod performance, novel object recognition, and rectal temperature but not ICSS thresholds. These findings suggest that the sarcosine-induced potentiation of NMDA receptors may reverse motor incoordination, memory impairment, and hypothermia but not the enhancement of brain stimulation reward function associated with toluene exposure. Sarcosine may be a promising compound to prevent acute toluene intoxications by occupational or intentional exposure. -- Highlights: ► Toluene induces impairments in Rotarod test and novel object recognition test. ► Toluene lowers rectal temperature and ICSS thresholds in mice. ► Sarcosine reverses toluene-induced changes in motor, memory and body temperature. ► Sarcosine pretreatment does not affect toluene-induced

  9. Sonomyography Analysis on Thickness of Skeletal Muscle During Dynamic Contraction Induced by Neuromuscular Electrical Stimulation: A Pilot Study.

    Qiu, Shuang; Feng, Jing; Xu, Jiapeng; Xu, Rui; Zhao, Xin; Zhou, Peng; Qi, Hongzhi; Zhang, Lixin; Ming, Dong

    2017-01-01

    Neuromuscular electrical stimulation (NMES) that stimulates skeletal muscles to induce contractions has been widely applied to restore functions of paralyzed muscles. However, the architectural changes of stimulated muscles induced by NMES are still not well understood. The present study applies sonomyography (SMG) to evaluate muscle architecture under NMES-induced and voluntary movements. The quadriceps muscles of seven healthy subjects were tested for eight cycles during an extension exercise of the knee joint with/without NMES, and SMG and the knee joint angle were recorded during the process of knee extension. A least squares support vector machine (LS-SVM) LS-SVM model was developed and trained using the data sets of six cycles collected under NMES, while the remaining data was used to test. Muscle thickness changes were extracted from ultrasound images and compared between NMES-induced and voluntary contractions, and LS-SVM was used to model a relationship between dynamical knee joint angles and SMG signals. Muscle thickness showed to be significantly correlated with joint angle in NMES-induced contractions, and a significant negative correlation was observed between Vastus intermedius (VI) thickness and rectus femoris (RF) thickness. In addition, there was a significant difference between voluntary and NMES-induced contractions . The LS-SVM model based on RF thickness and knee joint angle provided superior performance compared with the model based on VI thickness and knee joint angle or total thickness and knee joint angle. This suggests that a strong relation exists between the RF thickness and knee joint angle. These results provided direct evidence for the potential application of RF thickness in optimizing NMES system as well as measuring muscle state under NMES.

  10. Toll-Like Receptor 2 Stimulation of Osteoblasts Mediates Staphylococcus Aureus Induced Bone Resorption and Osteoclastogenesis through Enhanced RANKL

    Kassem, Ali; Lindholm, Catharina; Lerner, Ulf H

    2016-01-01

    Severe Staphylococcus aureus (S. aureus) infections pose an immense threat to population health and constitute a great burden for the health care worldwide. Inter alia, S. aureus septic arthritis is a disease with high mortality and morbidity caused by destruction of the infected joints and systemic bone loss, osteoporosis. Toll-Like receptors (TLRs) are innate immune cell receptors recognizing a variety of microbial molecules and structures. S. aureus recognition via TLR2 initiates a signaling cascade resulting in production of various cytokines, but the mechanisms by which S. aureus causes rapid and excessive bone loss are still unclear. We, therefore, investigated how S. aureus regulates periosteal/endosteal osteoclast formation and bone resorption. S. aureus stimulation of neonatal mouse parietal bone induced ex vivo bone resorption and osteoclastic gene expression. This effect was associated with increased mRNA and protein expression of receptor activator of NF-kB ligand (RANKL) without significant change in osteoprotegerin (OPG) expression. Bone resorption induced by S. aureus was abolished by OPG. S. aureus increased the expression of osteoclastogenic cytokines and prostaglandins in the parietal bones but the stimulatory effect of S. aureus on bone resorption and Tnfsf11 mRNA expression was independent of these cytokines and prostaglandins. Stimulation of isolated periosteal osteoblasts with S. aureus also resulted in increased expression of Tnfsf11 mRNA, an effect lost in osteoblasts from Tlr2 knockout mice. S. aureus stimulated osteoclastogenesis in isolated periosteal cells without affecting RANKL-stimulated resorption. In contrast, S. aureus inhibited RANKL-induced osteoclast formation in bone marrow macrophages. These data show that S. aureus enhances bone resorption and periosteal osteoclast formation by increasing osteoblast RANKL production through TLR2. Our study indicates the importance of using different in vitro approaches for studies of how S

  11. Microwave induced stimulation of 32Pi incorporation into phosphoinositides of rat brain synaptosomes

    Gandhi, C.R.; Ross, D.H.

    1989-01-01

    Exposure of synaptosomes to microwave radiation at a power density of 10 mW/sq cm or more produced stimulation of the 32 Pi-incorporation into phosphoinositides. The extent of 32 Pi incorporation was found to be much more pronounced in phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) as compared to phosphatidylinositol (PI) and phosphatidic acid (PA). Other lipids were also found to incorporate 32 Pi but no significant changes in their labeling were seen after exposure to microwave radiation. Inclusion of 10 mM lithium in the medium reduced the basal labeling of PIP 2 , PIP and PI and increased PA labeling. Li + also inhibited the microwave stimulated PIP 2 , PIP and PI labeling but had no effect on PA labeling. Calcium inophore, A 23187 , inhibited the basal and microwave stimulated 32 Pi labeling of PIP and PIP 2 , stimulated basal labeling of PA and PI and had no effect on microwave stimulated PA and PI labeling. Calcium chelator, EGTA, on the other hand, had no effect on basal labeling of PA and PI, stimulated basal PIP and PIP 2 labeling but did not alter microwave stimulated labeling of these lipids. Exposure of synaptosomes to microwave radiation did not alter the chemical concentration of phosphoinositides indicating that the turnover of these lipids was altered. These results suggest that low frequency microwave radiation alter the metabolism of inositol phospholipids by enhancing their turnover and thus may affect the transmembrane signalling in the nerve endings. (orig.)

  12. Antinociception induced by stimulating amygdaloid nuclei in rats: changes produced by systemically administered antagonists

    M.A. Oliveira

    1998-05-01

    Full Text Available The antinociceptive effects of stimulating the medial (ME and central (CE nuclei of the amygdala in rats were evaluated by the changes in the latency for the tail withdrawal reflex to noxious heating of the skin. A 30-s period of sine-wave stimulation of the ME or CE produced a significant and short increase in the duration of tail flick latency. A 15-s period of stimulation was ineffective. Repeated stimulation of these nuclei at 48-h intervals produced progressively smaller effects. The antinociception evoked from the ME was significantly reduced by the previous systemic administration of naloxone, methysergide, atropine, phenoxybenzamine, and propranolol, but not by mecamylamine, all given at the dose of 1.0 mg/kg. Previous systemic administration of naloxone, atropine, and propranolol, but not methysergide, phenoxybenzamine, or mecamylamine, was effective against the effects of stimulating the CE. We conclude that the antinociceptive effects of stimulating the ME involve at least opioid, serotonergic, adrenergic, and muscarinic cholinergic descending mechanisms. The effects of stimulating the CE involve at least opioid, ß-adrenergic, and muscarinic cholinergic descending mechanisms.

  13. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Aburto, Andrés [Program of M.Sc., Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Barría, Agustín [School of Biochemistry, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Cárdenas, Areli [Ph.D. Program, Faculty of Sciences, Universidad Austral de Chile, Valdivia (Chile); Carpio, Daniel; Figueroa, Carlos D. [Department of Anatomy, Histology and Pathology, Universidad Austral de Chile, Valdivia (Chile); Burgos, Maria E. [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile); Ardiles, Leopoldo, E-mail: leopoldoardiles@gmail.com [Department of Nephrology, Faculty of Medicine, Universidad Austral de Chile, Valdivia (Chile)

    2014-10-15

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity.

  14. Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons.

    Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

    2017-01-01

    According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca 2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca 2+ spike and Ca 2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information.

  15. Bidirectional Hebbian Plasticity Induced by Low-Frequency Stimulation in Basal Dendrites of Rat Barrel Cortex Layer 5 Pyramidal Neurons

    Díez-García, Andrea; Barros-Zulaica, Natali; Núñez, Ángel; Buño, Washington; Fernández de Sevilla, David

    2017-01-01

    According to Hebb's original hypothesis (Hebb, 1949), synapses are reinforced when presynaptic activity triggers postsynaptic firing, resulting in long-term potentiation (LTP) of synaptic efficacy. Long-term depression (LTD) is a use-dependent decrease in synaptic strength that is thought to be due to synaptic input causing a weak postsynaptic effect. Although the mechanisms that mediate long-term synaptic plasticity have been investigated for at least three decades not all question have as yet been answered. Therefore, we aimed at determining the mechanisms that generate LTP or LTD with the simplest possible protocol. Low-frequency stimulation of basal dendrite inputs in Layer 5 pyramidal neurons of the rat barrel cortex induces LTP. This stimulation triggered an EPSP, an action potential (AP) burst, and a Ca2+ spike. The same stimulation induced LTD following manipulations that reduced the Ca2+ spike and Ca2+ signal or the AP burst. Low-frequency whisker deflections induced similar bidirectional plasticity of action potential evoked responses in anesthetized rats. These results suggest that both in vitro and in vivo similar mechanisms regulate the balance between LTP and LTD. This simple induction form of bidirectional hebbian plasticity could be present in the natural conditions to regulate the detection, flow, and storage of sensorimotor information. PMID:28203145

  16. Plasticity Induced by Intermittent Theta Burst Stimulation in Bilateral Motor Cortices Is Not Altered in Older Adults

    Daina S. E. Dickins

    2015-01-01

    Full Text Available Numerous studies have reported that plasticity induced in the motor cortex by transcranial magnetic stimulation (TMS is attenuated in older adults. Those investigations, however, have focused solely on the stimulated hemisphere. Compared to young adults, older adults exhibit more widespread activity across bilateral motor cortices during the performance of unilateral motor tasks, suggesting that the manifestation of plasticity might also be altered. To address this question, twenty young (65 years underwent intermittent theta burst stimulation (iTBS whilst attending to the hand targeted by the plasticity-inducing procedure. The amplitude of motor evoked potentials (MEPs elicited by single pulse TMS was used to quantify cortical excitability before and after iTBS. Individual responses to iTBS were highly variable, with half the participants showing an unexpected decrease in cortical excitability. Contrary to predictions, however, there were no age-related differences in the magnitude or manifestation of plasticity across bilateral motor cortices. The findings suggest that advancing age does not influence the capacity for, or manifestation of, plasticity induced by iTBS.

  17. Plasticity Induced by Intermittent Theta Burst Stimulation in Bilateral Motor Cortices Is Not Altered in Older Adults

    Dickins, Daina S. E.; Sale, Martin V.

    2015-01-01

    Numerous studies have reported that plasticity induced in the motor cortex by transcranial magnetic stimulation (TMS) is attenuated in older adults. Those investigations, however, have focused solely on the stimulated hemisphere. Compared to young adults, older adults exhibit more widespread activity across bilateral motor cortices during the performance of unilateral motor tasks, suggesting that the manifestation of plasticity might also be altered. To address this question, twenty young (65 years) underwent intermittent theta burst stimulation (iTBS) whilst attending to the hand targeted by the plasticity-inducing procedure. The amplitude of motor evoked potentials (MEPs) elicited by single pulse TMS was used to quantify cortical excitability before and after iTBS. Individual responses to iTBS were highly variable, with half the participants showing an unexpected decrease in cortical excitability. Contrary to predictions, however, there were no age-related differences in the magnitude or manifestation of plasticity across bilateral motor cortices. The findings suggest that advancing age does not influence the capacity for, or manifestation of, plasticity induced by iTBS. PMID:26064691

  18. Pre-stimulation of the kallikrein system in cisplatin-induced acute renal injury: An approach to renoprotection

    Aburto, Andrés; Barría, Agustín; Cárdenas, Areli; Carpio, Daniel; Figueroa, Carlos D.; Burgos, Maria E.; Ardiles, Leopoldo

    2014-01-01

    Antineoplastic treatment with cisplatin is frequently complicated by nephrotoxicity. Although oxidative stress may be involved, the pathogenic mechanisms responsible for renal damage have not been completely clarified. In order to investigate the role of the renal kinin system in this condition, a group of rats was submitted to high potassium diet to stimulate the synthesis and excretion of tissue kallikrein 1 (rKLK1) previous to an intraperitoneal injection of 7 mg/kg cisplatin. A significant reduction in lipoperoxidation, evidenced by urinary excretion of malondialdehyde and renal immunostaining of hidroxy-nonenal, was accompanied by a decline in apoptosis. Coincident with these findings we observed a reduction in the expression of renal KIM-1 suggesting that renoprotection may be occurring. Stimulation or indemnity of the renal kinin system deserves to be evaluated as a complementary pharmacological measure to diminish cisplatin nephrotoxicity. - Highlights: • Mechanisms of cisplatin-induced-renal damage have not been completely clarified. • Cisplatin induces oxidative stress and apoptosis. • The renal kallikrein-kinin system is protective in experimental acute renal damage. • Kallikrein stimulation reduces oxidative stress and apoptosis induced by cisplatin. • Protection of the kallikrein-kinin system may reduce cisplatin toxicity

  19. Sphenopalatine ganglion stimulation induces changes in cardiac autonomic regulation in cluster headache

    Barloese, Mads; Petersen, Anja S; Guo, Song

    2018-01-01

    regulation. MATERIALS AND METHODS: In a double-blind, randomized, sham-controlled crossover design, patients received low-frequency and sham stimulation. RR intervals were recorded, and heart rate variability was analysed (time-domain, frequency-domain, nonlinear parameters). Headache characteristics......-frequency stimulation, there was a greater increase in heart rate compared to sham (Ptime domain (P...INTRODUCTION: Cluster headache is characterized by attacks of severe unilateral pain accompanied by cranial and systemic autonomic changes. Our knowledge of the latter is imperfect. This study aimed to investigate the effect of low-frequency sphenopalatine ganglion stimulation on cardiac autonomic...

  20. Cortical deactivation induced by visual stimulation in human slow-wave sleep

    Born, Alfred Peter; Law, Ian; Lund, Torben E

    2002-01-01

    . It is unresolved whether this negative BOLD response pattern is of developmental neurobiological origin particular to a given age or to a general effect of sleep or sedative drugs. To further elucidate this issue, we used fMRI and positron emission tomography (PET) to study the brain activation pattern during......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...

  1. Use of functional near-infrared spectroscopy to monitor cortical plasticity induced by transcranial direct current stimulation

    Khan, Bilal; Hervey, Nathan; Stowe, Ann; Hodics, Timea; Alexandrakis, George

    2013-03-01

    Electrical stimulation of the human cortex in conjunction with physical rehabilitation has been a valuable approach in facilitating the plasticity of the injured brain. One such method is transcranial direct current stimulation (tDCS) which is a non-invasive method to elicit neural stimulation by delivering current through electrodes placed on the scalp. In order to better understand the effects tDCS has on cortical plasticity, neuroimaging techniques have been used pre and post tDCS stimulation. Recently, neuroimaging methods have discovered changes in resting state cortical hemodynamics after the application of tDCS on human subjects. However, analysis of the cortical hemodynamic activity for a physical task during and post tDCS stimulation has not been studied to our knowledge. A viable and sensitive neuroimaging method to map changes in cortical hemodynamics during activation is functional near-infrared spectroscopy (fNIRS). In this study, the cortical activity during an event-related, left wrist curl task was mapped with fNIRS before, during, and after tDCS stimulation on eight healthy adults. Along with the fNIRS optodes, two electrodes were placed over the sensorimotor hand areas of both brain hemispheres to apply tDCS. Changes were found in both resting state cortical connectivity and cortical activation patterns that occurred during and after tDCS. Additionally, changes to surface electromyography (sEMG) measurements of the wrist flexor and extensor of both arms during the wrist curl movement, acquired concurrently with fNIRS, were analyzed and related to the transient cortical plastic changes induced by tDCS.

  2. Insights on the neural basis of motor plasticity induced by theta burst stimulation from TMS-EEG

    VERNET, Marine; BASHIR, Shahid; YOO, Woo-Kyoung; PEREZ, Jennifer M.; NAJIB, Umer; PASCUAL-LEONE, Alvaro

    2014-01-01

    Transcranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor-evoked potentials (MEPs) reflective of modulation of cortico-spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta-burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults; and we measured modulation of (i) motor evoked-potentials (MEPs), (ii) TMS-induced EEG evoked potentials (TEPs), (iii) TMS-induced EEG synchronization and (iv) eyes-closed resting EEG. Our results show the expected cTBS-induced decrease in MEPs size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes-closed resting EEG, whereas it decreased single-pulse TMS-induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes-closed resting EEG, whereas it increased single-pulse TMS-induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low frequency (theta and/or alpha) oscillators and desynchronizes high frequency (beta) oscillators. These results provide novel insights into the cortical effects of cTBS and could be useful for exploring cTBS-induced plasticity outside of the motor cortex. PMID:23190020

  3. Ethanol injected into the hypothalamic arcuate nucleus induces behavioral stimulation in rats: an effect prevented by catalase inhibition and naltrexone.

    Pastor, Raúl; Aragon, Carlos M G

    2008-10-01

    It is suggested that some of the behavioral effects of ethanol, including its psychomotor properties, are mediated by beta-endorphin and opioid receptors. Ethanol-induced increases in the release of hypothalamic beta-endorphin depend on the catalasemic conversion of ethanol to acetaldehyde. Here, we evaluated the locomotor activity in rats microinjected with ethanol directly into the hypothalamic arcuate nucleus (ArcN), the main site of beta-endorphin synthesis in the brain and a region with high levels of catalase expression. Intra-ArcN ethanol-induced changes in motor activity were also investigated in rats pretreated with the opioid receptor antagonist, naltrexone (0-2 mg/kg) or the catalase inhibitor 3-amino-1,2,4-triazole (AT; 0-1 g/kg). We found that ethanol microinjections of 64 or 128, but not 256 microg, produced locomotor stimulation. Intra-ArcN ethanol (128 microg)-induced activation was prevented by naltrexone and AT, whereas these compounds did not affect spontaneous activity. The present results support earlier evidence indicating that the ArcN and the beta-endorphinic neurons of this nucleus are necessary for ethanol to induce stimulation. In addition, our data suggest that brain structures that, as the ArcN, are rich in catalase may support the formation of ethanol-derived pharmacologically relevant concentrations of acetaldehyde and, thus be of particular importance for the behavioral effects of ethanol.

  4. Microwave induced stimulation of /sup 32/Pi incorporation into phosphoinositides of rat brain synaptosomes

    Gandhi, C.R.; Ross, D.H.

    1989-07-01

    Exposure of synaptosomes to microwave radiation at a power density of 10 mW/sq cm or more produced stimulation of the /sup 32/Pi-incorporation into phosphoinositides. The extent of /sup 32/Pi incorporation was found to be much more pronounced in phosphatidylinositol-4-phosphate (PIP), and phosphatidylinositol-4,5-bisphosphate (PIP/sub 2/) as compared to phosphatidylinositol (PI) and phosphatidic acid (PA). Other lipids were also found to incorporate /sup 32/Pi but no significant changes in their labeling were seen after exposure to microwave radiation. Inclusion of 10 mM lithium in the medium reduced the basal labeling of PIP/sub 2/, PIP and PI and increased PA labeling. Li/sup +/ also inhibited the microwave stimulated PIP/sub 2/, PIP and PI labeling but had no effect on PA labeling. Calcium inophore, A/sub 23187/, inhibited the basal and microwave stimulated /sup 32/Pi labeling of PIP and PIP/sub 2/, stimulated basal labeling of PA and PI and had no effect on microwave stimulated PA and PI labeling. Calcium chelator, EGTA, on the other hand, had no effect on basal labeling of PA and PI, stimulated basal PIP and PIP/sub 2/ labeling but did not alter microwave stimulated labeling of these lipids. Exposure of synaptosomes to microwave radiation did not alter the chemical concentration of phosphoinositides indicating that the turnover of these lipids was altered. These results suggest that low frequency microwave radiation alter the metabolism of inositol phospholipids by enhancing their turnover and thus may affect the transmembrane signalling in the nerve endings.

  5. Recording of the Neural Activity Induced by the Electrical Subthalamic Stimulation Using Ca2+ Imaging

    Tamura, Atsushi; Yagi, Tetsuya; Osanai, Makoto

    The basal ganglia (BG) have important roles in some kind of motor control and learning. Parkinson's disease is one of the motor impairment disease. Recently, to recover a motor severity in patients of Parkinsonism, the stimulus electrode is implanted to the subthalamic nucleus, which is a part of the basal ganglia, and the deep brain stimulation (DBS) is often conducted. However, the effects of the DBS on the subthalamic neurons have not been elucidated. Thus, to analyze the effects of the electrical stimulation on the subthalamic neurons, we conducted the calcium imaging at the mouse subthalamic nucleus. When the single stimulus was applied to the subthalamic nucleus, the intracellular calcium ([Ca2+]i) transients were observed. In the case of application of the single electrical stimulation, the [Ca2+]i arose near the stimulus position. When 100 Hz 10-100 times tetanic stimulations were applied, the responded area and the amplitudes of [Ca2+]i transients were increased. The [Ca2+]i transients were disappeared almost completely on the action potential blockade, but blockade of the excitatory and the inhibitory synaptic transmission had little effects on the responded area and the amplitudes of the [Ca2+]i transients. These results suggested that the electrical stimulation to the subthalamic neurons led to activate the subthalamic neurons directly but not via synaptic transmissions. Thus, DBS may change the activity of the subthalamic neurons, hence, may alter the input-output relationship of the subthalamic neurons

  6. Gold nanoparticle-mediated laser stimulation induces a complex stress response in neuronal cells.

    Johannsmeier, Sonja; Heeger, Patrick; Terakawa, Mitsuhiro; Kalies, Stefan; Heisterkamp, Alexander; Ripken, Tammo; Heinemann, Dag

    2018-04-25

    Stimulation of neuronal cells generally resorts to electric signals. Recent advances in laser-based stimulation methods could present an alternative with superior spatiotemporal resolution. The avoidance of electronic crosstalk makes these methods attractive for in vivo therapeutic application. In particular, nano-mediators, such as gold nanoparticles, can be used to transfer the energy from a laser pulse to the cell membrane and subsequently activate excitable cells. Although the underlying mechanisms of neuronal activation have been widely unraveled, the overall effect on the targeted cell is not understood. Little is known about the physiological and pathophysiological impact of a laser pulse targeted onto nanoabsorbers on the cell membrane. Here, we analyzed the reaction of the neuronal murine cell line Neuro-2A and murine primary cortical neurons to gold nanoparticle mediated laser stimulation. Our study reveals a severe, complex and cell-type independent stress response after laser irradiation, emphasizing the need for a thorough assessment of this approach's efficacy and safety.

  7. Theophylline-induced respiratory recovery following cervical spinal cord hemisection is augmented by serotonin 2 receptor stimulation.

    Basura, Gregory J; Nantwi, Kwaku D; Goshgarian, Harry G

    2002-11-22

    Cervical spinal cord hemisection leads to a disruption of bulbospinal innervation of phrenic motoneurons resulting in paralysis of the ipsilateral hemidiaphragm. We have previously demonstrated separate therapeutic roles for theophylline, and more recently serotonin (5-HT) as modulators to phrenic nerve motor recovery; mechanisms that likely occur via adenosine A1 and 5-HT2 receptors, respectively. The present study was designed to specifically determine if concurrent stimulation of 5-HT2 receptors may enhance motor recovery induced by theophylline alone. Adult female rats (250-350 g; n=7 per group) received a left cervical (C2) hemisection that resulted in paralysis of the ipsilateral hemidiaphragm. Twenty-four hours later rats were given systemic theophylline (15 mg/kg, i.v.), resulting in burst recovery in the ipsilateral phrenic nerve. Theophylline-induced recovery was enhanced with the 5-HT2A/2C receptor agonist, (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI; 1.0 mg/kg). DOI-evoked augmentation of theophylline-induced recovery was attenuated following subsequent injection of the 5-HT2 receptor antagonist, ketanserin (2.0 mg/kg). In a separate group, rats were pretreated with ketanserin, which did not prevent subsequent theophylline-induced respiratory recovery. However, pretreatment with ketanserin did prevent DOI-induced augmentation of the theophylline-evoked phrenic nerve burst recovery. Lastly, using immunocytochemistry and in situ hybridization, we showed for the first time a positive co-localization of adenosine A1 receptor mRNA and immunoreactivity with phrenic motoneurons of the cervical ventral horns. Taken together, the results of the present study suggest that theophylline may induce motor recovery likely at adenosine A1 receptors located at the level of the spinal cord, and the concurrent stimulation of converging 5-HT2 receptors may augment the response.

  8. Brain-derived neurotrophic factor--a major player in stimulation-induced homeostatic metaplasticity of human motor cortex?

    Claudia Mastroeni

    Full Text Available Repetitive transcranial magnetic stimulation (rTMS of the human motor hand area (M1HAND can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val(66met polymorphism in the brain-derived neurotrophic factor (BDNF gene. Here we used theta burst stimulation (TBS to examine whether the BDNF val(66met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS usually inducing a lasting increase and continuous TBS (cTBS a lasting decrease in corticospinal excitability. In three separate sessions, healthy val(66met (n = 12 and val(66val (n = 17 carriers received neuronavigated cTBS followed by cTBS (n = 27, cTBS followed by iTBS (n = 29, and iTBS followed by iTBS (n = 28. Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS and increase (iTBS in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val(66met carriers and val(66val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val(66met polymorphism, our results do not support the notion that the BDNF val(66met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.

  9. Brain-Derived Neurotrophic Factor – A Major Player in Stimulation-Induced Homeostatic Metaplasticity of Human Motor Cortex?

    Rizzo, Vincenzo; Ritter, Christoph; Klein, Christine; Pohlmann, Ines; Brueggemann, Norbert; Quartarone, Angelo; Siebner, Hartwig Roman

    2013-01-01

    Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val66met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val66met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val66met (n = 12) and val66val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val66met carriers and val66val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val66met polymorphism, our results do not support the notion that the BDNF val66met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND. PMID:23469118

  10. Brain-derived neurotrophic factor--a major player in stimulation-induced homeostatic metaplasticity of human motor cortex?

    Mastroeni, Claudia; Bergmann, Til Ole; Rizzo, Vincenzo; Ritter, Christoph; Klein, Christine; Pohlmann, Ines; Brueggemann, Norbert; Quartarone, Angelo; Siebner, Hartwig Roman

    2013-01-01

    Repetitive transcranial magnetic stimulation (rTMS) of the human motor hand area (M1HAND) can induce lasting changes in corticospinal excitability as indexed by a change in amplitude of the motor-evoked potential. The plasticity-inducing effects of rTMS in M1HAND show substantial inter-individual variability which has been partially attributed to the val(66)met polymorphism in the brain-derived neurotrophic factor (BDNF) gene. Here we used theta burst stimulation (TBS) to examine whether the BDNF val(66)met genotype can be used to predict the expression of TBS-induced homeostatic metaplasticity in human M1HAND. TBS is a patterned rTMS protocol with intermittent TBS (iTBS) usually inducing a lasting increase and continuous TBS (cTBS) a lasting decrease in corticospinal excitability. In three separate sessions, healthy val(66)met (n = 12) and val(66)val (n = 17) carriers received neuronavigated cTBS followed by cTBS (n = 27), cTBS followed by iTBS (n = 29), and iTBS followed by iTBS (n = 28). Participants and examiner were blinded to the genotype at the time of examination. As expected, the first TBS intervention induced a decrease (cTBS) and increase (iTBS) in corticospinal excitability, respectively, at the same time priming the after effects caused by the second TBS intervention in a homeostatic fashion. Critically, val(66)met carriers and val(66)val carriers showed very similar response patterns to cTBS and iTBS regardless of the order of TBS interventions. Since none of the observed TBS effects was modulated by the BDNF val(66)met polymorphism, our results do not support the notion that the BDNF val(66)met genotype is a major player with regard to TBS-induced plasticity and metaplasticity in the human M1HAND.

  11. Inhibitory effect of BIBN4096BS on cephalic vasodilatation induced by CGRP or transcranial electrical stimulation in the rat

    Petersen, Kenneth A; Birk, Steffen; Doods, Henri

    2004-01-01

    therapeutic principle. We used an improved closed cranial window model to measure changes of the middle meningeal artery (MMA) and cortical pial artery/arteriole diameter (PA) and changes in local cortical cerebral blood flow (LCBF(Flux)) in anaesthetised artificially ventilated rats. The ability of BIBN4096......BS (i.v.) to prevent the vasodilatatory actions of rat-alphaCGRP, betaCGRP and endogenously released CGRP following transcranial electrical stimulation (TES) was investigated. BIBN4096BS was per se without vasoactive effect on any of the measured variables and significantly inhibited the hypotension......CGRP. Transcranial electrical stimulation induced a 119.1 +/- 6.9% increase in MMA diameter. BIBN4096BS (333 microg kg(-1)) attenuated this increase (19.8 +/- 2.1%) (P

  12. Pulsating electromagnetic field stimulation of urothelial cells induces apoptosis and diminishes necrosis: new insight to magnetic therapy in urology.

    Juszczak, K; Kaszuba-Zwoinska, J; Thor, P J

    2012-08-01

    The evidence of electromagnetic therapy (EMT) efficacy in stress and/or urge urinary incontinence, as well as in detrusor overactivity is generally lacking in the literature. The potential EMT action of neuromuscular tissue depolarization has been described. Because there is no data on the influence of pulsating electromagnetic fields (PEMF) on the urothelium, we evaluated the effect of PEMF stimulation on rat urothelial cultured cells (RUCC). In our study 15 Wistar rats were used for RUCC preparation. RUCC were exposed to PEMF (50 Hz, 45±5 mT) three times for 4 hours each with 24-hour intervals. The unexposed RUCC was in the same incubator, but in a distance of 35 cm from the PEMF generator. Annexin V-APC (AnV+) labelled was used to determine the percentage of apoptotic cells and propidium iodide (PI+), as standard flow cytometric viability probe to distinguish necrotic cells from viable ones. The results are presented in percentage values. The flow cytometric analysis was carried out on a FACS calibur flow cytometer using Cell-Quest software. In PEMF-unstimulated RUCC, the percentage of AnV+, PI+, and AnV+PI+ positive cells were 1.24±0.34%, 11.03±1.55%, and 12.43±1.96%, respectively. The percentages of AnV+, PI+, and AnV+PI+ positive cells obtained after PEMF stimulation were 1.45±0.16% (p=0.027), 7.03±1.76% (p<0.001), and 9.48±3.40% (p=0.003), respectively. The PEMF stimulation of RUCC induces apoptosis (increase of AnV+ cells) and inhibits necrosis (decrease of PI+ cells) of urothelial cells. This leads us to the conclusion that a low-frequency pulsating electromagnetic field stimulation induces apoptosis and diminishes necrosis of rat urothelial cells in culture.

  13. Inhibition of breast cancer resistance protein (ABCG2 in human myeloid dendritic cells induces potent tolerogenic functions during LPS stimulation.

    Jun-O Jin

    Full Text Available Breast cancer resistance protein (ABCG2, a member of the ATP-binding cassette transporters has been identified as a major determinant of multidrug resistance (MDR in cancer cells, but ABC transporter inhibition has limited therapeutic value in vivo. In this research, we demonstrated that inhibition of efflux transporters ABCG2 induced the generation of tolerogenic DCs from human peripheral blood myeloid DCs (mDCs. ABCG2 expression was present in mDCs and was further increased by LPS stimulation. Treatment of CD1c+ mDCs with an ABCG2 inhibitor, Ko143, during LPS stimulation caused increased production of IL-10 and decreased production of pro-inflammatory cytokines and decreased expression of CD83 and CD86. Moreover, inhibition of ABCG2 in monocyte-derived DCs (MDDCs abrogated the up-regulation of co-stimulatory molecules and production of pro-inflammatory cytokines in these cells in response to LPS. Furthermore, CD1c+ mDCs stimulated with LPS plus Ko143 inhibited the proliferation of allogeneic and superantigen-specific syngenic CD4+ T cells and promoted expansion of CD25+FOXP3+ regulatory T (Treg cells in an IL-10-dependent fashion. These tolerogenic effects of ABCG2 inhibition could be abolished by ERK inhibition. Thus, we demonstrated that inhibition of ABCG2 in LPS-stimulated mDCs can potently induce tolerogenic potentials in these cells, providing crucial new information that could lead to development of better strategies to combat MDR cancer.

  14. Sensory trigeminal ULF-TENS stimulation reduces HRV response to experimentally induced arithmetic stress: A randomized clinical trial.

    Monaco, Annalisa; Cattaneo, Ruggero; Ortu, Eleonora; Constantinescu, Marian Vladimir; Pietropaoli, Davide

    2017-05-01

    Ultra Low Frequency Transcutaneous Electric Nervous Stimulation (ULF-TENS) is extensively used for pain relief and for the diagnosis and treatment of temporomandibular disorders (TMD). In addition to its local effects, ULF-TENS acts on the autonomic nervous system (ANS), with particular reference to the periaqueductal gray (PAG), promoting the release of endogenous opioids and modulating descending pain systems. It has been suggested that the PAG participates in the coupling between the emotional stimulus and the appropriate behavioral autonomic response. This function is successfully investigated by HRV. Therefore, our goal is to investigate the effects of trigeminal ULF-TENS stimulation on autonomic behavior in terms of HRV and respiratory parameters during an experimentally-induced arithmetic stress test in healthy subjects. Thirty healthy women between 25 and 35years of age were enrolled and randomly assigned to either the control (TENS stimulation off) or test group (TENS stimulation on). Heart (HR, LF, HF, LF/HF ratio, DET, RMSSD, PNN50, RR) and respiratory (BR) rate were evaluated under basal, T1 (TENS off/on), and stress (mathematical task) conditions. Results showed that HRV parameters and BR significantly changed during the arithmetic stress paradigm (pTENS and control group could be discriminated only by non-linear HRV data, namely RR and DET (p=0.038 and p=0.027, respectively). During the arithmetic task, LF/HF ratio was the most sensitive parameter to discriminate between groups (p=0.019). Our data suggest that trigeminal sensory ULF-TENS reduces the autonomic response in terms of HRV and BR during acute mental stress in healthy subjects. Future directions of our work aim at applying the HRV and BR analysis, with and without TENS stimulation, to individuals with dysfunctional ANS among those with TMD. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Network based statistical analysis detects changes induced by continuous theta burst stimulation on brain activity at rest.

    Chiara eMastropasqua

    2014-08-01

    Full Text Available We combined continuous theta burst stimulation (cTBS and resting state (RS -fMRI approaches to investigate changes in functional connectivity (FC induced by right dorso-lateral prefrontal cortex (DLPFC cTBS at rest in a group of healthy subjects. Seed based fMRI analysis revealed a specific pattern of correlation between the right prefrontal cortex and several brain regions: based on these results, we defined a 29-node network to assess changes in each network connection before and after, respectively, DLPFC-cTBS and sham sessions. A decrease of correlation between the right prefrontal cortex and right parietal cortex (Brodmann areas 46 and 40 respectively was detected after cTBS, while no significant result was found when analyzing sham-session data. To our knowledge, this is the first study that demonstrates within-subject changes in FC induced by cTBS applied on prefrontal area. The possibility to induce selective changes in a specific region without interfering with functionally correlated area could have several implications for the study of functional properties of the brain, and for the emerging therapeutic strategies based on transcranial stimulation.

  16. Paired-Associative Stimulation-Induced Long-term Potentiation-Like Motor Cortex Plasticity in Healthy Adolescents

    Jonathan C. Lee

    2017-05-01

    Full Text Available ObjectiveThe objective of this study was to evaluate the feasibility of using paired-associative stimulation (PAS to study excitatory and inhibitory plasticity in adolescents while examining variables that may moderate plasticity (such as sex and environment.MethodsWe recruited 34 healthy adolescents (aged 13–19, 13 males, 21 females. To evaluate excitatory plasticity, we compared mean motor-evoked potentials (MEPs elicited by single-pulse transcranial magnetic stimulation (TMS before and after PAS at 0, 15, and 30 min. To evaluate inhibitory plasticity, we evaluated the cortical silent period (CSP elicited by single-pulse TMS in the contracted hand before and after PAS at 0, 15, and 30 min.ResultsAll participants completed PAS procedures. No adverse events occurred. PAS was well tolerated. PAS-induced significant increases in the ratio of post-PAS MEP to pre-PAS MEP amplitudes (p < 0.01 at all post-PAS intervals. Neither socioeconomic status nor sex was associated with post-PAS MEP changes. PAS induced significant CSP lengthening in males but not females.ConclusionPAS is a feasible, safe, and well-tolerated index of adolescent motor cortical plasticity. Gender may influence PAS-induced changes in cortical inhibition. PAS is safe and well tolerated by healthy adolescents and may be a novel tool with which to study adolescent neuroplasticity.

  17. Monitoring transcranial direct current stimulation induced changes in cortical excitability during the serial reaction time task.

    Ambrus, Géza Gergely; Chaieb, Leila; Stilling, Roman; Rothkegel, Holger; Antal, Andrea; Paulus, Walter

    2016-03-11

    The measurement of the motor evoked potential (MEP) amplitudes using single pulse transcranial magnetic stimulation (TMS) is a common method to observe changes in motor cortical excitability. The level of cortical excitability has been shown to change during motor learning. Conversely, motor learning can be improved by using anodal transcranial direct current stimulation (tDCS). In the present study, we aimed to monitor cortical excitability changes during an implicit motor learning paradigm, a version of the serial reaction time task (SRTT). Responses from the first dorsal interosseous (FDI) and forearm flexor (FLEX) muscles were recorded before, during and after the performance of the SRTT. Online measurements were combined with anodal, cathodal or sham tDCS for the duration of the SRTT. Negative correlations between the amplitude of online FDI MEPs and SRTT reaction times (RTs) were observed across the learning blocks in the cathodal condition (higher average MEP amplitudes associated with lower RTs) but no significant differences in the anodal and sham conditions. tDCS did not have an impact on SRTT performance, as would be predicted based on previous studies. The offline before-after SRTT MEP amplitudes showed an increase after anodal and a tendency to decrease after cathodal stimulation, but these changes were not significant. The combination of different interventions during tDCS might result in reduced efficacy of the stimulation that in future studies need further attention. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Electroconvulsive stimulations prevent stress-induced morphological changes in the hippocampus

    Hageman, I; Nielsen, M; Wörtwein, Gitta

    2008-01-01

    whether repeated electroconvulsive stimulations (ECSs) could influence such changes in stressed rats. Furthermore, we investigated whether ECSs per se could influence neuronal branching and total length of the CA3 hippocampal neuronal dendritic tree in normal rats. Rats were stressed using the 21-day 6 h...

  19. Radiation-induced growth and isothermal decay of infrared-stimulated luminescence from feldspar

    Guralnik, Benny; Li, Bo; Jain, Mayank

    2015-01-01

    the growth and decay of laboratory-regenerated luminescence signals. Here we review a selection of common models describing the response of infrared stimulated luminescence (IRSL) of feldspar to constant radiation and temperature as administered in the laboratory. We use this opportunity to introduce...

  20. Evaluation of effect of transcutaneous electrical nerve stimulation on salivary flow rate in radiation induced xerostomia patients: a pilot study.

    Lakshman, Anusha Rangare; Babu, G Subhas; Rao, Suresh

    2015-01-01

    Xerostomia is a common sequel in patients undergoing irradiation of malignant tumors of the head and neck. Palliative treatments of xerostomia like topical agents such as ice-chips, saliva substitutes, systemic sialogogues like pilocarpine and cevimeline work well for some patients. Electrostimulation was studied in the past and showed moderate promise but never became part of the mainstream therapy for better management of xerostomia patients. The aim of the following study is to evaluate the effectiveness of a transcutaneous electrical nerve stimulation (TENS) unit in stimulating the whole salivary flow rate in radiation induced xerostomia patients. A total of 40 subjects were included in the study. The study group consisted of 30 individuals and was divided into Group S1 (n = 20), which was further subdivided into Group S1A (n = 10) subjects complaining of dry mouth who were undergoing head and neck radiotherapy with TENS stimulation during the commencement of radiotherapy, on the 3 rd , 6 th week and after a month of completion of radiotherapy and Group S1B (n = 10) with TENS stimulation daily during the full course of radiotherapy and Group S2 (n = 10) subjects complaining of dry mouth who had undergone head and neck radiotherapy that ended 1 month prior to their entry into the study. The control group (n = 10) consisted of healthy individuals not complaining of dry mouth and who have not undergone head and neck radiotherapy. Whole saliva was collected without stimulation for 10 min and after electrostimulation with TENS unit for additional 10 min in a graduated test tube. The results were statistically analyzed using Mann-Whitney U-test and Kruskal-Wallis's test. The data analysis revealed that control and S1B group showed increased salivary flow rate after stimulation by TENS therapy compared with the unstimulated salivary flow, whereas in S1A and S2 group it was found to be statistically non-significant. The present study gave us an insight about the

  1. Iron may induce both DNA synthesis and repair in rat hepatocytes stimulated by EGF/pyruvate

    Chenoufi, N.; Loreal, O.; Cariou, S.; Hubert, N.; Lescoat, G. [Univ. Hospital Pontchaillou, Unite de Recherches Hepatologiques, INSERM U 49, Rennes (France); Drenou, B. [Univ. Hospital Pontchaillou, Lab. d`Hematologie et d`Immunologie, Rennes (France); Leroyer, P.; Brissot, P. [Univ. Hospital Pontchaillou, Clinique des Maladies du Foie, Rennes (France)

    1997-03-01

    Background/Aims: Hepatocellular carcinoma develops frequently in the course of genetic hemochromatosis, and a role of iron overload in hepatic carcinogenesis is strongly suggested. Methods: The aim of our study was to investigate the effect of iron exposure on DNA synthesis of adult rat hepatocytes maintained in primary culture stimulated or not by EGF/pyruvate and exposed to iron-citrate complex. Results: In EGF/pyruvate-stimulated cultures, the level of [{sup 3}H] methyl thymidine incorporation was strongly increased as compared to unstimulated cultures. The addition of iron to stimulated cultures increased [{sup 3}H] methyl thymidine incorporation. The mitotic index was also significantly higher at 72 h. However,the number of cells found in the cell layer was not significantly different from iron-citrate free culture. By flow cytometry, no difference in cell ploidy was found between iron-treated and untreated EGF/pyruvate-stimulated cultures. A significant increase in LDH leakage reflecting a toxic effect of iron was found in the cell medium 48 h after cell seeding. In addition, [{sup 3}H] methyl thymidine incorporation in the presence of hydroxyurea was increased in iron-treated compared to untreated cultures. Conclusions: Our results show that DNA synthesis is increased in the presence of iron in rat hepatocyte cultures stimulated by EGF/pyruvate, and they suggest that DNA synthesis is likely to be related both to cell proliferation and to DNA repair. These observations may allow better understanding of the role of iron overload in the development of hepatocellular carcinoma. (au) 61 refs.

