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Sample records for depletion attenuates tonic

  1. Burst and Tonic Spinal Cord Stimulation Differentially Activate GABAergic Mechanisms to Attenuate Pain in a Rat Model of Cervical Radiculopathy.

    PubMed

    Crosby, Nathan D; Weisshaar, Christine L; Smith, Jenell R; Zeeman, Martha E; Goodman-Keiser, Melanie D; Winkelstein, Beth A

    2015-06-01

    Spinal cord stimulation (SCS) is widely used to treat neuropathic pain. Burst SCS, an alternative mode of stimulation, reduces neuropathic pain without paresthesia. However, the effects and mechanisms of burst SCS have not been compared to conventional tonic SCS in controlled investigations. This study compares the attenuation of spinal neuronal activity and tactile allodynia, and the role of γ-aminobutyric acid (GABA) signaling during burst or tonic SCS in a rat model of cervical radiculopathy. The effects of burst and tonic SCS were compared by recording neuronal firing before and after each mode of stimulation at day 7 following a painful cervical nerve root compression. Neuronal firing was also recorded before and after burst and tonic SCS in the presence of the GABAB receptor antagonist, CGP35348. Burst and tonic SCS both reduce neuronal firing. The effect of tonic SCS, but not burst SCS, is blocked by CGP35348. In a separate study, spinal cord stimulators were implanted to deliver burst or tonic SCS beginning on day 4 after painful nerve root compression; allodynia and serum GABA concentration were measured through day 14. Burst and tonic SCS both reduce allodynia. Tonic SCS attenuates injury-induced decreases in serum GABA, but GABA remains decreased from baseline during burst SCS. Together, these studies suggest that burst SCS does not act via spinal GABAergic mechanisms, despite its attenuation of spinal hyperexcitability and allodynia similar to that of tonic SCS; understanding other potential spinal inhibitory mechanisms may lead to enhanced analgesia during burst stimulation.

  2. Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder.

    PubMed

    Badgaiyan, Rajendra D; Sinha, Sampada; Sajjad, Munawwar; Wack, David S

    2015-01-01

    It is unclear whether attention deficit hyperactive disorder (ADHD) is a hypodopaminergic or hyperdopaminergic condition. Different sets of data suggest either hyperactive or hypoactive dopamine system. Since indirect methods used in earlier studies have arrived at contradictory conclusions, we directly measured the tonic and phasic release of dopamine in ADHD volunteers. The tonic release in ADHD and healthy control volunteers was measured and compared using dynamic molecular imaging technique. The phasic release during performance of Eriksen's flanker task was measured in the two groups using single scan dynamic molecular imaging technique. In these experiments volunteers were positioned in a positron emission tomography (PET) camera and administered a dopamine receptor ligand (11)C-raclopride intravenously. After the injection PET data were acquired dynamically while volunteers either stayed still (tonic release experiments) or performed the flanker task (phasic release experiments). PET data were analyzed to measure dynamic changes in ligand binding potential (BP) and other receptor kinetic parameters. The analysis revealed that at rest the ligand BP was significantly higher in the right caudate of ADHD volunteers suggesting reduced tonic release. During task performance significantly lower ligand BP was observed in the same area, indicating increased phasic release. In ADHD tonic release of dopamine is attenuated and the phasic release is enhanced in the right caudate. By characterizing the nature of dysregulated dopamine neurotransmission in ADHD, the results explain earlier findings of reduced or increased dopaminergic activity.

  3. Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure.

    PubMed

    Pandit, Sudip; Jo, Ji Yoon; Lee, Sang Ung; Lee, Young Jae; Lee, So Yeong; Ryu, Pan Dong; Lee, Jung Un; Kim, Hyun-Woo; Jeon, Byeong Hwa; Park, Jin Bong

    2015-08-01

    γ-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR δ subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of γ2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Similar and minimal Itonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF Itonic attenuation. Finally, the NPA-induced inhibition of spontaneous firing was greater in HF than in SHAM PVN-RVLM neurons, whereas diazepam induced less inhibition of spontaneous firing in HF than in SHAM neurons. Overall, our results showed that combined with reduced GABAARs function, the enhanced astroglial GABA uptake-induced attenuation of Itonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure.

  4. Tonic γ-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus is attenuated in the spontaneously hypertensive rat.

    PubMed

    Kawabe, Tetsuya; Kawabe, Kazumi; Sapru, Hreday N

    2013-08-01

    We tested the hypothesis that tonic γ-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus (ARCN) modulates blood pressure control and attenuation of this inhibitory activity contributes to hypertension in the spontaneously hypertensive rats (SHR). Mean arterial pressure (MAP), heart rate (HR), and greater splanchnic nerve activity (GSNA) were recorded in urethane-anesthetized, artificially ventilated, adult male SHR and Wistar-Kyoto rats (WKY). Microinjections of gabazine into the ARCN elicited significantly smaller increases in MAP, HR, and GSNA in baroreceptor-intact SHR compared with baroreceptor-intact WKY. Attenuation of the responses to gabazine in SHR persisted, despite lowering of their baseline MAP to levels of WKY or barodenervation. Microinjections of N-methyl-d-aspartic acid (NMDA) into the ARCN elicited decreases in MAP and GSNA and increases in HR in baroreceptor-intact WKY. However, after microinjections of gabazine into the ARCN, microinjections of NMDA into the same nucleus elicited pressor responses in baroreceptor-intact WKY. In barodenervated WKY, increases in MAP and GSNA were elicited by ARCN stimulation by NMDA and the increases in HR were exaggerated. In baroreceptor-intact SHR, ARCN stimulation by NMDA elicited increases in MAP, GSNA, and HR which persisted, despite lowering of baseline MAP or barodenervation. Increases in MAP and GSNA elicited by ARCN stimulation by NMDA in barodenervated SHR were significantly greater than corresponding increases in barodenervated WKY. These results indicated that attenuated γ-aminobutyric acid-ergic activity in the ARCN and impaired baroreflex function may contribute to increases in blood pressure and sympathetic nerve activity after ARCN stimulation by NMDA and elevation of baseline blood pressure in SHR.

  5. Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.

    PubMed

    Machnik, Agnes; Dahlmann, Anke; Kopp, Christoph; Goss, Jennifer; Wagner, Hubertus; van Rooijen, Nico; Eckardt, Kai-Uwe; Müller, Dominik N; Park, Joon-Keun; Luft, Friedrich C; Kerjaschki, Dontscho; Titze, Jens

    2010-03-01

    We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na(+) accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated mechanism in the skin to maintain

  6. Tonic sympathetic support of metabolic rate is attenuated with age, sedentary lifestyle, and female sex in healthy adults.

    PubMed

    Bell, C; Seals, D R; Monroe, M B; Day, D S; Shapiro, L F; Johnson, D G; Jones, P P

    2001-09-01

    We recently demonstrated in young adult humans that the sympathetic nervous system contributes to the control of resting metabolic rate via tonic beta-adrenergic receptor stimulation. In the present follow-up study we determined the respective effects of age, habitual exercise status, and sex on this regulatory mechanism. Resting metabolic rate (ventilated hood, indirect calorimetry) was determined in 55 healthy sedentary or endurance exercise-trained adults, aged 18-35 or 60-75 yr (29 men and 26 women), before (baseline) and during the infusion of either a nonselective beta-adrenergic receptor antagonist (propranolol) or saline (control). Relative to baseline values, during beta-adrenergic receptor antagonism resting metabolic rate adjusted for fat-free mass was reduced to a lesser extent in older (mean +/- SE, -130 +/- 46 kJ/d) compared with young (-297 +/- 46) adults, sedentary (-151 +/- 50) compared with endurance exercise-trained (-268 +/- 46) adults, and women (-105 +/- 33) compared with men (-318 +/- 50; all P < 0.01). Reductions in resting metabolic rate during beta-adrenergic receptor antagonism were positively related to higher baseline resting metabolic rate and plasma catecholamine concentrations and negatively related to adiposity (all P < 0.05). Resting metabolic rate was unchanged in response to saline control in all groups. These results provide experimental support for the hypothesis that aging, sedentary living, and female sex are associated with attenuated sympathetic nervous system support of resting metabolic rate in healthy adult humans.

  7. Retraction. Clc-2 knockout attenuated experimental temporal lobe epilepsy in mice by tonic inhibition mediated by GABAA receptors.

    PubMed

    Ge, Yu-Xing; Tian, Xiang-Zhu

    2016-03-01

    Temporal lobe epilepsy (TLE), the most prevalent form of epilepsy, is often associated with drug-resistant seizures. In TLE, altered function of γ-aminobutyric acid (GABA)A receptors (GABAARs) results in potentiation of excitatory and/or failure of inhibitory neurotransmission, which contributes to seizure induction and propagation. Our previous study suggested that chloride channel-2 (Clc-2) contributed to chronically elevated tonic inhibition mediated by GABAARs in a rat model of TLE. In the present study, we used Clc-2 knockout mice to investigate further the role of Clc-2 and its interaction with tonic GABAergic inhibition in a model of TLE. The results revealed that knockout of Clc-2 decreased tonic seizure protection, latency of clonic seizure, seizure threshold and mortality protection in mice. Clc-2 knockout decreased the action potential (AP)peak and APthreshold, Clc-2 currents and GABAAR-mediated tonic inhibition in CA1 pyramidal neurons. Thus, the voltage-gated chloride channel Clc-2, which was functionally upregulated in CA1 pyramidal cells after seizures, may provide protection against TLE by its regulation of action potentials, Clc-2 currents and GABAARs in the CA1 region of the hippocampus.

  8. High firing rate of neonatal hippocampal interneurons is caused by attenuation of afterhyperpolarizing potassium currents by tonically active kainate receptors.

    PubMed

    Segerstråle, Mikael; Juuri, Juuso; Lanore, Frédéric; Piepponen, Petteri; Lauri, Sari E; Mulle, Christophe; Taira, Tomi

    2010-05-12

    In the neonatal hippocampus, the activity of interneurons shapes early network bursts that are important for the establishment of neuronal connectivity. However, mechanisms controlling the firing of immature interneurons remain elusive. We now show that the spontaneous firing rate of CA3 stratum lucidum interneurons markedly decreases during early postnatal development because of changes in the properties of GluK1 (formerly known as GluR5) subunit-containing kainate receptors (KARs). In the neonate, activation of KARs by ambient glutamate exerts a tonic inhibition of the medium-duration afterhyperpolarization (mAHP) by a G-protein-dependent mechanism, permitting a high interneuronal firing rate. During development, the amplitude of the apamine-sensitive K+ currents responsible for the mAHP increases dramatically because of decoupling between KAR activation and mAHP modulation, leading to decreased interneuronal firing. The developmental shift in the KAR function and its consequences on interneuronal activity are likely to have a fundamental role in the maturation of the synchronous neuronal oscillations typical for adult hippocampal circuitry.

  9. Attenuated benzodiazepine-sensitive tonic GABAA currents of supraoptic magnocellular neuroendocrine cells in 24-h water-deprived rats.

    PubMed

    Pandit, S; Song, J G; Kim, Y J; Jeong, J A; Jo, J Y; Lee, G S; Kim, H-W; Jeon, B H; Lee, J U; Park, J B

    2014-01-01

    In supraoptic nucleus (SON) magnocellular neurosecretory cells (MNCs), γ-GABA, via activation of GABAA receptors (GABAA Rs), mediates persistent tonic inhibitory currents (Itonic ), as well as conventional inhibitory postsynaptic currents (IPSCs, Iphasic ). In the present study, we examined the functional significance of Itonic in SON MNCs challenged by 24-h water deprivation (24WD). Although the main characteristics of spontaneous IPSCs were similar in 24WD compared to euhydrated (EU) rats, Itonic , measured by bicuculline (BIC)-induced Iholding shifts, was significantly smaller in 24WD compared to EU rats (P < 0.05). Propofol and diazepam prolonged IPSC decay time to a similar extent in both groups but induced less Itonic in 24WD compared to EU rats, suggesting a selective decrease in GABAA receptors mediating Itonic over Iphasic in 24WD rats. THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential δ subunit agonist, and L-655,708, a GABAA receptor α5 subunit selective imidazobenzodiazepine, caused a significantly smaller inward and outward shift in Iholding , respectively, in 24WD compared to EU rats (P < 0.05 in both cases), suggesting an overall decrease in the α5 subunit-containing GABAA Rs and the δ subunit-containing receptors mediating Itonic in 24WD animals. Consistent with a decrease in 24WD Itonic , bath application of GABA induced significantly less inhibition of the neuronal firing activity in 24WD compared to EU SON MNCs (P < 0.05). Taken together, the results of the present study indicate a selective decrease in GABAA Rs functions mediating Itonic as opposed to those mediating Iphasic in SON MNCs, demonstrating the functional significance of Itonic with respect to increasing neuronal excitability and hormone secretion in 24WD rats.

  10. Kaiso depletion attenuates the growth and survival of triple negative breast cancer cells.

    PubMed

    Bassey-Archibong, Blessing I; Rayner, Lyndsay G A; Hercules, Shawn M; Aarts, Craig W; Dvorkin-Gheva, Anna; Bramson, Jonathan L; Hassell, John A; Daniel, Juliet M

    2017-03-23

    Triple negative breast cancers (TNBC) are highly aggressive and lack specific targeted therapies. Recent studies have reported high expression of the transcription factor Kaiso in triple negative tumors, and this correlates with their increased aggressiveness. However, little is known about the clinical relevance of Kaiso in the growth and survival of TNBCs. Herein, we report that Kaiso depletion attenuates TNBC cell proliferation, and delays tumor onset in mice xenografted with the aggressive MDA-231 breast tumor cells. We further demonstrate that Kaiso depletion attenuates the survival of TNBC cells and increases their propensity for apoptotic-mediated cell death. Notably, Kaiso depletion downregulates BRCA1 expression in TNBC cells expressing mutant-p53 and we found that high Kaiso and BRCA1 expression correlates with a poor overall survival in breast cancer patients. Collectively, our findings reveal a role for Kaiso in the proliferation and survival of TNBC cells, and suggest a relevant role for Kaiso in the prognosis and treatment of TNBCs.

  11. Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

    PubMed Central

    Shin, H J; Kim, H; Heo, R W; Kim, H J; Choi, W S; Kwon, H M; Roh, G S

    2014-01-01

    Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood–brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/−) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/−) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/−) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target. PMID:24608792

  12. Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures.

    PubMed

    Shin, H J; Kim, H; Heo, R W; Kim, H J; Choi, W S; Kwon, H M; Roh, G S

    2014-07-01

    Kainic acid (KA)-induced seizures followed by neuronal death are associated with neuroinflammation and blood-brain barrier (BBB) leakage. Tonicity-responsive enhancer binding protein (TonEBP) is known as a transcriptional factor activating osmoprotective genes, and in brain, it is expressed in neuronal nuclei. Thus dysregulation of TonEBP may be involved in the pathology of KA-induced seizures. Here we used TonEBP heterozygote (+/-) mice to study the roles of TonEBP. Electroencephalographic study showed that TonEBP (+/-) mice reduced seizure frequency and severity compared with wild type during KA-induced status epilepticus. Immunohistochemistry and western blotting analysis showed that KA-induced neuroinflammation and BBB leakage were dramatically reduced in TonEBP (+/-) mice. Similarly, TonEBP-specific siRNA reduced glutamate-induced death in HT22 hippocampal neuronal cells. TonEBP haplodeficiency prevented KA-induced nuclear translocation of NF-κB p65 and attenuated inflammation. Our findings identify TonEBP as a critical regulator of neuroinflammation and BBB leakage in KA-induced seizures, which suggests TonEBP as a good therapeutic target.

  13. Ser/thr phosphatases tonically attenuate the ERK-dependent pressor effect of ethanol in the rostral ventrolateral medulla in normotensive rats.

    PubMed

    El-Mas, Mahmoud M; Abdel-Rahman, Abdel A

    2014-08-19

    We recently reported that microinjection of ethanol into the rostral ventrolateral medulla (RVLM) elicits modest increases in local extracellular signal-regulated kinase (ERK) and blood pressure (BP) in conscious normotensive rats. In this study, we tested the hypothesis that RVLM ser/thr phosphatases dampen the ERK-dependent pressor effect of ethanol in normotensive rats. We show that the pressor response elicited by intra-RVLM ethanol (10 μg) was (i) abolished following local ERK inhibition with PD98059 (1 μg) and (ii) associated with significant reduction in local phosphatase activity. Inhibition of the RVLM ser/thr phosphatase activity by okadaic acid (OKA, 0.4 μg) or fostriecin (15 pg) caused significant increases in blood pressure (BP) and potentiated the magnitude and duration of the pressor response as well as the phosphatase inhibition elicited by subsequent intra-RVLM administration of ethanol. Intra-RVLM acetaldehyde (2 μg), the main metabolic product of ethanol, caused no changes in BP or RVLM phosphatase activity but it produced significant increases in BP and inhibition of local phosphatase activity in rats treated with OKA or fostriecin. Together, the RVLM phosphatase activity acts tonically to attenuate the ERK-dependent pressor effect of ethanol or acetaldehyde in normotensive rats.

  14. Neutrophil Depletion Attenuates Placental Ischemia-Induced Hypertension in the Rat

    PubMed Central

    Regal, Jean F.; Lillegard, Kathryn E.; Bauer, Ashley J.; Elmquist, Barbara J.; Loeks-Johnson, Alex C.; Gilbert, Jeffrey S.

    2015-01-01

    Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension. PMID:26135305

  15. Macrophage Depletion Attenuates Extracellular Matrix Deposition and Ductular Reaction in a Mouse Model of Chronic Cholangiopathies

    PubMed Central

    Syn, Wing-Kin; Lagaisse, Kimberly; van Hul, Noemi; Heindryckx, Femke; Sowa, Jan-Peter; Peeters, Liesbeth; Van Vlierberghe, Hans; Leclercq, Isabelle A.; Canbay, Ali

    2016-01-01

    Chronic cholangiopathies, such as primary and secondary sclerosing cholangitis, are progressive disease entities, associated with periportal accumulation of inflammatory cells, encompassing monocytes and macrophages, peribiliary extracellular matrix (ECM) deposition and ductular reaction (DR). This study aimed to elucidate the relevance of macrophages in the progression of chronic cholangiopathies through macrophage depletion in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse model. One group of mice received a single i.p. injection of Clodronate encapsulated liposomes (CLOLipo) at day 7 of a 14 day DDC treatment, while control animals were co-treated with PBSLipo instead. Mice were sacrificed after 7 or respectively 14 days of treatment for immunohistochemical assessment of macrophage recruitment (F4/80), ECM deposition (Sirius Red, Laminin) and DR (CK19). Macrophage depletion during a 14 day DDC treatment resulted in a significant inhibition of ECM deposition. Porto-lobular migration patterns of laminin-rich ECM and ductular structures were significantly attenuated and a progression of DR was effectively inhibited by macrophage depletion. CLOLipo co-treatment resulted in a confined DR to portal regions without amorphous cell clusters. This study suggests that therapeutic options selectively directed towards macrophages might represent a feasible treatment for chronic cholestatic liver diseases. PMID:27618307

  16. Attenuation of kindling-induced decreases in NT-3 mRNA by thyroid hormone depletion.

    PubMed

    Kim, S Y; Smith, M A; Post, R M; Rosen, J B

    1998-02-01

    The expression of neurotrophins is altered by amygdala kindled seizures. Because thyroid hormone can regulate the transcription of neurotrophins, we asked whether thyroid hormone regulates neurotrophin mRNA expression following amygdala kindling. Rats with electrodes implanted in the basolateral nucleus of the amygdala were either depleted of thyroid hormone or given excess thyroid hormone. The rats were then kindled daily until they had one generalized seizure. The brains were removed 4 h after the seizure and processed for in situ hybridization of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) mRNAs. In non-kindled rats, thyroid hormone depletion increased the levels of BDNF mRNA in the paraventricular nucleus of the hypothalamus and the pituitary gland. NGF and NT-3 mRNA expression was not altered. In addition, thyroid hormone manipulations had no effect on kindling or on kindling-induced BDNF and NGF mRNA. However, the kindling-induced decrease in NT-3 mRNA expression in the dentate gyrus granule cell layer was significantly attenuated by thyroid hormone depletion. These effects were reversed by thyroid hormone replacement. The results indicate that thyroid hormone plays a modulatory role in the seizure-induced changes of NT-3 mRNA expression found in the dentate gyrus.

  17. Dopamine depletion attenuates some behavioral abnormalities in a hyperdopaminergic mouse model of bipolar disorder

    PubMed Central

    van Enkhuizen, Jordy; Geyer, Mark A.; Halberstadt, Adam L.; Zhuang, Xiaoxi; Young, Jared W.

    2014-01-01

    Background Patients with BD suffer from multifaceted symptoms, including hyperactive and psychomotor agitated behaviors. Previously, we quantified hyperactivity, increased exploration, and straighter movements of patients with BD mania in the human Behavioral Pattern Monitor (BPM). A similar BPM profile is observed in mice that are hyperdopaminergic due to reduced dopamine transporter (DAT) functioning. We hypothesized that dopamine depletion through alpha-methyl-p-tyrosine (AMPT) administration would attenuate this mania-like profile. Methods Male and female DAT wild-type (WT; n=26) and knockdown (KD; n=28) mice on a C57BL/6 background were repeatedly tested in the BPM to assess profile robustness and stability. The optimal AMPT dose was identified by treating male C57BL/6 mice (n=39) with vehicle or AMPT (10, 30, or 100 mg/kg) at 24, 20, and 4 h prior to testing in the BPM. Then, male and female DAT WT (n=40) and KD (n=37) mice were tested in the BPM after vehicle or AMPT (30 mg/kg) treatment. Results Compared to WT littermates, KD mice exhibited increased activity, exploration, straighter movement, and disorganized behavior. AMPT-treatment reduced hyperactivity and increased path organization, but potentiated specific exploration in KD mice without affecting WT mice. Limitations AMPT is not specific to dopamine and also depletes norepinephrine. Conclusions KD mice exhibit abnormal exploration in the BPM similar to patients with BD mania. AMPT-induced dopamine depletion attenuated some, but potentiated other, aspects of this mania-like profile in mice. Future studies should extend these findings into other aspects of mania to determine the suitability of AMPT as a treatment for BD mania. PMID:24287168

  18. Attenuation and Transport Mechanisms of Depleted Uranium in Groundwater at Lawrence Livermore National Laboratory Site 300

    NASA Astrophysics Data System (ADS)

    Danny, K. R.; Taffet, M. J.; Brusseau, M. L. L.; Chorover, J.

    2015-12-01

    Lawrence Livermore National Laboratory (LLNL) Site 300 was established in 1955 to support weapons research and development. Depleted uranium was used as a proxy for fissile uranium-235 (235U) in open-air explosives tests conducted at Building 812. As a result, oxidized depleted uranium was deposited on the ground, eventually migrating to the underlying sandstone aquifer. Uranium (U) groundwater concentrations exceed the California and Federal Maximum Contaminant Level of 20 pCi L-1 (30 ug L-1). However, the groundwater plume appears to attenuate within 60 m of the source, beyond which no depleted U is detected. This study will determine the relative contribution of physical (e.g. dilution), chemical (e.g. surface adsorption, mineral precipitation), and biological (e.g. biotransformation) processes that contribute to the apparent attenuation of U, which exists as uranyl (UO22+) complexes, at the site. Methods of investigation include evaluating 15 yr of hydrogeologic and chemical data, creating a site conceptual model, and applying equilibrium (e.g. aqueous species complexation, mineral saturation indices) and reactive transport models using Geochemist's WorkbenchTM. Reactive transport results are constrained by direct field observations, including U major ion, and dissolved O2 concentrations, pH, and others, under varying chemical and hydraulic conditions. Aqueous speciation calculations indicate that U primarily exists as anionic CaUO2(CO3)32- or neutral Ca2UO2(CO3)30 species. Additionally, nucleation and growth of Ca/Mg uranyl carbonate solids are predicted to affect attenuation. Initial reactive transport results suggest surface adsorption (e.g. ion exchange, surface complexation) to layer silicate clays is limited under the aqueous geochemical conditions of the site. Current and future work includes XRD analysis of aquifer solids to constrain iron and aluminum (oxy)hydroxides, and coupling advective-dispersive transport with the chemical and physical processes

  19. CD200 attenuates methamphetamine-induced microglial activation and dopamine depletion.

    PubMed

    Yue, Xia; Qiao, Dongfang; Wang, Aifeng; Tan, Xiaohui; Li, Yanhong; Liu, Chao; Wang, Huijun

    2012-06-01

    This study examined the neuroprotective effect of cluster of differentiation molecule 200 (CD200) against methamphetamine (METH)-induced neurotoxicity. In the in vitro experiment, neuron-microglia cultures were treated with METH (20 μmol/L), METH (20 μmol/L)+CD200-Fc (10 μg/mL) or CD200-Fc (10 μg/mL). Those untreated served as control. Microglia activation expressed as the ratio of MHC-II/CD11b was assessed by flow cytometry. The cytokines (IL-1β, TNF-α) secreted by activated microglia were detected by enzyme-linked immunosorbent assay (ELISA). In the in vivo experiment, 40 SD rats were divided into control, METH, METH+CD200-Fc and CD200-Fc groups at random. Rats were intraperitoneally injected with METH (15 mg/kg 8 times at 12 h interval) in METH group, with METH (administered as the same dose and time as the METH group) and CD200-Fc (1 mg/kg at day 0, 2, 4 after METH injection) in METH+CD200-Fc group, with CD200-Fc (1 mg/kg injected as the same time as the METH+CD200-Fc group) or with physiological saline solution in the control group. The level of striatal dopamine (DA) in rats was measured by high-performance liquid chromatography (HPLC). The microglial cells were immunohistochemically detected for the expression of Iba-1, a marker for microglial activation. The results showed that METH could increase the microglia activation in the neuron-microglia cultures and elevate the secretion of IL-1β and TNF-α, which could be attenuated by CD200-Fc. Moreover, CD200-Fc could partially reverse the striatal DA depletion induced by METH and reduce the number of activated microglia, i.e. Iba-1-positive cells. It was concluded that CD200 may have neuroprotective effects against METH-induced neurotoxicity by inhibiting microglial activation and reversing DA depletion in striatum.

  20. Ibuprofen administration attenuates serum TNF-{alpha} levels, hepatic glutathione depletion, hepatic apoptosis and mouse mortality after Fas stimulation

    SciTech Connect

    Cazanave, Sophie; Vadrot, Nathalie; Tinel, Marina; Berson, Alain; Letteron, Philippe; Larosche, Isabelle; Descatoire, Veronique; Feldmann, Gerard; Robin, Marie-Anne |; Pessayre, Dominique |

    2008-09-15

    Fas stimulation recruits neutrophils and activates macrophages that secrete tumor necrosis factor-{alpha} (TNF-{alpha}), which aggravates Fas-mediated liver injury. To determine whether nonsteroidal anti-inflammatory drugs modify these processes, we challenged 24-hour-fasted mice with the agonistic Jo2 anti-Fas antibody (4 {mu}g/mouse), and treated the animals 1 h later with saline or ibuprofen (250 mg/kg), a dual cyclooxygenase (COX)-1 and COX-2 inhibitor. Ibuprofen attenuated the Jo2-mediated recruitment/activation of myeloperoxidase-secreting neutrophils/macrophages in the liver, and attenuated the surge in serum TNF-{alpha}. Ibuprofen also minimized hepatic glutathione depletion, Bid truncation, caspase activation, outer mitochondrial membrane rupture, hepatocyte apoptosis and the increase in serum alanine aminotransferase (ALT) activity 5 h after Jo2 administration, to finally decrease mouse mortality at later times. The concomitant administration of pentoxifylline (decreasing TNF-{alpha} secretion) and infliximab (trapping TNF-{alpha}) likewise attenuated the Jo2-mediated increase in TNF-{alpha}, the decrease in hepatic glutathione, and the increase in serum ALT activity 5 h after Jo2 administration. The concomitant administration of the COX-1 inhibitor, SC-560 (10 mg/kg) and the COX-2 inhibitor, celecoxib (40 mg/kg) 1 h after Jo2 administration, also decreased liver injury 5 h after Jo2 administration. In contrast, SC-560 (10 mg/kg) or celecoxib (40 or 160 mg/kg) given alone had no significant protective effects. In conclusion, secondary TNF-{alpha} secretion plays an important role in Jo2-mediated glutathione depletion and liver injury. The combined inhibition of COX-1 and COX-2 by ibuprofen attenuates TNF-{alpha} secretion, glutathione depletion, mitochondrial alterations, hepatic apoptosis and mortality in Jo2-treated fasted mice.

  1. Inducible satellite cell depletion attenuates skeletal muscle regrowth following a scald-burn injury.

    PubMed

    Finnerty, Celeste C; McKenna, Colleen F; Cambias, Lauren A; Brightwell, Camille R; Prasai, Anesh; Wang, Ye; El Ayadi, Amina; Herndon, David N; Suman, Oscar E; Fry, Christopher S

    2017-08-22

    Severe burns result in profound skeletal muscle atrophy; persistent muscle atrophy and weakness are major complications that hamper recovery from burn injury. Many factors contribute to the erosion of muscle mass following burn trauma, and we have previously shown concurrent activation and apoptosis of muscle satellite cells following a burn injury in pediatric patients. To determine the necessity of satellite cells during muscle recovery following a burn injury, we utilized a genetically modified mouse model (Pax7(CreER) -DTA) that allows for the conditional depletion of satellite cells in skeletal muscle. Additionally, mice were provided 5-ethynyl-2'-deoxyuridine to determine satellite cell proliferation, activation and fusion. Juvenile satellite cell-wild type (SC-WT) and satellite cell-depleted (SC-Dep) mice (8 weeks of age) were randomized to sham or burn injury consisting of a dorsal scald burn injury covering 30% of total body surface area. Both hind-limb and dorsal muscles were studied at 7, 14 and 21 days post-burn. SC-Dep mice had >93% depletion of satellite cells compared to SC-WT (P < 0.05). Burn injury induced robust atrophy in muscles located both proximal and distal to the injury site (∼30% decrease in fibre cross-sectional area [CSA], P < 0.05). Additionally, burn injury induced skeletal muscle regeneration, satellite cell proliferation, and fusion. Depletion of satellite cells impaired post-burn recovery of both muscle fibre CSA and volume (P < 0.05). These findings support an integral role for satellite cells in the etiology of lean tissue recovery following a severe burn injury. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. Mechanisms and Consequences of Dopamine Depletion-Induced Attenuation of the Spinophilin/Neurofilament Medium Interaction

    PubMed Central

    Hiday, Andrew C.; Edler, Michael C.; Salek, Asma B.; Morris, Cameron W.; Thang, Morrent; Rentz, Tyler J.; Rose, Kristie L.; Jones, Lisa M.

    2017-01-01

    Signaling changes that occur in the striatum following the loss of dopamine neurons in the Parkinson disease (PD) are poorly understood. While increases in the activity of kinases and decreases in the activity of phosphatases have been observed, the specific consequences of these changes are less well understood. Phosphatases, such as protein phosphatase 1 (PP1), are highly promiscuous and obtain substrate selectivity via targeting proteins. Spinophilin is the major PP1-targeting protein enriched in the postsynaptic density of striatal dendritic spines. Spinophilin association with PP1 is increased concurrent with decreases in PP1 activity in an animal model of PD. Using proteomic-based approaches, we observed dopamine depletion-induced decreases in spinophilin binding to multiple protein classes in the striatum. Specifically, there was a decrease in the association of spinophilin with neurofilament medium (NF-M) in dopamine-depleted striatum. Using a heterologous cell line, we determined that spinophilin binding to NF-M required overexpression of the catalytic subunit of protein kinase A and was decreased by cyclin-dependent protein kinase 5. Functionally, we demonstrate that spinophilin can decrease NF-M phosphorylation. Our data determine mechanisms that regulate, and putative consequences of, pathological changes in the association of spinophilin with NF-M that are observed in animal models of PD. PMID:28634551

  3. PDGFRα depletion attenuates glioblastoma stem cells features by modulation of STAT3, RB1 and multiple oncogenic signals

    PubMed Central

    Cenciarelli, Carlo; Marei, Hany E.; Felsani, Armando; Casalbore, Patrizia; Sica, Gigliola; Puglisi, Maria Ausiliatrice; Cameron, Angus J.M.; Olivi, Alessandro; Mangiola, Annunziato

    2016-01-01

    Platelet derived growth factor receptors (PDGFRs) play an important role in tumor pathogenesis, and they are frequently overexpressed in glioblastoma (GBM). Earlier we have shown a higher protein expression of PDGFR isoforms (α and β) in peritumoral-tissue derived cancer stem cells (p-CSC) than in tumor core (c-CSC) of several GBM affected patients. In the current study, in order to assess the activity of PDGFRα/PDGF-AA signaling axis, we performed time course experiments to monitor the effects of exogenous PDGF-AA on the expression of downstream target genes in c-CSC vs p-CSC. Interestingly, in p-CSC we detected the upregulation of Y705-phosphorylated Stat3, concurrent with a decrement of Rb1 protein in its active state, within minutes of PDGF-AA addition. This finding prompted us to elucidate the role of PDGFRα in self-renewal, invasion and differentiation in p-CSC by using short hairpin RNA depletion of PDGFRα expression. Notably, in PDGFRα-depleted cells, protein analysis revealed attenuation of stemness-related and glial markers expression, alongside early activation of the neuronal marker MAP2a/b that correlated with the induction of tumor suppressor Rb1. The in vitro reduction of the invasive capacity of PDGFRα-depleted CSC as compared to parental cells correlated with the downmodulation of markers of epithelial-mesenchymal transition phenotype and angiogenesis. Surprisingly, we observed the induction of anti-apoptotic proteins and compensatory oncogenic signals such as EDN1, EDNRB, PRKCB1, PDGF-C and PDGF-D. To conclude, we hypothesize that the newly discovered PDGFRα/Stat3/Rb1 regulatory axis might represent a potential therapeutic target for GBM treatment. PMID:27344175

  4. Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells.

    PubMed

    Hoshi, Reina; Watanabe, Yosuke; Ishizuka, Yoshiaki; Hirano, Takayuki; Nagasaki-Maeoka, Eri; Yoshizawa, Shinsuke; Uekusa, Shota; Kawashima, Hiroyuki; Ohashi, Kensuke; Sugito, Kiminobu; Fukuda, Noboru; Nagase, Hiroki; Soma, Masayoshi; Ozaki, Toshinori; Koshinaga, Tsugumichi; Fujiwara, Kyoko

    2017-04-01

    Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21WAF1 was markedly upregulated in TFAP2E‑knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21WAF1.

  5. Depletion of tissue plasminogen activator attenuates lung ischemia-reperfusion injury via inhibition of neutrophil extravasation

    PubMed Central

    Zhao, Yunge; Sharma, Ashish K.; LaPar, Damien J.; Kron, Irving L.; Ailawadi, Gorav; Liu, Yuan; Jones, David R.; Laubach, Victor E.

    2011-01-01

    Ischemia-reperfusion (IR) injury following lung transplantation remains a major source of early morbidity and mortality. Histologically, this inflammatory process is characterized by neutrophil infiltration and activation. We previously reported that lung IR injury was significantly attenuated in plasminogen activator inhibitor-1-deficient mice. In this study, we explored the potential role of tissue plasminogen activator (tPA) in a mouse lung IR injury model. As a result, tPA knockout (KO) mice were significantly protected from lung IR injury through several mechanisms. At the cellular level, tPA KO specifically blocked neutrophil extravasation into the interstitium, and abundant homotypic neutrophil aggregation (HNA) was detected in the lung microvasculature of tPA KO mice after IR. At the molecular level, inhibition of neutrophil extravasation was associated with reduced expression of platelet endothelial cell adhesion molecule-1 mediated through the tPA/ LDL receptor-related protein/NF-κB signaling pathway, whereas increased P-selectin triggered HNA. At the functional level, tPA KO mice incurred significantly decreased vascular permeability and improved lung function following IR. Protection from lung IR injury in tPA KO mice occurs through a fibrinolysis-independent mechanism. These results suggest that tPA could serve as an important therapeutic target for the prevention and treatment of acute IR injury after lung transplantation. PMID:21378024

  6. Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels.

    PubMed

    Dinesh, Neeradi; Neelagiri, Soumya; Kumar, Vinay; Singh, Sushma

    2017-02-24

    In the present study, glycyrrhizic acid (GA) the main component of Glycyrrhiza glabra was evaluated for its efficacy as antileishmanial agent and its mode of action explored. GA inhibits promastigotes and intracellular amastigotes in a dose dependent manner at an IC50 value of 34 ± 3.0 μM and 20 ± 4.2 μM respectively. GA was non-toxic against THP-1 macrophage host cell line. GA was found to inhibit recombinant Leishmania donovani HMG-CoA reductase (LdHMGR) enzyme at the half-maximum inhibitory concentration of 24 ± 4.3 μM indicating the sensitivity and specificity of GA towards the enzyme. However, GA could cause only 30% reduction in HMGR activity when measured in Leishmania promastigotes treated with 34 μM of GA. Interestingly western blot analysis revealed fivefold reduced HMGR expression in GLA treated promastigotes. To further study the mode of action of GA, we used transgenic parasites overexpressing LdHMGR. Results indicated that ∼2 fold resistance was exhibited by LdHMGR overexpressing promastigotes to GA with an IC50 value of 74 μM compared to the wild type parasite. This explained the specific binding of GA to LdHMGR enzyme. There was ∼2 fold depletion in ergosterol levels in wild type promastigotes compared to the HMGR overexpressors. This data was further validated by exogenous supplementation of GA treated cells with ergosterol and 40% reversal of growth inhibition was observed. The results obtained suggested that GA kills the parasite by affecting sterol biosynthetic pathway, especially by inhibiting the L. donovani HMGR and altering ergosterol levels. The finding from the current study shows that GA is a potential antileishmanial chemotherapeutic agent.

  7. Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats.

    PubMed

    Kaplan, Kara; Echert, Ashley E; Massat, Ben; Puissant, Madeleine M; Palygin, Oleg; Geurts, Aron M; Hodges, Matthew R

    2016-05-01

    Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DA(Tph2-/-)) rats. DA(Tph2-/-) rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DA(Tph2-/-) rats. Body temperature was also maintained in adult DA(Tph2-/-) rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DA(Tph2-/-) rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. Copyright © 2016 the American Physiological Society.

  8. Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats

    PubMed Central

    Kaplan, Kara; Echert, Ashley E.; Massat, Ben; Puissant, Madeleine M.; Palygin, Oleg; Geurts, Aron M.

    2016-01-01

    Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DATph2−/−) rats. DATph2−/− rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DATph2−/− rats. Body temperature was also maintained in adult DATph2−/− rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DATph2−/− rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat. PMID:26869713

  9. Dietary diallyl disulfide supplementation attenuates ethanol-mediated pulmonary vitamin D speciate depletion in C57Bl/6 mice

    PubMed Central

    McCaskill, Michael L.; Hottor, Henry T.; Sapkota, Muna; Wyatt, Todd A.

    2016-01-01

    Background Slightly more than 5 % of the United States population heavily consumes ethanol, i.e., more than 14 drinks for men and 7 drinks for women a week. Chronic ethanol consumption can result in increased liver disease, reduced recovery from burn injury, and more frequent and severe respiratory infections. Chronic ethanol over-consumption also leads to vitamin D dysmetabolism and depletion. Vitamin D is a fat-soluble pro-hormone that regulates musculoskeletal health, cellular proliferation/differentiation, and innate and adaptive immune response. Methods In this study, C57BL/6 mice were fed 20 % ethanol in their water ad libitum for 7 weeks. Some mice were fed either a standard chow or a modified diet containing 0.15 μg/day of diallyl disulfide (DADS). Whole blood, lung tissue, and bronchial alveolar lavage fluid (BALF) were collected at sacrifice and analyzed for 25(OH) D3, 1,25 (OH)2D3, vitamin D receptor VDR, CYP2E1, and CYP27B1 levels. Results Ethanol reduced 25(OH) D3 and 1,25 (OH)2D3 in lung tissue and BALF on average 31 %. The largest ethanol-mediated reduction was in the 1,25 (OH)2D3 (42 %) measured in the BALF. Dietary supplementation of DADS restored BALF and lung tissue protein of 25(OH) D3 and 1,25(OH)2D3 to control levels. Chronic ethanol consumption also resulted in tissue increases of vitamin D response (VDR) protein, Cyp2E1, and reductions in vitamin D-activating enzyme CYP27B1. All three of these effects were attenuated by dietary supplementation of DADS. Conclusions In conclusion, the pulmonary metabolic disturbances mediated by chronic ethanol consumption as measured by 1,25(OH)2D3 protein levels, epithelial lining fluid, and lung tissue can be ameliorated by dietary supplementation of DADS in C57BL/6 mice. PMID:27536382

  10. Dietary diallyl disulfide supplementation attenuates ethanol-mediated pulmonary vitamin D speciate depletion in C57Bl/6 mice.

    PubMed

    McCaskill, Michael L; Hottor, Henry T; Sapkota, Muna; Wyatt, Todd A

    Slightly more than 5 % of the United States population heavily consumes ethanol, i.e., more than 14 drinks for men and 7 drinks for women a week. Chronic ethanol consumption can result in increased liver disease, reduced recovery from burn injury, and more frequent and severe respiratory infections. Chronic ethanol over-consumption also leads to vitamin D dysmetabolism and depletion. Vitamin D is a fat-soluble pro-hormone that regulates musculoskeletal health, cellular proliferation/differentiation, and innate and adaptive immune response. In this study, C57BL/6 mice were fed 20 % ethanol in their water ad libitum for 7 weeks. Some mice were fed either a standard chow or a modified diet containing 0.15 μg/day of diallyl disulfide (DADS). Whole blood, lung tissue, and bronchial alveolar lavage fluid (BALF) were collected at sacrifice and analyzed for 25(OH) D3, 1,25 (OH)2D3, vitamin D receptor VDR, CYP2E1, and CYP27B1 levels. Ethanol reduced 25(OH) D3 and 1,25 (OH)2D3 in lung tissue and BALF on average 31 %. The largest ethanol-mediated reduction was in the 1,25 (OH)2D3 (42 %) measured in the BALF. Dietary supplementation of DADS restored BALF and lung tissue protein of 25(OH) D3 and 1,25(OH)2D3 to control levels. Chronic ethanol consumption also resulted in tissue increases of vitamin D response (VDR) protein, Cyp2E1, and reductions in vitamin D-activating enzyme CYP27B1. All three of these effects were attenuated by dietary supplementation of DADS. In conclusion, the pulmonary metabolic disturbances mediated by chronic ethanol consumption as measured by 1,25(OH)2D3 protein levels, epithelial lining fluid, and lung tissue can be ameliorated by dietary supplementation of DADS in C57BL/6 mice.

  11. [Tonic pupil caused by ischemia].

    PubMed

    Wilhelm, H

    1989-01-01

    Tonic pupil is usually an idiopathic condition. In some cases, the cause of the ciliary ganglion lesion leading to tonic pupils is obvious. Rarely ischemia causes a lesion of the ciliary ganglion or the short ciliary nerves due to the good blood supply of the ciliary ganglion. Only two cases of tonic pupils in the course of giant cell arteritis are mentioned in the literature, but tonic pupils are probably much more common with this disease. Five cases are demonstrated here. All had associated ischemic optic neuropathy, and stagnation of the blood flow in the supratrochlear artery could be demonstrated in two cases by Doppler sonography. Tonic pupils may also occur when an oclusion of the internal carotid artery resolves, probably because of transient stasis of the orbital blood flow. In another case, tonic pupils were associated with choroidal ischemia (proved by video fluorescent angiography) of unknown origin. The diagnosis of tonic pupils was made by pharmacological testing for cholinergic hypersensitivity with 0.1% pilocarpine.

  12. Depletion of NEAT1 lncRNA attenuates nucleolar stress by releasing sequestered P54nrb and PSF to facilitate c-Myc translation.

    PubMed

    Shen, Wen; Liang, Xue-Hai; Sun, Hong; De Hoyos, Cheryl L; Crooke, Stanley T

    2017-01-01

    Altered expression of NEAT1, the architectural long non-coding RNA (lncRNA) of nuclear paraspeckles, has been reported during tumorigenesis, as well as under various cellular stress conditions. Here we report that the depletion of NEAT1 lncRNA alleviates nucleolar stress during RNAP I inhibition through releasing sequestered P54nrb and PSF to facilitate the IRES-dependent translation of c-Myc. RNAP I inhibitor CX5461 disrupts the SL1-rDNA interaction and induces nucleolar disruption, demonstrated by the accumulation of fibrillarin-containing nucleoplasmic foci and nucleolar clearance of ribosomal proteins in HeLa cells. Antisense oligonucleotide-mediated depletion of NEAT1 lncRNA significantly attenuated the RNAP I inhibition and its related nucleolar disruption. Interestingly, induction in the levels of c-Myc protein was observed in NEAT1-depeleted cells under RNAP I inhibition. NEAT1-associated paraspeckle proteins P54nrb and PSF have been reported as positive regulators of c-Myc translation through interaction with c-Myc IRES. Indeed, an increased association of P54nrb and PSF with c-Myc mRNA was observed in NEAT1-depleted cells. Moreover, apoptosis was observed in HeLa cells depleted of P54nrb and PSF, further confirming the positive involvement of P54nrb and PSF in cell proliferation. Together, our results suggest that NEAT1 depletion rescues CX5461-induced nucleolar stress through facilitating c-Myc translation by relocating P54nrb/PSF from nuclear paraspeckles to c-Myc mRNAs.

  13. CD4+CD25+Foxp3+ Regulatory T Cells Depletion May Attenuate the Development of Silica-Induced Lung Fibrosis in Mice

    PubMed Central

    Chen, Ying; Song, Laiyu; He, Qincheng; Chen, Jie

    2010-01-01

    Background Silicosis is an occupational lung disease caused by inhalation of silica dust characterized by lung inflammation and fibrosis. Previous study showed that Th1 and Th2 cytokines are involved in silicosis, but Th1/Th2 polarization during the development of silicosis is still a matter of debate. Regulatory T cells (Treg cells) represent a crucial role in modulation of immune homeostasis by regulating Th1/Th2 polarization, but their possible implication in silicosis remains to be explored. Methodology/Principal Findings To evaluate the implication of Treg cells in the development of silicosis, we generated the Treg-depleted mice model by administration of anti-CD25 mAbs and mice were exposed to silica by intratracheal instillation to establish experimental model of silica-induced lung fibrosis. The pathologic examinations show that the Treg-depleted mice are susceptive to severer inflammation in the early stage, with enhanced infiltration of inflammatory cells. Also, depletion of Treg cells causes a delay of the progress of silica-induced lung fibrosis in mice model. Further study of mRNA expression of cytokines reveals that depletion of Tregs leads to the increased production of Th1-cytokines and decreased production of Th2-cytokine. The Flow Cytometry and realtime PCR study show that Treg cells exert the modulation function both directly by expressing CTLA-4 at the inflammatory stage, and indirectly by secreting increasing amount of IL-10 and TGF-β during the fibrotic stage in silica-induced lung fibrosis. Conclusion/Significance Our study suggests that depletion of Tregs may attenuate the progress of silica-induced lung fibrosis and enhance Th1 response and decelerate Th1/Th2 balance toward a Th2 phenotype in silica-induced lung fibrosis. The regulatory function of Treg cells may depend on direct mechanism and indirect mechanism during the inflammatory stage of silicosis. PMID:21072213

  14. Depletion of NEAT1 lncRNA attenuates nucleolar stress by releasing sequestered P54nrb and PSF to facilitate c-Myc translation

    PubMed Central

    Shen, Wen; Liang, Xue-hai; Sun, Hong; De Hoyos, Cheryl L.; Crooke, Stanley T.

    2017-01-01

    Altered expression of NEAT1, the architectural long non-coding RNA (lncRNA) of nuclear paraspeckles, has been reported during tumorigenesis, as well as under various cellular stress conditions. Here we report that the depletion of NEAT1 lncRNA alleviates nucleolar stress during RNAP I inhibition through releasing sequestered P54nrb and PSF to facilitate the IRES-dependent translation of c-Myc. RNAP I inhibitor CX5461 disrupts the SL1-rDNA interaction and induces nucleolar disruption, demonstrated by the accumulation of fibrillarin-containing nucleoplasmic foci and nucleolar clearance of ribosomal proteins in HeLa cells. Antisense oligonucleotide-mediated depletion of NEAT1 lncRNA significantly attenuated the RNAP I inhibition and its related nucleolar disruption. Interestingly, induction in the levels of c-Myc protein was observed in NEAT1-depeleted cells under RNAP I inhibition. NEAT1-associated paraspeckle proteins P54nrb and PSF have been reported as positive regulators of c-Myc translation through interaction with c-Myc IRES. Indeed, an increased association of P54nrb and PSF with c-Myc mRNA was observed in NEAT1-depleted cells. Moreover, apoptosis was observed in HeLa cells depleted of P54nrb and PSF, further confirming the positive involvement of P54nrb and PSF in cell proliferation. Together, our results suggest that NEAT1 depletion rescues CX5461-induced nucleolar stress through facilitating c-Myc translation by relocating P54nrb/PSF from nuclear paraspeckles to c-Myc mRNAs. PMID:28288210

  15. Monoamine depletion attenuates the REM sleep deprivation-induced increase in clonidine response in the forced swimming test.

    PubMed

    Asakura, W; Matsumoto, K; Ohta, H; Watanabe, H

    1994-09-01

    Effect of monoamine depletion on the REM sleep (REMs) deprivation-induced increase in clonidine response in the forced swimming test was investigated. Mice were deprived of REMs by the small pedestal method. Clonidine HCl (10-1000 micrograms/kg, IP), an alpha 2-adrenoceptor agonist, dose dependently increased swimming activities in group-housed and socially isolated mice used as the control groups. The dose-response relationship shifted to the left following REMs deprivation (ED50 values in the group-housed, isolated, and REMs-deprived mice were 250, 200, and 27 micrograms/kg, respectively). Monoamine depletion, induced by reserpine (5 mg/kg, IP) plus alpha-methyl-p-tyrosine (250 mg/kg, IP), did not produce any changes in the effects of clonidine in the control groups. However, in REMs-deprived mice, monoamine depletion significantly decreased the effect of 100 micrograms/kg clonidine, but not that of 300 micrograms/kg clonidine on swimming activity. These results indicate that clonidine-induced increase in swimming activity in the forced swimming test is mainly mediated by postsynaptic alpha 2-adrenoceptor, and that endogenous noradrenaline in the brain plays an important role in the increase of clonidine response following REMs deprivation treatment. The neuronal mechanism of the increase in clonidine response is discussed.

  16. No attenuation of ischemic and reperfusion injury in Kupffer cell-depleted, cold-preserved rat livers.

    PubMed

    Reinders, M E; van Wagensveld, B A; van Gulik, T M; Corssmit, N P; Frederiks, W M; Chamuleau, R A; van Rooijen, N; Obertop, H

    1997-02-15

    Activated Kupffer cells (KC) have been implicated in the damage sustained by preserved liver grafts during ischemia and reperfusion. The aim of this study was to compare ischemia/reperfusion injury in preserved, KC-depleted rat livers and preserved control livers, with special regard to sinusoidal endothelial cell (SEC) injury. Wistar rats were injected with liposome-encapsulated dichloromethylene diphosphonate, 48 hr before hepatectomy, to eliminate KC, or were withheld this pretreatment (controls). Livers were flushed with cold University of Wisconsin solution and after 0, 8, 16, or 24 hr of storage at 4 degrees C, were reperfused in a recirculation system with 200 ml of oxygenated Krebs-Henseleit solution at 37 degrees C for 90 min. Damage to SEC was measured by the uptake of hyaluronic acid (HA) from the perfusate and release of purine nucleoside phosphorylase (PNP). Perfusate samples were, furthermore, analyzed for aspartate aminotransferase (AST) and tumor necrosis factor-alpha. Carbon particles were infused in the perfusate to determine the phagocytotic capacity of KC. Biopsies were taken for histological examination and sections were stained with ED2 monoclonal antibodies to confirm the absence of KC. After 90 min of reperfusion, immediately after cold flush (t0), the uptake of HA was 72.2+/-2.3% and 69.3+/-1.3% in KC-depleted livers and in control livers, respectively (n.s.). After 8 hr of storage, HA uptake was 21.6+/-4.5% and 34.6+/-8.0%, respectively (n.s.). After 16 and 24 hr of storage and reperfusion, no uptake of HA was found in either KC-depleted or control livers, indicating abolished SEC function. PNP activities in the perfusate were higher in control livers (after 8 and 24 hr of storage), presumably due to release from damaged KC. No difference was found in AST and no tumor necrosis factor-alpha was measured in the perfusates of normal and KC-depleted livers. Electron microscopic studies showed that after 8 and 24 hr of storage and reperfusion

  17. Functional depletion of capsaicin-sensitive primary afferent fibers attenuates rat pain-related behaviors and paw edema induced by the venom of scorpion Buthus martensi Karch.

    PubMed

    Bai, Zhan-Tao; Liu, Tong; Pang, Xue-Yan; Jiang, Feng; Cheng, Ming; Ji, Yong-Hua

    2008-10-01

    The role of capsaicin-sensitive primary afferent fibers in rat pain-related behaviors and paw edema induced by scorpion Buthus martensi Karch (BmK) venom was investigated in this study. It was found that functional depletion of capsaicin-sensitive primary afferent fibers with a single systemic injection of resiniferatoxin (RTX) dramatically decreased spontaneous nociceptive behaviors, prevented the development of primary mechanical and thermal hyperalgesia as well as mirror-image mechanical hyperalgesia. RTX treatment significantly attenuated BmK venom-induced c-Fos expression in all laminaes of bilateral L4-L5 lumbar spinal cord, especially in superficial laminaes. Moreover, RTX treatment markedly reduced the early paw edema induced by BmK venom. Thus, the results indicate that capsaicin-sensitive primary afferent fibers play a critical role in various pain-related behaviors and paw edema induced by BmK venom in rats.

  18. Chronic hypoxia impairs murine hippocampal development and depletes the postnatal progenitor pool by attenuating mTOR signaling

    PubMed Central

    Raman, Lakshmi; Kong, Xiangmei; Gilley, Jennifer A.; Kernie, Steven G.

    2011-01-01

    Chronic hypoxia (CH) is a major risk factor for impaired cognitive function in various disease states, particularly in the context of cyanotic congenital heart disease. While most brain development occurs prenatally, the dentate gyrus (DG) of the hippocampus harbors progenitor stem cells that contribute to its ongoing development postnatally. It is unclear how exposure to CH might affect postnatal hippocampal development, so we utilized a transgenic mouse that expresses enhanced green fluorescent protein (eGFP) within this progenitor population to determine the effect of CH on the DG. We find that exposure to 10% oxygen from postnatal day 3 to 28, results in a smaller DG with long-term impairment of hippocampal neurogenesis. Since the mammalian target of rapamycin (mTOR) pathway is a well-known regulator of cell proliferation and growth and is sensitive to hypoxia, we investigated its activation upon exposure to CH and find it to be attenuated specifically in neural progenitor cells. Systemic inhibition of the mTOR pathway using rapamycin also caused impairment of hippocampal neurogenesis that mimics exposure to CH. Our findings demonstrate that CH results in long-term impairment of hippocampal neurogenesis and is mediated, in part, by attenuation of the mTOR pathway. PMID:21532529

  19. RCCD1 depletion attenuates TGF-β-induced EMT and cell migration by stabilizing cytoskeletal microtubules in NSCLC cells.

    PubMed

    Wu, Junyu; He, Zhimin; Yang, Xiao-Mei; Li, Kai-Le; Wang, Da-Liang; Sun, Fang-Lin

    2017-08-01

    Lung cancer is one of the most lethal cancers due to its highly metastatic spreading. The motility of lung cancer cells is regulated by paracrine factors, such as TGF-β, in the tumor microenvironment through the induction of epithelial-to-mesenchymal transition (EMT). The stability of microtubules is reported to be associated with the EMT process and the migration of cancer cells. Here, we observed that RCC1 domain-containing protein 1 (RCCD1) is highly expressed in non-small cell lung cancer (NSCLC) patients with poor prognosis, and RCCD1 is much higher expressed in tumor tissues compared with adjacent normal tissues. Depletion of RCCD1 using siRNAs significantly inhibits the migration of lung cancer cells. Subsequent studies reveal that the loss of RCCD1 results in upregulation of acetylated α-tubulin levels and stabilizes cytoskeletal microtubules. Mechanistically, we observed that RCCD1 modulates the stability of microtubules through interacting with JMJD5. Furthermore, RCCD1 depletion significantly attenuates the TGF-β-induced EMT process, as assessed by altered expression of epithelial and mesenchymal markers (Occludin, Vimentin and Snail), and inhibits TGF-β-induced cell migration. Collectively, these findings support RCCD1 as a novel regulator of TGF-β-induced EMT in NSCLC. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. WldS Reduces Paraquat-Induced Cytotoxicity via SIRT1 in Non-Neuronal Cells by Attenuating the Depletion of NAD

    PubMed Central

    Yu, Qiujing; Wang, Ting; Zhou, Xuexia; Wu, Jingxia; Chen, Xingmiao; Liu, Yang; Wu, Dongmei; Zhai, Qiwei

    2011-01-01

    WldS is a fusion protein with NAD synthesis activity, and has been reported to protect axonal and synaptic compartments of neurons from various mechanical, genetic and chemical insults. However, whether WldS can protect non-neuronal cells against toxic chemicals is largely unknown. Here we found that WldS significantly reduced the cytotoxicity of bipyridylium herbicides paraquat and diquat in mouse embryonic fibroblasts, but had no effect on the cytotoxicity induced by chromium (VI), hydrogen peroxide, etoposide, tunicamycin or brefeldin A. WldS also slowed down the death of mice induced by intraperitoneal injection of paraquat. Further studies demonstrated that WldS markedly attenuated mitochondrial injury including disruption of mitochondrial membrane potential, structural damage and decline of ATP induced by paraquat. Disruption of the NAD synthesis activity of WldS by an H112A or F116S point mutation resulted in loss of its protective function against paraquat-induced cell death. Furthermore, WldS delayed the decrease of intracellular NAD levels induced by paraquat. Similarly, treatment with NAD or its precursor nicotinamide mononucleotide attenuated paraquat-induced cytotoxicity and decline of ATP and NAD levels. In addition, we showed that SIRT1 was required for both exogenous NAD and WldS-mediated cellular protection against paraquat. These findings suggest that NAD and SIRT1 mediate the protective function of WldS against the cytotoxicity induced by paraquat, which provides new clues for the mechanisms underlying the protective function of WldS in both neuronal and non-neuronal cells, and implies that attenuation of NAD depletion may be effective to alleviate paraquat poisoning. PMID:21750730

  1. Paradoxical sleep deprivation modulates tyrosine hydroxylase expression in the nigrostriatal pathway and attenuates motor deficits induced by dopaminergic depletion.

    PubMed

    Lima, Marcelo M S; Andersen, Monica L; Reksidler, Angela B; Ferraz, Anete C; Vital, Maria A B F; Tufik, Sergio

    2012-06-01

    The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinson's disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.

  2. The myth of brain tonics.

    PubMed

    Kabra, S G

    1993-04-01

    In India, vitamin tonics are promoted and sold as a means to improve the intelligence of children. 3 research studies in the UK have attempted to evaluate the influence of vitamin intake on nonverbal and verbal intelligence. The University of Dundee study by Dr. D. Benton and Dr. G. Roberts in 1988 followed 12-13 year old children who received vitamin supplementation for 8 months and compared the group with a matched group of 30 children who received placebos and a 3rd group who received nothing. The results of pretest and posttest scores showed improvement in nonverbal intelligence (solving problems not requiring vocabulary or information) among the group receiving vitamin and mineral supplementation. Another group of researchers from King College, London, evaluated intelligence scores of 11-12 year old children receiving vitamin and mineral supplementation and found no improvement in scores. This study did not exactly replicate the Benton study. A 3rd group of researchers from the University of Dundee did replicate the Benton and Roberts' study and found supplementation did not improve either verbal or nonverbal scores. Children are used in these research projects because nonverbal intelligence reaches its peak maximum by 18-21 years of age. Verbal intelligence continues to grow throughout life. In India, there is an emphasis in schools on development of verbal intelligence. Manufacturers of "brain tonics" claim that tonics improve children's performance in examinations. Not only are the research findings debatable, but there are other considerations that do not support use of supplementation to increase reasoning performance. The tonics, which contain an excess of vitamins in the daily requirement, are excreted in the urine rather than being stored in the body. Vitamins are also costly and are available to only 30% of the India's population. Production of vitamins such as B-12, B-1, or B-2 are in excess of the amount required if there were vitamin deficiencies

  3. The effect of tonicity and hypertonic solutions on microvascular permeability.

    PubMed

    Victorino, Gregory P; Newton, Christopher R; Curran, Brian

    2002-05-15

    The effect of hypertonic saline (HS) on microvascular permeability is unclear. We hypothesized that varying degrees of tonicity and HS solutions alter microvascular fluid flux across the endothelium. Hydraulic permeability (L(p)) is a measure of water flow across the endothelial barrier. L(p) was measured in cannulated rat mesenteric venules using the modified Landis micro-occlusion technique. The effect of tonicity was tested by measuring L(p) after successive perfusions with Ringers' solutions of varying sodium chloride (NaCl) concentrations (85, 135, 185, and 235 mM) (n = 6). Additional venules were perfused with control Ringers' ([NaCl] = 135 mM) and measures of L(p) were obtained after subsequent perfusions with 7% NaCl followed by 7% NaCl with 6% dextran (n = 6). Tonicity had a significant dose-dependent effect on L(p) (P < 0.0001). Perfusion with 7% NaCl significantly increased L(p) (P < 0.0001). The addition of 6% dextran to 7% NaCl significantly decreased L(p) compared with perfusion with 7% NaCl alone (P = 0.002). We conclude that (1) tonicity influences microvascular permeability, (2) HS increases microvascular permeability, and (3) the addition of dextran to HS greatly attenuates this response. These findings suggest an important role for tonicity and a possible deleterious effect of HS in modulating microvascular permeability as well as the benefit of dextran with HS for maintaining intravascular volume. (c) 2002 Elsevier Science (USA).

  4. Medial frontal ∼4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion.

    PubMed

    Parker, Krystal L; Chen, Kuan-Hua; Kingyon, Johnathan R; Cavanagh, James F; Narayanan, Nandakumar S

    2015-08-01

    The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2-6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2- to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease. Copyright © 2015 the American Physiological Society.

  5. Medial frontal ∼4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion

    PubMed Central

    Parker, Krystal L.; Chen, Kuan-Hua; Kingyon, Johnathan R.; Cavanagh, James F.

    2015-01-01

    The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2–6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2- to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease. PMID:26133799

  6. Indices of serum tonicity in clinical practice.

    PubMed

    Rohrscheib, Mark; Rondon-Berrios, Helbert; Argyropoulos, Christos; Glew, Robert H; Murata, Glen H; Tzamaloukas, Antonios H

    2015-06-01

    Although disturbances of serum tonicity (effective osmolality) may have dire consequences, only surrogate indices of tonicity are available in practice. This report identifies the appropriate index for expressing clinical states of dystonicity. Serum sodium concentration ([Na]S) and osmolality ([Osm]S) may be incongruent. When the tonicity state shown by [Osm]S is higher than [Na]S and the difference between the 2 indices is caused by an excess of solute that distributes in total body water, tonicity is described by [Na]S. When this difference results from a gain of solute with extracellular distribution like mannitol or a decrease in serum water content, causing a falsely low measurement of [Na]S, [Osm]S accurately reflects tonicity. Two indices of tonicity are applicable during hyperglycemia: the tonicity formula (2 ·[Na]S + [Glucose]S/18) and the corrected [Na]S ([Na]S corrected to a normal [Glucose]S using an empirically derived coefficient). Clinicians should understand the uses and limitations of the tonicity indices.

  7. Translational Challenges With Tonic Immobility

    PubMed Central

    Zoellner, Lori A.

    2011-01-01

    Drawing heavily from the nonhuman animal literature, understanding of tonic immobility (TI), a sustained and involuntary physical immobility, may yield clear clinical implications and strong future translational research. Clinically, for individuals who potentially have experienced TI, psychoeducation regarding its involuntary and defensive nature may help normalize trauma-related reactions. This must be balanced with the reactive nature of the information and the recognition of potentially more common survival strategies. The application of TI for research purposes may pose translational obstacles regarding construct definition and assessment. Issues include separating the construct from non-TI-related event or perpetrator characteristics, peritraumatic dissociation, and event severity. Furthermore, with its assessment, clinical status and time may inflate endorsement of the presence or severity of TI reactions. PMID:22180702

  8. Dynamics of muscle activation during tonic-clonic seizures.

    PubMed

    Conradsen, Isa; Moldovan, Mihai; Jennum, Poul; Wolf, Peter; Farina, Dario; Beniczky, Sándor

    2013-03-01

    The purpose of our study was to elucidate the dynamics of muscle activation during generalised tonic-clonic seizures (GTCS). We recorded surface electromyography (EMG) from the deltoid muscle during 26 GTCS from 13 patients and compared it with GTCS-like events acted by 10 control subjects. GTCS consisted of a sequence of phases best described quantitatively by dynamics of the low frequency (LF) wavelet component (2-8Hz). Contrary to the traditional view, the tonic phase started with a gradual increase in muscle activity. A longer clonic phase was associated with a shorter onset of the tonic phase and a higher seizure occurrence. Increase in LF occurred during the onset phase and during the transition from the tonic to the clonic phase, corresponding to the vibratory movements. The clonic phase consisted of EMG discharges of remarkably constant duration (0.2s) separated by silent periods (SP) of exponentially increasing duration - features that could not be reproduced voluntarily. The last SP was longer in seizures with higher EMG peak frequency whereas the energy of the last clonus was higher in seizures with a short clonic phase. We found specific features of muscle activation dynamics during GTCS. Our findings suggest that the same inhibitory mechanisms that contribute to GTCS termination counteract seizure initiation, accounting for the gradual onset. Both active inhibition and mechanisms related to metabolic depletion act synergistically to stop the seizure. Analysis of the ictal EMG dynamics is a valuable tool for monitoring the balance between pro-convulsive and anti-convulsive factors. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Effects of Deception on Tonic Autonomic Arousal

    DTIC Science & Technology

    2007-11-02

    if tonic levels of electrodermal and cardiovascular activity can be used to improve the accuracy of polygraph examinations. Three hundred and thirty...use of absolute measures of electrodermal and cardiovascular activity would do little to improve the accuracy of computer algorithms for diagnosing...lie polygraph examinations. It also tested if tonic levels of electrodermal and cardiovascular activity can be used to improve the accuracy of

  10. Depletion of the cellular levels of Bag-1 proteins attenuates phorbol ester-induced downregulation of I{kappa}B{alpha} and nuclear accumulation of NF-{kappa}B

    SciTech Connect

    Maier, Jana V.; Volz, Yvonne; Berger, Caroline; Schneider, Sandra; Cato, Andrew C.B.

    2010-10-22

    Research highlights: {yields}Bag-1 depletion only marginally affects the action of the glucocorticoid receptor but strongly regulates the activity of NF-{kappa}B. {yields}Bag-1 depletion attenuates phosphorylation and degradation of I{kappa}B{alpha} and nuclear accumulation of NF-{kappa}B p65 and p50. {yields}Bag-1 interacts with I{kappa}B{alpha} and partially restores I{kappa}B{alpha} and NF-{kappa}B activation in Bag-1 depleted cells. -- Abstract: Bag-1 consists in humans of four isoforms generated from the same RNA by alternative translation. Overexpression of single Bag-1 isoforms has identified Bag-1 as a negative regulator of action of many proteins including the glucocorticoid receptor (GR). Here we have analysed the ability of Bag-1 to regulate the transrepression function of the GR. Silencing Bag-1 expression only marginally affects the transrepression action of the GR but decreased the action of the transcription factor NF-{kappa}B. Furthermore phosphorylation and degradation of the inhibitor protein I{kappa}B{alpha} and nuclear accumulation of p65 and p50 NF-{kappa}B proteins in response to phorbol ester was attenuated following Bag-1 depletion in HeLa cells. Reconstitution of Bag-1 in depleted cells partially restored I{kappa}B{alpha} and NF-{kappa}B activation. Knock-down of Bag-1 expression also did not significantly alter GR-mediated transactivation but affected the basal transcription of some of the target genes. Thus Bag-1 proteins function as regulators of the action of selective transcription factors.

  11. Surround Propinquity and Tonic Accommodation.

    PubMed

    Nguyen, Tammy; Stark, Lawrence R

    2017-07-01

    Previous studies of dark focus have found evidence of a propinquity response, in which subjects accommodate to the perceived distance of their surroundings despite being in absolute darkness. Their distance perception in a lighted room allows a spatial representation to persist within the darkened room. This study sought to establish the significance and magnitude of the propinquity response in a large sample of young adults, and to determine whether the propinquity response can be predicted by a subject's initial dark focus in an unknown dark room. Dark focus was measured with a dynamic infrared optometer (Plusoptix PowerRef 3) in 30 young adult subjects, 26 of whom were naive to the testing room and its dimensions. Dark focus was then measured at varying dioptric wall distances of 0.25-4D. The subject viewed the lighted room before each measurement. For each individual, the dark focus was plotted as a function of dioptric wall distance. The slope of this function was used as a measure of the propinquity response. The mean initial dark focus value was 1.05D (SD 1.04D) for the 26 naive subjects. The mean slope of the plot of dark focus as a function of dioptric wall distance was small (+0.097), yet highly statistically significant (P = .0002). The propinquity response function showed no statistically significant quadratic or cubic trends, and so may be considered linear. No statistically significant correlation was found between naive dark focus and propinquity response (r = +0.246, P = .226). Propinquity seems to be a small but statistically significant factor in dark focus measurements. Though it is unlikely to contaminate tonic accommodation measurements in large samples under normal laboratory conditions, a minority of individuals exhibit large propinquity responses equal to that of proximal accommodation in lighted conditions.

  12. Tonic Shock Induces Detachment of Giardia lamblia

    PubMed Central

    Hansen, Wendy R.; Fletcher, Daniel A.

    2008-01-01

    Background The parasite Giardia lamblia must remain attached to the host small intestine in order to proliferate and subsequently cause disease. However, little is known about the factors that may cause detachment in vivo, such as changes in the aqueous environment. Osmolality within the proximal small intestine can vary by nearly an order of magnitude between host fed and fasted states, while pH can vary by several orders of magnitude. Giardia cells are known to regulate their volume when exposed to changes in osmolality, but the short-timescale effects of osmolality and pH on parasite attachment are not known. Methodology and Principal Findings We used a closed flow chamber assay to test the effects of rapid changes in media osmolality, tonicity, and pH on Giardia attachment to both glass and C2Bbe-1 intestinal cell monolayer surfaces. We found that Giardia detach from both surfaces in a tonicity-dependent manner, where tonicity is the effective osmolality experienced by the cell. Detachment occurs with a characteristic time constant of 25 seconds (SD = 10 sec, n = 17) in both hypo- and hypertonic media but is otherwise insensitive to physiologically relevant changes in media composition and pH. Interestingly, cells that remain attached are able to adapt to moderate changes in tonicity. By exposing cells to a timed pattern of tonicity variations and adjustment periods, we found that it is possible to maximize the tonicity change experienced by the cells, overcoming the adaptive response and resulting in extensive detachment. Conclusions and Significance These results, conducted with human-infecting Giardia on human intestinal epithelial monolayers, highlight the ability of Giardia to adapt to the changing intestinal environment and suggest new possibilities for treatment of giardiasis by manipulation of tonicity in the intestinal lumen. PMID:18270543

  13. Methamphetamine neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum.

    PubMed

    Howard, Christopher D; Keefe, Kristen A; Garris, Paul A; Daberkow, David P

    2011-08-01

    Neurotoxic doses of methamphetamine (METH) are known to cause depletions in striatal dopamine (DA) tissue content. However, the effects of METH-induced insults on dopaminergic neurotransmission are not fully understood. Here, we employed fast-scan cyclic voltammetry at a carbon-fiber microelectrode in the anesthetized rat striatum to assess the effects of a neurotoxic regimen of METH on phasic and tonic modes of dopaminergic signaling and underlying mechanisms of DA release and uptake. Extracellular DA was electrically evoked by stimulation of the medial forebrain bundle mimicking tonic and phasic firing patterns for dopaminergic cells and was monitored simultaneously in both the dorsomedial and dorsolateral striatum. Kinetic analysis of evoked recordings determined parameters describing DA release and uptake. Striatal DA tissue content was quantified by high performance liquid chromatography with electrochemical detection. METH-pretreatment (four doses of 7.5 or 10.0 mg/kg s.c.) induced DA depletions of ∼ 40% on average, which are reported in both striatal subregions. METH pre-treatment significantly decreased the amplitude of signals evoked by phasic, but not tonic, stimulation. Parameters for DA release and uptake were also similarly reduced by ∼ 40%, consistent with effects on evoked phasic-like responses and DA tissue content. Taken together, these results suggest that METH-pretreatment selectively diminishes phasic, but not tonic, dopaminergic signaling in the dorsal striatum.

  14. Inhibition of tonic spinal glutamatergic activity induces antinociception in the rat.

    PubMed

    Tambeli, Claudia H; Parada, Carlos A; Levine, Jon D; Gear, Robert W

    2002-10-01

    Inhibition of tonic activity in spino-supraspinal projection neurons induces heterosegmental antinociception that is mediated by opioid receptors in nucleus accumbens. To investigate the origin of this tonic activity, we evaluated the ability of inhibiting neurotransmission in the spinal cord to produce heterosegmental antinociception in the trigeminal nociceptive jaw-opening reflex (JOR) in the rat. Spinal intrathecal administration of calcium channel blockers attenuated the JOR, suggesting that the tonic spinal activity depends on synaptic input. To identify the excitatory neurotransmitter receptors involved, selective antagonists for AMPA/kainate, mGluR1, NMDA or NK1 receptors were administered intrathecally to the spinal cord. The AMPA/kainate and mGluR1 receptor antagonists, but not the NMDA or NK1 receptor antagonists, induced antinociception, which was antagonized by intra-accumbens administration of the selective micro -opioid receptor antagonist CTOP. Thus, inhibition of tonic spinal glutamatergic activity resulted in supraspinally mediated antinociception. As this antinociception occurred in the absence of interventions that would produce a facilitated nociceptive state, this tonic glutamatergic activity is important in setting nociceptive threshold.

  15. Bilateral tonic pupils: Holmes Adie syndrome or generalised neuropathy?

    PubMed

    Bremner, F D; Smith, S E

    2007-12-01

    To compare the pupil signs in patients with bilateral pupillotonia caused by Holmes-Adie syndrome or generalised peripheral neuropathy. Infrared video pupillographic techniques were used to measure a number of pupil variables in patients with Holmes-Adie syndrome, generalised neuropathy (various aetiologies) and healthy age-matched control subjects. Regardless of aetiology, the patients generally had pupil signs typical of pupillotonia (small dark diameters, large light diameters, tonic near responses, attenuated light responses with light-near dissociation, and sector palsy). However, significant differences were found in the prevalence and magnitude of several pupil variables in the two patient groups. In particular, sector palsy and anisocoria exceeding 1 mm (in the light) were seen much more commonly in Holmes-Adie patients than patients with generalised neuropathy. The presence of both these pupil signs can be used to distinguish between these diagnoses with a sensitivity of 58% and a specificity of 90%. The tonic pupils of patients with Holmes-Adie syndrome are significantly different to those found in patients with generalised neuropathy; recognition of these differences may allow distinction between these diagnoses.

  16. A Single Amino Acid Mutation in the Envelope Cytoplasmic Tail Restores the Ability of an Attenuated Simian Immunodeficiency Virus Mutant To Deplete Mucosal CD4+ T Cells

    PubMed Central

    Breed, Matthew W.; Jordan, Andrea P. O.; Aye, Pyone P.; Sugimoto, Chie; Alvarez, Xavier; Kuroda, Marcelo J.; Pahar, Bapi; Keele, Brandon F.; Hoxie, James A.

    2013-01-01

    Disruption of the conserved motif GYxxØ in the simian immunodeficiency virus (SIV) SIVmac239 envelope (Env) cytoplasmic tail resulted in a virus (ΔGY) that exhibited a high plasma peak but uniquely failed to acutely deplete mucosal CD4+ T cells. Here, we show that ΔGY containing a flanking S727P mutation that was acquired in ΔGY-infected macaques reacquired the ability to rapidly deplete CD4+ T cells in lamina propria. This suggests that the GYxxØ motif and S727P each contribute to SIV's targeting to mucosal tissues. PMID:24027336

  17. Tonic vibration reflexes and background force level

    NASA Technical Reports Server (NTRS)

    Lackner, James R.; Dizio, Paul; Fisk, John

    1992-01-01

    On earth, the functional stretch reflex is an important component in the maintenance of posture and muscle tone. In parabolic flight experiments, it is evaluated whether the functional stretch reflex, as reflected in the tonic vibration reflex, adjusts appropriately for changes in background gravitoinertial force level. Virtually immediate alterations of appropriate sign occurred.

  18. Transcriptional regulation by changes in tonicity.

    PubMed

    Handler, J S; Kwon, H M

    2001-08-01

    Most organisms respond to a hypertonic environment by accumulating small organic solutes. In contrast to high concentrations of electrolytes, the small organic solutes do not perturb the activity of enzymes and other macromolecules within the cell. When the renal medulla becomes hypertonic during antidiuresis, multiple signaling pathways are activated. Here, we review the role of tonicity responsive enhancers (TonE) binding protein (TonEBP), a transcription factor activated in hypertonic cells. The activation of TonEBP by hypertonicity results from its translocation to the nucleus as well as an increase in TonEBP mRNA and protein. TonEBP may have a role beyond the response to tonicity since it is highly expressed in activated lymphocytes and in developing tissues.

  19. Ethyl glucuronide identified in commercial hair tonics.

    PubMed

    Arndt, Torsten; Schröfel, Stefanie; Stemmerich, Karsten

    2013-09-10

    Ethyl glucuronide (EtG) in hair is considered as a specific marker of ethanol consumption. Prompted by a report of positive EtG hair testings due to hair treatment with an EtG containing hair lotion, commercially available herbal hair tonics from supermarkets, drug-stores, and health food stores were analyzed for the presence of EtG and ethyl sulfate (EtS). LC-MS/MS (QTRAP 5500 mass spectrometer) was done in multiple reaction monitoring (MRM), enhanced product ion (EPI) and MS(3) mode. The lower limit of quantitation was 0.05 mg/L for EtG and the cut-off for the detection of EtS 0.01 mg/L. Altogether 11 hair tonics from 8 manufacturers were tested, with 1 product in 3 different lots. EtG ranged between 0.07 and 1.06 mg/L (7 products from 4 manufacturers) and was almost identical in the 3 lots of 1 product (1.01-1.06 mg/L). EtS was found in 3 out of the 11 hair tonics. EtG is quite frequently present in commercially available herbal hair tonics. Using EtG in hair as a marker of alcohol (ab)use, one has to consider external sources of EtG and has to assess the use of hair care products, esp. if the patient denies any ethanol intake. Whether EtS is a more reliable alcohol (ab)use marker, as sometimes discussed, should be critically assessed against the background of its broad use in large amounts in industrial chemistry. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Tonic inhibition of chemotaxis in human plasma

    PubMed Central

    Malawista, Stephen E.; de Boisfleury Chevance, Anne; van Damme, Jo; Serhan, Charles N.

    2008-01-01

    We found exaggerated chemotaxis in plasma treated with EDTA and thought that the EDTA might itself be inhibiting a tonic inhibitor(s) of chemotaxis. Our plasma fractionations suggested that evidence should be sought for a lipid moiety carrying this activity, and on spectrometry (LC-MS-MS together with GC-MS analyses), the biologically active but not the inactive fraction contained oleic and arachidonic acids. Because fatty acids are largely protein bound, we flooded plasma preparations with delipidated albumin, reasoning that it would bind enough fatty acids, including inhibitory ones, to counter their tonic inhibition. Indeed, we observed dramatic increases in chemotaxis. Hence, adding delipidated albumin to plasma has a similar effect to that of adding EDTA—amplification of the chemotactic response. Oleic acid in physiologic concentrations diminishes the magnifying effects of both EDTA and of delipidated albumin, and in fact diminishes the chemotactic response even without the presence of the amplifiers of chemotaxis. In contrast, arachidonic acid amplifies further the effect of EDTA but not of delipidated albumin, and this augmentation appears to be caused by an EDTA-dependent enrichment of the chemotactic gradient with leukotriene B4 (LTB4). We conclude that oleic acid, the blood levels of which vary among individuals, is at least one tonic inhibitor of chemotaxis in plasma. PMID:18997012

  1. Anti-IgD antibody attenuates collagen-induced arthritis by selectively depleting mature B-cells and promoting immune tolerance.

    PubMed

    Nguyen, Tue G; Little, Christopher B; Yenson, Vanessa M; Jackson, Christopher J; McCracken, Sharon A; Warning, Julia; Stevens, Veronica; Gallery, Eileen G; Morris, Jonathan M

    2010-08-01

    Membrane (m)IgD forms a major part of B-cell receptor complexes. Its wider role in the immune system has been enigmatic. Stimulation of mIgD with an antibody (anti-IgD) can activate B-cells and elicit a broad immune response in vivo. Given the role of B-cells in autoimmune diseases and the profound impact of anti-IgD on B-cells, the potential effects of anti-IgD on autoimmune conditions are intriguing and yet to be explored. Here we report a novel therapeutic effect of anti-IgD in the collagen-induced arthritis (CIA) mouse model. Administration of anti-IgD at the onset of early clinical symptoms as a therapeutic intervention, but not as a prophylactic treatment, significantly ameliorates disease severity and joint pathology. Anti-IgD treatment selectively depletes mature B cells while it spares regulatory B-cell subsets. This results in a significant reduction of autoantibody levels but does not affect antibody responses to a T-cell-dependent antigen. Therapeutic treatment with anti-IgD increases the numbers of regulatory B-cells and regulatory T-cells whilst it augments adaptive Th1/Th2 responses in vivo. In human PBMC samples, anti-IgD also promotes adaptive Th1/Th2 responses and modulates the innate responses toward an anti-inflammatory Th2-biased response. Collectively, anti-IgD treatment may offer a selective approach to B-cell depletion that also promotes immune tolerance and anti-inflammatory tendencies without compromising the general adaptive B-cell and T-cell responses. The multiple mechanisms of action by anti-IgD treatment suggest a wider clinical application for a number of chronic inflammatory and autoimmune conditions.

  2. Successful attenuation of humoral immunity to viral capsid and transgenic protein following AAV-mediated gene transfer with a non-depleting CD4 antibody and cyclosporine.

    PubMed

    McIntosh, J H; Cochrane, M; Cobbold, S; Waldmann, H; Nathwani, S A; Davidoff, A M; Nathwani, A C

    2012-01-01

    The ability of transient immunosuppression with a combination of a non-depleting anti-CD4 (NDCD4) antibody and cyclosporine (CyA) to abrogate immune reactivity to both adeno-associated viral vector (AAV) and its transgene product was evaluated. This combination of immunosuppressants resulted in a 20-fold reduction in the resulting anti-AAV8 antibody titres, to levels in naïve mice, following intravenous administration of 2 × 10(12) AAV8 vector particles per kg to immunocompetent mice. This allowed efficient transduction upon secondary challenge with vector pseudotyped with the same capsid. Persistent tolerance did not result, however, as an anti-AAV8 antibody response was elicited upon rechallenge with AAV8 without immunosuppression. The route of vector administration, vector dose, AAV serotype or the concomitant administration of adenoviral vector appeared to have little impact on the ability of the NDCD4 antibody and CyA combination to moderate the primary humoral response to AAV capsid proteins. The combination of NDCD4 and CyA also abrogated the humoral response to the transgene product, that otherwise invariably would occur, following intramuscular injection of AAV5, leading to stable transgene expression. These observations could significantly improve the prospects of using rAAV vectors for chronic disorders by allowing for repeated vector administration and avoiding the development of antibodies to the transgene product.

  3. Optogenetic Visualization of Presynaptic Tonic Inhibition of Cerebellar Parallel Fibers

    PubMed Central

    Berglund, Ken; Wen, Lei; Dunbar, Robert L.; Feng, Guoping

    2016-01-01

    Tonic inhibition was imaged in cerebellar granule cells of transgenic mice expressing the optogenetic chloride indicator, Clomeleon. Blockade of GABAA receptors substantially reduced chloride concentration in granule cells due to block of tonic inhibition. This indicates that tonic inhibition is a significant contributor to the resting chloride concentration of these cells. Tonic inhibition was observed not only in granule cell bodies, but also in their axons, the parallel fibers (PFs). This presynaptic tonic inhibition could be observed in slices both at room and physiological temperatures, as well as in vivo, and has many of the same properties as tonic inhibition measured in granule cell bodies. GABA application revealed that PFs possess at least two types of GABAA receptor: one high-affinity receptor that is activated by ambient GABA and causes a chloride influx that mediates tonic inhibition, and a second with a low affinity for GABA that causes a chloride efflux that excites PFs. Presynaptic tonic inhibition regulates glutamate release from PFs because GABAA receptor blockade enhanced both the frequency of spontaneous EPSCs and the amplitude of evoked EPSCs at the PF-Purkinje cell synapse. We conclude that tonic inhibition of PFs could play an important role in regulating information flow though cerebellar synaptic circuits. Such cross talk between phasic and tonic signaling could be a general mechanism for fine tuning of synaptic circuits. SIGNIFICANCE STATEMENT This paper demonstrates that an unconventional form of signaling, known as tonic inhibition, is found in presynaptic terminals and affects conventional synaptic communication. Our results establish the basic characteristics and mechanisms of presynaptic tonic inhibition and show that it occurs in vivo as well as in isolated brain tissue. PMID:27225762

  4. Tonic Dopamine Modulates Exploitation of Reward Learning

    PubMed Central

    Beeler, Jeff A.; Daw, Nathaniel; Frazier, Cristianne R. M.; Zhuang, Xiaoxi

    2010-01-01

    The impact of dopamine on adaptive behavior in a naturalistic environment is largely unexamined. Experimental work suggests that phasic dopamine is central to reinforcement learning whereas tonic dopamine may modulate performance without altering learning per se; however, this idea has not been developed formally or integrated with computational models of dopamine function. We quantitatively evaluate the role of tonic dopamine in these functions by studying the behavior of hyperdopaminergic DAT knockdown mice in an instrumental task in a semi-naturalistic homecage environment. In this “closed economy” paradigm, subjects earn all of their food by pressing either of two levers, but the relative cost for food on each lever shifts frequently. Compared to wild-type mice, hyperdopaminergic mice allocate more lever presses on high-cost levers, thus working harder to earn a given amount of food and maintain their body weight. However, both groups show a similarly quick reaction to shifts in lever cost, suggesting that the hyperdominergic mice are not slower at detecting changes, as with a learning deficit. We fit the lever choice data using reinforcement learning models to assess the distinction between acquisition and expression the models formalize. In these analyses, hyperdopaminergic mice displayed normal learning from recent reward history but diminished capacity to exploit this learning: a reduced coupling between choice and reward history. These data suggest that dopamine modulates the degree to which prior learning biases action selection and consequently alters the expression of learned, motivated behavior. PMID:21120145

  5. Non-Segmental Phonology: Noun-Phrase Tonicity in English

    ERIC Educational Resources Information Center

    Andre, Edgar

    1977-01-01

    A study of tonic placement in various types of English noun phrases used as elements of clause structure. The notion of nominal compound is broadened; reflection of grammatical relationships by stress and tendencies concerning tonic placement in noun phrases as these are related to the Headword are noted. (AMH)

  6. TONIC INFLUENCE OF NEOCORTEX ON HIPPOCAMPAL SEIZURES.

    PubMed

    Saralidze, E; Khuchua, L; Kobaidze, I

    2016-09-01

    The interaction between different brain structures could be crucial to predicting seizure occurrence, threshold and spread. Moreover, the sleep-wake cycle and electrical activity of brain structures in different phases of sleep could significantly affect the pattern and extent of seizure spread, and therefore the characteristics of epileptic activity. In this animal model using 15 Wistar rats, we show that the duration of hippocampal seizures, induced by electrical stimulation of the hippocampus, is significantly increased during slow sleep. Moreover, decreasing the electrical activity of the neocortex by cooling of the cortical surface or induction of cortical spreading depression also caused an increase in hippocampal seizure duration. Conversely, warming the cortical surface triggered a remission in spreading depression, in turn restoring the duration of epileptic episodes. Our data suggest that the neocortex probably exerts a tonic inhibitory influence on hippocampal seizures. Thus, cortico-hippocampal interaction could be an important component in the manifestation and generalization of limbic seizures.

  7. Albumin impacts the effects of tonicity on microvascular hydraulic permeability.

    PubMed

    Victorino, Gregory P; Chong, Terry J; Curran, Brian

    2004-12-01

    An increase in tonicity shrinks endothelial cells. This cell shrinkage may open inter-endothelial gaps and allow more fluid to escape from the microvasculature. This increase in microvascular permeability is not supported by clinical studies suggesting that water is pulled into the vascular space, not lost into the interstitium. We hypothesized that albumin influences the change in trans-endothelial water movement caused by alterations in tonicity by a mechanism other than oncotic pressure. Hydraulic permeability (L(p)) was measured in rat mesenteric venules using the Landis micro-occlusion model. Measures of L(p) were obtained after successive perfusions with 1% albumin solution (BSA) of varying sodium chloride (NaCl) concentrations (85, 135, 185, and 235 mm) (n = 6). Additional venules were perfused with 7% NaCl followed by 7% NaCl + BSA and L(p) measured (n = 6). Units for L(p) are x10(-7) cm/sec(-1) cm/H(2)O(-1). As the NaCl concentration in BSA increased from 85 mm to 235 mm, L(p) decreased from 1.93 +/- 0.41 to 0.97 +/- 0.11. Compared to results without albumin, BSA with 185 mm NaCl decreased L(p) from 3.93 +/- 0.08 to 1.25 +/- 0.18 (P = 0.04), and BSA with 235 mm NaCl decreased L(p) from 6.14 +/- 0.05 to 0.96 +/- 0.11 (P = 0.002). There was a three-fold decrease in L(p) when BSA was added to the 7% NaCl solution (P = 0.02). Albumin attenuated the increase in L(p) that is associated with higher NaCl concentrations. Because this model controls for oncotic pressure, albumin may impact L(p) by a mechanism other than oncotic force. Albumin appears to stabilize the endothelial barrier during HS perfusion and prevents the loss of intravascular fluid. Appropriate albumin levels may play an important clinical role in modulating trans-endothelial fluid efflux during HS administration.

  8. Bidirectional regulation of tonicity-responsive enhancer binding protein in response to changes in tonicity.

    PubMed

    Woo, S K; Dahl, S C; Handler, J S; Kwon, H M

    2000-06-01

    Tonicity-responsive enhancer binding protein (TonEBP) regulates transcription of tonicity responsive genes such as the sodium-myo-inositol cotransporter (SMIT), the sodium-chloride-betaine cotransporter (BGT1), and aldose reductase (AR). To characterize signals that activate TonEBP in Madin-Darby canine kidney (MDCK) cells, the abundance and nuclear distribution of TonEBP were studied after the osmolality of the culture medium was changed. Hypertonicity but not hyperosmolality is effective in activation of TonEBP as expected. Surprisingly, exposure to hypotonic medium leads to a dramatic downregulation of TonEBP both in abundance and nuclear distribution, indicating that under isotonic conditions, TonEBP is at a low-level activated state and can respond to both increase and decrease in tonicity. Additional experiments suggest that cellular ionic strength is the signal that initiates regulation of TonEBP. The increase in abundance of TonEBP is mediated by an increase in mRNA abundance and a parallel increase in synthesis of TonEBP. The stability of TonEBP mRNA is not affected by hypertonicity indicating that transcription plays a major role in the induction of TonEBP by hypertonicity.

  9. PKC delta-isoform translocation and enhancement of tonic contractions of gastrointestinal smooth muscle.

    PubMed

    Poole, Daniel P; Furness, John B

    2007-03-01

    PKC is involved in mediating the tonic component of gastrointestinal smooth muscle contraction in response to stimulation by agonists for G protein-coupled receptors. Here, we present pharmacological and immunohistochemical evidence indicating that a member of the novel PKC isoforms, PKC-delta, is involved in maintaining muscarinic receptor-coupled tonic contractions of the guinea pig ileum. The tonic component of carbachol-evoked contractions was enhanced by an activator of conventional and novel PKCs, phorbol 12,13-dibutyrate (PDBu; 200 nM or 1 microM), and by an activator of novel PKCs, ingenol 3,20-dibenzoate (IDB; 100 or 500 nM). Enhancement was unaffected by concentrations of bisindolylmaleimide I (BIM-I; 22 nM) that block conventional PKCs or by a PKC-epsilon-specific inhibitor peptide but was attenuated by higher doses of BIM-I (2.2 microM). Relevant proteins were localized at a cellular and subcellular level using confocal analysis. Immunohistochemical staining of the ileum showed that PKC-delta was exclusively expressed in smooth muscles distributed throughout the layers of the gut wall. PKC-epsilon immunoreactivity was prominent in enteric neurons but was largely absent from smooth muscle of the muscularis externa. Treatment with PDBu, IDB, or carbachol resulted in a time- and concentration-dependent translocation of PKC-delta from the cytoplasm to filamentous structures within smooth muscle cells. These were parallel to, but distinct from, actin filaments. The translocation of PKC-delta in response to carbachol was significantly reduced by scopolamine or calphostin C. The present study indicates that the tonic carbachol-induced contraction of the guinea pig ileum is mediated through a novel PKC, probably PKC-delta.

  10. The role of ERK in phasic and tonic contractile responses in rat femoral arteries after hindlimb unloading.

    PubMed

    Yuan, Ming; Li, Zhili; Wang, Desheng; Jiang, Shizhong

    2005-01-01

    The present study tested the hypothesis that the role of ERK in phasic and tonic contractile responses is declined by hindlimb unloading (HU) in rat femoral arteries. Male Wistar rats were randomised into HU and Control group (n=7). After 14d, the femoral arteries were isolated and cut into 3-mm ring segments. In the absence or presence of PD98059(MEK inhibitor), contractile response to NE(10μM) was measured in Krebs solution in a tissue bath at 37°C, isometric tension were recorded with Powerlab system. The area under curve (AUC), phasic and tonic contractile responses between two groups were compared. After 14d-HU, the AUC, phasic and tonic NE-induced contractile responses were declined compared with controls. PD98059 did not affect the AUC in arteries from HU, but significantly decreased the AUC in arteries from control (100±7.1% vs. 61.18±11.3%, P<0.05). In contrast to control, the inhibitory ratio of PD98059 was significantly lower in phasic (7.42±3.24% vs. 33.59± 9.19%, P=0.0198) and tonic (26.93±3.78% vs. 46.75±5.67%, P=0.0131) contractile responses of HU group. Moreover, the inhibitory ratio of PD98059 wasn't significantly different between the phasic and tonic contractile responses in control group (P=0.2464). But for HU group, the difference was statistically significant (P=0.002). We demonstrated that the role of ERK was declined in both phasic and tonic contractile responses in rat femoral arteries after hindlimb unloading. Simulated microgravity induced by HU may attenuate the contractile responses of femoral arteries by inhibiting the role of ERK in thick and thin filament regulatory pathways.

  11. d-Amino acid oxidase-mediated increase in spinal hydrogen peroxide is mainly responsible for formalin-induced tonic pain

    PubMed Central

    Lu, Jin-Miao; Gong, Nian; Wang, Yan-Chao; Wang, Yong-Xiang

    2012-01-01

    BACKGROUND AND PURPOSE Spinal reactive oxygen species (ROS) are critically involved in chronic pain. d-Amino acid oxidase (DAAO) oxidizes d-amino acids such as d-serine to form the byproduct hydrogen peroxide without producing other ROS. DAAO inhibitors are specifically analgesic in tonic pain, neuropathic pain and cancer pain. This study examined the role of spinal hydrogen peroxide in pain and the mechanism of the analgesic effects of DAAO inhibitors. EXPERIMENTAL APPROACH Formalin-induced pain behaviours and spinal hydrogen peroxide levels were measured in rodents. KEY RESULTS Formalin injected into the paw increased spinal hydrogen peroxide synchronously with enhanced tonic pain; both were effectively prevented by i.t. fluorocitrate, a selective astrocyte metabolic inhibitor. Given systemically, the potent DAAO inhibitor CBIO (5-chloro-benzo[d]isoxazol-3-ol) blocked spinal DAAO enzymatic activity and specifically prevented formalin-induced tonic pain in a dose-dependent manner. Although CBIO maximally inhibited tonic pain by 62%, it completely prevented the increase in spinal hydrogen peroxide. I.t. catalase, an enzyme specific for decomposition of hydrogen peroxide, completely depleted spinal hydrogen peroxide and prevented formalin-induced tonic pain by 65%. Given systemically, the ROS scavenger PBN (phenyl-N-tert-butylnitrone) also inhibited formalin-induced tonic pain and increase in spinal hydrogen peroxide. Formalin-induced tonic pain was potentiated by i.t. exogenous hydrogen peroxide. CBIO did not increase spinal d-serine level, and i.t. d-serine did not alter either formalin-induced tonic pain or CBIO's analgesic effect. CONCLUSIONS AND IMPLICATIONS Spinal hydrogen peroxide is specifically and largely responsible for formalin-induced pain, and DAAO inhibitors produce analgesia by blocking spinal hydrogen peroxide production rather than interacting with spinal d-serine. PMID:21950354

  12. Natremia, tonicity, and conductivity measurements in hemodialyzed patients.

    PubMed

    Gaillard, François; Laplanche, Sophie; Petitclerc, Thierry

    2015-05-01

    Natremia is usually considered to reflect tonicity in non-hemodialyzed patients. Some hemodialysis monitors provide an online value (NaCond) of natremia calculated from conductivity measurements. This study compared the relation between tonicity and natremia (NaLab) measured at laboratory with the relation between tonicity and NaCond in hemodialysis patients. Fifty-five hemodialysis sessions performed with a Fresenius 5008 dialysis monitor (Fresenius Medical Care, Bad Homburg, Germany) providing a value of NaCond were analyzed. Tonicity (calculated as "osmolality - urea"), NaLab and NaCond were measured at the beginning and end of sessions. The r2 correlation-coefficient between tonicity and NaLab is 0.48 (n = 110). The correlation between tonicity and NaCond is stronger (r2 =  0.71). Conductivity measurements provide a natremia value (NaCond) that is a better surrogate for tonicity than natremia measured at laboratory. Because NaCond is not obtained from sodium measurement, dialysis monitors should display a value for plasma conductivity (mS/cm) instead for natremia (mmol/l).

  13. Tonic cholinergic inhibition of spinal mechanical transmission.

    PubMed

    Zhuo, M; Gebhart, G F

    1991-08-01

    The present study examined the role of spinal cholinergic modulation of spinal mechanical and thermal transmission. Intrathecal administration of the cholinergic muscarinic receptor antagonists atropine or scopolamine in awake rats produced a dose-dependent decrease in the nociceptive mechanical withdrawal threshold of the rat tail. Pirenzepine, a selective muscarinic receptor type 1 antagonist, produced a similar effect at greater doses while mecamylamine, a nicotinic receptor antagonist, was without effect. The nociceptive tail flick (TF) reflex evoked by noxious heating was unaffected by the above drugs. Intrathecal administration of the cholinesterase inhibitor physostigmine produced a rapid, reversible and significant increase in the mechanical withdrawal threshold; TF latency was increased slightly but not significantly. Intrathecal administration of morphine, carbachol or clonidine all produced dose-dependent increases in TF latency; morphine and carbachol, but not clonidine, also increased the mechanical withdrawal threshold significantly. Intrathecal pretreatment with atropine reversed carbachol-produced increases in TF latency and the mechanical withdrawal threshold but did not affect increases in TF latency produced by intrathecal morphine or clonidine. The morphine-produced increase in the mechanical withdrawal threshold, however, was shifted rightward in a parallel fashion by intrathecal pretreatment with atropine. Intrathecal pretreatment with yohimbine did not affect the inhibitory effect of carbachol on either TF latency or the mechanical withdrawal threshold. These results suggest that a tonic, endogenous cholinergic muscarinic influence in the spinal cord, independent of spinal adrenergic mechanisms, modulates spinal mechanical transmission.

  14. Frequency evolution during tonic-clonic seizures.

    PubMed

    Quiroga, R Quian; Garcia, H; Rabinowicz, A

    2002-09-01

    By using the Short Time Fourier Transform, we analyzed the EEG frequency evolution during tonic-clonic seizures on 18 scalp recordings corresponding to 7 patients admitted for Video-EEG monitoring. This information was correlated with clinical findings observed in the video recordings. From the time-frequency plots, we recognized patterns related with brain activity even when embedded in a background of muscle artifacts. In 13/18 seizures we found a clear frequency dynamics characterized by an activity originally localized at about 8 Hz, later slowing down to about 1.5 Hz. In the remaining cases muscle artifacts hinder the disclosure of a clear frequency evolution. The clonic phases started when the main frequency slowed down to about 3 Hz. We conclude that the Short Time Fourier Transform is very useful for a quantitative analysis of epileptic seizures, especially when muscle artifacts contaminate the recordings. We further conclude that the clonic phase starts as a response to brain activity that can be only established when brain oscillations are slow enough to be followed by the muscles.

  15. Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment motivated heavy smokers

    PubMed Central

    Hitsman, Brian; Hogarth, Lee; Tseng, Li-Jung; Teige, Jordan C.; Shadel, William G.; DiBenedetti, Dana Britt; Danto, Spencer; Lee, Theodore C.; Price, Lawrence H.; Niaura, Raymond

    2017-01-01

    Rationale The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome. Objectives This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design. Methods Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2 mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-minute intervals. At 4-hours post-administration, a cue exposure session obtained the same subjective measures at three time-points following the physical handling of a lit cigarette versus the sharpening and handling of a pencil. Results At 4-hours post-administration, varenicline reduced tonic craving as well as craving across the smoking and neutral cue conditions, relative to placebo. By contrast, the capacity of the smoking cue to enhance craving relative to the neutral cue was unaffected by varenicline. Measures of withdrawal and positive and negative affect produced mixed results. Conclusions Acute varenicline selectively attenuates tonic but not cue-provoked craving. This dissociation provides insight into the specific psychological processes that might mediate the effectiveness of varenicline, and highlights cue-provoked craving as a discrete target for advancing smoking cessation pharmacotherapy. PMID:23201174

  16. Dissociable effect of acute varenicline on tonic versus cue-provoked craving in non-treatment-motivated heavy smokers.

    PubMed

    Hitsman, Brian; Hogarth, Lee; Tseng, Li-Jung; Teige, Jordan C; Shadel, William G; DiBenedetti, Dana Britt; Danto, Spencer; Lee, Theodore C; Price, Lawrence H; Niaura, Raymond

    2013-06-01

    The effectiveness of varenicline for smoking cessation has been established, but little is known about the psychological processes that mediate this clinical outcome. This study evaluated the effect of a single dose of varenicline on tonic and cue-provoked changes in craving, withdrawal, and affect using a randomized, double-blind, placebo-controlled, cross-over design. Following overnight abstinence, 38 non-treatment-motivated smokers received either varenicline 2mg or matched placebo, then tonic measures of craving, withdrawal, and positive and negative affect were obtained at 30-min intervals. At 4-h post-administration, a cue exposure session obtained the same subjective measures at three time-points following the physical handling of a lit cigarette versus the sharpening and handling of a pencil. At 4-h post-administration, varenicline reduced tonic craving as well as craving across the smoking and neutral cue conditions, relative to placebo. By contrast, the capacity of the smoking cue to enhance craving relative to the neutral cue was unaffected by varenicline. Measures of withdrawal and positive and negative affect produced mixed results. Acute varenicline selectively attenuates tonic but not cue-provoked craving. This dissociation provides insight into the specific psychological processes that might mediate the effectiveness of varenicline, and highlights cue-provoked craving as a discrete target for advancing smoking cessation pharmacotherapy. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  17. Decreased Glial GABA and Tonic Inhibition in Cerebellum of Mouse Model for Attention-Deficit/Hyperactivity Disorder (ADHD).

    PubMed

    Kim, Yoo Sung; Woo, Junsung; Lee, C Justin; Yoon, Bo-Eun

    2017-08-01

    About 5~12% of school-aged children suffer from the Attention-Deficit/Hyperactivity Disorder (ADHD). However, the core mechanism of ADHD remains unclear. G protein-coupled receptor kinase-interacting protein-1 (GIT1) has recently been reported to be associated with ADHD in human and the genetic deletion of GIT1 result in ADHD-like behaviors in mice. Mice lacking GIT1 shows a shift in neuronal excitation/inhibition (E/I) balance. However, the pricise mechanism for E/I imbalance and the role of neuron-glia interaction in GIT1 knockout (KO) mice have not been studied. Especially, a possible contribution of glial GABA and tonic inhibition mediated by astrocytic GABA release in the mouse model for ADHD remains unexplored. Therefore, we investigated the changes in the amount of GABA and degree of tonic inhibition in GIT1 KO mice. We observed a decreased glial GABA intensity in GIT1 KO mice compared to wild type (WT) mice and an attenuation of tonic current from cerebellar granule cells in GIT1 KO mice. Our study identifies the previously unknown mechanism of reduced astrocytic GABA and tonic inhibition in GIT1 lacking mice as a potential cause of hyperactivity disorder.

  18. Context-Dependent Modulation of GABAAR-Mediated Tonic Currents

    PubMed Central

    Patel, Bijal; Bright, Damian P.; Mortensen, Martin; Frølund, Bente

    2016-01-01

    Tonic GABA currents mediated by high-affinity extrasynaptic GABAA receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABAA receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABAA receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABAA receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABAA receptor-mediated tonic currents. By using recombinant GABAA receptors expressed in HEK293 cells, and native GABAA receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABAA receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABAA receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4-PIOL revealed a significant population of relatively low-affinity γ2 subunit-containing GABAA receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABAA receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABAA receptor subtypes, and on the ambient GABA levels. SIGNIFICANCE STATEMENT A background level of inhibition (tonic) is important in the brain for controlling neuronal excitability. Increased levels of tonic inhibition are associated with some neurological disorders

  19. Does upper blepharoplasty affect frontalis tonicity?

    PubMed

    Kim, Daejin; Son, Daegu; Kim, Minkyung; Harijan, Aram; Yang, Shimo; Lee, Soyoung

    2015-05-01

    Frontalis hypertonicity has long been implicated in patients with significant dermatochalasia or blepharoptosis, as evidenced by eyebrow changes that occur after the resection of redundant skin or after blepharoptosis operation. However, whether upper blepharoplasty affects the forehead muscle has not been reported. Thus, this study investigated electrophysiology of the frontalis muscle and eyebrow morphology in a population of patients undergoing double-eyelid blepharoplasty. Patients wishing to undergo upper blepharoplasty were recruited for this prospective study between June 2011 and February 2012. The subjects were excluded for complaints of visual obstruction, trauma history, and for any underlying medical condition that would affect eyebrow height or electromyogram (EMG) findings. Eyebrow morphology was ascertained in a standardized photogrammetric evaluation, and the frontalis muscle activity was recorded with needle EMG. These assessments were carried out at preoperation and at 2 weeks, 3 months, and 6 months. Root-mean-square (RMS) indices of various facial expressions were used to normalize the frontalis activity values across individuals. Thirteen patients with a mean age of 55.5 years were recruited. No statistical significance was observed for eyebrow heights at various assessment points. However, EMG recordings have demonstrated a gradual decrease in the proportional RMS index of the frontalis muscle activity. This difference was statistically significant between preoperation and 6 months postoperation (p < 0.05). Upper blepharoplasty was associated with gradual decreases in the frontalis muscle activity. A longer follow-up study is needed to evaluate whether this decreased tonicity results in morphologic changes such as decreased forehead wrinkles and depressed eyebrows. This research indicates that upper blepharoplasty has the potential to interfere with those human-computer interaction designs with facial EMG readings as an input. Copyright

  20. Tonic immobility differentiates stress responses in PTSD.

    PubMed

    Fragkaki, Iro; Stins, John; Roelofs, Karin; Jongedijk, Ruud A; Hagenaars, Muriel A

    2016-11-01

    Tonic immobility (TI) is a state of physical immobility associated with extreme stress and the development of posttraumatic stress disorder (PTSD). However, it is unknown whether TI is associated with a distinct actual stress response, i.e., objective immobility measured by a stabilometric platform. This study made a first step in exploring this as well as differences in body sway responses between PTSD patients and healthy controls. We hypothesized that PTSD would be related to increased body sway under stress, whereas TI would be related to decreased body sway under stress. Eye closure was selected as a PTSD-relevant stress induction procedure. Body sway and heart rate (HR) were measured in 12 PTSD patients and 12 healthy controls in four conditions: (1) maintaining a stable stance with eyes open, (2) with eyes closed, (3) during a mental arithmetic task with eyes open, and (4) with eyes closed. As predicted, PTSD patients showed increased body sway from eyes open to eyes closed compared to controls and this effect was eliminated by executing the arithmetic task. Most importantly, retrospective self-reported TI was associated with lower body sway increases in PTSD and higher body sway decreases in controls from eyes-open to eyes-closed conditions. These preliminary findings suggest that eye closure has a different effect on PTSD patients than controls and that high self-reported TI might indicate a distinct stress response pattern, i.e., a proneness for immobility. It may be relevant to take such individual differences in stress-response into account in PTSD treatment.

  1. Body fluid osmolality and tonicity in preterm infants.

    PubMed

    Semama, D S; Bouziane, M; Allaert, F A; Gouyon, J B

    2001-11-01

    In adult patients, a recent physiological approach for the osmoregulatory system based on body fluid tonicity (the so-called effective osmolality) seems to provide better information on water movements than does the classical body fluid osmolality. To evaluate whether plasma or urinary tonicities could give a better assessment of osmoregulation than plasma and urine osmolalities in sick preterm infants cared for in a NICU. A prospective study was conducted in 30 preterm infants (BW=1284+/-377 g; GA=28.8+/-1.7 weeks). Fifteen consecutive 8-h urine collections were performed for each infant from the 8th h of life (450 periods). A plasma sample was obtained at the end of each urine collection. Sodium, potassium, creatinine, osmolality and tonicity were measured or calculated in urine and blood samples as often as possible. Hypernatremia (PNa=146-149 mmol/l) was observed in seven infants (23.3%) and in 5.9% of the periods. Fifty-three percent of the infants and 20.4% of the periods presented with plasma hyperosmolality (>300 mosmol/kg H2O). The relationship between Posm and PNa was significant, but the clinical relevance was weak (r(2)=0.411; P<0.001). Plasma osmolality (Posm) positively correlated with urine osmolality (Uosm), but did not correlate significantly with CH2O/100 ml GFR. Plasma tonicity (2x(PNa+PK)) positively correlated with both urine tonicity (2x(UNa+UK)) and effective water clearance (EWC/100 ml GFR). On an individual basis, the linear relationship between urine and plasma osmolalities was significantly weaker than the relationship between urine and plasma tonicities. This study suggests that the calculation of plasma and urine tonicities allows a better assessment of water movements in body fluid compartments than plasma and urine osmolalities.

  2. Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

    PubMed Central

    Lee, Sang-Hun; Ledri, Marco; Tóth, Blanka; Marchionni, Ivan; Henstridge, Christopher M.; Dudok, Barna; Kenesei, Kata; Barna, László; Szabó, Szilárd I.; Renkecz, Tibor; Oberoi, Michelle; Watanabe, Masahiko; Limoli, Charles L.; Horvai, George; Soltesz, Ivan

    2015-01-01

    Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic

  3. Effects of tonicity-adjusting and surfactant agents on the antimicrobial activity of alexidine.

    PubMed

    Yanai, Ryoji; Ueda, Kiichi; Nishida, Teruo; Toyohara, Megumi; Mori, Osamu

    2011-03-01

    Alexidine is a bis-biguanide disinfectant with two cationic active sites and hydrophobic ethylhexyl end groups, both of which are believed to support its association with microbial cell membranes through electrostatic and hydrophobic interactions. We evaluated the effects of tonicity-adjusting and surfactant agents on the antimicrobial activity of alexidine to assess its suitability as a disinfectant in multipurpose solutions for contact lenses. The antimicrobial activity of alexidine (4.5 ppm) against various bacteria and fungi was measured with the stand-alone procedure (ISO 14729, 2001). The effect of NaCl as an ionic tonicity-adjusting agent on such activity was determined in comparison with that of propylene glycol as a nonionic tonicity-adjusting agent. The effect of the nonionic surfactant Poloxamer 407 (Px407) was similarly examined in the absence or presence of NaCl. Alexidine showed robust antimicrobial activity, with no organisms surviving after 1 hr. Antifungal activity was inhibited by NaCl in a concentration-dependent manner, whereas neither antibacterial nor antifungal activity was affected by propylene glycol. The activity of alexidine was not affected by Px407 (4%) alone but was attenuated by the combination of NaCl and Px407 with all microorganisms tested. The antifungal activity of alexidine was inhibited by adjustment of osmolality with the ionic agent NaCl but not by that with the nonionic agent propylene glycol. The surfactant Px407 reduced antimicrobial activity only in the presence of NaCl. These findings indicate that electrostatic and hydrophobic interactions with the microbial cell membrane are a key factor in the antimicrobial activity of alexidine.

  4. GABA-independent GABAA Receptor Openings Maintain Tonic Currents

    PubMed Central

    Wlodarczyk, Agnieszka I.; Sylantyev, Sergiy; Herd, Murray B.; Kersanté, Flavie; Lambert, Jeremy J.; Rusakov, Dmitri A.; Linthorst, Astrid C.E.; Semyanov, Alexey; Belelli, Delia; Pavlov, Ivan; Walker, Matthew C.

    2013-01-01

    Activation of GABAA receptors (GABAARs) produces two forms of inhibition: ‘phasic’ inhibition generated by the rapid, transient activation of synaptic GABAARs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of peri- or extrasynaptic GABAARs which can detect extracellular GABA. Such tonic GABAAR-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex-vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABAA receptor openings. This tonic GABAAR conductance is resistant to the competitive GABAAR antagonist SR95531, which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker picrotoxin. When slices are perfused with 200 nM GABA, a concentration that is comparable to cerebrospinal fluid concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABAARs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations. PMID:23447601

  5. Influence of the hypothalamus on the midbrain tonic inhibitory mechanism on metabolic heat production in rats.

    PubMed

    Uno, Tadashi; Roth, Joachim; Shibata, Masaaki

    2003-07-15

    Influence of the hypothalamus on increased body temperature was examined in male rats. Body temperature was increased by removing the midbrain tonic inhibitory mechanism (TIM) on heat production from brown adipose tissue (BAT) by microinjections of a local anesthetic, procaine, into the midbrain. Procaine microinjections in unanesthetized rats increased rectal temperature that was followed by a strong tail skin temperature rise. Procaine microinjections in unanesthetized and decerebrated rats also increased rectal temperature but without skin temperature rise. These decerebrated animals fatally developed hyperthermia. In anesthetized rats, procaine microinjections increased temperature of the interscapular BAT (IBAT) higher with shorter onset for temperature rise than rectal temperature. Increased IBAT temperature by procaine microinjections in anesthetized rats was attenuated during hypothalamic warming, and enhanced during hypothalamic cooling when compared with that observed during thermoneutral hypothalamic temperature. These results suggest that the midbrain TIM is able to function in unanesthetized conscious rats, and that the integrity of the midbrain mechanism to tonically inhibit metabolic heat production does not require the presence of intact hypothalamus. These results also suggest that the hypothalamus modulates directly or indirectly IBAT heat production that was induced by removal of the midbrain TIM.

  6. Fingertip skin wrinkling - the effect of varying tonicity.

    PubMed

    Tsai, N; Kirkham, S

    2005-06-01

    Fingertip skin wrinkling after prolonged immersion in water is a well-recognized phenomenon, whereas a denervated digit does not exhibit normal skin wrinkling while a finger with a regenerated or repaired nerve shows at least partial reappearance of wrinkling. This is the basis for the bedside immersion-wrinkling test of autonomic digital nerve function. The exact mechanism of fingertip skin wrinkling is still subject to controversy. The purpose of this study was to investigate the relationship between the tonicity of a solution and the time elapsed to skin wrinkling. Fourteen healthy volunteers (28 hands) were recruited for investigation. We submerged all 28 hands in solutions of varying tonicity while maintaining all other parameters constant. We found that increased tonicity significantly slowed the time to wrinkling (TTW). Hypotonic solutions such as water should be used when performing clinical bedside testing for autonomic digital nerve function.