  2. Pavlovian conditioning of psychomotor stimulant-induced behaviours: has convenience led us astray?

    Martin-Iverson, M.T.; Fawcett, S.L.

    1996-01-01

    In order to classically condition the behavioural effects of psychomotor stimulants within a test context, rats were treated for 10 days with (+)-amphetamine (1.5mg/kg), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 30µg/kg) or vehicle prior to a 1h placement into a test box. Conditioned behavioural effects were then measured in the previously drug-paired context after a vehicle injection (drug-free test day). Each rat was videotaped for the 1h test box exposure on days 1, 4, 7 and 10 of the drug conditioning trials, and on the drug-free test day. Eleven of 28 behaviours that were scored for frequency, duration and mean bout duration (bout length) were significantly influenced by at least one of the two drugs. Amphetamine predominantly increased bout lengths while PHNO predominantly increased bout frequency. Only two measures that were influenced by the drugs exhibited clear increases over controls in a manner consistent with a classical conditioning interpretation. Behavioural sensitization clearly occurred to some of the effects of amphetamine and PHNO, but these were not the same effects as those increased on the non-drug day testing for classical conditioning. Most behavioural effects of amphetamine and PHNO are not classically conditioned, and behavioural sensitization to these drugs, while perhaps context-specific, is not due to classical conditioning. Automated measures of behaviours have provided misleading evidence concerning the similarity among behavioural effects of stimulants, sensitization and effects of exposure to an environment previously paired with stimulants. Analysis of transitions between behaviours does not support the view that stimulants increase switching or response competition, or that behavioural reorganization is responsible for sensitization. Rather, it is suggested that stimulants selectively facilitate current stimulus-guided behaviours.

  3. Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin.

    Wilson, Fiona A; Orellana, Renán A; Suryawan, Agus; Nguyen, Hanh V; Jeyapalan, Asumthia S; Frank, Jason; Davis, Teresa A

    2008-07-01

    Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7-10 days of pST (150 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1.eIF4E complex association and increased active eIF4E.eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

  4. Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells.

    Kisfalvi, Krisztina; Hurd, Cliff; Guha, Sushovan; Rozengurt, Enrique

    2010-05-01

    Neurotensin (NT) stimulates protein kinase D1 (PKD1), extracellular signal regulated kinase (ERK), c-Jun N-terminal Kinase (JNK), and DNA synthesis in the human pancreatic adenocarcinoma cell line PANC-1. To determine the effect of PKD1 overexpression on these biological responses, we generated inducible stable PANC-1 clones that express wild-type (WT) or kinase-dead (K618N) forms of PKD1 in response to the ecdysone analog ponasterone-A (PonA). NT potently stimulated c-Jun Ser(63) phosphorylation in both wild type and clonal derivatives of PANC-1 cells. PonA-induced expression of WT, but not K618N PKD1, rapidly blocked NT-mediated c-Jun Ser(63) phosphorylation either at the level of or upstream of MKK4, a dual-specificity kinase that leads to JNK activation. This is the first demonstration that PKD1 suppresses NT-induced JNK/cJun activation in PANC-1 cells. In contrast, PKD1 overexpression markedly increased the duration of NT-induced ERK activation in these cells. The reciprocal influence of PKD1 signaling on pro-mitogenicERK and pro-apopotic JNK/c-Jun pathways prompted us to examine whether PKD1 overexpression promotes DNA synthesis and proliferation of PANC-1 cells. Our results show that PKD1 overexpression increased DNA synthesis and cell numbers of PANC-1 cells cultured in regular dishes or in polyhydroxyethylmethacrylate [Poly-(HEMA)]-coated dishes to eliminate cell adhesion (anchorage-independent growth). Furthermore, PKD1 overexpression markedly enhanced DNA synthesis induced by NT (1-10 nM). These results indicate that PKD1 mediates mitogenic signaling in PANC-1 and suggests that this enzyme could be a novel target for the development of therapeutic drugs that restrict the proliferation of these cells.

  5. Improvement of Upper Extremity Deficit after Constraint-Induced Movement Therapy Combined with and without Preconditioning Stimulation Using Dual-hemisphere Transcranial Direct Current Stimulation and Peripheral Neuromuscular Stimulation in Chronic Stroke Patients: A Pilot Randomized Controlled Trial

    Takashi Takebayashi

    2017-10-01

    Full Text Available In this study, we investigated the effects of dual-hemisphere transcranial direct current stimulation (dual-tDCS of both the affected (anodal tDCS and non-affected (cathodal tDCS primary motor cortex, combined with peripheral neuromuscular electrical stimulation (PNMES, on the effectiveness of constraint-induced movement therapy (CIMT as a neurorehabilitation intervention in chronic stroke. We conducted a randomized controlled trial of feasibility, with a single blind assessor, with patients recruited from three outpatient clinics. Twenty chronic stroke patients were randomly allocated to the control group, receiving conventional CIMT, or the intervention group receiving dual-tDCS combined with PNMES before CIMT. Patients in the treatment group first underwent a 20-min period of dual-tDCS, followed immediately by PNMES, and subsequent CIMT for 2 h. Patients in the control group only received CIMT (with no pretreatment stimulation. All patients underwent two CIMT sessions, one in the morning and one in the afternoon, each lasting 2 h, for a total of 4 h of CIMT per day. Upper extremity function was assessed using the Fugl-Meyer Assessment (primary outcome, as well as the amount of use (AOU and quality of movement (QOM scores, obtained via the Motor Activity Log (secondary outcome. Nineteen patients completed the study, with one patient withdrawing after allocation. Compared to the control group, the treatment improvement in upper extremity function and AOU was significantly greater in the treatment than control group (change in upper extremity score, 9.20 ± 4.64 versus 4.56 ± 2.60, respectively, P < 0.01, η2 = 0.43; change in AOU score, 1.10 ± 0.65 versus 0.62 ± 0.85, respectively, P = 0.02, η2 = 0.52. There was no significant effect of the intervention on the QOM between the intervention and control groups (change in QOM score, 1.00 ± 0.62 versus 0.71 ± 0.72, respectively, P = 0.07, η2

  6. Collision-induced stimulated photon echo generated at transition 0-1 on broad spectral line conditions

    Rubtsova, N. N.; Gol'dort, V. G.; Ishchenko, V. N.; Khvorostov, E. B.; Kochubei, S. A.; Borisov, G. M.; Ledovskikh, D. V.; Reshetov, V. A.

    2018-04-01

    For the first time, the collision induced stimulated photon echo generated at transition 1S0 → 3 P1 of 174Yb (type 0-1) in the mixture of gases Yb  +  Xe was investigated in the presence of weak longitudinal magnetic field, with experimental parameters corresponding to broad spectral line conditions. Comparison of the experimental echo amplitude versus magnetic field strength dependence with the theoretical curve shows a very good agreement, giving rise to an improved estimate for the difference between alignment and orientation decay rates.

  7. Gastric electrical stimulation decreases gastric distension-induced central nociception response through direct action on primary afferents.

    Wassila Ouelaa

    Full Text Available BACKGROUND & AIMS: Gastric electrical stimulation (GES is an effective therapy to treat patients with chronic dyspepsia refractory to medical management. However, its mechanisms of action remain poorly understood. METHODS: Gastric pain was induced by performing gastric distension (GD in anesthetized rats. Pain response was monitored by measuring the pseudo-affective reflex (e.g., blood pressure variation, while neuronal activation was determined using c-fos immunochemistry in the central nervous system. Involvement of primary afferents was assessed by measuring phosphorylation of ERK1/2 in dorsal root ganglia. RESULTS: GES decreased blood pressure variation induced by GD, and prevented GD-induced neuronal activation in the dorsal horn of the spinal cord (T9-T10, the nucleus of the solitary tract and in CRF neurons of the hypothalamic paraventricular nucleus. This effect remained unaltered within the spinal cord when sectioning the medulla at the T5 level. Furthermore, GES prevented GD-induced phosphorylation of ERK1/2 in dorsal root ganglia. CONCLUSIONS: GES decreases GD-induced pain and/or discomfort likely through a direct modulation of gastric spinal afferents reducing central processing of visceral nociception.

  8. Early application of tail nerve electrical stimulation-induced walking training promotes locomotor recovery in rats with spinal cord injury.

    Zhang, S-X; Huang, F; Gates, M; Shen, X; Holmberg, E G

    2016-11-01

    This is a randomized controlled prospective trial with two parallel groups. The objective of this study was to determine whether early application of tail nerve electrical stimulation (TANES)-induced walking training can improve the locomotor function. This study was conducted in SCS Research Center in Colorado, USA. A contusion injury to spinal cord T10 was produced using the New York University impactor device with a 25 -mm height setting in female, adult Long-Evans rats. Injured rats were randomly divided into two groups (n=12 per group). One group was subjected to TANES-induced walking training 2 weeks post injury, and the other group, as control, received no TANES-induced walking training. Restorations of behavior and conduction were assessed using the Basso, Beattie and Bresnahan open-field rating scale, horizontal ladder rung walking test and electrophysiological test (Hoffmann reflex). Early application of TANES-induced walking training significantly improved the recovery of locomotor function and benefited the restoration of Hoffmann reflex. TANES-induced walking training is a useful method to promote locomotor recovery in rats with spinal cord injury.

  9. Effects of Low-Level Autonomic Stimulation on Prevention of Atrial Fibrillation Induced by Acute Electrical Remodeling

    Yubi Lin

    2013-01-01

    Full Text Available Background. Rapid atrial pacing (RAP can induce electrical and autonomic remodeling and facilitate atrial fibrillation (AF. Recent reports showed that low-level vagosympathetic nerve stimulation (LLVNS can suppress AF, as an antiarrhythmic effect. We hypothesized that LLVNS can reverse substrate heterogeneity induced by RAP. Methods and Results. Mongrel dogs were divided into (LLVNS+RAP and RAP groups. Electrode catheters were sutured to multiple atrial sites, and LLVNS was applied to cervical vagosympathetic trunks with voltage 50% below the threshold slowing sinus rate by ⩽30 msec. RAP induced a significant decrease in effective refractory period (ERP and increase in the window of vulnerability at all sites, characterized by descending and elevated gradient differences towards the ganglionic plexi (GP sites, respectively. The ERP dispersion was obviously enlarged by RAP and more significant when the ERP of GP-related sites was considered. Recovery time from AF was also prolonged significantly as a result of RAP. LLVNS could reverse all these changes induced by RAP and recover the heterogeneous substrate to baseline. Conclusions. LLVNS can reverse the electrical and autonomic remodeling and abolish the GP-central gradient differences induced by RAP, and thus it can recover the homogeneous substrate, which may be the underlying mechanism of its antiarrhythmic effect.

  10. Permanent metabolic stimulation in leaves induced by small gamma irradiation doses and its bioenergetical bases

    Pozsar, B.

    1979-01-01

    According to Schober (1896) the physiological functions of plants can be stimulated by small-dose acute gamma irradiation. The activity of the alcohol dehydrogenase was tested by the production of the acetaldehyde mg, related to 200 mg fresh leaf weight of bean (Pinto variety) and peas (BR-13 and DCP-94 varieties) plants. The stimulating effect of different reducing compounds (glutathione, ascorbic acid, cysteine) in additive treatment was also investigated in the respect of the alcohol dehydrogenase activity. The reducing compounds remarkably increase the activity of the alcohol dehydrogenase. The experimental results indicate that the primary water ionization is followed by secondary long-lasting proton transport through the reducing compounds to the dehydrogenase system. (author)

  11. Cardiac autonomic responses induced by mental tasks and the influence of musical auditory stimulation.

    Barbosa, Juliana Cristina; Guida, Heraldo L; Fontes, Anne M G; Antonio, Ana M S; de Abreu, Luiz Carlos; Barnabé, Viviani; Marcomini, Renata S; Vanderlei, Luiz Carlos M; da Silva, Meire L; Valenti, Vitor E

    2014-08-01

    We investigated the acute effects of musical auditory stimulation on cardiac autonomic responses to a mental task in 28 healthy men (18-22 years old). In the control protocol (no music), the volunteers remained at seated rest for 10 min and the test was applied for five minutes. After the end of test the subjects remained seated for five more minutes. In the music protocol, the volunteers remained at seated rest for 10 min, then were exposed to music for 10 min; the test was then applied over five minutes, and the subjects remained seated for five more minutes after the test. In the control and music protocols the time domain and frequency domain indices of heart rate variability remained unchanged before, during and after the test. We found that musical auditory stimulation with baroque music did not influence cardiac autonomic responses to the mental task. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Magnetic resonance imaging of morphological and functional changes of the uterus induced by sacral surface electrical stimulation

    Ogura, Takahide; Murakami, Takashi; Ozawa, Yuka; Seki, Kazunori; Handa, Yasunobu

    2006-01-01

    The purpose of this study is to examine the morphological and kinematical changes of the uterus induced by electrical stimulation applied to the skin just above the second and fourth posterior sacral foramens (sacral surface electrical stimulation [ssES]) in 26 healthy subjects. Out of them, eight subjects who had severe pain subjectively during every menstruation received ssES just in menstruation. Morphological and functional changes of the uterus were examined by using T2-weighted magnetic resonance (MR) imaging and T1-weighted MR cinematography, respectively. Cyclic electrical stimulation for 15 min with 5 sec ON and 5 sec OFF was applied just before MR scanning. A decrease in thickness of the muscular layer of the uterus was observed in every subject after ssES for 15 min and was significant as compared with the thickness before ssES. Periodic uterine movement during menstruation was observed in the subjects with severe menstrual pain in MR cine and the power spectrum analysis of the movement showed a marked decrease in peak power and frequency after ssES treatment. We conclude that ssES causes a reduction of static muscle tension of the uterus in all menstrual cycle periods and suppression of uterine peristalsis during menstruation in the subjects with severe menstrual pain. Possible neural mechanisms for these static and dynamic effects of ssES on the uterus at spinal level are discussed. (author)

  13. Intermittent theta-burst stimulation induces correlated changes in cortical and corticospinal excitability in healthy older subjects.

    Gedankien, Tamara; Fried, Peter J; Pascual-Leone, Alvaro; Shafi, Mouhsin M

    2017-12-01

    We studied the correlation between motor evoked potentials (MEPs) and early TMS-evoked EEG potentials (TEPs) from single-pulse TMS before and after intermittent Theta Burst Stimulation (iTBS) to the left primary motor cortex (M1) in 17 healthy older participants. TMS was targeted to the hand region of M1 using a MRI-guided navigated brain stimulation system and a figure-of-eight biphasic coil. MEPs were recorded from the right first dorsal interosseous muscle using surface EMG. TEPs were extracted from a 61-channel EEG recording. Participants received 90 single TMS pulses at 120% of resting motor threshold before and after iTBS. Across all participants, the change in N15-P30 TEP and MEP amplitudes were significantly correlated (r=0.69; piTBS, whereas MEP amplitudes showed a significant increase. Changes in corticospinal reactivity and cortical reactivity induced by iTBS are related. However, the effect of iTBS on TEPs, unlike MEPs, is not straightforward. Our findings help elucidate the relationship between changes in cortical and corticospinal excitability in healthy older individuals. Going forward, TEPs may be used to evaluate the effects of theta-burst stimulation in non-motor brain regions. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  14. Influence of Concurrent Finger Movements on Transcranial Direct Current Stimulation (tDCS)-Induced Aftereffects.

    Shirota, Yuichiro; Terney, Daniella; Antal, Andrea; Paulus, Walter

    2017-01-01

    Transcranial direct current stimulation (tDCS) has been reported to have bidirectional influence on the amplitude of motor-evoked potentials (MEPs) in resting participants in a polarity-specific manner: anodal tDCS increased and cathodal tDCS decreased them. More recently, the effects of tDCS have been shown to depend on a number of additional factors. We investigated whether a small variety of movements involving target and non-target muscles could differentially modify the efficacy of tDCS. MEPs were elicited from the right first dorsal interosseous muscle, defined as the target muscle, by single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex (M1). During M1 tDCS, which lasted for 10 min applying anodal, cathodal, or sham condition, the participants were instructed to squeeze a ball with their right hand (Task 1), to move their right index finger only in the medial (Task 2), in the lateral direction (Task 3), or in medial and lateral direction alternatively (Task 4). Anodal tDCS reduced MEP amplitudes measured in Task 1 and Task 2, but to a lesser extent in the latter. In Task 3, anodal tDCS led to greater MEP amplitudes than cathodal stimulation. Alternating movements resulted in no effect of tDCS on MEP amplitude (Task 4). The results are congruent with the current notion that the aftereffects of tDCS are highly variable relying on a number of factors including the type of movements executed during stimulation.

  15. Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

    Rosskothen-Kuhl, Nicole; Hildebrandt, Heika; Birkenhäger, Ralf; Illing, Robert-Benjamin

    2018-01-01

    Neuron-glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron-glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

  16. Task-specific impairments and enhancements induced by magnetic stimulation of human visual area V5.

    Walsh, V; Ellison, A; Battelli, L; Cowey, A

    1998-01-01

    Transcranial magnetic stimulation (TMS) can be used to simulate the effects of highly circumscribed brain damage permanently present in some neuropsychological patients, by reversibly disrupting the normal functioning of the cortical area to which it is applied. By using TMS we attempted to recreate deficits similar to those reported in a motion-blind patient and to assess the specificity of deficits when TMS is applied over human area V5. We used six visual search tasks and showed that subje...

  17. Stimulation with Concanavalin-A Induces IL-17 Production by Canine Peripheral T Cells

    Michelle G. Ritt

    2015-04-01

    Full Text Available The characteristics of canine IL-17-producing cells are incompletely understood. Expression of mRNA encoding orthologs of IL-17 and the IL-17 receptor has been documented in tissues from dogs with arthritis, inflammatory bowel disease, and lymphoma; however, no associations have been found between IL-17 gene expression and disease phenotype in these conditions. Robust assessment of the role of IL-17-producing cells in dogs will require measuring the frequency of these cells in health and disease in balance with other lymphocyte subsets. The aim of this study was to confirm that the T-cell IL-17 response in dogs is evolutionarily conserved. Canine peripheral blood mononuclear cells were stimulated with Concanavalin A with or without polarizing cytokines. We used a canine specific IL-17 ELISA and flow cytometry to identify IL-17-producing T cells. Accumulation of intracellular IL-17 was observed in stimulated CD4 and CD8 T cells. The addition of pro-inflammatory cytokines appeared to enhance polarization of canine CD4 T cells to the Th17 phenotype. Conversely, the addition of IL-2 in the presence of TGF-β resulted in expansion of Treg cells. We conclude that canine IL-17-producing cells behave similarly to those from humans and mice when stimulated with mitogens and polarized with pro-inflammatory or immune regulatory cytokines.

  18. UV induced photoluminescence and thermally stimulated luminescence of ThO{sub 2}:Tb{sup 3+} phosphor

    Godbole, S.V.; Nagpal, J.S.; Page, A.G. E-mail: agpage@magnum.barc.ernet.in

    2000-08-15

    Thorium oxide doped with trivalent terbium ions offers itself as a novel phosphor with its photo- and thermally-stimulated luminescence (PL and TSL) characteristics showing a marked change on sustained exposure to 254 and 365 nm ultraviolet (UV) radiation. The reduction in luminescence intensity of Tb{sup 3+} ions, on irradiation with 254 nm photons and subsequent restoration on exposure to 365 nm, has been correlated with the complimentary behaviour in UV-induced TSL. These changes are, in turn, ascribed to inter-configurational (f-d) transitions and e-h formation and recombination processes. UV radiation induced TSL output increases linearly with incident UV radiant energy at a constant radiation flux; however, for a fixed exposure, TSL output increases with increase in radiant flux.

  19. Repetitive Transcranial Direct Current Stimulation Induced Excitability Changes of Primary Visual Cortex and Visual Learning Effects-A Pilot Study.

    Sczesny-Kaiser, Matthias; Beckhaus, Katharina; Dinse, Hubert R; Schwenkreis, Peter; Tegenthoff, Martin; Höffken, Oliver

    2016-01-01

    Studies on noninvasive motor cortex stimulation and motor learning demonstrated cortical excitability as a marker for a learning effect. Transcranial direct current stimulation (tDCS) is a non-invasive tool to modulate cortical excitability. It is as yet unknown how tDCS-induced excitability changes and perceptual learning in visual cortex correlate. Our study aimed to examine the influence of tDCS on visual perceptual learning in healthy humans. Additionally, we measured excitability in primary visual cortex (V1). We hypothesized that anodal tDCS would improve and cathodal tDCS would have minor or no effects on visual learning. Anodal, cathodal or sham tDCS were applied over V1 in a randomized, double-blinded design over four consecutive days (n = 30). During 20 min of tDCS, subjects had to learn a visual orientation-discrimination task (ODT). Excitability parameters were measured by analyzing paired-stimulation behavior of visual-evoked potentials (ps-VEP) and by measuring phosphene thresholds (PTs) before and after the stimulation period of 4 days. Compared with sham-tDCS, anodal tDCS led to an improvement of visual discrimination learning (p learning effect. For cathodal tDCS, no significant effects on learning or on excitability could be seen. Our results showed that anodal tDCS over V1 resulted in improved visual perceptual learning and increased cortical excitability. tDCS is a promising tool to alter V1 excitability and, hence, perceptual visual learning.

  20. Differences in motor evoked potentials induced in rats by transcranial magnetic stimulation under two separate anesthetics: implications for plasticity studies

    Matthew Sykes

    2016-10-01

    Full Text Available Repetitive transcranial magnetic stimulation (rTMS is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS, a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when

  1. Differences in Motor Evoked Potentials Induced in Rats by Transcranial Magnetic Stimulation under Two Separate Anesthetics: Implications for Plasticity Studies.

    Sykes, Matthew; Matheson, Natalie A; Brownjohn, Philip W; Tang, Alexander D; Rodger, Jennifer; Shemmell, Jonathan B H; Reynolds, John N J

    2016-01-01

    Repetitive transcranial magnetic stimulation (rTMS) is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs) are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however, results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS), a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when selecting an

  2. Local muscle metabolic demand induced by neuromuscular electrical stimulation and voluntary contractions at different force levels: a NIRS study

    Makii Muthalib

    2016-06-01

    Full Text Available Functional Muscle metabolic demand during contractions evoked by neuromuscular electrical stimulation (NMES has been consistently documented to be greater than voluntary contractions (VOL at the same force level (10-50% maximal voluntary contraction-MVC. However, we have shown using a near-infrared spectroscopy (NIRS technique that local muscle metabolic demand is similar between NMES and VOL performed at MVC levels, thus controversy exists. This study therefore compared biceps brachii muscle metabolic demand (tissue oxygenation index-TOI and total hemoglobin volume-tHb during a 10s isometric contraction of the elbow flexors between NMES (stimulation frequency of 30Hz and current level to evoke 30% MVC and VOL at 30% MVC (VOL-30%MVC and MVC (VOL-MVC level in 8 healthy men (23-33-y. Greater changes in TOI and tHb induced by NMES than VOL-30%MVC confirm previous studies of a greater local metabolic demand for NMES than VOL at the same force level. The same TOI and tHb changes for NMES and VOL-MVC suggest that local muscle metabolic demand and intramuscular pressure were similar between conditions. In conclusion, these findings indicate that NMES induce a similar local muscle metabolic demand as that of maximal VOL.

  3. Local Muscle Metabolic Demand Induced by Neuromuscular Electrical Stimulation and Voluntary Contractions at Different Force Levels: A NIRS Study.

    Muthalib, Makii; Kerr, Graham; Nosaka, Kazunori; Perrey, Stephane

    2016-06-13

    Functional Muscle metabolic demand during contractions evoked by neuromuscular electrical stimulation (NMES) has been consistently documented to be greater than voluntary contractions (VOL) at the same force level (10-50% maximal voluntary contraction-MVC). However, we have shown using a near-infrared spectroscopy (NIRS) technique that local muscle metabolic demand is similar between NMES and VOL performed at MVC levels, thus controversy exists. This study therefore compared biceps brachii muscle metabolic demand (tissue oxygenation index-TOI and total hemoglobin volume-tHb) during a 10s isometric contraction of the elbow flexors between NMES (stimulation frequency of 30Hz and current level to evoke 30% MVC) and VOL at 30% MVC (VOL-30%MVC) and MVC (VOL-MVC) level in 8 healthy men (23-33-y). Greater changes in TOI and tHb induced by NMES than VOL-30%MVC confirm previous studies of a greater local metabolic demand for NMES than VOL at the same force level. The same TOI and tHb changes for NMES and VOL-MVC suggest that local muscle metabolic demand and intramuscular pressure were similar between conditions. In conclusion, these findings indicate that NMES induce a similar local muscle metabolic demand as that of maximal VOL.

  4. Smoking cessation induced by deep repetitive transcranial magnetic stimulation of the prefrontal and insular cortices: a prospective, randomized controlled trial.

    Dinur-Klein, Limor; Dannon, Pinhas; Hadar, Aviad; Rosenberg, Oded; Roth, Yiftach; Kotler, Moshe; Zangen, Abraham

    2014-11-01

    Tobacco smoking is the leading cause of preventable death in developed countries. Our previous studies in animal models and humans suggest that repeated activation of cue-induced craving networks followed by electromagnetic stimulation of the dorsal prefrontal cortex (PFC) can cause lasting reductions in drug craving and consumption. We hypothesized that disruption of these circuitries by deep transcranial magnetic stimulation (TMS) of the PFC and insula bilaterally can induce smoking cessation. Adults (N = 115) who smoke at least 20 cigarettes/day and failed previous treatments were recruited from the general population. Participants were randomized to receive 13 daily sessions of high-frequency, low-frequency or sham stimulation following, or without, presentation of smoking cues. Deep TMS was administered using an H-coil version targeting the lateral PFC and insula bilaterally. Cigarette consumption was evaluated during the treatment by measuring cotinine levels in urine samples and recording participants' self-reports as a primary outcome variable. Dependence and craving were assessed using standardized questionnaires. High (but not low) frequency deep TMS treatment significantly reduced cigarette consumption and nicotine dependence. The combination of this treatment with exposure to smoking cues enhanced reduction in cigarette consumption leading to an abstinence rate of 44% at the end of the treatment and an estimated 33% 6 months following the treatment. This study further implicates the lateral PFC and insula in nicotine addiction and suggests the use of deep high-frequency TMS of these regions following presentation of smoking cues as a promising treatment strategy. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. Theta-burst stimulation-induced plasticity over primary somatosensory cortex changes somatosensory temporal discrimination in healthy humans.

    Antonella Conte

    Full Text Available BACKGROUND: The somatosensory temporal discrimination threshold (STDT measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols. METHODOLOGY/PRINCIPAL FINDINGS: To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS on the right primary somatosensory area (S1, pre-supplementary motor area (pre-SMA, right dorsolateral prefrontal cortex (DLPFC and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli. CONCLUSIONS/SIGNIFICANCE: Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson's disease.

  6. Theta-Burst Stimulation-Induced Plasticity over Primary Somatosensory Cortex Changes Somatosensory Temporal Discrimination in Healthy Humans

    Conte, Antonella; Rocchi, Lorenzo; Nardella, Andrea; Dispenza, Sabrina; Scontrini, Alessandra; Khan, Nashaba; Berardelli, Alfredo

    2012-01-01

    Background The somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Precisely how the single cerebral structures contribute in controlling the STDT is partially known and no information is available about whether STDT can be modulated by plasticity-inducing protocols. Methodology/Principal Findings To investigate how the cortical and cerebellar areas contribute to the STDT we used transcranial magnetic stimulation and a neuronavigation system. We enrolled 18 healthy volunteers and 10 of these completed all the experimental sessions, including the control experiments. STDT was measured on the left hand before and after applying continuous theta-burst stimulation (cTBS) on the right primary somatosensory area (S1), pre-supplementary motor area (pre-SMA), right dorsolateral prefrontal cortex (DLPFC) and left cerebellar hemisphere. We then investigated whether intermittent theta-burst stimulation (iTBS) on the right S1 improved the STDT. After right S1 cTBS, STDT values increased whereas after iTBS to the same cortical site they decreased. cTBS over the DLPFC and left lateral cerebellum left the STDT statistically unchanged. cTBS over the pre-SMA also left the STDT statistically unchanged, but it increased the number of errors subjects made in distinguishing trials testing a single stimulus and those testing paired stimuli. Conclusions/Significance Our findings obtained by applying TBS to the cortical areas involved in processing sensory discrimination show that the STDT is encoded in S1, possibly depends on intrinsic S1 neural circuit properties, and can be modulated by plasticity-inducing TBS protocols delivered over S1. Our findings, giving further insight into mechanisms involved in somatosensory temporal discrimination, help interpret STDT abnormalities in movement disorders including dystonia and Parkinson's disease. PMID:22412964

  7. Transcutaneous spinal direct current stimulation induces lasting fatigue resistance and enhances explosive vertical jump performance

    Tate, Rothwelle J.; Conway, Bernard A.

    2017-01-01

    Transcutaneous spinal direct current stimulation (tsDCS) is a non-invasive neuromodulatory intervention that has been shown to modify excitability in spinal and supraspinal circuits in animals and humans. Our objective in this study was to explore the functional neuromodulatory potential of tsDCS by examining its immediate and lasting effects over the repeated performance of a whole body maximal exercise in healthy volunteers. Using a double-blind, randomized, crossover, sham-controlled design we investigated the effects of 15 min of anodal tsDCS on repeated vertical countermovement jump (VCJ) performance at 0, 20, 60, and 180 minutes post-stimulation. Measurements of peak and take-off velocity, vertical displacement, peak power and work done during countermovement and push-off VCJ phases were derived from changes in vertical ground reaction force (12 performance parameters) in 12 healthy participants. The magnitude and direction of change in VCJ performance from pre- to post-stimulation differed significantly between sham and active tsDCS for 7 of the 12 VCJ performance measures (P 0.05). Our original findings demonstrate that one single session of anodal tsDCS in healthy subjects can prevent fatigue and maintain or enhance different aspects of whole body explosive motor power over repeated sets of VCJs performed over a period of three hours. The observed effects are discussed in relation to alterations in central fatigue mechanisms, muscle contraction mode during jump execution and changes in spinal cord excitability. These findings have important implications for power endurance sport performance and for neuromotor rehabilitation. PMID:28379980

  8. Transcutaneous spinal direct current stimulation induces lasting fatigue resistance and enhances explosive vertical jump performance.

    Helen R Berry

    Full Text Available Transcutaneous spinal direct current stimulation (tsDCS is a non-invasive neuromodulatory intervention that has been shown to modify excitability in spinal and supraspinal circuits in animals and humans. Our objective in this study was to explore the functional neuromodulatory potential of tsDCS by examining its immediate and lasting effects over the repeated performance of a whole body maximal exercise in healthy volunteers. Using a double-blind, randomized, crossover, sham-controlled design we investigated the effects of 15 min of anodal tsDCS on repeated vertical countermovement jump (VCJ performance at 0, 20, 60, and 180 minutes post-stimulation. Measurements of peak and take-off velocity, vertical displacement, peak power and work done during countermovement and push-off VCJ phases were derived from changes in vertical ground reaction force (12 performance parameters in 12 healthy participants. The magnitude and direction of change in VCJ performance from pre- to post-stimulation differed significantly between sham and active tsDCS for 7 of the 12 VCJ performance measures (P 0.05. Our original findings demonstrate that one single session of anodal tsDCS in healthy subjects can prevent fatigue and maintain or enhance different aspects of whole body explosive motor power over repeated sets of VCJs performed over a period of three hours. The observed effects are discussed in relation to alterations in central fatigue mechanisms, muscle contraction mode during jump execution and changes in spinal cord excitability. These findings have important implications for power endurance sport performance and for neuromotor rehabilitation.

  9. Detailed 3D models of the induced electric field of transcranial magnetic stimulation coils

    Salinas, F S; Lancaster, J L; Fox, P T

    2007-01-01

    Previous models neglected contributions from current elements spanning the full geometric extent of wires in transcranial magnetic stimulation (TMS) coils. A detailed account of TMS coil wiring geometry is shown to provide significant improvements in the accuracy of electric field (E-field) models. Modeling E-field dependence based on the TMS coil's wire width, height, shape and number of turns clearly improved the fit of calculated-to-measured E-fields near the coil body. Detailed E-field models were accurate up to the surface of the coil body (within 0.5% of measured) where simple models were often inadequate (up to 32% different from measured)

  10. Cortical deactivation induced by visual stimulation in human slow-wave sleep

    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. It is unreso...... that this decrease was secondary to a relative rCBF decrease. Possible mechanisms for the paradoxical response pattern during sleep include an active inhibition of the visual cortex or a disruption of an energy-consuming process...

  11. Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions.

    Arnt, J

    1985-08-26

    The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.

  12. Macrophage-stimulating protein attenuates gentamicin-induced inflammation and apoptosis in human renal proximal tubular epithelial cells

    Lee, Ko Eun [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Eun Young [Department of Physiology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Chang Seong; Choi, Joon Seok; Bae, Eun Hui; Ma, Seong Kwon [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Kyung Keun [Department of Pharmacology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Lee, Jong Un [Department of Physiology, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of); Kim, Soo Wan, E-mail: skimw@chonnam.ac.kr [Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757 (Korea, Republic of)

    2013-05-10

    Highlights: •MSP/RON system is activated in rat kidney damaged by gentamicin. •MSP inhibits GM-induced cellular apoptosis and inflammation in HK-2 cells. •MSP attenuates GM-induced activation of MAPKs and NF-κB pathways in HK-2 cells. -- Abstract: The present study aimed to investigate whether macrophage-stimulating protein (MSP) treatment attenuates renal apoptosis and inflammation in gentamicin (GM)-induced tubule injury and its underlying molecular mechanisms. To examine changes in MSP and its receptor, recepteur d’origine nantais (RON) in GM-induced nephropathy, rats were injected with GM for 7 days. Human renal proximal tubular epithelial (HK-2) cells were incubated with GM for 24 h in the presence of different concentrations of MSP and cell viability was measured by MTT assay. Apoptosis was determined by flow cytometry of cells stained with fluorescein isothiocyanate-conjugated annexin V protein and propidium iodide. Expression of Bcl-2, Bax, caspase-3, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-κB), IκB-α, and mitogen-activated protein kinases (MAPKs) was analyzed by semiquantitative immunoblotting. MSP and RON expression was significantly greater in GM-treated rats, than in untreated controls. GM-treatment reduced HK-2 cell viability, an effect that was counteracted by MSP. Flow cytometry and DAPI staining revealed GM-induced apoptosis was prevented by MSP. GM reduced expression of anti-apoptotic protein Bcl-2 and induced expression of Bax and cleaved caspase 3; these effects and GM-induced expression of COX-2 and iNOS were also attenuated by MSP. GM caused MSP-reversible induction of phospho-ERK, phospho-JNK, and phospho-p38. GM induced NF-κB activation and degradation of IκB-α; the increase in nuclear NF-κB was blocked by inhibitors of ERK, JNK, p-38, or MSP pretreatment. These findings suggest that MSP attenuates GM-induced inflammation and apoptosis by inhibition of the MAPKs

  13. Phencyclidine-Induced Social Withdrawal Results from Deficient Stimulation of Cannabinoid CB1 Receptors: Implications for Schizophrenia

    Seillier, Alexandre; Martinez, Alex A; Giuffrida, Andrea

    2013-01-01

    The neuronal mechanisms underlying social withdrawal, one of the core negative symptoms of schizophrenia, are not well understood. Recent studies suggest an involvement of the endocannabinoid system in the pathophysiology of schizophrenia and, in particular, of negative symptoms. We used biochemical, pharmacological, and behavioral approaches to investigate the role played by the endocannabinoid system in social withdrawal induced by sub-chronic administration of phencyclidine (PCP). Pharmacological enhancement of endocannabinoid levels via systemic administration of URB597, an inhibitor of endocannabinoid degradation, reversed social withdrawal in PCP-treated rats via stimulation of CB1 receptors, but reduced social interaction in control animals through activation of a cannabinoid/vanilloid-sensitive receptor. In addition, the potent CB agonist CP55,940 reversed PCP-induced social withdrawal in a CB1-dependent manner, whereas pharmacological blockade of CB1 receptors by either AM251 or SR141716 reduced the time spent in social interaction in control animals. PCP-induced social withdrawal was accompanied by a decrease of anandamide (AEA) levels in the amygdala and prefrontal cortex, and these deficits were reversed by URB597. As CB1 receptors are predominantly expressed on GABAergic interneurons containing the anxiogenic peptide cholecystokinin (CCK), we also examined whether the PCP-induced social withdrawal resulted from deficient CB1-mediated modulation of CCK transmission. The selective CCK2 antagonist LY225910 blocked both PCP- and AM251-induced social withdrawal, but not URB597 effect in control rats. Taken together, these findings indicate that AEA-mediated activation of CB1 receptors is crucial for social interaction, and that PCP-induced social withdrawal results from deficient endocannabinoid transmission. PMID:23563893

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

    Ryu, T.; Davis, J.M.; Schwartz, K.A.

    1990-01-01

    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

  15. Uniform decrease of alpha-global field power induced by intermittent photic stimulation of healthy subjects

    Rau R.

    2002-01-01

    Full Text Available Nineteen-channel EEGs were recorded from the scalp surface of 30 healthy subjects (16 males and 14 females, mean age: 34 years, SD: 11.7 years at rest and under trains of intermittent photic stimulation (IPS at rates of 5, 10 and 20 Hz. Digitalized data were submitted to spectral analysis with fast fourier transformation providing the basis for the computation of global field power (GFP. For quantification, GFP values in the frequency ranges of 5, 10 and 20 Hz at rest were divided by the corresponding data obtained under IPS. All subjects showed a photic driving effect at each rate of stimulation. GFP data were normally distributed, whereas ratios from photic driving effect data showed no uniform behavior due to high interindividual variability. Suppression of alpha-power after IPS with 10 Hz was observed in about 70% of the volunteers. In contrast, ratios of alpha-power were unequivocal in all subjects: IPS at 20 Hz always led to a suppression of alpha-power. Dividing alpha-GFP with 20-Hz IPS by alpha-GFP at rest (R = alpha-GFP IPS/alpha-GFPrest thus resulted in ratios lower than 1. We conclude that ratios from GFP data with 20-Hz IPS may provide a suitable paradigm for further investigations.

  16. Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.

    El-Bizri, Nesrine; Bkaily, Ghassan; Wang, Shimin; Jacques, Danielle; Regoli, Domenico; D'Orléans-Juste, Pedro; Sukarieh, Rami

    2003-03-01

    Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.

  17. SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice.

    Kolodziej, Angela; Lippert, Michael; Angenstein, Frank; Neubert, Jenni; Pethe, Annette; Grosser, Oliver S; Amthauer, Holger; Schroeder, Ulrich H; Reymann, Klaus G; Scheich, Henning; Ohl, Frank W; Goldschmidt, Jürgen

    2014-12-01

    Electrical and optogenetic methods for brain stimulation are widely used in rodents for manipulating behavior and analyzing functional connectivities in neuronal circuits. High-resolution in vivo imaging of the global, brain-wide, activation patterns induced by these stimulations has remained challenging, in particular in awake behaving mice. We here mapped brain activation patterns in awake, intracranially self-stimulating mice using a novel protocol for single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (rCBF). Mice were implanted with either electrodes for electrical stimulation of the medial forebrain bundle (mfb-microstim) or with optical fibers for blue-light stimulation of channelrhodopsin-2 expressing neurons in the ventral tegmental area (vta-optostim). After training for self-stimulation by current or light application, respectively, mice were implanted with jugular vein catheters and intravenously injected with the flow tracer 99m-technetium hexamethylpropyleneamine oxime (99mTc-HMPAO) during seven to ten minutes of intracranial self-stimulation or ongoing behavior without stimulation. The 99mTc-brain distributions were mapped in anesthetized animals after stimulation using multipinhole SPECT. Upon self-stimulation rCBF strongly increased at the electrode tip in mfb-microstim mice. In vta-optostim mice peak activations were found outside the stimulation site. Partly overlapping brain-wide networks of activations and deactivations were found in both groups. When testing all self-stimulating mice against all controls highly significant activations were found in the rostromedial nucleus accumbens shell. SPECT-imaging of rCBF using intravenous tracer-injection during ongoing behavior is a new tool for imaging regional brain activation patterns in awake behaving rodents providing higher spatial and temporal resolutions than 18F-2-fluoro-2-dexoyglucose positron emission tomography. Copyright © 2014 The Authors

  18. Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions.