  7. TONICITY-VOLUME RELATIONS IN PARTIALLY HEMOLYZED HYPOTONIC SYSTEMS

    PubMed Central

    Ponder, Eric

    1950-01-01

    The linear relation between the red cell volume V and the reciprocal of the tonicity T of a hypotonic medium is not the linear one expected on the basis of the van't Hoff-Mariotte law, particularly when a fraction p of the cells are hemolyzed and the volume V/(1 – p) of the (1 – p) cells which remain intact is considered. In systems of relatively high tonicity in which p is zero, the relation is linear but its slope is usually too small; at lower tonicities in which p has a value between zero and 0.35, the volumes are larger than those expected on the basis of the van't Hoff-Mariotte law, while at still smaller tonicities they are much smaller than expected. The volume measurements referred to are made with a high speed hematocrit; the results obtained in systems containing relatively high and relatively low volume concentrations of cells are contrasted with each other, and allowance is made in the calculations for the volume of the hypotonic medium surrounding the cells being limited. Attempts are made at an explanation of the anomalous results in terms of incomplete packing, of a stepwise as opposed to an all-or-none loss of Hb from the cells, of a heterogeneity in the swelling properties of the cells of the population, of a loss of osmotically active substances from the intact cells, and of the red cell ghost having some degree of rigidity. These explanations are not satisfying, although some of them in combination may account for the phenomena observed. It seems likely that the structures involved in the hemolytic process (cells and ghosts) have different properties in different tonicity ranges and even when the same tonicity is established in systems which are dense, as opposed to dilute, with respect to cell concentration. The form of the tonicity-volume relation can be changed substantially, although not in the direction of greater linearity, by treating the cells with resorcinol, colloidal silicic acid, iodoacetate, or sodium oxalate. Small changes in p

  8. Relative potency of tetrahydrocannabinol derivatives on tonic immobility in chickens.

    PubMed

    Maser, J D; Gallup, G G; Thorn, W R; Edson, P H

    1975-01-01

    Chickens were given varying dosages of delta 3-, delta 8-, and delta 9-THC and tested for duration of tonic immobility (TI). Although all derivatives had a profound facilitation effect, delta 9-THC was the most potent. These results are unusual in that TI is a well documented fear-potentiated reaction and THC generally has tranquilization-like effects.

  9. Critical Thinking as Miracle Tonic: Selling Snake Oil in Education.

    ERIC Educational Resources Information Center

    Hyslop-Margison, Emery J.

    This paper proposes that the current interest in critical thinking is based on important conceptual, epistemological, and procedural confusions. It suggests that the attempt to identify a successful critical thinking construct mirrors the search for miracle tonics often peddled by snake oil salesmen as a medicinal cure-all. It goes to suggest that…

  10. How perceived egocentric distance varies with changes in tonic vergence.

    PubMed

    Priot, Anne-Emmanuelle; Neveu, Pascaline; Sillan, Olivier; Plantier, Justin; Roumes, Corinne; Prablanc, Claude

    2012-06-01

    According to the eye muscle potentiation (EMP) hypothesis, sustained vergence leads to changes in egocentric perceived distance. This perceptual effect has been attributed to a change in the resting or tonic state of vergence. The goal of the present study was to test the EMP hypothesis by quantifying the relationship between prism-induced changes in tonic vergence and corresponding changes in perceived distance and by measuring the dynamics of changes in perceived distance. During a 10-min exposure to 5-diopter base-out prisms that increased the vergence demand, thirteen right-handed subjects pointed to visual targets located within reaching space using their left hand, without visual feedback. Pre- and post-exposure tests assessed tonic vergence through phoria measurements and egocentric distance estimate through pointing to visual targets with each hand successively, without visual feedback. Similar distance aftereffects were observed for both hands, although only the left hand was used during exposure, indicating that these aftereffects are mediated by visual processes rather than by visuomotor interactions. The distance aftereffects were significantly correlated with prism-induced changes in phoria, demonstrating a relationship between perceived distance and the level of tonic vergence. Changes in perceived distance increased monotonically across trials during prism exposure and remained stable during the post-test, indicating a long time constant for these perceptual effects, consistent with current models of the vergence control system. Overall, these results support the hypothesis that vergence plays a role in reduced-cue distance perception. They further illustrate that variations in tonic vergence influence perceived distance by altering the sensed vergence effort.

  11. Novel nuclear localization signal regulated by ambient tonicity in vertebrates.

    PubMed

    Kwon, Min Seong; Lee, Sang Do; Kim, Jeong-Ah; Colla, Emanuela; Choi, Yu Jeong; Suh, Pann-Ghil; Kwon, H Moo

    2008-08-15

    TonEBP is a Rel domain-containing transcription factor implicated in adaptive immunity, viral replication, and cancer. In the mammalian kidney, TonEBP is a central regulator of water homeostasis. Animals deficient in TonEBP suffer from life-threatening dehydration due to renal water loss. Ambient tonicity (effective osmolality) is the prominent signal for TonEBP in a bidirectional manner; TonEBP activity decreases in hypotonicity, whereas it increases in hypertonicity. Here we found that TonEBP displayed nuclear export in response to hypotonicity and nuclear import in response to hypertonicity. The nuclear export of TonEBP was not mediated by the nuclear export receptor CRM1 or discrete nuclear export signal. In contrast, a dominant nuclear localization signal (NLS) was found in a small region of 16 amino acid residues. When short peptides containing the NLS were fused to constitutively cytoplasmic proteins, the fusion proteins displayed tonicity-dependent nucleocytoplasmic trafficking like TonEBP. Thus, tonicity-dependent activation of the NLS is crucial in the nucleocytoplasmic trafficking of TonEBP. The novel NLS is present only in the vertebrates, indicating that it developed late in evolution.

  12. Novel Nuclear Localization Signal Regulated by Ambient Tonicity in Vertebrates*

    PubMed Central

    Kwon, Min Seong; Lee, Sang Do; Kim, Jeong-Ah; Colla, Emanuela; Choi, Yu Jeong; Suh, Pann-Ghil; Kwon, H. Moo

    2008-01-01

    TonEBP is a Rel domain-containing transcription factor implicated in adaptive immunity, viral replication, and cancer. In the mammalian kidney, TonEBP is a central regulator of water homeostasis. Animals deficient in TonEBP suffer from life-threatening dehydration due to renal water loss. Ambient tonicity (effective osmolality) is the prominent signal for TonEBP in a bidirectional manner; TonEBP activity decreases in hypotonicity, whereas it increases in hypertonicity. Here we found that TonEBP displayed nuclear export in response to hypotonicity and nuclear import in response to hypertonicity. The nuclear export of TonEBP was not mediated by the nuclear export receptor CRM1 or discrete nuclear export signal. In contrast, a dominant nuclear localization signal (NLS) was found in a small region of 16 amino acid residues. When short peptides containing the NLS were fused to constitutively cytoplasmic proteins, the fusion proteins displayed tonicity-dependent nucleocytoplasmic trafficking like TonEBP. Thus, tonicity-dependent activation of the NLS is crucial in the nucleocytoplasmic trafficking of TonEBP. The novel NLS is present only in the vertebrates, indicating that it developed late in evolution. PMID:18579527

  13. Tonic and Phasic Receptor Neurons in the Vertebrate Olfactory Epithelium

    PubMed Central

    Madrid, Rodolfo; Sanhueza, Magdalena; Alvarez, Osvaldo; Bacigalupo, Juan

    2003-01-01

    Olfactory receptor neurons (ORNs) respond to odorants with characteristic patterns of action potentials that are relevant for odor coding. Prolonged odorant exposures revealed three populations of dissociated toad ORNs, which were mimicked by depolarizing currents: tonic (TN, displaying sustained firing, 49% of 102 cells), phasic (PN, exhibiting brief action potential trains, 36%) and intermediate neurons (IN, generating trains longer than PN, 15%). We studied the biophysical properties underlying the differences between TNs and PNs, the most extreme cases among ORNs. TNs and PNs possessed similar membrane capacitances (∼4 pF), but they differed in resting potential (−82 versus −64 mV), input resistance (4.2 versus 2.9 GΩ) and unspecific current, Iu (TNs: 0 < Iu ≤ 1 pA/pF; and PNs: Iu > 1 pA/pF). Firing behavior did not correlate with differences in voltage-gated conductances. We developed a mathematical model that accurately simulates tonic and phasic patterns. Whole cell recordings from rat ORNs in fragments (∼4 mm2) of olfactory epithelium showed that such a tissue normally contains tonic and phasic receptor neurons, suggesting that this feature is common across a wide range of vertebrates. Our findings show that the individual passive electrical properties can govern the firing patterns of ORNs. PMID:12770919

  14. How do tonic glutamatergic synapses evade receptor desensitization?

    PubMed Central

    Pang, Ji-Jie; Gao, Fan; Barrow, Andrew; Jacoby, Roy A; Wu, Samuel M

    2008-01-01

    Photoreceptor output synapses are the best known tonic chemical synapses in the nervous system, in which glutamate is continuously released in darkness, activating AMPA/kainate receptors in postsynaptic neurons. It has been shown that glutamate receptors in certain types of second-order retinal cells are largely desensitized in darkness, leading to small postsynaptic currents and reduced response dynamic ranges. Here we show that the tonic glutamatergic synapses between photoreceptors and rod-dominated hyperpolarizing bipolar cells (HBCRs) in the salamander retina evade postsynaptic receptor desensitization by using (1) multiple invaginating ribbon junctions as releasing sites for low-frequency, synchronized multiquantal release at each site; and (2) the GluR4 AMPA receptors as the postsynaptic receptors. The multiquantal events exhibit faster decay time than the GluR4 receptor desensitization time constant and therefore self-desensitization is minimized, and the average inter-event duration in darkness is much longer than the GluR4 desensitization recovery time and thus mutual desensitization is avoided. Consequently, the HBCRs are not desensitized in darkness, allowing light signals to be encoded by the full operating range of the glutamate-gated postsynaptic currents. Our study illustrates for the first time how a tonic glutamatergic synapse avoids postsynaptic receptor desensitization, a strategy that may be shared by many other synapses in the nervous system that need extended operation capacity. PMID:18420706

  15. Anti-dandruff Hair Tonic Containing Lemongrass (Cymbopogon flexuosus) Oil.

    PubMed

    Chaisripipat, Wannee; Lourith, Nattaya; Kanlayavattanakul, Mayuree

    2015-01-01

    Natural remedies for treating dandruff are becoming popular. A randomized, double-blind, placebo-controlled, split-head efficacy evaluation was conducted 30 Thai volunteers aged 20-60 years experiencing dandruff measured at level 3 on D-Squame® scale. An easy to use hair tonic containing essential oil of lemongrass (Cymbopogon flexuosus) active against lipophilic yeasts was developed and then evaluated for efficacy and preference. The base formulation with the significantly highest preference (p < 0.05) was stowed with the oil at 5, 10 or 15%. Subjects applied the formulation twice a day, and an efficacy assessment with D-Squame® scale was conducted on days 7 and 14 of application. The application of lemongrass oil hair tonics with 5, 10, or 15% reduced dandruff significant (p < 0.005) at day 7 (33, 75, and 51%) and increased the effect even more (p < 0.005) at day 14 (52, 81, and 74%). The hair tonic formulation with 10% of lemongrass oil seems to be the most effective preparation. © 2015 S. Karger GmbH, Freiburg.

  16. Methods for recording and measuring tonic GABAA receptor-mediated inhibition.

    PubMed

    Bright, Damian P; Smart, Trevor G

    2013-12-05

    Tonic inhibitory conductances mediated by GABAA receptors have now been identified and characterized in many different brain regions. Most experimental studies of tonic GABAergic inhibition have been carried out using acute brain slice preparations but tonic currents have been recorded under a variety of different conditions. This diversity of recording conditions is likely to impact upon many of the factors responsible for controlling tonic inhibition and can make comparison between different studies difficult. In this review, we will firstly consider how various experimental conditions, including age of animal, recording temperature and solution composition, are likely to influence tonic GABAA conductances. We will then consider some technical considerations related to how the tonic conductance is measured and subsequently analyzed, including how the use of current noise may provide a complementary and reliable method for quantifying changes in tonic current.

  17. Methods for recording and measuring tonic GABAA receptor-mediated inhibition

    PubMed Central

    Bright, Damian P.; Smart, Trevor G.

    2013-01-01

    Tonic inhibitory conductances mediated by GABAA receptors have now been identified and characterized in many different brain regions. Most experimental studies of tonic GABAergic inhibition have been carried out using acute brain slice preparations but tonic currents have been recorded under a variety of different conditions. This diversity of recording conditions is likely to impact upon many of the factors responsible for controlling tonic inhibition and can make comparison between different studies difficult. In this review, we will firstly consider how various experimental conditions, including age of animal, recording temperature and solution composition, are likely to influence tonic GABAA conductances. We will then consider some technical considerations related to how the tonic conductance is measured and subsequently analyzed, including how the use of current noise may provide a complementary and reliable method for quantifying changes in tonic current. PMID:24367296

  18. Modulation of extrasynaptic NMDA receptors by synaptic and tonic zinc

    PubMed Central

    Anderson, Charles T.; Radford, Robert J.; Zastrow, Melissa L.; Zhang, Daniel Y.; Apfel, Ulf-Peter; Lippard, Stephen J.; Tzounopoulos, Thanos

    2015-01-01

    Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling. PMID:25947151

  19. [Tonic pupil, pupil Adie syndrome Adie Holmes: current reassessment of terminology -- a clinical case].

    PubMed

    Szabo, Bianca; Popescu, Livia Adriana; Rusu, Anca

    2012-01-01

    The benign syndrome of pupillotonia and absence of deep reflexes is not uncommon. It was clearly and accurately described by Adie (1932), although incompletely recognized many years, before. The pupillary abnormality was reported by ophthalmologists at the turn of the century (Saenger, 1902, Strasburger 1902), and the associated deep reflex change was described by Markus (1906), Roemheld (1921) and Parkes Weber (1923). Holmes (1932) was fully aware of the association of "partial iridoplegia" with diminished reflexes. Tonic pupils react poorly to light but constrict during viewing of a near stimulus. Adie's name is typically used in association with tonic pupils, but a review of Adie's articles reveals that he described the syndrome of tonic pupils and absent reflexes and not the pupillary abnormality per se. Therefore, it would be more appropriate to refer to a tonic pupil as simply a 'tonic pupil" and leave Adie's name for the syndrome. We report a typical case of tonic pupil.

  20. cAMP-independent role of PKA in tonicity-induced transactivation of tonicity-responsive enhancer/ osmotic response element-binding protein.

    PubMed

    Ferraris, Joan D; Persaud, Prita; Williams, Chester K; Chen, Ye; Burg, Maurice B

    2002-12-24

    Hypertonicity-induced increase in activity of the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP) protects renal cells by increasing transcription of genes, including those involved in increased accumulation of organic osmolytes. We previously showed that hypertonicity increases transactivating activity of TonEBP/OREBP. Assay with a binary GAL4 transactivation system showed that the 984 C-terminal amino acids of TonEBP/OREBP (amino acids 548-1531) contain a tonicity-dependent transactivation domain (TAD). Also, amino acids 548-1531 undergo tonicity-dependent phosphorylation, and some inhibitors of protein kinases reduce the tonicity-dependent transactivation. In the present studies we examined the role of protein kinase A (PKA). (i) An inhibitor of PKA (H89) reduces tonicity-dependent increases in transactivation, ORE/TonE reporter activity, and induction of aldose reductase and betaine transporter mRNAs. (ii) Overexpression of the catalytic subunit of PKA (PKAc) increases transactivation activity of amino acids 548-1531 and activity of an ORE/TonE reporter. The increases are much greater under isotonic than under hypertonic conditions. (iii) A dominant-negative PKAc reduces activity of an ORE/TonE reporter. (iv) PKAc activity increases with tonicity but cAMP does not. (v) TonEBP/OREBP and PKAc coimmunoprecipitate. (vi) amino acids 872-1271, including N- and C-terminal polyglutamine stretches, demonstrate tonicity-dependent transactivation, albeit less than amino acids 548-1531, and a similar role for PKA. (i) PKA plays an important role in TonEBP/OREBP activation of tonicity-dependent gene expression; (ii) PKA activation of TonEBP/OREBP appears to be cAMP-independent; and (iii) amino acids 872-1271 are sufficient for tonicity-dependent transactivation of TonEBP/OREBP.

  1. cAMP-independent role of PKA in tonicity-induced transactivation of tonicity-responsive enhancer/ osmotic response element-binding protein

    PubMed Central

    Ferraris, Joan D.; Persaud, Prita; Williams, Chester K.; Chen, Ye; Burg, Maurice B.

    2002-01-01

    Hypertonicity-induced increase in activity of the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP) protects renal cells by increasing transcription of genes, including those involved in increased accumulation of organic osmolytes. We previously showed that hypertonicity increases transactivating activity of TonEBP/OREBP. Assay with a binary GAL4 transactivation system showed that the 984 C-terminal amino acids of TonEBP/OREBP (amino acids 548–1531) contain a tonicity-dependent transactivation domain (TAD). Also, amino acids 548–1531 undergo tonicity-dependent phosphorylation, and some inhibitors of protein kinases reduce the tonicity-dependent transactivation. In the present studies we examined the role of protein kinase A (PKA). Results: (i) An inhibitor of PKA (H89) reduces tonicity-dependent increases in transactivation, ORE/TonE reporter activity, and induction of aldose reductase and betaine transporter mRNAs. (ii) Overexpression of the catalytic subunit of PKA (PKAc) increases transactivation activity of amino acids 548–1531 and activity of an ORE/TonE reporter. The increases are much greater under isotonic than under hypertonic conditions. (iii) A dominant-negative PKAc reduces activity of an ORE/TonE reporter. (iv) PKAc activity increases with tonicity but cAMP does not. (v) TonEBP/OREBP and PKAc coimmunoprecipitate. (vi) amino acids 872–1271, including N– and C-terminal polyglutamine stretches, demonstrate tonicity-dependent transactivation, albeit less than amino acids 548–1531, and a similar role for PKA. Conclusions: (i) PKA plays an important role in TonEBP/OREBP activation of tonicity-dependent gene expression; (ii) PKA activation of TonEBP/OREBP appears to be cAMP-independent; and (iii) amino acids 872–1271 are sufficient for tonicity-dependent transactivation of TonEBP/OREBP. PMID:12482947

  2. Ambient tonicity and intestinal cytochrome CYP3A.

    PubMed

    Chuang, Andrew I; Ito, Shinya

    2010-08-01

    Recently-discovered tonicity-dependence of human CYP3A expression in vitro may be a novel mechanism of CYP3A regulation in the intestinal epithelia, which exists in a dynamic osmotic environment influenced by food intake. A combination of focused and comprehensive literature searches to identify any relevant reports using Medline (from 1950 to 7 November 2009) through the OVID system. An update on current knowledge on osmotic environment in the gastrointestinal (GI) tract and its impact on intestinal CYP3A expression and function with special emphasis on the tonicity-sensitive transcription factor nuclear factor of activated T cells 5 (NFAT5). In vitro hypertonicity of ambient osmotic environment in cultured human cells increases expression of CYP3A through transcriptional enhancement by osmosensitive NFAT5. Although post-prandial osmolality in the GI lumen in vivo is substantially increased, NFAT5 activation has not been reported. Similarly, high-salt diet increases intestinal CYP3A function in humans, but it is not known whether these changes are mediated directly by NFAT5.

  3. Analysis of wavelet-filtered tonic-clonic electroencephalogram recordings.

    PubMed

    Rosso, O A; Figliola, A; Creso, J; Serrano, E

    2004-07-01

    EEG signals obtained during tonic-clonic epileptic seizures can be severely contaminated by muscle and physiological noise. Heavily contaminated EEG signals are hard to analyse quantitatively and also are usually rejected for visual inspection by physicians, resulting in a considerable loss of collected information. The aim of this work was to develop a computer-based method of time series analysis for such EEGs. A method is presented for filtering those frequencies associated with muscle activity using a wavelet transform. One of the advantages of this method over traditional filtering is that wavelet filtering of some frequency bands does not modify the pattern of the remaining ones. In consequence, the dynamics associated with them do not change. After generation of a 'noise free' signal by removal of the muscle artifacts using wavelets, a dynamic analysis was performed using non-linear dynamics metric tools. The characteristic parameters evaluated (correlation dimension D2 and largest Lyapunov exponent lambda1) were compatible with those obtained in previous works. The average values obtained were: D2=4.25 and lambda1=3.27 for the pre-ictal stage; D2=4.03 and lambda1=2.68 for the tonic seizure stage; D2=4.11 and lambda1=2.46 for the clonic seizure stage.

  4. Arousal thresholds during human tonic and phasic REM sleep.

    PubMed

    Ermis, Ummehan; Krakow, Karsten; Voss, Ursula

    2010-09-01

    The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub-states of REM to non-REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow-wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto-geniculo-occipital-like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub-states.

  5. Variable Action Potential Backpropagation during Tonic Firing and Low-Threshold Spike Bursts in Thalamocortical But Not Thalamic Reticular Nucleus Neurons.

    PubMed

    Connelly, William M; Crunelli, Vincenzo; Errington, Adam C

    2017-05-24

    Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca(2+)-imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-clamp recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that "tonic"' and low-threshold-spike (LTS) "burst" APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic amplitude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons.SIGNIFICANCE STATEMENT In most neurons, action potentials (APs) initiate in the axosomatic region and propagate into the dendritic tree to provide a retrograde signal that conveys information about the level of

  6. Water Depletion Threatens Agriculture

    NASA Astrophysics Data System (ADS)

    Brauman, K. A.; Richter, B. D.; Postel, S.; Floerke, M.; Malsy, M.

    2014-12-01

    Irrigated agriculture is the human activity that has by far the largest impact on water, constituting 85% of global water consumption and 67% of global water withdrawals. Much of this water use occurs in places where water depletion, the ratio of water consumption to water availability, exceeds 75% for at least one month of the year. Although only 17% of global watershed area experiences depletion at this level or more, nearly 30% of total cropland and 60% of irrigated cropland are found in these depleted watersheds. Staple crops are particularly at risk, with 75% of global irrigated wheat production and 65% of irrigated maize production found in watersheds that are at least seasonally depleted. Of importance to textile production, 75% of cotton production occurs in the same watersheds. For crop production in depleted watersheds, we find that one half to two-thirds of production occurs in watersheds that have not just seasonal but annual water shortages, suggesting that re-distributing water supply over the course of the year cannot be an effective solution to shortage. We explore the degree to which irrigated production in depleted watersheds reflects limitations in supply, a byproduct of the need for irrigation in perennially or seasonally dry landscapes, and identify heavy irrigation consumption that leads to watershed depletion in more humid climates. For watersheds that are not depleted, we evaluate the potential impact of an increase in irrigated production. Finally, we evaluate the benefits of irrigated agriculture in depleted and non-depleted watersheds, quantifying the fraction of irrigated production going to food production, animal feed, and biofuels.

  7. Simultaneous liquid chromatographic determination of water-soluble vitamins, caffeine, and preservative in oral liquid tonics.

    PubMed

    Maeda, Y; Yamamoto, M; Owada, K; Sato, S; Masui, T; Nakazawa, H

    1989-01-01

    A rapid, simple, and reliable liquid chromatographic method has been developed for the simultaneous determination of nicotinamide (niacinamide), thiamine, riboflavin, riboflavin sodium phosphate, pyridoxine, caffeine, and sodium benzoate in commercial oral liquid tonics. The 7 components are separated on a reverse phase C18 column using a mobile phase of acetonitrile-0.01M potassium dihydrogen phosphate-triethylamine (8 + 91.5 + 0.5 v/v/v) containing 5mM sodium octanesulfonate and adjusted to pH 2.8 with phosphoric acid. Components are detected at 254 nm with attenuation 0.02 AUFS. Acetanilide is used as an internal standard. In addition to the 7 components mentioned, nicotinic acid (niacin), cyanocobalamin, and folic acid are also separated under the same conditions. Sample preparation involves only addition to internal standard solution and dilution with mobile phase and then filtration. Recoveries of the 7 components and cyanocobalamin from spiked preparations ranged from 97 to 104% with coefficients of variation of 0.9-4.2%.

  8. Tonic fibres in axial muscle of cyprinid fish larvae: their definition, possible origins and functional importance.

    PubMed

    Stoiber, W; Haslett, J R; Steinbacher, P; Freimüller, M; Sänger, A M

    2002-05-01

    Teleost fish are known to develop small populations of muscle fibres that are assumed to be tonic in nature although their contractile properties and many other characteristics remain unknown. Here we attempt to resolve some of the ambiguity and confusions surrounding the definition and functional role of tonic fibres in teleosts and provide new information on their ontogeny. We investigate the differentiation of tonic muscle fibres in three species of cyprinid fish using electron microscopy, histochemistry, immunohistochemistry and in situ hybridization. The fine structure of the fibres defined as tonic in the larvae used in this study complies with patterns known from studies in teleost adults. This allows formal definition of tonic fibres in cyprinid larvae. The tonic fibres may be recognized by a variety of features: (1) by their characteristic position along the medial confines of the red muscle insertion at the horizontal septum, (2) their fine structure, including solid clusters of irregularly cleaved myofibrils, thick and wavy Z-lines, and T-tubules at the A-band/I-band transitions, (3) their histochemical features, specifically weak but obvious staining for mATPase after alkaline preincubation, and lack of SDH activity in the more advanced larval stages, (4) their unique immunological properties, being the only fibre type in the myotome that reacts with a serum against chicken tonic myosin (anti- T2). Expression of tonic characters usually begins within a few fibres in the dorsal domain of the superficial red muscle insertion at the horizontal septum and hence involves a high degree of dorso-ventral polarity. The present evidence indicates that tonic fibres arise from separate myogenic stem cells rather than by transdifferentiation from existing red fibres. First appearance of tonic fibres during ontogeny correlates closely with the onset of free swimming and exogeneous feeding. We use this fact to argue that tonic fibres are probably a prerequisite for

  9. Halo Star Lithium Depletion

    SciTech Connect

    Pinsonneault, M. H.; Walker, T. P.; Steigman, G.; Narayanan, Vijay K.

    1999-12-10

    The depletion of lithium during the pre-main-sequence and main-sequence phases of stellar evolution plays a crucial role in the comparison of the predictions of big bang nucleosynthesis with the abundances observed in halo stars. Previous work has indicated a wide range of possible depletion factors, ranging from minimal in standard (nonrotating) stellar models to as much as an order of magnitude in models that include rotational mixing. Recent progress in the study of the angular momentum evolution of low-mass stars permits the construction of theoretical models capable of reproducing the angular momentum evolution of low-mass open cluster stars. The distribution of initial angular momenta can be inferred from stellar rotation data in young open clusters. In this paper we report on the application of these models to the study of lithium depletion in main-sequence halo stars. A range of initial angular momenta produces a range of lithium depletion factors on the main sequence. Using the distribution of initial conditions inferred from young open clusters leads to a well-defined halo lithium plateau with modest scatter and a small population of outliers. The mass-dependent angular momentum loss law inferred from open cluster studies produces a nearly flat plateau, unlike previous models that exhibited a downward curvature for hotter temperatures in the 7Li-Teff plane. The overall depletion factor for the plateau stars is sensitive primarily to the solar initial angular momentum used in the calibration for the mixing diffusion coefficients. Uncertainties remain in the treatment of the internal angular momentum transport in the models, and the potential impact of these uncertainties on our results is discussed. The 6Li/7Li depletion ratio is also examined. We find that the dispersion in the plateau and the 6Li/7Li depletion ratio scale with the absolute 7Li depletion in the plateau, and we use observational data to set bounds on the 7Li depletion in main-sequence halo

  10. Depleted Uranium: Technical Brief

    EPA Pesticide Factsheets

    This technical brief provides accepted data and references to additional sources for radiological and chemical characteristics, health risks and references for both the monitoring and measurement, and applicable treatment techniques for depleted uranium.

  11. Battery depletion monitor

    SciTech Connect

    Lee, Y.S.

    1982-01-26

    A cmos inverter is used to compare pacemaker battery voltage to a referenced voltage. When the reference voltage exceeds the measured battery voltage, the inverter changes state to indicate battery depletion.

  12. Addressing Ozone Layer Depletion

    EPA Pesticide Factsheets

    Access information on EPA's efforts to address ozone layer depletion through regulations, collaborations with stakeholders, international treaties, partnerships with the private sector, and enforcement actions under Title VI of the Clean Air Act.

  13. Ross syndrome: Unilateral hyperhidrosis, Adie's tonic pupils and diffuse areflexia.

    PubMed

    Yaşar, Sirin; Aslan, Canan; Serdar, Zehra Aşiran; Demirci, Gülşen Tükenmez; Tutkavul, Kemal; Babalik, Dilek

    2010-12-01

    Ross syndrome is a rare disorder first described in 1958 with partial autonomic dysfunction. It has three basic components including unilateral or bilateral segmental anhidrosis, Adie's tonic pupils and areflexia or hyporeflexia of deep tendon reflexes. The most disturbing symptom in the patients is segmental compensatory hyperhidrosis and often the hypohidrosis or anhidrosis is not even noticed. While the pathogenesis of Ross syndrome is unclear, degenerative changes or damage to the peripheral autonomic nerve system or dorsal root ganglia have been suggested as possible causes. About 50 cases have been reported, usually by neurologists and ophthalmologists, and less often by dermatologists. We present a 26-year-old patient who displayed the classic triad of this syndrome, emphasizing that the presenting complaint may be hyperhidrosis and that multidisciplinary evaluation in neurology and ophthalmology is essential. © The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin.

  14. [Tonic pupil and tendon areflexia: the Holmes-Adie's syndrome].

    PubMed

    Martinelli, P; Minardi, C

    2001-10-01

    The Holmes-Adie syndrome (HAS) is characterised by initially monolateral, then bilateral enlargement of the pupil with delayed responses to near vision and subsequent redilation, and absent tendon reflexes. The diameter of the affected pupil is oval or irregular, sometimes with spontaneous movements of the pupillary sphincter muscle. Reaction to light may require several minutes' exposure to bright light, as it does redilation after a prolonged stay in a dark room. The reaction to near vision is tonic and delayed, as the subsequent redilation. In 10% of cases there is a permanent failure of the pupil to react either to light or to near vision. Absence of deep tendon reflexes is acquired and permanent, most frequently involving the Achilles' tendon reflex. Loss of different degrees of ciliary and spinal ganglia neurons, without evidence of inflammatory findings, are the neuropathological data accounting for the clinical signs of HAS. Polyneuropathies of different origin can be complicated by a symptomatic form of HAS.

  15. Pelvic floor tonicity affects urodynamic measurements in children with myelomeningocele.

    PubMed

    Gundogdu, Gokhan; Avlan, Dincer; Nayci, Ali; Tasdelen, Bahar

    2011-11-01

    In a cystometry procedure in a child with myelomeningocele (MMC), a pressure increase in the abdominal pressure (P (abd)) tracing was detected during filling. This pressure alteration was not related to other known events (straining, talking, rectal contractions). This study was conducted to investigate this phenomenon. Forty-three children with MMC were enrolled in the study. A slow and gradual pressure increase associated with the bladder filling was sought in the P (abd) tracings. End filling and initial P (abd) gradient more than 3 cm H(2)O were considered as increased P (abd). If the defined pressure event occurs, the bladder was evacuated for verifying the filling-pressure relation. Age, gender, study position, pelvic floor tonicity and cystometric capacity were correlated with the pressure alteration. P (abd) increase was noted in 18 (41.8%) children. The mean P (abd) gradient between end and initial filling was 4.78 ± 1.63 cm H(2)O in these children. No statistically significant difference was noted for age, gender and study position. Statistically significant differences were noted with decreased pelvic floor tonicity and high values of cystometric capacity (p = 0.003 and p < 0.001, respectively). The pressure increase is thought to be a consequence of a posterior positional change in the bladder during filling die to decreased pelvic floor support in MMC. This pressure alteration was more obvious with increased bladder capacity. Urodynamic studies of children with MMC should be carefully evaluated for the presence of this phenomenon to prevent low measurement of the detrusor pressure, compliance and detrusor leak point pressure values.

  16. Tonic postganglionic sympathetic inhibition induced by afferent renal nerves?

    PubMed

    Ditting, Tilmann; Freisinger, Wolfgang; Siegel, Kirsten; Fiedler, Christian; Small, Lisa; Neuhuber, Winfried; Heinlein, Sonja; Reeh, Peter W; Schmieder, Roland E; Veelken, Roland

    2012-02-01

    Other than efferent sympathetic innervation, the kidney has peptidergic afferent fibers expressing TRPV1 receptors and releasing substance P. We tested the hypothesis that stimulation of afferent renal nerve activity with the TRPV1 agonist capsaicin inhibits efferent renal sympathetic nerve activity tonically by a neurokinin 1 receptor-dependant mechanism. Anesthetized Sprague-Dawley rats were instrumented as follows: (1) arterial and venous catheters for recording of blood pressure and heart rate and drug administration; (2) left-sided renal arterial catheter for selective intrarenal administration of the TRPV1 agonist capsaicin (3.3, 6.6, 10, 33*10(-7) m; 10 μL; after 15, 30, 45, and 60 minutes, respectively) to stimulate afferent renal nerve activity; (3) right-sided bipolar electrode for continuous renal sympathetic nerve recording; and (4) specialized renal pelvic and renal artery catheters to separate pelvic from intrarenal afferent activity. Before and after intrarenal capsaicin application, increasing intravenous doses of the neurokinin 1 receptor blocker RP67580 were given. Intrarenal capsaicin decreased integrated renal sympathetic activity from 65.4±13.0 mV*s (baseline) to 12.8±3.2 mV*s (minimum; P<0.01). This sustained renal sympathetic inhibition reached its minimum within 70 minutes and was not directly linked to the transient electric afferent response to be expected with intrarenal capsaicin. Suppressed renal sympathetic activity transiently but completely recovered after intravenous administration of the neurokinin 1 blocker (maximum: 120.3±19.4 mV*s; P<0.01). Intrarenal afferent activity could be unequivocally separated from pelvic afferent activity. For the first time we provide direct evidence that afferent intrarenal nerves provide a tonically acting sympathoinhibitory system, which seems to be rather mediated by neurokinin release acting via neurokinin 1 receptor pathways rather than by electric afferent effects on central sympathetic

  17. [A new concept to explain dysnatremia: the tonicity balance of entries and exits].

    PubMed

    Mallié, J P; Halperin, M L

    2001-01-01

    Plasma sodium concentration, or natremia, results from three main factors: exchangeable sodium (Na+), exchangeable potassium (K+) and total body water (H2O). Its alterations often imply a change in cell volume. Understanding dysnatremias is essential for the treatment and prevention of hydromineral disorders. Extra-cellular fluid tonomoles consist almost exclusively of Na+ salts. Their dilution is the tonicity. K+ is an essential tonomole for intra-cellular fluid tonicity. The balance between intra and extracellular tonicities depends on water movements and is responsible for changes in intra- and extracellular fluid volumes. Cell volume is therefore depending on the tonicity balance. A change in body tonicity (which is not osmolality) can be correctly and rapidly appreciated by measuring the (Na+ + K+) and H2O balances. Clinical cases emphasize the misleadings resulting from the free-water clearance calculation or the only measurements of urinary losses. They also demonstrate that tonicity balance provides indications for therapy whereas analyses based upon electrolyte-free water do not. Intakes should be quantified with the same care than losses. The units used must be coherent to allow a quick and easy understanding at the bedside. Tonicity balance should be taught and Na+ + K+ and H2O balances should be routinely utilized by practitioners, dieticians and nurses in the concerned pediatrics, in particular intensive care, internal medicine, nephrology, pediatry and anesthesiology.

  18. Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation

    PubMed Central

    Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Wu, Tianxia; Hallett, Mark

    2016-01-01

    Motor surround inhibition is the neural mechanism that selectively favors the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) as the target muscle, and the abductor digiti minimi (ADM), flexor carpi radialis (FCR), and extensor carpi radialis (ECR) as surround muscles during rest and tonic activation of FDI in fourteen subjects. Cerebellar stimulation was performed under MRI-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90% to 120% of adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI was selected for use during tonic activation. During selective tonic activation of FDI, CBI was significantly reduced only for FDI but not for the surround muscles. Unconditioned MEP sizes were increased in all muscles during FDI tonic activation compared to rest, despite background EMG activity increasing only for the FDI. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle. PMID:26900871

  19. EEG spectral power in phasic and tonic REM sleep: different patterns in young adults and children.

    PubMed

    Simor, Péter; Gombos, Ferenc; Szakadát, Sára; Sándor, Piroska; Bódizs, Róbert

    2016-06-01

    Rapid eye movement sleep is composed of phasic and tonic periods, two distinguishable microstates in terms of arousal thresholds and sensory processing. Background electroencephalogram oscillations are also different between periods with (phasic state) and periods without (tonic state) eye movements. In Study 1, previous findings analysing electroencephalogram spectral power in phasic and tonic rapid eye movement sleep were replicated, and analyses extended to the high gamma range (52-90 Hz). In Study 2, phasic and tonic spectral power differences within a group of 4-8-year-old children were examined. Based on the polysomnographic data of 20 young adults, the phasic state yielded increased delta and theta power in anterior sites, as well as generally decreased high alpha and beta power in comparison to the tonic state. Moreover, phasic periods exhibited greater spectral power in the lower and the higher gamma band. Interestingly, children (n = 18) exhibited a different pattern, showing increased activity in the low alpha range during phasic periods. Moreover, during phasic in contrast to tonic rapid eye movement sleep, increased low and high gamma and enhanced low gamma band power emerged in anterior and posterior regions, respectively. The current findings show that spectral activity within the high gamma range substantially contributes to the differences between phasic and tonic rapid eye movement sleep, especially in adults. Moreover, the current data underscore the heterogeneity of rapid eye movement sleep, and point to marked differences between young adults and children regarding phasic/tonic electroencephalogram spectral power. These results suggest that the differentiation between phasic and tonic rapid eye movement periods undergoes maturation.

  20. Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells

    PubMed Central

    Sebe, Joy Y.; Looke-Stewart, Elizabeth C.; Estrada, Rosanne C.; Baraban, Scott C.

    2010-01-01

    Within the hippocampus and neocortex, GABA is considered excitatory in early development due to a relatively depolarized Cl- reversal potential. Although the depolarizing nature of synaptic GABAergic events has been well established, it is unknown whether cortical tonic currents mediated by extrasynaptically located GABAA receptors (GABAARs) are also excitatory. Here we examined the development of tonic currents in the neocortex and their effect on neuronal excitability. We found that mean tonic current, recorded from Layer 5 pyramidal cells of the mouse somatosensory cortex, is robust in newborns (P2-4) then decreases dramatically by the second postnatal week (P7-10 and P30-40). Pharmacological studies, in combination with Western blot analysis, show that neonatal tonic currents are partially mediated by the GABAAR α5, and likely the δ, subunit. In newborns, the charge due to tonic current accounts for nearly 100% of total GABA charge, a contribution that decreases to less than 50% in mature tissue. Current clamp recordings reveal that tonic current contributes to large fluctuations in the membrane potential that may disrupt its stability. Bath application of 5 μM GABA, to induce tonic currents, markedly decreased cell firing frequency in most recorded cells while increasing it in others. Gramicidin perforated patch recordings reveal heterogeneity in ECl recorded from P2-5 Layer 5 pyramidal cells. Taken together, these findings demonstrate that tonic currents activated by low GABA concentrations can dominate GABAergic transmission in newborn neocortical pyramidal cells and that tonic currents can exert heterogeneous effects on neuronal excitability. PMID:20846324

  1. The impact of luminance on tonic and phasic pupillary responses to sustained cognitive load.

    PubMed

    Peysakhovich, Vsevolod; Vachon, François; Dehais, Frédéric

    2017-02-01

    Pupillary reactions independent of light conditions have been linked to cognition for a long time. However, the light conditions can impact the cognitive pupillary reaction. Previous studies underlined the impact of luminance on pupillary reaction, but it is still unclear how luminance modulates the sustained and transient components of pupillary reaction - tonic pupil diameter and phasic pupil response. In the present study, we investigated the impact of the luminance on these two components under sustained cognitive load. Fourteen participants performed a novel working memory task combining mathematical computations with a classic n-back task. We studied both tonic pupil diameter and phasic pupil response under low (1-back) and high (2-back) working memory load and two luminance levels (gray and white). We found that the impact of working memory load on the tonic pupil diameter was modulated by the level of luminance, the increase in tonic pupil diameter with the load being larger under lower luminance. In contrast, the smaller phasic pupil response found under high load remained unaffected by luminance. These results showed that luminance impacts the cognitive pupillary reaction - tonic pupil diameter (phasic pupil response) being modulated under sustained (respectively, transient) cognitive load. These findings also support the relationship between the locus-coeruleus system, presumably functioning in two firing modes - tonic and phasic - and the pupil diameter. We suggest that the tonic pupil diameter tracks the tonic activity of the locus-coeruleus while phasic pupil response reflects its phasic activity. Besides, the designed novel cognitive paradigm allows the simultaneous manipulation of sustained and transient components of the cognitive load and is useful for dissociating the effects on the tonic pupil diameter and phasic pupil response.

  2. Inhibition of midbrain-evoked tonic and rhythmic motor activity by cutaneous stimulation in decerebrate cats.

    PubMed

    Beyaert, C A; Haouzi, P; Marchal, F

    2003-03-01

    The effect of mechanical and electrical stimulation of cervical cutaneous afferents was analysed on both the centrally induced tonic and rhythmic activities in hindlimb antagonist muscle nerves of 16 decerebrate paralysed cats. Electrical stimulation of dorsal midbrain evoked in the nerve to the tibialis anterior muscle (TAn) either rhythmic discharges (n=14), associated with tonic discharges in ten cats, or only tonic discharges (n=4). Centrally induced activity in the ipsilateral nerve to gastrocnemius medialis (GMn) occurred in fewer cats (n=12) and displayed similar patterns as in TAn. Manual traction of the scruff of the neck reduced the TAn tonic and rhythmic discharges (n=6) by 73% (P<0.05) and 71% (P<0.05), respectively, and reduced only the tonic component of GMn discharges (by 41%, n=3). Electrical stimulation (impulses 0.1-0.5 ms, 50 Hz) of cervical nerves belonging to C5 or C6 dermatomes, the intensity (0.4-4 mA) of which induced minimal inhibition of both TAn and GMn discharges, reduced significantly the tonic component of TAn discharges (by 39%, n=4). At higher intensities of electrical cervical nerve stimulation (2-6 mA) inducing maximal inhibitory effect, both tonic and rhythmic activities in TAn and GMn were both significantly reduced by, respectively, 81% and 94% in TAn (n=7), and by 49% and 43% in GMn (n=7). Electrical cervical nerve stimulation consistently reduced the isolated tonic discharge in TAn by 66% (n=4, P<0.05) and in GMn by 23% (n=3) when present. Thus the tonic component was more sensitive to inhibition than the rhythmic component of hindlimb muscle nerve activity.

  3. Contribution of tonic vibration reflex to the evaluation and diagnosis of cerebellar disorders.

    PubMed Central

    Abbruzzese, G; Abbruzzese, M; Ratto, S; Favale, E

    1982-01-01

    Biceps brachii tonic vibration reflexes were elicited in patients with either focal or diffuse cerebellar damage and spino-cerebellar degenerations. As compared to normal controls, tonic vibration reflex amplitude was reduced in cerebellar patients, particularly in cases with unilateral hemispheric lesion, who exhibited a clear cut tonic vibration reflex asymmetry even when clinical symptoms were mild. These reflexes were absent or very weak in patients with spino-cerebellar degenerations. Muscle vibration induced in most of the patients an enhancement of mild or latent clinical symptoms such as intention tremor, difficulty in muscle relaxation or motor incoordination. PMID:7119815

  4. Anticonvulsant drugs for generalized tonic-clonic epilepsy.

    PubMed

    Coppola, Giangennaro; Piccorossi, Alessandra; Operto, Francesca Felicia; Verrotti, Alberto

    2017-06-01

    Primary generalized tonic clonic seizures (pGTCS) are still linked to major concerns for the clinic and hazards for patients suffering from idiopathic generalized epilepsy (IGE), so a quick search of the most effective and appropriate therapy is needed to control them. The key criteria for proper treatment are syndromic diagnosis and distinction between newly diagnosed and refractory patients. Other criteria include age, gender and comorbidities. Areas covered: Treatment for pGTCS has expanded in the last two years, with new antiepileptic drugs like perampanel joining valproic acid, lamotrigine, levetiracetam, topiramate, while further evidence-based data are required for zonisamide and lacosamide. Expert opinion: Currently, valproic acid can be considered as a first choice in male or menopausal women, and in the absence of weight issue, both in adults and in children, and in the absence of side effects such as insomnia and headache. Today, valproic acid is not recommended in child-bearing age and in relation to possible cognitive problems, especially in children. Lamotrigine and levetiracetam can be a viable alternative as a first choice. Topiramate is also effective as a first choice, but concerns may arise from its potential cognitive and memory adverse side effects. Additionally, perampanel and lacosamide are promising treatments.

  5. Both happy and sad melodies modulate tonic human heat pain.

    PubMed

    Zhao, Huixuan; Chen, Andrew C N

    2009-09-01

    The mechanism of music effects on pain perception remains to be elucidated. To determine which component (mood or valence) of music is more important in music-induced hypoalgesia, we compared the effects of 2 melodies with different moods (happy vs sad) but with the same degree of valence (pleasant vs unpleasant) to an affective neutral lecture and a control (baseline) on the objective and subjective responses to tonic heat pain. Our hypothesis was that if mood was the key component, the happy melody would reduce pain, whereas the sad one would exacerbate pain; and if valence is the key component, the 2 melodies would both alleviate pain. Twenty females participated in this study which consisted of 4 conditions (baseline, happy melody, sad melody, and lecture). Pain tolerance time (PTT), pain intensity, and distress dynamics and the characteristics of pain were measured. A newly devised multiple affective rating scale (MARS) was employed to assess the subjective experience of auditory perception. Both happy and sad melodies of equal valence resulted in significant lower pain ratings during the pain test and were in contrast to the mood prediction. These results indicate that the valence of music, rather than the mood it induced, appears to be the most likely mediator of the hypoalgesic effect of the different music. This article provides new evidence that the valence of music is more crucial than mood in affective pain modulation. This finding gives impetus for health professionals to manage pain more effectively in patients with proper music.

  6. Ventrolateral periaqueductal gray matter and the control of tonic immobility.

    PubMed

    Monassi, C R; Leite-Panissi, C R; Menescal-de-Oliveira, L

    1999-10-01

    Tonic immobility is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. The periaqueductal gray matter (PAG) contains neural circuits involved in descending pain modulation, as well as in the modulation of TI. We have reported previously that the cholinergic stimulation of the ventrolateral PAG increases the duration of TI in guinea pigs. In the present study, we attempted to characterize further the modulation of TI by pharmacological alteration of the neurochemistry of the ventrolateral PAG circuitry. We observed that both cholinergic (carbachol, 5.4 nmol/0.2 microl) and opioidergic stimulations (morphine, 4.48 nmol/0.2 microl) of the ventrolateral PAG increase the duration of TI and that these effects can be reversed by pre-treatment with naloxone (2.74 nmol/0.2 microl). Our results also showed that microinjection of the GABAergic agonist muscimol (1, 0.5, and 0.26 nmol/0.2 microl) decreased the duration of TI episodes, while microinjection of the GABAergic antagonist bicuculline (1 nmol/microl) increased it. Moreover, we observed that preadministration of muscimol (0.13 nmol/0.2 microl) at a dose that had no effect per se at this site antagonized the potentiating effect of morphine. Our results suggest that this modulation of TI from the ventrolateral PAG circuitry is accomplished by a complex interaction of cholinergic, opioidergic, and GABAergic mechanisms, similar to that proposed for descending antinociceptive circuits.

  7. Rapid critical period induction by tonic inhibition in visual cortex.

    PubMed

    Iwai, Youichi; Fagiolini, Michela; Obata, Kunihiko; Hensch, Takao K

    2003-07-30

    Mice lacking a synaptic isoform of glutamic acid decarboxylase (GAD65) do not exhibit ocular dominance plasticity unless an appropriate level of GABAergic transmission is restored by direct infusion of benzodiazepines into the brain. To better understand how intracortical inhibition triggers experience-dependent changes, we dissected the precise timing requirement for GABA function in the monocular deprivation (MD) paradigm. Diazepam (DZ) or vehicle solution was infused daily before and/or during 4 d of MD in GAD65 knock-out mice. Extracellular single-unit recordings from the binocular zone of visual cortex were performed at the end of deprivation. We found that a minimum treatment of 2 d near the beginning of MD was sufficient to fully activate plasticity but did not need to overlap the deprivation per se. Extended delay after DZ infusion eventually led to loss of plasticity accompanied by improved intrinsic inhibitory circuit function. Two day DZ treatment just after eye opening similarly closed the critical period prematurely in wild-type mice. Raising wild-type mice in complete darkness from birth delayed the peak sensitivity to MD as in other mammals. Interestingly, 2 d DZ infusion in the dark also closed the critical period, whereas equally brief light exposure during dark-rearing had no such effect. Thus, enhanced tonic signaling through GABA(A) receptors rapidly creates a milieu for plasticity within neocortex capable of triggering a critical period for ocular dominance independent of visual experience itself.

  8. Tonic PKA Activity Regulates SK Channel Nanoclustering and Somatodendritic Distribution.

    PubMed

    Abiraman, Krithika; Sah, Megha; Walikonis, Randall S; Lykotrafitis, George; Tzingounis, Anastasios V

    2016-06-05

    Small-conductance calcium-activated potassium (SK) channels mediate a potassium conductance in the brain and are involved in synaptic plasticity, learning, and memory. SK channels show a distinct subcellular localization that is crucial for their neuronal functions. However, the mechanisms that control this spatial distribution are unknown. We imaged SK channels labeled with fluorophore-tagged apamin and monitored SK channel nanoclustering at the single molecule level by combining atomic force microscopy and toxin (i.e., apamin) pharmacology. Using these two complementary approaches, we found that native SK channel distribution in pyramidal neurons, across the somatodendritic domain, depends on ongoing cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) levels, strongly limiting SK channel expression at the pyramidal neuron soma. Furthermore, tonic cAMP-PKA levels also controlled whether SK channels were expressed in nanodomains as single entities or as a group of multiple channels. Our study reveals a new level of regulation of SK channels by cAMP-PKA and suggests that ion channel topography and nanoclustering might be under the control of second messenger cascades. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Interaction of tonic labyrinth and neck reflexes in man.

    PubMed

    Aiello, I; Rosati, G; Sau, G F; Lentinu, M E; Tidore, B S; Sotgiu, S; Cacciotto, R; Posadinu, D; Muzzu, S; Manca, I

    1992-04-01

    Interaction of tonic labyrinth and neck reflexes was studied in 3 healthy volunteers by analyzing changes in Soleus H-Reflex (SHR) area in relation to both lateral tiltings and neck rotations. By using a Kermath chair each subject was tilted laterally from the vertical to the left and to the right up 15 degrees in steps of 5 degrees and at the same time the longitudinal body axis, keeping the head fixed, was rotated to the right and to the left up to 15 degrees in steps of 5 degrees. All combinations of lateral tiltings and neck rotations were tested. Each test position was followed by a return to 0 degree for both rotation and tilting (control position). Twelve H-reflexes of right soleus muscle were recorded in each test and control position and the changes in RSHR area were expressed as percentage variations from the mean value absorbed in the pretest and post-test control position. Our data indicate that in man, as in animals, labyrinth and neck reflexes act in the opposite direction, and that in the static condition their contribution to postural stabilization is equal.

  10. Cholesterol depletion induces autophagy

    SciTech Connect

    Cheng, Jinglei; Ohsaki, Yuki; Tauchi-Sato, Kumi; Fujita, Akikazu; Fujimoto, Toyoshi . E-mail: tfujimot@med.nagoya-u.ac.jp

    2006-12-08

    Autophagy is a mechanism to digest cells' own components, and its importance in many physiological and pathological processes is being recognized. But the molecular mechanism that regulates autophagy is not understood in detail. In the present study, we found that cholesterol depletion induces macroautophagy. The cellular cholesterol in human fibroblasts was depleted either acutely using 5 mM methyl-{beta}-cyclodextrin or 10-20 {mu}g/ml nystatin for 1 h, or metabolically by 20 {mu}M mevastatin and 200 {mu}M mevalonolactone along with 10% lipoprotein-deficient serum for 2-3 days. By any of these protocols, marked increase of LC3-II was detected by immunoblotting and by immunofluorescence microscopy, and the increase was more extensive than that caused by amino acid starvation, i.e., incubation in Hanks' solution for several hours. The induction of autophagic vacuoles by cholesterol depletion was also observed in other cell types, and the LC3-positive membranes were often seen as long tubules, >50 {mu}m in length. The increase of LC3-II by methyl-{beta}-cyclodextrin was suppressed by phosphatidylinositol 3-kinase inhibitors and was accompanied by dephosphorylation of mammalian target of rapamycin. By electron microscopy, autophagic vacuoles induced by cholesterol depletion were indistinguishable from those seen after amino acid starvation. These results demonstrate that a decrease in cholesterol activates autophagy by a phosphatidylinositol 3-kinase-dependent mechanism.

  11. Variable Action Potential Backpropagation during Tonic Firing and Low-Threshold Spike Bursts in Thalamocortical But Not Thalamic Reticular Nucleus Neurons

    PubMed Central

    Crunelli, Vincenzo

    2017-01-01

    Backpropagating action potentials (bAPs) are indispensable in dendritic signaling. Conflicting Ca2+-imaging data and an absence of dendritic recording data means that the extent of backpropagation in thalamocortical (TC) and thalamic reticular nucleus (TRN) neurons remains unknown. Because TRN neurons signal electrically through dendrodendritic gap junctions and possibly via chemical dendritic GABAergic synapses, as well as classical axonal GABA release, this lack of knowledge is problematic. To address this issue, we made two-photon targeted patch-clamp recordings from rat TC and TRN neuron dendrites to measure bAPs directly. These recordings reveal that “tonic”' and low-threshold-spike (LTS) “burst” APs in both cell types are always recorded first at the soma before backpropagating into the dendrites while undergoing substantial distance-dependent dendritic amplitude attenuation. In TC neurons, bAP attenuation strength varies according to firing mode. During LTS bursts, somatic AP half-width increases progressively with increasing spike number, allowing late-burst spikes to propagate more efficiently into the dendritic tree compared with spikes occurring at burst onset. Tonic spikes have similar somatic half-widths to late burst spikes and undergo similar dendritic attenuation. In contrast, in TRN neurons, AP properties are unchanged between LTS bursts and tonic firing and, as a result, distance-dependent dendritic attenuation remains consistent across different firing modes. Therefore, unlike LTS-associated global electrical and calcium signals, the spatial influence of bAP signaling in TC and TRN neurons is more restricted, with potentially important behavioral-state-dependent consequences for synaptic integration and plasticity in thalamic neurons. SIGNIFICANCE STATEMENT In most neurons, action potentials (APs) initiate in the axosomatic region and propagate into the dendritic tree to provide a retrograde signal that conveys information about the level

  12. Short-term regulation of tyrosine hydroxylase in tonically-active and in tonically-inactive dopamine neurons: effects of haloperidol and protein phosphorylation.

    PubMed

    Iuvone, P M

    1983-09-26

    Dopamine (DA)-containing neurons of retina were employed as an experimental model for studying the short-term regulation of tyrosine hydroxylase (TH) in tonically-active and tonically-inactive neurons. These DA-containing neurons are trans-synaptically activated by light. Two mechanisms have been observed in this system for regulation of TH activity. A short-term activation of TH that is characterized by a decreased apparent Km for pteridine cofactors occurs in response to rapid increases of neuronal activity. A second mechanism occurs in response to prolonged, tonic changes of neuronal activity and is characterized by changes of Vmax. Both the Km changes and Vmax changes represent changes of specific activity of TH rather than enzyme induction. To determine the effects of short-term increases of neuronal activity on TH in tonically-active and tonically-inactive neurons, the effects of acute administration of haloperidol were examined in rats that were continuously light-exposed or light-deprived for 4 days. Haloperidol increased TH activity in both light-exposed and light-deprived retinas. The drug elicited the same percent stimulation in both experimental conditions. However, because the basal activity of TH was higher in the light-exposed than the light-deprived retinas, the absolute increase of TH specific activity was greater in the light-exposed samples. The effect of protein phosphorylation on TH activity in extracts of chronically light-exposed or light-deprived retinas was also examined to determine if the differences in the response to haloperidol might be due to a difference in the amount of TH available for short-term activation. Phosphorylation by endogenous cyclic AMP-dependent protein kinase (APK) or by purified catalytic subunit of APK resulted in larger increases of TH specific activity in extracts of light-exposed retinas than in those of light-deprived retinas. As was observed for haloperidol-induced activation, the percent stimulation elicited

  13. CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception.

    PubMed

    Hasanein, Parisa; Parviz, Mohsen; Keshavarz, Mansoor; Javanmardi, Kazem

    2007-01-01

    1. Recent studies have suggested that the basolateral nucleus of the amygdala (BLA) participates in the processing of pain information, especially noxious somatic information. Cannabinoid receptors or CB1 mRNA are expressed more in the BLA than in other nuclei of the amygdala. Thus, the aim of the present study was to examine whether CB1 receptors in the BLA may be involved in modulating acute and/or tonic nociceptive processing. 2. Adult rats were exposed to intra-BLA microinjection of the cannabinoid receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo [1,2,3,-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate [WIN 55,212-2 (1, 2.5, 5 or 10 microg/side)] and subjected to the tail flick and formalin tests. 3. The rats demonstrated a dose-dependent increase in latency to withdraw from a thermal noxious stimulus in the tail flick test and a decrease in formalin-induced pain behaviours. The antinociceptive effects of the CB1 receptor agonist WIN 55,212-2 (10 microg/side) in both tests were attenuated in the presence of the selective CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3- carboxamide (AM251; 0.55 ng/side). Administration of the CB1 receptor antagonist AM251 (0.55, 5.5, or 55.5 ng/side) alone did not alter the nociceptive thresholds in either test. Bilateral microinjection of the selective CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethyl bicyclo [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528; 1 microg/side) had no effect on the antinociception produced by WIN 55,212-2, suggesting that the antinociceptive actions of WIN 55,212-2 are mediated by CB1 receptors. 4. The findings suggest the existence of a CB1-mediated inhibitory system in the BLA that, when activated, can diminish responsivity to acute and tonic noxious stimuli, but that normally has no tonic effect on the response threshold of these stimuli.