    Nan Li

    Full Text Available Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG. In this study we used mouse embryonic stem (MES and mouse embryonic fibroblast (MEF cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs in Rad9-/- MES and Mdc1-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9-/- MES. As the exposure to SMG was prolonged, Rad9-/- MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9-/- MES were due to SMG-induced reactive oxygen species (ROS. Interestingly, Mdc1-/- MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1-/- MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR defects.

  19. Perceptual Spaces Induced by Cochlear Implant All-Polar Stimulation Mode

    Marozeau, Jeremy; McKay, Colette M

    2016-01-01

    sequentially or simultaneously. The dissimilarity ratings were analyzed using a multidimensional scaling technique and three-dimensional stimulus perceptual spaces were produced. For all the conditions (mode and simultaneity), the first perceptual dimension was highly correlated with the position of the most...... apical activated electrode of the electrical stimulation and the second dimension with the position of the most basal electrode. In both sequential and simultaneous conditions, the monopolar and all-polar stimuli were significantly separated by a third dimension, which may indicate that all-polar stimuli....... It was designed to activate all the electrodes simultaneously with appropriate current levels and polarities to recruit narrower regions of auditory nerves at specific intracochlear electrode positions (denoted all-polar electrodes). In this study, the all-polar mode was compared with the current commercial...

  20. Six-hydroxydopamine induced hyperactivity: neither sex differences nor caffeine stimulation are found.

    Erinoff, L; Kelly, P H; Basura, M; Snodgrass, S R

    1984-05-01

    We investigated possible sex differences in the development of locomotor activity in rats treated neonatally with desmethylimipramine (DMI) followed by intraventricular 6-hydroxydopamine (6-HDA). In addition, the locomotor response to the stimulant caffeine was investigated in the male rats after they had reached adulthood. Both male and female 6-HDA-treated rats exhibited increased activity relative to controls. No sex differences were seen in either the development or magnitude of this effect. Male rats were used to determine the dose effects function for caffeine (0.5, 5, 15, 30 mg/kg) on locomotor activity. Control rats exhibited increased locomotor activity whereas 6-HDA-treated rats showed no increases with any dose of caffeine. Large decreases in the dopamine content of the olfactory tubercle (-88%, -82%), nucleus accumbens (-96%, -95%), and striatum (-99%, -99%) were found in both male and female rats. Choline acetyltransferase and glutamic acid decarboxylase activities were unchanged.

  1. Detailed 3D models of the induced electric field of transcranial magnetic stimulation coils

    Salinas, F S; Lancaster, J L; Fox, P T [Research Imaging Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 (United States)

    2007-05-21

    Previous models neglected contributions from current elements spanning the full geometric extent of wires in transcranial magnetic stimulation (TMS) coils. A detailed account of TMS coil wiring geometry is shown to provide significant improvements in the accuracy of electric field (E-field) models. Modeling E-field dependence based on the TMS coil's wire width, height, shape and number of turns clearly improved the fit of calculated-to-measured E-fields near the coil body. Detailed E-field models were accurate up to the surface of the coil body (within 0.5% of measured) where simple models were often inadequate (up to 32% different from measured)

  2. Preheat-induced signal enhancement in the infrared stimulated luminescence of young and bleached sediment samples

    Richardson, C.A.

    2000-01-01

    Natural and laboratory bleached surface and young samples of potassium feldspar sand separates and polymineral silt had their infrared stimulated luminescence (IRSL) signal measured before and after preheating at 220 deg. C for 10 min or 160 deg. C for 16 h. For both preheats, the laboratory bleached sand samples underwent a signal enhancement which was stable with laboratory storage. The youngest samples also showed natural signal enhancement. The silt sample showed no recuperation of bleached signal on preheating, but some in the natural signal. A range of filtered bleaches was applied to one surface sand sample. Signal levels before and after preheating were reduced by filtering out the UV from the bleaching spectrum. The unfiltered bleach, however, most closely reproduced the behaviour of the natural sample

  3. Use of lectin-induced lymphocyte stimulation as a biodosimeter of radiation damage

    Shifrine, M.; Taylor, N.J.; DeRock, E.W.; Wiger, N.; Wilson, F.D.

    1979-01-01

    The purpose of this study was to determine the feasibility of utilizing an in vitro test to determine whether an individual has suffered radiation damage. It was not our purpose to develop a test capable of detecting low doses but rather to determine possible damage due to a radiation accident at medium to high doses. In a pilot study using the whole blood lymphocyte stimulation test (WB/LST), we pretested six dogs weekly for three weeks. One was sham irradiated and is referred to as the control and one each received an acute whole body dose of 10, 25, 50, 75, or 100 R. The dogs were tested one day post-irradiation and then weekly for 56 days. Our data indicate that, using Con-A and PHA in the WB/LST, a biodosimeter can be developed to determine recovery of lymphocyte function after suspected radiation exposure to confirm accidental radiation and estimate the magnitude of the dose

  4. Macrophage colony-stimulating factor induces prolactin expression in rat pituitary gland.

    Hoshino, Satoya; Kurotani, Reiko; Miyano, Yuki; Sakahara, Satoshi; Koike, Kanako; Maruyama, Minoru; Ishikawa, Fumio; Sakatai, Ichiro; Abe, Hiroyuki; Sakai, Takafumi

    2014-06-01

    We investigated the role of macrophage colony-stimulating factor (M-CSF) in the pituitary gland to understand the effect of M-CSF on pituitary hormones and the relationship between the endocrine and immune systems. When we attempted to establish pituitary cell lines from a thyrotropic pituitary tumor (TtT), a macrophage cell line, TtT/M-87, was established. We evaluated M-CSF-like activity in conditioned media (CM) from seven pituitary cell lines using TtT/M-87 cells. TtT/M-87 proliferation significantly increased in the presence of CM from TtT/GF cells, a pituitary folliculostellate (FS) cell line. M-CSF mRNA was detected in TtT/GF and MtT/E cells by reverse transcriptase-polymerase chain reaction (RT-PCR), and its expression in TtT/GF cells was increased in a lipopolysaccharide (LPS) dose-dependent manner. M-CSF mRNA expression was also increased in rat anterior pituitary glands by LPS. M-CSF receptor (M-CSFR) mRNA was only detected in TtT/ M-87 cells and increased in the LPS-stimulated rat pituitary glands. In rat pituitary glands, M-CSF and M-CSFR were found to be localized in FS cells and prolactin (PRL)-secreting cells, respectively, by immunohistochemistry. The PRL concentration in rat sera was significantly increased at 24 h after M-CSF administration, and mRNA levels significantly increased in primary culture cells of rat anterior pituitary glands. In addition, TNF-α mRNA was increased in the primary culture cells by M-CSF. These results revealed that M-CSF was secreted from FS cells and M-CSF regulated PRL expression in rat pituitary glands.

  5. Selective insecticide-induced stimulation on fecundity and biochemical changes in Tryporyza incertulas (Lepidoptera: Pyralidae).

    Wang, Ai-Hua; Wu, Jin-Cai; Yu, Yue-Shu; Liu, Jing-Lan; Yue, Jiang-Fei; Wang, Mei-Yue

    2005-08-01

    The use of selective insecticides in rice, Oryza sativa L., fields often causes resurgence of nontarget pest insects. This study was conducted to investigate the effect of two selective insecticides, buprofezin and imidacloprid, on Tryporyza incertulas (Walker), a nontarget pest. After larval feeding on rice plants treated with each insecticide, fecundity, ovary protein content, and titer of juvenile hormone III (JHIII) in the resulting female moths were determined with 'Xiushui 63' rice susceptible to T. incertulas and 'Zhendao 2' moderately resistant to T. incertulas. The fecundity of females developed from larvae that fed on the insecticide-treated Xiushui 63 plants was stimulated compared with that of moths from larvae that fed on rice plants that were not treated with either insecticide. There was no stimulating effect in females from larvae that fed on insecticide-treated Zhendao 2 plants. The weight of fourth instars (final instars) that fed on the insecticide-treated Xiushui 63 rice plants was significantly greater than that of control, increasing by 50.3 and 46.7% for 60 and 112.5 g (AI) ha(-1) buprofezin, and by 23.7 and 19.5% for 15 and 37.5 g (AI) ha(-1) imidacloprid treatments, respectively. Ovary protein content in adult females developed from larvae that fed on the rice treated with the high dose of buprofezin was significantly higher than that in control. For the high and low doses of imidacloprid during the second instar, and the low dose of imidacloprid during the fourth instar, JHIII titers in female adults were also significantly higher than that in control, increasing by 152.81, 90.52, and 114.19%, respectively.

  6. Synergistic effect of combined transcranial direct current stimulation/constraint-induced movement therapy in children and young adults with hemiparesis: study protocol.

    Gillick, Bernadette; Menk, Jeremiah; Mueller, Bryon; Meekins, Gregg; Krach, Linda E; Feyma, Timothy; Rudser, Kyle

    2015-11-12

    Perinatal stroke occurs in more than 1 in 2,500 live births and resultant congenital hemiparesis necessitates investigation into interventions which may improve long-term function and decreased burden of care beyond current therapies ( http://www.cdc.gov/ncbddd/cp/data.html ). Constraint-Induced Movement Therapy (CIMT) is recognized as an effective hemiparesis rehabilitation intervention. Transcranial direct current stimulation as an adjunct treatment to CIMT may potentiate neuroplastic responses and improve motor function. The methodology of a clinical trial in children designed as a placebo-controlled, serial -session, non-invasive brain stimulation trial incorporating CIMT is described here. The primary hypotheses are 1) that no serious adverse events will occur in children receiving non-invasive brain stimulation and 2) that children in the stimulation intervention group will show significant improvements in hand motor function compared to children in the placebo stimulation control group. A randomized, controlled, double-blinded clinical trial. Twenty children and/or young adults (ages 8-21) with congenital hemiparesis, will be enrolled. The intervention group will receive ten 2-hour sessions of transcranial direct current stimulation combined with constraint-induced movement therapy and the control group will receive sham stimulation with CIMT. The primary outcome measure is safety assessment of transcranial direct current stimulation by physician evaluation, vital sign monitoring and symptom reports. Additionally, hand function will be evaluated using the Assisting Hand Assessment, grip strength and assessment of goals using the Canadian Occupational Performance Measure. Neuroimaging will confirm diagnoses, corticospinal tract integrity and cortical activation. Motor cortical excitability will also be examined using transcranial magnetic stimulation techniques. Combining non-invasive brain stimulation and CIMT interventions has the potential to improve motor

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

    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.

  8. Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

    Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

    2010-09-01

    Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

  9. Effects of transcranial focal electrical stimulation via tripolar concentric ring electrodes on pentylenetetrazole-induced seizures in rats.

    Besio, W G; Makeyev, O; Medvedev, A; Gale, K

    2013-07-01

    To study the effects of noninvasive transcranial focal electrical stimulation (TFS) via tripolar concentric ring electrodes (TCRE) on the electrographic and behavioral activity from pentylenetetrazole (PTZ)-induced seizures in rats. The TCREs were attached to the rat scalp. PTZ was administered and, after the first myoclonic jerk was observed, TFS was applied to the TFS treated group. The electroencephalogram (EEG) and behavioral activity were recorded and studied. In the case of the TFS treated group, after TFS, there was a significant (p=0.001) decrease in power compared to the control group in delta, theta, and alpha frequency bands. The number of myoclonic jerks was significantly different (p=0.002) with median of 22 and 4.5 for the control group and the TFS treated groups, respectively. The duration of myoclonic activity was also significantly different (p=0.031) with median of 17.56 min for the control group versus 8.63 min for the TFS treated group. At the same time there was no significant difference in seizure onset latency and maximal behavioral seizure activity score between control and TFS treated groups. TFS via TCREs interrupted PTZ-induced seizures and electrographic activity was reduced toward the "baseline." The significantly reduced electrographic power, number of myoclonic jerks, and duration of myoclonic activity of PTZ-induced seizures suggests that TFS may have an anticonvulsant effect. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. Low-frequency stimulation cancels the high-frequency-induced long-lasting effects in the rat medial vestibular nuclei.

    Grassi, S; Pettorossi, V E; Zampolini, M

    1996-05-15

    In rat brainstem slices, we investigated the effects of low-frequency stimulation (LFS) of the primary vestibular afferents on the amplitude of the field potentials evoked in the medial vestibular nuclei (MVN). LFS induced long-term effects, the sign of which depended on whether the vestibular neurons were previously conditioned by HFS. In unconditioned slices, LFS evoked modifications of the responses that were similar to those observed after HFS but had a smaller extension. In fact, LFS caused long-lasting potentiation of the N1 wave in the MVN ventral portion (Vp) and long-lasting depression of the N2 wave in the MVN dorsal portion (Dp), whereas it provoked small and variable effects on the N1 wave. By contrast, when the synaptic transmission was already conditioned, LFS influenced the synaptic responses oppositely, reducing or annulling the HFS long-term effects. This phenomenon was specifically induced by LFS, because HFS was not able to cause it. The involvement of NMDA receptors in mediating the LFS long-term effects was supported by the fact that AP-5 prevented their induction. In addition, the annulment of HFS long-term effects by LFS was also demonstrated by the shift in the latency of the evoked unitary potentials after LFS. In conclusion, we suggest that the reduction of the previously induced conditioning could represent a cancellation mechanism, useful to quickly adapt the vestibular system to continuous different needs and to avoid saturation.

  11. Synthetic tactile perception induced by transcranial alternating-current stimulation can substitute for natural sensory stimulus in behaving rabbits.

    Márquez-Ruiz, Javier; Ammann, Claudia; Leal-Campanario, Rocío; Ruffini, Giulio; Gruart, Agnès; Delgado-García, José M

    2016-01-21

    The use of brain-derived signals for controlling external devices has long attracted the attention from neuroscientists and engineers during last decades. Although much effort has been dedicated to establishing effective brain-to-computer communication, computer-to-brain communication feedback for "closing the loop" is now becoming a major research theme. While intracortical microstimulation of the sensory cortex has already been successfully used for this purpose, its future application in humans partly relies on the use of non-invasive brain stimulation technologies. In the present study, we explore the potential use of transcranial alternating-current stimulation (tACS) for synthetic tactile perception in alert behaving animals. More specifically, we determined the effects of tACS on sensory local field potentials (LFPs) and motor output and tested its capability for inducing tactile perception using classical eyeblink conditioning in the behaving animal. We demonstrated that tACS of the primary somatosensory cortex vibrissa area could indeed substitute natural stimuli during training in the associative learning paradigm.

  12. Rac-mediated Stimulation of Phospholipase Cγ2 Amplifies B Cell Receptor-induced Calcium Signaling*♦

    Walliser, Claudia; Tron, Kyrylo; Clauss, Karen; Gutman, Orit; Kobitski, Andrei Yu.; Retlich, Michael; Schade, Anja; Röcker, Carlheinz; Henis, Yoav I.; Nienhaus, G. Ulrich; Gierschik, Peter

    2015-01-01

    The Rho GTPase Rac is crucially involved in controlling multiple B cell functions, including those regulated by the B cell receptor (BCR) through increased cytosolic Ca2+. The underlying molecular mechanisms and their relevance to the functions of intact B cells have thus far remained unknown. We have previously shown that the activity of phospholipase Cγ2 (PLCγ2), a key constituent of the BCR signalosome, is stimulated by activated Rac through direct protein-protein interaction. Here, we use a Rac-resistant mutant of PLCγ2 to functionally reconstitute cultured PLCγ2-deficient DT40 B cells and to examine the effects of the Rac-PLCγ2 interaction on BCR-mediated changes of intracellular Ca2+ and regulation of Ca2+-regulated and nuclear-factor-of-activated-T-cell-regulated gene transcription at the level of single, intact B cells. The results show that the functional Rac-PLCγ2 interaction causes marked increases in the following: (i) sensitivity of B cells to BCR ligation; (ii) BCR-mediated Ca2+ release from intracellular stores; (iii) Ca2+ entry from the extracellular compartment; and (iv) nuclear translocation of the Ca2+-regulated nuclear factor of activated T cells. Hence, Rac-mediated stimulation of PLCγ2 activity serves to amplify B cell receptor-induced Ca2+ signaling. PMID:25903139

  13. The Effect of Variation in Permittivity of Different Tissues on Induced Electric Field in the Brain during Transcranial Magnetic Stimulation

    Hadimani, Ravi; Porzig, Konstantin; Crowther, Lawrence; Brauer, Hartmut; Toepfer, Hannes; Jiles, David; Department of Electrical and Computer Engineering, Iowa State University Team; Department of Advanced Electromagnetics, Ilmenau University of Technology Team

    2013-03-01

    Estimation of electric field in the brain during Transcranial Magnetic Stimulation (TMS) requires knowledge of the electric property of brain tissue. Grey and white matters have unusually high relative permittivities of ~ 106 at low frequencies. However, relative permittivity of cerebrospinal fluid is ~ 102. With such a variation it is necessary to consider the effect of boundaries. A model consisting of 2 hemispheres was used in the model with the properties of one hemisphere kept constant at σ1 = 0.1Sm-1 and ɛr 1 = 10 while the properties of the second hemisphere were changed kept at σ2 = 0.1Sm-1 to 2Sm-1 and ɛr 2 = 102 to 105. A 70 mm diameter double coil was used as the source of the magnetic field. The amplitude of the current in the coil was 5488 A at a frequency of 2.9 kHz. The results show that the electric field, E induced during magnetic stimulation is independent of the relative permittivity, ɛr and varies with the conductivity. Thus the variation in E, calculated with homogeneous and heterogeneous head models was due to variation in conductivity of the tissues and not due to variation in permittivities.

  14. Sleep deprivation prevents stimulation-induced increases of levels of P-CREB and BDNF: protection by caffeine.

    Alhaider, Ibrahim A; Aleisa, Abdulaziz M; Tran, Trinh T; Alkadhi, Karim A

    2011-04-01

    It is well known that caffeine and sleep deprivation have opposing effects on learning and memory; therefore, this study was undertaken to determine the effects of chronic (4wks) caffeine treatment (0.3g/l in drinking water) on long-term memory deficit associated with 24h sleep deprivation. Animals were sleep deprived using the modified multiple platform method. The results showed that chronic caffeine treatment prevented the impairment of long-term memory as measured by performance in the radial arm water maze task and normalized L-LTP in area CA1 of the hippocampi of sleep-deprived anesthetized rats. Sleep deprivation prevents the high frequency stimulation-induced increases in the levels of phosphorylated-cAMP response element binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF) seen during the expression of late phase long-term potentiation (L-LTP). However, chronic caffeine treatment prevented the effect of sleep-deprivation on the stimulated levels of P-CREB and BDNF. The results suggest that chronic caffeine treatment may protect the sleep-deprived brain probably by preserving the levels of P-CREB and BDNF. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Quadri-Pulse Theta Burst Stimulation using Ultra-High Frequency Bursts - A New Protocol to Induce Changes in Cortico-Spinal Excitability in Human Motor Cortex

    Jung, Nikolai H; Gleich, Bernhard; Gattinger, Norbert

    2016-01-01

    Patterned transcranial magnetic stimulation (TMS) such as theta burst stimulation (TBS) or quadri-pulse stimulation (QPS) can induce changes in cortico-spinal excitability, commonly referred to as long-term potentiation (LTP)-like and long-term depression (LTD)-like effects in human motor cortex (M...... of sinusoidal TMS pulses elicited either a posterior-anterior (PA) or anterior-posterior (AP) directed current in M1. Motor evoked potentials (MEPs) were recorded before and after qTBS to probe changes in cortico-spinal excitability. PA-qTBS at 666 Hz caused a decrease in PA-MEP amplitudes, whereas AP...... in cortico-spinal excitability. Induced current direction in the brain appears to be relevant when qTBS targets I-wave periodicity, corroborating that high-fidelity spike timing mechanisms are critical for inducing bi-directional plasticity in human M1....

  16. Dynamic high pressure induced strong and weak hydrogen bonds enhanced by pre-resonance stimulated Raman scattering in liquid water.

    Wang, Shenghan; Fang, Wenhui; Li, Fabing; Gong, Nan; Li, Zhanlong; Li, Zuowei; Sun, Chenglin; Men, Zhiwei

    2017-12-11

    355 nm pulsed laser is employed to excite pre-resonance forward stimulated Raman scattering (FSRS) of liquid water at ambient temperature. Due to the shockwave induced dynamic high pressure, the obtained Raman spectra begin to exhibit double peaks distribution at 3318 and 3373 cm -1 with the input energy of 17 mJ,which correspond with OH stretching vibration with strong and weak hydrogen (H) bonds. With laser energy rising from 17 to 27 mJ, the Stokes line at 3318 cm -1 shifts to 3255 and 3230 cm -1 because of the high pressure being enlarged. When the energy is up to 32 mJ, only 3373 cm -1 peak exists. The strong and weak H bond exhibit quite different energy dependent behaviors.

  17. Ganoderma lucidum stimulates NK cell cytotoxicity by inducing NKG2D/NCR activation and secretion of perforin and granulysin.

    Chang, Chih-Jung; Chen, Yi-Yuan M; Lu, Chia-Chen; Lin, Chuan-Sheng; Martel, Jan; Tsai, Sheng-Hui; Ko, Yun-Fei; Huang, Tsung-Teng; Ojcius, David M; Young, John D; Lai, Hsin-Chih

    2014-04-01

    Ganoderma lucidum (G. lucidum) is a medicinal mushroom long used in Asia as a folk remedy to promote health and longevity. Recent studies indicate that G. lucidum activates NK cells, but the molecular mechanism underlying this effect has not been studied so far. To address this question, we prepared a water extract of G. lucidum and examined its effect on NK cells. We observed that G. lucidum treatment increases NK cell cytotoxicity by stimulating secretion of perforin and granulysin. The mechanism of activation involves an increased expression of NKG2D and natural cytotoxicity receptors (NCRs), as well as increased phosphorylation of intracellular MAPKs. Our results indicate that G. lucidum induces NK cell cytotoxicity against various cancer cell lines by activating NKG2D/NCR receptors and MAPK signaling pathways, which together culminate in exocytosis of perforin and granulysin. These observations provide a cellular and molecular mechanism to account for the reported anticancer effects of G. lucidum extracts in humans.

  18. Two weeks of metformin treatment induces AMPK dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

    Kristensen, Jonas Møller; Treebak, Jonas Thue; Schjerling, Peter

    2014-01-01

    signaling. Methods: Oral doses of metformin or saline treatment were given muscle-specific kinase α2 dead AMPK mice (KD) and wild type (WT) littermates either once or chronically for 2 weeks. Soleus and Extensor Digitorum Longus (EDL) muscles were used for measurements of glucose transport and Western blot......Background: Metformin-induced activation of AMPK has been associated with enhanced glucose uptake in skeletal muscle but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent upon AMPK...... analyzes. Results: Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (45%, P...

  19. Muscle Recruitment and Coordination following Constraint-Induced Movement Therapy with Electrical Stimulation on Children with Hemiplegic Cerebral Palsy: A Randomized Controlled Trial.

    Kaishou Xu

    Full Text Available To investigate changes of muscle recruitment and coordination following constraint-induced movement therapy, constraint-induced movement therapy plus electrical stimulation, and traditional occupational therapy in treating hand dysfunction.In a randomized, single-blind, controlled trial, children with hemiplegic cerebral palsy were randomly assigned to receive constraint-induced movement therapy (n = 22, constraint-induced movement therapy plus electrical stimulation (n = 23, or traditional occupational therapy (n = 23. Three groups received a 2-week hospital-based intervention and a 6-month home-based exercise program following hospital-based intervention. Constraint-induced movement therapy involved intensive functional training of the involved hand during which the uninvolved hand was constrained. Electrical stimulation was applied on wrist extensors of the involved hand. Traditional occupational therapy involved functional unimanual and bimanual training. All children underwent clinical assessments and surface electromyography (EMG at baseline, 2 weeks, 3 and 6 months after treatment. Surface myoelectric signals were integrated EMG, root mean square and cocontraction ratio. Clinical measures were grip strength and upper extremity functional test.Constraint-induced movement therapy plus electrical stimulation group showed both a greater rate of improvement in integrated EMG of the involved wrist extensors and cocontraction ratio compared to the other two groups at 3 and 6 months, as well as improving in root mean square of the involved wrist extensors than traditional occupational therapy group (p<0.05. Positive correlations were found between both upper extremity functional test scores and integrated EMG of the involved wrist as well as grip strength and integrated EMG of the involved wrist extensors (p<0.05.Constraint-induced movement therapy plus electrical stimulation is likely to produce the best outcome in improving muscle recruitment

  20. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase

    Rajfer, R. A.; Kilic, A.; Neviaser, A. S.; Schulte, L. M.; Hlaing, S. M.; Landeros, J.; Ferrini, M. G.; Ebramzadeh, E.; Park, S-H.

    2017-01-01

    Objectives We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. Materials and Methods Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression na...

  1. Partial deficiency of HIF-1 alpha stimulates pathological cardiac changes in streptozotocin-induced diabetic mice

    Bohuslavová, Romana; Kolář, František; Sedmera, David; Škvorová, Lada; Papoušek, František; Neckář, Jan; Pavlínková, Gabriela

    2014-01-01

    Roč. 14, Feb 6 (2014) ISSN 1472-6823 R&D Projects: GA ČR GA301/09/0117; GA MŠk(CZ) ED1.1.00/02.0109 Institutional research plan: CEZ:AV0Z50520701 Institutional support: RVO:68378271 Keywords : Echocardiographic parameters * Hypoxia inducible factor 1 alpha * Diabetic cardiomyopathy Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.710, year: 2014

  2. Changes in gait patterns induced by rhythmic auditory stimulation for adolescents with acquired brain injury.

    Kim, Soo Ji; Shin, Yoon-Kyum; Yoo, Ga Eul; Chong, Hyun Ju; Cho, Sung-Rae

    2016-12-01

    The effects of rhythmic auditory stimulation (RAS) on gait in adolescents with acquired brain injury (ABI) were investigated. A total of 14 adolescents with ABI were initially recruited, and 12 were included in the final analysis (n = 6 each). They were randomly assigned to the experimental (RAS) or the control (conventional gait training) groups. The experimental group received gait training with RAS three times a week for 4 weeks. For both groups, spatiotemporal parameters and kinematic data, such as dynamic motions of joints on three-dimensional planes during a gait cycle and the range of motion in each joint, were collected. Significant group differences in pre-post changes were observed in cadence, walking velocity, and step time, indicating that there were greater improvements in those parameters in the RAS group compared with the control group. Significant increases in hip and knee motions in the sagittal plane were also observed in the RAS group. The changes in kinematic data significantly differed between groups, particularly from terminal stance to mid-swing phase. An increase of both spatiotemporal parameters and corresponding kinematic changes of hip and knee joints after RAS protocol indicates that the use of rhythmic cueing may change gait patterns in adolescents with ABI. © 2016 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.

  3. Task-specific impairments and enhancements induced by magnetic stimulation of human visual area V5.

    Walsh, V; Ellison, A; Battelli, L; Cowey, A

    1998-03-22

    Transcranial magnetic stimulation (TMS) can be used to simulate the effects of highly circumscribed brain damage permanently present in some neuropsychological patients, by reversibly disrupting the normal functioning of the cortical area to which it is applied. By using TMS we attempted to recreate deficits similar to those reported in a motion-blind patient and to assess the specificity of deficits when TMS is applied over human area V5. We used six visual search tasks and showed that subjects were impaired in a motion but not a form 'pop-out' task when TMS was applied over V5. When motion was present, but irrelevant, or when attention to colour and form were required, TMS applied to V5 enhanced performance. When attention to motion was required in a motion-form conjunction search task, irrespective of whether the target was moving or stationary, TMS disrupted performance. These data suggest that attention to different visual attributes involves mutual inhibition between different extrastriate visual areas.

  4. Inducible colitis-associated glycome capable of stimulating the proliferation of memory CD4+ T cells.

    Nishida, Atsushi; Nagahama, Kiyotaka; Imaeda, Hirotsugu; Ogawa, Atsuhiro; Lau, Cindy W; Kobayashi, Taku; Hisamatsu, Tadakazu; Preffer, Frederic I; Mizoguchi, Emiko; Ikeuchi, Hiroki; Hibi, Toshifumi; Fukuda, Minoru; Andoh, Akira; Blumberg, Richard S; Mizoguchi, Atsushi

    2012-12-17

    Immune responses are modified by a diverse and abundant repertoire of carbohydrate structures on the cell surface, which is known as the glycome. In this study, we propose that a unique glycome that can be identified through the binding of galectin-4 is created on local, but not systemic, memory CD4+ T cells under diverse intestinal inflammatory conditions, but not in the healthy state. The colitis-associated glycome (CAG) represents an immature core 1-expressing O-glycan. Development of CAG may be mediated by down-regulation of the expression of core-2 β1,6-N-acetylglucosaminyltransferase (C2GnT) 1, a key enzyme responsible for the production of core-2 O-glycan branch through addition of N-acetylglucosamine (GlcNAc) to a core-1 O-glycan structure. Mechanistically, the CAG seems to contribute to super raft formation associated with the immunological synapse on colonic memory CD4+ T cells and to the consequent stabilization of protein kinase C θ activation, resulting in the stimulation of memory CD4+ T cell expansion in the inflamed intestine. Functionally, CAG-mediated CD4+ T cell expansion contributes to the exacerbation of T cell-mediated experimental intestinal inflammations. Therefore, the CAG may be an attractive therapeutic target to specifically suppress the expansion of effector memory CD4+ T cells in intestinal inflammation such as that seen in inflammatory bowel disease.

  5. Berberine-induced pigment dispersion in Bufo melanostictus melanophores by stimulation of beta-2 adrenergic receptors.

    Ali, Sharique A; Naaz, Ishrat; Choudhary, Ram Kumar

    2014-02-01

    Reduced production of melanin by decreased or the absence of melanocytes leads to various hypopigmentation disorders, and the development of melanogenetic agents for photoprotection and hypopigmentation disorders is one of the top priority areas of research. Hence, the present study was carried out to elucidate the ability of berberine, a principal active ingredient present in the roots of the herb Berberis vulgaris to stimulate pigment dispersion in the isolated skin melanophores of the toad Bufo melanostictus. In the present study, mean melanophore size index of the isolated skin melanophores of B. melanostictus was assayed after treating with various concentrations of berberine. A marked melanin dispersion response leading to skin darkening was observed in the isolated melanophores of toad in response to berberine, which was found to be mediated through beta-2 adrenergic receptors. The physiologically significant dose-related melanin dispersion effects of berberine per se were found to be completely abolished by propranolol, which is a specific beta-2 adrenergic receptor blocker. These per se melanin dispersal effects were also found to be markedly potentiated by isoprenaline, which is a specific beta-adrenoceptor agonist. The results indicate that berberine causes a tremendous, dose-dependent, physiologically significant pigment dispersing in the isolated skin melanophores of B. melanostictus.

  6. CCK1-Receptor Stimulation Protects Against Gut Mediator-Induced Lung Damage During Endotoxemia

    Friederike Eisner

    2013-12-01

    Full Text Available Background/Aims: Cholecystokinin 1-receptor (CCK1-R activation by long chain fatty acid (LCFA absorption stimulates vago-vagal reflex pathways in the brain stem. The present study determines whether this reflex also activates the cholinergic anti-inflammatory pathway, a pathway known to modulate cytokine release during endotoxemia. Methods:Mesenteric lymph was obtained from wild type (WT and CCK1-R knockout (CCK1-R-/- mice intraperitoneally challenged with Lipopolysaccharid (LPS (endotoxemic lymph, EL and intestinally infused with vehicle or LCFA-enriched solution. The lymph was analyzed for TNFα, IL-6 and IL-10 concentration and administered to healthy recipient mice via jugular infusion. Alveolar wall thickness, myeloperoxidase (MPO and TUNEL positive cells were determined in lung tissue of recipient mice. Results: LCFA infusion in WT mice reduced TNFα concentration in EL by 49% compared to vehicle infusion, but had no effect in CCK1-R-/- mice. EL significantly increased the alveolar wall thickness, the number of MPO-positive and TUNEL-positive cells compared to control lymph administration. LCFA infusion in WT, but not in CCK1R-/- mice, significantly reduced these pathological effects of EL. Conclusion: During endotoxemia enteral LCFA absorption reduces TNFα release into mesenteric lymph and attenuates histomorphologic parameters of lung dysfunction. Failure to elicit this effect in CCK1R-/- mice demonstrates that anti-inflammatory properties of LCFAs are mediated through CCK1-Rs.

  7. Anti-fatigue effect of percutaneous stimulation of the hepatic region by mid-frequency pulse current in different diadynamic cycles in soldiers with exercise-induced fatigue

    Peng-yi DAI

    2012-01-01

    Full Text Available Objective  To investigate the anti-fatigue effect of percutaneous stimulation of the hepatic region with the mid-frequency pulse current in different diadynamic cycles in exercise-induced fatigued soldiers. Methods  One hundred twenty healthy PLA recruits who did not have physical exercise were randomly divided into four groups with thirty ones in each: control, stimulation group A, stimulation group B, and stimulation group C. All the subjects of four groups were ordered intensive training (exercise from Monday to Saturday, with rest on Sunday for five weeks to establish the exercise-induced fatigue model. Each day after the exercise, the recruits of stimulation groups A, B, and C were treated immediately with mid-frequency (1204Hz, current intensity ≤80mA stimulation to the hepatic region with diadynamic cycles of 0.5, 1, and 2 seconds, respectively. No pulse current stimulation was given in the control group. Venous blood was collected before breakfast on Sundays to measure the fasting plasma glucose (FPG and blood lactate (LAC contents, and liver function was determined by determination of alanine aminotransferase (ALT, aspartate aminotransferase (AST, and lactate dehydrogenase (LDH. The 3000-m running performance of the recruits in each group was recorded on the same day. Results  There was no significant difference between the four groups in terms of the FPG level at the end of the first week (P>0.05. At the end of the third and fifth weeks, the FPG level was significantly higher in the three stimulation groups than in the control group (PPP>0.05. At the end of the first, third, and fifth weeks, the ALT, AST, LDH, and LAC levels were significantly lower in every stimulation group than in the control group (PPPPP>0.05. At the end of the first week, there was no significant difference in 3000-m running performance (P>0.05 between the 4 groups. At the end of the third and fifth weeks, the 3000-m running performance was significantly

  8. Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig

    Beaumont, Eric; Wright, Gary L.; Southerland, Elizabeth M.; Li, Ying; Chui, Ray; KenKnight, Bruce H.; Armour, J. Andrew

    2016-01-01

    Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling. PMID:26993230

  9. Nanopulse Stimulation (NPS Induces Tumor Ablation and Immunity in Orthotopic 4T1 Mouse Breast Cancer: A Review

    Stephen J. Beebe

    2018-03-01

    Full Text Available Nanopulse Stimulation (NPS eliminates mouse and rat tumor types in several different animal models. NPS induces protective, vaccine-like effects after ablation of orthotopic rat N1-S1 hepatocellular carcinoma. Here we review some general concepts of NPS in the context of studies with mouse metastatic 4T1 mammary cancer showing that the postablation, vaccine-like effect is initiated by dynamic, multilayered immune mechanisms. NPS eliminates primary 4T1 tumors by inducing immunogenic, caspase-independent programmed cell death (PCD. With lower electric fields, like those peripheral to the primary treatment zone, NPS can activate dendritic cells (DCs. The activation of DCs by dead/dying cells leads to increases in memory effector and central memory T-lymphocytes in the blood and spleen. NPS also eliminates immunosuppressive cells in the tumor microenvironment and blood. Finally, NPS treatment of 4T1 breast cancer exhibits an abscopal effect and largely prevents spontaneous metastases to distant organs. NPS with fast rise–fall times and pulse durations near the plasma membrane charging time constant, which exhibits transient, high-frequency components (1/time = Hz, induce responses from mitochondria, endoplasmic reticulum, and nucleus. Such effects may be responsible for release of danger-associated molecular patterns, including ATP, calreticulin, and high mobility group box 1 (HMBG1 from 4T1-Luc cells to induce immunogenic cell death (ICD. This likely leads to immunity and the vaccine-like response. In this way, NPS acts as a unique onco-immunotherapy providing distinct therapeutic advantages showing possible clinical utility for breast cancers as well as for other malignancies.

  10. Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.

    Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-Ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

    2016-03-01

    Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

  11. Follicle stimulating hormone alleviates radiation-induced degeneration of mouse ovarian follicles

    Lee, C.J. [Hanyang Univ., Seoul (Korea, Republic of); Kim, J.K.; Chun, K.J.

    2000-05-01

    The present study was performed to analyze the influences of (FSH) follicle stimulating hormone and {gamma}-radiation on the morphological changes of ovarian follicles and serum concentrations of testosterone, and estradiol-17{beta} in prepubertal mice. Female mice (ICR strain, three weeks old) were irradiated with 8.33 Gy of {gamma}-ray and followed by a 5 IU i.p.-injection of FSH to know the effect of FSH on the ovarian follicles. Left ovaries were collected at 0 h, 1 d, and 2 d after irradiation or saline/ FSH injection. Another group was received 5 IU of FSH 2 hours before irradiation to analyze the changes of ovarian steroidogenic abilities. By the morphometrical analysis, the number of normal or atretic follicles was counted and the ratio of normal to atretic follicle numbers was calculated. The percentage of atretic follicles was significantly reduced by the treatment of FSH. In the case of the FSH-injected group, the cellular debris caused by radiation was engulfed by the immune cells and the neighboring granulosa cells within the follicles. In concurrence with the morphometric analysis, the changes of the serum concentrations (pg/ml) of testosterone (T) and estradiol (E{sub 2}) were determined by radioimmunoassays. The concentration of T was 336.8{+-}61.3 in the control mice. One day after irradiation, the concentration went up to 484.8{+-}80.0 in the irradiated group, and down to 243.5{+-}80.7 in the FSH-treated one. The concentration of E{sub 2} was 174.9{+-}15.0 in the control group. One day after irradiation, however, the concentration was decreased to 94.8{+-}19.8, and 155.9{+-}8.7 in the irradiated and FSH-treated group, respectively. The alleviation of the follicular degeneration by the treatment of FSH is closely related to the elimination of the cellular debris and to the activities of the steroidogenic enzymes. (Author)

  12. Ebola virus-like particles produced in insect cells exhibit dendritic cell stimulating activity and induce neutralizing antibodies

    Ye Ling; Lin Jianguo; Sun Yuliang; Bennouna, Soumaya; Lo, Michael; Wu Qingyang; Bu Zhigao; Pulendran, Bali; Compans, Richard W.; Yang Chinglai

    2006-01-01

    Recombinant baculoviruses (rBV) expressing Ebola virus VP40 (rBV-VP40) or GP (rBV-GP) proteins were generated. Infection of Sf9 insect cells by rBV-VP40 led to assembly and budding of filamentous particles from the cell surface as shown by electron microscopy. Ebola virus-like particles (VLPs) were produced by coinfection of Sf9 cells with rBV-VP40 and rBV-GP, and incorporation of Ebola GP into VLPs was demonstrated by SDS-PAGE and Western blot analysis. Recombinant baculovirus infection of insect cells yielded high levels of VLPs, which were shown to stimulate cytokine secretion from human dendritic cells similar to VLPs produced in mammalian cells. The immunogenicity of Ebola VLPs produced in insect cells was evaluated by immunization of mice. Analysis of antibody responses showed that most of the GP-specific antibodies were of the IgG2a subtype, while no significant level of IgG1 subtype antibodies specific for GP was induced, indicating the induction of a Th1-biased immune response. Furthermore, sera from Ebola VLP immunized mice were able to block infection by Ebola GP pseudotyped HIV virus in a single round infection assay, indicating that a neutralizing antibody against the Ebola GP protein was induced. These results show that production of Ebola VLPs in insect cells using recombinant baculoviruses represents a promising approach for vaccine development against Ebola virus infection

  13. Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons

    Xanthi Antoniou

    2010-01-01

    Full Text Available The phosphorylation of Amyloid Precursor Protein (APP at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK, glycogen synthase kinase-3β (GSK-3β and cyclin-dependent kinase 5 (Cdk5 can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM for 30’-45’ led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.

  14. G9a stimulates CRC growth by inducing p53 Lys373 dimethylation-dependent activation of Plk1.

    Zhang, Jie; Wang, Yafang; Shen, Yanyan; He, Pengxing; Ding, Jian; Chen, Yi

    2018-01-01

    Rationale: G9a is genetically deregulated in various tumor types and is important for cell proliferation; however, the mechanism underlying G9a-induced carcinogenesis, especially in colorectal cancer (CRC), is unclear. Here, we investigated if G9a exerts oncogenic effects in CRC by increasing polo-like kinase 1 (Plk1) expression. Thus, we further characterized the detailed molecular mechanisms. Methods: The role of Plk1 in G9a aberrant CRC was determined by performing different in vitro and in vivo assays, including assessment of cell growth by performing cell viability assay and assessment of signaling transduction profiles by performing immunoblotting, in the cases of pharmacological inhibition or short RNA interference-mediated suppression of G9a. Detailed molecular mechanisms underlying the effect of G9a on Plk1 expression were determined by performing point mutation analysis, chromatin immunoprecipitation analysis, and luciferase reporter assay. Correlation between G9a and Plk1 expression was determined by analyzing clinical samples of patients with CRC by performing immunohistochemistry. Results: Our study is the first to report a significant positive correlation between G9a and Plk1 levels in 89 clinical samples of patients with CRC. Moreover, G9a depletion decreased Plk1 expression and suppressed CRC cell growth both in vitro and in vivo , thus confirming the significant correlation between G9a and Plk1 levels. Further, we observed that G9a-induced Plk1 regulation depended on p53 inhibition. G9a dimethylated p53 at lysine 373, which in turn increased Plk1 expression and promoted CRC cell growth. Conclusions: These results indicate that G9a-induced and p53-dependent epigenetic programing stimulates the growth of colon cancer, which also suggests that G9a inhibitors that restore p53 activity are promising therapeutic agents for treating colon cancer, especially for CRC expressing wild-type p53.

  15. Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils.

    Liu, L Y; Wang, H; Xenakis, J J; Spencer, L A

    2015-07-01

    Priming with cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances eosinophil migration and exacerbates the excessive accumulation of eosinophils within the bronchial mucosa of asthmatics. However, mechanisms that drive GM-CSF priming are incompletely understood. Notch signaling is an evolutionarily conserved pathway that regulates cellular processes, including migration, by integrating exogenous and cell-intrinsic cues. This study investigates the hypothesis that the priming-induced enhanced migration of human eosinophils requires the Notch signaling pathway. Using pan Notch inhibitors and newly developed human antibodies that specifically neutralize Notch receptor 1 activation, we investigated a role for Notch signaling in GM-CSF-primed transmigration of human blood eosinophils in vitro and in the airway accumulation of mouse eosinophils in vivo. Notch receptor 1 was constitutively active in freshly isolated human blood eosinophils, and inhibition of Notch signaling or specific blockade of Notch receptor 1 activation during GM-CSF priming impaired priming-enhanced eosinophil transendothelial migration in vitro. Inclusion of Notch signaling inhibitors during priming was associated with diminished ERK phosphorylation, and ERK-MAPK activation was required for GM-CSF priming-induced transmigration. In vivo in mice, eosinophil accumulation within allergic airways was impaired following systemic treatment with Notch inhibitor, or adoptive transfer of eosinophils treated ex vivo with Notch inhibitor. These data identify Notch signaling as an intrinsic pathway central to GM-CSF priming-induced eosinophil tissue migration. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Measurements of stimulated-Raman-scattering-induced tilt in spectral-amplitude-coding optical code-division multiple-access systems

    Al-Qazwini, Zaineb A. T.; Abdullah, Mohamad K.; Mokhtar, Makhfudzah B.

    2009-01-01

    We measure the stimulated Raman scattering (SRS)-induced tilt in spectral-amplitude-coding optical code-division multiple-access (SAC-OCDMA) systems as a function of system main parameters (transmission distance, power per chip, and number of users) via computer simulations. The results show that SRS-induced tilt significantly increases as transmission distance, power per chip, or number of users grows.

  17. Evidence for a role of nitric oxide in hindlimb vasodilation induced by hypothalamic stimulation in anesthetized rats

    Marcos L. Ferreira-Neto

    2005-06-01

    Full Text Available Electrical stimulation of the hypothalamus produces cardiovascular adjustments consisting of hypertension, tachycardia, visceral vasoconstriction and hindlimb vasodilation. Previous studies have demonstrated that hindlimb vasodilation is due a reduction of sympathetic vasoconstrictor tone and to activation of beta2-adrenergic receptors by catecholamine release. However, the existence of a yet unidentified vasodilator mechanism has also been proposed. Recent studies have suggested that nitric oxide (NO may be involved. The aim of the present study was to investigate the role of NO in the hindquarter vasodilation in response to hypothalamic stimulation. In pentobarbital-anesthetized rats hypothalamic stimulation (100 Hz, 150µA, 6 s produced hypertension, tachycardia, hindquarter vasodilation and mesenteric vasoconstriction. Alpha-adrenoceptor blockade with phentolamine (1.5 mg/kg, iv plus bilateral adrenalectomy did not modify hypertension, tachycardia or mesenteric vasoconstriction induced by hypothalamic stimulation. Hindquarter vasodilation was strongly reduced but not abolished. The remaining vasodilation was completely abolished after iv injection of the NOS inhibitor L-NAME (20 mg/kg, iv. To properly evaluate the role of the mechanism of NO in hindquarter vasodilation, in a second group of animals L-NAME was administered before alpha-adrenoceptor blockade plus adrenalectomy. L-NAME treatment strongly reduced hindquarter vasodilation in magnitude and duration. These results suggest that NO is involved in the hindquarter vasodilation produced by hypothalamic stimulation.Em animais anestesiados a EE do hipotálamo produz um padrão de ajustes cardiovasculares caracterizado por hipertensão arterial, taquicardia, vasodilatação muscular e vasoconstrição mesentérica, entretanto, os mecanismos periféricos envolvidos nestes ajustes cardiovasculares ainda não foram completamente esclarecidos. O presente estudo teve como objetivo caracterizar

  18. Melanogenesis stimulation in B16-F10 melanoma cells induces cell cycle alterations, increased ROS levels and a differential expression of proteins as revealed by proteomic analysis

    Cunha, Elizabeth S.; Kawahara, Rebeca [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil); Kadowaki, Marina K. [Universidade Estadual do Oeste do Parana, Cascavel, PR (Brazil); Amstalden, Hudson G.; Noleto, Guilhermina R.; Cadena, Silvia Maria S.C.; Winnischofer, Sheila M.B. [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil); Martinez, Glaucia R., E-mail: grmartinez@ufpr.br [Departamento de Bioquimica e Biologia Molecular, Setor de Ciencias Biologicas, Universidade Federal do Parana, P.O. Box 19046, CEP 81531-990, Curitiba, PR (Brazil)

    2012-09-10

    Considering that stimulation of melanogenesis may lead to alterations of cellular responses, besides melanin production, our main goal was to study the cellular effects of melanogenesis stimulation of B16-F10 melanoma cells. Our results show increased levels of the reactive oxygen species after 15 h of melanogenesis stimulation. Following 48 h of melanogenesis stimulation, proliferation was inhibited (by induction of cell cycle arrest in the G1 phase) and the expression levels of p21 mRNA were increased. In addition, melanogenesis stimulation did not induce cellular senescence. Proteomic analysis demonstrated the involvement of proteins from other pathways besides those related to the cell cycle, including protein disulfide isomerase A3, heat-shock protein 70, and fructose biphosphate aldolase A (all up-regulated), and lactate dehydrogenase (down-regulated). In RT-qPCR experiments, the levels of pyruvate kinase M2 mRNA dropped, whereas the levels of ATP synthase (beta-F1) mRNA increased. These data indicate that melanogenesis stimulation of B16-F10 cells leads to alterations in metabolism and cell cycle progression that may contribute to an induction of cell quiescence, which may provide a mechanism of resistance against cellular injury promoted by melanin synthesis. -- Highlights: Black-Right-Pointing-Pointer Melanogenesis stimulation by L-tyrosine+NH{sub 4}Cl in B16-F10 melanoma cells increases ROS levels. Black-Right-Pointing-Pointer Melanogenesis inhibits cell proliferation, and induced cell cycle arrest in the G1 phase. Black-Right-Pointing-Pointer Proteomic analysis showed alterations in proteins of the cell cycle and glucose metabolism. Black-Right-Pointing-Pointer RT-qPCR analysis confirmed alterations of metabolic targets after melanogenesis stimulation.

  19. Suppression of DHT-induced paracrine stimulation of endothelial cell growth by estrogens via prostate cancer cells.

    Wen, Juan; Zhao, Yuan; Li, Jinghe; Weng, Chunyan; Cai, Jingjing; Yang, Kan; Yuan, Hong; Imperato-McGinley, Julianne; Zhu, Yuan-Shan

    2013-07-01

    Androgen modulation of angiogenesis in prostate cancer may be not directly mediated by androgen receptor (AR) as AR is not detected in the prostatic endothelial cells. We examined the paracrine stimulation of cell proliferation by prostate tumor cells and its modulation by androgen and estrogens in a murine endothelial cell line (MEC) that does not express AR. Tumor cell conditioned media (TCM) collected from LAPC-4 or LNCaP prostatic tumor cells produced a time- and concentration-dependent induction of cell growth in MECs, which was parallel to the VEGF concentration in the TCM. This TCM-induced cell growth in MECs was enhanced by the treatment of prostatic tumor cells with dihydrotestosterone (DHT). Both the TCM-stimulation and DHT-enhancement effects in MECs were completely blocked by SU5416, a specific VEGF receptor antagonist. Co-administration of 17α-estradiol or 17β-estradiol with DHT in prostatic tumor cells completely inhibited the DHT-enhancement effect while treatment with DHT, 17α-estradiol or 17β-estradiol did not produce any significant direct effect in MECs. Moreover, administration of 17α-estradiol or 17β-estradiol in xenograft animals with LAPC-4 or LNCaP prostate tumor significantly decreased the microvessel number in the tumor tissues. Our study indicated that prostate tumor cells regulate endothelial cell growth through a paracrine mechanism, which is mainly mediated by VEGF; and DHT is able to modulate endothelial cell growth via tumor cells, which is inhibited by 17α-estradiol and 17β-estradiol. Thus, both17α-estradiol and 17β-estradiol are potential agents for anti-angiogenesis therapy in androgen-responsive prostate cancer. Copyright © 2013 Wiley Periodicals, Inc.

  20. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes.

    Xu, Lei; Zhou, Xinying; Wang, Wenshi; Wang, Yijin; Yin, Yuebang; Laan, Luc J W van der; Sprengers, Dave; Metselaar, Herold J; Peppelenbosch, Maikel P; Pan, Qiuwei

    2016-10-01

    IFN regulatory factor 1 (IRF1) is one of the most important IFN-stimulated genes (ISGs) in cellular antiviral immunity. Although hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide, how ISGs counteract HEV infection is largely unknown. This study was conducted to investigate the effect of IRF1 on HEV replication. Multiple cell lines were used in 2 models that harbor HEV. In different HEV cell culture systems, IRF1 effectively inhibited HEV replication. IRF1 did not trigger IFN production, and chromatin immunoprecipitation sequencing data analysis revealed that IRF1 bound to the promoter region of signal transducers and activators of transcription 1 (STAT1). Functional assay confirmed that IRF1 could drive the transcription of STAT1, resulting in elevation of total and phosphorylated STAT1 proteins and further activating the transcription of a panel of downstream antiviral ISGs. By pharmacological inhibitors and RNAi-mediated gene-silencing approaches, we revealed that antiviral function of IRF1 is dependent on the JAK-STAT cascade. Furthermore, induction of ISGs and the anti-HEV effect of IRF1 overlapped that of IFNα, but was potentiated by ribavirin. We demonstrated that IRF1 effectively inhibits HEV replication through the activation of the JAK-STAT pathway, and the subsequent transcription of antiviral ISGs, but independent of IFN production.-Xu, L., Zhou, X., Wang, W., Wang, Y., Yin, Y., van der Laan, L. J. W., Sprengers, D., Metselaar, H. J., Peppelenbosch, M. P., Pan, Q. IFN regulatory factor 1 restricts hepatitis E virus replication by activating STAT1 to induce antiviral IFN-stimulated genes. © FASEB.

  1. Neuropeptide Y as a possible homeostatic element for changes in cortical excitability induced by repetitive transcranial magnetic stimulation.

    Jazmati, Danny; Neubacher, Ute; Funke, Klaus

    2018-02-24

    Repetitive transcranial magnetic stimulation (rTMS) is able to modify cortical excitability. Rat rTMS studies revealed a modulation of inhibitory systems, in particular that of the parvalbumin-expressing (PV+) interneurons, when using intermittent theta-burst stimulation (iTBS). The potential disinhibitory action of iTBS raises the questions of how neocortical circuits stabilize excitatory-inhibitory balance within a physiological range. Neuropeptide Y (NPY) appears to be one candidate. Analysis of cortical expression of PV, NPY and vesicular glutamate transporter type 1 (vGluT1) by immunohistochemical means at the level of cell counts, mean neuropil expression and single cell pre-/postsynaptic expression, with and without intraventricular NPY-injection. Our results show that iTBS not only reduced the number of neurons with high-PV expression in a dose-dependent fashion, but also increased the cortical expression of NPY, discussed to reduce glutamatergic transmission, and this was further associated with a reduced vGluT1 expression, an indicator of glutamateric presynaptic activity. Interneurons showing a low-PV expression exhibit less presynaptic vGluT1 expression compared to those with a high-PV expression. Intraventricular application of NPY prior to iTBS prevented the iTBS-induced reduction in the number of high-PV neurons, the reduction in tissue vGluT1 level and that presynaptic to high-PV cells. We conclude that NPY, possibly via a global but also slow homeostatic control of glutamatergic transmission, modulates the strength and direction of the iTBS effects, likely preventing pathological imbalance of excitatory and inhibitory cortical activity but still allowing enough disinhibition beneficial for plastic changes as during learning. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Macrophage colony-stimulating factor and its receptor signaling augment glycated albumin-induced retinal microglial inflammation in vitro

    Jiang Chun H

    2011-01-01

    Full Text Available Abstract Background Microglial activation and the proinflammatory response are controlled by a complex regulatory network. Among the various candidates, macrophage colony-stimulating factor (M-CSF is considered an important cytokine. The up-regulation of M-CSF and its receptor CSF-1R has been reported in brain disease, as well as in diabetic complications; however, the mechanism is unclear. An elevated level of glycated albumin (GA is a characteristic of diabetes; thus, it may be involved in monocyte/macrophage-associated diabetic complications. Results The basal level of expression of M-CSF/CSF-1R was examined in retinal microglial cells in vitro. Immunofluorescence, real-time PCR, immunoprecipitation, and Western blot analyses revealed the up-regulation of CSF-1R in GA-treated microglial cells. We also detected increased expression and release of M-CSF, suggesting that the cytokine is produced by activated microglia via autocrine signaling. Using an enzyme-linked immunosorbent assay, we found that GA affects microglial activation by stimulating the release of tumor necrosis factor-α and interleukin-1β. Furthermore, the neutralization of M-CSF or CSF-1R with antibodies suppressed the proinflammatory response. Conversely, this proinflammatory response was augmented by the administration of M-CSF. Conclusions We conclude that GA induces microglial activation via the release of proinflammatory cytokines, which may contribute to the inflammatory pathogenesis of diabetic retinopathy. The increased microglial expression of M-CSF/CSF-1R not only is a response to microglial activation in diabetic retinopathy but also augments the microglial inflammation responsible for the diabetic microenvironment.

  3. Electroacupuncture stimulation at CV4 prevents ovariectomy-induced osteoporosis in rats via Wnt-β-catenin signaling.

    Fan, Huailing; Ji, Feng; Lin, Ying; Zhang, Mulan; Qin, Wei; Zhou, Qi; Wu, Qiang

    2016-03-01

    The present study aimed to investigate the effect of electroacupuncture stimulation at CV4 (also termed Guanyuan) on femoral osteocalcin also termed bone gla protein (BGP), alkaline phosphatase (ALP), bone mineral density (BMD) and biomechanics, as well as the Wnt‑β‑catenin signaling pathway in rats with postmenopausal osteoporosis. Female Sprague‑Dawley rats (4.5‑months old) were randomly divided into sham, Ovx, CV4 and mock groups (n=10/group). With the exception of those in the sham group, the rats were ovariectomized to induce postmenopausal osteoporosis. The rats in the CV4 and mock groups were given electroacupuncture at CV4 and non‑acupoint, respectively. The rats in the Ovx model and sham groups underwent identical fixing procedures, but did not undergo electroacupuncture. Following treatment, hematoxylin and eosin staining was used to observe morphological changes in the left femoral trabecular bone, and a three‑point‑bending test was used to analyze femur biomechanics and determine the BMD. In addition, an enzyme‑linked immunosorbent assay was used to measure the serum levels of ALP/BGP and reverse transcription‑quantitative polymerase chain reaction was used detect the expression levels of Wnt3a, β‑catenin and Runx2. In the present study, it was demonstrated that electroacupuncture at CV4 significantly improved the osteoporotic morphological changes that occurred in the ovariectomized rats, increased serum ALP and BGP levels, enhanced the maximum and fracture loads, increased BMD (Pelectroacupuncture stimulation at CV4 affected bone formation and promoted bone metabolism in rats with postmenopausal osteoporosis, possibly by activating the Wnt‑β‑catenin signaling pathway.

  4. Burn-induced stimulation of lysosomal enzyme synthesis in skeletal muscle

    Odessey, R.

    1986-01-01

    A localized burn injury to a rat hindlimb results in atrophy of soleus muscle (in the absence of cellular damage) which is attributable to an increase in muscle protein breakdown. Previous work has shown that lysosomal enzyme activities (cathepsins B, H, L, and D) are elevated in muscle from the burned leg by 50% to 100%. There is no change in endogenous neutral protease activity (+/- Ca ++ ). The increase in protease activity can not be attributed to changes in endogenous protease inhibitors. The latency [(Triton X100 treated - control)/triton treated] of lysosomal enzymes is approximately 50% and is not altered by burn injury. The rate of sucrose uptake is also not altered by burn. These experiments suggest that the rate of substrate supply to the lysosomal apparatus via endocytosis or autophagocytosis is not altered by burn. When muscles are preincubated with 3 H-phenylalanine or 3 H-mannose burn increased incorporation into protein of the fraction containing lysosomes by 100%. Preincubation in the presence of tunicamycin (an inhibitor of glycoprotein synthesis) inhibited incorporation of both labels into a microsomal fraction of the muscle from the burned leg, but has little effect on incorporation in the control muscle. These findings are consistent with the hypothesis that the burn-induced increase in protein breakdown is caused by an increase in lysosomal protease synthesis

  5. Constraint-Induced Movement Therapy Combined with Transcranial Direct Current Stimulation over Premotor Cortex Improves Motor Function in Severe Stroke: A Pilot Randomized Controlled Trial

    Suellen M. Andrade

    2017-01-01

    Full Text Available Objective. We compared the effects of transcranial direct current stimulation at different cortical sites (premotor and motor primary cortex combined with constraint-induced movement therapy for treatment of stroke patients. Design. Sixty patients were randomly distributed into 3 groups: Group A, anodal stimulation on premotor cortex and constraint-induced movement therapy; Group B, anodal stimulation on primary motor cortex and constraint-induced movement therapy; Group C, sham stimulation and constraint-induced movement therapy. Evaluations involved analysis of functional independence, motor recovery, spasticity, gross motor function, and muscle strength. Results. A significant improvement in primary outcome (functional independence after treatment in the premotor group followed by primary motor group and sham group was observed. The same pattern of improvement was highlighted among all secondary outcome measures regarding the superior performance of the premotor group over primary motor and sham groups. Conclusions. Premotor cortex can contribute to motor function in patients with severe functional disabilities in early stages of stroke. This study was registered in ClinicalTrials.gov database (NCT 02628561.

  6. Naturally Induced Secretions of the Potato Cyst Nematode Co-stimulate the Proliferation of Both Tobacco Leaf Protoplasts and Human Peripheral Blood Mononuclear Cells

    Goverse, A.; Rouppe van der Voort, J.N.A.M.; Rouppe van der voort, C.; Kavelaars, A.; Smant, G.; Schots, A.; Bakker, J.; Helder, J.

    1999-01-01

    Naturally induced secretions from infective juveniles of the potato cyst nematode Globodera rostochiensis co-stimulate the proliferation of tobacco leaf protoplasts in the presence of the synthetic phytohormones α-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP). With the use of a

  7. Prolonged electrical stimulation-induced gluteal and hamstring muscle activation and sitting pressure in spinal cord injury: Effect of duty cycle

    MSc Karin J.A. Legemate; MD Christof A. J. Smit; MSc Anja de Koning; PhD Sonja de Groot; MD, PhD Janneke M. Stolwijk-Swuste; PhD Thomas W.H. Janssen

    2013-01-01

    Abstract—Pressure ulcers (PUs) are highly prevalent in people with spinal cord injury (SCI). Electrical stimulation (ES) activates muscles and might reduce risk factors. Our objectives were to study and compare the effects of two duty cycles during 3 h of ES-induced gluteal and hamstring activation

  8. Prolonged electrical stimulation-induced gluteal and hamstring muscle activation and sitting pressure in spinal cord injury : Effect of duty cycle

    Smit, Christof A. J.; Legemate, Karin J. A.; de Koning, Anja; de Groot, Sonja; Stolwijk-Swuste, Janneke M.; Janssen, Thomas W. J.

    2013-01-01

    Pressure ulcers (PUs) are highly prevalent in people with spinal cord injury (SCI). Electrical stimulation (ES) activates muscles and might reduce risk factors. Our objectives were to study and compare the effects of two duty cycles during 3 h of ES-induced gluteal and hamstring activation on

  9. CXC chemokine receptor 3 expression on CD34(+) hematopoietic progenitors from human cord blood induced by granulocyte-macrophage colony-stimulating factor

    Jinquan, T; Quan, S; Jacobi, H H

    2000-01-01

    -induced CD34(+) progenitor chemotaxis. These chemotactic attracted CD34(+) progenitors are colony-forming units-granulocyte-macrophage. gamma IP-10 and Mig also induced GM-CSF-stimulated CD34(+) progenitor adhesion and aggregation by means of CXCR3, a finding confirmed by the observation that anti-CXCR3 m......Ab blocked these functions of gammaIP-10 and Mig but not of chemokine stromal cell-derived factor 1 alpha. gamma IP-10-induced and Mig-induced up-regulation of integrins (CD49a and CD49b) was found to play a crucial role in adhesion of GM-CSF-stimulated CD34(+) progenitors. Moreover, gamma IP-10 and Mig...... stimulated CXCR3 redistribution and cellular polarization in GM-CSF-stimulated CD34(+) progenitors. These results indicate that CXCR3-gamma IP-10 and CXCR3-Mig receptor-ligand pairs, as well as the effects of GM-CSF on them, may be especially important in the cytokine/chemokine environment...

  10. Gluteal blood flow and oxygenation during electrical stimulation-induced muscle activation versus pressure relief movements in wheelchair users with a spinal cord injury

    Smit, C. A. J.; Zwinkels, M.; van Dijk, T.; de Groot, S.; Stolwijk-Swuste, J. M.; Janssen, T. W. J.

    Background: Prolonged high ischial tuberosities pressure (IT pressure), decreased regional blood flow (BF) and oxygenation (%SO2) are risk factors for developing pressure ulcers (PUs) in patients with spinal cord injury (SCI). Electrical stimulation (ES)-induced gluteal and hamstring muscle

  11. Neuropeptide Y-stimulated [(35) S]GTPγs functional binding is reduced in the hippocampus after kainate-induced seizures in mice

    Elbrønd-Bek, Heidi; Olling, Janne Damm; Gøtzsche, Casper René

    2014-01-01

    , in this study, we explored functional NPY receptor activity in the mouse hippocampus and neocortex after kainate-induced seizures using NPY-stimulated [(35) S]GTPγS binding. Moreover, we also studied levels of [(125) I]-peptide YY (PYY) binding and NPY, Y1, Y2, and Y5 receptor mRNA in these kainate-treated mice...

  12. LTP in Hippocampal Area CA1 Is Induced by Burst Stimulation over a Broad Frequency Range Centered around Delta

    Grover, Lawrence M.; Kim, Eunyoung; Cooke, Jennifer D.; Holmes, William R.

    2009-01-01

    Long-term potentiation (LTP) is typically studied using either continuous high-frequency stimulation or theta burst stimulation. Previous studies emphasized the physiological relevance of theta frequency; however, synchronized hippocampal activity occurs over a broader frequency range. We therefore tested burst stimulation at intervals from 100…

  13. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages.

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto; Becker, María Inés

    2016-06-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5 Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. Copyright © 2016 by The American Association of

  14. Steroid receptor coactivators, HER-2 and HER-3 expression is stimulated by tamoxifen treatment in DMBA-induced breast cancer

    Moi, Line L Haugan; Flågeng, Marianne Hauglid; Gjerde, Jennifer; Madsen, Andre; Røst, Therese Halvorsen; Gudbrandsen, Oddrun Anita; Lien, Ernst A; Mellgren, Gunnar

    2012-01-01

    Steroid receptor coactivators (SRCs) may modulate estrogen receptor (ER) activity and the response to endocrine treatment in breast cancer, in part through interaction with growth factor receptor signaling pathways. In the present study the effects of tamoxifen treatment on the expression of SRCs and human epidermal growth factor receptors (HERs) were examined in an animal model of ER positive breast cancer. Sprague-Dawley rats with DMBA-induced breast cancer were randomized to 14 days of oral tamoxifen 40 mg/kg bodyweight/day or vehicle only (controls). Tumors were measured throughout the study period. Blood samples and tumor tissue were collected at sacrifice and tamoxifen and its main metabolites were quantified using LC-MS/MS. The gene expression in tumor of SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2), SRC-3/amplified in breast cancer 1 (AIB1), ER, HER-1, -2, -3 and HER-4, as well as the transcription factor Ets-2, was measured by real-time RT-PCR. Protein levels were further assessed by Western blotting. Tamoxifen and its main metabolites were detected at high concentrations in serum and accumulated in tumor tissue in up to tenfolds the concentration in serum. Mean tumor volume/rat decreased in the tamoxifen treated group, but continued to increase in controls. The mRNA expression levels of SRC-1 (P = 0.035), SRC-2/TIF-2 (P = 0.002), HER-2 (P = 0.035) and HER-3 (P = 0.006) were significantly higher in tamoxifen treated tumors compared to controls, and the results were confirmed at the protein level using Western blotting. SRC-3/AIB1 protein was also higher in tamoxifen treated tumors. SRC-1 and SRC-2/TIF-2 mRNA levels were positively correlated with each other and with HER-2 (P ≤ 0.001), and the HER-2 mRNA expression correlated with the levels of the other three HER family members (P < 0.05). Furthermore, SRC-3/AIB1 and HER-4 were positively correlated with each other and Ets-2 (P < 0.001). The expression of SRCs and HER-2 and -3 is stimulated

  15. Extended Remediation of Sleep Deprived-Induced Working Memory Deficits Using fMRI-guided Transcranial Magnetic Stimulation

    Luber, Bruce; Steffener, Jason; Tucker, Adrienne; Habeck, Christian; Peterchev, Angel V.; Deng, Zhi-De; Basner, Robert C.; Stern, Yaakov; Lisanby, Sarah H.

    2013-01-01

    Study Objectives: We attempted to prevent the development of working memory (WM) impairments caused by sleep deprivation using fMRI-guided repetitive transcranial magnetic stimulation (rTMS). Novel aspects of our fMRI-guided rTMS paradigm included the use of sophisticated covariance methods to identify functional networks in imaging data, and the use of fMRI-targeted rTMS concurrent with task performance to modulate plasticity effects over a longer term. Design: Between-groups mixed model. Setting: TMS, MRI, and sleep laboratory study. Participants: 27 subjects (13 receiving Active rTMS, and 14 Sham) completed the sleep deprivation protocol, with another 21 (10 Active, 11 Sham) non-sleep deprived subjects run in a second experiment. Interventions: Our previous covariance analysis had identified a network, including occipital cortex, which demonstrated individual differences in resilience to the deleterious effects of sleep deprivation on WM performance. Five Hz rTMS was applied to left lateral occipital cortex while subjects performed a WM task during 4 sessions over the course of 2 days of total sleep deprivation. Measurements and Results: At the end of the sleep deprivation period, Sham sleep deprived subjects exhibited degraded performance in the WM task. In contrast, those receiving Active rTMS did not show the slowing and lapsing typical in sleep deprivation, and instead performed similarly to non- sleep deprived subjects. Importantly, the Active sleep deprivation group showed rTMS-induced facilitation of WM performance a full 18 hours after the last rTMS session. Conclusions: Over the course of sleep deprivation, these results indicate that rTMS applied concurrently with WM task performance affected neural circuitry involved in WM to prevent its full impact. Citation: Luber B; Steffener J; Tucker A; Habeck C; Peterchev AV; Deng ZD; Basner RC; Stern Y; Lisanby SH. Extended remediation of sleep deprived-induced working memory deficits using f

  16. Mechanical stimulation induces mTOR signaling via an ERK-independent mechanism: implications for a direct activation of mTOR by phosphatidic acid.

    Jae Sung You

    Full Text Available Signaling by mTOR is a well-recognized component of the pathway through which mechanical signals regulate protein synthesis and muscle mass. However, the mechanisms involved in the mechanical regulation of mTOR signaling have not been defined. Nevertheless, recent studies suggest that a mechanically-induced increase in phosphatidic acid (PA may be involved. There is also evidence which suggests that mechanical stimuli, and PA, utilize ERK to induce mTOR signaling. Hence, we reasoned that a mechanically-induced increase in PA might promote mTOR signaling via an ERK-dependent mechanism. To test this, we subjected mouse skeletal muscles to mechanical stimulation in the presence or absence of a MEK/ERK inhibitor, and then measured several commonly used markers of mTOR signaling. Transgenic mice expressing a rapamycin-resistant mutant of mTOR were also used to confirm the validity of these markers. The results demonstrated that mechanically-induced increases in p70(s6k T389 and 4E-BP1 S64 phosphorylation, and unexpectedly, a loss in total 4E-BP1, were fully mTOR-dependent signaling events. Furthermore, we determined that mechanical stimulation induced these mTOR-dependent events, and protein synthesis, through an ERK-independent mechanism. Similar to mechanical stimulation, exogenous PA also induced mTOR-dependent signaling via an ERK-independent mechanism. Moreover, PA was able to directly activate mTOR signaling in vitro. Combined, these results demonstrate that mechanical stimulation induces mTOR signaling, and protein synthesis, via an ERK-independent mechanism that potentially involves a direct interaction of PA with mTOR. Furthermore, it appears that a decrease in total 4E-BP1 may be part of the mTOR-dependent mechanism through which mechanical stimuli activate protein synthesis.

  17. Characterization of three different sensory fibers by use of neonatal capsaicin treatment, spinal antagonism and a novel electrical stimulation-induced paw flexion test

    Yamaguchi Asuka

    2006-05-01

    Full Text Available Abstract In the present study, we first report an in vivo characterization of flexor responses induced by three distinct sine-wave stimuli in the electrical stimulation-induced paw flexion (EPF test in mice. The fixed sine-wave electric stimulations of 5 Hz (C-fiber, 250 Hz (Aδ-fiber and 2000 Hz (Aβ-fiber to the hind paw of mice induced a paw-flexion response and vocalization. The average threshold for paw flexor responses by sine-wave stimulations was much lower than that for vocalization. Neonatally (P3 pretreatment with capsaicin to degenerate polymodal substance P-ergic C-fiber neurons increased the threshold to 5 Hz (C-fiber stimuli, but not to 250 Hz (Aδ-fiber and 2000 Hz (Aβ-fiber. The flexor responses to 5 Hz stimuli were significantly blocked by intrathecal (i.t. pretreatment with both CP-99994 and MK-801, an NK1 and NMDA receptor antagonist, respectively, but not by CNQX, an AMPA/kainate receptor antagonist. On the other hand, the flexor responses induced by 250 Hz stimuli were blocked by MK-801 (i.t. but not by CP-99994 or CNQX. In contrast, flexor responses induced by 2000 Hz stimuli were only blocked by CNQX treatment. These data suggest that we have identified three pharmacologically different categories of responses mediated through different primary afferent fibers. Furthermore, we also carried out characterization of the in vivo functional sensitivity of each of the sensory fiber types in nerve-injured mice using the EPF test, and found that the threshold to both 250 Hz and 2000 Hz stimulations were markedly decreased, whereas the threshold to 5 Hz stimulations was significantly increased. Thus we found opposing effects on specific sensory fiber-mediated responses as a result of nerve injury in mice. These results also suggest that the EPF analysis is useful for the evaluation of plasticity in sensory functions in animal disease models.

  18. Budget impact analysis on erythropoiesis-stimulating agents use for the management of chemotherapy-induced anaemia in Greece.

    Nikolaidi, Eleftheria; Hatzikou, Magdalini; Geitona, Mary

    2013-07-16

    Chemotherapy-induced anaemia is a common and significant complication of chemotherapy treatment. Blood transfusion and administration of Erythropoiesis-Stimulating Agents (ESAs) either alone or in combination with iron are the most widely used therapeutic options. In Greece, ESAs are among the top ten therapeutic groups with the highest pharmaceutical expenditure, since they are fully reimbursed by social security funds. The objective of the study is to determine potential cost savings related with the use of biosimilar over originator ESAs for the management of the newly diagnosed chemotherapy-induced anemic patients. A budget impact analysis has been carried through the elaboration of national epidemiological, clinical and economic data. Epidemiological data derived from WHO (GLOBOCAN) and the European Cancer Anaemia Survey. Clinical data reflect oncology patients' disease management. ESAs consumption was based on data from the biggest social security fund (IKA). The administration of ESAs under different dosing schemes and time periods has been estimated by separating them in originators and biosimilars as well as by classifying anaemic patients in responders and non-responders. Cost analysis is based on newly diagnosed patients' alternative treatment scenarios. Treatment costs and prices are used in 2012 values. The Social Security Funds's perspective was undertaken. Based on the annual incidence rates, 2.551 newly diagnosed chemotherapy-induced anemic patients are expected to be treated with ESAs. Average cost of treatment on originators ESAs for responders is €2.887 for the 15-week ESAs treatment and €5.019 for non-responders, while on biosimilars €2.623 and €4.009 respectively. Treatment cost on biosimilars is 10.1% lower than originators for responders and 25.2% for non-responders. Budget impact estimates show that treating anemic patients with originator ESAs was estimated at €10.084.800 compared to €8.460.119 when biosimilar ESAs were used

  19. The NMDA antagonist memantine affects training induced motor cortex plasticity – a study using transcranial magnetic stimulation [ISRCTN65784760

    Schwenkreis Peter

    2005-05-01

    Full Text Available Abstract Background Training of a repetitive synchronised movement of two limb muscles leads to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS mapping. We used this paradigm to study the effect of memantine, a NDMA antagonist, on short-term motor cortex plasticity in 20 healthy human subjects, and we were especially interested in possible differential effects of different treatment regimens. In a randomised double-blinded cross over study design we therefore administered placebo or memantine either as a single dosage or as an ascending dosage over 8 days. Before and after one hour of motor training, which consisted of a repetitive co-contraction of the abductor pollicis brevis (APB and the deltoid muscle, we assessed the motor output map of the APB muscle by TMS under the different conditions. Results We found a significant medial shift of the APB motor output map after training in the placebo condition, indicating training-induced short-term plastic changes in the motor cortex. A single dosage of memantine had no significant effect on this training-induced plasticity, whereas memantine administered in an ascending dosage over 8 days was able to block the cortical effect of the motor training. The memantine serum levels after 8 days were markedly higher than the serum levels after a single dosage of memantine, but there was no individual correlation between the shift of the motor output map and the memantine serum level. Besides, repeated administration of a low memantine dosage also led to an effective blockade of training-induced cortical plasticity in spite of serum levels comparable to those reached after single dose administration, suggesting that the repeated administration was more important for the blocking effect than the memantine serum levels. Conclusion We conclude that the NMDA-antagonist memantine is able to block training-induced motor cortex plasticity when

  20. Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers.

    Judit Váradi

    Full Text Available Alpha-melanocyte-stimulating hormone (α-MSH is a potent anti-inflammatory peptide with cytoprotective effect in various tissues. The present investigation demonstrates the ability of α-MSH to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. The barrier integrity was assessed by measuring transepithelial electric resistance (TEER and permeability for marker molecules. Caco-2 monolayers were evaluated by immunohistochemistry for expression of melanocortin-1 receptor and tight junction proteins ZO-1 and claudin-4. The activation of nuclear factor kappa beta (NF-κB was detected by fluorescence microscopy and inflammatory cytokine expression was assessed by flow cytometric bead array cytokine assay. Exposure of Caco-2 monolayers to proinflammatory cytokines lowered TEER and increased permeability for fluorescein and albumin, which was accompanied by changes in ZO-1 and claudin-4 immunostaining. α-MSH was able to prevent inflammation-associated decrease of TEER in a dose-dependent manner and reduce the increased permeability for paracellular marker fluorescein. Further immunohistochemistry analysis revealed proinflammatory cytokine induced translocation of the NF-κB p65 subunit into Caco-2 cell nuclei, which was inhibited by α-MSH. As a result the IL-6 and IL-8 production of Caco-2 monolayers were also decreased with different patterns by the addition of α-MSH to the culture medium. In conclusion, Caco-2 cells showed a positive immunostaining for melanocortin-1 receptor and α-MSH protected Caco-2 cells against inflammatory barrier dysfunction and inflammatory activation induced by tumor necrosis factor-α and interleukin-1β cytokines.

  1. Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis.

    Eisenstein, Sarah A; Dewispelaere, William B; Campbell, Meghan C; Lugar, Heather M; Perlmutter, Joel S; Black, Kevin J; Hershey, Tamara

    2014-01-01

    Deep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood. The study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS. Thirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal. STN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS. PD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Nano-Pulse Stimulation induces immunogenic cell death in human papillomavirus-transformed tumors and initiates an adaptive immune response.

    Joseph G Skeate

    Full Text Available Nano-Pulse Stimulation (NPS is a non-thermal pulsed electric field modality that has been shown to have cancer therapeutic effects. Here we applied NPS treatment to the human papillomavirus type 16 (HPV 16-transformed C3.43 mouse tumor cell model and showed that it is effective at eliminating primary tumors through the induction of immunogenic cell death while subsequently increasing the number of tumor-infiltrating lymphocytes within the tumor microenvironment. In vitro NPS treatment of C3.43 cells resulted in a doubling of activated caspase 3/7 along with the translocation of phosphatidylserine (PS to the outer leaflet of the plasma membrane, indicating programmed cell death activity. Tumor-bearing mice receiving standard NPS treatment showed an initial decrease in tumor volume followed by clearing of tumors in most mice, and a significant increase in overall survival. Intra-tumor analysis of mice that were unable to clear tumors showed an inverse correlation between the number of tumor infiltrating lymphocytes and the size of the tumor. Approximately half of the mice that cleared established tumors were protected against tumor re-challenge on the opposite flank. Selective depletion of CD8+ T cells eliminated this protection, suggesting that NPS treatment induces an adaptive immune response generating CD8+ T cells that recognize tumor antigen(s associated with the C3.43 tumor model. This method may be utilized in the future to not only ablate primary tumors, but also to induce an anti-tumor response driven by effector CD8+ T cells capable of protecting individuals from disease recurrence.

  3. Nano-Pulse Stimulation induces immunogenic cell death in human papillomavirus-transformed tumors and initiates an adaptive immune response.

    Skeate, Joseph G; Da Silva, Diane M; Chavez-Juan, Elena; Anand, Snjezana; Nuccitelli, Richard; Kast, W Martin

    2018-01-01

    Nano-Pulse Stimulation (NPS) is a non-thermal pulsed electric field modality that has been shown to have cancer therapeutic effects. Here we applied NPS treatment to the human papillomavirus type 16 (HPV 16)-transformed C3.43 mouse tumor cell model and showed that it is effective at eliminating primary tumors through the induction of immunogenic cell death while subsequently increasing the number of tumor-infiltrating lymphocytes within the tumor microenvironment. In vitro NPS treatment of C3.43 cells resulted in a doubling of activated caspase 3/7 along with the translocation of phosphatidylserine (PS) to the outer leaflet of the plasma membrane, indicating programmed cell death activity. Tumor-bearing mice receiving standard NPS treatment showed an initial decrease in tumor volume followed by clearing of tumors in most mice, and a significant increase in overall survival. Intra-tumor analysis of mice that were unable to clear tumors showed an inverse correlation between the number of tumor infiltrating lymphocytes and the size of the tumor. Approximately half of the mice that cleared established tumors were protected against tumor re-challenge on the opposite flank. Selective depletion of CD8+ T cells eliminated this protection, suggesting that NPS treatment induces an adaptive immune response generating CD8+ T cells that recognize tumor antigen(s) associated with the C3.43 tumor model. This method may be utilized in the future to not only ablate primary tumors, but also to induce an anti-tumor response driven by effector CD8+ T cells capable of protecting individuals from disease recurrence.

  4. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance

    Houthuijzen, Julia M; Oosterom, Ilse; Hudson, Brian D

    2017-01-01

    Although chemotherapy is designed to eradicate tumor cells, it also has significant effects on normal tissues. The platinum-induced fatty acid 16:4(n-3) (hexadeca-4,7,10,13-tetraenoic acid) induces systemic resistance to a broad range of DNA-damaging chemotherapeutics. We show that 16:4(n-3) exerts....... M., Peeper, D. S., Jafari Sadatmand, S., Roodhart, J. M. L., van de Lest, C. H. A., Ulven, T., Ishihara, K., Milligan, G., Voest, E. E. Fatty acid 16:4(n-3) stimulates a GPR120-induced signaling cascade in splenic macrophages to promote chemotherapy resistance....