  14. Glycine and GABAA receptors mediate tonic and phasic inhibitory processes that contribute to prepulse inhibition in the goldfish startle network

    PubMed Central

    Curtin, Paul C. P.; Preuss, Thomas

    2015-01-01

    Prepulse inhibition (PPI) is understood as a sensorimotor gating process that attenuates sensory flow to the startle pathway during early stages (20–1000 ms) of information processing. Here, we applied in vivo electrophysiology and pharmacology to determine if PPI is mediated by glycine receptors (GlyRs) and/or GABAA receptors (GABAARs) in the goldfish auditory startle circuit. Specifically, we used selective antagonists to dissect the contributions of target receptors on sound-evoked postsynaptic potentials (PSPs) recorded in the neurons that initiate startle, the Mauthner-cells (M-cell). We found that strychnine, a GlyR antagonist, disrupted a fast-activated (5 ms) and rapidly (<50 ms) decaying (feed-forward) inhibitory process that contributes to PPI at 20 ms prepulse/pulse inter-stimulus intervals (ISI). Additionally we observed increases of the evoked postsynaptic potential (PSP) peak amplitude (+87.43 ± 21.53%, N = 9) and duration (+204 ± 48.91%, N = 9). In contrast, treatment with bicuculline, a GABAAR antagonist, caused a general reduction in PPI across all tested interstimulus intervals (ISIs) (20–500 ms). Bicuculline also increased PSP peak amplitude (+133.8 ± 10.3%, N = 5) and PSP duration (+284.95 ± 65.64%, N = 5). Treatment with either antagonist also tonically increased post-synaptic excitability in the M-cells, reflected by an increase in the magnitude of antidromically-evoked action potentials (APs) by 15.07 ± 3.21%, N = 7 and 16.23 ± 7.08%, N = 5 for strychnine and bicuculline, respectively. These results suggest that GABAARs and GlyRs are functionally segregated to short- and longer-lasting sound-evoked (phasic) inhibitory processes that contribute to PPI, with the mediation of tonic inhibition by both receptor systems being critical for gain control within the M-cell startle circuit. PMID:25852486

  15. Attenuation of Leishmania infantum chagasi metacyclic promastigotes by sterol depletion.

    PubMed

    Yao, Chaoqun; Gaur Dixit, Upasna; Barker, Jason H; Teesch, Lynn M; Love-Homan, Laurie; Donelson, John E; Wilson, Mary E

    2013-07-01

    The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl-beta-cyclodextrin (MβCD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. MβCD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, MβCD-treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of MβCD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that MβCD promotes the release of proteins into the extracellular medium, including both MSP and MSP-like protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins.

  16. Attenuation of Leishmania infantum chagasi Metacyclic Promastigotes by Sterol Depletion

    PubMed Central

    Gaur Dixit, Upasna; Barker, Jason H.; Teesch, Lynn M.; Love-Homan, Laurie; Donelson, John E.; Wilson, Mary E.

    2013-01-01

    The infectious metacyclic promastigotes of Leishmania protozoa establish infection in a mammalian host after they are deposited into the dermis by a sand fly vector. Several Leishmania virulence factors promote infection, including the glycosylphosphatidylinositol membrane-anchored major surface protease (MSP). Metacyclic Leishmania infantum chagasi promastigotes were treated with methyl-beta-cyclodextrin (MβCD), a sterol-chelating reagent, causing a 3-fold reduction in total cellular sterols as well as enhancing MSP release without affecting parasite viability in vitro. MβCD-treated promastigotes were more susceptible to complement-mediated lysis than untreated controls and reduced the parasite load 3-fold when inoculated into BALB/c mice. Paradoxically, MβCD-treated promastigotes caused a higher initial in vitro infection rate in human or murine macrophages than untreated controls, although their intracellular multiplication was hindered upon infection establishment. There was a corresponding larger amount of covalently bound C3b than iC3b on the parasite surfaces of MβCD-treated promastigotes exposed to healthy human serum in vitro, as well as loss of MSP, a protease that enhances C3b cleavage to iC3b. Mass spectrometry showed that MβCD promotes the release of proteins into the extracellular medium, including both MSP and MSP-like protein (MLP), from virulent metacyclic promastigotes. These data support the hypothesis that plasma membrane sterols are important for the virulence of Leishmania protozoa at least in part through retention of membrane virulence proteins. PMID:23630964

  17. Remote preoperative tonic-clonic seizures do not influence outcome after surgery for temporal lobe epilepsy.

    PubMed

    Asadi-Pooya, Ali A; Rabiei, Amin H; Gracely, Edward J; Sperling, Michael R

    2016-10-15

    Tonic-clonic seizures are associated with greater chance of seizure relapse after anterior temporal lobectomy. We investigated whether the interval between the last preoperative tonic-clonic seizure and surgery relates to seizure outcome in patients with drug-resistant mesial temporal lobe epilepsy (MTLE). In this retrospective study, patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was categorized as seizure freedom or relapse. The relationship between surgical outcome and the interval between the last preoperative tonic-clonic seizure and surgery was investigated. One-hundred seventy-one patients were studied. Seventy nine (46.2%) patients experienced tonic-clonic seizures before surgery. Receiver operating characteristic curve of timing of the last preoperative tonic-clonic seizure was a moderate indicator to anticipate surgery failure (area under the curve: 0.657, significance; 0.016). The best cutoff that maximizes sensitivity and specificity was 27months; with a sensitivity of 0.76 and specificity of 0.60. Cox-Mantel analysis confirmed that the chance of becoming free of seizures after surgery in patients with no or remote history of preoperative tonic-clonic seizures was significantly higher compared with patients with a recent history (i.e., in 27months before surgery) (p=0.0001). The more remote the occurrence of preoperative tonic-clonic seizures, the better the postsurgical seizure outcome, with at least a two year gap being more favorable. A recent history of tonic-clonic seizures in a patient with MTLE may reflect more widespread epileptogenicity extending beyond the borders of mesial temporal structures. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Depletion of Intense Fields

    NASA Astrophysics Data System (ADS)

    Seipt, D.; Heinzl, T.; Marklund, M.; Bulanov, S. S.

    2017-04-01

    The interaction of charged particles and photons with intense electromagnetic fields gives rise to multiphoton Compton and Breit-Wheeler processes. These are usually described in the framework of the external field approximation, where the electromagnetic field is assumed to have infinite energy. However, the multiphoton nature of these processes implies the absorption of a significant number of photons, which scales as the external field amplitude cubed. As a result, the interaction of a highly charged electron bunch with an intense laser pulse can lead to significant depletion of the laser pulse energy, thus rendering the external field approximation invalid. We provide relevant estimates for this depletion and find it to become important in the interaction between fields of amplitude a0˜1 03 and electron bunches with charges of the order of 10 nC.

  19. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy

    PubMed Central

    Krauss, Gregory L.; Wechsler, Robert T.; Wang, Xue-Feng; DiVentura, Bree; Brandt, Christian; Trinka, Eugen; O'Brien, Terence J.; Laurenza, Antonio; Patten, Anna; Bibbiani, Francesco

    2015-01-01

    Objective: To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE). Methods: In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel uptitrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving ≥50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored. Results: Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (−38.4% vs −76.5%; p < 0.0001) and greater 50% PGTC seizure responder rate (39.5% vs 64.2%; p = 0.0019). During maintenance, 12.3% of placebo-treated patients and 30.9% of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%). Conclusions: Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE. Classification of evidence: This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE. PMID:26296511

  20. Association between maintenance fluid tonicity and hospital-acquired hyponatremia.

    PubMed

    Carandang, Francis; Anglemyer, Andrew; Longhurst, Christopher A; Krishnan, Gomathi; Alexander, Steven R; Kahana, Madelyn; Sutherland, Scott M

    2013-12-01

    To evaluate whether the administration of hypotonic fluids compared with isotonic fluids is associated with a greater risk for hyponatremia in hospitalized children. Informatics-enabled cohort study of all hospitalizations at Lucile Packard Children's Hospital between April 2009 and March 2011. Extraction and analysis of electronic medical record data identified normonatremic hospitalized children who received either hypotonic or isotonic intravenous maintenance fluids upon admission. The primary exposure was the administration of hypotonic maintenance fluids, and the primary outcome was the development of hyponatremia (serum sodium <135 mEq/L). A total of 1048 normonatremic children received either hypotonic (n = 674) or isotonic (n = 374) maintenance fluids upon admission. Hyponatremia developed in 260 (38.6%) children who received hypotonic fluids and 104 (27.8%) of those who received isotonic fluids (unadjusted OR 1.63; 95% CI 1.24-2.15, P < .001). After we controlled for intergroup differences and potential confounders, patients receiving hypotonic fluids remained more likely to develop hyponatremia (aOR 1.37, 95% CI 1.03-1.84). Multivariable analysis identified additional factors associated with the development of hyponatremia, including surgical admission (aOR 1.44, 95% CI 1.09-1.91), cardiac admitting diagnosis (aOR 2.08, 95% CI 1.34-3.20), and hematology/oncology admitting diagnosis (aOR 2.37, 95% CI 1.74-3.25). Hyponatremia was common regardless of maintenance fluid tonicity; however, the administration of hypotonic maintenance fluids compared with isotonic fluids was associated with a greater risk of developing hospital-acquired hyponatremia. Additional clinical characteristics modified the hyponatremic effect of hypotonic fluid, and it is possible that optimal maintenance fluid therapy now requires a more individualized approach. Copyright © 2013 Mosby, Inc. All rights reserved.

  1. Osmolytes in renal medulla during rapid changes in papillary tonicity.

    PubMed

    Beck, F X; Schmolke, M; Guder, W G; Dörge, A; Thurau, K

    1992-05-01

    The effect of acute changes in extracellular tonicity on cell electrolyte concentrations at the renal papillary tip and on organic osmolytes in different kidney zones was studied using electron microprobe analysis and high-performance liquid chromatography in four groups of rats: controls, 1- or 4-h water diuresis, and 4-h water diuresis followed by 30-min deamino-[Cys1,D-Arg8]vasopressin (ddAVP). The sum of the papillary interstitial concentrations of Na, K, and Cl was reduced from 981 mmol/kg wet wt in controls to 318 mmol/kg wet wt after 4-h diuresis and increased after ddAVP to 840 mmol/kg wet wt. In papillary collecting ducts intracellular electrolytes fell from 225 to 156 mmol/kg wet wt after 4-h diuresis and rose to 268 mmol/kg wet wt (significantly higher than control) after ddAVP. Organic osmolytes [sum of glycerophosphorylcholine (GPC), betaine, myo-inositol, and sorbitol] at the papillary tip decreased from 2,018 (control) to 1,037 mmol/kg protein after 4-h diuresis and did not increase after ddAVP. After ddAVP, cell P concentration, an index of cell GPC concentration, increased, indicating cell shrinkage. GPC concentration increased, indicating cell shrinkage. The results suggest that the concentrations of all osmoeffectors in papillary cells initially increase due to cell shrinkage in response to hypertonic stress. The higher intracellular ionic strength may be a signal for modulation of transport and metabolism of organic osmolytes.

  2. Neuromyelitis optica: association with paroxysmal painful tonic spasms.

    PubMed

    Carnero Contentti, E; Leguizamón, F; Hryb, J P; Celso, J; Pace, J L Di; Ferrari, J; Knorre, E; Perassolo, M B

    2016-10-01

    Paroxysmal painful tonic spasms (PPTS) were initially described in multiple sclerosis (MS) but they are more frequent in neuromyelitis optica (NMO). The objective is to report their presence in a series of cases of NMO and NMO spectrum disorders (NMOSD), as well as to determine their frequency and clinical features. We conducted a retrospective assessment of medical histories of NMO/NMOSD patients treated in 2 hospitals in Buenos Aires (Hospital Durand and Hospital Álvarez) between 2009 and 2013. Out of 15 patients with NMOSD (7 with definite NMO and 8 with limited NMO), 4 presented PPTS (26.66%). PPTS frequency in the definite NMO group was 57.14% (4/7). Of the 9 patients with longitudinally extensive transverse myelitis (LETM), 44.44% (9/15) presented PPTS. Mean age was 35 years (range, 22-38 years) and all patients were women. Mean time between NMO diagnosis and PPTS onset was 7 months (range, 1-29 months) and mean time from last relapse of LETM was 30 days (range 23-40 days). LETM (75% cervicothoracic and 25% thoracic) was observed by magnetic resonance imaging (MRI) in all patients. Control over spasms and pain was achieved in all patients with carbamazepine (associated with gabapentin in one case). No favourable responses to pregabalin, gabapentin, or phenytoin were reported. PPTS are frequent in NMO. Mean time of PPTS onset is approximately one month after an LETM relapse, with extensive cervicothoracic lesions appearing on the MRI scan. They show an excellent response to carbamazepine but little or no response to pregabalin and gabapentin. Prospective studies with larger numbers of patients are necessary in order to confirm these results. Copyright © 2014 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Tonic signaling from O2 sensors sets neural circuit activity and behavioral state

    PubMed Central

    Busch, Karl Emanuel; Laurent, Patrick; Soltesz, Zoltan; Murphy, Robin Joseph; Faivre, Olivier; Hedwig, Berthold; Thomas, Martin; Smith, Heather L.; de Bono, Mario

    2012-01-01

    Tonic receptors convey stimulus duration and intensity and are implicated in homeostatic control. However, how tonic homeostatic signals are generated, and how they reconfigure neural circuits and modify animal behavior is poorly understood. Here we show that C. elegans O2-sensing neurons are tonic receptors that continuously signal ambient [O2] to set the animal’s behavioral state. Sustained signalling relies on a Ca2+ relay involving L-type voltage-gated Ca2+ channels, the ryanodine and the IP3 receptors. Tonic activity evokes continuous neuropeptide release, which helps elicit the enduring behavioral state associated with high [O2]. Sustained O2 receptor signalling is propagated to downstream neural circuits, including the hub interneuron RMG. O2 receptors evoke similar locomotory states at particular [O2], regardless of previous d[O2]/dt. However, a phasic component of the URX receptors’ response to high d[O2]/dt, as well as tonic-to-phasic transformations in downstream interneurons, enable transient reorientation movements shaped by d[O2]/dt. Our results highlight how tonic homeostatic signals can generate both transient and enduring behavioral change. PMID:22388961

  4. Depleted uranium management alternatives

    SciTech Connect

    Hertzler, T.J.; Nishimoto, D.D.

    1994-08-01

    This report evaluates two management alternatives for Department of Energy depleted uranium: continued storage as uranium hexafluoride, and conversion to uranium metal and fabrication to shielding for spent nuclear fuel containers. The results will be used to compare the costs with other alternatives, such as disposal. Cost estimates for the continued storage alternative are based on a life-cycle of 27 years through the year 2020. Cost estimates for the recycle alternative are based on existing conversion process costs and Capital costs for fabricating the containers. Additionally, the recycle alternative accounts for costs associated with intermediate product resale and secondary waste disposal for materials generated during the conversion process.

  5. Tank depletion flow controller

    DOEpatents

    Georgeson, Melvin A.

    1976-10-26

    A flow control system includes two bubbler tubes installed at different levels within a tank containing such as radioactive liquid. As the tank is depleted, a differential pressure transmitter monitors pressure differences imparted by the two bubbler tubes at a remote, shielded location during uniform time intervals. At the end of each uniform interval, balance pots containing a dense liquid are valved together to equalize the pressures. The resulting sawtooth-shaped signal generated by the differential pressure transmitter is compared with a second sawtooth signal representing the desired flow rate during each time interval. Variations in the two signals are employed by a control instrument to regulate flow rate.

  6. Reward prediction-related increases and decreases in tonic neuronal activity of the pedunculopontine tegmental nucleus

    PubMed Central

    Okada, Ken-ichi; Kobayashi, Yasushi

    2013-01-01

    The neuromodulators serotonin, acetylcholine, and dopamine have been proposed to play important roles in the execution of movement, control of several forms of attentional behavior, and reinforcement learning. While the response pattern of midbrain dopaminergic neurons and its specific role in reinforcement learning have been revealed, the roles of the other neuromodulators remain elusive. Reportedly, neurons in the dorsal raphe nucleus, one major source of serotonin, continually track the state of expectation of future rewards by showing a correlated response to the start of a behavioral task, reward cue presentation, and reward delivery. Here, we show that neurons in the pedunculopontine tegmental nucleus (PPTN), one major source of acetylcholine, showed similar encoding of the expectation of future rewards by a systematic increase or decrease in tonic activity. We recorded and analyzed PPTN neuronal activity in monkeys during a reward conditioned visually guided saccade task. The firing patterns of many PPTN neurons were tonically increased or decreased throughout the task period. The tonic activity pattern of neurons was correlated with their encoding of the predicted reward value; neurons exhibiting an increase or decrease in tonic activity showed higher or lower activity in the large reward-predicted trials, respectively. Tonic activity and reward-related modulation ended around the time of reward delivery. Additionally, some tonic changes in activity started prior to the appearance of the initial stimulus, and were related to the anticipatory fixational behavior. A partially overlapping population of neurons showed both the initial anticipatory response and subsequent predicted reward value-dependent activity modulation by their systematic increase or decrease of tonic activity. These bi-directional reward- and anticipatory behavior-related modulation patterns are suitable for the presumed role of the PPTN in reward processing and motivational control. PMID

  7. Selective postsynaptic inhibition of tonic-firing neurons in substantia gelatinosa by mu-opioid agonist.

    PubMed

    Santos, Sónia F A; Melnick, Igor V; Safronov, Boris V

    2004-11-01

    Spinal substantia gelatinosa (SG) is a site of action of administered and endogenous opioid agonists and is an important element in the system of antinociception. However, little is known about the types of neurons serving as specific postsynaptic targets for opioid action within the SG. To study the spinal mechanisms of opioidergic analgesia, the authors compared the action of mu-opioid agonist [D-Ala, N-Me-Phe, Gly-ol]-enkephalin (DAMGO) on SG neurons with different intrinsic firing properties. Whole cell patch clamp recordings from spinal cord slices of Wistar rats were used to study the sensitivity of SG neurons to DAMGO. Three groups of neurons with distinct distributions in SG were classified: tonic-, adapting-, and delayed-firing neurons. DAMGO at 1 microm concentration selectively hyperpolarized all tonic-firing neurons tested, whereas none of the adapting- or delayed-firing neurons were affected. The effect of DAMGO on tonic-firing neurons was due to activation of G protein-coupled inward-rectifier K conductance, which could be blocked by 500 microm Ba and 500 microm Cs but increased by 50 microm baclofen. As a functional consequence of DAMGO action, a majority of tonic-firing neurons changed their pattern of intrinsic firing from tonic to adapting. It is suggested that tonic-firing neurons, presumably functioning as excitatory interneurons, are primary postsynaptic targets for administered and endogenous opioid agonists in spinal SG. Functional transition of cells in this group from tonic to adapting firing mode may represent an important mechanism facilitating opioidergic analgesia.

  8. Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation.

    PubMed

    Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Wu, Tianxia; Hallett, Mark

    2016-04-01

    Motor surround inhibition is the neural mechanism that selectively favours the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) muscle as the target muscle, and the abductor digiti minimi, flexor carpi radialis and extensor carpi radialis muscles as surround muscles, during rest and tonic activation of the FDI muscle in 21 subjects. Cerebellar stimulation was performed under magnetic resonance imaging-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90-120% of the adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI muscle was selected for use during tonic activation. During selective tonic activation of the FDI muscle, CBI was significantly reduced only for the FDI muscle, and not for the surround muscles. Unconditioned motor evoked potential sizes were increased in all muscles during FDI muscle tonic activation as compared with rest, despite background electromyography activity increasing only for the FDI muscle. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle.

  9. Depletion of intense fields

    NASA Astrophysics Data System (ADS)

    Bulanov, S. S.; Seipt, D.; Heinzl, T.; Marklund, M.

    2017-03-01

    The problem of backreaction of quantum processes on the properties of the background field still remains on the list of outstanding questions of high intensity particle physics. Usually, photon emission by an electron or positron, photon decay into electron-positron pairs in strong electromagnetic fields, or electron-positron pair production by such fields are described in the framework of the external field approximation. It is assumed that the external field has infinite energy and is not affected by these processes. However, the above-mentioned processes have a multi-photon nature, i.e., they occur with the absorption of a significant number of field photons. As a result, the interaction of an intense electromagnetic field with either a highly charged electron bunch or a fast growing population of electrons, positrons, and gamma photons (as in the case of an electromagnetic cascade) may lead to a depletion of the field energy, thus making the external field approximation invalid. Taking the multi-photon Compton process as an example, we estimate the threshold of depletion and find it to become significant at field strengths (a0˜103) and electron bunch charge of about tens of nC.

  10. A critical firing rate associated with tonic-to-bursting transitions in synchronized gap-junction coupled neurons

    NASA Astrophysics Data System (ADS)

    Shaffer, Annabelle; Follmann, Rosangela; Harris, Allison L.; Postnova, Svetlana; Braun, Hans; Rosa, Epaminondas

    2017-06-01

    A transition between tonic and bursting neuronal behaviors is studied using a linear chain of three electrically coupled model neurons. Numerical simulations show that, depending on their individual dynamical states, the neurons first synchronize either in a tonic or in a bursting regime. Additionally, a characteristic firing rate, mediating tonic-to-bursting transitions in networked neurons, is found to be associated with a firing rate encountered in the single neuron's equivalent transition. A few cases describing this peculiar phenomenon are presented.

  11. Physiological tonicity improves human chondrogenic marker expression through nuclear factor of activated T-cells 5 in vitro.

    PubMed

    van der Windt, Anna E; Haak, Esther; Das, Ruud H J; Kops, Nicole; Welting, Tim J M; Caron, Marjolein M J; van Til, Niek P; Verhaar, Jan A N; Weinans, Harrie; Jahr, Holger

    2010-01-01

    Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype. Human articular chondrocytes were isolated and subsequently expanded at control tonicity (280 mOsm) or at moderately elevated, physiological tonicity (380 mOsm). The effects of physiological tonicity on chondrocyte proliferation and chondrogenic marker expression were evaluated. The role of Tonicity-responsive Enhancer Binding Protein in response to physiological tonicity was investigated using nuclear factor of activated T-cells 5 (NFAT5) RNA interference. Moderately elevated, physiological tonicity (380 mOsm) did not affect chondrocyte proliferation, while higher tonicities inhibited proliferation and diminished cell viability. Physiological tonicity improved expression of chondrogenic markers and NFAT5 and its target genes, while suppressing dedifferentiation marker collagen type I and improving type II/type I expression ratios >100-fold. Effects of physiological tonicity were similar in osteoarthritic and normal (nonosteoarthritic) chondrocytes, indicating a disease-independent mechanism. NFAT5 RNA interference abolished tonicity-mediated effects and revealed that NFAT5 positively regulates collagen type II expression, while suppressing type I. Physiological tonicity provides a simple, yet effective, means to improve phenotypical characteristics during cytokine-free isolation and in vitro expansion of human articular chondrocytes. Our findings will lead to the development of improved cell-based repair strategies for chondral lesions and provides important

  12. Physiological tonicity improves human chondrogenic marker expression through nuclear factor of activated T-cells 5 in vitro

    PubMed Central

    2010-01-01

    Introduction Chondrocytes experience a hypertonic environment compared with plasma (280 mOsm) due to the high fixed negative charge density of cartilage. Standard isolation of chondrocytes removes their hypertonic matrix, exposing them to nonphysiological conditions. During in vitro expansion, chondrocytes quickly lose their specialized phenotype, making them inappropriate for cell-based regenerative strategies. We aimed to elucidate the effects of tonicity during isolation and in vitro expansion on chondrocyte phenotype. Methods Human articular chondrocytes were isolated and subsequently expanded at control tonicity (280 mOsm) or at moderately elevated, physiological tonicity (380 mOsm). The effects of physiological tonicity on chondrocyte proliferation and chondrogenic marker expression were evaluated. The role of Tonicity-responsive Enhancer Binding Protein in response to physiological tonicity was investigated using nuclear factor of activated T-cells 5 (NFAT5) RNA interference. Results Moderately elevated, physiological tonicity (380 mOsm) did not affect chondrocyte proliferation, while higher tonicities inhibited proliferation and diminished cell viability. Physiological tonicity improved expression of chondrogenic markers and NFAT5 and its target genes, while suppressing dedifferentiation marker collagen type I and improving type II/type I expression ratios >100-fold. Effects of physiological tonicity were similar in osteoarthritic and normal (nonosteoarthritic) chondrocytes, indicating a disease-independent mechanism. NFAT5 RNA interference abolished tonicity-mediated effects and revealed that NFAT5 positively regulates collagen type II expression, while suppressing type I. Conclusions Physiological tonicity provides a simple, yet effective, means to improve phenotypical characteristics during cytokine-free isolation and in vitro expansion of human articular chondrocytes. Our findings will lead to the development of improved cell-based repair strategies for

  13. Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network

    PubMed Central

    Pavlov, Ivan; Savtchenko, Leonid P.; Song, Inseon; Koo, Jaeyeon; Pimashkin, Alexey; Rusakov, Dmitri A.; Semyanov, Alexey

    2014-01-01

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns. PMID:24344272

  14. Unilateral Adie's Tonic Pupil and Viral Hepatitis - Report of Two Cases.

    PubMed

    Karadžić, Jelena; Jaković, Natalija; Kovačević, Igor

    2015-01-01

    Adie's (tonic) pupil is a neuro-ophthalmological disorder characterized by a tonically dilated pupil, which is unresponsive to light. It is caused by damage to postganglionic fibers of the parasympathetic innervation of the eye, usually by a viral.or bacterial infection. Adie's syndrome includes diminished deep tendon reflexes. We report data of a 59-year-old female with unequal pupil sizes. She complained of blurred vision and headache mainly while reading. She had a 35-year history of hepatitis B and liver cirrhosis. On exam, left pupil was mydriatic and there was no response to light and at slit lamp we saw segments of the sphincter constrict. We performed 0.125% pilocarpine test and there was a remarkable reduction of size in the left pupil. The second case is a 55-year-old female who was referred to the University Eye Clinic because of a headache and mydriatic left pupil. She had diabetes mellitus type 2, as well as hepatitis A virus 20 years earlier. On exam, the left pupil was mydriatic, with no response to light. Test with diluted pilocarpine was positive. Neurological examinations revealed no abnormality in either case so we excluded Adie's syndrome. Adie's tonic pupil is benign neuro-ophthalmological disorder of unknown etiology. Most patients commonly present no symptoms and anisocoria is noticed accidentally. Although the etiology is unknown, there are some conditions that cause tonic pupil. It may be a part of a syndrome in which tonic pupil is associated with absent deep tendon reflexes.

  15. Is there tonic immobility in humans? Biological evidence from victims of traumatic stress.

    PubMed

    Volchan, Eliane; Souza, Gabriela G; Franklin, Camila M; Norte, Carlos E; Rocha-Rego, Vanessa; Oliveira, Jose M; David, Isabel A; Mendlowicz, Mauro V; Coutinho, Evandro Silva Freire; Fiszman, Adriana; Berger, William; Marques-Portella, Carla; Figueira, Ivan

    2011-09-01

    Tonic immobility, characterized by profound motor inhibition, is elicited under inescapable threat in many species. To fully support the existence of tonic immobility in humans, our aim was to elicit this reaction in a laboratory setting and measure it objectively. To mimic exposure to life-threatening events in the lab, trauma-exposed participants with PTSD (n=18) and without PTSD (n=15) listened to the script of their autobiographical trauma. Posturography and electrocardiography were employed. Reports of script-induced immobility were associated with restricted area of body sway and were correlated with accelerated heart rate and diminished heart rate variability, implying that tonic immobility is preserved in humans as an involuntary defensive strategy. Immobility reports seemed more evident in PTSD, suggesting that, in some patients, tonic immobility may be elicited during re-experiencing episodes in daily life. This study provided a measure of tonic immobility, a peritraumatic reaction for which cumulative clinical evidence had linked to the severity of PTSD.

  16. The effect of varying tonicity on nasal epithelial ion transport in cystic fibrosis.

    PubMed

    Davies, Michael G; Geddes, Duncan M; Alton, Eric W F W

    2005-04-01

    There is reasonable evidence that the fluid layer of the airway epithelium is exposed to changes in tonicity. The inspiration of cool, dry air causes an increased tonicity, whereas this tonicity may be decreased by glandular secretions. We hypothesized that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the responses to changes in tonicity and that these may be altered in cystic fibrosis (CF). Using nasal potential difference (PD) protocols in 8 subjects with CF and 10 subjects without CF, we investigated the effects of hyper- and hypotonicity on ion transport processes. We found significant differences between the two groups. In response to a hypertonic challenge (mannitol 500 mM), there was a decreased PD in both groups, suggesting decreased sodium absorption. However, after the prior inhibition of sodium transport using amiloride, there was an increased PD in the non-CF group alone, suggesting CFTR-mediated chloride secretion in response to luminal hypertonicity. For the hypotonic solution, we found that hypotonicity inhibited CFTR-mediated chloride secretion in the non-CF group. These data suggest that CFTR plays a role in the recognition and regulation of airway fluid tonicity.

  17. Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network.

    PubMed

    Pavlov, Ivan; Savtchenko, Leonid P; Song, Inseon; Koo, Jaeyeon; Pimashkin, Alexey; Rusakov, Dmitri A; Semyanov, Alexey

    2014-01-07

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns.

  18. Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons.

    PubMed

    Mann, Edward O; Mody, Istvan

    2010-02-01

    Gamma-frequency oscillations depend on phasic synaptic GABA(A) receptor (GABA(A)R)-mediated inhibition to synchronize spike timing. The spillover of synaptically released GABA can also activate extrasynaptic GABA(A)Rs, and such tonic inhibition may also contribute to modulating network dynamics. In many neuronal cell types, tonic inhibition is mediated by delta subunit-containing GABA(A)Rs. We found that the frequency of in vitro cholinergically induced gamma oscillations in the mouse hippocampal CA3 region was increased by the activation of NMDA receptors (NMDARs) on interneurons. The NMDAR-dependent increase of gamma oscillation frequency was counteracted by the tonic inhibition of the interneurons mediated by delta subunit-containing GABA(A)Rs. Recordings of synaptic currents during gamma activity revealed that NMDAR-mediated increases in oscillation frequency correlated with a progressive synchronization of phasic excitation and inhibition in the network. Thus, the balance between tonic excitation and tonic inhibition of interneurons may modulate gamma frequency by shaping interneuronal synchronization.

  19. Emerging principles and neural substrates underlying tonic sleep-state-dependent influences on respiratory motor activity.

    PubMed

    Horner, Richard L

    2009-09-12

    Respiratory muscles with dual respiratory and non-respiratory functions (e.g. the pharyngeal and intercostal muscles) show greater suppression of activity in sleep than the diaphragm, a muscle almost entirely devoted to respiratory function. This sleep-related suppression of activity is most apparent in the tonic component of motor activity, which has functional implications of a more collapsible upper airspace in the case of pharyngeal muscles, and decreased functional residual capacity in the case of intercostal muscles. A major source of tonic drive to respiratory motoneurons originates from neurons intimately involved in states of brain arousal, i.e. neurons not classically involved in generating respiratory rhythm and pattern per se. The tonic drive to hypoglossal motoneurons, a respiratory motor pool with both respiratory and non-respiratory functions, is mediated principally by noradrenergic and glutamatergic inputs, these constituting the essential components of the wakefulness stimulus. These tonic excitatory drives are opposed by tonic inhibitory glycinergic and gamma-amino butyric acid (GABA) inputs that constrain the level of respiratory-related motor activity, with the balance determining net motor tone. In sleep, the excitatory inputs are withdrawn and GABA release into the brainstem is increased, thus decreasing respiratory motor tone and predisposing susceptible individuals to hypoventilation and obstructive sleep apnoea.

  20. Stimulated Emission Depletion Microscopy.

    PubMed

    Blom, Hans; Widengren, Jerker

    2017-06-14

    Despite its short history, diffraction-unlimited fluorescence microscopy techniques have already made a substantial imprint in the biological sciences. In this review, we describe how stimulated emission depletion (STED) imaging originally evolved, how it compares to other optical super-resolution imaging techniques, and what advantages it provides compared to previous golden-standards for biological microscopy, such as diffraction-limited optical microscopy and electron microscopy. We outline the prerequisites for successful STED imaging experiments, emphasizing the equally critical roles of instrumentation, sample preparation, and photophysics, and describe major evolving strategies for how to push the borders of STED imaging even further in life science. Finally, we provide examples of how STED nanoscopy can be applied, within three different fields with particular potential for STED imaging experiments: neuroscience, plasma membrane biophysics, and subcellular clinical diagnostics. In these areas, and in many more, STED imaging can be expected to play an increasingly important role in the future.

  1. Ozone Depletion by Hydrofluorocarbons

    NASA Astrophysics Data System (ADS)

    Hurwitz, M.; Fleming, E. L.; Newman, P. A.; Li, F.; Mlawer, E. J.; Cady-Pereira, K. E.; Bailey, R.

    2015-12-01

    Hydrofluorocarbons (HFCs) are second-generation replacements for the chlorofluorocarbons (CFCs), halons and other substances that caused the 'ozone hole'. Atmospheric concentrations of HFCs are projected to increase dramatically in the coming decades. Coupled chemistry-climate simulations forced by these projections show that HFCs will impact the global atmosphere in 2050. As strong radiative forcers, HFCs modulate atmospheric temperature, thereby changing ozone-destroying catalytic cycles and enhancing the stratospheric circulation. These changes lead to a weak depletion of stratospheric ozone. Sensitivity simulations with the NASA Goddard Space Flight Center (GSFC) 2D model show that HFC-125 is the most important contributor to atmospheric change in 2050, as compared with HFC-23, HFC-32, HFC-134a and HFC-143a. Incorporating the interactions between chemistry, radiation and dynamics, for a likely 2050 climate, ozone depletion potentials (ODPs) for HFCs range from 4.3x10-4 to 3.5x10-2; previously HFCs were assumed to have negligible ODPs since these species lack chlorine or bromine atoms. The ozone impacts of HFCs are further investigated with the Goddard Earth Observing System Chemistry-Climate Model (GEOSCCM). The GEOSCCM is a three-dimensional, fully coupled ocean-atmosphere model with interactive stratospheric chemistry. Sensitivity simulations in which CO2, CFC-11 and HCFC-22 are enhanced individually are used as proxies for the atmospheric response to the HFC concentrations expected by the mid-21st century. Sensitivity simulations provide quantitative estimates of the impacts of these greenhouse gases on global total ozone, and can be used to assess their effects on the recovery of Antarctic ozone.

  2. Insulation for Daydreams: A Role for Tonic Norepinephrine in the Facilitation of Internally Guided Thought

    PubMed Central

    Smallwood, Jonathan; Brown, Kevin S.; Baird, Benjamin; Mrazek, Michael D.; Franklin, Michael S.; Schooler, Jonathan W.

    2012-01-01

    Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment. PMID:22493672

  3. (R)-roscovitine, a cyclin-dependent kinase inhibitor, enhances tonic GABA inhibition in rat hippocampus.

    PubMed

    Ivanov, A; Tyzio, R; Zilberter, Y; Ben-Ari, Yehezkel

    2008-10-02

    Pharmacological agents that mediate a persistent GABAergic conductance are of considerable interest for treatment of epilepsy. (R)-roscovitine is a membrane permeable cyclin-dependent kinase inhibitor, designed to block cell division. It is currently undergoing a phase II clinical trial as an anticancer drug. We show that (R)-roscovitine increases a tonic GABA-mediated current in rat hippocampal neurons. This enhanced tonic current appears independent of synaptic GABA release and requires functional transmembrane GABA transport. The effect of (R)-roscovitine is associated with neither modification of GABAA receptors nor protein kinase activity, but is associated with a significant increase in intracellular GABA concentration in hippocampal GABAergic neurons. (R)-roscovitine-induced tonic inhibition significantly suppresses spontaneous spiking activity of hippocampal pyramidal cells. Therefore, (R)-roscovitine is a potent modulator of neuronal activity in rat hippocampus and may provide a tool for preventing paroxysmal activity.

  4. Insulation for daydreams: a role for tonic norepinephrine in the facilitation of internally guided thought.

    PubMed

    Smallwood, Jonathan; Brown, Kevin S; Baird, Benjamin; Mrazek, Michael D; Franklin, Michael S; Schooler, Jonathan W

    2012-01-01

    Although consciousness can be brought to bear on both perceptual and internally generated information, little is known about how these different cognitive modes are coordinated. Here we show that between-participant variance in thoughts unrelated to the task being performed (known as task unrelated thought, TUT) is associated with longer response times (RT) when target presentation occurs during periods when baseline Pupil Diameter (PD) is increased. As behavioral interference due to high baseline PD can reflect increased tonic activity in the norepinephrine system (NE), these results might implicate high tonic NE activity in the facilitation of TUTs. Based on these findings, it is hypothesised that high tonic mode NE leads to a generalised de-amplification of task relevant information that prioritses internally generated thought and insulates it from the potentially disruptive events taking place in the external environment.

  5. The Immune Effects of an African Traditional Energy Tonic in In Vitro and In Vivo Models.

    PubMed

    Ngcobo, Mlungisi; Gqaleni, Nceba; Naidoo, Vinny; Cele, Protus

    2017-01-01

    Most of the African traditional medicines (ATM) are formulated as energy tonics to boost and maintain immune defences. In this study, we aimed to evaluate the immune effects of a traditional energy tonic using peripheral blood mononuclear cells (PBMCs), THP-1 monocytes, and bacteria infected rats. When tested in mitogen and peptidoglycan stimulated PBMCs, this energy tonic showed minimal cytotoxicity, while in acute toxicity studies in rats it did not exhibit any significant toxicity at doses up to 2000 mg/mL/kg. The energy tonic doses between 100 and 10 μg/mL were shown to stimulate secretion of cytokines and increase sIL-2R levels in PHA-treated PBMCs. Similar doses in PG-S. aureus-stimulated PBMCs significantly (p < 0.05) increased IL-1α, IL-2, and GM-CSF while causing a significant (p < 0.05) decrease in sIL-2R levels. NF-κβ transcriptional activity was increased in LPS stimulated THP-1 cells. In Sprague Dawley rats pretreated with the energy tonic and then infected with S. aureus, there were insignificant increases in cytokines and sIL-2R when compared to bacteria infected only and 5% Enrofloxacin treated rats. Posttreatment with energy tonic doses after infection with S. aureus did not enhance inflammatory cytokines significantly but changed the immune response profile and decreased corticosterone levels. This ATM showed promising immunomodulatory effects on isolated immune cells and modulated the immune response of rat models infected with S. aureus.

  6. Tonic B-cell receptor signaling in diffuse large B-cell lymphoma.

    PubMed

    Havranek, Ondrej; Xu, Jingda; Köhrer, Stefan; Wang, Zhiqiang; Becker, Lisa; Comer, Justin M; Henderson, Jared; Ma, Wencai; Man Chun Ma, John; Westin, Jason R; Ghosh, Dipanjan; Shinners, Nicholas; Sun, Luhong; Yi, Allen F; Karri, Anusha R; Burger, Jan A; Zal, Tomasz; Davis, R Eric

    2017-08-24

    We used clustered regularly interspaced short palindromic repeats/Cas9-mediated genomic modification to investigate B-cell receptor (BCR) signaling in cell lines of diffuse large B-cell lymphoma (DLBCL). Three manipulations that altered BCR genes without affecting surface BCR levels showed that BCR signaling differs between the germinal center B-cell (GCB) subtype, which is insensitive to Bruton tyrosine kinase inhibition by ibrutinib, and the activated B-cell (ABC) subtype. Replacing antigen-binding BCR regions had no effect on BCR signaling in GCB-DLBCL lines, reflecting this subtype's exclusive use of tonic BCR signaling. Conversely, Y188F mutation in the immunoreceptor tyrosine-based activation motif of CD79A inhibited tonic BCR signaling in GCB-DLBCL lines but did not affect their calcium flux after BCR cross-linking or the proliferation of otherwise-unmodified ABC-DLBCL lines. CD79A-GFP fusion showed BCR clustering or diffuse distribution, respectively, in lines of ABC and GCB subtypes. Tonic BCR signaling acts principally to activate AKT, and forced activation of AKT rescued GCB-DLBCL lines from knockout (KO) of the BCR or 2 mediators of tonic BCR signaling, SYK and CD19. The magnitude and importance of tonic BCR signaling to proliferation and size of GCB-DLBCL lines, shown by the effect of BCR KO, was highly variable; in contrast, pan-AKT KO was uniformly toxic. This discrepancy was explained by finding that BCR KO-induced changes in AKT activity (measured by gene expression, CXCR4 level, and a fluorescent reporter) correlated with changes in proliferation and with baseline BCR surface density. PTEN protein expression and BCR surface density may influence clinical response to therapeutic inhibition of tonic BCR signaling in DLBCL. © 2017 by The American Society of Hematology.

  7. The Immune Effects of an African Traditional Energy Tonic in In Vitro and In Vivo Models

    PubMed Central

    Ngcobo, Mlungisi; Naidoo, Vinny; Cele, Protus

    2017-01-01

    Most of the African traditional medicines (ATM) are formulated as energy tonics to boost and maintain immune defences. In this study, we aimed to evaluate the immune effects of a traditional energy tonic using peripheral blood mononuclear cells (PBMCs), THP-1 monocytes, and bacteria infected rats. When tested in mitogen and peptidoglycan stimulated PBMCs, this energy tonic showed minimal cytotoxicity, while in acute toxicity studies in rats it did not exhibit any significant toxicity at doses up to 2000 mg/mL/kg. The energy tonic doses between 100 and 10 μg/mL were shown to stimulate secretion of cytokines and increase sIL-2R levels in PHA-treated PBMCs. Similar doses in PG-S. aureus-stimulated PBMCs significantly (p < 0.05) increased IL-1α, IL-2, and GM-CSF while causing a significant (p < 0.05) decrease in sIL-2R levels. NF-κβ transcriptional activity was increased in LPS stimulated THP-1 cells. In Sprague Dawley rats pretreated with the energy tonic and then infected with S. aureus, there were insignificant increases in cytokines and sIL-2R when compared to bacteria infected only and 5% Enrofloxacin treated rats. Posttreatment with energy tonic doses after infection with S. aureus did not enhance inflammatory cytokines significantly but changed the immune response profile and decreased corticosterone levels. This ATM showed promising immunomodulatory effects on isolated immune cells and modulated the immune response of rat models infected with S. aureus. PMID:28408939

  8. The relation between tonicity and impulse-evoked transmitter release in the frog

    PubMed Central

    Kita, Hiroshi; Narita, Kazuhiko; van der Kloot, William

    1982-01-01

    1. The increase in miniature end-plate potential (m.e.p.p.) frequency in response to tetanic stimulation of the motor nerve at frog neuromuscular junctions in Ca2+-free, Mg2+ EGTA-containing (0 Ca2+—Mg2+ EGTA) solutions of varying tonicity has been studied. The response to stimulation is markedly increased in hypertonic solutions and is decreased in hypotonic solutions. Under these conditions changes in tonicity have comparable effects on stimulated and spontaneous quantal release. 2. The tonicity was raised by adding sucrose, NaCl or glycine to the extracellular solution. The effects of the addition depended primarily on the increase in osmolarity of the solution, not on the chemical species producing it. 3. The tonicity was decreased by lowering [NaCl]o. The hypotonic solution decreased the response to tetanic stimulation. When the tonicity of the solution with the low [NaCl]o was restored to normal by adding sucrose, the response was restored to its usual level. These results suggest that in 0 Ca2+—Mg2+ EGTA solutions stimulation does not enhance the probability of quantal release by raising [Na+]i. 4. Repeated bouts of tetanic stimulation produced almost identical responses. In some instances the frequency continued to rise after the end of the tetanic stimulation, as reported by Erulkar & Rahamimoff (1978). This suggests that the stimulation of the nerve leads to the elevation within the terminal of a substance that in turn liberates an activator for quantal release. 5. The Q10 for the increase in probability of quantal release is as high as 7. High Q10 values have also been reported for spontaneous m.e.p.p. frequencies. Tonicity and temperature appear to affect spontaneous and stimulated quantal release similarly. PMID:6286938

  9. Effective water clearance and tonicity balance: the excretion of water revisited.

    PubMed

    Mallie, J P; Bichet, D G; Halperin, M L

    1997-02-01

    To demonstrate (1) that hyponatremia is usually due to an inappropriately low rate of excretion of electrolyte-free water and (2) that the measure "effective water clearance" (EWC) provides better information about renal defence of the body tonicity than does the classic measure free-water clearance, and to provide the rationale for calculating a "tonicity balance," which involves using water and sodium plus potassium intakes and their renal excretion to reveal the basis for changes in body tonicity. Prospective study. Four normal subjects with no conditions affecting excretion, 10 patients with advanced congestive heart failure (CHF) and 5 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Normals and patients were administered a standard water load (20 mL per kg of body weight) during 45 minutes, and blood and urine samples were taken before, during and after the load was given. Urine and blood sodium and potassium concentrations, osmolar clearance, free-water clearance, electrolyte clearance and EWC. The water load was excreted rapidly by normals, more slowly by patients with CHF, and not at all by patients with SIADH. The EWC was positive in normals and those with CHF, but negative in those with SIADH. In patients with CHF, the EWC, but not the free-water clearance, helped explain why hyponatremia was corrected after the water load was given. In subjects with abnormal water excretion, the EWC provides the physiologic explanation for the renal role in variations in natremia. The authors propose a bedside evaluation of renal water and electrolyte handling that takes into consideration the role of urinary potassium in body tonicity. Changes in body tonicity can be explained by a "tonicity balance," a calculation in which the source and the net balance of sodium, potassium and water are considered.

  10. Protein kinase C regulates tonic GABAA receptor-mediated inhibition in the hippocampus and thalamus

    PubMed Central

    Bright, Damian P; Smart, Trevor G

    2013-01-01

    Tonic inhibition mediated by extrasynaptic GABAA receptors (GABAARs) is an important regulator of neuronal excitability. Phosphorylation by protein kinase C (PKC) provides a key mode of regulation for synaptic GABAARs underlying phasic inhibition; however, less attention has been focused on the plasticity of tonic inhibition and whether this can also be modulated by receptor phosphorylation. To address this issue, we used whole-cell patch clamp recording in acute murine brain slices at both room and physiological temperatures to examine the effects of PKC-mediated phosphorylation on tonic inhibition. Recordings from dentate gyrus granule cells in the hippocampus and dorsal lateral geniculate relay neurons in the thalamus demonstrated that PKC activation caused downregulation of tonic GABAAR-mediated inhibition. Conversely, inhibition of PKC resulted in an increase in tonic GABAAR activity. These findings were corroborated by experiments on human embryonic kidney 293 cells expressing recombinant α4β2δ GABAARs, which represent a key extrasynaptic GABAAR isoform in the hippocampus and thalamus. Using bath application of low GABA concentrations to mimic activation by ambient neurotransmitter, we demonstrated a similar inhibition of receptor function following PKC activation at physiological temperature. Live cell imaging revealed that this was correlated with a loss of cell surface GABAARs. The inhibitory effects of PKC activation on α4β2δ GABAAR activity appeared to be mediated by direct phosphorylation at a previously identified site on the β2 subunit, serine 410. These results indicate that PKC-mediated phosphorylation can be an important physiological regulator of tonic GABAAR-mediated inhibition. PMID:24102973

  11. Tonic Pupil, a Paraneoplastic Neuro-Ophtalmological Disease Associated with Occult Breast Cancer.

    PubMed

    Peyman, Alireza; Kabiri, Majid; Peyman, Mohammadreza

    2015-01-01

    Here, we present a case of tonic pupil associated with occult breast cancer as a paraneoplastic neuro-ophthalmology syndrome. A 45-year-old woman developed progressive photophobia and blurred vision due to unilateral Adie's tonic pupil. Magnetic resonance image of her brain and neurological examination (including deep tendon reflexes) were normal at first visit. Follow-up examinations performed by ophthalmologist every 6 month without any change in her condition. After 2 years, patient discovered a mass in her breast which identified to be malignant after diagnostic procedures. Despite surgical and medical treatment for cancer, no change in the ocular condition was happened.

  12. Rottlerin inhibits tonicity-dependent expression and action of TonEBP in a PKCdelta-independent fashion.

    PubMed

    Zhao, Hongyu; Tian, Wei; Cohen, David M

    2002-04-01

    Novel protein kinase C (PKC) isoforms PKCdelta and PKCepsilon have recently been implicated in signaling by hypertonic stress. We investigated the role of the putative PKCdelta inhibitor rottlerin on tonicity-dependent gene regulation. In the renal medullary mIMCD3 cell line, rottlerin blocked tonicity-dependent transcription of a tonicity enhancer (TonE)-driven luciferase reporter gene, as well as tonicity-dependent transcription of the physiological tonicity effector gene aldose reductase, but not urea-dependent transcription. Consistent with these data, rottlerin inhibited tonicity-dependent expression of TonE binding protein (TonEBP) at the mRNA and protein levels. Another inhibitor of both novel and conventional PKC isoforms, GF-109203X, suppressed TonEBP-dependent transcription but failed to influence tonicity-inducible TonEBP expression. Global PKC downregulation with protracted phorbol ester treatment, however, failed to influence tonicity-dependent signaling, arguing against a PKCdelta-dependent mechanism of rottlerin action in this model. In addition, hypertonic stress failed to induce phosphorylation of PKCdelta. Furthermore, in a PC-12 cell model with a comparable degree of tonicity-dependent transcription, constitutive overexpression of dominant negative-acting PKCdelta or PKCepsilon effectively decreased tonicity signaling to extracellular signal-regulated kinase activation, as expected, but failed to influence TonE-dependent transcription. TonE-dependent transcription, however, remained rottlerin sensitive in this PC-12 cell model. In the aggregate, these data indicate that rottlerin dramatically inhibits tonicity-dependent TonEBP expression and TonE-dependent transcription but, despite its reputed mode of action, does so through a PKCdelta-independent pathway.

  13. Ozone Depletion and Biologically Relevant Ultraviolet Radiation.

    NASA Astrophysics Data System (ADS)

    Zeng, Jun

    1995-01-01

    early spring, when ozone depletion is expected to be the most severe. The sensitivities of irradiance reflectance and diffuse attenuation coefficients to solar zenith angle, sky conditions, and chlorophyll concentration are discussed by using a coupled atmosphere-ocean radiative transfer model. The irradiance reflectance is sensitive to solar zenith angle, cloud cover, and chlorophyll concentration; the diffuse attenuation coefficient is sensitive to solar zenith angle and chlorophyll concentration, but less sensitive to sky conditions.

  14. 12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    12. VIEW OF DEPLETED URANIUM INGOT AND MOLDS. DEPLETED URANIUM CASTING OPERATIONS CEASED IN 1988. (11/14/57) - Rocky Flats Plant, Non-Nuclear Production Facility, South of Cottonwood Avenue, west of Seventh Avenue & east of Building 460, Golden, Jefferson County, CO

  15. Depleted Uranium in Repositories

    SciTech Connect

    Haire, M.J.; Croff, A.G.

    1997-12-31

    For uranium to be useful in most fission nuclear reactors, it must be enriched (i.e. the concentration of the fissile isotope 235U must be increased). Therefore, depleted uranium (DU)-uranium which has less than naturally occurring concentrations of 235U-is a co-product of the enrichment process. Four to six tons of DU exist for every ton of fresh light water reactor fuel. There were 407,006 MgU 407,000 metric tons (t) of DU stored on U.S. Department of Energy (DOE) sites as of July 1993. If this DU were to be declared surplus, converted to a stable oxide form, and emplaced in a near surface disposal facility, the costs are estimated to be several billion dollars. However, the U.S. Nuclear Regulatory Commission has stated that near surface disposal of large quantities of DU tails is not appropriate. Thus, there is the possibility that disposition via disposal will be in a deep geological repository. One alternative that may significantly reduce the cost of DU disposition is to use it beneficially. In fact, DOE has begun the Beneficial Uses of DU Project to identify large scale uses of DU and to encourage its reuse. Several beneficial uses, many of which involve applications in the repository per se or in managing the wastes to go into the repository, are discussed in this report.

  16. The Toxicity of Depleted Uranium

    PubMed Central

    Briner, Wayne

    2010-01-01

    Depleted uranium (DU) is an emerging environmental pollutant that is introduced into the environment primarily by military activity. While depleted uranium is less radioactive than natural uranium, it still retains all the chemical toxicity associated with the original element. In large doses the kidney is the target organ for the acute chemical toxicity of this metal, producing potentially lethal tubular necrosis. In contrast, chronic low dose exposure to depleted uranium may not produce a clear and defined set of symptoms. Chronic low-dose, or subacute, exposure to depleted uranium alters the appearance of milestones in developing organisms. Adult animals that were exposed to depleted uranium during development display persistent alterations in behavior, even after cessation of depleted uranium exposure. Adult animals exposed to depleted uranium demonstrate altered behaviors and a variety of alterations to brain chemistry. Despite its reduced level of radioactivity evidence continues to accumulate that depleted uranium, if ingested, may pose a radiologic hazard. The current state of knowledge concerning DU is discussed. PMID:20195447

  17. Ego depletion impairs implicit learning.

    PubMed

    Thompson, Kelsey R; Sanchez, Daniel J; Wesley, Abigail H; Reber, Paul J

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent.

  18. Missionaries and Tonic Sol-fa Music Pedagogy in 19th-Century China

    ERIC Educational Resources Information Center

    Southcott, Jane E.; Lee, Angela Hao-Chun

    2008-01-01

    In the 19th century, Christian missionaries in China, as elsewhere, used the Tonic Sol-fa method of music instruction to aid their evangelizing. This system was designed to improve congregational singing in churches, Sunday schools and missions. The London Missionary Society and other evangelical groups employed the method. These missionaries took…

  19. Selective reinnervation of twitch and tonic muscle fibres of the frog.

    PubMed Central

    Elizalde, A; Huerta, M; Stefani, E

    1983-01-01

    The electrical properties and innervation of piriformis muscle fibres and the conduction velocities and thresholds of the corresponding motor axons were studied. In normal muscles all fibres clearly fell into the category of twitch or tonic. Tonic muscle fibres were selectively reinnervated by small motor axons after crushing or cutting the piriformis nerve. Twitch fibres were reinnervated by large motor axons. Tonic fibres were also selectively reinnervated by small motor axons when the proximal stump of the piriformis nerve was cut and attached to the caudal end of the muscle. With this procedure the possibility of mechanical guidance by remaining neural sheaths was eliminated. Polyneuronal innervation in twitch fibres in piriformis muscles of normal frogs was 4.7% and in contralateral muscles of operated frogs with the piriformis nerve cut it was 22.6%. Unexpectedly three out of seventeen tonic fibres in contralateral muscles were simultaneously innervated by both small and large motor axons. It is concluded that reinnervation is highly specific for fibre type in frog skeletal muscles. PMID:6604153

  20. Estimates of mouse oviductal fluid tonicity based on osmotic responses of embryos.

    PubMed

    Collins, J L; Baltz, J M

    1999-05-01

    Zygotes and early cleavage-stage embryos are very sensitive to increased osmolality in vitro, although the tonicity of their in vivo environment, oviductal fluid, is unknown. A preference for low osmolality in vitro might imply similar conditions in vivo or be specific to culture. Previous electron probe x-ray microanalysis measurements of total ion content predicted oviductal fluid osmolalities of 310-360 mOs/kg, higher than osmolalities tolerated by mouse zygotes in vitro. However, such indirect estimates may not reflect the tonicity experienced by embryos. We have now used embryos themselves as osmosensors to determine the tonicity of mouse oviductal fluid. In one method, we measured the mean volume of zygotes in undiluted oviductal fluid and compared this to the mean volumes measured for zygotes in media spanning a range of osmolalities. The osmolality corresponding to the measured mean volume in oviductal fluid was taken to be isotonic. In another, independent method, the sizes of zygotes and two-cell embryos were measured as a function of time beginning immediately after removal from oviducts. The osmolality in which the embryos neither swelled nor shrank was taken to be isotonic. Both methods yielded approximately the same range for the tonicity of oviductal fluid: around 290-300 mOs/kg.

  1. Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5).

    PubMed

    Halterman, Julia A; Kwon, H Moo; Wamhoff, Brian R

    2012-01-01

    Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by tonicity, but that it can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease.

  2. Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5)

    PubMed Central

    Halterman, Julia A.; Kwon, H. Moo

    2012-01-01

    Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by tonicity, but that it can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease. PMID:21998140

  3. The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

    PubMed

    Maia, Tiago V; Conceição, Vasco A

    2017-09-15

    Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Tonic Firing Rate Controls Dendritic Ca2+ Signaling and Synaptic Gain in Substantia Nigra Dopamine Neurons

    PubMed Central

    Hage, Travis A.

    2015-01-01

    Substantia nigra dopamine neurons fire tonically resulting in action potential backpropagation and dendritic Ca2+ influx. Using Ca2+ imaging in acute mouse brain slices, we find a surprisingly steep relationship between tonic firing rate and dendritic Ca2+. Increasing the tonic rate from 1 to 6 Hz generated Ca2+ signals up to fivefold greater than predicted by linear summation of single spike-evoked Ca2+-transients. This “Ca2+ supralinearity” was produced largely by depolarization of the interspike voltage leading to activation of subthreshold Ca2+ channels and was present throughout the proximal and distal dendrites. Two-photon glutamate uncaging experiments show somatic depolarization enhances NMDA receptor-mediated Ca2+ signals >400 μm distal to the soma, due to unusually tight electrotonic coupling of the soma to distal dendrites. Consequently, we find that fast tonic firing intensifies synaptically driven burst firing output in dopamine neurons. These results show that modulation of background firing rate precisely tunes dendritic Ca2+ signaling and provides a simple yet powerful mechanism to dynamically regulate the gain of synaptic input. PMID:25855191

  5. Tonic and phasic drive to medullary respiratory neurons during periodic breathing

    PubMed Central

    Lovering, Andrew T.; Fraigne, Jimmy J.; Dunin-Barkowski, Witali L.; Vidruk, Edward H.; Orem, John M.

    2012-01-01

    It is unknown how central neural activity produces the repetitive termination and restart of periodic breathing (PB). We hypothesized that inspiratory and expiratory neural activities would be greatest during the waxing phase and least during the waning phase. We analyzed diaphragmatic and medullary respiratory neural activities during PB in intact unanesthetized adult cats. Diaphragmatic activity was increased and phasic during the waxing phase and was decreased and tonic during the waning phase. Activity of expiratory (n=21) and inspiratory (n=40) neurons was generally increased and phasic during the waxing phase and was decreased and more tonic during the waning phase. During apneas associated with PB, diaphragmatic activity was silent and most, but not all, inspiratory cells were inactive whereas most expiratory cells decreased activity but remained tonically active. We suggest that reduced strength of reciprocal inhibition, secondary to reduced respiratory drive, allows for simultaneous tonic activity of inspiratory and expiratory neurons of the central pattern generator, ultimately resulting in central apnea. PMID:22484379

  6. Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors.

    PubMed

    Mikhailova, Maria A; Bass, Caroline E; Grinevich, Valentina P; Chappell, Ann M; Deal, Alex L; Bonin, Keith D; Weiner, Jeff L; Gainetdinov, Raul R; Budygin, Evgeny A

    2016-10-01

    Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Tonic Immobility in Childhood Sexual Abuse Survivors and Its Relationship to Posttraumatic Stress Symptomatology

    ERIC Educational Resources Information Center

    Humphreys, Kathryn L.; Sauder, Colin L.; Martin, Elaine K.; Marx, Brian P.

    2010-01-01

    Past research has shown that 37% to 52% of sexual assault survivors report experiencing a set of peritraumatic responses, which include gross motor inhibition, analgesia, and fixed or unfocused staring. This response set closely resembles a set of unconditioned responses, collectively known as Tonic Immobility (TI). This study examined TI among…

  8. Tonic Immobility in Childhood Sexual Abuse Survivors and Its Relationship to Posttraumatic Stress Symptomatology

    ERIC Educational Resources Information Center

    Humphreys, Kathryn L.; Sauder, Colin L.; Martin, Elaine K.; Marx, Brian P.

    2010-01-01

    Past research has shown that 37% to 52% of sexual assault survivors report experiencing a set of peritraumatic responses, which include gross motor inhibition, analgesia, and fixed or unfocused staring. This response set closely resembles a set of unconditioned responses, collectively known as Tonic Immobility (TI). This study examined TI among…

  9. Missionaries and Tonic Sol-fa Music Pedagogy in 19th-Century China

    ERIC Educational Resources Information Center

    Southcott, Jane E.; Lee, Angela Hao-Chun

    2008-01-01

    In the 19th century, Christian missionaries in China, as elsewhere, used the Tonic Sol-fa method of music instruction to aid their evangelizing. This system was designed to improve congregational singing in churches, Sunday schools and missions. The London Missionary Society and other evangelical groups employed the method. These missionaries took…

  10. Stratospheric ozone depletion.

    PubMed

    Rowland, F Sherwood

    2006-05-29

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290-320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime-the 'Antarctic ozone hole'. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules.

  11. Stratospheric ozone depletion

    PubMed Central

    Rowland, F. Sherwood

    2006-01-01

    Solar ultraviolet radiation creates an ozone layer in the atmosphere which in turn completely absorbs the most energetic fraction of this radiation. This process both warms the air, creating the stratosphere between 15 and 50 km altitude, and protects the biological activities at the Earth's surface from this damaging radiation. In the last half-century, the chemical mechanisms operating within the ozone layer have been shown to include very efficient catalytic chain reactions involving the chemical species HO, HO2, NO, NO2, Cl and ClO. The NOX and ClOX chains involve the emission at Earth's surface of stable molecules in very low concentration (N2O, CCl2F2, CCl3F, etc.) which wander in the atmosphere for as long as a century before absorbing ultraviolet radiation and decomposing to create NO and Cl in the middle of the stratospheric ozone layer. The growing emissions of synthetic chlorofluorocarbon molecules cause a significant diminution in the ozone content of the stratosphere, with the result that more solar ultraviolet-B radiation (290–320 nm wavelength) reaches the surface. This ozone loss occurs in the temperate zone latitudes in all seasons, and especially drastically since the early 1980s in the south polar springtime—the ‘Antarctic ozone hole’. The chemical reactions causing this ozone depletion are primarily based on atomic Cl and ClO, the product of its reaction with ozone. The further manufacture of chlorofluorocarbons has been banned by the 1992 revisions of the 1987 Montreal Protocol of the United Nations. Atmospheric measurements have confirmed that the Protocol has been very successful in reducing further emissions of these molecules. Recovery of the stratosphere to the ozone conditions of the 1950s will occur slowly over the rest of the twenty-first century because of the long lifetime of the precursor molecules. PMID:16627294

  12. Tonic pain evoked by pulsating heat: temporal summation mechanisms and perceptual qualities.

    PubMed

    Lautenbacher, S; Roscher, S; Strian, F

    1995-01-01

    The properties of a newly developed tonic heat pain model (THPM), which makes use of pulsating contact heat, were investigated in 18 young men. The most important feature of this model is that repetitive heat pulses with an intensity of 1 degree C above the individual pain threshold are employed. This approach was used to tailor the tonic pain stimulation to the individual pain sensitivity. In the first of two experiments, the effects of pulse frequencies ranging from 5 to 30 pulses per minute (ppm) on ratings of pain intensity and pain unpleasantness (visual analogue scales) were examined. At all frequencies, both ratings increased steadily over the 5-min test period. Frequencies of 15 ppm or more appeared to enhance pain intensity throughout the test period compared to the lower frequencies, but did not appear to alter pain unpleasantness. This suggests that only pain intensity is influenced by slow temporal summation and that a sort of frequency threshold exists for this kind of summation. In the second experiment, the THPM was compared to a well-established form of tonic pain stimulation, the cold-pressor test (CPT); visual analogue scales were again used, and in addition the McGill Pain Questionnaire was employed. The CPT appeared to produce stronger tonic pain than the THPM. However, as is typical with tonic pain, both tonic pain models induced relatively higher values on the affective pain dimension than on the sensory pain dimension. The time course of pain was dynamic in the CPT, with an increase followed by a plateau phase, at least in those subjects who could tolerate the CPT for more than 60 sec. In contrast, as in the first experiment, the pain ratings in the THPM were characterized by a slow and steady increase over time. Moreover, there was absolutely no indication of a dichotomy between "pain-sensitive" and "pain-tolerant" individuals in the THPM, although such a dichotomy was evident in the CPT. This implies that the distinction between pain

  13. In vitro effects of medium tonicity, nutrient concentration, and free chlorine content on Acanthamoeba.

    PubMed

    Bergmanson, Jan P G; Wang, Eva; Gire, Anisa I; Osato, Michael S

    2011-08-01

    The environment preferred by Acanthamoeba trophozoites and the mechanism by which the amebae enters the cornea are not yet fully understood. A better understanding of the pathogenesis of this disease may help with prevention and treatment. To define the preferred environments for Acanthamoeba survival and proliferation in vitro by examining the effect of tonicity, nutrient concentration, and free chlorine content on Acanthamoeba. Human corneal isolates of Acanthamoeba castellanii and Acanthamoeba polyphaga trophozoites were cultured at 22°C (room temperature) in PYG (peptone-yeast extract-glucose) medium. The effect of tonicity on amebae was determined by incubating trophozoites in sodium chloride solutions in concentrations ranging from 0% to 10% for 19 days. Two different sets of media were prepared-one with and the other without added nutrients. The tonicity varied from 50 to 3438 mOsm/L while the pH was maintained at 6.7-6.8. Aliquots were recovered to determine the number and morphologic type of the amebae. To test the effect of chlorine, Acanthamoeba trophozoites were incubated for 7 days in buffered solutions with free chlorine concentrations varying from 0 to 5 mg/L free chlorine at 22°C. The pH was maintained at 7.2 and the tonicity varied from 88 to 92 mOsm/L. Trophozoites were enumerated by hemocytometer. Low tonicity solutions (<300 mOsm/L) favored the trophozoite stage, but elevating tonicity encouraged encystment. Only 3.3-3.9% of the trophozoites remained in 10% NaCl, while 46-58% of the trophozoites were present in distilled water. Increasing osmolality yielded a smaller number of Acanthamoeba with a greater proportion of cysts. Nutrients improved the replication rate at lower concentrations, increased the number of trophozoites and reduced the percentage of cysts. Chlorine completely inhibited both species of Acanthamoeba at free chlorine levels of 5mg/L, while lesser concentrations were less inhibitory. Acanthamoeba prefer hypotonic environments

  14. Bestrophin1 Channels are Insensitive to Ethanol and Do not Mediate Tonic GABAergic Currents in Cerebellar Granule Cells.

    PubMed

    Diaz, Marvin R; Wadleigh, Aya; Hughes, Benjamin A; Woodward, John J; Valenzuela, C Fernando

    2011-01-01

    The granule cell layer of the cerebellum functions in spatio-temporal encoding of information. Granule cells (GCs) are tonically inhibited by spillover of GABA released from Golgi cells and this tonic inhibition is facilitated by acute ethanol. Recently, it was demonstrated that a specialized Ca(2+)-activated anion-channel, bestrophin1 (Best1), found on glial cells, can release GABA that contributes up to 50-75% of the tonic GABAergic current. However, it is unknown if ethanol has any actions on Best1 function. Using whole-cell electrophysiology, we found that recombinant Best1 channels expressed in HEK-293 cells were insensitive to 40 and 80 mM ethanol. We attempted to measure the Best1-mediated component of the tonic current in slices using 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We confirmed that this agent blocks recombinant Best1 channels. Unexpectedly, we found that NPPB significantly potentiated the tonic current and the area and decay of GABA(A)-mediated spontaneous inhibitory post-synaptic currents (IPSCs) in GCs in rodent slices under two different recording conditions. To better isolate the Best1-dependent tonic current component, we blocked the Golgi cell component of the tonic current with tetrodotoxin and found that NPPB similarly and significantly potentiated the tonic current amplitude and decay time of miniature IPSCs. Two other Cl(-)-channel blockers were also tested: 4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate (DIDS) showed no effect on GABAergic transmission, while niflumic acid (NFA) significantly suppressed the tonic current noise, as well as the mIPSC frequency, amplitude, and area. These data suggest that acute ethanol exposure does not modulate Best1 channels and these findings serve to challenge recent data indicating that these channels participate in the generation of tonic GABAergic currents in cerebellar GCs.

  15. Bestrophin1 Channels are Insensitive to Ethanol and Do not Mediate Tonic GABAergic Currents in Cerebellar Granule Cells

    PubMed Central

    Diaz, Marvin R.; Wadleigh, Aya; Hughes, Benjamin A.; Woodward, John J.; Valenzuela, C. Fernando

    2012-01-01

    The granule cell layer of the cerebellum functions in spatio-temporal encoding of information. Granule cells (GCs) are tonically inhibited by spillover of GABA released from Golgi cells and this tonic inhibition is facilitated by acute ethanol. Recently, it was demonstrated that a specialized Ca2+-activated anion-channel, bestrophin1 (Best1), found on glial cells, can release GABA that contributes up to 50–75% of the tonic GABAergic current. However, it is unknown if ethanol has any actions on Best1 function. Using whole-cell electrophysiology, we found that recombinant Best1 channels expressed in HEK-293 cells were insensitive to 40 and 80 mM ethanol. We attempted to measure the Best1-mediated component of the tonic current in slices using 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB). We confirmed that this agent blocks recombinant Best1 channels. Unexpectedly, we found that NPPB significantly potentiated the tonic current and the area and decay of GABAA-mediated spontaneous inhibitory post-synaptic currents (IPSCs) in GCs in rodent slices under two different recording conditions. To better isolate the Best1-dependent tonic current component, we blocked the Golgi cell component of the tonic current with tetrodotoxin and found that NPPB similarly and significantly potentiated the tonic current amplitude and decay time of miniature IPSCs. Two other Cl−-channel blockers were also tested: 4′-diisothiocyanatostilbene-2,2′-disulfonic acid disodium salt hydrate (DIDS) showed no effect on GABAergic transmission, while niflumic acid (NFA) significantly suppressed the tonic current noise, as well as the mIPSC frequency, amplitude, and area. These data suggest that acute ethanol exposure does not modulate Best1 channels and these findings serve to challenge recent data indicating that these channels participate in the generation of tonic GABAergic currents in cerebellar GCs. PMID:22275879

  16. Tonic and phasic co-variation of peripheral arousal indices in infants

    PubMed Central

    Wass, S.V.; de Barbaro, K.; Clackson, K.

    2015-01-01

    Tonic and phasic differences in peripheral autonomic nervous system (ANS) indicators strongly predict differences in attention and emotion regulation in developmental populations. However, virtually all previous research has been based on individual ANS measures, which poses a variety of conceptual and methodlogical challenges to comparing results across studies. Here we recorded heart rate, electrodermal activity (EDA), pupil size, head movement velocity and peripheral accelerometry concurrently while a cohort of 37 typical 12-month-old infants completed a mixed assessment battery lasting approximately 20 min per participant. We analysed covariation of these autonomic indices in three ways: first, tonic (baseline) arousal; second, co-variation in spontaneous (phasic) changes during testing; third, phasic co-variation relative to an external stimulus event. We found that heart rate, head velocity and peripheral accelerometry showed strong positive co-variation across all three analyses. EDA showed no co-variation in tonic activity levels but did show phasic positive co-variation with other measures, that appeared limited to sections of high but not low general arousal. Tonic pupil size showed significant positive covariation, but phasic pupil changes were inconsistent. We conclude that: (i) there is high covariation between autonomic indices in infants, but that EDA may only be sensitive at extreme arousal levels, (ii) that tonic pupil size covaries with other indices, but does not show predicted patterns of phasic change and (iii) that motor activity appears to be a good proxy measure of ANS activity. The strongest patterns of covariation were observed using epoch durations of 40 s per epoch, although significant covariation between indices was also observed using shorter epochs (1 and 5 s). PMID:26316360

  17. The effect of extracellular tonicity on the anatomy of triad complexes in amphibian skeletal muscle.

    PubMed

    Martin, Claire A; Petousi, Nayia; Chawla, Sangeeta; Hockaday, Austin R; Burgess, Antony J; Fraser, James A; Huang, Christopher L H; Skepper, Jeremy N

    2003-01-01

    Ultrastructural features of tubular-sarcoplasmic (T-SR) triad junctions and measures of cell volume following graded increases of extracellular tonicity were compared under physiological conditions recently shown to produce spontaneous release of intracellularly stored Ca2+ in fully polarized amphibian skeletal muscle fibres. The fibres were fixed using solutions of equivalent tonicities prior to processing for electron microscopy. The resulting anatomical sections demonstrated a partially reversible cell shrinkage corresponding to substantial increases in intracellular solute or ionic strength graded with extracellular tonicity. Serial thin sections through triad structures confirmed the presence of geometrically close but anatomically isolated transverse (T-) tubular and sarcoplasmic reticular (SR) membranes contrary to earlier suggestions for the development of luminal continuities between these structures in hypertonic solutions. They also quantitatively demonstrated accompanying decreases in T-SR distances, increased numbers of sections that showed closely apposed T and SR membranes, tubular luminal swelling and reductions in luminal volume of the junctional SR, all correlated with the imposed increases in extracellular osmolarity. Fully polarized fibres correspondingly showed elementary Ca(2+)-release events ('sparks', in 100 mM-sucrose-Ringer solution), sustained Ca2+ elevations and propagated Ca2+ waves (> or = 350-500 mM sucrose) following exposure to physiological Ringer solutions of successively greater tonicities. These were absent in hypotonic, isotonic or less strongly hypertonic (approximately 50 mM sucrose-Ringer) solutions. Yet exposure to hypotonic solutions also disrupted T-SR junctional anatomy. It increased the tubular diameters and T-SR distances and reduced their area of potential contact. The spontaneous release of intracellularly stored Ca2+ thus appears more closely to correlate with the expected changes in intracellular solute strength or

  18. Tyrosine Phosphorylation of GABAA Receptor γ2-Subunit Regulates Tonic and Phasic Inhibition in the Thalamus

    PubMed Central

    Nani, Francesca; Bright, Damian P.; Revilla-Sanchez, Raquel; Tretter, Verena; Moss, Stephen J.

    2013-01-01

    GABA-mediated tonic and phasic inhibition of thalamic relay neurons of the dorsal lateral geniculate nucleus (dLGN) was studied after ablating tyrosine (Y) phosphorylation of receptor γ2-subunits. As phosphorylation of γ2 Y365 and Y367 reduces receptor internalization, to understand their importance for inhibition we created a knock-in mouse in which these residues are replaced by phenylalanines. On comparing wild-type (WT) and γ2Y365/367F+/− (HT) animals (homozygotes are not viable in utero), the expression levels of GABAA receptor α4-subunits were increased in the thalamus of female, but not male mice. Raised δ-subunit expression levels were also observed in female γ2Y365/367F +/− thalamus. Electrophysiological analyses revealed no difference in the level of inhibition in male WT and HT dLGN, while both the spontaneous inhibitory postsynaptic activity and the tonic current were significantly augmented in female HT relay cells. The sensitivity of tonic currents to the δ-subunit superagonist THIP, and the blocker Zn2+, were higher in female HT relay cells. This is consistent with upregulation of extrasynaptic GABAA receptors containing α4- and δ-subunits to enhance tonic inhibition. In contrast, the sensitivity of GABAA receptors mediating inhibition in the female γ2Y356/367F +/− to neurosteroids was markedly reduced compared with WT. We conclude that disrupting tyrosine phosphorylation of the γ2-subunit activates a sex-specific increase in tonic inhibition, and this most likely reflects a genomic-based compensation mechanism for the reduced neurosteroid sensitivity of inhibition measured in female HT relay neurons. PMID:23904608

  19. Tyrosine phosphorylation of GABAA receptor γ2-subunit regulates tonic and phasic inhibition in the thalamus.

    PubMed

    Nani, Francesca; Bright, Damian P; Revilla-Sanchez, Raquel; Tretter, Verena; Moss, Stephen J; Smart, Trevor G

    2013-07-31

    GABA-mediated tonic and phasic inhibition of thalamic relay neurons of the dorsal lateral geniculate nucleus (dLGN) was studied after ablating tyrosine (Y) phosphorylation of receptor γ2-subunits. As phosphorylation of γ2 Y365 and Y367 reduces receptor internalization, to understand their importance for inhibition we created a knock-in mouse in which these residues are replaced by phenylalanines. On comparing wild-type (WT) and γ2(Y365/367F)+/- (HT) animals (homozygotes are not viable in utero), the expression levels of GABAA receptor α4-subunits were increased in the thalamus of female, but not male mice. Raised δ-subunit expression levels were also observed in female γ2(Y365/367F) +/- thalamus. Electrophysiological analyses revealed no difference in the level of inhibition in male WT and HT dLGN, while both the spontaneous inhibitory postsynaptic activity and the tonic current were significantly augmented in female HT relay cells. The sensitivity of tonic currents to the δ-subunit superagonist THIP, and the blocker Zn(2+), were higher in female HT relay cells. This is consistent with upregulation of extrasynaptic GABAA receptors containing α4- and δ-subunits to enhance tonic inhibition. In contrast, the sensitivity of GABAA receptors mediating inhibition in the female γ2(Y356/367F) +/- to neurosteroids was markedly reduced compared with WT. We conclude that disrupting tyrosine phosphorylation of the γ2-subunit activates a sex-specific increase in tonic inhibition, and this most likely reflects a genomic-based compensation mechanism for the reduced neurosteroid sensitivity of inhibition measured in female HT relay neurons.

  20. Testing fully depleted CCD

    NASA Astrophysics Data System (ADS)

    Casas, Ricard; Cardiel-Sas, Laia; Castander, Francisco J.; Jiménez, Jorge; de Vicente, Juan

    2014-08-01

    The focal plane of the PAU camera is composed of eighteen 2K x 4K CCDs. These devices, plus four spares, were provided by the Japanese company Hamamatsu Photonics K.K. with type no. S10892-04(X). These detectors are 200 μm thick fully depleted and back illuminated with an n-type silicon base. They have been built with a specific coating to be sensitive in the range from 300 to 1,100 nm. Their square pixel size is 15 μm. The read-out system consists of a Monsoon controller (NOAO) and the panVIEW software package. The deafualt CCD read-out speed is 133 kpixel/s. This is the value used in the calibration process. Before installing these devices in the camera focal plane, they were characterized using the facilities of the ICE (CSIC- IEEC) and IFAE in the UAB Campus in Bellaterra (Barcelona, Catalonia, Spain). The basic tests performed for all CCDs were to obtain the photon transfer curve (PTC), the charge transfer efficiency (CTE) using X-rays and the EPER method, linearity, read-out noise, dark current, persistence, cosmetics and quantum efficiency. The X-rays images were also used for the analysis of the charge diffusion for different substrate voltages (VSUB). Regarding the cosmetics, and in addition to white and dark pixels, some patterns were also found. The first one, which appears in all devices, is the presence of half circles in the external edges. The origin of this pattern can be related to the assembly process. A second one appears in the dark images, and shows bright arcs connecting corners along the vertical axis of the CCD. This feature appears in all CCDs exactly in the same position so our guess is that the pattern is due to electrical fields. Finally, and just in two devices, there is a spot with wavelength dependence whose origin could be the result of a defectous coating process.

  1. Transequatorial Propagation and Depletion Precursors

    NASA Astrophysics Data System (ADS)

    Miller, E. S.; Bust, G. S.; Kaeppler, S. R.; Frissell, N. A.; Paxton, L. J.

    2014-12-01

    The bottomside equatorial ionosphere in the afternoon and evening sector frequently evolves rapidly from smoothly stratified to violently unstable with large wedges of depleted plasma growing through to the topside on timescales of a few tens of minutes. These depletions have numerous practical impacts on radio propagation, including amplitude scintillation, field-aligned irregularity scatter, HF blackouts, and long-distance transequatorial propagation at frequencies above the MUF. Practical impacts notwithstanding, the pathways and conditions under which depletions form remain a topic of vigorous inquiry some 80 years after their first report. Structuring of the pre-sunset ionosphere---morphology of the equatorial anomalies and long-wavelength undulations of the isodensity contours on the bottomside---are likely to hold some clues to conditions that are conducive to depletion formation. The Conjugate Depletion Experiment is an upcoming transequatorial forward-scatter HF/VHF experiment to investigate pre-sunset undulations and their connection with depletion formation. We will present initial results from the Conjugate Depletion Experiment, as well as a companion analysis of a massive HF propagation data set.

  2. Rotary antenna attenuator

    NASA Technical Reports Server (NTRS)

    Dickinson, R. M.; Hardy, J. C.

    1969-01-01

    Radio frequency attenuator, having negligible insertion loss at minimum attenuation, can be used for making precise antenna gain measurements. It is small in size compared to a rotary-vane attenuator.

  3. Tonic immobility during sexual assault - a common reaction predicting post-traumatic stress disorder and severe depression.

    PubMed

    Möller, Anna; Söndergaard, Hans Peter; Helström, Lotti

    2017-08-01

    Active resistance is considered to be the 'normal' reaction during rape. However, studies have indicated that similar to animals, humans exposed to extreme threat may react with a state of involuntary, temporary motor inhibition known as tonic immobility. The aim of the present study was to assess the occurrence of tonic immobility during rape and subsequent post-traumatic stress disorder and severe depression. Tonic immobility at the time of the assault was assessed using the Tonic Immobility Scale in 298 women who had visited the Emergency clinic for raped women within 1 month of a sexual assault. Information about the assault and the victim characteristics were taken from the structured clinical data files. After 6 months, 189 women were assessed regarding the development of post-traumatic stress disorder and depression. Of the 298 women, 70% reported significant tonic immobility and 48% reported extreme tonic immobility during the assault. Tonic immobility was associated with the development of post-traumatic stress disorder (OR 2.75; 95% CI 1.50-5.03, p = 0.001) and severe depression (OR 3.42; 95% CI 1.51-7.72, p = 0.003) at 6 months. Further, previous trauma history (OR 2.36; 95% CI 1.48-3.77, p < 0.001) and psychiatric treatment history (OR 2.00; 95% CI 1.26-3.19, p = 0.003) were associated with the tonic immobility response. Tonic immobility during rape is a common reaction associated with subsequent post-traumatic stress disorder and severe depression. Knowledge of this reaction in sexual assault victims is important in legal matters and for healthcare follow up. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

  4. Tonic Electromyogram Density in Multiple System Atrophy with Predominant Parkinsonism and Parkinson's Disease

    PubMed Central

    Wang, Yi; Shen, Yun; Xiong, Kang-Ping; He, Pei-Cheng; Mao, Cheng-Jie; Li, Jie; Wang, Fu-Yu; Wang, Ya-Li; Huang, Jun-Ying; Liu, Chun-Feng

    2017-01-01

    Background: Both Parkinson's disease (PD) and multiple system atrophy (MSA) have associated sleep disorders related to the underlying neurodegenerative pathology. Clinically, MSA with predominant parkinsonism (MSA-P) resembles PD in the manifestation of prominent parkinsonism. Whether the amount of rapid eye movement (REM) sleep without atonia could be a potential marker for differentiating MSA-P from PD has not been thoroughly investigated. This study aimed to examine whether sleep parameters could provide a method for differentiating MSA-P from PD. Methods: This study comprised 24 MSA-P patients and 30 PD patients, and they were of similar age, gender, and REM sleep behavior disorder (RBD) prevalence. All patients underwent clinical evaluation and one night of video-polysomnography recording. The tonic and phasic chin electromyogram (EMG) activity was manually quantified during REM sleep of each patient. We divided both groups in terms of whether they had RBD to make subgroup analysis. Results: No significant difference between MSA-P group and PD group had been found in clinical characteristics and sleep architecture. However, MSA-P patients had higher apnea-hypopnea index (AHI; 1.15 [0.00, 8.73]/h vs. 0.00 [0.00, 0.55]/h, P = 0.024) and higher tonic chin EMG density (34.02 [18.48, 57.18]% vs. 8.40 [3.11, 13.06]%, P < 0.001) as compared to PD patients. Subgroup analysis found that tonic EMG density in MSA + RBD subgroup was higher than that in PD + RBD subgroup (55.04 [26.81, 69.62]% vs. 11.40 [8.51, 20.41]%, P < 0.001). Furthermore, no evidence of any difference in tonic EMG density emerged between PD + RBD and MSA - RBD subgroups (P > 0.05). Both disease duration (P = 0.056) and AHI (P = 0.051) showed no significant differences during subgroup analysis although there was a trend toward longer disease duration in PD + RBD subgroup and higher AHI in MSA - RBD subgroup. Stepwise multiple linear regression analysis identified the presence of MSA-P (β = 0.552, P

  5. Inhibiting calcineurin activity under physiologic tonicity elevates anabolic but suppresses catabolic chondrocyte markers.

    PubMed

    van der Windt, Anna E; Haak, Esther; Kops, Nicole; Verhaar, Jan A N; Weinans, Harrie; Jahr, Holger

    2012-06-01

    The physiologic interstitial tonicity of healthy articular cartilage (350-480 mOsm) is lowered to 280-350 mOsm in osteoarthritis (OA). This results in loss of tissue prestress, altered compressive behavior, and, thus, inferior tissue properties. This study was undertaken to determine whether physiologic tonicity in combination with the inhibition of calcineurin (Cn) activity by FK-506 has synergistic effects on human articular chondrocytes and explants in vitro. OA chondrocytes and explants and non-OA chondrocytes were cultured in cytokine-free medium of 280 mOsm or 380 mOsm with or without Cn inhibition by FK-506. Chondrogenic, hypertrophic, and catabolic marker expression was evaluated at the messenger RNA (mRNA), protein, and activity levels. Compared to OA chondrocytes cultured at 280 mOsm, those cultured at 380 mOsm had increased expression of mRNA for chondrogenic markers (e.g., ∼13 fold for COL2; P < 0.001), and decreased COL1 expression (∼0.5 fold, P < 0.01). Inhibiting Cn activity under physiologic tonicity further enhanced the expression of anabolic markers at the mRNA level (∼50 fold for COL2; P < 0.001, ∼2 fold for AGC1; P < 0.001, and ∼3.5 fold for SOX9; P < 0.001) and at the protein level (∼6 fold for type II collagen; P < 0.001). Cn inhibition suppressed relevant collagenases as well as hypertropic and mineralization markers at the mRNA and activity levels. Expression of aggrecanase 1 and aggrecanase 2 was not influenced by tonicity or FK-506 alone, but the combination suppressed both, by ∼50% (P < 0.05) and ∼40% (P < 0.001), respectively. Generally, similar anabolic and antihypertrophic effects were observed in ex vivo cartilage explant cultures and non-OA chondrocytes. Our findings indicate that Cn at physiologic tonicity exerts a superior effect compared to physiologic tonicity or FK-506 alone, increasing anabolic markers while suppressing hypertrophic and catabolic markers. Our data may aid in the development of improved cell

  6. Ego Depletion Impairs Implicit Learning

    PubMed Central

    Thompson, Kelsey R.; Sanchez, Daniel J.; Wesley, Abigail H.; Reber, Paul J.

    2014-01-01

    Implicit skill learning occurs incidentally and without conscious awareness of what is learned. However, the rate and effectiveness of learning may still be affected by decreased availability of central processing resources. Dual-task experiments have generally found impairments in implicit learning, however, these studies have also shown that certain characteristics of the secondary task (e.g., timing) can complicate the interpretation of these results. To avoid this problem, the current experiments used a novel method to impose resource constraints prior to engaging in skill learning. Ego depletion theory states that humans possess a limited store of cognitive resources that, when depleted, results in deficits in self-regulation and cognitive control. In a first experiment, we used a standard ego depletion manipulation prior to performance of the Serial Interception Sequence Learning (SISL) task. Depleted participants exhibited poorer test performance than did non-depleted controls, indicating that reducing available executive resources may adversely affect implicit sequence learning, expression of sequence knowledge, or both. In a second experiment, depletion was administered either prior to or after training. Participants who reported higher levels of depletion before or after training again showed less sequence-specific knowledge on the post-training assessment. However, the results did not allow for clear separation of ego depletion effects on learning versus subsequent sequence-specific performance. These results indicate that performance on an implicitly learned sequence can be impaired by a reduction in executive resources, in spite of learning taking place outside of awareness and without conscious intent. PMID:25275517

  7. Relationship between the tonic elevator mandibular activity and the vertical dimension during the states of vigilance and hypnosis.

    PubMed

    Manns, A; Zuazola, R V; Sirhan, R M; Quiroz, M; Rocabado, M

    1990-04-01

    The variation of the tonic EMG elevator mandibular activity was studied as well as the consequent variation of the vertical dimension in two different experimental states: those of vigilance and hypnosis. In the state of vigilance, normal values of tonic EMG activity were recorded and a space of inocclusion (X = 2.22 mm) coincident with the postural mandibular position. Under hypnosis a significant reduction of the tonic EMG activity was observed (43 to 50%), together with a great increase of the inocclusion space (X = 8.90 mm).

  8. "When the going gets tough, who keeps going?" Depletion sensitivity moderates the ego-depletion effect.

    PubMed

    Salmon, Stefanie J; Adriaanse, Marieke A; De Vet, Emely; Fennis, Bob M; De Ridder, Denise T D

    2014-01-01

    Self-control relies on a limited resource that can get depleted, a phenomenon that has been labeled ego-depletion. We argue that individuals may differ in their sensitivity to depleting tasks, and that consequently some people deplete their self-control resource at a faster rate than others. In three studies, we assessed individual differences in depletion sensitivity, and demonstrate that depletion sensitivity moderates ego-depletion effects. The Depletion Sensitivity Scale (DSS) was employed to assess depletion sensitivity. Study 1 employs the DSS to demonstrate that individual differences in sensitivity to ego-depletion exist. Study 2 shows moderate correlations of depletion sensitivity with related self-control concepts, indicating that these scales measure conceptually distinct constructs. Study 3 demonstrates that depletion sensitivity moderates the ego-depletion effect. Specifically, participants who are sensitive to depletion performed worse on a second self-control task, indicating a stronger ego-depletion effect, compared to participants less sensitive to depletion.

  9. Tonic blood pressure modulates the relationship between baroreceptor cardiac reflex sensitivity and cognitive performance.

    PubMed

    Del Paso, Gustavo A Reyes; González, M Isabel; Hernández, José Antonio; Duschek, Stefan; Gutiérrez, Nicolás

    2009-09-01

    This study explored the effects of tonic blood pressure on the association between baroreceptor cardiac reflex sensitivity and cognitive performance. Sixty female participants completed a mental arithmetic task. Baroreceptor reflex sensitivity was assessed using sequence analysis. An interaction was found, indicating that the relationship between baroreceptor reflex sensitivity and cognitive performance is modulated by blood pressure levels. Reflex sensitivity was inversely associated to performance indices in the subgroup of participants with systolic blood pressure above the mean, whereas the association was positive in participants with systolic values below the mean. These results are in accordance with the findings in the field of pain perception and suggest that tonic blood pressure modulates the inhibitory effects of baroreceptor stimulation on high central nervous functions.

  10. Selective responses to tonic descending commands by temporal summation in a spinal motor pool

    PubMed Central

    Wang, Wei-Chun; McLean, David L.

    2014-01-01

    Summary Motor responses of varying intensities rely on descending commands to heterogeneous pools of motoneurons. In vertebrates, numerous sources of descending excitatory input provide systematically more drive to progressively less excitable spinal motoneurons. While this presumably facilitates simultaneous activation of motor pools, it is unclear how selective patterns of recruitment could emerge from inputs weighted this way. Here, using in vivo electrophysiological and imaging approaches in larval zebrafish, we find that, despite weighted excitation, more excitable motoneurons are preferentially activated by a midbrain reticulospinal nucleus, by virtue of longer membrane time constants that facilitate temporal summation of tonic drive. We confirm the utility of this phenomenon by assessing the activity of the midbrain and motoneuron populations during a light-driven behavior. Our findings demonstrate that weighted descending commands can generate selective motor responses by exploiting systematic differences in the biophysical properties of target motoneurons and their relative sensitivity to tonic input. PMID:25066087

  11. Role of support afferentation in control of the tonic muscle activity

    NASA Astrophysics Data System (ADS)

    Kozlovskaya, I. B.; Sayenko, I. V.; Sayenko, D. G.; Miller, T. F.; Khusnutdinova, D. R.; Melnik, K. A.

    2007-02-01

    The paper summarizes the results of experimental studies advocating for the leading role of support afferentation in control of the functional organization of the tonic muscle system. It is shown that transition to supportless conditions is followed by a significant decline of transverse stiffness and maximal voluntary force of postural (extensor) muscles limiting their participation in locomotion and increasing involvement of phasic muscles. Mechanical stimulation of the support zones of the soles under the supportless conditions eliminates all the above-mentioned effects, including changes in transverse stiffness and maximal voluntary forces of postural muscles, and consequent loss of influence of postural muscles in the locomotor activity. It is suggested that support afferentation, facilitating (support is present) or suppressing (support is absent) the tonic motor units (MUs) activities, defines the coordination patterns of postural synergies, and ensures the optimal strategy of corrective postural responses.

  12. How tonicity regulates genes: story of TonEBP transcriptional activator.

    PubMed

    Jeon, U S; Kim, J-A; Sheen, M R; Kwon, H M

    2006-01-01

    TonEBP stimulates genes whose products drive cellular accumulation of organic osmolytes and HSP70, which protect cells from the deleterious effects of hypertonicity and urea, respectively. Mice deficient in the TonEBP gene display severe atrophy of the renal medulla because cells failed to adapt to the hyperosmolality. Emerging data suggest that TonEBP plays a key role in the urinary concentrating mechanism by stimulating the UT-A urea transporters and possibly AQP2 water channel. Thus, TonEBP is an essential regulator in the urinary concentrating mechanism. Studies on structural basis of TonEBP function have revealed the structure of the DNA binding domain, and defined the transactivation domains. Molecular mechanisms underlying the nucleocytoplasmic trafficking, transactivation, and phosphorylation in response to changes in tonicity need to be understood in molecular detail. Such knowledge is needed for the identification of the sensor that detects changes in ambient tonicity and signals to TonEBP.

  13. Influence of pulsing and postpulsing media tonicity on electrotransformation of intact yeast cells.

    PubMed

    Ganeva, V; Galutzov, B

    1993-08-15

    The maximal transformation yield of intact yeast cells in hypotonic medium was obtained by application of nine pulses with a duration of 990 microseconds at 2.5 kV cm-1. Pulsation at the same electrical parameters in isotonic solution did not lead to any transformation and the electropermeability decreased by 50%. The transfer of cells, 1 min after pulsation in hypotonic medium, into media with different tonicity led to an increase of the number of transformed cells, depending on the sorbitol concentration of up to 250 mM. Further augmentation of the tonicity of postpulse medium in the range 330-1000 mM provoked strong decrease of transformation. This effect was present even when cells were resuspended in isotonic medium 30 min after pulsation.

  14. [Effects of electromagnetic fields on tonicity of cerebral vessels and arterial pressure].

    PubMed

    Razumov, A N; Bobrovnitskiĭ, I P; Kolesnikova, I V; Kasparov, E V; Anan'in, N N; El'chininov, N V; Gallinger, V E; Mineeva, E N

    2006-01-01

    Investigations performed by the authors show that normalization of the mechanisms of vegetative regulation of arterial pressure and cerebral vessels tonicity in young patients with sympathico-tonic vegetative dystonia can be achieved by combined use of constant magnetic field (magnetic induction 60 mTl, penetration 10 mm, area 1.5 cm2) and monochromatic electromagnetic wave (length 0.47 mcm, frequency 6 x 10(14) Hz, penetration 1.5 mm and light spot 7 mm) which are directed to a biologically active point C7 shen-men from both sides simultaneously for 3 min, at 11 a.m. to 13 p.m. once a day, for 10 days.

  15. Painful tonic spasms and brainstem involvement in a patient with neuromyelitis optica spectrum disorder.

    PubMed

    Roman-Filip, Corina; Ungureanu, Aurelian; Cernuşcă-Miţaru, Mihaela

    2016-01-01

    Neuromyelitis optica (NMO) is an inflammatory-demyelinating disease of the central nervous system classically characterized by optic neuritis and severe myelitis. New diagnostic criteria defined neuromyelitis optica spectrum disorder as limited forms of NMO or diverse neurologic presentations in the presence of specific antiaquaporin-4 antibodies. We report the case of a 57-year-old woman admitted in our department for recurrent attacks of optic neuritis, tetraparesis with severe painful tonic spasms of the left limbs and brainstem involvement. Painful tonic spasms have been described as movement disorders associated with multiple sclerosis, but a growing number of reports describe them in cases of NMO. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  16. Dream recall after night awakenings from tonic/phasic REM sleep.

    PubMed

    Hodoba, Danilo; Hrabrić, Kremimir; Krmpotić, Pavao; Brecić, Petra; Kujundzić-Tiljak, Mirjana; Majdaneić, Zeljko

    2008-01-01

    Eleven healthy subjects, 9 females and 2 males aged 21-23, were submitted to all night polygraphic recording and awaken in REM (Rapid Eye Movements) sleep, randomly upon tonic or phasic REM. Immediately upon awakening subjects were asked about possible dreaming according to the standardized questionnaire. Seventy-seven dreams, i.e. 79% of all 97 REM awakenings, were reported and analyzed. There were no significant differences in reported frequency of dreamings after awakening, mood and dream content due to phasic/tonic REM sleep. Dreams from phasic REM were a bit more colorful. Predictor of morning remembering of dreams was meaninglessness, not meaningfulness of dreams, and, in lesser extent, good mood, colorfulness, dreams with words and phasic REM sleep.

  17. Deficient tonic GABAergic conductance and synaptic balance in the fragile X syndrome amygdala

    PubMed Central

    Martin, Brandon S.; Corbin, Joshua G.

    2014-01-01

    Fragile X syndrome (FXS) is the leading cause of inherited intellectual disability. Comorbidities of FXS such as autism are increasingly linked to imbalances in excitation and inhibition (E/I) as well as dysfunction in GABAergic transmission in a number of brain regions including the amygdala. However, the link between E/I imbalance and GABAergic transmission deficits in the FXS amygdala is poorly understood. Here we reveal that normal tonic GABAA receptor-mediated neurotransmission in principal neurons (PNs) of the basolateral amygdala (BLA) is comprised of both δ- and α5-subunit-containing GABAA receptors. Furthermore, tonic GABAergic capacity is reduced in these neurons in the Fmr1 knockout (KO) mouse model of FXS (1.5-fold total, 3-fold δ-subunit, and 2-fold α5-subunit mediated) as indicated by application of gabazine (50 μM), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, 1 μM), and α5ia (1.5 μM) in whole cell patch-clamp recordings. Moreover, α5-containing tonic GABAA receptors appear to preferentially modulate nonsomatic compartments of BLA PNs. Examination of evoked feedforward synaptic transmission in these cells surprisingly revealed no differences in overall synaptic conductance or E/I balance between wild-type (WT) and Fmr1 KO mice. Instead, we observed altered feedforward kinetics in Fmr1 KO PNs that supports a subtle yet significant decrease in E/I balance at the peak of excitatory conductance. Blockade of α5-subunit-containing GABAA receptors replicated this condition in WT PNs. Therefore, our data suggest that tonic GABAA receptor-mediated neurotransmission can modulate synaptic E/I balance and timing established by feedforward inhibition and thus may represent a therapeutic target to enhance amygdala function in FXS. PMID:24848467

  18. Honeybee Kenyon cells are regulated by a tonic GABA receptor conductance.

    PubMed

    Palmer, Mary J; Harvey, Jenni

    2014-10-15

    The higher cognitive functions of insects are dependent on their mushroom bodies (MBs), which are particularly large in social insects such as honeybees. MB Kenyon cells (KCs) receive multisensory input and are involved in associative learning and memory. In addition to receiving sensory input via excitatory nicotinic synapses, KCs receive inhibitory GABAergic input from MB feedback neurons. Cultured honeybee KCs exhibit ionotropic GABA receptor currents, but the properties of GABA-mediated inhibition in intact MBs are currently unknown. Here, using whole cell recordings from KCs in acutely isolated honeybee brain, we show that KCs exhibit a tonic current that is inhibited by picrotoxin but not by bicuculline. Bath application of GABA (5 μM) and taurine (1 mM) activate a tonic current in KCs, but l-glutamate (0.1-0.5 mM) has no effect. The tonic current is strongly potentiated by the allosteric GABAA receptor modulator pentobarbital and is reduced by inhibition of Ca(2+) channels with Cd(2+) or nifedipine. Noise analysis of the GABA-evoked current gives a single-channel conductance value for the underlying receptors of 27 ± 3 pS, similar to that of resistant to dieldrin (RDL) receptors. The amount of injected current required to evoke action potential firing in KCs is significantly lower in the presence of picrotoxin. KCs recorded in an intact honeybee head preparation similarly exhibit a tonic GABA receptor conductance that reduces neuronal excitability, a property that is likely to contribute to the sparse coding of sensory information in insect MBs. Copyright © 2014 the American Physiological Society.

  19. Reduced GABAAR-mediated tonic inhibition in aged rat auditory thalamus

    PubMed Central

    Richardson, Ben D.; Ling, Lynne L.; Uteshev, Victor V.; Caspary, Donald M.

    2013-01-01

    Age-related deficits in detecting and understanding speech, which can lead to social withdrawal and isolation, have been linked to changes in the central auditory system. Many of these central age-related changes involve altered mechanisms of inhibitory neurotransmission, essential for accurate and reliable auditory processing. In sensory thalamus, GABA mediates fast (phasic) inhibition via synaptic GABAAR and long-lasting (tonic) inhibition via high affinity (extrasynaptic) GABAARs which provide a majority of the overall inhibitory tone in sensory thalamus. Due to a delicate balance between excitation and inhibition, alteration of normal thalamic inhibitory function with age and a reduction of tonic GABAAR-mediated inhibition may disrupt normal adult auditory processing, sensory gating, thalamocortical rhythmicity and slow-wave sleep. The present study examined age-related homeostatic plasticity of GABAAR function in auditory thalamus or medial geniculate body (MGB). Using thalamic slices from young adult (3–8 months) and aged (28–32 months) rats, these studies found a 45.5% reduction in GABAAR density and a 50.4% reduction in GABAAR-mediated tonic whole cell Cl− currents in the aged MGB. Synaptic GABAAR-mediated inhibition appeared differentially affected in aged lemniscal and non-lemniscal MGB. Except for resting membrane potential, basic properties were unaltered with age, including neuronal Cl− homeostasis determined using the gramicidin perforated patch-clamp method. Results demonstrate selective significant age-dependent deficits in the tonic inhibitory tone within the MGB. These data suggest that selective GABAAR subtype agonists or modulators might be used to augment MGB inhibitory neurotransmission, improving speech understanding, sensory gating and slow-wave sleep for a subset of elderly individuals. PMID:23325258

  20. Analysis of Diet Tonic Water Using Capillary Electrophoresis. An Undergraduate Instrumental Analysis Experiment

    NASA Astrophysics Data System (ADS)

    Herman, Harvey B.; Jezorek, John R.; Tang, Zhe

    2000-06-01

    An experiment for instrumental analysis is described in which components of diet tonic water are determined using capillary electrophoresis. Separation of quinine, saccharin, and benzoate in pH 7 phosphate buffer, with phenol as internal standard, is accomplished in about 12 minutes. The equipment requirements are modest: UV detection on an unmodified column. One of the components, quinine, is quantitated using a four-point standard addition calibration curve.

  1. Tonic immobility: differences in susceptibility of experimental and normal sheep and goats.

    PubMed

    MOORE, A U; AMSTEY, M S

    1962-03-02

    Tonic immobility ("animal hypnosis" or catatonic trance) could not be induced in 1-year-old foster lambs and kids. Control animals, conforming to a characteristic of their species, could be readily immobilized. The suggested explanation for this difference in behavior is that the foster animals did not develop a normal flight distance because of the ambivalent behavior of the "stepmother," who alternately permitted and refused nursing.

  2. Dynamics of Intrinsic Dendritic Calcium Signaling during Tonic Firing of Thalamic Reticular Neurons

    PubMed Central

    Chausson, Patrick; Leresche, Nathalie; Lambert, Régis C.

    2013-01-01

    The GABAergic neurons of the nucleus reticularis thalami that control the communication between thalamus and cortex are interconnected not only through axo-dendritic synapses but also through gap junctions and dendro-dendritic synapses. It is still unknown whether these dendritic communication processes may be triggered both by the tonic and the T-type Ca2+ channel-dependent high frequency burst firing of action potentials displayed by nucleus reticularis neurons during wakefulness and sleep, respectively. Indeed, while it is known that activation of T-type Ca2+ channels actively propagates throughout the dendritic tree, it is still unclear whether tonic action potential firing can also invade the dendritic arborization. Here, using two-photon microscopy, we demonstrated that dendritic Ca2+ responses following somatically evoked action potentials that mimic wake-related tonic firing are detected throughout the dendritic arborization. Calcium influx temporally summates to produce dendritic Ca2+ accumulations that are linearly related to the duration of the action potential trains. Increasing the firing frequency facilitates Ca2+ influx in the proximal but not in the distal dendritic compartments suggesting that the dendritic arborization acts as a low-pass filter in respect to the back-propagating action potentials. In the more distal compartment of the dendritic tree, T-type Ca2+ channels play a crucial role in the action potential triggered Ca2+ influx suggesting that this Ca2+ influx may be controlled by slight changes in the local dendritic membrane potential that determine the T-type channels’ availability. We conclude that by mediating Ca2+ dynamic in the whole dendritic arborization, both tonic and burst firing of the nucleus reticularis thalami neurons might control their dendro-dendritic and electrical communications. PMID:23991078

  3. Classic yin and yang tonic formula for osteopenia: study protocol for a randomized controlled trial

    PubMed Central

    2011-01-01

    Background Osteoporosis is a growing worldwide problem, with the greatest burden resulting from fractures. Nevertheless, the majority of fractures in adults occur in those with "osteopenia" (bone mineral density (BMD) only moderately lower than young normal individuals). Since long-term drug therapy is an expensive option with uncertain consequences and side effects, natural herbal therapy offers an attractive alternative. The purpose of this study is to evaluate the effect on BMD and safety of the Classic Yin and Yang Tonic Formula for treatment of osteopenia and to investigate the mechanism by which this efficacy is achieved. Methods/design We propose a multicenter double-blind randomized placebo-controlled trial to evaluate the efficacy and safety of the Classic Yin and Yang Tonic Formula for the treatment of osteopenia. Participants aged 55 to 75 with low bone mineral density (T-score between -1 and -2.5) and kidney deficiency in TCM will be included and randomly allocated into two groups: treatment group and control group. Participants in the treatment group will be treated with Classic Yin and Yang Tonic Granule, while the controlled group will receive placebo. Primary outcome measure will be BMD of the lumbar spine and proximal femur using dual-energy X-ray absorptiometry. Secondary outcomes will include pain intensity measured with visual analogue scales, quality of life, serum markers of bone metabolism, indices of Neuro-endocrino-immune network and safety. Discussion If the Classic Yin and Yang Tonic Formula can increase bone mass without adverse effects, it may be a novel strategy for the treatment of osteoporosis. Furthermore, the mechanism of the Chinese medical formula for osteoporosis will be partially elucidated. Trial registration This study is registered at ClinicalTrials.gov, NCT01271647. PMID:21806837

  4. Decrease in tonic inhibition contributes to increase in dentate semilunar granule cell excitability after brain injury.

    PubMed

    Gupta, Akshay; Elgammal, Fatima S; Proddutur, Archana; Shah, Samik; Santhakumar, Vijayalakshmi

    2012-02-15

    Brain injury is an etiological factor for temporal lobe epilepsy and can lead to memory and cognitive impairments. A recently characterized excitatory neuronal class in the dentate molecular layer, semilunar granule cell (SGC), has been proposed to regulate dentate network activity patterns and working memory formation. Although SGCs, like granule cells, project to CA3, their typical sustained firing and associational axon collaterals suggest that they are functionally distinct from granule cells. We find that brain injury results in an enhancement of SGC excitability associated with an increase in input resistance 1 week after trauma. In addition to prolonging miniature and spontaneous IPSC interevent intervals, brain injury significantly reduces the amplitude of tonic GABA currents in SGCs. The postinjury decrease in SGC tonic GABA currents is in direct contrast to the increase observed in granule cells after trauma. Although our observation that SGCs express Prox1 indicates a shared lineage with granule cells, data from control rats show that SGC tonic GABA currents are larger and sIPSC interevent intervals shorter than in granule cells, demonstrating inherent differences in inhibition between these cell types. GABA(A) receptor antagonists selectively augmented SGC input resistance in controls but not in head-injured rats. Moreover, post-traumatic differences in SGC firing were abolished in GABA(A) receptor blockers. Our data show that cell-type-specific post-traumatic decreases in tonic GABA currents boost SGC excitability after brain injury. Hyperexcitable SGCs could augment dentate throughput to CA3 and contribute substantively to the enhanced risk for epilepsy and memory dysfunction after traumatic brain injury.

  5. Clinical course of untreated tonic-clonic seizures in childhood: prospective, hospital based study.

    PubMed Central

    van Donselaar, C. A.; Brouwer, O. F.; Geerts, A. T.; Arts, W. F.; Stroink, H.; Peters, A. C.

    1997-01-01

    OBJECTIVE: To assess decleration and acceleration in the disease process in the initial phase of epilepsy in children with new onset tonic-clonic seizures. STUDY DESIGN: Hospital based follow up study. SETTING: Two university hospitals, a general hospital, and a children's hospital in the Netherlands. PATIENTS: 204 children aged 1 month to 16 years with idiopathic or remote symptomatic, newly diagnosed, tonic-clonic seizures, of whom 123 were enrolled at time of their first ever seizure; all children were followed until the start of drug treatment (78 children), the occurrence of the fourth untreated seizure (41 children), or the end of the follow up period of two years (85 untreated children). MAIN OUTCOME MEASURES: Analysis of disease pattern from first ever seizure. The pattern was categorised as decelerating if the child became free of seizures despite treatment being withheld. In cases with four seizures, the pattern was categorised as decelerating if successive intervals increased or as accelerating if intervals decreased. Patterns in the remaining children were classified as uncertain. RESULTS: A decelerating pattern was found in 83 of 85 children who became free of seizures without treatment. Three of the 41 children with four or more untreated seizures showed a decelerating pattern and eight an accelerating pattern. In 110 children the disease process could not be classified, mostly because drug treatment was started after the first, second, or third seizure. The proportion of children with a decelerating pattern (42%, 95% confidence interval 35% to 49%) may be a minimum estimate because of the large number of patients with an uncertain disease pattern. CONCLUSIONS: Though untreated epilepsy is commonly considered to be a progressive disorder with decreasing intervals between seizures, a large proportion of children with newly diagnosed, unprovoked tonic-clonic seizures have a decelerating disease process. The fear that tonic-clonic seizures commonly

  6. Modulation of an inhibitory reflex in single motor units in human masseter by tonic painful stimulation.

    PubMed

    Svensson, P; McMillan, A S; Graven-Nielsen, T; Wang, K; Arendt-Nielsen, L

    1999-12-01

    Perioral electrical stimuli cause inhibitory reflex responses in single motor-units (SMU) and surface electromyographic (EMG) recordings from voluntary contracted human jaw-closing muscles. Tonic experimental masseter pain has recently been shown to reduce the inhibitory reflex response in surface EMG recordings but the effect on SMU activity has not been described. In this study, motor-unit action potentials were recorded with wire electrodes inserted into the left masseter in eleven subjects. The subjects kept the SMU firing rate around 10 Hz by feedback. Ninety-nine electrical stimuli were applied sequentially to the left mental nerve with increasing stimulus delays in steps of 1 ms after the preceding motor unit action potential. The inhibitory reflex in SMU was recorded before, during and after infusion of hypertonic saline (5%) into the ipsilateral masseter muscle. Spike train data were used to calculate (1) the mean pre- and post-stimulus inter-spike-intervals (ISI) in all of the 99 trials, (2) cumulative changes in firing probability, and (3) estimation of the compound inhibitory post-synaptic potential (IPSP) in the masseter motoneuron. Tonic masseter pain did not change pre-stimulus SMU firing characteristics but the mean ISI for the first post-stimulus discharge (158.2+/-9.2 ms) was significantly decreased compared to the pre-pain (175.8+/-11.3 ms, P<0.05) and post-pain conditions (172. 6+/-11.6 ms, P<0.05). The post-stimulus firing probability was significantly increased and the relative amplitude of the estimated IPSP significantly decreased during tonic masseter pain compared to pre-pain and post-pain conditions. In conclusion, this study indicates that tonic masseter pain has a net excitatory effect on the inhibitory jaw-reflexes, which could be mediated by presynaptic mechanisms on the involved motoneurons.

  7. Depleting depletion: Polymer swelling in poor solvent mixtures

    NASA Astrophysics Data System (ADS)

    Mukherji, Debashish; Marques, Carlos; Stuehn, Torsten; Kremer, Kurt

    A polymer collapses in a solvent when the solvent particles dislike monomers more than the repulsion between monomers. This leads to an effective attraction between monomers, also referred to as depletion induced attraction. This attraction is the key factor behind standard polymer collapse in poor solvents. Strikingly, even if a polymer exhibits poor solvent condition in two different solvents, it can also swell in mixtures of these two poor solvents. This collapse-swelling-collapse scenario is displayed by poly(methyl methacrylate) (PMMA) in aqueous alcohol. Using molecular dynamics simulations of a thermodynamically consistent generic model and theoretical arguments, we unveil the microscopic origin of this phenomenon. Our analysis suggests that a subtle interplay of the bulk solution properties and the local depletion forces reduces depletion effects, thus dictating polymer swelling in poor solvent mixtures.

  8. Effects of conventional anticonvulsant drugs on generalized tonic-clonic seizures in Noda epileptic rats.

    PubMed

    Inoue, Maki; Yamamoto, Ayaka; Kaneko, Yuka; Noda, Atsushi; Naito, Hiroyuki

    2014-09-01

    Noda epileptic rats (NERs) present with clinico-pathological manifestations reminiscent of human generalized tonic-clonic epilepsy. Thus, this strain of rat has been a model of primary, generalized, tonic-clonic epilepsy. However, the infrequency of seizures in these rats makes the assessment of antiepileptic drugs (AEDs) difficult. Therefore, traditional AEDs have only been tested in NERs against audiogenic seizures evoked by weekly acoustic priming from 3 to 22 weeks of age or by using the kindling procedure in adult animals. Adult NERs are susceptible to changes in their environment, such as bedding replacement or unpleasant sensory stimuli. In the present study, traditional AEDs-phenobarbital (PB) and sodium valproate (VPA)-were evaluated against seizures evoked by strong environmental stimuli in mature NERs that had not been previously primed. The number of animals presenting with seizures decreased in a dose-dependent manner following administration of either PB (dose range 1.0-5.0mg/kg) or VPA (50 and 100mg/kg). Consequently, the utility of NERs as a model of generalized tonic-clonic epilepsy was confirmed. This type of protocol can be used to further evaluate AEDs and test effects of chronic administration of AEDs. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Ras activation of Erk restores impaired tonic BCR signaling and rescues immature B cell differentiation

    PubMed Central

    Rowland, Sarah L.; DePersis, Corinne L.; Torres, Raul M.

    2010-01-01

    B cell receptors (BCRs) generate tonic signals critical for B cell survival and early B cell development. To determine whether these signals also mediate the development of transitional and mature B cells, we examined B cell development using a mouse strain in which nonautoreactive immunoglobulin heavy and light chain–targeted B cells express low surface BCR levels. We found that reduced BCR expression translated into diminished tonic BCR signals that strongly impaired the development of transitional and mature B cells. Constitutive expression of Bcl-2 did not rescue the differentiation of BCR-low B cells, suggesting that this defect was not related to decreased cell survival. In contrast, activation of the Ras pathway rescued the differentiation of BCR-low immature B cells both in vitro and in vivo, whereas extracellular signal-regulated kinase (Erk) inhibition impaired the differentiation of normal immature B cells. These results strongly suggest that tonic BCR signaling mediates the differentiation of immature into transitional and mature B cells via activation of Erk, likely through a pathway requiring Ras. PMID:20176802

  10. Nuclear redistribution of tonicity-responsive enhancer binding protein requires proteasome activity.

    PubMed

    Woo, S K; Maouyo, D; Handler, J S; Kwon, H M

    2000-02-01

    Tonicity-responsive enhancer binding protein (TonEBP) is the transcription factor that regulates tonicity-responsive expression of the genes for the sodium-myo-inositol cotransporter (SMIT) and the sodium-chloride-betaine cotransporter (BGT1). Hypertonicity stimulates the activity of TonEBP due to a combination of increased protein abundance and increased nuclear distribution (proportion of TonEBP that is in the nucleus). We found that inhibitors of proteasome activity markedly reduce the induction of SMIT and BGT1 mRNA in response to hypertonicity. These inhibitors also reduce hypertonicity-induced stimulation of expression of a reporter gene controlled by the tonicity-responsive enhancer. Western and immunohistochemical analyses revealed that the proteasome inhibitors reduce the hypertonicity-induced increase of TonEBP in the nucleus by inhibiting its nuclear redistribution without affecting its abundance. Although the nuclear distribution of TonEBP is sensitive to inhibition of proteasome activity as is that of nuclear factor (NF)-kappaB, the signaling pathways appear to be different in that hypertonicity does not affect the nuclear distribution of NF-kappaB. Conversely, treatment with tumor necrosis factor-alpha increases the nuclear distribution of NF-kappaB but not TonEBP.