  5. Rab39a interacts with phosphatidylinositol 3-kinase and negatively regulates autophagy induced by lipopolysaccharide stimulation in macrophages.

    Shintaro Seto

    Full Text Available Rab39a has pleiotropic functions in phagosome maturation, inflammatory activation and neuritogenesis. Here, we characterized Rab39a function in membrane trafficking of phagocytosis and autophagy induction in macrophages. Rab39a localized to the periphery of LAMP2-positive vesicles and showed the similar kinetics on the phagosome to that of LAMP1. The depletion of Rab39a did not influence the localization of LAMP2 to the phagosome, but it augments the autophagosome formation and LC3 processing by lipopolysaccharide (LPS stimulation. The augmentation of autophagosome formation in Rab39a-knockdown macrophages was suppressed by Atg5 depletion or an inhibitor for phosphatidylinostol 3-kinase (PI3K. Immunoprecipitation analysis revealed that Rab39a interacts with PI3K and that the amino acid residues from 34(th to 41(st in Rab39a were indispensable for this interaction. These results suggest that Rab39a negatively regulates the LPS-induced autophagy in macrophages.

  6. Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

    Kristensen, Jonas Møller; Treebak, Jonas T.; Schjerling, Peter; Goodyear, Laurie

    2014-01-01

    Metformin-induced activation of the 5′-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr308/Ser473 and TBC1D4 Thr642/Ser711 phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment. PMID:24644243

  7. The Impact of Stimulation Induced Short Term Synaptic Plasticity on Firing Patterns in the Globus Pallidus of the Rat

    Jenia eBugaysen

    2011-03-01

    Full Text Available Electrical stimulation in the globus pallidus (GP leads to complex modulations of neuronal activity in the stimulated nucleus. Multiple in-vivo studies have demonstrated the modulation of both firing rates and patterns during and immediately following the GP stimulation. Previous in-vitro studies, together with computational studies, have suggested the involvement of short-term synaptic plasticity (STP during the stimulation. The aim of the current study was to explore in-vitro the effects of STP on neuronal activity of GP neurons during local repetitive stimulation. We recorded synaptic potentials and assessed the modulations of spontaneous firing in a postsynaptic neuron in acute brain slices via a whole-cell pipette. Low-frequency repetitive stimulation locked the firing of the neuron to the stimulus. However, high-frequency repetitive stimulation in the GP generated a biphasic modulation of the firing frequency consisting of inhibitory and excitatory phases. Using blockers of synaptic transmission, we show that GABAergic synapses mediated the inhibitory and glutamatergic synapses the excitatory part of the response. Furthermore, we report that at high stimulation frequencies both types of synapses undergo short-term depression leading to a time dependent modulation of the neuronal firing. These findings indicate that STP modulates the dynamic responses of pallidal activity during electrical stimulation, and may contribute to a better understanding of the mechanism underlying deep brain stimulation (DBS like protocols.

  8. Mechanisms underlying enhancements in muscle force and power output during maximal cycle ergometer exercise induced by chronic β2-adrenergic stimulation in men

    Hostrup, Morten; Kalsen, Anders; Onslev, Johan

    2015-01-01

    The study was a randomized placebo-controlled trial investigating mechanisms by which chronic β2-adrenergic stimulation enhances muscle force and power output during maximal cycle ergometer exercise in young men. Eighteen trained men were assigned to an experimental group (oral terbutaline 5 mg∙30...... of muscle proteins involved in growth, ion handling, lactate production and clearance increased (P≤0.05) with the intervention in TER compared to PLA, with no change in oxidative enzymes. Our observations suggest that muscle hypertrophy is the primary mechanism underlying enhancements in muscle force...... and peak power during maximal cycling induced by chronic β2-adrenergic stimulation in humans....

  9. Role of KATP channels in cephalic vasodilatation induced by calcitonin gene-related peptide, nitric oxide, and transcranial electrical stimulation in the rat

    Gozalov, Aydin; Jansen-Olesen, Inger; Klærke, Dan Arne

    2008-01-01

    OBJECTIVE: The objective of this study was to explore the role of K(ATP) channels in vasodilatation induced by calcitonin gene-related peptide (CGRP), nitric oxide (NO), and transcranial electrical stimulation (TES) in intracranial arteries of rat. BACKGROUND: Dilatation of cerebral and dural...... CGRP, NO, and endogenous CGRP after electrical stimulation. Also diameter changes of pial arteries, mean arterial blood pressure and local cerebral blood flow by Laser Doppler flowmetry (LCBF(Flux)) were measured. RESULTS: CGRP, NO, and TES caused dilatation of the 2 arteries in vivo and in vitro...

  10. Wake-promoting actions of median nerve stimulation in TBI-induced coma: An investigation of orexin-A and orexin receptor 1 in the hypothalamic region.

    Zhong, Ying-Jun; Feng, Zhen; Wang, Liang; Wei, Tian-Qi

    2015-09-01

    A coma is a serious complication, which can occur following traumatic brain injury (TBI), for which no effective treatment has been established. Previous studies have suggested that neural electrical stimulation, including median nerve stimulation (MNS), may be an effective method for treating patients in a coma, and orexin‑A, an excitatory hypothalamic neuropeptide, may be involved in wakefulness. However, the exact mechanisms underlying this involvement remain to be elucidated. The present study aimed to examine the arousal‑promoting role of MNS in rats in a TBI‑induced coma and to investigate the potential mechanisms involved. A total of 90 rats were divided into three groups, comprising a control group, sham‑stimulated (TBI) group and a stimulated (TBI + MNS) group. MNS was performed on the animals, which were in a TBI‑induced comatose state. Changes in the behavior of the rats were observed following MNS. Subsequently, hypothalamic tissues were extracted from the rats 6, 12 and 24 h following TBI or MNS, respectively. The expression levels of orexin‑A and orexin receptor‑1 (OX1R) in the hypothalamus were examined using immunohistochemistry, western blotting and an enzyme‑linked immunosorbent assay. The results demonstrated that 21 rats subjected to TBI‑induced coma exhibited a restored righting reflex and response to pain stimuli following MNS. In addition, ignificant differences in the expression levels of orexin‑A and OXIR were observed among the three groups and among the time‑points. Orexin‑A and OX1R were upregulated following MNS. The rats in the stimulated group reacted to the MNS and exhibited a re‑awakening response. The results of the present study indicated that MNS may be a therapeutic option for TBI‑induced coma. The mechanism may be associated with increasing expression levels of the excitatory hypothalamic neuropeptide, orexin-A, and its receptor, OX1R, in the hypothalamic region.

  11. Ribosomal Protein S6 Kinase (RSK-2 as a central effector molecule in RON receptor tyrosine kinase mediated epithelial to mesenchymal transition induced by macrophage-stimulating protein

    Zhang Rui-Wen

    2011-05-01

    Full Text Available Abstract Background Epithelial to mesenchymal transition (EMT occurs during cancer cell invasion and malignant metastasis. Features of EMT include spindle-like cell morphology, loss of epithelial cellular markers and gain of mesenchymal phenotype. Activation of the RON receptor tyrosine kinase by macrophage-stimulating protein (MSP has been implicated in cellular EMT program; however, the major signaling determinant(s responsible for MSP-induced EMT is unknown. Results The study presented here demonstrates that RSK2, a downstream signaling protein of the Ras-Erk1/2 pathway, is the principal molecule that links MSP-activated RON signaling to complete EMT. Using MDCK cells expressing RON as a model, a spindle-shape based screen was conducted, which identifies RSK2 among various intracellular proteins as a potential signaling molecule responsible for MSP-induced EMT. MSP stimulation dissociated RSK2 with Erk1/2 and promoted RSK2 nuclear translocation. MSP strongly induced RSK2 phosphorylation in a dose-dependent manner. These effects relied on RON and Erk1/2 phosphorylation, which is significantly potentiated by transforming growth factor (TGF-β1, an EMT-inducing cytokine. Specific RSK inhibitor SL0101 completely prevented MSP-induced RSK phosphorylation, which results in inhibition of MSP-induced spindle-like morphology and suppression of cell migration associated with EMT. In HT-29 cancer cells that barely express RSK2, forced RSK2 expression results in EMT-like phenotype upon MSP stimulation. Moreover, specific siRNA-mediated silencing of RSK2 but not RSK1 in L3.6pl pancreatic cancer cells significantly inhibited MSP-induced EMT-like phenotype and cell migration. Conclusions MSP-induced RSK2 activation is a critical determinant linking RON signaling to cellular EMT program. Inhibition of RSK2 activity may provide a therapeutic opportunity for blocking RON-mediated cancer cell migration and subsequent invasion.

  12. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial

    Bayram, Neriman; van Wely, Madelon; Kaaijk, Eugenie M; Bossuyt, Patrick M M; van der Veen, Fulco

    2004-01-01

    Objective To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with polycystic ovary syndrome. Design Randomised controlled trial. Setting Secondary and tertiary hospitals in the Netherlands. Participants 168 patients with clomiphene citrate resistant polycystic ovary syndrome: 83 were allocated electrocautery and 85 were allocated recombinant follicle stimulating hormone. Intervention Laparoscopic electrocautery of the ovaries followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or induction of ovulation with recombinant follicle stimulating hormone. Main outcome measure Ongoing pregnancy within 12 months. Results. The cumulative rate of ongoing pregnancy after recombinant follicle stimulating hormone was 67%. With only electrocautery it was 34%, which increased to 49% after clomiphene citrate was given. Subsequent recombinant follicle stimulating hormone increased the rate to 67% at 12 months (rate ratio 1.01, 95% confidence interval 0.81 to 1.24). No complications occurred from electrocautery with or without clomiphene citrate. Patients allocated to electrocautery had a significantly lower risk of multiple pregnancy (0.11, 0.01 to 0.86). Conclusion The ongoing pregnancy rate from ovulation induction with laparoscopic electrocautery followed by clomiphene citrate and recombinant follicle stimulating hormone if anovulation persisted, or recombinant follicle stimulating hormone, seems equivalent to ovulation induction with recombinant follicle stimulating hormone, but the former procedure carries a lower risk of multiple pregnancy. PMID:14739186

  13. Inhibition of Follicle-Stimulating Hormone-Induced Preovulatory Follicles in Rats Treated with a Nonsteroidal Negative Allosteric Modulator of Follicle-Stimulating Hormone Receptor1

    Dias, James A.; Campo, Brice; Weaver, Barbara A.; Watts, Julie; Kluetzman, Kerri; Thomas, Richard M.; Bonnet, Béatrice; Mutel, Vincent; Poli, Sonia M.

    2013-01-01

    We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive. Toward this end, a high-throughput screen using human F...

  14. Motor and Nonmotor Circuitry Activation Induced by Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease: Intraoperative Functional Magnetic Resonance Imaging for Deep Brain Stimulation.

    Knight, Emily J; Testini, Paola; Min, Hoon-Ki; Gibson, William S; Gorny, Krzysztof R; Favazza, Christopher P; Felmlee, Joel P; Kim, Inyong; Welker, Kirk M; Clayton, Daniel A; Klassen, Bryan T; Chang, Su-youne; Lee, Kendall H

    2015-06-01

    To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. clinicaltrials.gov Identifier: NCT01809613. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  15. Activity in the primary somatosensory cortex induced by reflexological stimulation is unaffected by pseudo-information: a functional magnetic resonance imaging study.

    Miura, Naoki; Akitsuki, Yuko; Sekiguchi, Atsushi; Kawashima, Ryuta

    2013-05-27

    Reflexology is an alternative medical practice that produces beneficial effects by applying pressure to specific reflex areas. Our previous study suggested that reflexological stimulation induced cortical activation in somatosensory cortex corresponding to the stimulated reflex area; however, we could not rule out the possibility of a placebo effect resulting from instructions given during the experimental task. We used functional magnetic resonance imaging (fMRI) to investigate how reflexological stimulation of the reflex area is processed in the primary somatosensory cortex when correct and pseudo-information about the reflex area is provided. Furthermore, the laterality of activation to the reflexological stimulation was investigated. Thirty-two healthy Japanese volunteers participated. The experiment followed a double-blind design. Half of the subjects received correct information, that the base of the second toe was the eye reflex area, and pseudo-information, that the base of the third toe was the shoulder reflex area. The other half of the subjects received the opposite information. fMRI time series data were acquired during reflexological stimulation to both feet. The experimenter stimulated each reflex area in accordance with an auditory cue. The fMRI data were analyzed using a conventional two-stage approach. The hemodynamic responses produced by the stimulation of each reflex area were assessed using a general linear model on an intra-subject basis, and a two-way repeated-measures analysis of variance was performed on an intersubject basis to determine the effect of reflex area laterality and information accuracy. Our results indicated that stimulation of the eye reflex area in either foot induced activity in the left middle postcentral gyrus, the area to which tactile sensation to the face projects, as well as in the postcentral gyrus contralateral foot representation area. This activity was not affected by pseudo information. The results also indicate

  16. Activity in the primary somatosensory cortex induced by reflexological stimulation is unaffected by pseudo-information: a functional magnetic resonance imaging study

    2013-01-01

    Background Reflexology is an alternative medical practice that produces beneficial effects by applying pressure to specific reflex areas. Our previous study suggested that reflexological stimulation induced cortical activation in somatosensory cortex corresponding to the stimulated reflex area; however, we could not rule out the possibility of a placebo effect resulting from instructions given during the experimental task. We used functional magnetic resonance imaging (fMRI) to investigate how reflexological stimulation of the reflex area is processed in the primary somatosensory cortex when correct and pseudo-information about the reflex area is provided. Furthermore, the laterality of activation to the reflexological stimulation was investigated. Methods Thirty-two healthy Japanese volunteers participated. The experiment followed a double-blind design. Half of the subjects received correct information, that the base of the second toe was the eye reflex area, and pseudo-information, that the base of the third toe was the shoulder reflex area. The other half of the subjects received the opposite information. fMRI time series data were acquired during reflexological stimulation to both feet. The experimenter stimulated each reflex area in accordance with an auditory cue. The fMRI data were analyzed using a conventional two-stage approach. The hemodynamic responses produced by the stimulation of each reflex area were assessed using a general linear model on an intra-subject basis, and a two-way repeated-measures analysis of variance was performed on an intersubject basis to determine the effect of reflex area laterality and information accuracy. Results Our results indicated that stimulation of the eye reflex area in either foot induced activity in the left middle postcentral gyrus, the area to which tactile sensation to the face projects, as well as in the postcentral gyrus contralateral foot representation area. This activity was not affected by pseudo information

  17. Effect of low frequency electrical stimulation on seizure-induced short- and long-term impairments in learning and memory in rats.

    Esmaeilpour, Khadijeh; Sheibani, Vahid; Shabani, Mohammad; Mirnajafi-Zadeh, Javad

    2017-01-01

    Kindled seizures can impair learning and memory. In the present study the effect of low-frequency electrical stimulation (LFS) on kindled seizure-induced impairment in spatial learning and memory was investigated and followed up to one month. Animals were kindled by electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations per day). One group of animals received four trials of LFS at 30s, 6h, 24h, and 30h following the last kindling stimulation. Each LFS trial was consisted of 4 packages at 5min intervals. Each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The Open field, Morris water maze, and novel object recognition tests were done 48h, 1week, 2weeks, and one month after the last kindling stimulation respectively. Kindled animals showed a significant impairment in learning and memory compared to control rats. LFS decreased the kindling-induced learning and memory impairments at 24h and one week following its application, but not at 2week or 1month after kindling. In the group of animals that received the same 4 trials of LFS again one week following the last kindling stimulation, the improving effect of LFS was observed even after one month. Obtained results showed that application of LFS in fully kindled animals has a long-term improving effect on spatial learning and memory. This effect can remain for a long duration (one month in this study) by increasing the number of applied LFS. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Repetitive transcranial magnetic stimulation once a week induces sustainable long-term relief of central poststroke pain.

    Kobayashi, Masahito; Fujimaki, Takamitsu; Mihara, Ban; Ohira, Takayuki

    2015-06-01

    Central poststroke pain is a serious problem for some patients after stroke. Repetitive transcranial magnetic stimulation (rTMS) has been reported to relieve poststroke pain but its efficacy is still controversial. We tested the possibility that rTMS, when applied once a week, would induce sustainable relief of poststroke pain. Eighteen patients with central poststroke pain were included in this study. rTMS (10 trains of 10-sec 5 Hz-rTMS) was delivered over the primary motor cortex on the affected side. The rTMS session was repeated once a week for 12 weeks, and for six patients the intervention was continued for one year. The degree of the pain was assessed before each weekly rTMS session to evaluate sustainable effects. The effects of the rTMS reached a plateau at the eighth week. At the 12th week, the rTMS was effective in 61.1% of the patients; 5 of the 18 patients showed more than 70% reduction based on a visual analog scale, 6 patients showed 40-69% reduction, and 7 remained at a pain reduction level of less than 40%. When patients were divided into two groups with or without severe dysesthesia, it was found that eight patients with severe dysesthesia showed less pain relief than those without. In the six patients who continued rTMS for one year, the pain relief effects also were sustained. Although this was an open-label study without a control group, our findings suggest that rTMS of the primary motor cortex, when maintained once a week, could help to relieve poststroke pain. © 2015 International Neuromodulation Society.

  19. Meat quality and rigor mortis development in broiler chickens with gas-induced anoxia and postmortem electrical stimulation.

    Sams, A R; Dzuik, C S

    1999-10-01

    This study was conducted to evaluate the combined rigor-accelerating effects of postmortem electrical stimulation (ES) and argon-induced anoxia (Ar) of broiler chickens. One hundred broilers were processed in the following treatments: untreated controls, ES, Ar, or Ar with ES (Ar + ES). Breast fillets were harvested at 1 h postmortem for all treatments or at 1 and 6 h postmortem for the control carcasses. Fillets were sampled for pH and ratio of inosine to adenosine (R-value) and were then individually quick frozen (IQF) or aged on ice (AOI) until 24 h postmortem. Color was measured in the AOI fillets at 24 h postmortem. All fillets were then cooked and evaluated for Allo-Kramer shear value. The Ar treatment accelerated the normal pH decline, whereas the ES and AR + ES treatments yielded even lower pH values at 1 h postmortem. The Ar + ES treatment had a greater R-value than the ES treatment, which was greater than either the Ar or 1-h controls, which, in turn, were not different from each other. The ES treatment had the lowest L* value, and ES, Ar, and Ar + ES produced significantly higher a* values than the 1-h controls. For the IQF fillets, the ES and Ar + ES treatments were not different in shear value but were lower than Ar, which was lower than the 1-h controls. The same was true for the AOI fillets except that the ES and the Ar treatments were not different. These results indicated that although ES and Ar had rigor-accelerating and tenderizing effects, ES seemed to be more effective than Ar; there was little enhancement when Ar was added to the ES treatment and fillets were deboned at 1 h postmortem.

  20. Prolonged asymmetric vestibular stimulation induces opposite, long-term effects on self-motion perception and ocular responses.

    Pettorossi, V E; Panichi, R; Botti, F M; Kyriakareli, A; Ferraresi, A; Faralli, M; Schieppati, M; Bronstein, A M

    2013-04-01

    Self-motion perception and the vestibulo-ocular reflex (VOR) were investigated in healthy subjects during asymmetric whole body yaw plane oscillations while standing on a platform in the dark. Platform oscillation consisted of two half-sinusoidal cycles of the same amplitude (40°) but different duration, featuring a fast (FHC) and a slow half-cycle (SHC). Rotation consisted of four or 20 consecutive cycles to probe adaptation further with the longer duration protocol. Self-motion perception was estimated by subjects tracking with a pointer the remembered position of an earth-fixed visual target. VOR was measured by electro-oculography. The asymmetric stimulation pattern consistently induced a progressive increase of asymmetry in motion perception, whereby the gain of the tracking response gradually increased during FHCs and decreased during SHCs. The effect was observed already during the first few cycles and further increased during 20 cycles, leading to a totally distorted location of the initial straight-ahead. In contrast, after some initial interindividual variability, the gain of the slow phase VOR became symmetric, decreasing for FHCs and increasing for SHCs. These oppositely directed adaptive effects in motion perception and VOR persisted for nearly an hour. Control conditions using prolonged but symmetrical stimuli produced no adaptive effects on either motion perception or VOR. These findings show that prolonged asymmetric activation of the vestibular system leads to opposite patterns of adaptation of self-motion perception and VOR. The results provide strong evidence that semicircular canal inputs are processed centrally by independent mechanisms for perception of body motion and eye movement control. These divergent adaptation mechanisms enhance awareness of movement toward the faster body rotation, while improving the eye stabilizing properties of the VOR.

  1. Allergen-stimulated T lymphocytes from allergic patients induce vascular cell adhesion molecule-1 (VCAM-1) expression and IL-6 production by endothelial cells.

    Delneste, Y; Jeannin, P; Gosset, P; Lassalle, P; Cardot, E; Tillie-Leblond, I; Joseph, M; Pestel, J; Tonnel, A B

    1995-01-01

    Adhesion of inflammatory cells to endothelium is a critical step for their transvascular migration to inflammatory sites. To evaluate the relationship between T lymphocytes (TL) and vascular endothelium, supernatants from allergen-stimulated TL obtained from patients sensitive to Dermatophagoides pteronyssinus (Dpt) versus healthy subjects were added to endothelial cell (EC) cultures. TL were stimulated by autologous-activated antigen-presenting cells (APC) previously fixed in paraformaldehyde to prevent monokine secretion. Two parameters were measured: the expression of adhesion molecule and the production of IL-6. Related allergen-stimulated TL supernatants from allergic patients induced an increase of VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) expression when supernatants of the control groups (TL exposed to an unrelated allergen or not stimulated or TL obtained from healthy subjects) did not. E-selectin expression was not modulated whatever the supernatant added to EC culture. IL-6 production by EC was significantly enhanced after activation with related allergen-stimulated TL supernatants from allergics compared with control supernatants. Induction of VCAM-1 expression was inhibited by adding neutralizing antibodies against IL-4, whereas IL-6 production and ICAM-1 expression were inhibited by anti-interferon-gamma (IFN-gamma) antibodies. Enhanced production of IL-4 and IFN-gamma was detected in related allergen-stimulated TL supernatants from allergic subjects compared with the different supernatants. These data suggest that allergen-specific TL present in the peripheral blood of allergic patients are of Th1 and Th2 subtypes. Their stimulation in allergic patients may lead to the activation of endothelial cells and thereby participate in leucocyte recruitment towards the inflammatory site. PMID:7542574

  2. Two types of exercise-induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study.

    Juenger, Hendrik; Kuhnke, Nicola; Braun, Christoph; Ummenhofer, Frank; Wilke, Marko; Walther, Michael; Koerte, Inga; Delvendahl, Igor; Jung, Nikolai H; Berweck, Steffen; Staudt, Martin; Mall, Volker

    2013-10-01

    Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but 'healthy' contralateral motor projections (contra). Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10-30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11-31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly

  3. BCR ligation induced by IgM stimulation results in gene expression and functional changes only in IgV H unmutated chronic lymphocytic leukemia (CLL) cells.

    Guarini, Anna; Chiaretti, Sabina; Tavolaro, Simona; Maggio, Roberta; Peragine, Nadia; Citarella, Franca; Ricciardi, Maria Rosaria; Santangelo, Simona; Marinelli, Marilisa; De Propris, Maria Stefania; Messina, Monica; Mauro, Francesca Romana; Del Giudice, Ilaria; Foà, Robert

    2008-08-01

    Chronic lymphocytic leukemia (CLL) patients exhibit a variable clinical course. To investigate the association between clinicobiologic features and responsiveness of CLL cells to anti-IgM stimulation, we evaluated gene expression changes and modifications in cell-cycle distribution, proliferation, and apoptosis of IgV(H) mutated (M) and unmutated (UM) samples upon BCR cross-linking. Unsupervised analysis highlighted a different response profile to BCR stimulation between UM and M samples. Supervised analysis identified several genes modulated exclusively in the UM cases upon BCR cross-linking. Functional gene groups, including signal transduction, transcription, cell-cycle regulation, and cytoskeleton organization, were up-regulated upon stimulation in UM cases. Cell-cycle and proliferation analyses confirmed that IgM cross-linking induced a significant progression into the G(1) phase and a moderate increase of proliferative activity exclusively in UM patients. Moreover, we observed only a small reduction in the percentage of subG(0/1) cells, without changes in apoptosis, in UM cases; contrariwise, a significant increase of apoptotic levels was observed in stimulated cells from M cases. These results document that a differential genotypic and functional response to BCR ligation between IgV(H) M and UM cases is operational in CLL, indicating that response to antigenic stimulation plays a pivotal role in disease progression.

  4. 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

    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

  5. Effects of Transcranial Direct Current Stimulation Block Remifentanil-Induced Hyperalgesia: A Randomized, Double-Blind Clinical Trial

    Gilberto Braulio

    2018-02-01

    Full Text Available Background: Remifentanil-induced hyperalgesia (r-IH involves an imbalance in the inhibitory and excitatory systems. As the transcranial Direct Current Stimulation (tDCS modulates the thalamocortical synapses in a top-down manner, we hypothesized that the active (a-t-DCS would be more effective than sham(s-tDCS to prevent r-IH. We used an experimental paradigm to induce temporal summation of pain utilizing a repetitive cold test (rCOLDT assessed by the Numerical Pain Score (NPS 0-10 and we evaluated the function of the descending pain modulatory system (DPMS by the change on the NPS (0–10 during the conditioned pain modulation (CPM-task (primary outcomes. We tested whether a-tDCS would be more effective than s-tDCS to improve pain perception assessed by the heat pain threshold (HPT and the reaction time during the ice-water pain test (IPT (secondary outcomes.Methods: This double-blinded, factorial randomized trial included 48 healthy males, ages ranging 19–40 years. They were randomized into four equal groups: a-tDCS/saline, s-tDCS/saline, a-tDCS/remifentanil and s-tDCS/remifentanil. tDCS was applied over the primary motor cortex, during 20 min at 2 mA, which was introduced 10 min after starting remifentanil infusion at 0.06 μg⋅kg-1⋅min-1 or saline.Results: An ANCOVA mixed model revealed that during the rCOLDT, there was a significant main effect on the NPS scores (F = 3.81; P = 0.01. The s-tDCS/remifentanil group presented larger pain scores during rCOLDT, [mean (SD 5.49 (1.04] and a-tDCS/remifentanil group had relative lower pain scores [4.15 (1.62]; showing its blocking effect on r-IH. a-tDCS/saline and s-tDCS/saline groups showed lowest pain scores during rCOLDT, [3.11 (1.2] and [3.15 (1.62], respectively. The effect of sedation induced by remifentanil during the rCOLDT was not significant (F = 0.76; P = 0.38. Remifentanil groups showed positive scores in the NPS (0–10 during the CPM-task, that is, it produced a disengagement of

  6. Prolonged electrical stimulation-induced gluteal and hamstring muscle activation and sitting pressure in spinal cord injury: Effect of duty cycle

    Christof A. J. Smit, MD; Karin J. A. Legemate, MSc; Anja de Koning, MSc; Sonja de Groot, PhD; Janneke M. Stolwijk-Swuste, MD, PhD; Thomas W. J. Janssen, PhD

    2013-01-01

    Pressure ulcers (PUs) are highly prevalent in people with spinal cord injury (SCI). Electrical stimulation (ES) activates muscles and might reduce risk factors. Our objectives were to study and compare the effects of two duty cycles during 3 h of ES-induced gluteal and hamstring activation on interface pressure distribution in sitting individuals with SCI and study the usability of a newly developed electrode garment (ES shorts). Ten individuals with SCI participated in this study, in which t...

  7. Transcutaneous electrical nerve stimulation attenuates CFA-induced hyperalgesia and inhibits spinal ERK1/2-COX-2 pathway activation in rats

    Fang, Jun-Fan; Liang, Yi; Du, Jun-Ying; Fang, Jian-Qiao

    2013-01-01

    Background Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacologic treatment for pain relief. In previous animal studies, TENS effectively alleviated Complete Freund?s Adjuvant (CFA)- or carrageenan-induced inflammatory pain. Although TENS is known to produce analgesia via opioid activation in the brain and at the spinal level, few reports have investigated the signal transduction pathways mediated by TENS. Prior studies have verified the importance of the activation of extr...

  8. Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2 /Akt/NF-κB pathway.

    Onphachanh, Xaykham; Lee, Hyun Jik; Lim, Jae Ryong; Jung, Young Hyun; Kim, Jun Sung; Chae, Chang Woo; Lee, Sei-Jung; Gabr, Amr Ahmed; Han, Ho Jae

    2017-09-01

    Hyperglycemia is a representative hallmark and risk factor for diabetes mellitus (DM) and is closely linked to DM-associated neuronal cell death. Previous investigators reported on a genome-wide association study and showed relationships between DM and melatonin receptor (MT), highlighting the role of MT signaling by assessing melatonin in DM. However, the role of MT signaling in DM pathogenesis is unclear. Therefore, we investigated the role of mitophagy regulators in high glucose-induced neuronal cell death and the effect of melatonin against high glucose-induced mitophagy regulators in neuronal cells. In our results, high glucose significantly increased PTEN-induced putative kinase 1 (PINK1) and LC-3B expressions; as well it decreased cytochrome c oxidase subunit 4 expression and Mitotracker™ fluorescence intensity. Silencing of PINK1 induced mitochondrial reactive oxygen species (ROS) accumulation and mitochondrial membrane potential impairment, increased expressions of cleaved caspases, and increased the number of annexin V-positive cells. In addition, high glucose-stimulated melatonin receptor 1B (MTNR1B) mRNA and PINK1 expressions were reversed by ROS scavenger N-acetyl cysteine pretreatment. Upregulation of PINK1 expression in neuronal cells is suppressed by pretreatment with MT 2 receptor-specific inhibitor 4-P-PDOT. We further showed melatonin stimulated Akt phosphorylation, which was followed by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation. Silencing of PINK1 expression abolished melatonin-regulated mitochondrial ROS production, cleaved caspase-3 and caspase-9 expressions, and the number of annexin V-positive cells. In conclusion, we have demonstrated the melatonin stimulates PINK1 expression via an MT 2 /Akt/NF-κB pathway, and such stimulation is important for the prevention of neuronal cell apoptosis under high glucose conditions. © 2017 The Authors. Journal of Pineal Research

  9. Role of catechins on ET-1 induced stimulation of PLD and NADPH oxidase activities in pulmonary smooth muscle cells: Determination of the probable mechanism by molecular docking studies.

    Chakraborti, Sajal; Sarkar, Jaganmay; Bhuyan, Rajabrata; Chakraborti, Tapati

    2017-12-05

    Treatment of human pulmonary artery smooth muscle cells with ET-1 stimulated PLD and NADPH oxidase activities, which were inhibited upon pretreatment with bosentan (ET-1 receptor antagonist), FIPI (PLD inhibitor), apocynin (NADPH oxidase inhibitor) and EGCG & ECG (catechins having galloyl group), but not EGC & EC (catechins devoid of galloyl group). Herein, we determined the probable mechanism by which the galloyl group containing catechins inhibit ET-1 induced stimulation of PLD activity by molecular docking analyses based on our biochemical studies. ET-1 induced stimulation of PLD activity was inhibited by SecinH3 (inhibitor of cytohesin). Arf-6 and cytohesin-1 were associated in the cell membrane, which was not inhibited by the catechins during ET-1 treatment to the cells. However, EGCG and ECG inhibited binding of GTPγS with Arf-6 even in presence of cytohesin-1. The molecular docking analyses revealed that the galloyl group containing catechins (EGCG/ECG) with cytohesin1-Arf6GDP, but not the non-galloyl-containing catechins (EGC and EC), prevents GDP/GTP exchange in Arf-6 which seems to be an important mechanism for inhibition of ET-1 induced activation of PLD and subsequently increase in NADPH oxidase activities.

  10. Comparison of Brain Activation Images Associated with Sexual Arousal Induced by Visual Stimulation and SP6 Acupuncture: fMRI at 3 Tesla

    Choi, Nam Gil [Dept. of Radiology, Chonnam National University Hospital, Gwangju (Korea, Republic of); Han, Jae Bok; Jang, Seong Joo [Dept. of Radiology, Dongshin University, Naju (Korea, Republic of)

    2009-06-15

    This study was performed not only to compare the brain activation regions associated with sexual arousal induced by visual stimulation and SP6 acupuncture, but also to evaluate its differential neuro-anatomical mechanism in healthy women using functional magnetic resonance imaging (fMRI) at 3 Tesla (T). A total of 21 healthy right-handed female volunteers (mean age 22 years, range 19 to 32) underwent fMRI on a 3T MR scanner. The stimulation paradigm for sexual arousal consisted of two alternating periods of rest and activation. It began with a 1-minute rest period, 3 minutes of stimulation with either of an erotic video film or SP6 acupuncture, followed by 1-minute rest. In addition, a comparative study on the brain activation patterns between an acupoint and a shampoint nearby GB37 was performed. The fMRI data were obtained from 20 slices parallel to the AC-PC line on an axial plane, giving a total of 2,000 images. The mean activation maps were constructed and analyzed by using the statistical parametric mapping (SPM99) software. As comparison with the shampoint, the acupoint showed 5 times and 2 times higher activities in the neocortex and limbic system, respectively. Note that brain activation in response to stimulation with the shampoint was not observed in the regions including the HTHL in the diencephalon, GLO and AMYG in the basal ganglia, and SMG in the parietal lobe. In the comparative study of visual stimulation vs. SP6 acupuncture, the mean activation ratio of stimulus was not significantly different to each other in both the neocortex and the limbic system (p < 0.05). The mean activities induced by both stimuli were not significantly different in the neocortex, whereas the acupunctural stimulation showed higher activity in the limbic system (p < 0.05). This study compared the differential brain activation patterns and the neural mechanisms for sexual arousal, which were induced by visual stimulation and SP6 acupuncture by using 3T fMRI. These findings

  11. Comparison of Brain Activation Images Associated with Sexual Arousal Induced by Visual Stimulation and SP6 Acupuncture: fMRI at 3 Tesla

    Choi, Nam Gil; Han, Jae Bok; Jang, Seong Joo

    2009-01-01

    This study was performed not only to compare the brain activation regions associated with sexual arousal induced by visual stimulation and SP6 acupuncture, but also to evaluate its differential neuro-anatomical mechanism in healthy women using functional magnetic resonance imaging (fMRI) at 3 Tesla (T). A total of 21 healthy right-handed female volunteers (mean age 22 years, range 19 to 32) underwent fMRI on a 3T MR scanner. The stimulation paradigm for sexual arousal consisted of two alternating periods of rest and activation. It began with a 1-minute rest period, 3 minutes of stimulation with either of an erotic video film or SP6 acupuncture, followed by 1-minute rest. In addition, a comparative study on the brain activation patterns between an acupoint and a shampoint nearby GB37 was performed. The fMRI data were obtained from 20 slices parallel to the AC-PC line on an axial plane, giving a total of 2,000 images. The mean activation maps were constructed and analyzed by using the statistical parametric mapping (SPM99) software. As comparison with the shampoint, the acupoint showed 5 times and 2 times higher activities in the neocortex and limbic system, respectively. Note that brain activation in response to stimulation with the shampoint was not observed in the regions including the HTHL in the diencephalon, GLO and AMYG in the basal ganglia, and SMG in the parietal lobe. In the comparative study of visual stimulation vs. SP6 acupuncture, the mean activation ratio of stimulus was not significantly different to each other in both the neocortex and the limbic system (p < 0.05). The mean activities induced by both stimuli were not significantly different in the neocortex, whereas the acupunctural stimulation showed higher activity in the limbic system (p < 0.05). This study compared the differential brain activation patterns and the neural mechanisms for sexual arousal, which were induced by visual stimulation and SP6 acupuncture by using 3T fMRI. These findings

  12. Epac is required for exogenous and endogenous stimulation of adenosine A2B receptor for inhibition of angiotensin II-induced collagen synthesis and myofibroblast differentiation.

    Phosri, Sarawuth; Bunrukchai, Kwanchai; Parichatikanond, Warisara; Sato, Vilasinee H; Mangmool, Supachoke

    2018-01-10

    Angiotensin II (Ang II) plays an important role on the pathogenesis of cardiac fibrosis. Prolong and overstimulation of angiotensin II type 1 receptor with Ang II-induced collagen synthesis and myofibroblast differentiation in cardiac fibroblasts, leading to cardiac fibrosis. Although adenosine and its analogues are known to have cardioprotective effects, the mechanistic by which adenosine A 2 receptors (A 2 Rs) inhibit Ang II-induced cardiac fibrosis is not clearly understood. In the present study, we examined the effects of exogenous adenosine and endogenous adenosine on Ang II-induced collagen and myofibroblast differentiation determined by α-smooth muscle action (α-SMA) overexpression and their underlying signal transduction. Elevation of endogenous adenosine levels resulted in the inhibition of Ang II-induced collagen type I and III and α-SMA synthesis in cardiac fibroblasts. Moreover, treatment with exogenous adenosine which selectively stimulated A 2 Rs also suppressed Ang II-induced collagen synthesis and α-SMA production. These antifibrotic effects of both endogenous and exogenous adenosines are mediated through the A 2B receptor (A 2B R) subtype. Stimulation of A 2B R exhibited antifibrotic effects via the cAMP-dependent and Epac-dependent pathways. Our results provide new mechanistic insights regarding the role for cAMP and Epac on A 2B R-mediated antifibrotic effects. Thus, A 2B R is one of the potential therapeutic targets against cardiac fibrosis.

  13. H2S-induced S-sulfhydration of lactate dehydrogenase a (LDHA) stimulates cellular bioenergetics in HCT116 colon cancer cells.

    Untereiner, Ashley A; Oláh, Gabor; Módis, Katalin; Hellmich, Mark R; Szabo, Csaba

    2017-07-15

    Cystathionine-β-synthase (CBS) is upregulated and hydrogen sulfide (H 2 S) production is increased in colon cancer cells. The functional consequence of this response is stimulation of cellular bioenergetics and tumor growth and proliferation. Lactate dehydrogenase A (LDHA) is also upregulated in various colon cancer cells and has been previously implicated in tumor cell bioenergetics and proliferation. In the present study, we sought to determine the potential interaction between the H 2 S pathway and LDH activity in the control of bioenergetics and proliferation of colon cancer, using the colon cancer line HCT116. Low concentrations of GYY4137 (a slow-releasing H 2 S donor) enhanced mitochondrial function (oxygen consumption, ATP production, and spare respiratory capacity) and glycolysis in HCT116 cells. SiRNA-mediated transient silencing of LDHA attenuated the GYY4137-induced stimulation of mitochondrial respiration, but not of glycolysis. H 2 S induced the S-sulfhydration of Cys163 in recombinant LDHA, and stimulated LDHA activity. The H 2 S-induced stimulation of LDHA activity was absent in C163A LDHA. As shown in HCT116 cell whole extracts, in addition to LDHA activation, GYY4137 also stimulated LDHB activity, although to a smaller extent. Total cellular lactate and pyruvate measurements showed that in HCT116 cells LDHA catalyzes the conversion of pyruvate to lactate. Total cellular lactate levels were increased by GYY4137 in wild-type cells (but not in cells with LDHA silencing). LDHA silencing sensitized HCT116 cells to glucose oxidase (GOx)-induced oxidative stress; this was further exacerbated with GYY4137 treatment. Treatment with low concentrations of GYY4137 (0.3mM) or GOx (0.01U/ml) significantly increased the proliferation rate of HCT116 cells; the effect of GOx, but not the effect of GYY4137 was attenuated by LDHA silencing. The current report points to the involvement of LDHA in the stimulatory effect of H 2 S on mitochondrial respiration in colon

  14. Using an electrocautery strategy or recombinant follicle stimulating hormone to induce ovulation in polycystic ovary syndrome: randomised controlled trial

    Bayram, Neriman; van Wely, Madelon; Kaaijk, Eugenie M.; Bossuyt, Patrick M. M.; van der Veen, Fulco

    2004-01-01

    Objective To compare the effectiveness of an electrocautery strategy with ovulation induction using recombinant follicle stimulating hormone in patients with clomiphene resistant polycystic ovary syndrome. Design Randomised controlled trial. Setting Secondary and tertiary hospitals in the

  15. [Positions of the implanted stimulating electrodes for artificial facial nerve for inducing contraction of the orbicularis oris muscle in rabbit with peripheral facial paralysis].

    Xu, D Y; Zhao, N J; Zhao, Y X; Luo, D; Sun, Y J; Li, K Y

    2017-11-07

    Objective: To explore the optimal positions of the implanted stimulating eletrodes for artificial facial nerve (AFN) for inducing contraction of the orbicularis oris muscle (OOM) in rabbit with peripheral facial paralysis. Methods: According to the four microelectrodes of the AFN stimulating side, four modes of the implanted positions were divided. In line with different modes, the electrodes were implanted into the affected OOM of the rabbits with unilateral peripheral facial paralysis. AFN output electric stimulation to induce contraction of the affected OOM with uniform stimulating frequency and pulse length in vitro. Then compared the stimulus threshold amplitude and the peak amplitude separately among different modes by SAS 9.3 version statistical software. Results: The differences of the stimulus threshold amplitude and the peak amplitude had no statistically significant separately between the first mode and the second mode ( P >0.05), but there were statistically significant differences between the third mode and the fourth mode ( P <0.05). Both kinds of the amplitudes were approximated between the first mode and the second mode respectively, and higher than those in the third mode or the fourth mode. Furthermore, both kinds of the amplitudes in the fourth mode were higher than those in the third mode. Conclusions: The microelectrodes of the AFN stimulating lateral are implanted into the upper lip with a public microelectrode and an output microelectrode, into the lower lip with an output microelectrode, and into the way, which is located to the angle 40° to 45° about the line joining between the midpoint of the ipsilateral auricle root and the corner of the mouth with an output microelectrode. This is the third positional mode which requires lowest effective stimulus current intensity. Thus the mode is suitable as the optimal placement programme.