  11. Interstitial tonicity controls TonEBP expression in the renal medulla.

    PubMed

    Sheen, Mee R; Kim, Jeong-Ah; Lim, Sun W; Jung, Ju-Y; Han, Ki-H; Jeon, Un S; Park, Soo-H; Kim, Jin; Kwon, H Moo

    2009-03-01

    Cells in the hyperosmotic kidney medulla, express a transcriptional activator termed tonicity responsive enhancer binding protein (TonEBP). Genes targeted by TonEBP protect kidney cells from the deleterious effects of hyperosmolality by inducing the expression of organic osmolytes and molecular chaperones, and other genes that mediate urine concentration such as aquaporin-2 and urea transporters. We tested here the effect of hypertonicity and hyperosmotic salt in the renal medullary interstitium on the expression TonEBP. When massive water diuresis was induced in rats the medullary sodium concentrations did not change, neither did TonEBP expression. In these animals the medullary tonicity was unchanged despite the production of dilute urine. On the other hand, treatment with the loop diurectic furosemide resulted in a dose-dependent decrease in the medullary sodium concentration causing a reduction in interstitial tonicity. Here, TonEBP expression was blunted in the outer and inner medulla which was due, in part, to decreased mRNA abundance. As expected, the expression of TonEBP target genes in the renal medulla also decreased in response to furosemide. Hence TonEBP expression in the renal medulla is stimulated by interstitial hypertonicity.

  12. Regulation of TonEBP transcriptional activator in MDCK cells following changes in ambient tonicity.

    PubMed

    Neuhofer, Wolfgang; Woo, Seung Kyoon; Na, Ki Young; Grunbein, Rita; Park, Won Kun; Nahm, Ohnn; Beck, Franz-X; Kwon, H Moo

    2002-12-01

    In response to ambient hypertonicity, TonEBP (tonicity-responsive enhancer binding protein) stimulates certain genes including those encoding cytokines, transporters for organic solutes, and a molecular chaperone. TonEBP is regulated in a bidirectional manner, upregulated by an increase in ambient tonicity while downregulated by a decrease. To investigate the role of intracellular ionic strength in the activity of TonEBP, we subjected Madin-Darby canine kidney cells to a variety of conditions. Electron microprobe analysis was performed to measure intracellular electrolytes. Under conditions in which changes in cell volume were similar, TonEBP activity correlated with the intracellular ionic strength regardless of the external tonicity. On the other hand, inhibition of the Na+/K+-ATPase and high external K+ concentration led to a decreased activity of TonEBP despite a marked increase in the intracellular ionic strength. Because isotonic swelling is known to occur under these conditions, these data suggest that dilution of the cytoplasmic constituents inhibits the activity of TonEBP. We conclude that intracellular ionic strength and water content are major factors that determine the activity of TonEBP.

  13. Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold.

    PubMed

    McCoy, Eric S; Taylor-Blake, Bonnie; Street, Sarah E; Pribisko, Alaine L; Zheng, Jihong; Zylka, Mark J

    2013-04-10

    Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown whether these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin, and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch-stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception.

  14. Role of tonic GABAergic currents during pre- and early postnatal rodent development

    PubMed Central

    Kilb, Werner; Kirischuk, Sergei; Luhmann, Heiko J.

    2013-01-01

    In the last three decades it became evident that the GABAergic system plays an essential role for the development of the central nervous system, by influencing the proliferation of neuronal precursors, neuronal migration and differentiation, as well as by controlling early activity patterns and thus formation of neuronal networks. GABA controls neuronal development via depolarizing membrane responses upon activation of ionotropic GABA receptors. However, many of these effects occur before the onset of synaptic GABAergic activity and thus require the presence of extrasynaptic tonic currents in neuronal precursors and immature neurons. This review summarizes our current knowledge about the role of tonic GABAergic currents during early brain development. In this review we compare the temporal sequence of the expression and functional relevance of different GABA receptor subunits, GABA synthesizing enzymes and GABA transporters. We also refer to other possible endogenous agonists of GABAA receptors. In addition, we describe functional consequences mediated by the GABAergic system during early developmental periods and discuss current models about the origin of extrasynaptic GABA and/or other endogenous GABAergic agonists during early developmental states. Finally, we present evidence that tonic GABAergic activity is also critically involved in the generation of physiological as well as pathophysiological activity patterns before and after the establishment of functional GABAergic synaptic connections. PMID:24027498

  15. Role of rho kinase in the functional and dysfunctional tonic smooth muscles.

    PubMed

    de Godoy, Márcio A F; Rattan, Satish

    2011-07-01

    Tonic smooth muscles play pivotal roles in the pathophysiology of debilitating diseases of the gastrointestinal and cardiovascular systems. Tonic smooth muscles differ from phasic smooth muscles in the ability to spontaneously develop myogenic tone. This ability has been primarily attributed to the local production of specific neurohumoral substances that can work in conjunction with calcium sensitization via signal transduction events associated with the Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase 2 (ROCK II) pathways. In this article, we discuss the molecular pathways involved in the myogenic properties of tonic smooth muscles, particularly the contribution of protein kinase C vs the RhoA/ROCK II pathway in the genesis of basal tone, pathophysiology and novel therapeutic approaches for certain gastrointestinal and cardiovascular diseases. Emerging evidence suggests that manipulation of RhoA/ROCK II activity through inhibitors or silencing of RNA interface techniques could represent a new therapeutic approach for various gastrointestinal and cardiovascular diseases.

  16. T-type calcium channels consolidate tonic action potential output of thalamic neurons to neocortex.

    PubMed

    Deleuze, Charlotte; David, François; Béhuret, Sébastien; Sadoc, Gérard; Shin, Hee-Sup; Uebele, Victor N; Renger, John J; Lambert, Régis C; Leresche, Nathalie; Bal, Thierry

    2012-08-29

    The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic high-frequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.

  17. Human cervical spinal cord circuitry activated by tonic input can generate rhythmic arm movements.

    PubMed

    Solopova, I A; Selionov, V A; Zhvansky, D S; Gurfinkel, V S; Ivanenko, Y

    2016-02-01

    The coordination between arms and legs during human locomotion shares many features with that in quadrupeds, yet there is limited evidence for the central pattern generator for the upper limbs in humans. Here we investigated whether different types of tonic stimulation, previously used for eliciting stepping-like leg movements, may evoke nonvoluntary rhythmic arm movements. Twenty healthy subjects participated in this study. The subject was lying on the side, the trunk was fixed, and all four limbs were suspended in a gravity neutral position, allowing unrestricted low-friction limb movements in the horizontal plane. The results showed that peripheral sensory stimulation (continuous muscle vibration) and central tonic activation (postcontraction state of neuronal networks following a long-lasting isometric voluntary effort, Kohnstamm phenomenon) could evoke nonvoluntary rhythmic arm movements in most subjects. In ∼40% of subjects, tonic stimulation elicited nonvoluntary rhythmic arm movements together with rhythmic movements of suspended legs. The fact that not all participants exhibited nonvoluntary limb oscillations may reflect interindividual differences in responsiveness of spinal pattern generation circuitry to its activation. The occurrence and the characteristics of induced movements highlight the rhythmogenesis capacity of cervical neuronal circuitries, complementing the growing body of work on the quadrupedal nature of human gait.

  18. Peptidergic CGRPα primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold

    PubMed Central

    McCoy, Eric S.; Taylor-Blake, Bonnie; Street, Sarah E.; Pribisko, Alaine L.; Zheng, Jihong; Zylka, Mark J.

    2013-01-01

    SUMMARY Calcitonin gene-related peptide (CGRP) is a classic molecular marker of peptidergic primary somatosensory neurons. Despite years of research, it is unknown if these neurons are required to sense pain or other sensory stimuli. Here, we found that genetic ablation of CGRPα-expressing sensory neurons reduced sensitivity to noxious heat, capsaicin and itch (histamine and chloroquine) and impaired thermoregulation but did not impair mechanosensation or β-alanine itch—stimuli associated with nonpeptidergic sensory neurons. Unexpectedly, ablation enhanced behavioral responses to cold stimuli and cold mimetics without altering peripheral nerve responses to cooling. Mechanistically, ablation reduced tonic and evoked activity in postsynaptic spinal neurons associated with TRPV1/heat, while profoundly increasing tonic and evoked activity in spinal neurons associated with TRPM8/cold. Our data reveal that CGRPα sensory neurons encode heat and itch and tonically cross-inhibit cold-responsive spinal neurons. Disruption of this crosstalk unmasks cold hypersensitivity, with mechanistic implications for neuropathic pain and temperature perception. PMID:23523592

  19. p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus

    PubMed Central

    Xia, Shuting; Zhou, Zikai; Leung, Celeste; Zhu, Yuehua; Pan, Xingxiu; Qi, Junxia; Morena, Maria; Hill, Matthew N; Xie, Wei; Jia, Zhengping

    2016-01-01

    PAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies. DOI: http://dx.doi.org/10.7554/eLife.14653.001 PMID:27296803

  20. DC attenuation meter

    DOEpatents

    Hargrove, Douglas L.

    2004-09-14

    A portable, hand-held meter used to measure direct current (DC) attenuation in low impedance electrical signal cables and signal attenuators. A DC voltage is applied to the signal input of the cable and feedback to the control circuit through the signal cable and attenuators. The control circuit adjusts the applied voltage to the cable until the feedback voltage equals the reference voltage. The "units" of applied voltage required at the cable input is the system attenuation value of the cable and attenuators, which makes this meter unique. The meter may be used to calibrate data signal cables, attenuators, and cable-attenuator assemblies.

  1. Selective modulation of GABAergic tonic current by dopamine in the nucleus accumbens of alcohol-dependent rats.

    PubMed

    Liang, Jing; Marty, Vincent N; Mulpuri, Yatendra; Olsen, Richard W; Spigelman, Igor

    2014-07-01

    The nucleus accumbens (NAcc) is a key structure of the mesolimbic dopaminergic reward system and plays an important role in mediating alcohol-seeking behaviors. Alterations in glutamatergic and GABAergic signaling were recently demonstrated in the NAcc of rats after chronic intermittent ethanol (CIE) treatment, a model of alcohol dependence. Here we studied dopamine (DA) modulation of GABAergic signaling and how this modulation might be altered by CIE treatment. We show that the tonic current (I(tonic)) mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABA(A)Rs) of medium spiny neurons (MSNs) in the NAcc core is differentially modulated by DA at concentrations in the range of those measured in vivo (0.01-1 μM), without affecting the postsynaptic kinetics of miniature inhibitory postsynaptic currents (mIPSCs). Use of selective D1 receptor (D1R) and D2 receptor (D2R) ligands revealed that I(tonic) potentiation by DA (10 nM) is mediated by D1Rs while I(tonic) depression by DA (0.03-1 μM) is mediated by D2Rs in the same MSNs. Addition of guanosine 5'-O-(2-thiodiphosphate) (GDPβS) to the recording pipettes eliminated I(tonic) decrease by the selective D2R agonist quinpirole (5 nM), leaving intact the quinpirole effect on mIPSC frequency. Recordings from CIE and vehicle control (CIV) MSNs during application of D1R agonist (SKF 38393, 100 nM) or D2R agonist (quinpirole, 2 nM) revealed that SKF 38393 potentiated I(tonic) to the same extent, while quinpirole reduced I(tonic) to a similar extent, in both groups of rats. Our data suggest that the selective modulatory effects of DA on I(tonic) are unaltered by CIE treatment and withdrawal.

  2. Affinity for MgADP and force of unbinding from actin of myosin purified from tonic and phasic smooth muscle

    PubMed Central

    Léguillette, Renaud; Zitouni, Nedjma B.; Govindaraju, Karuthapillai; Fong, Laura M.; Lauzon, Anne-Marie

    2008-01-01

    Smooth muscle is unique in its ability to maintain force at low MgATP consumption. This property, called the latch state, is more prominent in tonic than phasic smooth muscle. Studies performed at the muscle strip level have suggested that myosin from tonic muscle has a greater affinity for MgADP and therefore remains attached to actin longer than myosin from phasic muscle, allowing for cross-bridge dephosphorylation and latch-bridge formation. An alternative hypothesis is that after dephosphorylation, myosin reattaches to actin and maintains force. We investigated these fundamental properties of smooth muscle at the molecular level. We used an in vitro motility assay to measure actin filament velocity (νmax) when propelled by myosin purified from phasic or tonic muscle at increasing [MgADP]. Myosin was 25% thiophosphorylated and 75% unphosphorylated to approximate in vivo conditions. The slope of νmax versus [MgADP] was significantly greater for tonic (−0.51 ± 0.04) than phasic muscle myosin (−0.15 ± 0.04), demonstrating the greater MgADP affinity of myosin from tonic muscle. We then used a laser trap assay to measure the unbinding force from actin of populations of unphosphorylated tonic and phasic muscle myosin. Both myosin types attached to actin, and their unbinding force (0.092 ± 0.022 pN for phasic muscle and 0.084 ± 0.017 pN for tonic muscle) was not statistically different. We conclude that the greater affinity for MgADP of tonic muscle myosin and the reattachment of dephosphorylated myosin to actin may both contribute to the latch state. PMID:18614813

  3. Status epilepticus enhances tonic GABA currents and depolarizes GABA reversal potential in dentate fast-spiking basket cells

    PubMed Central

    Yu, Jiandong; Proddutur, Archana; Elgammal, Fatima S.; Ito, Takahiro

    2013-01-01

    Temporal lobe epilepsy is associated with loss of interneurons and inhibitory dysfunction in the dentate gyrus. While status epilepticus (SE) leads to changes in granule cell inhibition, whether dentate basket cells critical for regulating granule cell feedforward and feedback inhibition express tonic GABA currents (IGABA) and undergo changes in inhibition after SE is not known. We find that interneurons immunoreactive for parvalbumin in the hilar-subgranular region express GABAA receptor (GABAAR) δ-subunits, which are known to underlie tonic IGABA. Dentate fast-spiking basket cells (FS-BCs) demonstrate baseline tonic IGABA blocked by GABAAR antagonists. In morphologically and physiologically identified FS-BCs, tonic IGABA is enhanced 1 wk after pilocarpine-induced SE, despite simultaneous reduction in spontaneous inhibitory postsynaptic current (sIPSC) frequency. Amplitude of tonic IGABA in control and post-SE FS-BCs is enhanced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), demonstrating the contribution of GABAAR δ-subunits. Whereas FS-BC resting membrane potential is unchanged after SE, perforated-patch recordings from FS-BCs show that the reversal potential for GABA currents (EGABA) is depolarized after SE. In model FS-BCs, increasing tonic GABA conductance decreased excitability when EGABA was shunting and increased excitability when EGABA was depolarizing. Although simulated focal afferent activation evoked seizurelike activity in model dentate networks with FS-BC tonic GABA conductance and shunting EGABA, excitability of identical networks with depolarizing FS-BC EGABA showed lower activity levels. Thus, together, post-SE changes in tonic IGABA and EGABA maintain homeostasis of FS-BC activity and limit increases in dentate excitability. These findings have implications for normal FS-BC function and can inform studies examining comorbidities and therapeutics following SE. PMID:23324316

  4. Modality-specific facilitation and adaptation to painful tonic stimulation in humans.

    PubMed

    Polianskis, Romanas; Graven-Nielsen, Thomas; Arendt-Nielsen, Lars

    2002-01-01

    The study assessed the influence of stimulus modality on adaptation or facilitation of pain during tonic cold and tourniquet pressure stimulation. Experimental set-up for the cold stimulation consisted of a thermo-tank with water, cooled to 3 degrees C, circulation pump, electronic thermometer and an electronic 10 cm visual analogue scale (VAS). Experimental set-up for the tonic pressure stimulation consisted of a pneumatic tourniquet cuff, a computer-controlled air compressor, and an electronic VAS. The first experiment assessed temporal profiles of pain intensity and skin temperature during immersion of the non-dominant hand and lower arm into cold water for 3 min or until the pain tolerance limit was reached. The second experiment assessed temporal profile of cuff pain intensity during constant compressions for 10 min beginning at pain intensities of 2, 4, and 6 cm on the VAS ("VAS 2", "VAS 4" and "VAS 6" sessions). Subjects enduring cold stimulation for less than 3 min were defined as non-adapting to cold and vice versa. The intensity of cold pain in non-adapting subjects increased significantly faster than in adapting subjects and reached significantly higher magnitude. The course of pain intensity during constant compression, estimated by a linear regression line, was increasing or decreasing, representing facilitation or adaptation of pain, respectively. The typical profile of adaptation consisted of an "overshoot" in pain intensity, followed by a decrease in pain intensity. There was significant correlation in VAS slopes between sessions separated by 2-5 days, suggesting consistent pattern in pain responses to tonic pressure stimulation. Adaptation or facilitation rates and the overshoot magnitude were dependent on the initial pain intensity (2, 4, or 6 cm on the VAS). The facilitation rate was highest and the adaptation rate was lowest during the "VAS 2" session, while the facilitation rate was lowest and the adaptation rate was highest during the "VAS 6

  5. Fully depleted back illuminated CCD

    DOEpatents

    Holland, Stephen Edward

    2001-01-01

    A backside illuminated charge coupled device (CCD) is formed of a relatively thick high resistivity photon sensitive silicon substrate, with frontside electronic circuitry, and an optically transparent backside ohmic contact for applying a backside voltage which is at least sufficient to substantially fully deplete the substrate. A greater bias voltage which overdepletes the substrate may also be applied. One way of applying the bias voltage to the substrate is by physically connecting the voltage source to the ohmic contact. An alternate way of applying the bias voltage to the substrate is to physically connect the voltage source to the frontside of the substrate, at a point outside the depletion region. Thus both frontside and backside contacts can be used for backside biasing to fully deplete the substrate. Also, high resistivity gaps around the CCD channels and electrically floating channel stop regions can be provided in the CCD array around the CCD channels. The CCD array forms an imaging sensor useful in astronomy.

  6. Charge depletion in organic heterojunction

    NASA Astrophysics Data System (ADS)

    Ng, T. W.; Lo, M. F.; Lee, S. T.; Lee, C. S.

    2012-03-01

    Until now two types of organic-organic heterojunction (OHJ) have been observed in P-N junctions formed between undoped-organic semiconductors. Charge-transfers across OHJs are either negligible or showing electron transfer from P-type to N-type materials, leading to charges accumulation near the interface. Here, we observed that junction of 4,4',4''-tris(2-methylphenyl-phenylamino)triphenylamine (m-MTDATA)/bathocuproine (BCP) show the third-behavior. Electrons in BCP (N-type) transfer to m-MTDATA (P-type), leading to depletion of mobile majority carriers near the junction. While "depletion junctions" are typical in inorganic semiconductors, there are no reports in undoped-OHJ. Formation mechanism of depletion OHJs and fundamental differences between inorganic and organic HJs are discussed.

  7. Serotonin depletion increases seizure susceptibility and worsens neuropathological outcomes in kainate model of epilepsy.

    PubMed

    Maia, Gisela H; Brazete, Cátia S; Soares, Joana I; Luz, Liliana L; Lukoyanov, Nikolai V

    2017-09-01

    Serotonin is implicated in the regulation of seizures, but whether or not it can potentiate the effects of epileptogenic factors is not fully established. Using the kainic acid model of epilepsy in rats, we tested the effects of serotonin depletion on (1) susceptibility to acute seizures, (2) development of spontaneous recurrent seizures and (3) behavioral and neuroanatomical sequelae of kainic acid treatment. Serotonin was depleted by pretreating rats with p-chlorophenylalanine. In different groups, kainic acid was injected at 3 different doses: 6.5mg/kg, 9.0mg/kg or 12.5mg/kg. A single dose of 6.5mg/kg of kainic acid reliably induced status epilepticus in p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats. The neuroexcitatory effects of kainic acid in the p-chlorophenylalanine-pretreated rats, but not in saline-pretreated rats, were associated with the presence of tonic-clonic convulsions and high lethality. Compared to controls, a greater portion of serotonin-depleted rats showed spontaneous recurrent seizures after kainic acid injections. Loss of hippocampal neurons and spatial memory deficits associated with kainic acid treatment were exacerbated by prior depletion of serotonin. The present findings are of particular importance because they suggest that low serotonin activity may represent one of the major risk factors for epilepsy and, thus, offer potentially relevant targets for prevention of epileptogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Phosphorylation by Casein Kinase 1 Regulates Tonicity-induced Osmotic Response Element-binding Protein/Tonicity Enhancer-binding Protein Nucleocytoplasmic Trafficking*

    PubMed Central

    Xu, SongXiao; Wong, Catherine C. L.; Tong, Edith H. Y.; Chung, Stephen S. M.; Yates, John R.; Yin, YiBing; Ko, Ben C. B.

    2008-01-01

    The osmotic response element-binding protein (OREBP), also known as tonicity enhancer-binding protein (TonEBP) or NFAT5, is the only known osmo-sensitive transcription factor that mediates cellular adaptations to extracellular hypertonic stress. Although it is well documented that the subcellular localization and transactivation activity of OREBP/TonEBP are tightly regulated by extracellular tonicity, the molecular mechanisms involved remain elusive. Here we show that nucleocytoplasmic trafficking of OREBP/TonEBP is regulated by the dual phosphorylation of Ser-155 and Ser-158. Alanine scanning mutagenesis revealed that Ser-155 is an essential residue that regulates OREBP/TonEBP nucleocytoplasmic trafficking. Tandem mass spectrometry revealed that Ser-155 and Ser-158 of OREBP/TonEBP are both phosphorylated in living cells under hypotonic conditions. In vitro phosphorylation assays further suggest that phosphorylation of the two serine residues proceeds in a hierarchical manner with phosphorylation of Ser-155 priming the phosphorylation of Ser-158 and that these phosphorylations are essential for nucleocytoplasmic trafficking of the transcription factor. Finally, we have shown that the pharmacological inhibition of casein kinase 1 (CK1) abolishes the phosphorylation of Ser-158 and impedes OREBP/TonEBP nuclear export and that recombinant CK1 phosphorylates Ser-158. Knockdown of CK1α1L, a novel isoform of CK1, inhibits hypotonicity-induced OREBP/TonEBP nuclear export. Together these data highlight the importance of Ser-155 and Ser-158 in the nucleocytoplasmic trafficking of OREBP/TonEBP and indicate that CK1 plays a major role in regulating this process. PMID:18411282

  9. Phosphorylation by casein kinase 1 regulates tonicity-induced osmotic response element-binding protein/tonicity enhancer-binding protein nucleocytoplasmic trafficking.

    PubMed

    Xu, SongXiao; Wong, Catherine C L; Tong, Edith H Y; Chung, Stephen S M; Yates, John R; Yin, YiBing; Ko, Ben C B

    2008-06-20

    The osmotic response element-binding protein (OREBP), also known as tonicity enhancer-binding protein (TonEBP) or NFAT5, is the only known osmo-sensitive transcription factor that mediates cellular adaptations to extracellular hypertonic stress. Although it is well documented that the subcellular localization and transactivation activity of OREBP/TonEBP are tightly regulated by extracellular tonicity, the molecular mechanisms involved remain elusive. Here we show that nucleocytoplasmic trafficking of OREBP/TonEBP is regulated by the dual phosphorylation of Ser-155 and Ser-158. Alanine scanning mutagenesis revealed that Ser-155 is an essential residue that regulates OREBP/TonEBP nucleocytoplasmic trafficking. Tandem mass spectrometry revealed that Ser-155 and Ser-158 of OREBP/TonEBP are both phosphorylated in living cells under hypotonic conditions. In vitro phosphorylation assays further suggest that phosphorylation of the two serine residues proceeds in a hierarchical manner with phosphorylation of Ser-155 priming the phosphorylation of Ser-158 and that these phosphorylations are essential for nucleocytoplasmic trafficking of the transcription factor. Finally, we have shown that the pharmacological inhibition of casein kinase 1 (CK1) abolishes the phosphorylation of Ser-158 and impedes OREBP/TonEBP nuclear export and that recombinant CK1 phosphorylates Ser-158. Knockdown of CK1alpha1L, a novel isoform of CK1, inhibits hypotonicity-induced OREBP/TonEBP nuclear export. Together these data highlight the importance of Ser-155 and Ser-158 in the nucleocytoplasmic trafficking of OREBP/TonEBP and indicate that CK1 plays a major role in regulating this process.

  10. The effects of perilymphatic tonicity on endolymph composition and synaptic activity at the frog semicircular canal.

    PubMed

    Rossi, M L; Ferrary, E; Martini, M; Pelucchi, B; Bernard, C; Teixeira, M; Sterkers, O; Rubbini, G; Fesce, R

    1998-07-01

    The effects of changes in perilymphatic tonicity on the semicircular canal were investigated by combining the measurements of transepithelial potential and endolymphatic ionic composition in the isolated frog posterior canal with the electrophysiological assessment of synaptic activity and sensory spike firing at the posterior canal in the isolated intact labyrinth. In the isolated posterior canal, the endolymph was replaced by an endolymph-like solution of known composition, in the presence of basolateral perilymph-like solutions of normal (230 mosmol/kg), reduced (105 mosmol/kg, low NaCl) or increased osmolality (550 mosmol/kg, Na-Gluconate added). Altered perilymphatic tonicity did not produce significant changes in endolymphatic ionic concentrations during up to 5 min. In the presence of hypotonic perilymph, decreased osmolality, K and Cl concentrations were observed at 10 min. In the presence of hypertonic perilymph, the endolymphatic osmolality began to increase at 5 min and by 10 min Na concentration had also significantly increased. On decreasing the tonicity of the external solution an immediate decline was observed in transepithelial potential, whereas hypertonicity produced the opposite effect. In the intact frog labyrinth, mEPSPs and spike potentials were recorded from single fibers of the posterior nerve in normal Ringer's (240 mosmol/kg) as well as in solutions with modified tonicity. Hypotonic solutions consistently decreased and hypertonic solutions consistently increased mEPSP and spike frequencies, independent of the species whose concentration was altered. These effects ensued within 1-2 min after the start of perfusion with the test solutions. In particular, when the tonicity was changed by varying Na concentration the mean mEPSP rate was directly related to osmolality. Size histograms of synaptic potentials were well described by single log-normal distribution functions under all experimental conditions. Hypotonic solutions (105 mosmol

  11. Preventing NAD+ Depletion Protects Neurons against Excitotoxicity

    PubMed Central

    Liu, Dong; Pitta, Michael; Mattson, Mark P.

    2008-01-01

    Neurons are excitable cells that require large amounts of energy to support their survival and functions and are therefore prone to excitotoxicity, which involves energy depletion. By examining bioenergetic changes induced by glutamate, we found that the cellular nicotinamide adenine dinucleotide (NAD+) level is a critical determinant of neuronal survival. The bioenergetic effects of mitochondrial uncoupling and caloric restriction were also examined in cultured neurons and rodent brain. 2, 4-dinitrophenol (DNP) is a chemical mitochondrial uncoupler that stimulates glucose uptake and oxygen consumption on cultured neurons, which accelerates oxidation of NAD(P)H to NAD+ in mitochondria. The NAD+-dependent histone deacetylase sirtulin 1 (SIRT1) and glucose transporter 1 (GLUT1) mRNA are upregulated mouse brain under caloric restriction. To examine whether NAD+ mediates neuroprotective effects, nicotinamide, a precursor of NAD+ and inhibitor of SIRT1 and poly (ADP-ribose) polymerase 1 (PARP1) (two NAD+-dependent enzymes), was employed. Nicotinamide attenuated excitotoxic death and preserved cellular NAD+ levels to support SIRT1 and PARP 1 activities. Our findings suggest that mild mitochondrial uncoupling and caloric restriction exert hormetic effects by stimulating bioenergetics in neurons thereby increasing tolerance of neurons to metabolic stress. PMID:19076449

  12. Pressure surge attenuator

    DOEpatents

    Christie, Alan M.; Snyder, Kurt I.

    1985-01-01

    A pressure surge attenuation system for pipes having a fluted region opposite crushable metal foam. As adapted for nuclear reactor vessels and heads, crushable metal foam is disposed to attenuate pressure surges.

  13. Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons

    PubMed Central

    Lau, Benjamin K; Karim, Shafinaz; Goodchild, Ann K; Vaughan, Christopher W; Drew, Geoffrey M

    2014-01-01

    Background and Purpose Menthol, a naturally occurring compound in the essential oil of mint leaves, is used for its medicinal, sensory and fragrant properties. Menthol acts via transient receptor potential (TRPM8 and TRPA1) channels and as a positive allosteric modulator of recombinant GABAA receptors. Here, we examined the actions of menthol on GABAA receptor-mediated currents in intact midbrain slices. Experimental Approach Whole-cell voltage-clamp recordings were made from periaqueductal grey (PAG) neurons in midbrain slices from rats to determine the effects of menthol on GABAA receptor-mediated phasic IPSCs and tonic currents. Key Results Menthol (150–750 μM) produced a concentration-dependent prolongation of spontaneous GABAA receptor-mediated IPSCs, but not non-NMDA receptor-mediated EPSCs throughout the PAG. Menthol actions were unaffected by TRPM8 and TRPA1 antagonists, tetrodotoxin and the benzodiazepine antagonist, flumazenil. Menthol also enhanced a tonic current, which was sensitive to the GABAA receptor antagonists, picrotoxin (100 μM), bicuculline (30 μM) and Zn2+ (100 μM), but unaffected by gabazine (10 μM) and a GABAC receptor antagonist, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA; 50 μM). In addition, menthol potentiated currents induced by the extrasynaptic GABAA receptor agonist THIP/gaboxadol (10 μM). Conclusions and Implications These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies. PMID:24460753

  14. Cytoplasmic free calcium, myosin light chain phosphorylation, and force in phasic and tonic smooth muscle

    PubMed Central

    1988-01-01

    The time course of [Ca2+]i, tension, and myosin light chain phosphorylation were determined during prolonged depolarization with high K+ in intact tonic (rabbit pulmonary artery) and phasic (longitudinal layer of guinea pig ileum) smooth muscles. [Ca2+]i was monitored with the 340 nm/380 nm signal ratio of the fluorescent indicator fura-2. The fluorescence ratio had a similar time course in both muscle types during depolarization with 109 mM [K+]o; after a transient peak, there was a decline to 70% of its peak value in tonic smooth muscle, and to 60% in phasic smooth muscle. Tension, however, continued to increase in the pulmonary artery, while in the ileum it declined in parallel with the [Ca2+]i. On changing [K+]o from 109 to 20 mM, tension and [Ca2+]i either remained unchanged or declined in parallel in the pulmonary artery. Phosphorylation of the 20-kD myosin light chain, measured during stimulation of muscle strips with 109 mM [K+]o in another set of experiments, increased from 3% to a peak of 50% in the intact pulmonary artery, and then declined to a steady state value of 23%. In the intact ileum, a very rapid, early transient phosphorylation (up to 50%) at 2-3 s was seen. This transient declined by 30 s to a value that was close to the resting level (7%), while tension remained at 55% of its peak force. A quick release during maintained stimulation induced no detectable change in the [Ca2+]i in either type of smooth muscle. We discuss the possibility that the slowly rising tonic tension in pulmonary artery could be due to cooperativity between phosphorylated and nonphosphorylated crossbridges. PMID:3216188

  15. Tonic and phasic phenomena underlying eye movements during sleep in the cat

    PubMed Central

    Márquez-Ruiz, Javier; Escudero, Miguel

    2008-01-01

    Mammalian sleep is not a homogenous state, and different variables have traditionally been used to distinguish different periods during sleep. Of these variables, eye movement is one of the most paradigmatic, and has been used to differentiate between the so-called rapid eye movement (REM) and non-REM (NREM) sleep periods. Despite this, eye movements during sleep are poorly understood, and the behaviour of the oculomotor system remains almost unknown. In the present work, we recorded binocular eye movements during the sleep–wake cycle of adult cats by the scleral search-coil technique. During alertness, eye movements consisted of conjugated saccades and eye fixations. During NREM sleep, eye movements were slow and mostly unconjugated. The two eyes moved upwardly and in the abducting direction, producing a tonic divergence and elevation of the visual axis. During the transition period between NREM and REM sleep, rapid monocular eye movements of low amplitude in the abducting direction occurred in coincidence with ponto-geniculo-occipital waves. Along REM sleep, the eyes tended to maintain a tonic convergence and depression, broken by high-frequency bursts of complex rapid eye movements. In the horizontal plane, each eye movement in the burst comprised two consecutive movements in opposite directions, which were more evident in the eye that performed the abducting movements. In the vertical plane, rapid eye movements were always upward. Comparisons of the characteristics of eye movements during the sleep–wake cycle reveal the uniqueness of eye movements during sleep, and the noteworthy existence of tonic and phasic phenomena in the oculomotor system, not observed until now. PMID:18499729

  16. Treatment of Nonalcoholic Fatty Liver Disease in Children: TONIC Trial Design

    PubMed Central

    2010-01-01

    Background Nonalcoholic fatty liver disease (NAFLD) in children can lead to steatohepatitis, cirrhosis, and end-stage liver disease. The cause of NAFLD is unknown, but it is commonly associated with obesity, insulin resistance, and dyslipidemia. Objectives TONIC is conducted to test whether treatment with metformin, an insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvements in biochemical and histological features of nondiabetic children with biopsy-proven NAFLD. Design TONIC is a randomized, multicenter, double-masked, placebo-controlled trial of 96 weeks of treatment with metformin or vitamin E. The primary outcome measure chosen for the trial is improvement in serum alanine aminotransferase (ALT) levels with treatment as compared to placebo. An improvement in ALT is defined as reduction in serum ALT levels to below 50% of the baseline values or into the normal range (40 U/L or less) during the last 48 weeks of treatment. Histological improvement is defined by changes in liver histology between a baseline and end-of-treatment liver biopsy in regards to (1) steatohepatitis, (2) NAFLD Activity Score, consisting of scores for steatosis, lobular inflammation, and hepatocellular injury (ballooning), and (3) fibrosis score. Methods Between September 2005 and September 2007, 173 children were enrolled into TONIC at 10 clinical centers in the United States. Participants were randomized to receive either metformin (500 mg b.i.d.), vitamin E (400 IU b.i.d.), or placebo for 96 weeks. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB). (ClinicalTrials.gov number, NCT00063635.) PMID:19761871

  17. Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia

    PubMed Central

    Maldonado-Avilés, Jaime G.; Curley, Allison A.; Hashimoto, Takanori; Morrow, A. Leslie; Ramsey, Amy J.; O’Donnell, Patricio; Volk, David W.; Lewis, David A.

    2010-01-01

    Objective Cognitive impairments in schizophrenia are associated with lower expression of markers of γ-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABAA receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABAA receptor α4 and δ subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia. Method The authors used in situ hybridization to quantify expression patterns of GABAA receptor α4 and δ subunits in pre-frontal cortex from 23 matched pairs of schizophrenia and comparison subjects. Results Levels of δ mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas α4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between α 4 and δ subunit expression in schizophrenia, the authors used similar methods to quantify α4 and δ mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of α4 mRNA decreased, whereas δ mRNA levels increased. In addition, δ mRNA levels, but not α4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABAA receptor α1 subunit, and neither δ nor α4 mRNA levels were altered in rodent models of altered excitatory neurotransmission. Conclusions Since GABAA receptor α1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with δ subunits to form functional GABAA receptors, lower δ mRNA levels in schizophrenia might reflect a reduced number of α1βxδ GABAA receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia. PMID:19289452

  18. Tonic central and sensory stimuli facilitate involuntary air-stepping in humans.

    PubMed

    Selionov, V A; Ivanenko, Y P; Solopova, I A; Gurfinkel, V S

    2009-06-01

    Air-stepping can be used as a model for investigating rhythmogenesis and its interaction with sensory input. Here we show that it is possible to entrain involuntary rhythmic movement patterns in healthy humans by using different kinds of stimulation techniques. The subjects lay on their sides with one or both legs suspended, allowing low-friction horizontal rotation of the limb joints. To evoke involuntary stepping of the suspended leg, either we used continuous muscle vibration, electrical stimulation of the superficial peroneal or sural nerves, the Jendrassik maneuver, or we exploited the postcontraction state of neuronal networks (Kohnstamm phenomenon). The common feature across all stimulations was that they were tonic. Air-stepping could be elicited by most techniques in about 50% of subjects and involved prominent movements at the hip and the knee joint (approximately 40-70 degrees). Typically, however, the ankle joint was not involved. Minimal loading forces (4-25 N) applied constantly to the sole (using a long elastic cord) induced noticeable (approximately 5-20 degrees) ankle-joint-angle movements. The aftereffect of a voluntary long-lasting (30-s) contraction in the leg muscles featured alternating rhythmic leg movements that lasted for about 20-40 s, corresponding roughly to a typical duration of the postcontraction activity in static conditions. The Jendrassik maneuver per se did not evoke air-stepping. Nevertheless, it significantly prolonged rhythmic leg movements initiated manually by an experimenter or by a short (5-s) period of muscle vibration. Air-stepping of one leg could be evoked in both forward and backward directions with frequent spontaneous transitions, whereas involuntary alternating two-legged movements were more stable (no transitions). The hypothetical role of tonic influences, contact forces, and bilateral coordination in rhythmogenesis is discussed. The results overall demonstrated that nonspecific tonic drive may cause air

  19. Tonic eye movements induced by bilateral and unilateral galvanic vestibular stimulation (GVS) in guinea pigs.

    PubMed

    Kim, Juno

    2013-01-01

    Galvanic vestibular stimulation (GVS) stimulates primary vestibular afferents innervating the semicircular canals (SCCs) and otoliths found in the inner ear of humans and other mammals, including guinea pigs. To determine which pathways contribute to eye movements generated by this artificial vestibular stimulation in guinea pigs, low current intensities of GVS were passed either bilaterally between the tensor-tympani muscles of the two ears (up to 30 μA) or unilaterally between one tensor-tympani electrode and an indifferent on the back of the neck (up to 60 μA). Both forms of GVS were found to selectively generate tonic eye movements without nystagmus, characteristic of the otolith-ocular reflex; the axis of eye rotation did not align with any semicircular canal plane, but was oriented close to the expected axis of eye rotation that would occur in response to the net stimulation of otolith afferents. The induced eye rotation was predominantly vertical with a smaller horizontal deviation and very little torsion. Consistent with the results of previous human studies, the tonic eye movements were found to exhibit bilateral gain enhancement, whereby bilateral GVS generated twice the amplitude of eye rotation as unilateral anodal or cathodal stimulation alone. Eye movement responses to unilateral GVS were symmetrical in amplitude during equivalent intensities of anodal and cathodal stimulation, consistent with the known responses of more regularly and intermediately discharging primary vestibular afferents to GVS. These results together suggest that more regularly discharging otolith-ocular projections may mediate the tonic changes in eye position induced during maintained, low-intensity GVS in guinea pigs. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Fluctuations in intracellular calcium concentration and their effect on tonic tension in canine cardiac Purkinje fibres.

    PubMed Central

    Kort, A A; Lakatta, E G; Marban, E; Stern, M D; Wier, W G

    1985-01-01

    Ca2+-activated aequorin luminescence and tension were measured in dog Purkinje fibres during twitches and during the increase in resting force produced by exposure of the fibres to a low-Na+ solution after 3 min without external K+. Over the restricted range which could be examined, the relation between tension and 'mean' aequorin luminescence (luminescence filtered at 0.2 Hz) was approximately linear during the development and maintenance of contracture. For a given level of force, the mean aequorin luminescence during contracture was up to 20 times greater than the peak luminescence during the twitch. Noise analysis of aequorin luminescence and tension during contracture indicated the presence of periodic fluctuations, with a predominant frequency in the range 1-4 Hz. Ryanodine (1 microM) or caffeine (10 mM) abolished the fluctuations in luminescence and tension and made the relation between tension and mean aequorin luminescence much steeper. A mathematical model, the key feature of which is periodicity in the asynchronous occurrence of spatially localized regions of relatively high [Ca2+], reproduces the experimental data derived from contractures. From the model analysis, we infer that tonic tension is produced by recruitment of increasing numbers of regions of high [Ca2+], rather than by homogeneous graded activation. These results indicate that during contracture or 'tonic tension', intracellular [Ca2+] is not at steady state, but rather undergoes large, asynchronous spatio-temporal fluctuations. Thus the assumptions that intracellular [Ca2+] is at steady state or homogeneous during tonic tension are not valid. PMID:4057100

  1. Relations between biased tonicity of the body and vertical judgement in poststroke hemiplegic persons.

    PubMed

    Ishikura, K

    1999-06-01

    The influence of muscular tension upon visual vertical judgement in a standing posture was investigated in 16 hemiplegic persons and 12 normal elderly persons. The normal elderly group showed that their judgements of verticality were accurate and stable. In hemiplegic persons, judgements were displaced opposite to the side in which there was high tension in the body. Differences between groups in body tension and the side to which judgement was displaced were significant. The peculiar judgement errors made by hemiplegic persons are thus an overcorrection for tonicity. It was related to one's own body perception.

  2. A study of gabapentin in the treatment of tonic-clonic seizures of alcohol withdrawal syndrome.

    PubMed

    Rustembegovic, Avdo; Sofic, Emin; Tahirović, Ismet; Kundurović, Zlata

    2004-01-01

    In this study for thirty (30) patients with alcohol withdrawal syndrome, the response to anticolvusant gabapentin was assessed. Thirty (30) patients with median age of 57.0 years and median body weight of 79.1 kg were treated with gabapentin 3 x 300 mg daily for up 30 days. The preliminary findings of this study suggest that gabapentin is very effective against tonic-clonic seizures in alcohol withdrawal syndrome. Gabapentin was safe and well tolerated. For twenty (20) patients no side effect were observed.

  3. Tonic and phasic differential GABAergic inhibition of synaptic actions of joint afferents in the cat.

    PubMed

    Rudomin, P; Hernández, E; Lomelí, J

    2007-01-01

    The aim of this study was to examine the functional organization of the spinal neuronal networks activated by myelinated afferent fibers in the posterior articular nerve (PAN) of the anesthetized cat. Particular attention was given to the tonic and phasic GABAa inhibitory modulation of these networks. Changes in the synaptic effectiveness of the joint afferents were inferred from changes in the intraspinal focal potentials produced by electrical stimulation of the PAN. We found that conditioning stimulation of cutaneous nerves (sural, superficial peroneus and saphenous) and of the nucleus raphe magnus often inhibited, in a differential manner, the early and late components of the intraspinal focal potentials produced by stimulation of low and high threshold myelinated PAN afferents, respectively. The degree of the inhibition depended on the strength of both the conditioning and test stimuli and on the segmental level of recording. Conditioning stimulation of group I muscle afferents was less effective, but marked depression of the early and late focal potentials was produced by stimuli exceeding 5 xT. The i.v. injection of 1-2.5 mg/kg of picrotoxin, a GABAa blocker, had relatively minor effects on the early components of the PAN focal potentials, but was able to induce a significant increase of the late components. It also reduced the inhibitory effects of cutaneous and joint nerve conditioning on PAN focal responses. Conditioning autogenetic stimulation with high-frequency trains depressed the PAN focal potentials. The late components of the PAN responses remained depressed several minutes after discontinuing the conditioning train, even after picrotoxin administration. The present observations indicate that the neuronal networks activated by the low threshold PAN afferents show a relatively small post-activation depression and appear to be subjected to a minor tonic inhibitory GABAa control. In contrast, the pathways activated by stimulation of high threshold

  4. Successful treatment of paroxysmal tonic spasms with topiramate in a patient with neuromyelitis optica.

    PubMed

    Iida, Shin; Nakamura, Masataka; Wate, Reika; Kaneko, Satoshi; Kusaka, Hirofumi

    2015-09-01

    A 49-year-old woman with neuromyelitis optica (NMO) developed severe quadriplegia and frequent paroxysmal tonic spasms (PTS). Carbamazepine, although initially effective against PTS, caused drug eruption and she was unable to continue. PTS re-emerged after discontinuation of carbamazepine and hindered rehabilitation. Then topiramate was started, and PTS promptly disappeared. The patient became able to resume rehabilitation and her activity of daily life improved significantly. Carbamazepine and topiramate have a common pharmacological action to block voltage-gated sodium channels. The action may have contributed to inhibition of ephaptic transmission in the demyelinating lesions by NMO and eventually improved PTS. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. Searching for hidden information with Gabor Transform in generalized tonic-clonic seizures.

    PubMed

    Quian Quiroga, R; Blanco, S; Rosso, O A; Garcia, H; Rabinowicz, A

    1997-10-01

    The analysis of generalized tonic clonic seizures is usually difficult with scalp EEG due to muscle artifact. We applied Gabor Transform to evaluate 20 seizures from 8 consecutive patients admitted for video-EEG monitoring. We studied the relative intensity ratios of alpha, theta and delta bands over time. In 14/20 events we found a significant decremental activity in the delta band at the onset of the seizure indicating that this is dominated by theta and alpha bands. We conclude that GT is a useful auxiliary tool in the analysis of ictal activity that sheds light on the underlying pathophysiological mechanisms.

  6. Sex differences in hypothalamic-mediated tonic norepinephrine release for thermal hyperalgesia in rats.

    PubMed

    Wagner, M; Banerjee, T; Jeong, Y; Holden, J E

    2016-06-02

    Neuropathic pain is treated using serotonin norepinephrine reuptake inhibitors with mixed results. Pain facilitation mediated by α1-adrenoceptors may be involved, but whether norepinephrine (NE) is tonically released is unclear. The aim of this study was to determine whether NE is tonically released from A7 cells following chronic constriction injury (CCI), and if the lateral hypothalamus (LH) plays a role in this release in male and female rats with nociceptive and neuropathic pain types. Neuropathic groups received left CCI while nociceptive groups remained naïve to injury. Fourteen days later, rats were given intrathecal infusion of either the α1-adrenoceptor antagonist WB4101, the α2-adrenoceptor antagonist yohimbine (74 μg), or normal saline for control. Paw withdrawal latency (PWL) from a thermal stimulus was measured. The generalized estimated equation method was used for statistical analysis. Nociceptive rats given WB4101 had a PWL significantly longer than saline control (7.89 ± 0.63 vs. 5.87 ± 0.52 s), while the PWL of neuropathic rats given WB4101 was 13.20 ± 0.52 s compared to 6.78 ± 0.52 s for the saline control rats. Yohimbine had no significant effect. Microinjection of cobalt chloride (CoCl) in the A7 catecholamine cell group to prevent synaptic transmission blocked the effect of WB4101 in all groups, supporting the notion that spinally descending A7 cells tonically release NE that contributes to α1-mediated nociceptive facilitation. Microinjection of CoCl into the left LH blocked the effect of WB4101 in nociceptive and neuropathic male rats, but had no effect in female rats of either pain type, suggesting differential innervation. These findings indicate that tonic release of NE acts at pronociceptive α1-adrenoceptors, that this effect is greater in rats with nerve damage, and that, while NE comes primarily from the A7 cell group, LH innervation of the A7 cell group is different between the sexes. Copyright © 2016 IBRO. Published by

  7. Ozone Depletion from Nearby Supernovae

    NASA Technical Reports Server (NTRS)

    Gehrels, Neil; Laird, Claude M.; Jackman, Charles H.; Cannizzo, John K.; Mattson, Barbara J.; Chen, Wan; Bhartia, P. K. (Technical Monitor)

    2002-01-01

    Estimates made in the 1970's indicated that a supernova occurring within tens of parsecs of Earth could have significant effects on the ozone layer. Since that time improved tools for detailed modeling of atmospheric chemistry have been developed to calculate ozone depletion, and advances have been made also in theoretical modeling of supernovae and of the resultant gamma ray spectra. In addition, one now has better knowledge of the occurrence rate of supernovae in the galaxy, and of the spatial distribution of progenitors to core-collapse supernovae. We report here the results of two-dimensional atmospheric model calculations that take as input the spectral energy distribution of a supernova, adopting various distances from Earth and various latitude impact angles. In separate simulations we calculate the ozone depletion due to both gamma rays and cosmic rays. We find that for the combined ozone depletion from these effects roughly to double the 'biologically active' UV flux received at the surface of the Earth, the supernova must occur at approximately or less than 8 parsecs.

  8. Ozone depletion, paradigms, and politics

    SciTech Connect

    Iman, R.L.

    1993-10-01

    The destruction of the Earth`s protective ozone layer is a prime environmental concern. Industry has responded to this environmental problem by: implementing conservation techniques to reduce the emission of ozone-depleting chemicals (ODCs); using alternative cleaning solvents that have lower ozone depletion potentials (ODPs); developing new, non-ozone-depleting solvents, such as terpenes; and developing low-residue soldering processes. This paper presents an overview of a joint testing program at Sandia and Motorola to evaluate a low-residue (no-clean) soldering process for printed wiring boards (PWBs). Such processes are in widespread use in commercial applications because they eliminate the cleaning operation. The goal of this testing program was to develop a data base that could be used to support changes in the mil-specs. In addition, a joint task force involving industry and the military has been formed to conduct a follow-up evaluation of low-residue processes that encompass the concerns of the tri-services. The goal of the task force is to gain final approval of the low-residue technology for use in military applications.

  9. In the developing rat hippocampus a tonic GABAA-mediated conductance selectively enhances the glutamatergic drive of principal cells

    PubMed Central

    Marchionni, Ivan; Omrani, Azar; Cherubini, Enrico

    2007-01-01

    In the adult hippocampus, two different forms of GABAA receptor-mediated inhibition have been identified: phasic and tonic. The first is due to the activation of GABAA receptors facing the presynaptic releasing sites, whereas the second is due to the activation of receptors localized away from the synapses. Because of their high affinity and low desensitization rate, extrasynaptic receptors are persistently able to sense low concentrations of GABA. Here we show that, early in postnatal life, between postnatal day (P) 2 and P6, CA1 and CA3 pyramidal cells but not stratum radiatum interneurons, express a tonic GABAA-mediated conductance. Block of the neuronal GABA transporter GAT-1 slightly enhanced the persistent GABA conductance in principal cells but not in GABAergic interneurons. However, in adulthood, a tonic GABAA-mediated conductance could be revealed in stratum radiatum interneurons, indicating that the ability of these cells to sense ambient GABA levels is developmentally regulated. Pharmacological analysis of the tonic conductance in principal cells demonstrated the involvement of β2/β3, α5 and γ2 GABAA receptor subunits. Removal of the tonic depolarizing action of GABA with picrotoxin, reduced the excitability and the glutamatergic drive of principal cells but did not modify the excitability of stratum radiatum interneurons. The increased cell excitability and synaptic activity following the activation of extrasynaptic GABAA receptors by ambient GABA would facilitate the induction of giant depolarizing potentials. PMID:17317750

  10. Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata

    PubMed Central

    Hasson, H.; Bojar, M.; Moshé, S. L.; Galanopoulou, A. S.

    2015-01-01

    Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age-and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved. PMID:25645446

  11. Anticonvulsant effects of mefloquine on generalized tonic-clonic seizures induced by two acute models in rats.

    PubMed

    Franco-Pérez, Javier; Ballesteros-Zebadúa, Paola; Manjarrez-Marmolejo, Joaquín

    2015-03-01

    Mefloquine can cross the blood-brain barrier and block the gap junction intercellular communication in the brain. Enhanced electrical coupling mediated by gap junctions is an underlying mechanism involved in the generation and maintenance of seizures. For this reason, the aim of this study was to analyze the effects of the systemic administration of mefloquine on tonic-clonic seizures induced by two acute models such as pentylenetetrazole and maximal electroshock. All the control rats presented generalized tonic-clonic seizures after the administration of pentylenetetrazole. However, the incidence of seizures induced by pentylenetetrazole significantly decreased in the groups administered systematically with 40 and 80 mg/kg of mefloquine. In the control group, none of the rats survived after the generalized tonic-clonic seizures induced by pentylenetetrazole, but survival was improved by mefloquine. Besides, mefloquine significantly modified the total spectral power as well as the duration, amplitude and frequency of the epileptiform activity induced by pentylenetetrazole. For the maximal electroshock model, mefloquine did not change the occurrence of tonic hindlimb extension. However, this gap junction blocker significantly decreased the duration of the tonic hindlimb extension induced by the acute electroshock. These data suggest that mefloquine at low doses might be eliciting some anticonvulsant effects when is systemically administered to rats.

  12. Tracer attenuation in groundwater

    NASA Astrophysics Data System (ADS)

    Cvetkovic, Vladimir

    2011-12-01

    The self-purifying capacity of aquifers strongly depends on the attenuation of waterborne contaminants, i.e., irreversible loss of contaminant mass on a given scale as a result of coupled transport and transformation processes. A general formulation of tracer attenuation in groundwater is presented. Basic sensitivities of attenuation to macrodispersion and retention are illustrated for a few typical retention mechanisms. Tracer recovery is suggested as an experimental proxy for attenuation. Unique experimental data of tracer recovery in crystalline rock compare favorably with the theoretical model that is based on diffusion-controlled retention. Non-Fickian hydrodynamic transport has potentially a large impact on field-scale attenuation of dissolved contaminants.

  13. Aberrant long-range functional connectivity density in generalized tonic-clonic seizures.

    PubMed

    Zhu, Ling; Li, Yibo; Wang, Yifeng; Li, Rong; Zhang, Zhiqiang; Lu, Guangming; Chen, Huafu

    2016-06-01

    Studies in generalized tonic-clonic seizures (GTCS) have reported both structural and functional alterations in the brain. However, changes in spontaneous neuronal functional organization in GTCS remain largely unknown.In this study, 70 patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures and 70 age- and sex-matched healthy controls were recruited. Here, functional connectivity density (FCD) mapping, an ultrafast data-driven method based on functional magnetic resonance imaging (fMRI), was applied for the first time to investigate the changes of spontaneous functional brain activity caused by epilepsy.The results showed significantly decreased long-range FCD in the middle and inferior temporal, prefrontal, and inferior parietal cortices as well as increased long-range FCD in the cerebellum anterior lobe and sensorimotor areas. Negative correlation between duration of disease and reduced long-range FCD was found. In addition, most regions with reduced long-range FCD showed decreased resting-state functional connectivity (rsFC) within default mode network.Negative correlation between duration of disease and long-range FCD may reflect an adverse consequence eventually from original. Furthermore, the observed FCD and rsFC alterations have been speculated to be associated with the social-cognitive impairments as well as motor control. Our study provided novel evidences to look into neuro-pathophysiological mechanisms underlying GTCS.

  14. Tonic inhibition and ponto-geniculo-occipital-related activities shape abducens motoneuron discharge during REM sleep

    PubMed Central

    Escudero, Miguel; Márquez-Ruiz, Javier

    2008-01-01

    Eye movements, ponto-geniculo-occipital (PGO) waves, muscular atonia and desynchronized cortical activity are the main characteristics of rapid eye movement (REM) sleep. Although eye movements designate this phase, little is known about the activity of the oculomotor system during REM sleep. In this work, we recorded binocular eye movements by the scleral search-coil technique and the activity of identified abducens (ABD) motoneurons along the sleep–wake cycle in behaving cats. The activity of ABD motoneurons during REM sleep was characterized by a tonic decrease of their mean firing rate throughout this period, and short bursts and pauses coinciding with the occurrence of PGO waves. We demonstrate that the decrease in the mean firing discharge was due to an active inhibition of ABD motoneurons, and that the occurrence of primary and secondary PGO waves induced a pattern of simultaneous but opposed phasic activation and inhibition on each ABD nucleus. With regard to eye movements, during REM sleep ABD motoneurons failed to codify eye position as during alertness, but continued to codify eye velocity. The pattern of tonic inhibition and the phasic activations and inhibitions shown by ABD motoneurons coincide with those reported in other non-oculomotor motoneurons, indicating that the oculomotor system – contrary to what has been accepted until now – is not different from other motor systems during REM sleep, and that all motor systems are receiving similar command signals during this period. PMID:18499728

  15. Characterization of cortical source generators based on electroencephalography during tonic pain.

    PubMed

    Hansen, Tine Maria; Mark, Esben Bolvig; Olesen, Søren Schou; Gram, Mikkel; Frøkjær, Jens Brøndum; Drewes, Asbjørn Mohr

    2017-01-01

    The aim of the present study was to characterize the cortical source generators evoked by experimental tonic pain. Electroencephalography (EEG) was recorded on two separate days during rest and with immersion of the hand in ice water for 2 minutes (cold pressor test). Exact low-resolution brain electromagnetic tomography source localization was performed in 31 healthy volunteers to characterize the cortical source generators. Reliability was high in all eight frequency bands during rest and cold pressor conditions (intraclass coefficients =0.47-0.83 in the cingulate and insula). Tonic pain increased cortical activities in the delta (1-4 Hz), theta (4-8 Hz), beta1 (12-18 Hz), beta2 (18-24 Hz), beta3 (24-32 Hz), and gamma (32-60 Hz) bands (all P<0.011) in widespread areas mainly in the limbic system, whereas decreased cortical activities were found in cingulate and pre- and postcentral gyri in the alpha2 (10-12 Hz) band (P=0.007). The pain intensity was correlated with cingulate activity in the beta2, beta3, and gamma bands (all P<0.04). Source localization of EEG is a reliable method to estimate cortical source generators. Activities in different brain regions, mainly in the limbic system, showed fluctuations in various frequency bands. Cingulate changes were correlated with pain intensity. This method might add information to the objective assessment of the cortical pain response in future experimental pain studies.

  16. Hydration status affects nuclear distribution of transcription factor tonicity responsive enhancer binding protein in rat kidney.

    PubMed

    Cha, J H; Woo, S K; Han, K H; Kim, Y H; Handler, J S; Kim, J; Kwon, H M

    2001-11-01

    Tonicity responsive enhancer binding protein (TonEBP) is the transcription factor that regulates tonicity responsive expression of proteins that catalyze cellular accumulation of compatible osmolytes. In cultured MDCK cells, hypertonicity stimulates the activity of TonEBP via a combination of increased protein abundance and increased nuclear localization. For investigating regulation of TonEBP in the kidney, rats were subjected to water loading or dehydration. Water loading lowered urine osmolality and mRNA expression of sodium/myo-inositol cotransporter (SMIT), a target gene of TonEBP, in the renal medulla; dehydration doubled the urine osmolality and increased SMIT mRNA expression. In contrast, overall abundance of TonEBP and its mRNA measured by immunoblot and ribonuclease protection assay, respectively, was not affected. Immunohistochemical analysis, however, revealed that nuclear distribution of TonEBP is generally increased throughout the medulla in dehydrated animals compared with water loaded animals. Increased nuclear localization was particularly dramatic in thin limbs. Notable exceptions were the middle to terminal portions of the inner medullary collecting ducts and blood vessels, where a change in TonEBP distribution was not evident. Immunohistochemical detection of SMIT mRNA revealed that the changes in nuclear distribution of TonEBP correlate with expression of SMIT. It is concluded that under physiologic conditions, nucleocytoplasmic distribution is the dominant mode of regulation of TonEBP in the renal medulla.