  16. Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKϵ-IRF3 axis activation.

    Tsukamoto, Hiroki; Takeuchi, Shino; Kubota, Kanae; Kobayashi, Yohei; Kozakai, Sao; Ukai, Ippo; Shichiku, Ayumi; Okubo, Misaki; Numasaki, Muneo; Kanemitsu, Yoshitomi; Matsumoto, Yotaro; Nochi, Tomonori; Watanabe, Kouichi; Aso, Hisashi; Tomioka, Yoshihisa

    2018-05-14

    Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS-induced TLR4 internalization and clarified the roles of the extracellular LPS-binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol-anchored protein (CD14). LPS stimulation of CD14-expressing cells induced TLR4 internalization in the presence of serum, and an inhibitory anti-LBP mAb blocked its internalization. Addition of LBP to serum-free cultures restored LPS-induced TLR4 internalization to comparable levels of serum. The secretory form of the CD14 (sCD14) induced internalization but required a much higher concentration than LBP. An inhibitory anti-sCD14 mAb was ineffective for serum-mediated internalization. LBP lacking the domain for LPS transfer to CD14 and a CD14 mutant with reduced LPS binding both attenuated TLR4 internalization. Accordingly, LBP is an essential serum molecule for TLR4 internalization, and its LPS transfer to membrane-anchored CD14 (mCD14) is a prerequisite. LBP induced the LPS-stimulated phosphorylation of TBK1, IKKϵ, and IRF3, leading to IFN-β expression. However, LPS-stimulated late activation of NFκB or necroptosis were not affected. Collectively, our results indicate that LBP controls LPS-induced TLR4 internalization, which induces TLR adaptor molecule 1 (TRIF)-dependent activation of the TBK1-IKKϵ-IRF3-IFN-β pathway. In summary, we showed that LBP-mediated LPS transfer to mCD14 is required for serum-dependent TLR4 internalization and activation of the TRIF pathway. Copyright © 2018, The American Society for Biochemistry and Molecular Biology.

  17. Increase in short-term memory capacity induced by down-regulating individual theta frequency via transcranial alternating current stimulation.

    Vosskuhl, Johannes; Huster, René J; Herrmann, Christoph S

    2015-01-01

    Working memory (WM) and short-term memory (STM) supposedly rely on the phase-amplitude coupling (PAC) of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual's memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS). To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N = 33) were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG) was measured before stimulation and analyzed with regard to the properties of PAC between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity.

  18. Increase in short-term memory capacity induced by down-regulating individual theta frequency via transcranial alternating current stimulation

    Johannes eVosskuhl

    2015-05-01

    Full Text Available Working memory (WM and short-term memory (STM supposedly rely on the phase-amplitude coupling of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual’s memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS. To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N=33 were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG was measured before stimulation and analyzed with regard to the properties of phase-amplitude coupling between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity.

  19. Inhibition of follicle-stimulating hormone-induced preovulatory follicles in rats treated with a nonsteroidal negative allosteric modulator of follicle-stimulating hormone receptor.

    Dias, James A; Campo, Brice; Weaver, Barbara A; Watts, Julie; Kluetzman, Kerri; Thomas, Richard M; Bonnet, Béatrice; Mutel, Vincent; Poli, Sonia M

    2014-01-01

    We previously described a negative allosteric modulator (NAM) of FSHR (ADX61623) that blocked FSH-induced cAMP and progesterone production but did not block estradiol production. That FSHR NAM did not affect FSH-induced preovulatory follicle development as evidenced by the lack of an effect on the number of FSH-dependent oocytes found in the ampullae following ovulation with hCG. A goal is the development of a nonsteroidal contraceptive. Toward this end, a high-throughput screen using human FSHR identified an additional nonsteroidal small molecule (ADX68692). Although ADX68692 behaved like ADX61623 in inhibiting production of cAMP and progesterone, it also inhibited FSH-induced estradiol in an in vitro rat granulosa primary cell culture bioassay. When immature, noncycling female rats were injected subcutaneously or by oral dosing prior to exogenous FSH administration, it was found that ADX68692 decreased the number of oocytes recovered from the ampullae. The estrous cycles of mature female rats were disrupted by administration by oral gavage of 25 mg/kg and 10 mg/kg ADX68692. In the highest dose tested (25 mg/kg), 55% of animals cohabited with mature males had implantation sites compared to 33% in the 10 mg/kg group and 77% in the control group. A surprising finding was that a structural analog ADX68693, while effectively blocking progesterone production with similar efficacy as ADX68692, did not block estrogen production and despite better oral availability did not decrease the number of oocytes found in the ampullae even when used at 100 mg/kg. These data demonstrate that because of biased antagonism of the FSHR, nonsteroidal contraception requires that both arms of the FSHR steroidogenic pathway must be effectively blocked, particularly estrogen biosynthesis. Thus, a corollary to these findings is that it seems reasonable to propose that the estrogen-dependent diseases such as endometriosis may benefit from inhibition of FSH action at the ovary using the FSHR

  20. High Definition Transcranial Direct Current Stimulation Induces Both Acute and Persistent Changes in Broadband Cortical Synchronization: a Simultaneous tDCS-EEG Study

    Roy, Abhrajeet; Baxter, Bryan

    2014-01-01

    The goal of this study was to develop methods for simultaneously acquiring electrophysiological data during high definition transcranial direct current stimulation (tDCS) using high resolution electroencephalography (EEG). Previous studies have pointed to the after effects of tDCS on both motor and cognitive performance, and there appears to be potential for using tDCS in a variety of clinical applications. However, little is known about the real-time effects of tDCS on rhythmic cortical activity in humans due to the technical challenges of simultaneously obtaining electrophysiological data during ongoing stimulation. Furthermore, the mechanisms of action of tDCS in humans are not well understood. We have conducted a simultaneous tDCS-EEG study in a group of healthy human subjects. Significant acute and persistent changes in spontaneous neural activity and event related synchronization (ERS) were observed during and after the application of high definition tDCS over the left sensorimotor cortex. Both anodal and cathodal stimulation resulted in acute global changes in broadband cortical activity which were significantly different than the changes observed in response to sham stimulation. For the group of 8 subjects studied, broadband individual changes in spontaneous activity during stimulation were apparent both locally and globally. In addition, we found that high definition tDCS of the left sensorimotor cortex can induce significant ipsilateral and contralateral changes in event related desynchronization (ERD) and ERS during motor imagination following the end of the stimulation period. Overall, our results demonstrate the feasibility of acquiring high resolution EEG during high definition tDCS and provide evidence that tDCS in humans directly modulates rhythmic cortical synchronization during and after its administration. PMID:24956615

  1. Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury.

    Wang, Ruihao; Hösl, Katharina M; Ammon, Fabian; Markus, Jörg; Koehn, Julia; Roy, Sankanika; Liu, Mao; de Rojas Leal, Carmen; Muresanu, Dafin; Flanagan, Steven R; Hilz, Max J

    2018-06-01

    After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. In 51 post-moderate-severe-TBI patients (32.7 ± 10.5 years old, 43.1 ± 33.4 months post-injury), and 30 controls (29.1 ± 9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  2. Effect of bradykinin antagonists on bradykinin-induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit.

    Griesbacher, T.; Lembeck, F.

    1987-01-01

    1 The inhibition of the bradykinin-induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the does used. B4310 (Lys-Lys-3-Hyp-5,8-Thi-7-DPhe-Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B4310 (5-500 nM) antagonized the bradykinin-induced reduction of the venous outflow from the rabbit isolated ear in dose-dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin-induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nM) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nM). The antagonism was dose-dependent and reversible. The parallel shift of the dose-response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine-induced nociceptor stimulation. 5 B4310 inhibited bradykinin-induced stimulation of the trigeminal nerve which results in a substance P-mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin-induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role. PMID:3479223

  3. NR4A1 (Nur77 mediates thyrotropin-releasing hormone-induced stimulation of transcription of the thyrotropin β gene: analysis of TRH knockout mice.

    Yasuyo Nakajima

    Full Text Available Thyrotropin-releasing hormone (TRH is a major stimulator of thyrotropin-stimulating hormone (TSH synthesis in the anterior pituitary, though precisely how TRH stimulates the TSHβ gene remains unclear. Analysis of TRH-deficient mice differing in thyroid hormone status demonstrated that TRH was critical for the basal activity and responsiveness to thyroid hormone of the TSHβ gene. cDNA microarray and K-means cluster analyses with pituitaries from wild-type mice, TRH-deficient mice and TRH-deficient mice with thyroid hormone replacement revealed that the largest and most consistent decrease in expression in the absence of TRH and on supplementation with thyroid hormone was shown by the TSHβ gene, and the NR4A1 gene belonged to the same cluster as and showed a similar expression profile to the TSHβ gene. Immunohistochemical analysis demonstrated that NR4A1 was expressed not only in ACTH- and FSH- producing cells but also in thyrotrophs and the expression was remarkably reduced in TRH-deficient pituitary. Furthermore, experiments in vitro demonstrated that incubation with TRH in GH4C1 cells increased the endogenous NR4A1 mRNA level by approximately 50-fold within one hour, and this stimulation was inhibited by inhibitors for PKC and ERK1/2. Western blot analysis confirmed that TRH increased NR4A1 expression within 2 h. A series of deletions of the promoter demonstrated that the region between bp -138 and +37 of the TSHβ gene was responsible for the TRH-induced stimulation, and Chip analysis revealed that NR4A1 was recruited to this region. Conversely, knockdown of NR4A1 by siRNA led to a significant reduction in TRH-induced TSHβ promoter activity. Furthermore, TRH stimulated NR4A1 promoter activity through the TRH receptor. These findings demonstrated that 1 TRH is a highly specific regulator of the TSHβ gene, and 2 TRH mediated induction of the TSHβ gene, at least in part by sequential stimulation of the NR4A1-TSHβ genes through a PKC and

  4. Rapid Electrical Stimulation Increased Cardiac Apoptosis Through Disturbance of Calcium Homeostasis and Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

    Le Geng

    2018-06-01

    Full Text Available Background/Aims: Heart failure induced by tachycardia, the most common arrhythmia, is frequently observed in clinical practice. This study was designed to investigate the underlying mechanisms. Methods: Rapid electrical stimulation (RES at a frequency of 3 Hz was applied on human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs for 7 days, with 8 h/day and 24 h/day set to represent short-term and long-term tachycardia, respectively. Age-matched hiPSC-CMs without electrical stimulation or with slow electrical stimulation (1 Hz were set as no electrical stimulation (NES control or low-frequency electrical stimulation (LES control. Following stimulation, JC-1 staining flow cytometry analysis was performed to examine mitochondrial conditions. Apoptosis in hiPSC-CMs was evaluated using Hoechst staining and Annexin V/propidium iodide (AV/PI staining flow cytometry analysis. Calcium transients and L-type calcium currents were recorded to evaluate calcium homeostasis. Western blotting and qPCR were performed to evaluate the protein and mRNA expression levels of apoptosis-related genes and calcium homeostasis-regulated genes. Results: Compared to the controls, hiPSC-CMs following RES presented mitochondrial dysfunction and an increased apoptotic percentage. Amplitudes of calcium transients and L-type calcium currents were significantly decreased in hiPSC-CMs with RES. Molecular analysis demonstrated upregulated expression of Caspase3 and increased Bax/Bcl-2 ratio. Genes related to calcium re-sequence were downregulated, while phosphorylated Ca2+/calmodulin-dependent protein kinase II (CaMKII was significantly upregulated following RES. There was no significant difference between the NES control and LES control groups in these aspects. Inhibition of CaMKII with 1 µM KN93 partly reversed these adverse effects of RES. Conclusion: RES on hiPSC-CMs disturbed calcium homeostasis, which led to mitochondrial stress, promoted cell apoptosis and

  5. Crocin Suppresses LPS-Stimulated Expression of Inducible Nitric Oxide Synthase by Upregulation of Heme Oxygenase-1 via Calcium/Calmodulin-Dependent Protein Kinase 4

    Ji-Hee Kim

    2014-01-01

    Full Text Available Crocin is a water-soluble carotenoid pigment that is primarily used in various cuisines as a seasoning and coloring agent, as well as in traditional medicines for the treatment of edema, fever, and hepatic disorder. In this study, we demonstrated that crocin markedly induces the expression of heme oxygenase-1 (HO-1 which leads to an anti-inflammatory response. Crocin inhibited inducible nitric oxide synthase (iNOS expression and nitric oxide production via downregulation of nuclear factor kappa B activity in lipopolysaccharide- (LPS- stimulated RAW 264.7 macrophages. These effects were abrogated by blocking of HO-1 expression or activity. Crocin also induced Ca2+ mobilization from intracellular pools and phosphorylation of Ca2+/calmodulin-dependent protein kinase 4 (CAMK4. CAMK4 knockdown and kinase-dead mutant inhibited crocin-mediated HO-1 expression, Nrf2 activation, and phosphorylation of Akt, indicating that HO-1 expression is mediated by CAMK4 and that Akt is a downstream mediator of CAMK4 in crocin signaling. Moreover, crocin-mediated suppression of iNOS expression was blocked by CAMK4 inhibition. Overall, these results suggest that crocin suppresses LPS-stimulated expression of iNOS by inducing HO-1 expression via Ca2+/calmodulin-CAMK4-PI3K/Akt-Nrf2 signaling cascades. Our findings provide a novel molecular mechanism for the inhibitory effects of crocin against endotoxin-mediated inflammation.

  6. Culicoides antigen extract stimulates equine blood mononuclear (BMN) cell proliferation and the release of eosinophil adherence-inducing factor(s).

    Mckelvie, J; Foster, A P; Hamblin, A S; Cunningham, F M

    2001-04-01

    Intradermal injection of a Culicoides antigen extract (CAgX) induces T lymphocyte and eosinophil accumulation in the skin of horses with sweet itch. Blood mononuclear (BMN) cells from normal ponies proliferate when stimulated by mitogen (phytohaemagglutinin, PHA) or antigen (tetanus toxoid, TT) and, as shown here, release soluble factor(s) that induce eosinophil adherence. CAgX also caused concentration dependent proliferation of BMN cells from sweet itch and normal ponies [stimulation index: 29 (13) and 17 (7) for BMN cells from sweet itch and normal ponies, respectively during the active phase of disease; 4 microg protein ml(-1)CAgX; 168 h]. A heat labile factor(s) which caused eosinophil adherence was also released [sweet itch ponies: 6.0 (1.6) per cent adherence versus 1.3 (0.4) per cent; normal ponies: 6.6 (0.5) per cent adherence versus 0.9 (0.1) per cent for supernatants from CAgX (4 microg protein ml(-1); 48 hours) stimulated versus unstimulated BMN cells, respectively]. These results suggest that soluble proteins released from T lymphocytes could affect eosinophil function in the lesional skin of sweet itch horses. Copyright 2001 Harcourt Publishers Ltd.

  7. Naturally induced secretions of the potato cyst nematode co-stimulate the proliferation of both tobacco leaf protoplasts and human peripheral blood mononuclear cells.

    Goverse, A; Rouppe van der Voort, J; Roppe van der Voort, C; Kavelaars, A; Smant, G; Schots, A; Bakker, J; Helder, J

    1999-10-01

    Naturally induced secretions from infective juveniles of the potato cyst nematode Globodera rostochiensis co-stimulate the proliferation of tobacco leaf protoplasts in the presence of the synthetic phytohormones alpha-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP). With the use of a protoplast-based bioassay, a low-molecular-weight peptide(s) (cyst nematode secretions also co-stimulated mitogenesis in human peripheral blood mononuclear cells (PBMC). The stimulation of plant cells isolated from nontarget tissue--these nematodes normally invade the roots of potato plants--suggests the activation of a general signal transduction mechanism(s) by an oligopeptide(s) secreted by the nematode. Whether a similar oligopeptide-induced mechanism underlies human PBMC activation remains to be investigated. Reactivation of the cell cycle is a crucial event in feeding cell formation by cyst nematodes. The secretion of a mitogenic low-molecular-weight peptide(s) by infective juveniles of the potato cyst nematode could contribute to the redifferentiation of plant cells into such a feeding cell.

  8. Electrical stimulation to the trigeminal proprioceptive fibres that innervate the mechanoreceptors in Müller's muscle induces involuntary reflex contraction of the frontalis muscles.

    Matsuo, Kiyoshi; Osada, Yoshiro; Ban, Ryokuya

    2013-02-01

    The levator and frontalis muscles lack interior muscle spindles, despite consisting of slow-twitch fibres that involuntarily sustain eyelid-opening and eyebrow-raising against gravity. To compensate for this anatomical defect, this study hypothetically proposes that initial voluntary contraction of the levator fast-twitch muscle fibres stretches the mechanoreceptors in Müller's muscle and evokes proprioception, which continuously induces reflex contraction of slow-twitch fibres of the levator and frontalis muscles. This study sought to determine whether unilateral transcutaneous electrical stimulation to the trigeminal proprioceptive fibres that innervate the mechanoreceptors in Müller's muscle could induce electromyographic responses in the frontalis muscles, with monitoring responses in the orbicularis oculi muscles. The study population included 27 normal subjects and 23 subjects with aponeurotic blepharoptosis, who displayed persistently raised eyebrows on primary gaze and light eyelid closure. The stimulation induced a short-latency response in the ipsilateral frontalis muscle of all subjects and long-latency responses in the bilateral frontalis muscles of normal subjects. However, it did not induce long-latency responses in the bilateral frontalis muscles of subjects with aponeurotic blepharoptosis. The orbicularis oculi muscles showed R1 and/or R2 responses. The stimulation might reach not only the proprioceptive fibres, but also other sensory fibres related to the blink or corneal reflex. The experimental system can provoke a monosynaptic short-latency response in the ipsilateral frontalis muscle, probably through the mesencephalic trigeminal proprioceptive neuron and the frontalis motor neuron, and polysynaptic long-latency responses in the bilateral frontalis muscles through an unknown pathway. The latter neural circuit appeared to be engaged by the circumstances of aponeurotic blepharoptosis.

  9. Staurosporine induces ganglion cell differentiation in part by stimulating urokinase-type plasminogen activator expression and activation in the developing chick retina

    Kim, Yeoun-Hee; Chang, Yongmin; Jung, Jae-Chang

    2012-01-01

    Highlights: ► Staurosporine mediates stimulation of RGC differentiation in vitro cultured retinal neuroblasts. ► Staurosporine mediates uPA activation during RGC differentiation in vitro. ► Inhibition of uPA blocks the staurosporine mediated RGC differentiation both in vitro and in ovo. ► Thus, uPA may play a role in the staurosporine-mediated stimulation of RGC differentiation. -- Abstract: Here, we investigated whether staurosporine-mediated urokinase-type plasminogen activator (uPA) activation is involved in retinal ganglion cell (RGC) differentiation. Retinal cells were isolated from developing chick retinas at embryonic day 6 (E6). Relatively few control cells grown in serum-free medium started to form processes by 12 h. In contrast, staurosporine-treated cells had processes within 3 h, and processes were evident at 8 h. Immunofluorescence staining showed that Tuj-1-positive cells with shorter neurites could be detected in control cultures at 18 h, whereas numerous Tuj-1 positive ganglion cells with longer neuritic extensions were seen in staurosporine-treated cultures. BrdU-positive proliferating cells were more numerous in control cultures than in staurosporine-treated cultures, and the BrdU staining was not detected in post-mitotic Tuj-1 positive ganglion cells. Western blotting of cell lysates showed that staurosporine induced high levels of the active form of uPA. The staurosporine-induced uPA signal was localized predominantly in the soma, neurites and axons of Tuj-1-positive ganglion cells. Amiloride, an inhibitor of uPA, markedly reduced staurosporine-induced Tuj-1 staining, neurite length, neurite number, and uPA staining versus controls. In developing retinas in ovo, amiloride administration remarkably reduced the staurosporine-induced uPA staining and RGC differentiation. Taken together, our in vitro and in vivo data collectively indicate that uPA plays a role in the staurosporine-mediated stimulation of RGC differentiation.

  10. Plant Polyphenols Stimulate Adhesion to Intestinal Mucosa and Induce Proteome Changes in the Probiotic Lactobacillus acidophilus NCFM

    Celebioglu, Hasan Ufuk; Delsoglio, Marta; Brix, Susanne

    2017-01-01

    pathways, such as glycolysis, nucleotide metabolism and stress response as well as being known moonlighting or surface-associated proteins. Conclusion: The five plant phenolics found in various foods stimulate the adhesive capacity of NCFM in diverse ways and elicited relative abundancy changes of specific...... of resveratrol and ferulic acid during bacterial growth stimulated adhesion of NCFM to mucin and human intestinal HT-29 cells, while tannic acid improved adhesion only to HT-29 cells and caffeic acid had very modest effect overall. Some dosage dependence was found for the four phenolics supplemented at 100, 250...... or 500 μg/mL to the cultures. Notably, 500 μg/mL ferulic acid only stimulated adhesion to mucin. Analyses of differential whole-cell as well as surface proteomes revealed relative abundancy changes for a total of 27 and 22 NCFM proteins, respectively. These changes include enzymes acting in metabolic...

  11. The influence of radiation-induced defects on thermoluminescence and optically stimulated luminescence of α-Al_2O_3:C

    Nyirenda, A.N.; Chithambo, M.L.

    2017-01-01

    It is known that when α-Al_2O_3:C is exposed to excessive amounts of ionising radiation, defects are induced within its matrix. We report the influence of radiation-induced defects on the thermoluminescence (TL) and optically stimulated luminescence (OSL) measured from α-Al_2O_3:C after irradiation to 1000 Gy. These radiation-induced defects are thermally unstable in the region 450–650 °C and result in TL peaks in this range when the TL is measured at 1 °C/s. Heating a sample to 700 °C obliterates the radiation-induced defects, that is, the TL peaks corresponding to the radiation induced defects are no longer observed in the subsequent TL measurements when moderate irradiation doses below 10 Gy are used. The charge traps associated with these radiation-induced defects are more stable than the dosimetric trap when the sample is exposed to either sunlight or 470-nm blue light from LEDs. TL glow curves measured following the defect-inducing irradiation produce a dosimetric peak that is broader and positioned at a higher temperature than observed in glow curves obtained before the heavy irradiation. In addition, sample sensitization/desensitization occurs due to the presence of these radiation-induced defects. Furthermore, both the activation energy and the kinetic order of the dosimetric peak evaluated when the radiation-induced defects are present in the sample are significantly lower in value than those obtained when these defects are absent. The radiation-induced defects also affect the shape and total light sum of the OSL signal as well as the position and width of the resultant residual phototransferred thermoluminescence main peak.

  12. The influence of radiation-induced defects on thermoluminescence and optically stimulated luminescence of α-Al{sub 2}O{sub 3}:C

    Nyirenda, A.N., E-mail: anyirenda@gmail.com; Chithambo, M.L.

    2017-04-15

    It is known that when α-Al{sub 2}O{sub 3}:C is exposed to excessive amounts of ionising radiation, defects are induced within its matrix. We report the influence of radiation-induced defects on the thermoluminescence (TL) and optically stimulated luminescence (OSL) measured from α-Al{sub 2}O{sub 3}:C after irradiation to 1000 Gy. These radiation-induced defects are thermally unstable in the region 450–650 °C and result in TL peaks in this range when the TL is measured at 1 °C/s. Heating a sample to 700 °C obliterates the radiation-induced defects, that is, the TL peaks corresponding to the radiation induced defects are no longer observed in the subsequent TL measurements when moderate irradiation doses below 10 Gy are used. The charge traps associated with these radiation-induced defects are more stable than the dosimetric trap when the sample is exposed to either sunlight or 470-nm blue light from LEDs. TL glow curves measured following the defect-inducing irradiation produce a dosimetric peak that is broader and positioned at a higher temperature than observed in glow curves obtained before the heavy irradiation. In addition, sample sensitization/desensitization occurs due to the presence of these radiation-induced defects. Furthermore, both the activation energy and the kinetic order of the dosimetric peak evaluated when the radiation-induced defects are present in the sample are significantly lower in value than those obtained when these defects are absent. The radiation-induced defects also affect the shape and total light sum of the OSL signal as well as the position and width of the resultant residual phototransferred thermoluminescence main peak.

  13. Prolonged Repeated Acupuncture Stimulation Induces Habituation Effects in Pain-Related Brain Areas: An fMRI Study

    Li, Chuanfu; Yang, Jun; Park, Kyungmo; Wu, Hongli; Hu, Sheng; Zhang, Wei; Bu, Junjie; Xu, Chunsheng; Qiu, Bensheng; Zhang, Xiaochu

    2014-01-01

    Most previous studies of brain responses to acupuncture were designed to investigate the acupuncture instant effect while the cumulative effect that should be more important in clinical practice has seldom been discussed. In this study, the neural basis of the acupuncture cumulative effect was analyzed. For this experiment, forty healthy volunteers were recruited, in which more than 40 minutes of repeated acupuncture stimulation was implemented at acupoint Zhusanli (ST36). Three runs of acupuncture fMRI datasets were acquired, with each run consisting of two blocks of acupuncture stimulation. Besides general linear model (GLM) analysis, the cumulative effects of acupuncture were analyzed with analysis of covariance (ANCOVA) to find the association between the brain response and the cumulative duration of acupuncture stimulation in each stimulation block. The experimental results showed that the brain response in the initial stage was the strongest although the brain response to acupuncture was time-variant. In particular, the brain areas that were activated in the first block and the brain areas that demonstrated cumulative effects in the course of repeated acupuncture stimulation overlapped in the pain-related areas, including the bilateral middle cingulate cortex, the bilateral paracentral lobule, the SII, and the right thalamus. Furthermore, the cumulative effects demonstrated bimodal characteristics, i.e. the brain response was positive at the beginning, and became negative at the end. It was suggested that the cumulative effect of repeated acupuncture stimulation was consistent with the characteristic of habituation effects. This finding may explain the neurophysiologic mechanism underlying acupuncture analgesia. PMID:24821143

  14. Preirradiation of medium induces a subsequent stimulation or inhibition of growth according to the physiological state in Synechococcus lividus in culture

    Conter, A.

    1987-01-01

    The proliferation of Synechococcus lividus cells grown in preirradiated medium was compared with the proliferation of cells grown in a shielded or freshly prepared medium. Aging of medium in a shielded chamber resulted in a slight inhibiting effect on growth in every phase of the cell cycle which was used. Preirradiation of medium resulted in a stimulation of growth observed on Day 7 in cultures inoculated with cells selected in the deceleration phase and an inhibition of growth in cultures inoculated with exponentially growing cells. Addition of catalase (100 U X ml-1) counteracted the stimulating effect but did not modify the inhibiting effect induced by preirradiated medium. Results demonstrated the indirect effect of low doses of irradiation, implying the presence of hydrogen peroxide in radiostimulation and other radioproducts in the inhibitory effect

  15. Mechanical stimulation of cyclic tensile strain induces reduction of pluripotent related gene expressions via activation of Rho/ROCK and subsequent decreasing of AKT phosphorylation in human induced pluripotent stem cells

    Teramura, Takeshi; Takehara, Toshiyuki; Onodera, Yuta; Nakagawa, Koichi; Hamanishi, Chiaki; Fukuda, Kanji

    2012-01-01

    Highlights: ► Mechanical stimulation is an important factor for regulation of stem cell fate. ► Cyclic stretch to human induced pluripotent stem cells activated small GTPase Rho. ► Rho-kinase activation attenuated pluripotency via inhibition of AKT activation. ► This reaction could be reproduced only by transfection of dominant active Rho. ► Rho/ROCK are important molecules in mechanotransduction and control of stemness. -- Abstract: Mechanical stimulation has been shown to regulate the proliferation and differentiation of stem cells. However, the effects of the mechanical stress on the stemness or related molecular mechanisms have not been well determined. Pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are used as good materials for cell transplantation therapy and research of mammalian development, since they can self-renew infinitely and differentiate into various cell lineages. Here we demonstrated that the mechanical stimulation to human iPS cells altered alignment of actin fibers and expressions of the pluripotent related genes Nanog, POU5f1 and Sox2. In the mechanically stimulated iPS cells, small GTPase Rho was activated and interestingly, AKT phosphorylation was decreased. Inhibition of Rho-associated kinase ROCK recovered the AKT phosphorylation and the gene expressions. These results clearly suggested that the Rho/ROCK is a potent primary effector of mechanical stress in the pluripotent stem cells and it participates to pluripotency-related signaling cascades as an upper stream regulator.

  16. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors

    Nader, Joëlle; Rapino, Cinzia; Gennequin, Benjamin; Chavant, Francois; Francheteau, Maureen; Makriyannis, Alexandros; Duranti, Andrea; Maccarrone, Mauro; Solinas, Marcello; Thiriet, Nathalie

    2016-01-01

    Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ9-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of meth-amphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled ‘CNS Stimulants’. PMID:24709540

  17. Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.

    Joseph, Elizabeth K; Green, Paul G; Bogen, Oliver; Alvarez, Pedro; Levine, Jon D

    2013-02-13

    Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of hyperalgesia (SIEH) by endothelin. However, administering antisense oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1 hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1 hyperalgesia. A role for protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1 hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to hyperalgesia in two ergonomic pain models (eccentric exercise and hindlimb vibration) and in a model of endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of ATP in response to mechanical stimulation; ATP in turn acts at the nociceptor P2X(2/3) receptor.

  18. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

    Volkow, Nora D; Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. Copyright © 2015 the authors 0270-6474/15/353248-08$15.00/0.

  19. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Kojori, Eshan Shokri; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET- 18 FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal

  20. Enhanced brain responses to C-fiber input in the area of secondary hyperalgesia induced by high-frequency electrical stimulation of the skin.

    van den Broeke, Emanuel N; Mouraux, André

    2014-11-01

    High-frequency electrical stimulation (HFS) of the human skin induces an increase in both mechanical and heat pain sensitivity in the surrounding unconditioned skin. The aim of this study was to investigate the effect of HFS on the intensity of perception and brain responses elicited by the selective activation of C fibers. HFS was applied to the ventral forearm of 15 healthy volunteers. Temperature-controlled CO2 laser stimulation was used to activate selectively low-threshold C-fiber afferents without concomitantly activating Aδ-fiber afferents. These stimuli were detected with reaction times compatible with the conduction velocity of C fibers. The intensity of perception and event-related brain potentials (ERPs) elicited by thermal stimuli delivered to the surrounding unconditioned skin were recorded before (T0) and after HFS (T1: 20 min after HFS; T2: 45 min after HFS). The contralateral forearm served as a control. Mechanical hyperalgesia following HFS was confirmed by measuring the change in the intensity of perception elicited by mechanical punctate stimuli. HFS resulted in increased intensity of perception to mechanical punctate stimulation and selective C-fiber thermal stimulation at both time points. In contrast, the N2 wave of the ERP elicited by C-fiber stimulation (679 ± 88 ms; means ± SD) was enhanced at T1 but not at T2. The P2 wave (808 ± 105 ms) was unaffected by HFS. Our results suggest that HFS enhances the sensitivity to thermal C-fiber input in the area of secondary hyperalgesia. However, there was no significant enhancement of the magnitude of the C-fiber ERPs at T2, suggesting that quickly adapting C fibers do not contribute to this enhancement. Copyright © 2014 the American Physiological Society.

  1. Mechanical stimulation enhanced estrogen receptor expression and callus formation in diaphyseal long bone fracture healing in ovariectomy-induced osteoporotic rats.

    Chow, S K H; Leung, K S; Qin, J; Guo, A; Sun, M; Qin, L; Cheung, W H

    2016-10-01

    Estrogen receptor (ER) in ovariectomy-induced osteoporotic fracture was reported to exhibit delayed expression. Mechanical stimulation enhanced ER-α expression in osteoporotic fracture callus at the tissue level. ER was also found to be required for the effectiveness of vibrational mechanical stimulation treatment in osteoporotic fracture healing. Estrogen receptor(ER) is involved in mechanical signal transduction in bone metabolism. Its expression was reported to be delayed in osteoporotic fracture healing. The purpose of this study was to investigate the roles played by ER during osteoporotic fracture healing enhanced with mechanical stimulation. Ovariectomy-induced osteoporotic SD rats that received closed femoral fractures were divided into five groups, (i) SHAM, (ii) SHAM-VT, (iii) OVX, (iv) OVX-VT, and (v) OVX-VT-ICI, where VT stands for whole-body vibration treatment and ICI for ER antagonization by ICI 182,780. Callus formation and gene expression were assessed at 2, 4, and 8 weeks postfracture. In vitro osteoblastic differentiation, mineralization, and ER-α expression were assessed. The delayed ER expression was found to be enhanced by vibration treatment. Callus formation enhancement was shown by callus morphometry and micro-CT analysis. Enhancement effects by vibration were partially abolished when ER was modulated by ICI 182,780, in terms of callus formation capacity at 2-4 weeks and ER gene and protein expression at all time points. In vitro, ER expression in osteoblasts was not enhanced by VT treatment, but osteoblastic differentiation and mineralization were enhanced under estrogen-deprived condition. When osteoblastic cells were modulated by ICI 182,780, enhancement effects of VT were eliminated. Vibration was able to enhance ER expression in ovariectomy-induced osteoporotic fracture healing. ER was essential in mechanical signal transduction and enhancement in callus formation effects during osteoporotic fracture healing enhanced by vibration

  2. Transcutaneous electrical nerve stimulation on Yongquan acupoint reduces CFA-induced thermal hyperalgesia of rats via down-regulation of ERK2 phosphorylation and c-Fos expression.

    Yang, Lin; Yang, Lianxue; Gao, Xiulai

    2010-07-01

    Activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and its involvement in regulating gene expression in spinal dorsal horn, cortical and subcortical neurons by peripheral noxious stimulation contribute to pain hypersensitivity. Transcutaneous electrical nerve stimulation (TENS) is a treatment used in physiotherapy practice to promote analgesia in acute and chronic inflammatory conditions. In this study, a total number of 114 rats were used for three experiments. Effects of complete Freund's adjuvant (CFA)-induced inflammatory pain hypersensitivity and TENS analgesia on ERK1/2 phosphorylation and c-Fos protein expression were examined by using behavioral test, Western blot, and immunostaining methods. We found that CFA injection caused an area of localized swelling, erythema, hypersensitivity to thermal stimuli, the decreased response time of hind paw licking (HPL), as well as upregulation of c-Fos protein expression and ERK2 phosphorylation in the ipsilateral spinal dorsal horn and the contralateral primary somatosensory area of cortex and the amygdala of rats. TENS on Yongquan acupoint for 20 min produced obvious analgesic effects as demonstrated with increased HPL to thermal stimuli of CFA-treated rats. In addition, TENS application suppressed the CFA-induced ERK2 activation and c-Fos protein expression. These results suggest that down-regulation of ERK2 phosphorylation and c-Fos expression were involved in TENS inhibition on CFA-induced thermal hyperalgesia of rats.

  3. Changes in Regional Brain Homogeneity Induced by Electro-Acupuncture Stimulation at the Baihui Acupoint in Healthy Subjects: A Functional Magnetic Resonance Imaging Study.

    Deng, Demao; Duan, Gaoxiong; Liao, Hai; Liu, Yanfei; Wang, Geliang; Liu, Huimei; Tang, Lijun; Pang, Yong; Tao, Jien; He, Xin; Yuan, Wenzhao; Liu, Peng

    2016-10-01

    According to the Traditional Chinese Medicine theory of acupuncture, Baihui (GV20) is applied to treat neurological and psychiatric disorders. However, the relationships between neural responses and GV20 remain unknown. Thus, the main aim of this study was to examine the brain responses induced by electro-acupuncture stimulation (EAS) at GV20. Functional magnetic resonance imaging (fMRI) was performed in 33 healthy subjects. Based on the non-repeated event-related (NRER) paradigm, group differences were examined between GV20 and a sham acupoint using the regional homogeneity (ReHo) method. Compared with the sham acupoint, EAS at GV20 induced increased ReHo in regions including the orbital frontal cortex (OFC), middle cingulate cortex (MCC), precentral cortex, and precuneus (preCUN). Decreased ReHo was found in the anterior cingulate cortex (ACC), supplementary motor area (SMA), thalamus, putamen, and cerebellum. The current findings provide preliminary neuroimaging evidence to indicate that EAS at GV20 could induce a specific pattern of neural responses by analysis of ReHo of brain activity. These findings might improve the understanding of mechanisms of acupuncture stimulation at GV20.

  4. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis

    Nielsen, H

    1993-01-01

    After 10 weeks of treatment with clozapine, severe agranulocytosis was diagnosed in a 33-year-old female. The patient was treated with filgrastim (granulocyte colony-stimulating factor [G-CSF]) 5 micrograms kg-1 day-1. The neutrophil count was 0.234 x 10(9) l-1 on admission, with a further decrease...

  5. Involuntary switching into the native language induced by electrocortical stimulation of the superior temporal gyrus: a multimodal mapping study.

    Tomasino, Barbara; Marin, Dario; Canderan, Cinzia; Maieron, Marta; Budai, Riccardo; Fabbro, Franco; Skrap, Miran

    2014-09-01

    We describe involuntary language switching from L2 to L1 evoked by electro-stimulation in the superior temporal gyrus in a 30-year-old right-handed Serbian (L1) speaker who was also a late Italian learner (L2). The patient underwent awake brain surgery. Stimulation of other portions of the exposed cortex did not cause language switching as did not stimulation of the left inferior frontal gyrus, where we evoked a speech arrest. Stimulation effects on language switching were selective, namely, interfered with counting behaviour but not with object naming. The coordinates of the positive site were combined with functional and fibre tracking (DTI) data. Results showed that the language switching site belonged to a significant fMRI cluster in the left superior temporal gyrus/supramarginal gyrus found activated for both L1 and L2, and for both the patient and controls, and did not overlap with the inferior fronto-occipital fasciculus (IFOF), the inferior longitudinal fasciculus (ILF) and the superior longitudinal fasciculus (SLF). This area, also known as Stp, has a role in phonological processing. Language switching phenomenon we observed can be partly explained by transient dysfunction of the feed-forward control mechanism hypothesized by the DIVA (Directions Into Velocities of Articulators) model (Golfinopoulos, E., Tourville, J. A., & Guenther, F. H. (2010). The integration of large-scale neural network modeling and functional brain imaging in speech motor control. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Evaluation of effect of transcutaneous electrical nerve stimulation on salivary flow rate in radiation induced xerostomia patients: A pilot study

    Anusha Rangare Lakshman

    2015-01-01

    Conclusion: The present study gave us an insight about the effectiveness of TENS therapy in stimulating salivary flow in healthy subjects and it is very effective when used in conjunction with radiation therapy by reducing the side-effects of radiation therapy. Hence, TENS therapy can be used as an adjunctive method for the treatment of xerostomia along with other treatment modalities.

  7. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation.

    Uvnäs-Moberg, Kerstin; Handlin, Linda; Petersson, Maria

    2014-01-01

    Oxytocin, a hypothalamic nonapeptide, is linked to increased levels of social interaction, well-being and anti-stress effects. The effects of oxytocin that is released by sensory stimulation during different kinds of interactive behaviors are often underestimated or even forgotten. In fact, many of the positive effects caused during interaction, such a wellbeing, stress reduction and even health promotion, are indeed linked to oxytocin released in response to activation of various types of sensory nerves. Oxytocin is released in response to activation of sensory nerves during labor, breastfeeding and sexual activity. In addition oxytocin is released in response to low intensity stimulation of the skin, e.g., in response to touch, stroking, warm temperature, etc. Consequently oxytocin is not only released during interaction between mothers and infants, but also during positive interaction between adults or between humans and animals. Finally oxytocin is also released in response to suckling and food intake. Oxytocin released in the brain in response to sensory stimulation as a consequence of these types of interactive behaviors, contributes to every day wellbeing and ability to handle stress. Food intake or sex may be used or even abused to achieve oxytocin-linked wellbeing and stress relief to compensate for lack of good relationships or when the levels of anxiety are high. The present review article will summarize the role played by oxytocin released by sensory (in particular somatosensory) stimulation, during various kinds of interactive behaviors. Also the fact that the anti-stress effects of oxytocin are particularly strong when oxytocin is released in response to "low intensity" stimulation of the skin will be highlighted.

  8. Asymmetric wavefront aberrations and pupillary shapes induced by electrical stimulation of ciliary nerve in cats measured with compact wavefront aberrometer.