  17. Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion

    PubMed Central

    Gradilone, Sergio A.; Masyuk, Anatoliy I.; Splinter, Patrick L.; Banales, Jesus M.; Huang, Bing Q.; Tietz, Pamela S.; Masyuk, Tatyana V.; LaRusso, Nicholas F.

    2007-01-01

    Cholangiocytes, epithelial cells lining the biliary tree, have primary cilia extending from their apical membrane into the ductal lumen. Although important in disease, cilia also play a vital role in normal cellular functions. We reported that cholangiocyte cilia are sensory organelles responding to mechanical stimuli (i.e., luminal fluid flow) by alterations in intracellular Ca2+ and cAMP. Because cholangiocyte cilia are also ideally positioned to detect changes in composition and tonicity of bile, we hypothesized that cilia also function as osmosensors. TRPV4, a Ca2+-permeable ion channel, has been implicated in signal transduction of osmotic stimuli. Using purified rat cholangiocytes and perfused intrahepatic bile duct units (IBDUs), we found that TRPV4 is expressed on cholangiocyte cilia, and that hypotonicity induces an increase in intracellular Ca2+ in a TRPV4-, ciliary-, and extracellular calcium-dependent manner. The osmosensation of luminal tonicity by ciliary TRPV4 induces bicarbonate secretion, the main determinant of ductal bile formation, by a mechanism involving apical ATP release. Furthermore, the activation of TRPV4 in vivo, by its specific agonist, 4αPDD, induces an increase in bile flow as well as ATP release and bicarbonate secretion. Our results suggest that cholangiocyte primary cilia play an important role in ductal bile formation by acting as osmosensors. PMID:18024594

  18. Regulation of Urea Transporters by Tonicity-responsive Enhancer Binding Protein.

    PubMed

    Jung, Ju-Young; Kwon, H Moo; Kim, Jim

    2007-06-01

    Urea accumulation in the renal inner medulla plays a key role in the maintenance of maximal urinary concentrating ability. Urea transport in the kidney is mediated by transporter proteins that include renal urea transporter (UT-A) and erythrocyte urea transporter (UT-B). UT-A1 and UT-A2 are produced from the same gene. There is an active tonicity-responsive enhancer (TonE) in the promoter of UT-A1, and the UT-A1 promoter is stimulated by hypertonicity via tonicity-responsive enhancer binding protein (TonEBP). The downregulation of UT-A2 raises the possibility that TonEBP also regulates its promoter. There is some evidence that TonEBP regulates expression of UT-A in vivo; (1) during the renal development of the urinary concentrating ability, expression of TonEBP precedes that of UT-A1; (2) in transgenic mice expressing a dominant negative form of TonEBP, expression of UT-A1 and UT-A2 is severely impaired; (3) in treatment with cyclosporine A, TonEBP was significantly downregulated after 28 days. This downregulation involves mRNA levels of UT-A2; (4) in hypokalemic animals, downregulation of TonEBP contributed to the down regulation of UT-A in the inner medulla. These data support that TonEBP directly contributes to the urinary concentration and renal urea recycling by the regulation of urea transporters.

  19. [Effects of endotheline and nitric oxide on vascular tonicity in patients with chronic cardiac failure].

    PubMed

    Denisov, E N; Kots, Ia I; Bakhtiiarov, R Z; Gumanova, N G

    2007-01-01

    To examine effects of endotheline-1 (ET-1) and nitric oxide (NO) on endothelium-dependent mechanisms of vascular tonicity regulation in patients with chronic cardiac failure (CCF) of FC I-IV (NYHA). Vascular reactions of 94 patients with CCF of FC I-IV were examined according to D.S. Celermajer method using ultrasound of high resolution. Tissue oxygenation was studied with transcutaneous polarography (TCM-2, Radiometer). Parameters of circulating erythrocytes were studied by impurity spectrum. Endothelial NO-synthase expression was determined with application of monoclonal antibodies to endothelial NO-synthase. NO metabolites were studied with colorimetric method using Griss reagent. ET-1 was measured in plasma by enzyme immunoassay. The control group consisted of 28 healthy men aged 20 to 54 years. Patients with CCF of FC I-IV have reduced endothelium-dependent vascular reactions progressing with aggravation of CCF. The causes of the disorders lie in altered metabolism of ET-1 and NO in CCF. CCF patients demonstrate changes in endothelium-dependent mechanisms of vascular tonicity regulation caused by disturbed metabolism of ET-1 and NO developing in abnormal regime of tissue oxygenation and depending on CCF severity.

  20. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression.

    PubMed

    López-Rodríguez, Cristina; Antos, Christopher L; Shelton, John M; Richardson, James A; Lin, Fangming; Novobrantseva, Tatiana I; Bronson, Roderick T; Igarashi, Peter; Rao, Anjana; Olson, Eric N

    2004-02-24

    The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl--coupled betaine/gamma-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function.

  1. Regulation of Urea Transporters by Tonicity-responsive Enhancer Binding Protein

    PubMed Central

    Kwon, H. Moo; Kim, Jim

    2007-01-01

    Urea accumulation in the renal inner medulla plays a key role in the maintenance of maximal urinary concentrating ability. Urea transport in the kidney is mediated by transporter proteins that include renal urea transporter (UT-A) and erythrocyte urea transporter (UT-B). UT-A1 and UT-A2 are produced from the same gene. There is an active tonicity-responsive enhancer (TonE) in the promoter of UT-A1, and the UT-A1 promoter is stimulated by hypertonicity via tonicity-responsive enhancer binding protein (TonEBP). The downregulation of UT-A2 raises the possibility that TonEBP also regulates its promoter. There is some evidence that TonEBP regulates expression of UT-A in vivo; (1) during the renal development of the urinary concentrating ability, expression of TonEBP precedes that of UT-A1; (2) in transgenic mice expressing a dominant negative form of TonEBP, expression of UT-A1 and UT-A2 is severely impaired; (3) in treatment with cyclosporine A, TonEBP was significantly downregulated after 28 days. This downregulation involves mRNA levels of UT-A2; (4) in hypokalemic animals, downregulation of TonEBP contributed to the down regulation of UT-A in the inner medulla. These data support that TonEBP directly contributes to the urinary concentration and renal urea recycling by the regulation of urea transporters. PMID:24459497

  2. Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion.

    PubMed

    Gradilone, Sergio A; Masyuk, Anatoliy I; Splinter, Patrick L; Banales, Jesus M; Huang, Bing Q; Tietz, Pamela S; Masyuk, Tatyana V; Larusso, Nicholas F

    2007-11-27

    Cholangiocytes, epithelial cells lining the biliary tree, have primary cilia extending from their apical membrane into the ductal lumen. Although important in disease, cilia also play a vital role in normal cellular functions. We reported that cholangiocyte cilia are sensory organelles responding to mechanical stimuli (i.e., luminal fluid flow) by alterations in intracellular Ca(2+) and cAMP. Because cholangiocyte cilia are also ideally positioned to detect changes in composition and tonicity of bile, we hypothesized that cilia also function as osmosensors. TRPV4, a Ca(2+)-permeable ion channel, has been implicated in signal transduction of osmotic stimuli. Using purified rat cholangiocytes and perfused intrahepatic bile duct units (IBDUs), we found that TRPV4 is expressed on cholangiocyte cilia, and that hypotonicity induces an increase in intracellular Ca(2+) in a TRPV4-, ciliary-, and extracellular calcium-dependent manner. The osmosensation of luminal tonicity by ciliary TRPV4 induces bicarbonate secretion, the main determinant of ductal bile formation, by a mechanism involving apical ATP release. Furthermore, the activation of TRPV4 in vivo, by its specific agonist, 4alphaPDD, induces an increase in bile flow as well as ATP release and bicarbonate secretion. Our results suggest that cholangiocyte primary cilia play an important role in ductal bile formation by acting as osmosensors.

  3. Tonic pupil after botulinum toxin-A injection for treatment of esotropia in children

    PubMed Central

    2016-01-01

    A total of 27 children with esotropia (mean age, 3.9 years; range, 9 months to 13.8 years) were enrolled in a 9-month observational study following botulinum toxin A (BTX-A) injection of one (n = 7) or both (n = 20) medial rectus muscles. BTX-A dosage ranged from 3.0 to 6.0 units per muscle. Three participants developed tonic pupil, noted at the first follow-up visit, occurring 12-19 days after injection. All 3 cases occurred in the left eye of participants who underwent bilateral BTX-A injection by the same surgeon. Anisocoria diminished from a maximum of 4 mm at the 2-week visit to 1–2 mm in all patients over the 9-month postinjection data collection period. No adverse visual outcomes were noted. Tonic pupil is an infrequently reported complication of BTX-A injection for strabismus. The experience of our investigator group suggests the need for careful injection technique and thorough preinjection counseling. PMID:26917081

  4. A matching pursuit algorithm for inferring tonic sympathetic arousal from spontaneous skin conductance fluctuations

    PubMed Central

    Staib, Matthias

    2015-01-01

    Abstract Tonic sympathetic arousal is often inferred from spontaneous fluctuations in skin conductance, and this relies on assumptions about the shape of these fluctuations and how they are generated. We have previously furnished a psychophysiological model for this relation, and an efficient and reliable inversion method to estimate tonic arousal from given data in the framework of dynamic causal modeling (DCM). Here, we provide a fast alternative inversion method in the form of a matching pursuit (MP) algorithm. Analyzing simulated data, this algorithm approximates the true underlying arousal up to about 10 spontaneous fluctuations per minute of data. For empirical data, we assess predictive validity as the ability to differentiate two known psychological arousal states. Predictive validity is comparable between the methods for three datasets, and also comparable to visual peak scoring. Computation time of the MP algorithm is 2–3 orders of magnitude faster for the MP than the DCM algorithm. In summary, the new MP algorithm provides a fast and reliable alternative to DCM inversion for SF data, in particular when the expected number of fluctuations is lower than 10 per minute, as in typical experimental situations. PMID:25930177

  5. The vanilloid receptor TRPV1 is tonically activated in vivo and involved in body temperature regulation.

    PubMed

    Gavva, Narender R; Bannon, Anthony W; Surapaneni, Sekhar; Hovland, David N; Lehto, Sonya G; Gore, Anu; Juan, Todd; Deng, Hong; Han, Bora; Klionsky, Lana; Kuang, Rongzhen; Le, April; Tamir, Rami; Wang, Jue; Youngblood, Brad; Zhu, Dawn; Norman, Mark H; Magal, Ella; Treanor, James J S; Louis, Jean-Claude

    2007-03-28

    The vanilloid receptor TRPV1 (transient receptor potential vanilloid 1) is a cation channel that serves as a polymodal detector of pain-producing stimuli such as capsaicin, protons (pH <5.7), and heat. TRPV1 antagonists block pain behaviors in rodent models of inflammatory, neuropathic, and cancer pain, suggesting their utility as analgesics. Here, we report that TRPV1 antagonists representing various chemotypes cause an increase in body temperature (hyperthermia), identifying a potential issue for their clinical development. Peripheral restriction of antagonists did not eliminate hyperthermia, suggesting that the site of action is predominantly outside of the blood-brain barrier. Antagonists that are ineffective against proton activation also caused hyperthermia, indicating that blocking capsaicin and heat activation of TRPV1 is sufficient to produce hyperthermia. All TRPV1 antagonists evaluated here caused hyperthermia, suggesting that TRPV1 is tonically activated in vivo and that TRPV1 antagonism and hyperthermia are not separable. TRPV1 antagonists caused hyperthermia in multiple species (rats, dogs, and monkeys), demonstrating that TRPV1 function in thermoregulation is conserved from rodents to primates. Together, these results indicate that tonic TRPV1 activation regulates body temperature.

  6. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression

    PubMed Central

    López-Rodríguez, Cristina; Antos, Christopher L.; Shelton, John M.; Richardson, James A.; Lin, Fangming; Novobrantseva, Tatiana I.; Bronson, Roderick T.; Igarashi, Peter; Rao, Anjana; Olson, Eric N.

    2004-01-01

    The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl–-coupled betaine/γ-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function. PMID:14983020

  7. Diffuse noxious inhibitory control evoked by tonic craniofacial pain in humans.

    PubMed

    Sowman, P F; Wang, K; Svensson, P; Arendt-Nielsen, L

    2011-02-01

    Tonic pain in one body segment can inhibit the perception of pain in another body segment. This phenomenon is mediated by diffuse noxious inhibitory controls (DNIC), and its efficacy in craniofacial regions is investigated in this study. A compressive device that evoked a tonic, moderate/severe, headache-like, conditioning pain (∼8/10 on a visual analogue scale) was applied for 15min. Eleven males participated in the study. Pressure pain threshold (PPT) and pressure pain tolerance (PPTol) at multiple heterosegmental body sites (right masseter, splenius capitis, second intermediate phalange, brachioradialis and tibialis anterior) were measured before, during and at multiple time points (5, 20 and 35min) after the termination of the conditioning pain. PPTs and PPTols were compared within participants across two experimental sessions; one that included painful conditioning stimulation, and a separate control session on a different day. Painful conditioning increased PPT significantly during pain over the masseter (p<0.05) and over the tibialis anterior (p<0.01). PPTol was unchanged. In the period after the painful conditioning stimulation PPT was depressed compared to control. This study shows that pain evoked from the craniofacial region evokes DNIC-like mechanisms on segmental as well as heterosegmental sites.

  8. To Take Risk is to Face Loss: A Tonic Pupillometry Study

    PubMed Central

    Yechiam, Eldad; Telpaz, Ariel

    2011-01-01

    The construct of risk taking is studied through the prism of the relation between tonic arousal and risk taking behavior. Several theories have proposed that high aroused individuals tend to exhibit risk aversion. We posit that this arousal–behavior association is activated much more strongly in risks with losses, as losses increase arousal and trigger relevant traits associated with the sensitivity to risk. In three studies we examined risk taking in experience-based decision tasks, with either token losses or relative-losses (in the gain domain). In Study 1 we found a negative correlation between pre-task pupil diameter and risk taking in the loss domain but not in the gain domain. In Study 2 we re-analyzed a previous pupillometry dataset involving symmetric mixed gains and losses. We found that the negative correlation in this mixed condition emerged even while the participants did not show loss aversion. This finding was replicated in Study 3. Thus, the effect of losses on arousal provides sufficient conditions for the moderation of the tonic arousal–behavior association. The findings suggest an important role for losses in the psychological and physiological experience of risk. PMID:22125546

  9. Phasic and tonic alerting in mild cognitive impairment: A preliminary study.

    PubMed

    Martella, Diana; Manzanares, Salvadora; Campoy, Guillermo; Roca, Javier; Antúnez, Carmen; Fuentes, Luis J

    2014-01-01

    In this preliminary study we assessed the functioning of the different attentional networks in mild cognitive impairment (MCI) patients, taking as theoretical framework the Posner's cognitive neuroscience approach. Two groups of participants were tested in a single short experiment: 20 MCI patients (6 amnestic, 6 non-amnestic and 8 multiple-domain) and 18 healthy matched controls (HC). For attentional assessment we used a version of the Attention Network Test (the ANTI-V) that provided not only a score of the orienting, the executive, and the alerting networks and their interactions, but also an independent measure of vigilance (tonic alerting). The results showed that all subtypes of MCI patients exhibited a selective impairment in the tonic component of alerting, as indexed by a decrease in the d' sensitivity index, and their performance in executive network increased up to the HC group level when phasic alerting was provided by a warning tone. Our findings suggest that a core attentional deficit, especially the endogenous component of alerting, may significantly contribute to the behavioral and cognitive deficits associated with MCI.

  10. The electroclinical-semiology of generalized tonic-clonic seizures among different epilepsies.

    PubMed

    Pan, S P; Wang, F; Zhang, Y; Wang, J

    2015-11-01

    The study reported here discusses the duration of the generalized tonic-clonic seizures (GTCS) among frontal lobe epilepsy (FLE), medial temporal lobe epilepsy (MTLE) and idiopathic generalized epilepsy (IGE). The study was done by analyzing the data from patients who had undergone video-EEG in 2009 and had GTCS during the monitoring. The patients were selected for the frontal lobe epilepsy (FLE), medial temporal lobe epilepsy (MTLE), and idiopathic generalized epilepsy (IGE). Once they met the criteria, the durations of all the phases were measured, then discussed if there were any difference in duration for different epilepsies. On comparison of the total duration of various types of seizures it was found that the duration of FLE (177 ± 212.6 sec.) was significantly different from the duration of MTLE (104.6 ± 51.8 sec.) and IGE (63.9 ± 28.2 sec.). It can be found in the comparison of GTCS that the duration of phase 6,7 of FLE (63.5 ± 30.9 sec.) was statistically significant compared with MTLE (37.3 ± 13.8 sec.) and IGE (46.4 ± 30.1 sec.). The duration of various types of epilepsy in the generalized tonic-clonic period was not statistically significant. Through this study, we found the differences of the duration of different types of epilepsies that provide the clinical basis for further studies of seizure mechanism and neural network conduction.

  11. Attentional control affects the relationship between tonic immobility and intrusive memories.

    PubMed

    Hagenaars, Muriel A; Putman, Peter

    2011-09-01

    Cognitive control and tonic immobility (TI) have both been implicated in the development of PTSD, but it is not known how these factors are related. The present study investigated if a specific form of cognitive control (attentional control) would moderate the relationship between TI and intrusive memories. Participants (N = 43) completed the Attentional Control Scale (ACS) before watching an aversive film. They completed the Tonic Immobility Scale (TIS, with an immobility and fear subscale: TIS-TI and TIS-Fear) afterwards and recorded intrusive memories of the film in the subsequent week. TIS-TI was related to intrusion frequency, while ACS was not. However, ACS had a moderating role; the relationship between TIS-TI and intrusion frequency was significant in low ACS but not in high ACS participants. The TIS-Fear subscale was not related to intrusion frequency in low ACS or high ACS participants. Replication of the results is merited in selected extreme groups and males. The results may imply that enhanced attentional control serves as a protective factor against the development of intrusive memories after trauma. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Analgesia induced by morphine microinjected into the nucleus raphe magnus: effects on tonic pain.

    PubMed

    Dualé, Christian; Sierralta, Fernando; Dallel, Radhouane

    2007-07-01

    One of the possible sites of action of the analgesic effect of morphine is the Nucleus Raphe Magnus, as morphine injected into this structure induces analgesia in transient pain models. In order to test if morphine in the Nucleus Raphe Magnus is also analgesic in a tonic pain model, 5 microg of morphine or saline (control) were microinjected into the Nucleus Raphe Magnus of the rat. Analgesic effects were assessed following nociceptive stimulation using transient heating of the tail (phasic pain) and subcutaneous orofacial injection of 1.5 % formalin (tonic pain). While morphine was strongly analgesic for the tail-flick response (p <0.0001 compared to control), analgesia on the response to formalin was also observed for both early (p = 0.007) and late responses (p = 0.02). However, the response to formalin was not completely blunted. These results suggest that the Nucleus Raphe Magnus is not the exclusive site of action of morphine-induced analgesia in clinical conditions.

  13. Role of SM22 in the differential regulation of phasic vs. tonic smooth muscle

    PubMed Central

    Ali, Mehboob

    2015-01-01

    Preliminary proteomics studies between tonic vs. phasic smooth muscles identified three distinct protein spots identified to be those of transgelin (SM22). The latter was found to be distinctly downregulated in the internal anal sphincter (IAS) vs. rectal smooth muscle (RSM) SMC. The major focus of the present studies was to examine the differential molecular control mechanisms by SM22 in the functionality of truly tonic smooth muscle of the IAS vs. the adjoining phasic smooth muscle of the RSM. We monitored SMC lengths before and after incubation with pFLAG-SM22 (for SM22 overexpression), and SM22 small-interfering RNA. pFLAG-SM22 caused concentration-dependent and significantly greater relaxation in the IAS vs. the RSM SMCs. Conversely, temporary silencing of SM22 caused contraction in both types of the SMCs. Further studies revealed a significant reverse relationship between the levels of SM22 phosphorylation and the amount of SM22-actin binding in the IAS and RSM SMC. Data showed higher phospho-SM22 levels and decreased SM22-actin binding in the IAS, and reverse to be the case in the RSM SMCs. Experiments determining the mechanism for SM22 phosphorylation in these smooth muscles revealed that Y-27632 (Rho kinase inhibitor) but not Gö-6850 (protein kinase C inhibitor) caused concentration-dependent decreased phosphorylation of SM22. We speculate that SM22 plays an important role in the regulation of basal tone via Rho kinase-induced phosphorylation of SM22. PMID:25617350

  14. The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons

    PubMed Central

    Lutas, Andrew; Lahmann, Carolina; Soumillon, Magali; Yellen, Gary

    2016-01-01

    Certain neuron types fire spontaneously at high rates, an ability that is crucial for their function in brain circuits. The spontaneously active GABAergic neurons of the substantia nigra pars reticulata (SNr), a major output of the basal ganglia, provide tonic inhibition of downstream brain areas. A depolarizing 'leak' current supports this firing pattern, but its molecular basis remains poorly understood. To understand how SNr neurons maintain tonic activity, we used single-cell RNA sequencing to determine the transcriptome of individual mouse SNr neurons. We discovered that SNr neurons express the sodium leak channel, NALCN, and that SNr neurons lacking NALCN have impaired spontaneous firing. In addition, NALCN is involved in the modulation of excitability by changes in glycolysis and by activation of muscarinic acetylcholine receptors. Our findings suggest that disruption of NALCN could impair the basal ganglia circuit, which may underlie the severe motor deficits in humans carrying mutations in NALCN. DOI: http://dx.doi.org/10.7554/eLife.15271.001 PMID:27177420

  15. Systematic changes in tonic physiological activities during the Concealed Information Test.

    PubMed

    Ogawa, Tokihiro; Matsuda, Izumi; Hirota, Akihisa; Takasawa, Noriyoshi

    2014-12-01

    Many studies on the Concealed Information Test have focused on phasic physiological changes that are temporally locked to stimulus presentation. However, little is known about changes in tonic, basal physiological levels throughout a stimulus series. This study focused on changes in tonic physiological activities during the CIT. Thirty-nine participants carried out a mock theft and subsequently received a CIT. Skin conductance, heart rate, and normalized pulse volume (NPV) were recorded. The pre-stimulus physiological level of these measures throughout the CIT series was compared across a question series with different serial positions of the relevant item. Results showed that changes in the pre-stimulus level differed depending on the serial position of the relevant item. Skin conductance declined throughout the series, but showed a transient increase after relevant item presentation. Heart rate was relatively constant throughout the series, but decreased after relevant item presentation. NPV continued to decrease until the relevant item, but increased thereafter, indicating a pattern similar to the classic Peak of Tension concept. In addition, the pre-stimulus NPV showed a significant relevant-irrelevant difference. Theoretical and practical implications of these findings are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Issues in Stratospheric Ozone Depletion.

    NASA Astrophysics Data System (ADS)

    Lloyd, Steven Andrew

    Following the announcement of the discovery of the Antarctic ozone hole in 1985 there have arisen a multitude of questions pertaining to the nature and consequences of polar ozone depletion. This thesis addresses several of these specific questions, using both computer models of chemical kinetics and the Earth's radiation field as well as laboratory kinetic experiments. A coupled chemical kinetic-radiative numerical model was developed to assist in the analysis of in situ field measurements of several radical and neutral species in the polar and mid-latitude lower stratosphere. Modeling was used in the analysis of enhanced polar ClO, mid-latitude diurnal variation of ClO, and simultaneous measurements of OH, HO_2, H_2 O and O_3. Most importantly, such modeling was instrumental in establishing the link between the observed ClO and BrO concentrations in the Antarctic polar vortex and the observed rate of ozone depletion. The principal medical concern of stratospheric ozone depletion is that ozone loss will lead to the enhancement of ground-level UV-B radiation. Global ozone climatology (40^circS to 50^ circN latitude) was incorporated into a radiation field model to calculate the biologically accumulated dosage (BAD) of UV-B radiation, integrated over days, months, and years. The slope of the annual BAD as a function of latitude was found to correspond to epidemiological data for non-melanoma skin cancers for 30^circ -50^circN. Various ozone loss scenarios were investigated. It was found that a small ozone loss in the tropics can provide as much additional biologically effective UV-B as a much larger ozone loss at higher latitudes. Also, for ozone depletions of > 5%, the BAD of UV-B increases exponentially with decreasing ozone levels. An important key player in determining whether polar ozone depletion can propagate into the populated mid-latitudes is chlorine nitrate, ClONO_2 . As yet this molecule is only indirectly accounted for in computer models and field

  17. Orbitofrontal Dopamine Depletion Upregulates Caudate Dopamine and Alters Behavior via Changes in Reinforcement Sensitivity

    PubMed Central

    Cardinal, R. N.; Rygula, R.; Hong, Y. T.; Fryer, T. D.; Sawiak, S. J.; Ferrari, V.; Cockcroft, G.; Aigbirhio, F. I.; Robbins, T. W.; Roberts, A. C.

    2014-01-01

    Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia. PMID:24872570

  18. [Clinical observations on effects on prognostic factor treating hepatitis B-related cirrhosis with purification purgation dispersion tonicity].

    PubMed

    Yang, Hongzhi; Li, Chuntao; Wang, Yongze; Guan, Weibin; Yang, Yuewu

    2003-11-01

    With prognostic factors as assessment standards, the effects of combination of TCM(purification purgation dispersion tonicity) and western medicine treating hepatitis B-related cirrhosis and its complications were assessed. In this study, study group and control group were divided, the number of each group was 30. In order to keep balance between the two groups, matching control design was adopted with Wang's 8 prognostic factors as matching conditions. In study group, except Hb, TBIL, ALB and PT had statistic difference, and the complications of cirrhosis such as ascites, HEP and UGH were treated with significant effects. Between study group and control group, in all of prognostic factors only TBIL had statistical diffirence. It suggested the effects were significant treating hepatitis B-related cirrhosis and its complications with combination of TCM(purification purgation dispersion tonicity) and western medicine. It also suggested that TCM therapy combining purification, purgation, dispersion and tonicity had significant effects on reducing jaundice.

  19. Physiological implications of anthropogenic environmental calcium depletion

    Treesearch

    Catherine H. Borer; Paul G. Schaberg; Donald H. DeHayes; Gary J. Hawley

    2001-01-01

    Recent evidence indicates that numerous anthropogenic factors can deplete calcium (Ca) from forested ecosystems. Although it is difficult to quantify the extent of this depletion, some reports indicate that the magnitude of Ca losses may be substantial. The potential for Ca depletion raises important questions about tree health. Only a fraction of foliar Ca is...

  20. Exposure to nature counteracts aggression after depletion.

    PubMed

    Wang, Yan; She, Yihan; Colarelli, Stephen M; Fang, Yuan; Meng, Hui; Chen, Qiuju; Zhang, Xin; Zhu, Hongwei

    2017-08-31

    Acts of self-control are more likely to fail after previous exertion of self-control, known as the ego depletion effect. Research has shown that depleted participants behave more aggressively than non-depleted participants, especially after being provoked. Although exposure to nature (e.g., a walk in the park) has been predicted to replenish resources common to executive functioning and self-control, the extent to which exposure to nature may counteract the depletion effect on aggression has yet to be determined. The present study investigated the effects of exposure to nature on aggression following depletion. Aggression was measured by the intensity of noise blasts participants delivered to an ostensible opponent in a competition reaction-time task. As predicted, an interaction occurred between depletion and environmental manipulations for provoked aggression. Specifically, depleted participants behaved more aggressively in response to provocation than non-depleted participants in the urban condition. However, provoked aggression did not differ between depleted and non-depleted participants in the natural condition. Moreover, within the depletion condition, participants in the natural condition had lower levels of provoked aggression than participants in the urban condition. This study suggests that a brief period of nature exposure may restore self-control and help depleted people regain control over aggressive urges. © 2017 Wiley Periodicals, Inc.

  1. Tonic inhibition of accumbal spiny neurons by extrasynaptic α4βδ GABAA receptors modulates the actions of psychostimulants.

    PubMed

    Maguire, Edward P; Macpherson, Tom; Swinny, Jerome D; Dixon, Claire I; Herd, Murray B; Belelli, Delia; Stephens, David N; King, Sarah L; Lambert, Jeremy J

    2014-01-15

    Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ(-/-) or α4(-/-) mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4(-/-) mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4(D1-/-)) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4(-/-) or α4(D1-/-) mice, blocked cocaine enhancement of CPP. In comparison, α4(D2-/-) mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors.

  2. Brain dysplasia evoked by gamma irradiation at different stages of prenatal development leads to different tonic and clonic seizure reactivity.

    PubMed

    Setkowicz, Zuzanna; Gzieło-Jurek, Kinga; Uram, Łukasz; Janicka, Dominika; Janeczko, Krzysztof

    2014-01-01

    Rats with brain dysplasia evoked by interruption of different stages of prenatal neurogenesis show characteristic variations in susceptibility to seizures depending on the neurochemical specificity of pharmacological agents used to evoke seizures. To verify a discrepancy between the data obtained using different pharmacological models, neurochemically neutral electroshocks were applied here. To produce brain dysplasia of different degrees, pregnant Wistar rats were exposed to a single 1.0Gy dose of gamma rays on gestation days 13, 15, 17 or 19. From the postnatal day 60, their male offspring (E13s, E15s, E17s and E19s, respectively) were subjected to 21 daily electrical stimulations to evoke seizures. Profiles of tonic and clonic reactivity to electrical stimulation significantly differed from those observed following pilocarpine or kainic acid administration. E17s showed minimal intensity of tonic but maximal of clonic responses. On the contrary, very high tonic and low clonic reactivity was observed in E13s and E15s. Periventricular nodular heterotopias (PNHs) were observed exclusively in E15s and E17s. Generally, the size of PNHs was correlated positively with susceptibility to tonic seizures but negatively with susceptibility to clonic seizures. Analogous correlations with the size of the neocortex were opposite. E13s and E19s had brains devoid PNHs but showed high tonic seizure susceptibility similar to that in E15s. It can therefore be concluded that PNHs modified the type of seizure reactivity from tonic to clonic, depending of their size, but the presence of PNHs was not necessary for the development of seizure susceptibility itself.

  3. Agreement between clinical and laboratory methods assessing tonic and cross-link components of accommodation and vergence.

    PubMed

    Neveu, Pascaline; Priot, Anne-Emmanuelle; Philippe, Matthieu; Fuchs, Philippe; Roumes, Corinne

    2015-09-01

    Several tests are available to optometrists for investigating accommodation and vergence. This study sought to investigate the agreement between clinical and laboratory methods and to clarify which components are actually measured when tonic and cross-link of accommodation and vergence are assessed. Tonic vergence, tonic accommodation, accommodative vergence (AC/A) and vergence accommodation (CA/C) were measured using several tests. Clinical tests were compared to the laboratory assessment, the latter being regarded as an absolute reference. The repeatability of each test and the degree of agreement between the tests were quantified using Bland-Altman analysis. The values obtained for each test were found to be stable across repetitions; however, in most cases, significant differences were observed between tests supposed to measure the same oculomotor component. Tonic and cross-link components cannot be easily assessed because proximal and instrumental responses interfere with the assessment. Other components interfere with oculomotor assessment. Specifically, accommodative divergence interferes with tonic vergence estimation and the type of accommodation considered in the AC/A ratio affects its magnitude. Results on clinical tonic accommodation and clinical CA/C show that further investigation is needed to clarify the limitations associated with the use of difference of Gaussian as visual targets to open the accommodative loop. Although different optometric tests of accommodation and vergence rely on the same basic principles, the results of this study indicate that clinical and laboratory methods actually involve distinct components. These differences, which are induced by methodological choices, must be taken into account, when comparing studies or when selecting a test to investigate a particular oculomotor component. © 2015 The Authors. Clinical and Experimental Optometry © 2015 Optometry Australia.

  4. Tonic Inhibition of Accumbal Spiny Neurons by Extrasynaptic α4βδ GABAA Receptors Modulates the Actions of Psychostimulants

    PubMed Central

    Maguire, Edward P.; Macpherson, Tom; Swinny, Jerome D.; Dixon, Claire I.; Herd, Murray B.; Belelli, Delia; Stephens, David N.

    2014-01-01

    Within the nucleus accumbens (NAc), synaptic GABAA receptors (GABAARs) mediate phasic inhibition of medium spiny neurons (MSNs) and influence behavioral responses to cocaine. We demonstrate that both dopamine D1- and D2-receptor-expressing MSNs (D-MSNs) additionally harbor extrasynaptic GABAARs incorporating α4, β, and δ subunits that mediate tonic inhibition, thereby influencing neuronal excitability. Both the selective δ-GABAAR agonist THIP and DS2, a selective positive allosteric modulator, greatly increased the tonic current of all MSNs from wild-type (WT), but not from δ−/− or α4−/− mice. Coupling dopamine and tonic inhibition, the acute activation of D1 receptors (by a selective agonist or indirectly by amphetamine) greatly enhanced tonic inhibition in D1-MSNs but not D2-MSNs. In contrast, prolonged D2 receptor activation modestly reduced the tonic conductance of D2-MSNs. Behaviorally, WT and constitutive α4−/− mice did not differ in their expression of cocaine-conditioned place preference (CPP). Importantly, however, mice with the α4 deletion specific to D1-expressing neurons (α4D1−/−) showed increased CPP. Furthermore, THIP administered systemically or directly into the NAc of WT, but not α4−/− or α4D1−/− mice, blocked cocaine enhancement of CPP. In comparison, α4D2−/− mice exhibited normal CPP, but no cocaine enhancement. In conclusion, dopamine modulation of GABAergic tonic inhibition of D1- and D2-MSNs provides an intrinsic mechanism to differentially affect their excitability in response to psychostimulants and thereby influence their ability to potentiate conditioned reward. Therefore, α4βδ GABAARs may represent a viable target for the development of novel therapeutics to better understand and influence addictive behaviors. PMID:24431441

  5. Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain.

    PubMed

    McCracken, Lindsay M; Lowes, Daniel C; Salling, Michael C; Carreau-Vollmer, Cyndel; Odean, Naomi N; Blednov, Yuri A; Betz, Heinrich; Harris, R Adron; Harrison, Neil L

    2017-08-22

    Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3(-/-)) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2(-/Y) animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.

  6. Effects of solution tonicity on crossbridge properties and myosin lever arm disposition in intact frog muscle fibres

    PubMed Central

    Colombini, Barbara; Bagni, Maria Angela; Cecchi, Giovanni; Griffiths, Peter John

    2007-01-01

    The aims of this study were to investigate the effects of solution tonicity on muscle properties, and to verify their consistence with the lever arm theory of force generation. Experiments were made in single muscle fibres and in fibre bundles from the frog, using both fast stretches and time-resolved X-ray diffraction, in isotonic Ringer solution (1T), hypertonic (1.4T) and hypotonic (0.8T) solutions. Fast stretches (0.4–0.6 ms duration and 16–25 nm per half-sarcomere (nm hs−1) amplitude) were applied at various tensions during the force development in isometric tetani. Force increased during the stretch up to a peak (critical tension, Pc) at which it started to fall, in spite of continued stretching. In all solutions, Pc was proportional to the initial isometric tension developed. For a given isometric tension, Pc increased with solution tonicity and occurred at a precise sarcomere elongation (critical length, Lc) which also increased with tonicity. M3 meridional layer line intensity (IM3) was measured during the application of sinusoidal length oscillations (1 kHz frequency, and about 2% fibre length amplitude) at tetanus plateau. IM3 changed during the length oscillations in a sinusoidal manner in phase opposition to length changes, but a double peak distortion occurred at the peak of the release phase. The presence of the distortion, which decreased with tonicity, allowed calculation of the mean position of the myosin head (S1) during the oscillation cycle. In agreement with the lever arm theory, both X-ray diffraction and mechanical data show that solution tonicity affects S1 mean position and consequently crossbridge individual extension and force, with no effect on crossbridge number. The force needed to break the single crossbridge was insensitive to solution tonicity suggesting a non-ionic nature of the actomyosin bond. PMID:17023505

  7. Effects of solution tonicity on crossbridge properties and myosin lever arm disposition in intact frog muscle fibres.

    PubMed

    Colombini, Barbara; Bagni, Maria Angela; Cecchi, Giovanni; Griffiths, Peter John

    2007-01-01

    The aims of this study were to investigate the effects of solution tonicity on muscle properties, and to verify their consistence with the lever arm theory of force generation. Experiments were made in single muscle fibres and in fibre bundles from the frog, using both fast stretches and time-resolved X-ray diffraction, in isotonic Ringer solution (1T), hypertonic (1.4T) and hypotonic (0.8T) solutions. Fast stretches (0.4-0.6 ms duration and 16-25 nm per half-sarcomere (nm hs(-1)) amplitude) were applied at various tensions during the force development in isometric tetani. Force increased during the stretch up to a peak (critical tension, Pc) at which it started to fall, in spite of continued stretching. In all solutions, Pc was proportional to the initial isometric tension developed. For a given isometric tension, Pc increased with solution tonicity and occurred at a precise sarcomere elongation (critical length, Lc) which also increased with tonicity. M3 meridional layer line intensity (I M3) was measured during the application of sinusoidal length oscillations (1 kHz frequency, and about 2% fibre length amplitude) at tetanus plateau. I M3 changed during the length oscillations in a sinusoidal manner in phase opposition to length changes, but a double peak distortion occurred at the peak of the release phase. The presence of the distortion, which decreased with tonicity, allowed calculation of the mean position of the myosin head (S1) during the oscillation cycle. In agreement with the lever arm theory, both X-ray diffraction and mechanical data show that solution tonicity affects S1 mean position and consequently crossbridge individual extension and force, with no effect on crossbridge number. The force needed to break the single crossbridge was insensitive to solution tonicity suggesting a non-ionic nature of the actomyosin bond.

  8. Initiation of hyperpermeability in energy-depleted coronary endothelial monolayers.

    PubMed

    Noll, T; Muhs, A; Besselmann, M; Watanabe, H; Piper, H M

    1995-04-01

    How the initiation of energy depletion affects macromolecule permeability of a barrier of coronary endothelial cells was investigated. Cultured monolayers of adult rat coronary endothelial cells were exposed to 5 mM KCN and 5 mM 2-deoxy-D-glucose (2-DG). Transendothelial flux of albumin, cellular ATP content, and cytosolic Ca2+ concentration were monitored. Within the first minute, a merely partial loss (28%) of ATP reserves provoked a distinct increase (41%) in albumin flux. Rise of permeability was dependent on Ca2+ release from a thapsigargin- and ATP-sensitive endogenous store, and hyperpermeability was greatly attenuated when energy depletion was extremely rapid, as under sequential addition of 20 mM 2-DG and 5 mM KCN. Attenuation of hyperpermeability could also be achieved by use of 5-20 mM 2,3-butanedione monoxime, an inhibitor of actin-myosin interaction. This finding, together with dependence on Ca2+ and availability of residual energy, indicates that the rapid initiation of hyperpermeability is caused by a contractile mechanism.

  9. The Case of Ozone Depletion

    NASA Technical Reports Server (NTRS)

    Lambright, W. Henry

    2005-01-01

    While the National Aeronautics and Space Administration (NASA) is widely perceived as a space agency, since its inception NASA has had a mission dedicated to the home planet. Initially, this mission involved using space to better observe and predict weather and to enable worldwide communication. Meteorological and communication satellites showed the value of space for earthly endeavors in the 1960s. In 1972, NASA launched Landsat, and the era of earth-resource monitoring began. At the same time, in the late 1960s and early 1970s, the environmental movement swept throughout the United States and most industrialized countries. The first Earth Day event took place in 1970, and the government generally began to pay much more attention to issues of environmental quality. Mitigating pollution became an overriding objective for many agencies. NASA's existing mission to observe planet Earth was augmented in these years and directed more toward environmental quality. In the 1980s, NASA sought to plan and establish a new environmental effort that eventuated in the 1990s with the Earth Observing System (EOS). The Agency was able to make its initial mark via atmospheric monitoring, specifically ozone depletion. An important policy stimulus in many respects, ozone depletion spawned the Montreal Protocol of 1987 (the most significant international environmental treaty then in existence). It also was an issue critical to NASA's history that served as a bridge linking NASA's weather and land-resource satellites to NASA s concern for the global changes affecting the home planet. Significantly, as a global environmental problem, ozone depletion underscored the importance of NASA's ability to observe Earth from space. Moreover, the NASA management team's ability to apply large-scale research efforts and mobilize the talents of other agencies and the private sector illuminated its role as a lead agency capable of crossing organizational boundaries as well as the science-policy divide.

  10. Reward and Behavioral Factors Contributing to the Tonic Activity of Monkey Pedunculopontine Tegmental Nucleus Neurons during Saccade Tasks

    PubMed Central

    Okada, Ken-ichi; Kobayashi, Yasushi

    2016-01-01

    The pedunculopontine tegmental nucleus (PPTg) in the brainstem plays a role in controlling reinforcement learning and executing conditioned behavior. We previously examined the activity of PPTg neurons in monkeys during a reward-conditioned, visually guided saccade task, and reported that a population of these neurons exhibited tonic responses throughout the task period. These tonic responses might depend on prediction of the upcoming reward, successful execution of the task, or both. Here, we sought to further distinguish these factors and to investigate how each contributes to the tonic neuronal activity of the PPTg. In our normal visually guided saccade task, the monkey initially fixated on the central fixation target (FT), then made saccades to the peripheral saccade target and received a juice reward after the saccade target disappeared. Most of the tonic activity terminated shortly after the reward delivery, when the monkey broke fixation. To distinguish between reward and behavioral epochs, we then changed the task sequence for a block of trials, such that the saccade target remained visible after the reward delivery. Under these visible conditions, the monkeys tended to continue fixating on the saccade target even after the reward delivery. Therefore, the prediction of the upcoming reward and the end of an individual trial were separated in time. Regardless of the task conditions, half of the tonically active PPTg neurons terminated their activity around the time of the reward delivery, consistent with the view that PPTg neurons might send reward prediction signals until the time of reward delivery, which is essential for computing reward prediction error in reinforcement learning. On the other hand, the other half of the tonically active PPTg neurons changed their activity dependent on the task condition. In the normal condition, the tonic responses terminated around the time of the reward delivery, while in the visible condition, the activity continued

  11. Regulation of excitability in tonic firing substantia gelatinosa neurons of the spinal cord by small-conductance Ca(2+)-activated K(+) channels.

    PubMed

    Yang, Kun

    2016-06-01

    The excitability of substantia gelatinosa (SG) neurons in the spinal dorsal horn determines the processing of nociceptive information from the periphery to the central nervous system. Small conductance Ca(2+)-activated K(+) (SK) channels on neurons supply strong negative feedback control on neuronal excitability by affecting afterhyperpolarization (AHP). However, the role of SK channels in regulating tonic-firing SG neuron excitability remains elusive. In the present study, whole-cell recordings were conducted in SG neurons from acute spinal cord slices of adult rats. The SK channel opener 1-ethyl-2-benzimidazolinone (1-EBIO) attenuated spike discharges and increased AHP amplitudes; this effect was mimicked by a high Ca(2+) external solution. Systemic administration of 1-EBIO attenuated the thermal-induced nociception behavior. Conversely, the inhibition of SK channels with apamin, a specific SK channel inhibitor, increased neuronal excitability and decreased the AHP amplitudes; this effect was mimicked by a Ca(2+)-free external solution. Apamin increased excitatory synaptic transmission by increasing the amplitudes of evoked excitatory postsynaptic potentials (eEPSPs). This facilitation depended on N-methyl-d-aspartate (NMDA) receptors, extracellular Mg(2+) and intracellular Ca(2+). Voltage-gated Ca(2+) channels (VGCCs) were also involved in the apamin-induced effects. Strikingly, 1-EBIO action on decreasing excitability persisted in the presence of apamin, indicating that 1-EBIO manipulates SK channels via a pathway rather than via apamin-sensitive SK channels. The data reveal a previously uncharacterized mechanism for manipulating SG neuronal excitability by Ca(2+) conductances via both apamin-sensitive and apamin-insensitive pathways. Because SG neurons in the dorsal horn are involved in regulating nociception, manipulating neuronal excitability via SK channels indicates a potential therapeutic target. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Tonic Regulation of GABAergic Synaptic Activity on Vasopressin Neurones by Cannabinoids

    PubMed Central

    Wang, Lie; Armstrong, William E.

    2011-01-01

    Synaptic activity in magnocellular neurosecretory neurones is influenced by the retrograde (i.e., somatodendritic) release of vasopressin, oxytocin and cannabinoids (CBs). For oxytocin neurones, oxytocin exerts constitutive effects on presynaptic activity through its ability to release CBs postsynaptically. In the present study we examined evoked and spontaneous inhibitory postsynaptic currents (IPSCs) in identified vasopressin (VP) neurones in coronal slices from virgin rats to determine: 1) the extent to which CBs may also tonically modulate VP synaptic activity; and 2) to determine if depolarization induced suppression of inhibition was present in VP neurones, and if so, whether it was mediated by VP or CBs. The CB1 antagonists AM251 (1 μM) and SR14171 (1 μM) consistently increased the frequency of spontaneous IPSCs (sIPSCs) in VP neurones without affecting their amplitude, suggesting a tonic CB presence. This effect on frequency was independent of action potential activity, and blocked by chelating intracellular calcium with10 mM EGTA. AM251 also increased the amplitude of evoked IPSCs (eIPSCs) and decreased the paired-pulse ratio (PPR) in VP neurones- effects that were completely blocked with even low (1 mM EGTA) internal calcium chelation. Bouts of evoked firing of VP neurones consistently suppressed sIPSCs, but had no effect on eIPSCs or the PPR. This depolarization-induced suppression of IPSCs was reduced by AM251, and was totally blocked by 10 μM of the mixed vasopressin/oxytocin antagonist, Manning Compound. We then tested the effect of vasopressin on IPSCs while blocking CB1 receptors. Vasopressin (10-100 nM) inhibited sIPSC frequency, but had no effect on sIPSC or eIPSC amplitudes, or on the PPR, in the presence of AM251. Together these results suggest a tonic, presynaptic inhibitory modulation of IPSCs in VP neurones by CBs that is largely dependent on postsynaptic calcium, and an inhibitory effect of VP on IPSCs that is independent of CB release

  13. Tonic regulation of GABAergic synaptic activity on vasopressin neurones by cannabinoids.

    PubMed

    Wang, L; Armstrong, W E

    2012-04-01

    Synaptic activity in magnocellular neurosecretory neurones is influenced by the retrograde (i.e. somatodendritic) release of vasopressin, oxytocin and cannabinoids (CBs). For oxytocin neurones, oxytocin exerts constitutive effects on pre-synaptic activity through its ability to release CBs post-synaptically. In the present study, we examined evoked inhibitory post-synaptic currents (eIPSCs) and spontaneous inhibitory post-synaptic currents (sIPSCs) in identified vasopressin (VP) neurones in coronal slices from virgin rats to determine: (i) the extent to which CBs may also tonically modulate VP synaptic activity; and (ii) to determine whether depolarisation-induced suppression of inhibition was present in VP neurones, and if so, whether it was mediated by VP or CBs. The CB1 antagonists AM251 (1 μm) and SR14171 (1 μm) consistently increased the frequency of sIPSCs in VP neurones without affecting their amplitude, suggesting a tonic CB presence. This effect on frequency was independent of action potential activity, and blocked by chelating intracellular calcium with 10 mm ethylene glycol tetraacetic acid (EGTA). AM251 also increased the amplitude of eIPSCs and decreased the paired-pulse ratio (PPR) in VP neurones-effects that were completely blocked with even low (1 mm EGTA) internal calcium chelation. Bouts of evoked firing of VP neurones consistently suppressed sIPSCs but had no effect on eIPSCs or the PPR. This depolarisation-induced suppression of IPSCs was reduced by AM251, and was totally blocked by 10 μm of the mixed vasopressin/oxytocin antagonist, Manning compound. We then tested the effect of vasopressin on IPSCs at the same time as blocking CB1 receptors. Vasopressin (10-100 nm) inhibited sIPSC frequency but had no effect on sIPSC or eIPSC amplitudes, or on the PPR, in the presence of AM251. Taken together, these results suggest a tonic, pre-synaptic inhibitory modulation of IPSCs in VP neurones by CBs that is largely dependent on post-synaptic calcium

  14. Tonic and phasic tetrodotoxin block of sodium channels with point mutations in the outer pore region.

    PubMed Central

    Boccaccio, A; Moran, O; Imoto, K; Conti, F

    1999-01-01

    Tonic and use-dependent block by tetrodotoxin (TTX) has been studied in cRNA-injected Xenopus oocytes expressing mutants W386Y, E945Q, D1426K, and D1717Q, of the outer-pore region of the rat brain IIA alpha-subunit of sodium channels. The various phenotypes are tonically half-blocked at TTX concentrations, IC50(t), that span a range of more than three orders of magnitude, from 4 nM in mutant D1426K to 11 microM in mutant D1717Q. When stimulated with repetitive depolarizing pulses at saturating frequencies, all channels showed a monoexponential increase in their TTX-binding affinity with time constants that span an equally wide range of values ([TTX] approximately IC50(t), from approximately 60 s for D1426K to approximately 30 ms for D1717Q) and are in most phenotypes roughly inversely proportional to IC50(t). In contrast, all phenotypes show the same approximately threefold increase in their TTX affinity under stimulation. The invariance of the free-energy difference between tonic and phasic configurations of the toxin-receptor complex, together with the extreme variability of phasic block kinetics, is fully consistent with the trapped-ion mechanism of use dependence suggested by and developed by. Using this model, we estimated for each phenotype both the second-order association rate constant, kon, and the first-order dissociation rate constant, koff, for TTX binding. Except for mutant E945Q, all phenotypes have roughly the same value of kon approximately 2 microM-1 s-1 and owe their large differences in IC50(t) to different koff values. However, a 60-fold reduction in kon is the main determinant of the low TTX sensitivity of mutant E945Q. This suggests that the carboxyl group of E945 occupies a much more external position in the pore vestibule than that of the homologous residue D1717. PMID:10388752

  15. Variable laser attenuator

    DOEpatents

    Foltyn, Stephen R.

    1988-01-01

    The disclosure relates to low loss, high power variable attenuators comprng one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength.

  16. Variable laser attenuator

    DOEpatents

    Foltyn, S.R.

    1987-05-29

    The disclosure relates to low loss, high power variable attenuators comprising one or more transmissive and/or reflective multilayer dielectric filters. The attenuator is particularly suitable to use with unpolarized lasers such as excimer lasers. Beam attenuation is a function of beam polarization and the angle of incidence between the beam and the filter and is controlled by adjusting the angle of incidence the beam makes to the filter or filters. Filters are selected in accordance with beam wavelength. 9 figs.

  17. Biomedical consequences of ozone depletion

    NASA Astrophysics Data System (ADS)

    Coohill, Thomas P.

    1994-07-01

    It is widely agreed that a portion of the earth's protective stratospheric ozone layer is being depleted. The major effect of this ozone loss will be an increase in the amount of ultraviolet radiation (UV reaching the biosphere. This increase will be completely contained within the UVB (290nm - 320nm). It is imperative that assessments be made of the effects of this additional UVB on living organisms. This requires a detailed knowledge of the UVB photobiology of these life forms. One analytical technique to aid in the approximations is the construction of UV action spectra for such important biological end-points as human skin cancer, cataracts, immune suppression; plant photosynthesis and crop yields; and aquatic organism responses to UVB, especially the phytoplankton. Combining these action spectra with the known solar spectrum (and estimates for various ozone depletion scenarios) can give rise to a series of effectiveness spectra for these parameters. This manuscript gives a first approximation, rough estimate, for the effectiveness spectra for some of these bioresponses, and a series of crude temporary values for how a 10% ozone loss would affect the above end-points. These are not intended to masquerade as final answers, but rather, to serve as beginning attempts for a process which should be continually refined. It is hoped that these estimates will be of some limited use to agencies, such as government and industry, that have to plan now for changes in human activities that might alter future atmospheric chemistry in a beneficial manner.

  18. Microwave variable waveguide attenuator.

    PubMed

    Fabeni, P; Mugnai, D; Pazzi, G P; Ranfagni, A

    2008-06-01

    A new type of cutoff attenuator is presented. The attenuator works in the X-band in conditions of almost perfect matching. This means that the phase of the wave, which propagates inside the guide, does not suffer sensible variation in the passage between X- and K(u)-bands. Moreover, the attenuator works directly in the X-band, avoiding the passage between waveguide and cable, thus eliminating spurious effects due to this (double) passage. Experimental results of attenuation and dephasing using a prototype are also presented.

  19. Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

    PubMed

    Nolan, Sarah J; Marson, Anthony G; Pulman, Jennifer; Tudur Smith, Catrin

    2013-08-23

    This is an updated version of the previously published Cochrane review (Issue 4, 2009)Worldwide, phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset seizures, and that valproate is more effective for generalised onset tonic-clonic seizures with or without other generalised seizure types. To review the best evidence comparing phenytoin and valproate when used as monotherapy in individuals with partial onset seizures or generalised onset tonic-clonic seizures with or without other generalised seizure types. We searched the Cochrane Epilepsy Group's Specialised Register (19 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, The Cochrane Library, January 2013), MEDLINE (1946 to 18 February 2013), SCOPUS (19 February 2013), ClinicalTrials.gov (19 February 2013), and WHO International Clinical Trials Registry Platform ICTRP (19 February 2013). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of valproate monotherapy versus phenytoin monotherapy. This was an individual patient data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. Individual patient data were available for 669 individuals out of 1119 eligible individuals from five out of 11 trials, 60% of the potential data. Results apply to generalised tonic-clonic seizures, but not absence or myoclonus seizure types. For remission outcomes, HR > 1 indicates an

  20. The tripartite origins of the tonic neck reflex: Gesell, Gerstmann, and Magnus.

    PubMed

    Shevell, Michael

    2009-03-03

    The standard neurologic examination of the newborn and infant includes the elicitation of the tonic neck reflex. Normally present, its persistence is suggestive of neurologic dysfunction and a prognostic marker highly suggestive of an adverse outcome. Working in different fields, with different approaches and largely independently, three leaders of early 20th century neurosciences (Rudolf Magnus, Josef Gerstmann, and Arnold Gesell) elaborated different aspects of this primitive reflex. Magnus provided the first description in an animal model utilizing a meticulously prepared decerebrate cat correctly identifying the reflex's reliance on proprioceptors in the neck and processing in the upper cervical segment. Gerstmann first described its occurrence in the setting of neurologic disease, providing a meticulous written description in an early description of the index case of what would later be eponymously designated Gerstmann-Straussler-Scheinker syndrome. Gesell initially described the reflex's fundamental occurrence in normal young infants, highlighting its adaptive role in early development and its persistence as a hallmark of neurologic pathology.

  1. Relationships among Eysenck's extraversion, Rorschach's Erlebnistypus, and tolerance of experimental tonic pain (Cold Water Pressor Test).

    PubMed

    Ferracuti, Stefano; De Carolis, Antonella

    2005-02-01

    In a group of 42 healthy volunteers the correlations between the concept of Extraversion-Introversion as defined by Eysenck and Erlebnistypus as defined by Rorschach were analysed to relate these with the tolerance of an experimentally induced tonic pain. We conducted an experimental procedure comprising a test and retest. At test the subjects were administered the Rorschach, the Eysenck Personality Inventory, the Cold Water Pressor Test, a nongraduated Visual Analogue Scale, and the Italian version of the McGill Pain Questionnaire. At retest the experimental induction of pain was measured again. At test subjects who scored higher on the EPI Extraversion scale tolerated pain longer and did not modify their performance at retest. Also, the concepts of Extroversion defined by the Rorschach test and by the Extraversion scale of the Eysenck Personality Inventory shared some psychophysiological features of higher tolerance to pain. These personality features did not influence how subjects qualitatively describe the immediate painful experience.

  2. Segmental facial anhidrosis and tonic pupils with preserved deep tendon reflexes: a novel autonomic neuropathy.

    PubMed

    Kalapesi, Freny B; Krishnan, Arun V; Kiernan, Matthew C

    2005-03-01

    A 31-year-old woman had exertional right-sided hemifacial flushing and sweating. Examination demonstrated slightly dilated pupils with absent constriction to light and a tonic near response and redilatation, features consistent with Adie syndrome. Neurological examination was otherwise normal, including preservation of deep tendon reflexes. Magnetic resonance imaging of brain and spine were normal. The combination of unilateral loss of sudomotor and vasomotor activity without loss of ocular sympathetic innervation fulfills the diagnosis of Harlequin syndrome. The combination of Harlequin and Adie syndromes has been called Ross syndrome, but the preservation of deep tendon reflexes precludes a diagnosis of Ross syndrome in our patient. This previously undescribed variant adds further complexity to the spectrum of autonomic neuropathies.

  3. Painful generalised clonic and tonic-clonic seizures with retained consciousness

    PubMed Central

    Bell, W.; Walczak, T.; Shin, C.; Radtke, R.

    1997-01-01

    Two patients in whom consciousness and memory were retained during bilateral clonic or tonic-clonic seizures are reported on, and three patients reported on previously are reviewed. Ictal semiology differed from myoclonic and supplementary motor seizures, which are other seizure types characterised by bilateral motor movements and retained awareness. In the two new patients ictal pain was a prominent feature. It is proposed that propagation of seizure activity may be confined to the sensorimotor areas bilaterally while sparing the neural structures involved in maintaining consciousness and in processing language and memory. This unusual type of seizure may be misdiagnosed as a pseudoseizure. Detailed description of the ictal events and further laboratory evaluation including video-EEG monitoring may be necessary to make the distinction.

 PMID:9416819

  4. Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel.

    PubMed

    Kitchen, Philip; Day, Rebecca E; Taylor, Luke H J; Salman, Mootaz M; Bill, Roslyn M; Conner, Matthew T; Conner, Alex C

    2015-07-03

    The aquaporin family of integral membrane proteins is composed of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves PKA activation, influx of extracellular calcium, and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain edema. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. Identification and Molecular Mechanisms of the Rapid Tonicity-induced Relocalization of the Aquaporin 4 Channel*

    PubMed Central

    Kitchen, Philip; Day, Rebecca E.; Taylor, Luke H. J.; Salman, Mootaz M.; Bill, Roslyn M.; Conner, Matthew T.; Conner, Alex C.