    Suguru Miyagawa

    Full Text Available To investigate the changes in the wavefront aberrations and pupillary shape in response to electrical stimulation of the branches of the ciliary nerves in cats. Seven eyes of seven cats were studied under general anesthesia. Trains of monophasic pulses (current, 0.1 to 1.0 mA; duration, 0.5 ms/phase; frequency, 5 to 40 Hz were applied to the lateral or medial branch of the short ciliary nerve near the posterior pole of the eye. A pair of electrodes was hooked onto one or both branch of the short ciliary nerve. The electrodes were placed about 5 mm from the scleral surface. The wavefront aberrations were recorded continuously for 2 seconds before, 8 seconds during, and for 20 seconds after the electrical stimulation. The pupillary images were simultaneously recorded during the stimulation period. Both the wavefront aberrations and the pupillary images were obtained 10 times/sec with a custom-built wavefront aberrometer. The maximum accommodative amplitude was 1.19 diopters (D produced by electrical stimulation of the short ciliary nerves. The latency of the accommodative changes was very short, and the accommodative level gradually increased up to 4 seconds and reached a plateau. When only one branch of the ciliary nerve was stimulated, the pupil dilated asymmetrically, and the oblique astigmatism and one of the asymmetrical wavefront terms was also altered. Our results showed that the wavefront aberrations and pupillary dilations can be measured simultaneously and serially with a compact wavefront aberrometer. The asymmetric pupil dilation and asymmetric changes of the wavefront aberrations suggest that each branch of the ciliary nerve innervates specific segments of the ciliary muscle and dilator muscle of the pupil.

  9. Self-soothing behaviors with particular reference to oxytocin release induced by non-noxious sensory stimulation

    Kerstin eUvnäs-Moberg

    2015-01-01

    Full Text Available Oxytocin, a hypothalamic nonapeptide, is linked to increased levels of social interaction, well-being and anti-stress effects. The effects of oxytocin that is released by sensory stimulation during different kinds of interactive behaviors are often underestimated or even forgotten. In fact, many of the positive effects caused during interaction, such a wellbeing, stress reduction and even health promotion, are indeed linked to oxytocin released in response to activation of various types of sensory nerves. Oxytocin is released in response to activation of sensory nerves during labor, breastfeeding and sexual activity. In addition oxytocin is released in response to low intensity stimulation of the skin, e.g. in response to touch, stroking, warm temperature etc . Consequently oxytocin is not only released during interaction between mothers and infants, but also during positive interaction between adult or between humans and animals. Finally oxytocin is also released in response to suckling and food intake. Oxytocin released in the brain in response to sensory stimulation as a consequence of these types of interactive behaviors, contributes to every day wellbeing and ability to handle stress. Food intake or sex may be used or even abused to achieve oxytocin-linked wellbeing and stress relief to compensate for lack of good relationships or when the levels of anxiety are high. The present review article will summarize the role played by oxytocin released by sensory (in particular somatosensory stimulation, during various kinds of interactive behaviors. Also the fact that the anti-stress effects of oxytocin are particularly strong when oxytocin is released in response to low intensity stimulation of the skin will be highlighted.

  10. Tumor cell-released TLR4 ligands stimulate Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells.

    Liu, Yan-Yan; Sun, Ling-Cong; Wei, Jing-Jing; Li, Dong; Yuan, Ye; Yan, Bin; Liang, Zhi-Hui; Zhu, Hui-Fen; Xu, Yong; Li, Bo; Song, Chuan-Wang; Liao, Sheng-Jun; Lei, Zhang; Zhang, Gui-Mei; Feng, Zuo-Hua

    2010-09-01

    Gr-1(+)CD11b(+)F4/80(+) cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1(+)CD11b(+)F4/80(+) cells to induce apoptosis of activated T cells but not nonstimulated T cells. The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1(+)CD11b(+)F4/80(+) cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms-stimulated Gr-1(+)CD11b(+)F4/80(+) cells could be enhanced by IL-10. IFN-gamma may reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells only if their response to IFN-gamma was not attenuated. However, the potential of Gr-1(+)CD11b(+)F4/80(+) cells to express IL-12 in response to IFN-gamma could be attenuated by tumor, partially due to the existence of active STAT3 in Gr-1(+)CD11b(+)F4/80(+) cells and NTC-Ms from tumor. In this situation, IFN-gamma could not effectively reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells. Tumor immunotherapy with 4-1BBL/soluble programmed death-1 may significantly reduce, but not abolish the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells in local microenvironment. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth. These findings indicate the relationship of distinct signaling pathways with apoptosis-inducing capacity of Gr-1(+)CD11b(+)F4/80(+) cells and emphasize the importance of blocking TLR4 signaling to prevent the induction of T cell apoptosis by Gr-1(+)CD11b(+)F4/80(+) cells.

  11. Bilateral stimulation of the subthalamic nucleus has differential effects on reactive and proactive inhibition and conflict-induced slowing in Parkinson's disease.

    Obeso, Ignacio; Wilkinson, Leonora; Rodríguez-Oroz, Maria-Cruz; Obeso, Jose A; Jahanshahi, Marjan

    2013-05-01

    It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.

  12. Effect of irradiation on human T-cell proliferation: low dose irradiation stimulates mitogen-induced proliferation and function of the suppressor/cytotoxic T-cell subset

    Gualde, N.; Goodwin, J.S.

    1984-01-01

    Unfractionated human T cells exposed to 10-50 rad of X irradiation incorporated less [ 3 H]thymidine than nonirradiated T cells when subsequently cultured with PHA or Con A. The cytotoxic/suppressor T-cell subset, isolated as either OKT8(+) or OKT4(-) cells, demonstrated significantly enhanced [ 3 H]thymidine incorporation in PHA- or Con A-stimulated cultures after exposure to 10-50 rad, compared to unirradiated cells, while the proliferation of the OKT4(+) helper/inducer subset was inhibited by low dose irradiation. It has been previously reported that approximately 30% of the cytotoxic/suppressor subset also stains with OKM1. When the cytotoxic/suppressor subset was further subdivided into OKT4(-), OKM1(+), and OKT4(-), OKM1(-) cells, proliferation of the OKT4(-), OKM1(+) population was inhibited by exposure to 25 rad while proliferation of the OKT4(-), OKM1(-) population was stimulated. The increase in proliferation of the cytotoxic/suppressor T-cell subset after low dose irradiation is paralleled by an increase in suppressor activity of these cells. T cells exposed to 25 rad and then cultured with Con A for 48 hr caused greater inhibition of IgG production when added to fresh autologous lymphocytes stimulated by pokeweed mitogen than did unirradiated cells. Thus, low dose irradiation enhances both the proliferation and function of the human suppressor T-cell subset

  13. Drugs elevating extracellular adenosine administered in vivo induce serum colony-stimulating activity and interleukin-6 in mice

    Weiterová, Lenka; Hofer, Michal; Pospíšil, Milan; Znojil, V.; Štreitová, Denisa

    2007-01-01

    Roč. 56, č. 4 (2007), s. 463-473 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GP305/03/D050 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : extracellular adenosine * serum colony-stimulating activity * interleukin-6 Subject RIV: BO - Biophysics Impact factor: 1.505, year: 2007

  14. Temporal correlation between auditory neurons and the hippocampal theta rhythm induced by novel stimulations in awake guinea pigs.

    Liberman, Tamara; Velluti, Ricardo A; Pedemonte, Marisa

    2009-11-17

    The hippocampal theta rhythm is associated with the processing of sensory systems such as touch, smell, vision and hearing, as well as with motor activity, the modulation of autonomic processes such as cardiac rhythm, and learning and memory processes. The discovery of temporal correlation (phase locking) between the theta rhythm and both visual and auditory neuronal activity has led us to postulate the participation of such rhythm in the temporal processing of sensory information. In addition, changes in attention can modify both the theta rhythm and the auditory and visual sensory activity. The present report tested the hypothesis that the temporal correlation between auditory neuronal discharges in the inferior colliculus central nucleus (ICc) and the hippocampal theta rhythm could be enhanced by changes in sensory stimulation. We presented chronically implanted guinea pigs with auditory stimuli that varied over time, and recorded the auditory response during wakefulness. It was observed that the stimulation shifts were capable of producing the temporal phase correlations between the theta rhythm and the ICc unit firing, and they differed depending on the stimulus change performed. Such correlations disappeared approximately 6 s after the change presentation. Furthermore, the power of the hippocampal theta rhythm increased in half of the cases presented with a stimulation change. Based on these data, we propose that the degree of correlation between the unitary activity and the hippocampal theta rhythm varies with--and therefore may signal--stimulus novelty.

  15. 3D modeling of the total electric field induced by transcranial magnetic stimulation using the boundary element method

    Salinas, F S; Lancaster, J L; Fox, P T [Research Imaging Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229 (United States)

    2009-06-21

    Transcranial magnetic stimulation (TMS) delivers highly localized brain stimulations via non-invasive externally applied magnetic fields. This non-invasive, painless technique provides researchers and clinicians with a unique tool capable of stimulating both the central and peripheral nervous systems. However, a complete analysis of the macroscopic electric fields produced by TMS has not yet been performed. In this paper, we addressed the importance of the secondary E-field created by surface charge accumulation during TMS using the boundary element method (BEM). 3D models were developed using simple head geometries in order to test the model and compare it with measured values. The effects of tissue geometry, size and conductivity were also investigated. Finally, a realistically shaped head model was used to assess the effect of multiple surfaces on the total E-field. Secondary E-fields have the greatest impact at areas in close proximity to each tissue layer. Throughout the head, the secondary E-field magnitudes typically range from 20% to 35% of the primary E-field's magnitude. The direction of the secondary E-field was generally in opposition to the primary E-field; however, for some locations, this was not the case (i.e. going from high to low conductivity tissues). These findings show that realistically shaped head geometries are important for accurate modeling of the total E-field.

  16. 3D modeling of the total electric field induced by transcranial magnetic stimulation using the boundary element method

    Salinas, F S; Lancaster, J L; Fox, P T

    2009-01-01

    Transcranial magnetic stimulation (TMS) delivers highly localized brain stimulations via non-invasive externally applied magnetic fields. This non-invasive, painless technique provides researchers and clinicians with a unique tool capable of stimulating both the central and peripheral nervous systems. However, a complete analysis of the macroscopic electric fields produced by TMS has not yet been performed. In this paper, we addressed the importance of the secondary E-field created by surface charge accumulation during TMS using the boundary element method (BEM). 3D models were developed using simple head geometries in order to test the model and compare it with measured values. The effects of tissue geometry, size and conductivity were also investigated. Finally, a realistically shaped head model was used to assess the effect of multiple surfaces on the total E-field. Secondary E-fields have the greatest impact at areas in close proximity to each tissue layer. Throughout the head, the secondary E-field magnitudes typically range from 20% to 35% of the primary E-field's magnitude. The direction of the secondary E-field was generally in opposition to the primary E-field; however, for some locations, this was not the case (i.e. going from high to low conductivity tissues). These findings show that realistically shaped head geometries are important for accurate modeling of the total E-field.

  17. Kynurenic Acid Inhibits the Electrical Stimulation Induced Elevated Pituitary Adenylate Cyclase-Activating Polypeptide Expression in the TNC

    Tamás Körtési

    2018-01-01

    Full Text Available BackgroundMigraine is a primary headache of imprecisely known mechanism, but activation of the trigeminovascular system (TS appears to be essential during the attack. Intensive research has recently focused on pituitary adenylate cyclase-activating polypeptide (PACAP and the kynurenine systems as potential pathogenic factors.AimWe investigated the link between these important mediators and the effects of kynurenic acid (KYNA and its synthetic analog (KYNA-a on PACAP expression in the rat trigeminal nucleus caudalis (TNC in a TS stimulation model related to migraine mechanisms.MethodsAdult male Sprague-Dawley rats were pretreated with KYNA, KYNA-a, the NMDA receptor antagonist MK-801, or saline (vehicle. Next, the trigeminal ganglion (TRG was electrically stimulated, the animals were transcardially perfused following 180 min, and the TNC was removed. In the TNC samples, 38 amino acid form of PACAP (PACAP1–38-like radioimmunoactivity was measured by radioimmunoassay, the relative optical density of preproPACAP was assessed by Western blot analysis, and PACAP1–38 mRNA was detected by real-time PCR.Results and conclusionElectrical TRG stimulation resulted in significant increases of PACAP1–38-LI, preproPACAP, and PACAP1–38 mRNA in the TNC. These increases were prevented by the pretreatments with KYNA, KYNA-a, and MK-801. This is the first study to provide evidence for a direct link between PACAP and the kynurenine system during TS activation.

  18. 3D modeling of the total electric field induced by transcranial magnetic stimulation using the boundary element method

    Salinas, F. S.; Lancaster, J. L.; Fox, P. T.

    2009-06-01

    Transcranial magnetic stimulation (TMS) delivers highly localized brain stimulations via non-invasive externally applied magnetic fields. This non-invasive, painless technique provides researchers and clinicians with a unique tool capable of stimulating both the central and peripheral nervous systems. However, a complete analysis of the macroscopic electric fields produced by TMS has not yet been performed. In this paper, we addressed the importance of the secondary E-field created by surface charge accumulation during TMS using the boundary element method (BEM). 3D models were developed using simple head geometries in order to test the model and compare it with measured values. The effects of tissue geometry, size and conductivity were also investigated. Finally, a realistically shaped head model was used to assess the effect of multiple surfaces on the total E-field. Secondary E-fields have the greatest impact at areas in close proximity to each tissue layer. Throughout the head, the secondary E-field magnitudes typically range from 20% to 35% of the primary E-field's magnitude. The direction of the secondary E-field was generally in opposition to the primary E-field; however, for some locations, this was not the case (i.e. going from high to low conductivity tissues). These findings show that realistically shaped head geometries are important for accurate modeling of the total E-field.

  19. Proliferation of Prostate Stromal Cell Induced by Benign Prostatic Hyperplasia Epithelial Cell Stimulated With Trichomonas vaginalis via Crosstalk With Mast Cell.

    Kim, Jung-Hyun; Kim, Sang-Su; Han, Ik-Hwan; Sim, Seobo; Ahn, Myoung-Hee; Ryu, Jae-Sook

    2016-11-01

    Chronic inflammation has a role in the pathogenesis of benign prostatic hyperplasia (BPH) and prostate cancer. Mast cells have been detected in chronic inflammatory infiltrate of the prostate, and it is possible that the interaction between prostate epithelial cells and Trichomonas vaginalis influences the activity of mast cells in the prostate stroma. Activated mast cells might influence the biological functions of nearby tissues and cells. In this study, we investigated whether mast cells reacted with the culture supernatant of BPH epithelial cells infected with T. vaginalis may induce the proliferation of prostate stromal cells. To measure the proliferation of prostate stromal cells in response to chronic inflammation caused by the infection of BPH-1 cells with T. vaginalis, the CCK-8 assay and wound healing assay were used. ELISAs, quantitative real-time PCR, western blotting and immunofluorescence were used to measure the production and expression of inflammatory cytokine and cytokine receptor. BPH-1 cells incubated with live trichomonads produced increased levels of CCL2, IL-1β, IL-6, and CXCL8, and induced the migration of mast cells and monocytes. When the culture supernatant of BPH-1 cells stimulated with trichomonads (TCM) was added to mast cells, they became activated, as confirmed by release of β-hexosaminidase and CXCL8. Prostate stromal cells incubated with the culture supernatant of mast cells activated with TCM (M-TCM) proliferated and expressed increased levels of CXCL8, CCL2, and the cytokine receptors CXCR1 and CCR2. Blocking the chemokine receptors reduced the proliferation of stromal cells and also decreased the production of CXCL8 and CCL2. Moreover, the expression of FGF2, cyclin D1, and Bcl-2 was increased in the proliferated stromal cells stimulated with M-TCM. Additionally, the M-TCM-treated stromal cells were more invasive than control cells. The inflammatory mediators released by BPH epithelial cells in response to infection by

  20. Neutrophil-induced transmigration of tumour cells treated with tumour-conditioned medium is facilitated by granulocyte-macrophage colony-stimulating factor.

    Wu, Q D

    2012-02-03

    OBJECTIVE: To investigate the effect of different cytokines that are present in tumour-conditioned medium on human neutrophil (PMN)-induced tumour cell transmigration. DESIGN: Laboratory study. SETTING: University hospital, Ireland. MATERIAL: Isolated human PMN and cultured human breast tumour cell line, MDA-MB-231. Interventions: Human PMN treated with either tumour-conditioned medium or different media neutralised with monoclonal antibodies (MoAb), and MDA-MB-231 cells were plated on macrovascular and microvascular endothelial monolayers in collagen-coated transwells to assess migration of tumour cells. MAIN OUTCOME MEASURES: Cytokines present in tumour-conditioned medium, PMN cytocidal function and receptor expression, and tumour cell transmigration. RESULTS: tumour-conditioned medium contained high concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), and interleukin 8 (IL-8), but not granulocyte colony-stimulating factor (G-CSF) and interleukin 3 (IL-3). Anti-GM-CSF MoAb significantly reduced PMN-induced transmigration of tumour cells treated with tumour-conditioned medium (p < 0.05), whereas anti-VEGF and anti-IL-8 MoAbs did not affect their migration. In addition, anti-GM-CSF MoAb, but not anti-VEGF or anti-IL-8 MoAb, reduced PMN CD11b and CD18 overexpression induced by tumour-conditioned medium (p < 0.05). CONCLUSION: These results indicate that the GM-CSF that is present in tumour-conditioned medium may be involved, at least in part, in alterations in PMN function mediated by the medium and subsequently PMN-induced transmigration of tumour cells.

  1. Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation.

    Anitua, Eduardo; Sanchez, Mikel; Merayo-Lloves, Jesus; De la Fuente, Maria; Muruzabal, Francisco; Orive, Gorka

    2011-08-01

    Plasma rich in growth factors (PRGF-Endoret) technology is an autologous platelet-enriched plasma obtained from patient's own blood, which after activation with calcium chloride allows the release of a pool of biologically active proteins that influence and promote a range of biological processes including cell recruitment, and growth and differentiation. Because ocular surface wound healing is mediated by different growth factors, we decided to explore the potential of PRGF-Endoret technology in stimulating the biological processes related with fibroblast-induced tissue repair. Furthermore, the anti-fibrotic properties of this technology were also studied. Blood from healthy donors was collected, centrifuged and, whole plasma column (WP) and the plasma fraction with the highest platelet concentration (F3) were drawn off, avoiding the buffy coat. Primary human cells including keratocytes and conjunctival fibroblasts were used to perform the "in vitro" investigations. The potential of PRGF-Endoret in promoting wound healing was evaluated by means of a proliferation and migration assays. Fibroblast cells were induced to myofibroblast differentiation after the treatment with 2.5 ng/mL of TGF-β1. The capability of WP and F3 to prevent and inhibit TGF-β1-induced differentiation was evaluated. Results show that this autologous approach significantly enhances proliferation and migration of both keratocytes and conjunctival fibroblasts. In addition, plasma rich in growth factors prevents and inhibits TGF-β1-induced myofibroblast differentiation. No differences were found between WP and F3 plasma fractions. These results suggest that PRGF-Endoret could reduce scarring while stimulating wound healing in ocular surface. F3 or whole plasma column show similar biological effects in keratocytes and conjunctival fibroblast cells.

  2. Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells.

    Stephen-Victor, Emmanuel; Karnam, Anupama; Fontaine, Thierry; Beauvais, Anne; Das, Mrinmoy; Hegde, Pushpa; Prakhar, Praveen; Holla, Sahana; Balaji, Kithiganahalli N; Kaveri, Srini V; Latgé, Jean-Paul; Aimanianda, Vishukumar; Bayry, Jagadeesh

    2017-12-05

    Human dendritic cell (DC) response to α-(1,3)-glucan polysaccharide of Aspergillus fumigatus and ensuing CD4+ T-cell polarization are poorly characterized. α-(1,3)-Glucan was isolated from A. fumigatus conidia and mycelia cell wall. For the analysis of polarization, DCs and autologous naive CD4+ T cells were cocultured. Phenotype of immune cells was analyzed by flow cytometry, and cytokines by enzyme-linked immunosorbent assay (ELISA). Blocking antibodies were used to dissect the role of Toll-like receptor 2 (TLR2) and programmed death-ligand 1 (PD-L1) in regulating α-(1,3)-glucan-mediated DC activation and T-cell responses. DCs from TLR2-deficient mice were additionally used to consolidate the findings. α-(1,3)-Glucan induced the maturation of DCs and was dependent in part on TLR2. "α-(1,3)-Glucan-educated" DCs stimulated the activation of naive T cells and polarized a subset of these cells into CD4+CD25+FoxP3+ regulatory T cells (Tregs). Mechanistically, Treg stimulation by α-(1,3)-glucan was dependent on the PD-L1 pathway that negatively regulated interferon-gamma (IFN-γ) secretion. Short α-(1,3)-oligosaccharides lacked the capacity to induce maturation of DCs but significantly blocked α-(1,3)-glucan-induced Treg polarization. PD-L1 dictates the balance between Treg and IFN-γ responses induced by α-(1,3)-glucan. Our data provide a rationale for the exploitation of immunotherapeutic approaches that target PD-1-PD-L1 to enhance protective immune responses to A. fumigatus infections. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  3. CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in nasopharyngeal carcinoma

    Liu, Zhen; Cheng, Chao; Luo, Xiaojun; Xia, Qiong; Zhang, Yejie; Long, Xiaobing; Jiang, Qingping; Fang, Weiyi

    2016-01-01

    In previous investigation, we reported that stably knocking down cyclin-dependent kinase 4(CDK4) induced expression of let-7c, which further suppressed cell cycle transition and cell growth by modulating cell cycle signaling in nasopharyngeal carcinoma (NPC). In this study, we further explored the molecular function and mechanism of CDK4 modulating miRNAs to stimulate cell cycle transition, cell growth, and Cisplatin (DDP) -resistance on in NPC. We identified changes in miRNAs by miRNA array and real-time PCR and the effect on DDP after knocking down CDK4 in NPC cells. Further, we investigated the molecular mechanisms by which CDK4 modulated miR-15a in NPC. Moreover, we also explored the role of miR-15a and the effect on DDP in NPC. Finally, we analyzed the correlation of miR-15a and CDK4 expression in NPC tissues. In addition to let-7 family members, we observed that upregulated expression of miR-15a was significantly induced in CDK4-suppressed NPC cells. Further, we found that knocking down CDK4 suppressed c-Myc expression, and the latter directly suppressed the expression of miR-15a in NPC. Furthermore, miR-15a as a tumor suppressor antagonized CDK4 repressing cell cycle progression and cell growth in vitro and in vivo and induced the sensitivity of cells to DDP by regulating the c-Myc/CCND1/CDK4/E2F1 pathway in NPC. Finally, miR-15a was negatively weak correlated with the expression of CDK4 in NPC. Our studies demonstrate that CDK4 and miR-15a comprise an abnormal automodulatory feedback loop stimulating the pathogenesis and inducing chemotherapy resistance in NPC. The online version of this article (doi:10.1186/s12885-016-2277-2) contains supplementary material, which is available to authorized users

  4. Transgene IL-6 Enhances DC-Stimulated CTL Responses by Counteracting CD4+25+Foxp3+ Regulatory T Cell Suppression via IL-6-Induced Foxp3 Downregulation

    Kalpana Kalyanasundaram Bhanumathy

    2014-03-01

    Full Text Available Dendritic cells (DCs, the most potent antigen-presenting cells have been extensively applied in clinical trials for evaluation of antitumor immunity. However, the efficacy of DC-mediated cancer vaccines is still limited as they are unable to sufficiently break the immune tolerance. In this study, we constructed a recombinant adenoviral vector (AdVIL-6 expressing IL-6, and generated IL-6 transgene-engineered DC vaccine (DCOVA/IL-6 by transfection of murine bone marrow-derived ovalbumin (OVA-pulsed DCs (DCOVA with AdVIL-6. We then assessed DCOVA/IL-6-stimulated cytotoxic T-lymphocyte (CTL responses and antitumor immunity in OVA-specific animal tumor model. We demonstrate that DCOVA/IL-6 vaccine up-regulates expression of DC maturation markers, secretes transgene-encoded IL-6, and more efficiently stimulates OVA-specific CTL responses and therapeutic immunity against OVA-expressing B16 melanoma BL6-10OVA in vivo than the control DCOVA/Null vaccine. Moreover, DCOVA/IL-6-stimulated CTL responses were relatively maintained in mice with transfer of CD4+25+Foxp3+ Tr-cells, but significantly reduced when treated with anti-IL-6 antibody. In addition, we demonstrate that IL-6 down-regulates Foxp3-expression of CD4+25+Foxp3+ Tr-cells in vitro. Taken together, our results demonstrate that AdV-mediated IL-6 transgene-engineered DC vaccine stimulates potent CTL responses and antitumor immunity by counteracting CD4+25+ Tr immunosuppression via IL-6-induced Foxp3 down-regulation. Thus, IL-6 may be a good candidate for engineering DCs for cancer immunotherapy.

  5. Kilohertz and Low-Frequency Electrical Stimulation With the Same Pulse Duration Have Similar Efficiency for Inducing Isometric Knee Extension Torque and Discomfort.

    Medeiros, Flávia Vanessa; Bottaro, Martim; Vieira, Amilton; Lucas, Tiago Pires; Modesto, Karenina Arrais; Bo, Antonio Padilha L; Cipriano, Gerson; Babault, Nicolas; Durigan, João Luiz Quagliotti

    2017-06-01

    To test the hypotheses that, as compared with pulsed current with the same pulse duration, kilohertz frequency alternating current would not differ in terms of evoked-torque production and perceived discomfort, and as a result, it would show the same current efficiency. A repeated-measures design with 4 stimuli presented in random order was used to test 25 women: (1) 500-microsecond pulse duration, (2) 250-microsecond pulse duration, (3) 500-microsecond pulse duration and low carrier frequency (1 kHz), (4) 250-microsecond pulse duration and high carrier frequency (4 kHz). Isometric peak torque of quadriceps muscle was measured using an isokinetic dynamometer. Discomfort was measured using a visual analog scale. Currents with long pulse durations induced approximately 21% higher evoked torque than short pulse durations. In addition, currents with 500 microseconds delivered greater amounts of charge than stimulation patterns using 250-microsecond pulse durations (P torque and discomfort. However, neuromuscular electrical stimulation (NMES) with longer pulse duration induces higher NMES-evoked torque, regardless of the carrier frequency. Pulse duration is an important variable that should receive more attention for an optimal application of NMES in clinical settings.

  6. Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.

    Rusconi, Laura; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2011-10-21

    Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-D-aspartate receptors and suggest regulation of CDKL5 by cell death pathways.

  7. Extrasynaptic N-Methyl-d-aspartate (NMDA) Receptor Stimulation Induces Cytoplasmic Translocation of the CDKL5 Kinase and Its Proteasomal Degradation*

    Rusconi, Laura; Kilstrup-Nielsen, Charlotte; Landsberger, Nicoletta

    2011-01-01

    Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-d-aspartate receptors and suggest regulation of CDKL5 by cell death pathways. PMID:21832092

  8. Construction of TSL lector equipment with spectral resolution for the determination of thermally stimulated luminescence (TSL) properties of NaCl: Tl+ induced by UV-visible radiation

    Alvarez Romero, J.T.

    1993-01-01

    A revision of physical models of thermally stimulated luminescence (TSL) in crystals induced by both ionizing and non-ionizing radiation is presented. Particular emphasis is given to the connection of TSL with other thermally stimulated processes and physico-chemical phenomena because basic information on physical mechanics for TSL can be obtained through them. Glow curves of TSL induced by UV-visible radiation in NaCl: Tl + were measured. Additionally, the following spectrums were obtained for the same samples: optical absorption, excitation, fluorescent emission, and TSL emission. An optical absorption peak was correlated with the Thallium ion concentration. With respect to the TSL emission spectrums, some peaks associated to Thallium dimmers were at 298 and at 480 nm; others which were attributed to NaCl intrinsic properties were at 365, 430, 450 and 525 nm. Also TSL glow curves were studied as a function of the Thallium ion concentration (0.8 ppm to 14.8 ppm). They were de convoluted so as to calculate the activation energy, the frequency factor and the kinetic order for each separate TSL peak. Anomalous values were observed for some frequency factors. A method and TSL lector equipment to obtain TSL emission spectra were developed. (Author)

  9. Role of capsaicin- and heat-sensitive afferents in stimulation of acupoint-induced pain and analgesia in humans.

    Lei, Jing; Ye, Gang; Wu, Jiang-Tao; Pertovaara, Antti; You, Hao-Jun

    2017-09-01

    We investigated role of capsaicin-sensitive afferents within and without the areas of Zusanli (ST36)/Shangjuxu (ST37) acupoints along the stomach (ST) meridian in the perception and modulation of pain assessed by visual analog scale of pain and its distribution rated by subjects, pressure pain threshold (PPT), and heat pain threshold (HPT) in humans. Compared with the treatment of non-acupoint area, capsaicin (100µg/50µl) administered into either ST36 or ST37 acupoint caused the strongest pain intensity and the most extensive pain distribution, followed by rapid onset, bilateral, long-lasting secondary mechanical hyperalgesia and slower onset secondary heat hypoalgesia (1day after the capsaicin treatment). Between treatments of different acupoints, capsaicin administrated into the ST36 acupoint exhibited the stronger pain intensity and more widespread pain distribution compared with the treatment of ST37 acupoint. A period of 30- to 45-min, but not 15-min, 43°C heating-needle stimulation applied to the ST36 acupoint significantly enhanced the HPT, and had no effect on PPT. Upon trapezius muscle pain elicited by the i.m. injection of 5.8% saline, pre-emptive treatment of the contralateral ST36 acupoint with 43°C heating-needle stimulation alleviated the ongoing muscle pain, reduced painful area, and reversed the decrease in HPT. It is suggested that (1) pain elicited from the acupoint and non-acupoint areas differs significantly, which are supposed to be dependent on the different distributions and contributions of capsaicin-sensitive afferents. (2) Non-painful heat stimulation is a valid approach in prevention of ongoing muscle pain with associated post-effects of peripheral and central sensitization. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. In-vivo Imaging of Magnetic Fields Induced by Transcranial Direct Current Stimulation (tDCS) in Human Brain using MRI

    Jog, Mayank V.; Smith, Robert X.; Jann, Kay; Dunn, Walter; Lafon, Belen; Truong, Dennis; Wu, Allan; Parra, Lucas; Bikson, Marom; Wang, Danny J. J.

    2016-10-01

    Transcranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique that applies mA currents at the scalp to modulate cortical excitability. Here, we present a novel magnetic resonance imaging (MRI) technique, which detects magnetic fields induced by tDCS currents. This technique is based on Ampere’s law and exploits the linear relationship between direct current and induced magnetic fields. Following validation on a phantom with a known path of electric current and induced magnetic field, the proposed MRI technique was applied to a human limb (to demonstrate in-vivo feasibility using simple biological tissue) and human heads (to demonstrate feasibility in standard tDCS applications). The results show that the proposed technique detects tDCS induced magnetic fields as small as a nanotesla at millimeter spatial resolution. Through measurements of magnetic fields linearly proportional to the applied tDCS current, our approach opens a new avenue for direct in-vivo visualization of tDCS target engagement.

  11. Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats.

    Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher

    2015-03-15

    Stimuli previously associated with drug taking can become triggers that can elicit craving and lead to relapse of drug-seeking behavior. Here, we examined the influence of deep brain stimulation (DBS) in the nucleus accumbens shell on cue-induced reinstatement of cocaine seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.254 mg, i.v.) for 2 h daily for 21 days, with each infusion of cocaine being paired with a cue light. After 21 days of self-administration, cocaine-taking behavior was extinguished by replacing cocaine with saline in the absence of the cue light. Next, during the reinstatement phase, DBS was administered bilaterally into the nucleus accumbens shell through bipolar stainless steel electrodes immediately prior to re-exposure to cues previously associated with cocaine reinforcement. DBS continued throughout the 2 h reinstatement session. Parallel studies examined the influence of accumbens shell DBS on reinstatement induced by cues previously associated with sucrose reinforcement. Results indicated that DBS of the nucleus accumbens shell significantly attenuated cue-induced reinstatement of cocaine and sucrose seeking. Together, these results indicate that DBS of the accumbens shell disrupts cue-induced reinstatement associated with both a drug and a natural reinforcer. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs

    Nitsche, Michael A; Müller-Dahlhaus, Florian; Paulus, Walter; Ziemann, Ulf

    2012-01-01

    The term neuroplasticity encompasses structural and functional modifications of neuronal connectivity. Abnormal neuroplasticity is involved in various neuropsychiatric diseases, such as dystonia, epilepsy, migraine, Alzheimer's disease, fronto-temporal degeneration, schizophrenia, and post cerebral stroke. Drugs affecting neuroplasticity are increasingly used as therapeutics in these conditions. Neuroplasticity was first discovered and explored in animal experimentation. However, non-invasive brain stimulation (NIBS) has enabled researchers recently to induce and study similar processes in the intact human brain. Plasticity induced by NIBS can be modulated by pharmacological interventions, targeting ion channels, or neurotransmitters. Importantly, abnormalities of plasticity as studied by NIBS are directly related to clinical symptoms in neuropsychiatric diseases. Therefore, a core theme of this review is the hypothesis that NIBS-induced plasticity can explore and potentially predict the therapeutic efficacy of CNS-acting drugs in neuropsychiatric diseases. We will (a) review the basics of neuroplasticity, as explored in animal experimentation, and relate these to our knowledge about neuroplasticity induced in humans by NIBS techniques. We will then (b) discuss pharmacological modulation of plasticity in animals and humans. Finally, we will (c) review abnormalities of plasticity in neuropsychiatric diseases, and discuss how the combination of NIBS with pharmacological intervention may improve our understanding of the pathophysiology of abnormal plasticity in these diseases and their purposeful pharmacological treatment. PMID:22869014

  14. Thalidomide Induces Limb Anomalies by PTEN Stabilization, Akt Suppression, and Stimulation of Caspase-Dependent Cell Death▿

    Knobloch, Jürgen; Schmitz, Ingo; Götz, Katrin; Schulze-Osthoff, Klaus; Rüther, Ulrich

    2007-01-01

    Thalidomide, a drug used for the treatment of multiple myeloma and inflammatory diseases, is also a teratogen that causes birth defects, such as limb truncations and microphthalmia, in humans. Thalidomide-induced limb truncations result from increased cell death during embryonic limb development and consequential disturbance of limb outgrowth. Here we demonstrate in primary human embryonic cells and in the chicken embryo that thalidomide-induced signaling through bone morphogenetic proteins (...

  15. Stimulation of Inducible Nitric Oxide Synthase Expression by Beta Interferon Increases Necrotic Death of Macrophages upon Listeria monocytogenes Infection▿

    Zwaferink, Heather; Stockinger, Silvia; Reipert, Siegfried; Decker, Thomas

    2008-01-01

    Murine macrophage death upon infection with Listeria monocytogenes was previously shown to be increased by beta interferon, produced by the infected cells. We saw that interferon-upregulated caspase activation or other interferon-inducible, death-associated proteins, including TRAIL, protein kinase R, and p53, were not necessary for cell death. Macrophage death was reduced when inducible nitric oxide synthase (iNOS) was inhibited during infection, and iNOS-deficient macrophages were less susc...

  16. A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population

    WATANABE, YUSAKU; YOSHIMURA, KIYOSHI; YOSHIKAWA, KOICHI; TSUNEDOMI, RYOICHI; SHINDO, YOSHITARO; MATSUKUMA, SOU; MAEDA, NORIKO; KANEKIYO, SHINSUKE; SUZUKI, NOBUAKI; KURAMASU, ATSUO; SONODA, KOUHEI; TAMADA, KOJI; KOBAYASHI, SEI; SAYA, HIDEYUKI; HAZAMA, SHOICHI; OKA, MASAAKI

    2014-01-01

    Cancer stem cells (CSCs) have been studied for their self-renewal capacity and pluripotency, as well as their resistance to anticancer therapy and their ability to metastasize to distant organs. CSCs are difficult to study because their population is quite low in tumor specimens. To overcome this problem, we established a culture method to induce a pancreatic cancer stem-like cell (P-CSLC)-enriched population from human pancreatic cancer cell lines. Human pancreatic cancer cell lines established at our department were cultured in CSC-inducing media containing epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), neural cell survivor factor-1 (NSF-1), and N-acetylcysteine. Sphere cells were obtained and then transferred to a laminin-coated dish and cultured for approximately two months. The surface markers, gene expression, aldehyde dehydrogenase (ALDH) activity, cell cycle, and tumorigenicity of these induced cells were examined for their stem cell-like characteristics. The population of these induced cells expanded within a few months. The ratio of CD24high, CD44high, epithelial specific antigen (ESA) high, and CD44variant (CD44v) high cells in the induced cells was greatly enriched. The induced cells stayed in the G0/G1 phase and demonstrated mesenchymal and stemness properties. The induced cells had high tumorigenic potential. Thus, we established a culture method to induce a P-CSLCenriched population from human pancreatic cancer cell lines. The CSLC population was enriched approximately 100-fold with this method. Our culture method may contribute to the precise analysis of CSCs and thus support the establishment of CSC-targeting therapy. PMID:25118635

  17. HIF-2α-induced chemokines stimulate motility of fibroblast-like synoviocytes and chondrocytes into the cartilage-pannus interface in experimental rheumatoid arthritis mouse models.

    Huh, Yun Hyun; Lee, Gyuseok; Lee, Keun-Bae; Koh, Jeong-Tae; Chun, Jang-Soo; Ryu, Je-Hwang

    2015-10-29

    Pannus formation and resulting cartilage destruction during rheumatoid arthritis (RA) depends on the migration of synoviocytes to cartilage tissue. Here, we focused on the role of hypoxia-inducible factor (HIF)-2α-induced chemokines by chondrocytes in the regulation of fibroblast-like synoviocyte (FLS) migration into the cartilage-pannus interface and cartilage erosion. Collagen-induced arthritis (CIA), K/BxN serum transfer, and tumor necrosis factor-α transgenic mice were used as experimental RA models. Expression patterns of HIF-2α and chemokines were determined via immunostaining, Western blotting and RT-PCR. FLS motility was evaluated using transwell migration and invasion assays. The specific role of HIF-2α was determined via local deletion of HIF-2α in joint tissues or using conditional knockout (KO) mice. Cartilage destruction, synovitis and pannus formation were assessed via histological analysis. HIF-2α and various chemokines were markedly upregulated in degenerating cartilage and pannus of RA joints. HIF-2α induced chemokine expression by chondrocytes in both primary culture and cartilage tissue. HIF-2α -induced chemokines by chondrocytes regulated the migration and invasion of FLS. Local deletion of HIF-2α in joint tissues inhibited pannus formation adjacent to cartilage tissue and cartilage destruction caused by K/BxN serum transfer. Furthermore, conditional knockout of HIF-2α in cartilage blocked pannus formation in adjacent cartilage but not bone tissue, along with inhibition of cartilage erosion caused by K/BxN serum transfer. Our findings suggest that chemokines induced by IL-1β or HIF-2α in chondrocytes regulate pannus expansion by stimulating FLS migration and invasion, leading to cartilage erosion during RA pathogenesis.

  18. Garlic (Allium sativum) stimulates lipopolysaccharide-induced tumor necrosis factor-alpha production from J774A.1 murine macrophages.

    Sung, Jessica; Harfouche, Youssef; De La Cruz, Melissa; Zamora, Martha P; Liu, Yan; Rego, James A; Buckley, Nancy E

    2015-02-01

    Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion. © 2014 The Authors. Phytotherapy Research published by John Wiley & Sons, Ltd.

  19. Laser stimulating ST36 with optical fiber induce blood component changes in mice: a Raman spectroscopy study.

    Zhang, Heng; Chen, Zhenyi; Wu, Jiping; Chen, Na; Xu, Wenjie; Li, Taihao; Liu, Shupeng

    2018-02-15

    ST36 is a commonly-used acupoint in traditional Chinese medicine (TCM) for treatment of inflammations, pains and gastrointestinal disturbs. For decades, the low power laser acupuncture has been widely applied as an alternative therapy to traditional metal needle acupuncture and achieved relatively fine therapeutic effect for ST36-related symptoms with reduction of uncomfortableness and infection risks. However its disadvantages of low penetrativity and lack of manipulation skills limit its potential performance. An optical fiber laser acupuncture introduced by the previous study combines traditional needling acupuncture and the laser stimulation together, making a stronger therapeutic effect and showing a potential value in clinical application. To evaluate its acupunctural effect on blood, mice are taken as experimental model and Raman spectroscopic technique is used to analysis the changes of blood components after stimulating on ST36. The results show that both the traditional needling acupuncture and optical fiber acupuncture could lead to some spectral changes of blood in mice. This study explores the optical fiber acupuncture's effect on blood in mice using Raman spectroscopy technique for mechanism of acupuncture therapy. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. Test-retest assessment of cortical activation induced by repetitive transcranial magnetic stimulation with brain atlas-guided optical topography

    Tian, Fenghua; Kozel, F. Andrew; Yennu, Amarnath; Croarkin, Paul E.; McClintock, Shawn M.; Mapes, Kimberly S.; Husain, Mustafa M.; Liu, Hanli

    2012-11-01

    Repetitive transcranial magnetic stimulation (rTMS) is a technology that stimulates neurons with rapidly changing magnetic pulses with demonstrated therapeutic applications for various neuropsychiatric disorders. Functional near-infrared spectroscopy (fNIRS) is a suitable tool to assess rTMS-evoked brain responses without interference from the magnetic or electric fields generated by the TMS coil. We have previously reported a channel-wise study of combined rTMS/fNIRS on the motor and prefrontal cortices, showing a robust decrease of oxygenated hemoglobin concentration (Δ[HbO2]) at the sites of 1-Hz rTMS and the contralateral brain regions. However, the reliability of this putative clinical tool is unknown. In this study, we develop a rapid optical topography approach to spatially characterize the rTMS-evoked hemodynamic responses on a standard brain atlas. A hemispherical approximation of the brain is employed to convert the three-dimensional topography on the complex brain surface to a two-dimensional topography in the spherical coordinate system. The test-retest reliability of the combined rTMS/fNIRS is assessed using repeated measurements performed two to three days apart. The results demonstrate that the Δ[HbO2] amplitudes have moderate-to-high reliability at the group level; and the spatial patterns of the topographic images have high reproducibility in size and a moderate degree of overlap at the individual level.

  1. Pharmacological stimulation of p53 with low-dose doxorubicin ameliorates diet-induced nonalcoholic steatosis and steatohepatitis

    Begoña Porteiro

    2018-02-01

    Full Text Available Objective: Recent reports have implicated the p53 tumor suppressor in the regulation of lipid metabolism. We hypothesized that the pharmacological activation of p53 with low-dose doxorubicin, which is widely used to treat several types of cancer, may have beneficial effects on nonalcoholic fatty liver disease (NAFLD and nonalcoholic steatohepatitis (NASH. Methods: We used long-term pharmacological activation of p53 by i.p. or oral administration of low-dose doxorubicin in different animal models of NAFLD (high fat diet containing 45% and 60% kcal fat and NASH (methionine- and choline-deficient diet and choline deficiency combined with high fat diet. We also administered doxorubicin in mice lacking p53 in the liver and in two human hepatic cells lines (HepG2 and THLE2. Results: The attenuation of liver damage was accompanied by the stimulation of fatty acid oxidation and decrease of lipogenesis, inflammation, and ER stress. The effects of doxorubicin were abrogated in mice with liver-specific ablation of p53. Finally, the effects of doxorubicin on lipid metabolism found in animal models were also present in two human hepatic cells lines, in which the drug stimulated fatty acid oxidation and inhibited de novo lipogenesis at doses that did not cause changes in apoptosis or cell viability. Conclusion: These data provide new evidence for targeting p53 as a strategy to treat liver disease. Keywords: Obesity, Lipid metabolism, Inflammation

  2. Comparison of imaging modalities and source-localization algorithms in locating the induced activity during deep brain stimulation of the STN.

    Mideksa, K G; Singh, A; Hoogenboom, N; Hellriegel, H; Krause, H; Schnitzler, A; Deuschl, G; Raethjen, J; Schmidt, G; Muthuraman, M

    2016-08-01

    One of the most commonly used therapy to treat patients with Parkinson's disease (PD) is deep brain stimulation (DBS) of the subthalamic nucleus (STN). Identifying the most optimal target area for the placement of the DBS electrodes have become one of the intensive research area. In this study, the first aim is to investigate the capabilities of different source-analysis techniques in detecting deep sources located at the sub-cortical level and validating it using the a-priori information about the location of the source, that is, the STN. Secondly, we aim at an investigation of whether EEG or MEG is best suited in mapping the DBS-induced brain activity. To do this, simultaneous EEG and MEG measurement were used to record the DBS-induced electromagnetic potentials and fields. The boundary-element method (BEM) have been used to solve the forward problem. The position of the DBS electrodes was then estimated using the dipole (moving, rotating, and fixed MUSIC), and current-density-reconstruction (CDR) (minimum-norm and sLORETA) approaches. The source-localization results from the dipole approaches demonstrated that the fixed MUSIC algorithm best localizes deep focal sources, whereas the moving dipole detects not only the region of interest but also neighboring regions that are affected by stimulating the STN. The results from the CDR approaches validated the capability of sLORETA in detecting the STN compared to minimum-norm. Moreover, the source-localization results using the EEG modality outperformed that of the MEG by locating the DBS-induced activity in the STN.

  3. Raclopride or high-frequency stimulation of the subthalamic nucleus stops cocaine-induced motor stereotypy and restores related alterations in prefrontal basal ganglia circuits.

    Aliane, Verena; Pérez, Sylvie; Deniau, Jean-Michel; Kemel, Marie-Louise

    2012-11-01

    Motor stereotypy is a key symptom of various neurological or neuropsychiatric disorders. Neuroleptics or the promising treatment using deep brain stimulation stops stereotypies but the mechanisms underlying their actions are unclear. In rat, motor stereotypies are linked to an imbalance between prefrontal and sensorimotor cortico-basal ganglia circuits. Indeed, cortico-nigral transmission was reduced in the prefrontal but not sensorimotor basal ganglia circuits and dopamine and acetylcholine release was altered in the prefrontal but not sensorimotor territory of the dorsal striatum. Furthermore, cholinergic transmission in the prefrontal territory of the dorsal striatum plays a crucial role in the arrest of motor stereotypy. Here we found that, as previously observed for raclopride, high-frequency stimulation of the subthalamic nucleus (HFS STN) rapidly stopped cocaine-induced motor stereotypies in rat. Importantly, raclopride and HFS STN exerted a strong effect on cocaine-induced alterations in prefrontal basal ganglia circuits. Raclopride restored the cholinergic transmission in the prefrontal territory of the dorsal striatum and the cortico-nigral information transmissions in the prefrontal basal ganglia circuits. HFS STN also restored the N-methyl-d-aspartic-acid-evoked release of acetylcholine and dopamine in the prefrontal territory of the dorsal striatum. However, in contrast to raclopride, HFS STN did not restore the cortico-substantia nigra pars reticulata transmissions but exerted strong inhibitory and excitatory effects on neuronal activity in the prefrontal subdivision of the substantia nigra pars reticulata. Thus, both raclopride and HFS STN stop cocaine-induced motor stereotypy, but exert different effects on the related alterations in the prefrontal basal ganglia circuits. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  4. High Glucose-Induced Reactive Oxygen Species Stimulates Human Mesenchymal Stem Cell Migration Through Snail and EZH2-Dependent E-Cadherin Repression

    Ji Young Oh

    2018-04-01

    Full Text Available Background/Aims: Glucose plays an important role in stem cell fate determination and behaviors. However, it is still not known how glucose contributes to the precise molecular mechanisms responsible for stem cell migration. Thus, we investigate the effect of glucose on the regulation of the human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC migration, and analyze the mechanism accompanied by this effect. Methods: Western blot analysis, wound healing migration assays, immunoprecipitation, and chromatin immunoprecipitation assay were performed to investigate the effect of high glucose on hUCB-MSC migration. Additionally, hUCB-MSC transplantation was performed in the mouse excisional wound splinting model. Results: High concentration glucose (25 mM elicits hUCB-MSC migration compared to normal glucose and high glucose-pretreated hUCB-MSC transplantation into the wound sites in mice also accelerates skin wound repair. We therefore elucidated the detailed mechanisms how high glucose induces hUCB-MSC migration. We showed that high glucose regulates E-cadherin repression through increased Snail and EZH2 expressions. And, we found high glucose-induced reactive oxygen species (ROS promotes two signaling; JNK which regulates γ–secretase leading to the cleavage of Notch proteins and PI3K/Akt signaling which enhances GSK-3β phosphorylation. High glucose-mediated JNK/Notch pathway regulates the expression of EZH2, and PI3K/Akt/GSK-3β pathway stimulates Snail stabilization, respectively. High glucose enhances the formation of EZH2/Snail/HDAC1 complex in the nucleus, which in turn causes E-cadherin repression. Conclusion: This study reveals that high glucose-induced ROS stimulates the migration of hUCB-MSC through E-cadherin repression via Snail and EZH2 signaling pathways.

  5. Effects of electrical stimulation-induced gluteal versus gluteal and hamstring muscles activation on sitting pressure distribution in persons with a spinal cord injury.

    Smit, C A J; Haverkamp, G L G; de Groot, S; Stolwijk-Swuste, J M; Janssen, T W J

    2012-08-01

    Ten participants underwent two electrical stimulation (ES) protocols applied using a custom-made electrode garment with built-in electrodes. Interface pressure was measured using a force-sensitive area. In one protocol, both the gluteal and hamstring (g+h) muscles were activated, in the other gluteal (g) muscles only. To study and compare the effects of electrically induced activation of g+h muscles versus g muscles only on sitting pressure distribution in individuals with a spinal cord injury (SCI). Ischial tuberosities interface pressure (ITs pressure) and pressure gradient. In all participants, both protocols of g and g+h ES-induced activation caused a significant decrease in IT pressure. IT pressure after g+h muscles activation was reduced significantly by 34.5% compared with rest pressure, whereas a significant reduction of 10.2% after activation of g muscles only was found. Pressure gradient reduced significantly only after stimulation of g+h muscles (49.3%). g+h muscles activation showed a decrease in pressure relief (Δ IT) over time compared with g muscles only. Both protocols of surface ES-induced of g and g+h activation gave pressure relief from the ITs. Activation of both g+h muscles in SCI resulted in better IT pressure reduction in sitting individuals with a SCI than activation of g muscles only. ES might be a promising method in preventing pressure ulcers (PUs) on the ITs in people with SCI. Further research needs to show which pressure reduction is sufficient in preventing PUs.

  6. Trans-cranial infrared laser stimulation induces hemodynamic and metabolic response measured by broadband near infrared spectroscopy in vivo on human forehead (Conference Presentation)

    Wang, Xinlong; Nalawade, Sahil Sunil; Reddy, Divya Dhandapani; Tian, Fenghua; Gonzalez-Lima, F.; Liu, Hanli

    2017-02-01

    Transcranial infrared laser stimulation (TILS) uses infrared light (lasers or LEDs) for nondestructive and non-thermal photobiomodulation on the human brain. Although TILS has shown its beneficial effects to a variety of neurological and psychological conditions, its physiological mechanism remains unknown. Cytochrome-c-oxidase (CCO), the last enzyme in the electron transportation chain, is proposed to be the primary photoacceptor of this infrared laser. In this study, we wish to validate this proposed mechanism. We applied 8 minutes in vivo TILS on the right forehead of 11 human participants with a 1064-nm laser. Broad-band near infrared spectroscopy (bb-NIRS) from 740-900nm was also employed near the TILS site to monitor hemodynamic and metabolic responses during the stimulation and 5-minute recovery period. For rigorous comparison, we also performed similar 8-min bb-NIR measurements under placebo conditions. A multi-linear regression analysis based on the modified Beer-Lambert law was performed to estimate concentration changes of oxy-hemoglobin (Δ[HbO]), deoxy-hemoglobin (Δ[Hb]), and cytochrome-c-oxidase (Δ[CCO]). We found that TILS induced significant increases of [CCO], [HbO] and a decrease of [Hb] with dose-dependent manner as compared with placebo treatments. Furthermore, strong linear relationships or interplays between [CCO] versus [HbO] and [CCO] versus [Hb] induced by TILS were observed in vivo for the first time. These relationships have clearly revealed close coupling/relationship between the hemodynamic oxygen supply and blood volume versus up-regulation of CCO induced by photobiomodulation. Our results demonstrate the tremendous potential of bb-NIRS as a non-invasive in vivo means to study photobiomodulation mechanisms and perform treatment evaluations of TILS.

  7. Streptococcus gordonii induces nitric oxide production through its lipoproteins stimulating Toll-like receptor 2 in murine macrophages.

    Kim, Hyun Young; Baik, Jung Eun; Ahn, Ki Bum; Seo, Ho Seong; Yun, Cheol-Heui; Han, Seung Hyun

    2017-02-01

    Streptococcus gordonii, a Gram-positive commensal in the oral cavity, is an opportunistic pathogen that can cause endodontic and systemic infections resulting in infective endocarditis. Lipoteichoic acid (LTA) and lipoprotein are major virulence factors of Gram-positive bacteria that are preferentially recognized by Toll-like receptor 2 (TLR2) on immune cells. In the present study, we investigated the effect of S. gordonii LTA and lipoprotein on the production of the representative inflammatory mediator nitric oxide (NO) by the mouse macrophages. Heat-killed S. gordonii wild-type and an LTA-deficient mutant (ΔltaS) but not a lipoprotein-deficient mutant (Δlgt) induced NO production in mouse primary macrophages and the cell line, RAW 264.7. S. gordonii wild-type and ΔltaS also induced the expression of inducible NO synthase (iNOS) at the mRNA and protein levels. In contrast, the Δlgt mutant showed little effect under the same condition. Furthermore, S. gordonii wild-type and ΔltaS induced NF-κB activation, STAT1 phosphorylation, and IFN-β expression, which are important for the induction of iNOS gene expression, with little activation by Δlgt. S. gordonii wild-type and ΔltaS showed an increased adherence and internalization to RAW 264.7 cells compared to Δlgt. In addition, S. gordonii wild-type and ΔltaS, but not Δlgt, substantially increased TLR2 activation while none of these induced NO production in TLR2-deficient macrophages. Triton X-114-extracted lipoproteins from S. gordonii were sufficient to induce NO production. Collectively, we suggest that lipoprotein is an essential cell wall component of S. gordonii to induce NO production in macrophages through TLR2 triggering NF-κB and STAT1 activation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Amniotic Membrane Modifies the Genetic Program Induced by TGFß, Stimulating Keratinocyte Proliferation and Migration in Chronic Wounds.

    Antonia Alcaraz

    Full Text Available Post-traumatic large-surface or deep wounds often cannot progress to reepithelialisation because they become irresponsive in the inflammatory stage, so intervention is necessary to provide the final sealing epidermis. Previously we have shown that Amniotic Membrane (AM induced a robust epithelialisation in deep traumatic wounds.To better understand this phenomenon, we used keratinocytes to investigate the effect of AM on chronic wounds. Using keratinocytes, we saw that AM treatment is able to exert an attenuating effect upon Smad2 and Smad3 TGFß-induced phosphorylation while triggering the activation of several MAPK signalling pathways, including ERK and JNK1, 2. This also has a consequence for TGFß-induced regulation on cell cycle control key players CDK1A (p21 and CDK2B (p15. The study of a wider set of TGFß regulated genes showed that the effect of AM was not wide but very concrete for some genes. TGFß exerted a powerful cell cycle arrest; the presence of AM however prevented TGFß-induced cell cycle arrest. Moreover, AM induced a powerful cell migration response that correlates well with the expression of c-Jun protein at the border of the healing assay. Consistently, the treatment with AM of human chronic wounds induced a robust expression of c-Jun at the wound border.The effect of AM on the modulation of TGFß responses in keratinocytes that favours proliferation together with AM-induced keratinocyte migration is the perfect match that allows chronic wounds to move on from their non-healing state and progress into epithelialization. Our results may explain why the application of AM on chronic wounds is able to promote epithelialisation.

  9. Mechanical stimulation of cyclic tensile strain induces reduction of pluripotent related gene expressions via activation of Rho/ROCK and subsequent decreasing of AKT phosphorylation in human induced pluripotent stem cells

    Teramura, Takeshi, E-mail: teramura@med.kindai.ac.jp [Institute of Advanced Clinical Medicine, Kinki University, Faculty of Medicine, Osaka (Japan); Takehara, Toshiyuki; Onodera, Yuta [Institute of Advanced Clinical Medicine, Kinki University, Faculty of Medicine, Osaka (Japan); Nakagawa, Koichi; Hamanishi, Chiaki [Department of Orthopaedic Surgery, Kinki University, Faculty of Medicine, Osaka (Japan); Fukuda, Kanji [Institute of Advanced Clinical Medicine, Kinki University, Faculty of Medicine, Osaka (Japan); Department of Orthopaedic Surgery, Kinki University, Faculty of Medicine, Osaka (Japan)

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer Mechanical stimulation is an important factor for regulation of stem cell fate. Black-Right-Pointing-Pointer Cyclic stretch to human induced pluripotent stem cells activated small GTPase Rho. Black-Right-Pointing-Pointer Rho-kinase activation attenuated pluripotency via inhibition of AKT activation. Black-Right-Pointing-Pointer This reaction could be reproduced only by transfection of dominant active Rho. Black-Right-Pointing-Pointer Rho/ROCK are important molecules in mechanotransduction and control of stemness. -- Abstract: Mechanical stimulation has been shown to regulate the proliferation and differentiation of stem cells. However, the effects of the mechanical stress on the stemness or related molecular mechanisms have not been well determined. Pluripotent stem cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are used as good materials for cell transplantation therapy and research of mammalian development, since they can self-renew infinitely and differentiate into various cell lineages. Here we demonstrated that the mechanical stimulation to human iPS cells altered alignment of actin fibers and expressions of the pluripotent related genes Nanog, POU5f1 and Sox2. In the mechanically stimulated iPS cells, small GTPase Rho was activated and interestingly, AKT phosphorylation was decreased. Inhibition of Rho-associated kinase ROCK recovered the AKT phosphorylation and the gene expressions. These results clearly suggested that the Rho/ROCK is a potent primary effector of mechanical stress in the pluripotent stem cells and it participates to pluripotency-related signaling cascades as an upper stream regulator.

  10. Nutrient-induced stimulation of protein synthesis in mouse skeletal muscle is limited by the mTORC1 repressor REDD1.

    Gordon, Bradley S; Williamson, David L; Lang, Charles H; Jefferson, Leonard S; Kimball, Scot R

    2015-04-01

    In skeletal muscle, the nutrient-induced stimulation of protein synthesis requires signaling through the mechanistic target of rapamycin complex 1 (mTORC1). Expression of the repressor of mTORC1 signaling, regulated in development and DNA damage 1 (REDD1), is elevated in muscle during various atrophic conditions and diminished under hypertrophic conditions. The question arises as to what extent REDD1 limits the nutrient-induced stimulation of protein synthesis. The objective was to examine the role of REDD1 in limiting the response of muscle protein synthesis and mTORC1 signaling to a nutrient stimulus. Wild type REDD1 gene (REDD1(+/+)) and disruption in the REDD1 gene (REDD1(-/-)) mice were feed deprived for 16 h and randomized to remain feed deprived or refed for 15 or 60 min. The tibialis anterior was then removed for analysis of protein synthesis and mTORC1 signaling. In feed-deprived mice, protein synthesis and mTORC1 signaling were significantly lower in REDD1(+/+) than in REDD1(-/-) mice. Thirty minutes after the start of refeeding, protein synthesis in REDD1(+/+) mice was stimulated by 28%, reaching a value similar to that observed in feed-deprived REDD1(-/-) mice, and was accompanied by increased phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) by 81%, 167%, and 207%, respectively. In refed REDD1(-/-) mice, phosphorylation of mTOR (Ser2448), p70S6K1 (Thr389), and 4E-BP1 (Ser65) were significantly augmented above the values observed in refed REDD1(+/+) mice by 258%, 405%, and 401%, respectively, although protein synthesis was not coordinately increased. Seventy-five minutes after refeeding, REDD1 expression in REDD1(+/+) mice was reduced (∼15% of feed-deprived REDD1(+/+) values), and protein synthesis and mTORC1 signaling were not different between refed REDD1(+/+) mice and REDD1(-/-) mice. The results show that REDD1 expression limits protein synthesis in mouse skeletal muscle by inhibiting mTORC1 signaling during periods of feed

  11. Latency modulation of collicular neurons induced by electric stimulation of the auditory cortex in Hipposideros pratti: In vivo intracellular recording.

    Kang Peng

    Full Text Available In the auditory pathway, the inferior colliculus (IC receives and integrates excitatory and inhibitory inputs from the lower auditory nuclei, contralateral IC, and auditory cortex (AC, and then uploads these inputs to the thalamus and cortex. Meanwhile, the AC modulates the sound signal processing of IC neurons, including their latency (i.e., first-spike latency. Excitatory and inhibitory corticofugal projections to the IC may shorten and prolong the latency of IC neurons, respectively. However, the synaptic mechanisms underlying the corticofugal latency modulation of IC neurons remain unclear. Thus, this study probed these mechanisms via in vivo intracellular recording and acoustic and focal electric stimulation. The AC latency modulation of IC neurons is possibly mediated by pre-spike depolarization duration, pre-spike hyperpolarization duration, and spike onset time. This study suggests an effective strategy for the timing sequence determination of auditory information uploaded to the thalamus and cortex.

  12. Laser-Induced Evoked Potentials in the Brain after Nonperceptible Optical Stimulation at the Neiguan Acupoint: A Preliminary Report

    Gerhard Litscher

    2012-01-01

    Full Text Available We report on small but reproducible human cerebral evoked potentials after bilateral nonperceptible laser needle (658 nm, 40 mW, 500 μm, 1 Hz irradiation of the Neiguan acupoint (PC6. The results which are unique in scientific literature were obtained in a 26-year-old female healthy volunteer within a joint study between the Medical University of Graz, the Karl-Franzens University of Graz, and the Graz University of Technology. The findings of the 32-channel evoked potential analysis indicate that exposure to laser needle stimulation with a frequency of 1 Hz can modulate the ascending reticular activating system. Further studies are absolutely necessary to confirm or refute the preliminary findings.

  13. Tissue expander stimulated lengthening of arteries (TESLA) induces early endothelial cell proliferation in a novel rodent model.

    Potanos, Kristina; Fullington, Nora; Cauley, Ryan; Purcell, Patricia; Zurakowski, David; Fishman, Steven; Vakili, Khashayar; Kim, Heung Bae

    2016-04-01

    We examine the mechanism of aortic lengthening in a novel rodent model of tissue expander stimulated lengthening of arteries (TESLA). A rat model of TESLA was examined with a single stretch stimulus applied at the time of tissue expander insertion with evaluation of the aorta at 2, 4 and 7day time points. Measurements as well as histology and proliferation assays were performed and compared to sham controls. The aortic length was increased at all time points without histologic signs of tissue injury. Nuclear density remained unchanged despite the increase in length suggesting cellular hyperplasia. Cellular proliferation was confirmed in endothelial cell layer by Ki-67 stain. Aortic lengthening may be achieved using TESLA. The increase in aortic length can be achieved without tissue injury and results at least partially from cellular hyperplasia. Further studies are required to define the mechanisms involved in the growth of arteries under increased longitudinal stress. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. [Effects of the renal blood flow at different levels by transcutaneous electrical acupoint stimulation combined general anesthesia induced controlled hypotension].

    Fang, Jian-Qiao; Zhang, Le-Le; Shao, Xiao-Mei

    2012-11-01

    To observe the intervention of transcutaneous electrical acupoint stimulation (TEAS) on the renal blood flow at different levels of mean arterial pressure (MAP) in controlled hypotension. Forty-two male beagle dogs were randomly divided into seven groups, i. e., the general anesthesia group, the 50% controlled group, the 40% controlled group, the 30% controlled group, the 50% experimental group, the 40% experimental group, and the 30% experimental group, 6 in each group. Beagles in the general anesthesia group were not treated with controlled hypotension, and the target MAP was achieved in those of the rest groups and maintained for 60 min. In the experimental groups, TEAS was applied to bilateral Hegu (LI4), Zusanli (ST36), Sanyinjiao (SP6), and Quchi (LI11) at 2/100 Hz with the stimulation strength of (4 +/- 1) mA starting from the stability of their physiological conditions to 60 min of maintaining the target MAP level. The changes of the renal blood flow were monitored at different time points using laser Doppler. From starting pressure control to the target MAP level, the renal blood flow was significantly lower in the 30% controlled group than in the general anesthesia group and the basic level of the same group (P blood pressure, the renal blood flow was significantly lower in the 50% controlled group, the 40% controlled group, the 30% controlled group, and the 30% experimental group than in the general anesthesia group (P blood pressure recovery, the renal blood flow restored to the basic level in the 50% controlled group, the 50% experimental group, and the 40% experimental group (P > 0.05), while it was not restored to the basic level in the 40% controlled group, the 30% controlled group, and the 30% experimental group (P renal blood flow, thus protecting the kidney.

  15. mGluR5 stimulating Homer–PIKE formation initiates icariin induced cardiomyogenesis of mouse embryonic stem cells by activating reactive oxygen species

    Zhou, Limin; Huang, Yujie; Zhang, Yingying [Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, No. 866, Yu Hang Tang Road, Hangzhou 310058 (China); Zhao, Qingwei [The First Affiliated Hospital, College of Medicine, Zhejiang University, No. 79, Qing Chun Road, Hangzhou 310003 (China); Zheng, Bei; Lou, Yijia [Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, No. 866, Yu Hang Tang Road, Hangzhou 310058 (China); Zhu, Danyan, E-mail: zdyzxb@zju.edu.cn [Institute of Pharmacology, Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, No. 866, Yu Hang Tang Road, Hangzhou 310058 (China)

    2013-06-10

    Icariin (ICA) has been reported to facilitate cardiac differentiation of mouse embryonic stem (ES) cells; however, the mechanism by which ICA induced cardiomyogenesis has not been fully elucidated yet. Here, an underlying signaling network including metabotropic glutamate receptor 5 (mGluR5), Homer, phosphatidylinositol 3-Kinase Enhancer (PIKE), phosphatidylinositol 3-Kinase (PI3K), reactive oxygen species (ROS) and nuclear factor-kappaB (NF-κB) was investigated in ICA induced cardiomyogenesis. Our results showed that the co-expression of mGluR5 together with α-actinin or Troponin T in embryoid bodies (EBs) treated with ICA was elevated to 10.86% and 9.62%, compared with the case in the control (4.04% and 3.45%, respectively). Exposure of EBs to ICA for 2 h remarkably increased the dimeric form of mGluR5, which was inhibited by small interfering RNA targeting mGluR5 (si-mGluR5). Moreover, the extracellular glutamate concentration in ICA treatment medium was elevated to 28.9±3.5 μM. Furthermore, the activation of mGluR5 by ICA triggered the formation of Homer–PIKE complex and activated PI3K, stimulating ROS generation and NF-κB nuclear translocation. Knockdown of mGluR5 or inhibition of PI3K by LY294002 blocked ICA induced cardiomyogenesis via repressing mGluR5 pathway, reducing ROS and NF-κB activation. These results revealed that the inducible mechanisms of ICA were related to activate mGluR5 pathway. -- Highlights: • ICA increased mGluR5 expression in cardiac differentiation of ES cells. • ICA enhanced the glutamate level and the receptor mGluR5 dimerization, stimulating the formation of Homer–PIKE complex. • Knockdown of mGluR5 or inhibition of PI3K by LY294002 inhibited ICA induced ROS generation and NF-κB nuclear translocation.

  16. Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice.

    Araki, Ryota; Hiraki, Yosuke; Nishida, Shoji; Kuramoto, Nobuyuki; Matsumoto, Kinzo; Yabe, Takeshi

    2016-02-01

    In isolation-reared mice, social encounter stimulation induces locomotor hyperactivity and activation of the dorsal raphe nucleus (DRN), suggesting that dysregulation of dorsal raphe function may be involved in abnormal behaviors. In this study, we examined the involvement of dorsal raphe GABAergic dysregulation in the abnormal behaviors of isolation-reared mice. We also studied an epigenetic mechanism underlying abnormalities of the dorsal raphe GABAergic system. Both mRNA and protein levels of GABA(B1a), a GABA(B) receptor subunit, were increased in the DRN of isolation-reared mice, compared with these levels in group-reared mice. In contrast, mRNA levels for other GABAergic system-related genes (GABA(A) receptor α1, β2 and γ2 subunits, GABA(B) receptor 1b and 2 subunits, and glutamate decarboxylase 67 and 65) were unchanged. Intra-DRN microinjection of 0.06 nmol baclofen (a GABA(B) receptor agonist) exacerbated encounter-induced hyperactivity and aggressive behavior, while microinjection of 0.3 nmol phaclofen (a GABA(B) receptor antagonist) attenuated encounter-induced hyperactivity and aggressive behavior in isolation-reared mice. Furthermore, microinjection of 0.06 nmol baclofen elicited encounter-induced hyperactivity in group-reared mice. Neither baclofen nor phaclofen affected immobility time in the forced swim test and hyperactivity in a novel environment of isolation reared mice. Bisulfite sequence analyses revealed that the DNA methylation level of the CpG island around the transcription start site (TSS) of GABA(B1a) was decreased in the DRN of isolation-reared mice. Chromatin immunoprecipitation analysis showed that histone H3 was hyperacetylated around the TSS of GABA(B1a) in the DRN of isolation-reared mice. These findings indicate that an increase in dorsal raphe GABA(B1a) expression via epigenetic regulation is associated with abnormal responses to social stimulation such as encounter-induced hyperactivity and aggressive behavior in isolation

  17. Electrical stimulation-induced Gluteal and Hamstring muscle activation can reduce sitting pressure in individuals with a spinal cord injury

    Janssen, T. W J; De Koning, A.; Legemate, K. J A; Smit, C. A J

    2010-01-01

    Individuals with spinal cord injury (SCI) are at high risk of developing pressure sores, in part due to high sitting pressures under the buttocks. PURPOSE: To evaluate the effect of ES-induced activation of the gluteal and hamstring muscles on the sitting pressure in individuals with SCI. METHODS:

  18. Persistent attenuation and enhancement of the earthworm main muscle contraction generator response induced by repeated stimulation of a peripheral neuron

    Y.C. Chang

    1998-10-01

    Full Text Available Responses evoked in the earthworm, Amynthas hawayanus, main muscle contraction generator M-2 (postsynaptic mechanical-stimulus-sensitive neuron by threshold mechanical stimuli in 2-s intertrial intervals (ITI were used as the control or unconditioned responses (UR. Their attenuation induced by decreasing these intervals in non-associative conditioning and their enhancement induced by associating the unconditioned stimuli (US to a train of short (0.1 s hyperpolarizing electrical substitutive conditioning stimuli (SCS in the Peri-Kästchen (PK neuron were measured in four parameters, i.e., peak numbers (N and amplitude (averaged from 120 responses, sum of these amplitudes (SAMP and the highest peak amplitude (V over a period of 4 min. Persistent attenuation similar to habituation was induced by decreasing the control ITI to 0.5 s and 2.0 s in non-associative conditioning within less than 4 min. Dishabituation was induced by randomly pairing one of these habituated US to an electrical stimulus in the PK neuron. All four parameters of the UR were enhanced by forward (SCS-US, but not backward (US-SCS, association of the US with 25, 100 and 250-Hz trains of SCS with 40-ms interstimulus intervals (ISI for 4 min and persisted for another 4 min after turning off the SCS. The enhancement of these parameters was proportional to the SCS frequencies in the train. No UR was evoked by the SCS when the US was turned off after 4 min of classical conditioning.

  19. Lipolysis stimulating peptides of potato protein hydrolysate effectively suppresses high-fat-diet-induced hepatocyte apoptosis and fibrosis in aging rats

    Wen-Dee Chiang

    2016-07-01

    Full Text Available Background: Non-alcoholic fatty liver disease (NAFLD is one of the most common outcomes of obesity and is characterized by the accumulation of triglycerides, increased tissue apoptosis, and fibrosis. NAFLD is more common among elderly than in younger age groups, and it causes serious hepatic complications. Objective: In this study, alcalase treatment derived potato protein hydrolysate (APPH with lipolysis-stimulating property has been evaluated for its efficiency to provide hepato-protection in a high-fat-diet (HFD-fed aging rats. Design: Twenty-four-month-old SD rats were randomly divided into six groups (n=8: aged rats fed with standard chow, HFD-induced aged obese rats, HFD with low-dose (15 mg/kg/day APPH treatment, HFD with moderate (45 mg/kg/day APPH treatment, HFD with high (75 mg/kg/day APPH treatment, and HFD with probucol. Results: APPH was found to reduce the NAFLD-related effects in rat livers induced by HFD and all of the HFD-fed rats exhibited heavier body weight than those with control chow diet. However, the HFD-induced hepatic fat accumulation was effectively attenuated in rats administered with low (15 mg/kg/day, moderate (45 mg/kg/day, and high (75 mg/kg/day doses of APPH. APPH oral administration also suppressed the hepatic apoptosis- and fibrosis-related proteins induced by HFD. Conclusions: Our results thus indicate that APPH potentially attenuates hepatic lipid accumulation and anti-apoptosis and fibrosis effects in HFD-induced rats. APPH may have therapeutic potential in the amelioration of NAFLD liver damage.

  20. Low-frequency stimulation in anterior nucleus of thalamus alleviates kainate-induced chronic epilepsy and modulates the hippocampal EEG rhythm.

    Wang, Yi; Liang, Jiao; Xu, Cenglin; Wang, Ying; Kuang, Yifang; Xu, Zhenghao; Guo, Yi; Wang, Shuang; Gao, Feng; Chen, Zhong

    2016-02-01

    High-frequency stimulation (HFS) of the anterior nucleus of thalamus (ANT) is a new and alternative option for the treatment of intractable epilepsy. However, the responder rate is relatively low. The present study was designed to determine the effect of low-frequency stimulation (LFS) in ANT on chronic spontaneous recurrent seizures and related pathological pattern in intra-hippocampal kainate mouse model. We found that LFS (1 Hz, 100 μs, 300 μA), but not HFS (100 Hz, 100 μs, 30 μA), in bilateral ANT significantly decreased the frequency of spontaneous recurrent seizures, either non-convulsive focal seizures or tonic-clonic generalized seizures. The anti-epileptic effect persisted for one week after LFS cessation, which manifested as a long-term inhibition of the frequency of seizures with short (20-60 s) and intermediate duration (60-120 s). Meanwhile, LFS decreased the frequency of high-frequency oscillations (HFOs) and interictal spikes, two indicators of seizure severity, whereas HFS increased the HFO frequency. Furthermore, LFS decreased the power of the delta band and increased the power of the gamma band of hippocampal background EEG. In addition, LFS, but not HFS, improved the performance of chronic epileptic mice in objection-location task, novel objection recognition and freezing test. These results provide the first evidence that LFS in ANT alleviates kainate-induced chronic epilepsy and cognitive impairment, which may be related to the modulation of the hippocampal EEG rhythm. This may be of great therapeutic significance for clinical treatment of epilepsy with deep brain stimulation. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Modeling transcranial magnetic stimulation from the induced electric fields to the membrane potentials along tractography-based white matter fiber tracts

    De Geeter, Nele; Dupré, Luc; Crevecoeur, Guillaume

    2016-04-01

    Objective. Transcranial magnetic stimulation (TMS) is a promising non-invasive tool for modulating the brain activity. Despite the widespread therapeutic and diagnostic use of TMS in neurology and psychiatry, its observed response remains hard to predict, limiting its further development and applications. Although the stimulation intensity is always maximum at the cortical surface near the coil, experiments reveal that TMS can affect deeper brain regions as well. Approach. The explanation of this spread might be found in the white matter fiber tracts, connecting cortical and subcortical structures. When applying an electric field on neurons, their membrane potential is altered. If this change is significant, more likely near the TMS coil, action potentials might be initiated and propagated along the fiber tracts towards deeper regions. In order to understand and apply TMS more effectively, it is important to capture and account for this interaction as accurately as possible. Therefore, we compute, next to the induced electric fields in the brain, the spatial distribution of the membrane potentials along the fiber tracts and its temporal dynamics. Main results. This paper introduces a computational TMS model in which electromagnetism and neurophysiology are combined. Realistic geometry and tissue anisotropy are included using magnetic resonance imaging and targeted white matter fiber tracts are traced using tractography based on diffusion tensor imaging. The position and orientation of the coil can directly be retrieved from the neuronavigation system. Incorporating these features warrants both patient- and case-specific results. Significance. The presented model gives insight in the activity propagation through the brain and can therefore explain the observed clinical responses to TMS and their inter- and/or intra-subject variability. We aspire to advance towards an accurate, flexible and personalized TMS model that helps to understand stimulation in the connected

  2. (p-ClPhSe)2 stimulates carbohydrate metabolism and reverses the metabolic alterations induced by high fructose load in rats.

    Quines, Caroline B; Rosa, Suzan G; Chagas, Pietro M; Velasquez, Daniela; Prado, Vinicius C; Nogueira, Cristina W

    2017-09-01

    The modern life leads to excess consumption of food rich in fructose; however, the long-term changes in carbohydrate and lipid metabolism could lead to metabolic dysfunction in humans. The present study evaluated the in vitro insulin-mimetic action of p-chloro-diphenyl diselenide (p-ClPhSe) 2 . The second aim of this study was to investigate if (p-ClPhSe) 2 reverses metabolic dysfunction induced by fructose load in Wistar rats. The insulin-mimetic action of (p-ClPhSe) 2  at concentrations of 50 and 100 μM was determined in slices of rat skeletal muscle. (p-ClPhSe) 2  at a concentration of 50 μM stimulated the glucose uptake by 40% in skeletal muscle. A dose-response curve revealed that (p-ClPhSe) 2  at a dose of 25 mg/kg reduced (∼20%) glycemia in rats treated with fructose (5 g/kg, i.g.). The administration of fructose impaired the liver homeostasis and (p-ClPhSe) 2 (25 mg/kg) protected against the increase (∼25%) in the G-6-Pase and isocitrate dehydrogenase activities and reduced the triglyceride content (∼25%) in the liver. (p-ClPhSe) 2 regulated the liver homeostasis by stimulating hexokinase activity (∼27%), regulating the TCA cycle activity (increased the ATP and citrate synthase activity (∼15%)) and increasing the glycogen levels (∼67%). In conclusion, (p-ClPhSe) 2 stimulated carbohydrate metabolism and reversed metabolic dysfunction in rats fed with fructose. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory.

    Sui, Li; Huang, SiJia; Peng, BinBin; Ren, Jie; Tian, FuYing; Wang, Yan

    2014-07-01

    Deep brain stimulation (DBS) of the amygdala has been demonstrated to modulate hyperactivity of the amygdala, which is responsible for the symptoms of post-traumatic stress disorder (PTSD), and thus might be used for the treatment of PTSD. However, the underlying mechanism of DBS of the amygdala in the modulation of the amygdala is unclear. The present study investigated the effects of DBS of the amygdala on synaptic transmission and synaptic plasticity at cortical inputs to the amygdala, which is critical for the formation and storage of auditory fear memories, and fear memories. The results demonstrated that auditory fear conditioning increased single-pulse-evoked field excitatory postsynaptic potentials in the cortical-amygdala pathway. Furthermore, auditory fear conditioning decreased the induction of paired-pulse facilitation and long-term potentiation, two neurophysiological models for studying short-term and long-term synaptic plasticity, respectively, in the cortical-amygdala pathway. In addition, all these auditory fear conditioning-induced changes could be reversed by DBS of the amygdala. DBS of the amygdala also rescued auditory fear conditioning-induced enhancement of long-term retention of fear memory. These findings suggested that DBS of the amygdala alleviating fear conditioning-induced alterations in synaptic plasticity in the cortical-amygdala pathway and fear memory may underlie the neuromodulatory role of DBS of the amygdala in activities of the amygdala.

  4. Vitamin C-linker-conjugated tripeptide AHK stimulates BMP-2-induced osteogenic differentiation of mouse myoblast C2C12 cells.

    Jung, Jung-Il; Park, Kyeong-Yong; Lee, Yura; Park, Mira; Kim, Jiyeon

    2018-03-15

    Vitamin C-linker-conjugated Ala-His-Lys tripeptide (Vit C-AHK) is a derivative of Vitamin C-conjugated tripeptides, which were originally developed as a component of a product for collagen synthesis enhancement or human dermal fibroblast growth. Here, we investigated the effect of Vit C-AHK on bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Vit C-AHK enhanced proliferation of C2C12 cells and induction of BMP-2-induced alkaline phosphatase, a typical marker of osteoblast differentiation. Vit C-AHK also stimulated the phosphorylation and translocation of Smad1/5/8 to the nucleus and phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK1/2 and p38. In addition, Vit C-AHK enhanced the BMP-2-induced mRNA expression of osteoblast differentiation-related genes such as ALP, BMP-2, Osteocalcin, and Runx2. Our results suggest that Vit C-AHK exerts an enhancing effect on osteoblast proliferation and differentiation through activation of Smad1/5/8 and MAPK ERK1/2 and p38 signaling and without significant cytotoxicity. These results provide important data for the development of peptide-based bone-regenerative agents and treatment of bone-related disorders. Copyright © 2018 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

  5. Acute total sleep deprivation potentiates amphetamine-induced locomotor-stimulant effects and behavioral sensitization in mice.

    Saito, Luis P; Fukushiro, Daniela F; Hollais, André W; Mári-Kawamoto, Elisa; Costa, Jacqueline M; Berro, Laís F; Aramini, Tatiana C F; Wuo-Silva, Raphael; Andersen, Monica L; Tufik, Sergio; Frussa-Filho, Roberto

    2014-02-01

    It has been demonstrated that a prolonged period (48 h) of paradoxical sleep deprivation (PSD) potentiates amphetamine (AMP)-induced behavioral sensitization, an animal model of addiction-related neuroadaptations. In the present study, we examined the effects of an acute short-term deprivation of total sleep (TSD) (6h) on AMP-induced behavioral sensitization in mice and compared them to the effects of short-term PSD (6 h). Three-month-old male C57BL/6J mice underwent TSD (experiment 1-gentle handling method) or PSD (experiment 2-multiple platforms method) for 6 h. Immediately after the sleep deprivation period, mice were tested in the open field for 10 min under the effects of saline or 2.0 mg/kg AMP. Seven days later, to assess behavioral sensitization, all of the mice received a challenge injection of 2.0 mg/kg AMP and were tested in the open field for 10 min. Total, peripheral, and central locomotion, and grooming duration were measured. TSD, but not PSD, potentiated the hyperlocomotion induced by an acute injection of AMP and this effect was due to an increased locomotion in the central squares of the apparatus. Similarly, TSD facilitated the development of AMP-induced sensitization, but only in the central locomotion parameter. The data indicate that an acute period of TSD may exacerbate the behavioral effects of AMP in mice. Because sleep architecture is composed of paradoxical and slow wave sleep, and 6-