    2015-01-01

    The aquaporin family of integral membrane proteins is composed of channels that mediate cellular water flow. Aquaporin 4 (AQP4) is highly expressed in the glial cells of the central nervous system and facilitates the osmotically driven pathological brain swelling associated with stroke and traumatic brain injury. Here we show that AQP4 cell surface expression can be rapidly and reversibly regulated in response to changes of tonicity in primary cortical rat astrocytes and in transfected HEK293 cells. The translocation mechanism involves PKA activation, influx of extracellular calcium, and activation of calmodulin. We identify five putative PKA phosphorylation sites and use site-directed mutagenesis to show that only phosphorylation at one of these sites, serine 276, is necessary for the translocation response. We discuss our findings in the context of the identification of new therapeutic approaches to treating brain edema. PMID:26013827

  6. Luminal fluid tonicity regulates airway ciliary beating by altering membrane stretch and intracellular calcium.

    PubMed

    Horváth, György; Sorscher, Eric J

    2008-06-01

    The coordinated, directional beating of airway cilia drives airway mucociliary clearance. Here we explore the hypothesis that airway surface liquid osmolarity is a key regulator of ciliary beating. Cilia in freshly isolated human and murine airways visualized with streaming video-microscopy exhibited a reciprocal dependence on a physiological range of luminal fluid osmolarities, across the entire range of ciliary activity (0-20 beats per sec). Increasing osmolarity slowed or completely abrogated, while lower osmolarity dramatically stimulated ciliary beating. In parallel, epithelial cell height and importantly, intracellular calcium levels (as judged by fluorescence imaging) also changed. Moreover, ciliary beating was stimulated by isosmotic solutions containing membrane permeant osmolytes, suggesting that cell size and membrane stretch (governed by apical fluid tonicity), rather than osmolarity itself, contribute to the activation. These findings shed light on the pathophysiology of diseases of mucociliary clearance such as cystic fibrosis and other chronic inflammatory lung diseases. Copyright 2008 Wiley-Liss, Inc.

  7. Program running versus problem solving: mental task effect on tonic heart rate.

    PubMed

    Sosnowski, Tytus; Krzywosz-Rynkiewicz, Beata; Roguska, Joanna

    2004-05-01

    It was hypothesized that mental tasks that involve program running (RUN tasks) would cause a greater tonic heart rate (HR) increase than tasks that require the search for problem solutions (EDIT tasks). Three experiments using verbal, numeric, and graphic material were run to compare tasks matched for difficulty but differing in qualitative demands (RUN vs. EDIT tasks). As predicted, filling in missing letters in words caused a larger HR increase than finding words that were logical continuations of a series of words (Experiment 1) and performing arithmetic operations caused a greater HR increase than logical completion of a series of digits (Experiment 2). In Experiment 3, two of three tasks that demanded counting of graphic elements caused a larger HR increase than a task that required logical completion of a series of graphic elements. Experiments 1 and 2 also showed that RUN tasks evoked greater phasic HR acceleration than EDIT tasks.

  8. Toward a theoretical role for tonic norepinephrine in the orbitofrontal cortex in facilitating flexible learning.

    PubMed

    Sadacca, Brian F; Wikenheiser, Andrew M; Schoenbaum, Geoffrey

    2017-03-14

    To adaptively respond in a complex, changing world, animals need to flexibly update their understanding of the world when their expectations are violated. Though several brain regions in rodents and primates have been implicated in aspects of this updating, current models of orbitofrontal cortex (OFC) and norepinephrine neurons of the locus coeruleus (LC-NE) suggest that each plays a role in responding to environmental change, where the OFC allows updating of prior learning to occur without overwriting or unlearning one's previous understanding of the world that changed, while elevated tonic NE allows for increased flexibility in behavior that tracks an animal's uncertainty. In light of recent studies highlighting a specific LC-NE projection to the OFC, in this review we discuss current models of OFC and NE function, and their potential synergy in the updating of associations following environmental change.

  9. The Effect of Tonicity and Metabolic Inhibitors on Respiration and Ripening of Avocado Fruit Slices 1

    PubMed Central

    Tingwa, Peter O.; Young, Roy E.

    1974-01-01

    The ripening of avocado (Persea americana Mill.) fruit slices was inhibited whether they were floated in water or in buffered aqueous 0.3 m mannitol, 0.25 m KCl, and sucrose. There was no evidence to support the contention that ripening occurred when the tonicity of the bathing medium was increased. Decreased gaseous exchange is considered to be a major cause of this inhibition because by utilizing a technique that afforded better aeration, slices could be water infiltrated and still ripen normally. Metabolic studies on the ripening of slices using this method indicated that several metabolic inhibitors, malonate, cyanide, acetaldehyde, dinitrophenol, and fluoride did not prevent ripening, but that their effect on the respiration pattern was marked. This technique provides a suitable way to study control of ripening at the tissue level. PMID:16658998

  10. Guaraná's Journey from Regional Tonic to Aphrodisiac and Global Energy Drink.

    PubMed

    Smith, Nigel; Atroch, André Luiz

    2010-09-01

    Guaraná (Paullinia cupana H.B.K., Sapindaceae) is a rainforest vine that was domesticated in the Amazon for its caffeine-rich fruits. Guaraná has long been used as a tonic and to treat various disorders in Brazil and abroad and became a national soda in Brazil about a century ago. In the last two decades or so, guaraná has emerged as a key ingredient in various 'sports' and energy drinks as well as concoctions that allegedly boost one's libido. For some time, guaraná's high caffeine content was thought to be a detriment because of health concerns about excessive intake of caffeine-rich drinks. But it is precisely this quality, and the fact that it has a mysterious name and comes from an exotic land, that has propelled guaraná into a global beverage.

  11. Guaraná's Journey from Regional Tonic to Aphrodisiac and Global Energy Drink

    PubMed Central

    Atroch, André Luiz

    2010-01-01

    Guaraná (Paullinia cupana H.B.K., Sapindaceae) is a rainforest vine that was domesticated in the Amazon for its caffeine-rich fruits. Guaraná has long been used as a tonic and to treat various disorders in Brazil and abroad and became a national soda in Brazil about a century ago. In the last two decades or so, guaraná has emerged as a key ingredient in various ‘sports’ and energy drinks as well as concoctions that allegedly boost one's libido. For some time, guaraná's high caffeine content was thought to be a detriment because of health concerns about excessive intake of caffeine-rich drinks. But it is precisely this quality, and the fact that it has a mysterious name and comes from an exotic land, that has propelled guaraná into a global beverage. PMID:18955289

  12. Hypomyelinating leukoencephalopathy with paroxysmal tonic upgaze and absence of psychomotor development.

    PubMed

    Blumkin, Lubov; Lev, Dorit; Watemberg, Nathan; Lerman-Sagie, Tally

    2007-01-15

    Hypomyelinating leukoencephalopathies are characterized by a substantial and permanent deficit in myelin deposition in the brain. Although our knowledge and understanding of the etiology of white matter diseases has progressively increased, many cases with this disorder remain undiagnosed, despite extensive evaluations. Recently, new disease entities have been defined by combining magnetic resonance imaging pattern recognition and clinical features. We describe a 1-year-old Ashkenazi Jewish girl with a hypomyelinating leukoencephalopathy, who presented in the neonatal period with episodes of sustained paroxysmal tonic upward gaze, roving eye movements, pendular nystagmus, and severe hypotonia, with the later appearance of pyramidal and extrapyramidal signs and no development. In addition, she has dysmorphic signs. This clinical picture is not consistent with any of the previously described hypomyelinating leukoencephalopathies and may represent a new entity.

  13. Tectal-derived interneurons contribute to phasic and tonic inhibition in the visual thalamus

    PubMed Central

    Jager, Polona; Ye, Zhiwen; Yu, Xiao; Zagoraiou, Laskaro; Prekop, Hong-Ting; Partanen, Juha; Jessell, Thomas M.; Wisden, William; Brickley, Stephen G.; Delogu, Alessio

    2016-01-01

    The release of GABA from local interneurons in the dorsal lateral geniculate nucleus (dLGN-INs) provides inhibitory control during visual processing within the thalamus. It is commonly assumed that this important class of interneurons originates from within the thalamic complex, but we now show that during early postnatal development Sox14/Otx2-expressing precursor cells migrate from the dorsal midbrain to generate dLGN-INs. The unexpected extra-diencephalic origin of dLGN-INs sets them apart from GABAergic neurons of the reticular thalamic nucleus. Using optogenetics we show that at increased firing rates tectal-derived dLGN-INs generate a powerful form of tonic inhibition that regulates the gain of thalamic relay neurons through recruitment of extrasynaptic high-affinity GABAA receptors. Therefore, by revising the conventional view of thalamic interneuron ontogeny we demonstrate how a previously unappreciated mesencephalic population controls thalamic relay neuron excitability. PMID:27929058

  14. T-Type Calcium Channels Mediate the Transition between Tonic and Phasic Firing in Thalamic Neurons

    NASA Astrophysics Data System (ADS)

    Suzuki, Setsuo; Rogawski, Michael A.

    1989-09-01

    Thalamic neurons undergo a shift from tonic to phasic (burst) firing upon hyperpolarization. This state transition results from deinactivation of a regenerative depolarizing event referred to as the low-threshold spike. Isolated adult guinea pig thalamic (dorsal lateral geniculate) neurons exhibited low-threshold spikes that could be blocked by low concentrations of nickel but were unaffected by the dihydropyridine nimodipine. Whole-cell voltage-clamp recordings from these cells demonstrated a low-threshold, rapidly inactivating (T) Ca2+ current that manifested similar voltage dependency and time course as the low-threshold spike. Like low-threshold spikes, the T-type Ca2+ current was eliminated by nickel but was unaffected by nimodipine. In thalamic neurons, T-type Ca2+ channels underlie the low-threshold spike and, therefore, play a critical role in regulating the firing pattern of these cells.

  15. Micro- and nano-mechanics of osteoarthritic cartilage: The effects of tonicity and disease severity.

    PubMed

    Moshtagh, P R; Pouran, B; van Tiel, J; Rauker, J; Zuiddam, M R; Arbabi, V; Korthagen, N M; Weinans, H; Zadpoor, A A

    2016-06-01

    The present study aims to discover the contribution of glycosaminoglycans (GAGs) and collagen fibers to the mechanical properties of the osteoarthritic (OA) cartilage tissue. We used nanoindentation experiments to understand the mechanical behavior of mild and severe osteoarthritic cartilage at micro- and nano-scale at different swelling conditions. Contrast enhanced micro-computed tomography (EPIC-μCT) was used to confirm that mild OA specimens had significantly higher GAGs content compared to severe OA specimens. In micro-scale, the semi-equilibrium modulus of mild OA specimens significantly dropped after immersion in a hypertonic solution and at nano-scale, the histograms of the measured elastic modulus revealed three to four components. Comparing the peaks with those observed for healthy cartilage in a previous study indicated that the first and third peaks represent the mechanical properties of GAGs and the collagen network. The third peak shows considerably stiffer elastic modulus for mild OA samples as compared to the severe OA samples in isotonic conditions. Furthermore, this peak clearly dropped when the tonicity increased, indicating the loss of collagen (pre-) stress in the shrunk specimen. Our observations support the association of the third peak with the collagen network. However, our results did not provide any direct evidence to support the association of the first peak with GAGs. For severe OA specimens, the peak associated with the collagen network did not drop when the tonicity increased, indicating a change in the response of OA cartilage to hypertonicity, likely collagen damage, as the disease progresses to its latest stages.

  16. Flor-Essence? Herbal Tonic Promotes Mammary Tumor Development in Sprague Dawley Rats

    SciTech Connect

    Bennett, L; Montgomery, J; Steinberg, S; Kulp, K

    2004-01-28

    Background: Women who are diagnosed with breast cancer often self-administer complementary and alternative medicines to augment their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} Tonic is a complex mixture of herbal extracts used by cancer patients because of anecdotal evidence that it can treat or prevent disease. Methods: Female Sprague Dawley rats were given water or exposed to 3% or 6% Flor-Essence{reg_sign} beginning at one day of age. Mammary tumors were induced with a single oral 40 mg/kg/bw dose of dimethylbenz(a)anthracene at 50 days of age and sacrificed at 23 weeks. Rats were maintained on AIN-76A diet. Results: Control rats had palpable mammary tumor incidence of 51.0% at 19 weeks of age compared to 65.0% and 59.4% for the 3% and 6% Flor-Essence{reg_sign} groups respectively. Overall, no significant difference in time until first palpable tumor was detected among any of the groups. At necropsy, mammary tumor incidence was 82.5% for controls compared to 90.0% and 97.3% for rats consuming 3% and 6% Flor-Essence{reg_sign}, respectively. Mean mammary tumor multiplicity ({+-}SES) for the controls was 2.8 ({+-} 0.5) and statistically different from the 3% or 6% Flor- Essence{reg_sign} groups with 5.2 ({+-} 0.7), and 4.8 ({+-} 0.6), respectively (p{<=}0.01). As expected, the majority of isolated tumors were diagnosed as adenocarcinomas. Conclusions: Flor-Essence{reg_sign} can promote mammary tumor development in the Sprague Dawley rat model. This observation is contrary to widely available anecdotal evidence as well as the desire of the consumer that this commercially available herbal tonic will suppress and/or inhibit tumor growth.

  17. Are effects of the symmetric and asymmetric tonic neck reflexes still visible in healthy adults?

    PubMed

    Bruijn, S M; Massaad, F; Maclellan, M J; Van Gestel, L; Ivanenko, Y P; Duysens, J

    2013-11-27

    When a cat's head is rotated in a transverse plane to one side, the legs on that side of the body extend, while on the other side, they flex (asymmetric tonic neck reflexes ATNR). On the contrary, when the head is rotated in a sagittal plane both legs flex when the head flexes, and extend when the head extends (symmetric tonic neck reflexes STNR). These reflexes have also been found in newborn babies and are thought to be a motor primitive, which is suppressed later in life. Still, using a test in which children sit on hand and knees, the ATNR and STNR can be found in children up to 9 years of age. This may suggest that these reflexes may still be involved in motor control in these children. Whether this is also the case in full-grown adults has thus far only been studied using coarse methods. Thus, for the current study, we set out to measure in detail whether the ATNR/STNR can still be evoked in healthy adult subjects. We measured 10 subjects who were asked to sit on their hands and knees while (1) their head was rotated left and right by an experimenter, (2) their head was flexed and extended by an experimenter. Kinematics was registered using a Vicon system. Elbow and head angles were detrended, and a regression analysis was performed, to investigate the effects of head angle on elbow angle. Results clearly showed the existence of the ATNR and STNR in adult subjects. A next step will be to assess the effects of the ATNR and STNR during everyday motor control tasks, such as making head rotations while driving a bike.

  18. Tonic Stretch Reflex Threshold as a Measure of Ankle Plantar-Flexor Spasticity After Stroke.

    PubMed

    Blanchette, Andreanne K; Mullick, Aditi A; Moïn-Darbari, Karina; Levin, Mindy F

    2016-05-01

    Commonly used spasticity scales assess the resistance felt by the evaluator during passive stretching. These scales, however, have questionable validity and reliability. The tonic stretch reflex threshold (TSRT), or the angle at which motoneuronal recruitment begins in the resting state, is a promising alternative for spasticity measurement. Previous studies showed that spasticity and voluntary motor deficits after stroke may be characterized by a limitation in the ability of the central nervous system to regulate the range of the TSRT. The study objective was to assess interevaluator reliability for TSRT plantar-flexor spasticity measurement. This was an interevaluator reliability study. In 28 people after stroke, plantar-flexor spasticity was evaluated twice on the same day. Plantar-flexor muscles were stretched 20 times at different velocities assigned by a portable device. Plantar-flexor electromyographic signals and ankle angles were used to determine dynamic velocity-dependent thresholds. The TSRT was computed by extrapolating a regression line through dynamic velocity-dependent thresholds to the angular axis. Mean TSRTs in evaluations 1 and 2 were 66.0 degrees (SD=13.1°) and 65.8 degrees (SD=14.1°), respectively, with no significant difference between them. The intraclass correlation coefficient (2,1) was .851 (95% confidence interval=.703, .928). The notion of dynamic stretch reflex threshold does not exclude the possibility that spasticity is dependent on acceleration, as well as on velocity; future work will study both possibilities. Tonic stretch reflex threshold interevaluator reliability for evaluating stroke-related plantar-flexor spasticity was very good. The TSRT is a reliable measure of spasticity. More information may be gained by combining the TSRT measurement with a measure of velocity-dependent resistance. © 2016 American Physical Therapy Association.

  19. Phasic and tonic stress-strain data obtained in intact intestinal segment in vitro.

    PubMed

    Zhao, Jingbo; Liao, Donghua; Gregersen, Hans

    2008-12-01

    The function of the small intestine is to a large degree mechanical, and it has the capability of deforming its shape by generating phasic (short-lasting) and tonic (sustained) contraction of the smooth muscle layers. The aim of this study was to obtain phasic and tonic stress-strain (normalized force-length) curves during distension of isolated rat jejunum and ileum (somewhat similar to the isometric length-tension diagram known from in vitro studies of muscle strips). We hypothesized that the circumferential stress-strain data depend on longitudinal stretch of the intestine. Intestinal segments were isolated from ten Wistar rats and put into an organ bath containing 37 degrees C aerated Krebs solution. Ramp distension was done on active and passive intestinal segments at longitudinal stretch ratios of 0, 10, and 20%. Ramp pressures from 0 to 7.5 cmH(2)O were applied to the intestinal lumen at each longitudinal stretch ratio. Passive conditions were obtained by adding the calcium antagonist papaverine to the solution. Total and passive circumferential stress and strain were computed from the length, diameter and pressure data and from the zero-stress state geometry. The active stress was defined as the total stress minus the passive stress. The total and passive circumferential stresses increased exponentially as a function of the strain. The amplitude of both the total and passive stress was biggest in the jejunum. The total circumferential stress decreased whereas the passive circumferential stress increased when the intestine was stretched longitudinally. Consequently, longitudinal stretching caused the active circumferential stress to decrease. The passive circumferential stress during longitudinal stretching increased more in the jejunum than in the ileum. Therefore, the active circumferential stress decreased most in the jejunum. In conclusion, the circumferential active-passive stress and strain depend on the longitudinal stretch and differs between the

  20. Timing of cortical excitability changes during the reaction time of movements superimposed on tonic motor activity.

    PubMed

    Schneider, Cyril; Lavoie, Brigitte A; Barbeau, Hugues; Capaday, Charles

    2004-12-01

    Seated subjects were instructed to react to an auditory cue by simultaneously contracting the tibialis anterior (TA) muscle of each ankle isometrically. Focal transcranial magnetic stimulation of the leg area of the motor cortex (MCx) was used to determine the time course of changes in motor-evoked potential amplitude (MEP) during the reaction time (RT). In one condition the voluntary contraction was superimposed on tonic EMG activity maintained at 10% of maximal voluntary contraction. In the other condition the voluntary contraction was made starting from rest. MEPs in the TA contralateral to the stimulation coil were evoked at various times during the RT in each condition. These were compared to the control MEPs evoked during tonic voluntary activity or with the subject at rest. The RT was measured trial by trial from the EMG activity of the TA ipsilateral to the magnetic stimulus, taking into account the nearly constant time difference between the two sides. The MEPs became far greater than control MEPs during the RT (mean = 332%, SD = 44 %, of control MEPs, P < 0.001) without any measurable change in the background level of EMG activity. The onset of this facilitation occurred on average 12.80 ms (SD = 7.55 ms) before the RT. There was no difference in the onset of facilitation between the two conditions. Because MEPs were facilitated without a change in the background EMG activity, it is concluded that this facilitation is specifically due to an increase of MCx excitability just before voluntary muscle activation. This conclusion is further reinforced by the observation that MEPs evoked by near-threshold anodal stimuli to the MCx were not facilitated during the RT, in contrast to those evoked by near-threshold transcranial magnetic stimulation. However, several observations in the present and previous studies indicate that MEP amplitude may be more sensitive to alpha-motoneuron activity than to motor cortical neuron activity, an idea that has important

  1. A study of a respiratory related variation of muscle tone during the decrement of decerebrate tonicity in ECT

    PubMed Central

    Tresise, P. C. C.

    1971-01-01

    An oscillating decerebrate tonicity following the clonus phase in electroplexy was found to occur in the upper limbs, their tendon reflexes and the jaw; this increased with each expiration and decreased with inspiration. The times of these occurrences in the upper limbs were measured in groups where no anaesthesia, diazepam or methohexital were used. The mean times of their onset and end were related to other phenomena of ECT. The times of occurrence and duration of decerebrate tonicity were established and compared in the three cohorts. There was a definite relationship to the onset of respiratory rhythmicity in all three groups. The evidence for the existence of decerebrate tonicity and atonicity are discussed from experimental contributions and more recent clinical evidence of the clonus phase as an example of an oscillation between tonic and atonic decerebrate states. Further clinical and experimental data are discussed which show connections between the decerebrate state, cerebral and cerebellar functions, respiratory centres, brain-stem and gravity afferents during rest and locomotion. An explanation is offered that the oscillatory phenomena are probably a mechanism to aid respiration and motor efficiency. Images PMID:5551693

  2. Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic seizures, and frequent absence status

    PubMed Central

    Panayiotopoulos, C; Koutroumanidis, M; Giannakodimos, S; Agathonikou, A

    1997-01-01

    OBJECTIVES—To describe the clinical and EEG features of adult patients with very mild absences, late onset generalised tonic clonic seizures, and frequent absence status.
METHODS—Patients were referrals to a clinic for epilepsies. They all had clinical assessment and EEG, video EEG, or both for documentation of absences.
RESULTS—Of 86 adults with idiopathic generalised epilepsies and EEG/video-EEG documented absences, 13 patients showed similar clinico-EEG features with: (a) "phantom absences" consisting of mild ictal impairment of cognition associated with brief (3-4 s), generalised 3-4 Hz spike/multiple spike and slow wave discharges; (b) infrequent, mainly late onset, generalised tonic clonic seizures, and (c), absence status which occurred in six of them either in isolation or terminating with generalised tonic clonic seizures. None of the patients had myoclonic jerks or photosensitivity. Two patients were father and daughter and another patient had a family history of infrequent generalised tonic clonic seizures.
CONCLUSION—It seems that this is an idiopathic generalised epilepsy syndrome in adults which has not been previously recognised.

 PMID:9408104

  3. Neurosteroid interactions with synaptic and extrasynaptic GABAa receptors: regulation of subunit plasticity, phasic and tonic inhibition, and neuronal network excitability

    PubMed Central

    Chase Matthew, Carver; Doodipala Samba, Reddy

    2013-01-01

    Rationale Neurosteroids are steroids synthesized within the brain with rapid effects on neuronal excitability. Allopregnanolone, allotetrahydrodeoxycorticosterone, and androstanediol are three widely explored prototype endogenous neurosteroids. They have very different targets and functions compared to conventional steroid hormones. Neuronal GABAa receptors are one of the prime molecular targets of neurosteroids. Objective This review provides a critical appraisal of recent advances in the pharmacology of endogenous neurosteroids that interact with GABAa receptors in the brain. Neurosteroids possess distinct, characteristic effects on the membrane potential and current conductance of the neuron, mainly via potentiation of GABAa receptors at low concentrations and direct activation of receptor chloride channel at higher concentrations. The GABAa receptor mediates two types of inhibition, now characterized as synaptic (phasic) and extrasynaptic (tonic) inhibition. Synaptic release of GABA results in the activation of low-affinity γ2-containing synaptic receptors, while high-affinity δ-containing extrasynaptic receptors are persistently activated by the ambient GABA present in the extracellular fluid. Neurosteroids are potent positive allosteric modulators of synaptic and extrasynaptic GABAa receptors and therefore enhance both phasic and tonic inhibition. Tonic inhibition is specifically more sensitive to neurosteroids. The resulting tonic conductance generates a form of shunting inhibition that controls neuronal network excitability, seizure susceptibility, and behavior. Conclusion The growing understanding of the mechanisms of neurosteroid regulation of the structure and function of the synaptic and extrasynaptic GABAa receptors provide many opportunities to create improved therapies for sleep, anxiety, stress, epilepsy, and other neuropsychiatric conditions. PMID:24071826

  4. The effect of tonic contraction of the finger muscle on the motor cortical representation of the contracting adjacent muscle.

    PubMed

    Jono, Yasutomo; Chujo, Yuta; Nomura, Yoshifumi; Tani, Keisuke; Nikaido, Yasutaka; Hatanaka, Ryota; Hiraoka, Koichi

    2015-01-01

    This study examined the effect of tonic contraction of the finger muscle on the motor cortical representation of the contracting adjacent muscle. A representation map of the motor evoked potential (MEP) in the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles was obtained with the subject at rest or during tonic contraction of the ADM muscle while the FDI muscle was tonically contracted. The center of gravity (COG) of the MEP map in the FDI muscle shifted medially during contraction of the ADM muscle. Motor cortical excitability in the motor cortical representation of the FDI muscle that did not overlap with the motor cortical representation of the ADM muscle was suppressed, but motor cortical excitability in the motor cortical representation of the FDI muscle overlapping with the motor cortical representation of the ADM muscle was not suppressed during contraction of the ADM muscle. The motor cortical representation of the FDI muscle not overlapping with the motor cortical representation of the ADM muscle was located lateral to that of the FDI muscle that did overlap with the motor cortical representation of the ADM muscle. Medial shift of the COG of the motor cortical representation of the contracting finger muscle induced by tonic contraction of the adjacent finger muscle must be due to suppression of motor cortical excitability in the lateral part of the representation, which is not shared by the adjacent representation.

  5. Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model.

    PubMed

    Sakkaki, Sophie; Gangarossa, Giuseppe; Lerat, Benoit; Françon, Dominique; Forichon, Luc; Chemin, Jean; Valjent, Emmanuel; Lerner-Natoli, Mireille; Lory, Philippe

    2016-02-01

    T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy. Here we have characterized the anticonvulsant properties of TTA-A2, a selective T-type channel blocker, in mouse. Using the maximal electroshock seizure (MES) as a model of tonic-clonic generalized seizures, we report that mice treated with TTA-A2 (0.3 mg/kg and higher doses) were significantly protected against tonic seizures. Although no major change in Local Field Potential (LFP) pattern was observed during the MES seizure, analysis of the late post-ictal period revealed a significant increase in the delta frequency power in animals treated with TTA-A2. Similar results were obtained for Cav3.1-/- mice, which were less prone to develop tonic seizures in the MES test, but not for Cav3.2-/- mice. Analysis of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and c-Fos expression revealed a rapid and elevated neuronal activation in the hippocampus following MES clonic seizures, which was unchanged in TTA-A2 treated animals. Overall, our data indicate that TTA-A2 is a potent anticonvulsant and that the Cav3.1 isoform plays a prominent role in mediating TTA-A2 tonic seizure protection. Copyright © 2015. Published by Elsevier Ltd.

  6. Depleted Argon from Underground Sources

    SciTech Connect

    Back, H. O.; Galbiati, C.; Goretti, A.; Loer, B.; Montanari, D.; Mosteiro, P.; Alexander, T.; Alton, A.; Rogers, H.; Kendziora, C.; Pordes, S.

    2011-04-27

    Argon is a strong scintillator and an ideal target for Dark Matter detection; however {sup 39}Ar contamination in atmospheric argon from cosmic ray interactions limits the size of liquid argon dark matter detectors due to pile-up. Argon from deep underground is depleted in {sup 39}Ar due to the cosmic ray shielding of the earth. In Cortez, Colorado, a CO{sub 2} well has been discovered to contain approximately 600 ppm of argon as a contamination in the CO{sub 2}. We first concentrate the argon locally to 3% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation, and then the N{sub 2} and He will be removed by continuous distillation to purify the argon. We have collected 26 kg of argon from the CO{sub 2} facility and a cryogenic distillation column is under construction at Fermilab to further purify the argon.

  7. Depleted uranium disposal options evaluation

    SciTech Connect

    Hertzler, T.J.; Nishimoto, D.D.; Otis, M.D.

    1994-05-01

    The Department of Energy (DOE), Office of Environmental Restoration and Waste Management, has chartered a study to evaluate alternative management strategies for depleted uranium (DU) currently stored throughout the DOE complex. Historically, DU has been maintained as a strategic resource because of uses for DU metal and potential uses for further enrichment or for uranium oxide as breeder reactor blanket fuel. This study has focused on evaluating the disposal options for DU if it were considered a waste. This report is in no way declaring these DU reserves a ``waste,`` but is intended to provide baseline data for comparison with other management options for use of DU. To PICS considered in this report include: Retrievable disposal; permanent disposal; health hazards; radiation toxicity and chemical toxicity.

  8. Kindling alters neurosteroid-induced modulation of phasic and tonic GABAA receptor-mediated currents: role of phosphorylation.

    PubMed

    Kia, Arash; Ribeiro, Fabiola; Nelson, Renee; Gavrilovici, Cezar; Ferguson, Stephen S G; Poulter, Michael O

    2011-03-01

    We have previously shown that after kindling (a model of temporal lobe epilepsy), the neuroactive steroid tetrahydrodeoxycorticosterone (THDOC) was unable to augment GABA type A receptor (GABA(A))-mediated synaptic currents occurring on pyramidal cells of the piriform cortex. Phosphorylation of GABA(A) receptors has been shown previously to alter the activity of THDOC, so we tested the hypothesis that kindling induces changes in the phosphorylation of GABA(A) receptors and this accounts for the loss in efficacy. To assay whether GABA(A) receptors are more phosphorylated after kindling, we examined the phosphorylation state of the β3 subunit and found that it was increased. Incubation of brain slices with the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) (100 nM) also increased phosphorylation in the same assay. In patch clamp, recordings from non-kindled rat brain slices PMA also reduced the activity of THDOC in a manner that was identical to what is observed after kindling. We also found that the tonic current was no longer augmented by THODC after kindling and PMA treatment. The protein kinase C (PKC) antagonist bisindolylmaleimide I blocked the effects PMA on the synaptic but not the tonic currents. However, the broad spectrum PKC antagonist staurosporine blocked the effects of PMA on the tonic currents, implying that different PKC isoforms phosphorylate GABA(A) receptors responsible for phasic and tonic currents. The phosphatase activator Li(+) palmitate restored the 'normal' activity of THDOC on synaptic currents in kindled brain slices but not the tonic currents. These data demonstrate that kindling enhances the phosphorylation state of GABA(A) receptors expressed in pyramidal neurons reducing THDOC efficacy.

  9. Monitoring In Vivo Changes in Tonic Extracellular Dopamine Level by Charge-Balancing Multiple Waveform Fast-Scan Cyclic Voltammetry.

    PubMed

    Oh, Yoonbae; Park, Cheonho; Kim, Do Hyoung; Shin, Hojin; Kang, Yu Min; DeWaele, Mark; Lee, Jeyeon; Min, Hoon-Ki; Blaha, Charles D; Bennet, Kevin E; Kim, In Young; Lee, Kendall H; Jang, Dong Pyo

    2016-11-15

    Dopamine (DA) modulates central neuronal activity through both phasic (second to second) and tonic (minutes to hours) terminal release. Conventional fast-scan cyclic voltammetry (FSCV), in combination with carbon fiber microelectrodes, has been used to measure phasic DA release in vivo by adopting a background subtraction procedure to remove background capacitive currents. However, measuring tonic changes in DA concentrations using conventional FSCV has been difficult because background capacitive currents are inherently unstable over long recording periods. To measure tonic changes in DA concentrations over several hours, we applied a novel charge-balancing multiple waveform FSCV (CBM-FSCV), combined with a dual background subtraction technique, to minimize temporal variations in background capacitive currents. Using this method, in vitro, charge variations from a reference time point were nearly zero for 48 h, whereas with conventional background subtraction, charge variations progressively increased. CBM-FSCV also demonstrated a high selectivity against 3,4-dihydroxyphenylacetic acid and ascorbic acid, two major chemical interferents in the brain, yielding a sensitivity of 85.40 ± 14.30 nA/μM and limit of detection of 5.8 ± 0.9 nM for DA while maintaining selectivity. Recorded in vivo by CBM-FSCV, pharmacological inhibition of DA reuptake (nomifensine) resulted in a 235 ± 60 nM increase in tonic extracellular DA concentrations, while inhibition of DA synthesis (α-methyl-dl-tyrosine) resulted in a 72.5 ± 4.8 nM decrease in DA concentrations over a 2 h period. This study showed that CBM-FSCV may serve as a unique voltammetric technique to monitor relatively slow changes in tonic extracellular DA concentrations in vivo over a prolonged time period.

  10. Relationship between intracellular ionic strength and expression of tonicity-responsive genes in rat papillary collecting duct cells.

    PubMed

    Neuhofer, Wolfgang; Bartels, Helmut; Fraek, Maria-L; Beck, Franz-X

    2002-08-15

    Intracellular ionic strength may play an important role in regulating the expression of genes encoding osmolyte-accumulating molecules. To establish whether a strict relation exists between these variables, intracellular ionic strength (sum of Na+, Cl- and K+ concentrations) and the relative abundance of mRNA derived from various tonicity-sensitive genes was examined using electron microprobe analysis and Northern blots on primary cultures of rat papillary collecting duct (PCD) cells following acute or long-term alterations in medium tonicity. Hypertonic medium (450 mosmol kg(-1)) evoked an initial rise in intracellular ionic strength (269 +/- 5 vs. 194 +/- 7 mmol (kg wet weight (wt))(-1) in isotonic controls; means +/- S.E.M.), which subsequently declined gradually, and a significantly higher abundance of bgt1 (Na+- and Cl- -dependent betaine transporter), smit (Na+/myo-inositol cotransporter), ar (aldose reductase) and osp94 (osmotic stress protein 94) mRNAs. Conversely, exposure to hypotonic medium (200 mosmol kg(-1)) for 12 h was associated with significantly reduced intracellular ionic strength (153 +/- 4 mmol (kg wet wt)(-1)) and significantly reduced the abundance of smit and ar mRNAs. PCD cells preconditioned in hypotonic medium and re-exposed to isotonic medium showed significantly higher abundance of these mRNAs than isotonic controls, although the intracellular ionic strength did not differ. Two further tonicity-sensitive genes responded differently to medium tonicity: while the abundance of hsp70 (heat shock protein 70) mRNA increased significantly following both hypo- and hypertonic stress, inos (inducible nitric oxide synthase) mRNA abundance correlated inversely with medium tonicity. These findings support the view that the effect of intracellular ionic strength on the expression of bgt1, smit, ar and osp94 is modulated by additional factors such as cell volume, and that its effect on the pathways regulating hsp70 and inos is even more complex.

  11. Relationship between intracellular ionic strength and expression of tonicity-responsive genes in rat papillary collecting duct cells

    PubMed Central

    Neuhofer, Wolfgang; Bartels, Helmut; Fraek, Maria-L; Beck, Franz-X

    2002-01-01

    Intracellular ionic strength may play an important role in regulating the expression of genes encoding osmolyte-accumulating molecules. To establish whether a strict relation exists between these variables, intracellular ionic strength (sum of Na+, Cl− and K+ concentrations) and the relative abundance of mRNA derived from various tonicity-sensitive genes was examined using electron microprobe analysis and Northern blots on primary cultures of rat papillary collecting duct (PCD) cells following acute or long-term alterations in medium tonicity. Hypertonic medium (450 mosmol kg−1) evoked an initial rise in intracellular ionic strength (269 ± 5 vs. 194 ± 7 mmol (kg wet weight (wt))−1 in isotonic controls; means ± s.e.m.), which subsequently declined gradually, and a significantly higher abundance of bgt1 (Na+- and Cl−-dependent betaine transporter), smit (Na+/myo-inositol cotransporter), ar (aldose reductase) and osp94 (osmotic stress protein 94) mRNAs. Conversely, exposure to hypotonic medium (200 mosmol kg−1) for 12 h was associated with significantly reduced intracellular ionic strength (153 ± 4 mmol (kg wet wt)−1) and significantly reduced the abundance of smit and ar mRNAs. PCD cells preconditioned in hypotonic medium and re-exposed to isotonic medium showed significantly higher abundance of these mRNAs than isotonic controls, although the intracellular ionic strength did not differ. Two further tonicity-sensitive genes responded differently to medium tonicity: while the abundance of hsp70 (heat shock protein 70) mRNA increased significantly following both hypo- and hypertonic stress, inos (inducible nitric oxide synthase) mRNA abundance correlated inversely with medium tonicity. These findings support the view that the effect of intracellular ionic strength on the expression of bgt1, smit, ar and osp94 is modulated by additional factors such as cell volume, and that its effect on the pathways regulating hsp70 and inos is even more complex. PMID

  12. Downregulation of renal sodium transporters and tonicity-responsive enhancer binding protein by long-term treatment with cyclosporin A.

    PubMed

    Lim, Sun Woo; Ahn, Kyung Ohk; Sheen, Mee Rie; Jeon, Un Sil; Kim, Jin; Yang, Chul Woo; Kwon, H Moo

    2007-02-01

    Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient tonicity. TonEBP protects the renal medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters-sodium/potassium/chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na(+),K(+)-ATPase-along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced tonicity of the renal medullary interstitium.

  13. Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents.

    PubMed

    Chen, Songcang; Grigsby, Christopher L; Law, Christopher S; Ni, Xiping; Nekrep, Nada; Olsen, Keith; Humphreys, Michael H; Gardner, David G

    2009-06-01

    In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1-/- mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity.

  14. Tonicity-dependent induction of Sgk1 expression has a potential role in dehydration-induced natriuresis in rodents

    PubMed Central

    Chen, Songcang; Grigsby, Christopher L.; Law, Christopher S.; Ni, Xiping; Nekrep, Nada; Olsen, Keith; Humphreys, Michael H.; Gardner, David G.

    2009-01-01

    In various mammalian species, including humans, water restriction leads to an acute increase in urinary sodium excretion. This process, known as dehydration natriuresis, helps prevent further accentuation of hypernatremia and the accompanying rise in extracellular tonicity. Serum- and glucocorticoid-inducible kinase (Sgk1), which is expressed in the renal medulla, is regulated by extracellular tonicity. However, the mechanism of its regulation and the physiological role of hypertonicity-induced SGK1 gene expression remain unclear. Here, we identified a tonicity-responsive enhancer (TonE) upstream of the rat Sgk1 transcriptional start site. The transcription factor NFAT5 associated with TonE in a tonicity-dependent fashion in cultured rat renal medullary cells, and selective blockade of NFAT5 activity resulted in suppression of the osmotic induction of the Sgk1 promoter. In vivo, water restriction of rats or mice led to increased urine osmolality, increased Sgk1 expression, increased expression of the type A natriuretic peptide receptor (NPR-A), and dehydration natriuresis. In cultured rat renal medullary cells, siRNA-mediated Sgk1 knockdown blocked the osmotic induction of natriuretic peptide receptor 1 (Npr1) gene expression. Furthermore, Npr1–/– mice were resistant to dehydration natriuresis, which suggests that Sgk1-dependent activation of the NPR-A pathway may contribute to this response. Collectively, these findings define a specific mechanistic pathway for the osmotic regulation of Sgk1 gene expression and suggest that Sgk1 may play an important role in promoting the physiological response of the kidney to elevations in extracellular tonicity. PMID:19436108

  15. The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.

    PubMed

    Grace, A A

    2000-08-01

    All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike-dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release-inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico-accumbens afferents. This steady-state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug-related stimuli are proposed to increase tonic dopamine levels, again triggering drug-seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a

  16. Corticospinal excitability of the biceps brachii is higher during arm cycling than an intensity-matched tonic contraction.

    PubMed

    Forman, Davis; Raj, Amita; Button, Duane C; Power, Kevin E

    2014-09-01

    Human studies have not assessed corticospinal excitability of an upper-limb prime mover during arm cycling. The purpose of the present study was to determine whether supraspinal and/or spinal motoneuron excitability of the biceps brachii was different between arm cycling and an intensity-matched tonic contraction. We hypothesized that spinal motoneuron excitability would be higher during arm cycling than an intensity-matched tonic contraction. Supraspinal and spinal motoneuron excitability were assessed using transcranial magnetic stimulation (TMS) of the motor cortex and transmastoid electrical stimulation (TMES) of the corticospinal tract, respectively. TMS-induced motor-evoked potentials (MEPs) and TMES-induced cervicomedullary-evoked potentials (CMEPs) were assessed at three separate positions (3, 6, and 12 o'clock relative to a clock face) during arm cycling and an intensity-matched tonic contraction. MEP amplitudes were 7.2 and 8.8% maximum amplitude of the compound muscle action potential (Mmax) larger during arm cycling compared with a tonic contraction at the 3 (P < 0.001) and 6 o'clock (P < 0.001) positions, respectively. There was no difference between tasks during elbow extension (12 o'clock). CMEP amplitudes were 5.2% Mmax larger during arm cycling compared with a tonic contraction at the 3 o'clock position (P < 0.001) with no differences seen at midflexion (6 o'clock) or extension (12 o'clock). The data indicate an increase in the excitability of corticospinal neurons, which ultimately project to biceps brachii during the elbow flexion portion of arm cycling, and increased spinal motoneuron excitability at the onset of elbow flexion during arm cycling. We conclude that supraspinal and spinal motoneuron excitability are phase- and task-dependent.

  17. High-voltage-compatible, fully depleted CCDs

    SciTech Connect

    Holland, Stephen E.; Bebek, Chris J.; Dawson, Kyle S.; Emes, JohnE.; Fabricius, Max H.; Fairfield, Jessaym A.; Groom, Don E.; Karcher, A.; Kolbe, William F.; Palaio, Nick P.; Roe, Natalie A.; Wang, Guobin

    2006-05-15

    We describe charge-coupled device (CCD) developmentactivities at the Lawrence Berkeley National Laboratory (LBNL).Back-illuminated CCDs fabricated on 200-300 mu m thick, fully depleted,high-resistivity silicon substrates are produced in partnership with acommercial CCD foundry.The CCDs are fully depleted by the application ofa substrate bias voltage. Spatial resolution considerations requireoperation of thick, fully depleted CCDs at high substrate bias voltages.We have developed CCDs that are compatible with substrate bias voltagesof at least 200V. This improves spatial resolution for a given thickness,and allows for full depletion of thicker CCDs than previously considered.We have demonstrated full depletion of 650-675 mu m thick CCDs, withpotential applications in direct x-ray detection. In this work we discussthe issues related to high-voltage operation of fully depleted CCDs, aswell as experimental results on high-voltage-compatible CCDs.

  18. Duration of focal complex, secondarily generalized tonic-clonic, and primarily generalized tonic-clonic seizures--A video-EEG analysis.

    PubMed

    Dobesberger, Judith; Ristić, Aleksandar J; Walser, Gerald; Kuchukhidze, Giorgi; Unterberger, Iris; Höfler, Julia; Amann, Edda; Trinka, Eugen

    2015-08-01

    Identifying seizures with prolonged duration during video-electroencephalographic (EEG) monitoring is of importance to inform clinicians when to start emergency treatment of seizures to prevent status epilepticus. The aims of this study were to assess the clinical and EEG seizure duration (SD) in consecutive patients with epilepsy who underwent prolonged video-EEG monitoring and to identify a seizure type-dependent time point to start emergency treatment based on the likelihood that seizures will not stop spontaneously. Furthermore, we sought to determine predictors of SD and explored the relationship between antiepileptic drug (AED) serum levels and SD. We retrospectively analyzed 1796 seizures in 200 patients undergoing video-EEG monitoring between January 2006 and March 2008. Focal simple seizures lasted significantly shorter (clinical SD: 28s, EEG SD: 42 s) compared with focal complex seizures (clinical SD: 64 s, EEG SD: 62 s), and both seizure types lasted significantly shorter compared with secondarily generalized tonic-clonic seizures (GTCSs; clinical SD: 90 s, EEG SD: 96 s). There was no difference between the duration of the convulsive phase of primary GTCSs (defined as nonfocal) and that of secondarily GTCSs (each 65 s). Cumulative clinical SD (99%) was 7 min in focal complex seizures and 11 min in focal simple seizures. Mixed linear regression model demonstrated that history of status epilepticus (P = 0.034), temporal lobe seizure onset (P = 0.040), and MRI lesions (P = 0.013) were significantly associated with logarithmic EEG SD in focal epilepsies recorded with scalp electrodes. We found significant negative correlations between the AED serum level and the EEG SD in patients treated with monotherapy: carbamazepine (P < 0.001), levetiracetam (P = 0.001), oxcarbazepine (P = 0.001), and valproic acid (P = 0.038) but not with lamotrigine monotherapy and EEG SD. Based on the results of this study, we propose 2 min of convulsive seizure activity

  19. CO depletion in the Gould Belt clouds

    NASA Astrophysics Data System (ADS)

    Christie, H.; Viti, S.; Yates, J.; Hatchell, J.; Fuller, G. A.; Duarte-Cabral, A.; Sadavoy, S.; Buckle, J. V.; Graves, S.; Roberts, J.; Nutter, D.; Davis, C.; White, G. J.; Hogerheijde, M.; Ward-Thompson, D.; Butner, H.; Richer, J.; Di Francesco, J.

    2012-05-01

    We present a statistical comparison of CO depletion in a set of local molecular clouds within the Gould Belt using Sub-millimetre Common User Bolometer Array (SCUBA) and Heterodyne Array Receiver Programme (HARP) data. This is the most wide-ranging study of depletion thus far within the Gould Belt. We estimate CO column densities assuming local thermodynamic equilibrium and, for a selection of sources, using the radiative transfer code RADEX in order to compare the two column density estimation methods. High levels of depletion are seen in the centres of several dust cores in all the clouds. We find that in the gas surrounding protostars, levels of depletion are somewhat lower than for starless cores with the exception of a few highly depleted protostellar cores in Serpens and NGC 2024. There is a tentative correlation between core mass and core depletion, particularly in Taurus and Serpens. Taurus has, on average, the highest levels of depletion. Ophiuchus has low average levels of depletion which could perhaps be related to the anomalous dust grain size distribution observed in this cloud. High levels of depletion are often seen around the edges of regions of optical emission (Orion) or in more evolved or less dynamic regions such as the bowl of L1495 in Taurus and the north-western region of Serpens.

  20. Ego depletion increases risk-taking.

    PubMed

    Fischer, Peter; Kastenmüller, Andreas; Asal, Kathrin

    2012-01-01

    We investigated how the availability of self-control resources affects risk-taking inclinations and behaviors. We proposed that risk-taking often occurs from suboptimal decision processes and heuristic information processing (e.g., when a smoker suppresses or neglects information about the health risks of smoking). Research revealed that depleted self-regulation resources are associated with reduced intellectual performance and reduced abilities to regulate spontaneous and automatic responses (e.g., control aggressive responses in the face of frustration). The present studies transferred these ideas to the area of risk-taking. We propose that risk-taking is increased when individuals find themselves in a state of reduced cognitive self-control resources (ego-depletion). Four studies supported these ideas. In Study 1, ego-depleted participants reported higher levels of sensation seeking than non-depleted participants. In Study 2, ego-depleted participants showed higher levels of risk-tolerance in critical road traffic situations than non-depleted participants. In Study 3, we ruled out two alternative explanations for these results: neither cognitive load nor feelings of anger mediated the effect of ego-depletion on risk-taking. Finally, Study 4 clarified the underlying psychological process: ego-depleted participants feel more cognitively exhausted than non-depleted participants and thus are more willing to take risks. Discussion focuses on the theoretical and practical implications of these findings.

  1. RADIO FREQUENCY ATTENUATOR

    DOEpatents

    Giordano, S.

    1963-11-12

    A high peak power level r-f attenuator that is readily and easily insertable along a coaxial cable having an inner conductor and an outer annular conductor without breaking the ends thereof is presented. Spaced first and second flares in the outer conductor face each other with a slidable cylindrical outer conductor portion therebetween. Dielectric means, such as water, contact the cable between the flares to attenuate the radio-frequency energy received thereby. The cylindrical outer conductor portion is slidable to adjust the voltage standing wave ratio to a low level, and one of the flares is slidable to adjust the attenuation level. An integral dielectric container is also provided. (AFC)

  2. Landing gear noise attenuation

    NASA Technical Reports Server (NTRS)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)

    2011-01-01

    A landing gear noise attenuator mitigates noise generated by airframe deployable landing gear. The noise attenuator can have a first position when the landing gear is in its deployed or down position, and a second position when the landing gear is in its up or stowed position. The noise attenuator may be an inflatable fairing that does not compromise limited space constraints associated with landing gear retraction and stowage. A truck fairing mounted under a truck beam can have a compliant edge to allow for non-destructive impingement of a deflected fire during certain conditions.

  3. Beneficial Uses of Depleted Uranium

    SciTech Connect

    Brown, C.; Croff, A.G.; Haire, M. J.

    1997-08-01

    Naturally occurring uranium contains 0.71 wt% {sup 235}U. In order for the uranium to be useful in most fission reactors, it must be enriched the concentration of the fissile isotope {sup 235}U must be increased. Depleted uranium (DU) is a co-product of the processing of natural uranium to produce enriched uranium, and DU has a {sup 235}U concentration of less than 0.71 wt%. In the United States, essentially all of the DU inventory is in the chemical form of uranium hexafluoride (UF{sub 6}) and is stored in large cylinders above ground. If this co-product material were to be declared surplus, converted to a stable oxide form, and disposed, the costs are estimated to be several billion dollars. Only small amounts of DU have at this time been beneficially reused. The U.S. Department of Energy (DOE) has begun the Beneficial Uses of DU Project to identify large-scale uses of DU and encourage its reuse for the primary purpose of potentially reducing the cost and expediting the disposition of the DU inventory. This paper discusses the inventory of DU and its rate of increase; DU disposition options; beneficial use options; a preliminary cost analysis; and major technical, institutional, and regulatory issues to be resolved.

  4. Depleted argon from underground sources

    SciTech Connect

    Back, H.O.; Alton, A.; Calaprice, F.; Galbiati, C.; Goretti, A.; Kendziora, C.; Loer, B.; Montanari, D.; Mosteiro, P.; Pordes, S.; /Fermilab

    2011-09-01

    Argon is a powerful scintillator and an excellent medium for detection of ionization. Its high discrimination power against minimum ionization tracks, in favor of selection of nuclear recoils, makes it an attractive medium for direct detection of WIMP dark matter. However, cosmogenic {sup 39}Ar contamination in atmospheric argon limits the size of liquid argon dark matter detectors due to pile-up. The cosmic ray shielding by the earth means that Argon from deep underground is depleted in {sup 39}Ar. In Cortez Colorado a CO{sub 2} well has been discovered to contain approximately 500ppm of argon as a contamination in the CO{sub 2}. In order to produce argon for dark matter detectors we first concentrate the argon locally to 3-5% in an Ar, N{sub 2}, and He mixture, from the CO{sub 2} through chromatographic gas separation. The N{sub 2} and He will be removed by continuous cryogenic distillation in the Cryogenic Distillation Column recently built at Fermilab. In this talk we will discuss the entire extraction and purification process; with emphasis on the recent commissioning and initial performance of the cryogenic distillation column purification.

  5. Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.

    PubMed

    Huang, Weifeng; Liu, Huili; Wang, Tao; Zhang, Tiantian; Kuang, Juntao; Luo, Yu; Chung, Stephen S M; Yuan, Li; Yang, James Y

    2011-01-01

    Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3'-untranslated region of OREBP (OREBP-3'UTR). Furthermore, overexpression of OREBP-3'UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR-717 being most significantly down-regulated. Moreover, increased miR-200b or miR-717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA-3'UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR-200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells.

  6. Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity

    PubMed Central

    Huang, Weifeng; Liu, Huili; Wang, Tao; Zhang, Tiantian; Kuang, Juntao; Luo, Yu; Chung, Stephen S. M.; Yuan, Li; Yang, James Y.

    2011-01-01

    Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3′-untranslated region of OREBP (OREBP-3′UTR). Furthermore, overexpression of OREBP-3′UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR-717 being most significantly down-regulated. Moreover, increased miR-200b or miR-717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA–3′UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR-200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells. PMID:20852262

  7. Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.

    PubMed

    Nolan, Sarah J; Tudur Smith, Catrin; Pulman, Jennifer; Marson, Anthony G

    2013-01-31

    This is an updated version of the original Cochrane review published in The Cochrane Library 2001, Issue 4.Worldwide, particularly in the developing world, phenytoin and phenobarbitone are commonly used antiepileptic drugs, primarily because they are inexpensive. The aim of this review is to summarise data from existing trials comparing phenytoin and phenobarbitone. To review the best evidence comparing phenobarbitone and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. We searched the Cochrane Epilepsy Group trials register (31 May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 5 of 12, The Cochrane Library 2012) and MEDLINE (1946 to May week 4, 2012). We hand-searched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field.   Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of phenobarbitone monotherapy with phenytoin monotherapy. This was an individual participant data (IPD) review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. Cox proportional hazards regression models were used to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) with the generic inverse variance method used to obtain the overall pooled estimate of HRs and 95% CIs. Data have been obtained for four of eight studies meeting the inclusion criteria, amounting to 599 individuals, or approximately 63% of the potential data.The main overall results (pooled HR, 95% CI) were (a) time to treatment withdrawal 1.62 (1.23 to 2.14); (b) time to 12-month remission 0.90 (0.69 to 1.18) (c) time to six-month remission 0.92 (0.73 to 1.16) and (d) time to first seizure 0.85 (0.68 to 1.05). These results

  8. Low tonicity mediates a downregulation of cyclooxygenase-1 expression by furosemide in the rat renal papilla.

    PubMed

    Castrop, Hayo; Vitzthum, Helga; Schumacher, Karl; Schweda, Frank; Kurtz, Armin

    2002-05-01

    It is well known that loop diuretics enhance the renal excretion of prostanoids; therefore, this study aimed to characterize the influence of loop diuretics on the intrarenal expression of cyclooxygenases, which are the key enzymes for prostanoid formation. Male Sprague-Dawley rats were infused with furosemide (12 mg/kg per d) for 6 d, and the expression of cyclooxygenase-1 and -2 (Cox-1 and Cox-2) was analyzed in the different kidney zones. Furosemide increased Cox-2 mRNA expression approximately twofold in the cortex, but it left Cox-1 mRNA expression unaltered there. In the outer medulla, furosemide changed neither Cox-1 nor Cox-2 mRNA expression. In the inner medulla, however, furosemide decreased Cox-1 and Cox-2 mRNA levels to approximately 30% and 60% of their control levels, respectively. The downregulation of mRNA was paralleled by a decrease of Cox protein in the collecting ducts and interstitial cells. Moreover, tissue prostaglandin E(2) (PGE(2)) concentrations in the papilla were markedly decreased by furosemide to about 30% of the control level. Furosemide lowered urine osmolality from 1550 mosmol/kg to 480 mosmol/kg; therefore, further consideration was given to the influence of tonicity as a possible mediator of the effects of furosemide on the Cox expression. Water loading was therefore used to reduce the medullary tonicity by a second maneuver. Water loading led to a similar reduction in papillary Cox mRNA expression and PGE(2) content like furosemide. To investigate the influence of the osmolarity on the expression of Cox and the production of PGE(2) under defined in vitro conditions, inner medullary collecting duct cells were incubated with culture medium containing graded amounts of NaCl ranging from 200 mmol/L to 600 mmol/L, and Cox-1 and Cox-2 mRNA abundance were determined after 24 h an 48 h. Cox-1 and Cox-2 mRNA abundance changed in parallel with the osmolarity. The data suggest that loop diuretics decrease the expression of cyclooxygenases

  9. Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity

    PubMed Central

    Roussy, Geneviève; Dansereau, Marc-André; Baudisson, Stéphanie; Ezzoubaa, Faouzi; Belleville, Karine; Beaudet, Nicolas; Martinez, Jean; Richelson, Elliott; Sarret, Philippe

    2009-01-01

    Background Central neurotensin (NT) administration results in a naloxone-insensitive antinociceptive response in animal models of acute and persistent pain. Both NTS1 and NTS2 receptors were shown to be required for different aspects of NT-induced analgesia. We recently demonstrated that NTS2 receptors were extensively associated with ascending nociceptive pathways, both at the level of the dorsal root ganglia and of the spinal dorsal horn. Then, we found that spinally administered NTS2-selective agonists induced dose-dependent antinociceptive responses in the acute tail-flick test. In the present study, we therefore investigated whether activation of spinal NTS2 receptors suppressed the persistent inflammatory pain symptoms observed after intraplantar injection of formalin. Results We first demonstrated that spinally administered NT and NT69L agonists, which bind to both NTS1 and NTS2 receptors, significantly reduced pain-evoked responses during the inflammatory phase of the formalin test. Accordingly, pretreatment with the NTS2-selective analogs JMV-431 and levocabastine was effective in inhibiting the aversive behaviors induced by formalin. With resolution at the single-cell level, we also found that activation of spinal NTS2 receptors reduced formalin-induced c-fos expression in dorsal horn neurons. However, our results also suggest that NTS2-selective agonists and NTS1/NTS2 mixed compounds differently modulated the early (21–39 min) and late (40–60 min) tonic phase 2 and recruited endogenous pain inhibitory mechanisms integrated at different levels of the central nervous system. Indeed, while non-selective drugs suppressed pain-related behaviors activity in both part of phase 2, intrathecal injection of NTS2-selective agonists was only efficient in reducing pain during the late phase 2. Furthermore, assessment of the stereotypic pain behaviors of lifting, shaking, licking and biting to formalin also revealed that unlike non-discriminative NTS1/NTS2 analogs

  10. Reflex and cerebellar influences on α and on `rhythmic' and `tonic' γ activity in the intercostal muscle

    PubMed Central

    Corda, M.; von Euler, C.; Lennerstrand, G.

    1966-01-01

    1. Efferent intercostal α and γ activity and afferent intercostal muscle spindle activity were studied in decerebrate cats in response to stimulation of the anterior lobe of the cerebellum and to postural and other reflexes. 2. Low threshold intercostal responses were elicited from lobuli IV and V of the anterior lobe of the cerebellum. 3. The existence of two functionally different types of intercostal γ neurones has been confirmed. These are the `rhythmic' or `specifically respiratory' γ neurones, and the `tonic' γ neurones. 4. In response to cerebellar stimulation, facilitatory, inhibitory and diphasic tetanic and post-tetanic effects were obtained from α and the two types of γ fibres in both external and internal intercostal nerve branches. 5. Generally both inspiratory and expiratory α and γ activity was facilitated in response to tetanic stimulation at contralateral stimulus sites, and inhibited in response to stimulation of ipsilateral sites. 6. `Rhythmic' γ activity appeared to be rather closely linked to the respiratory α activity but the balance between `rhythmic' γ and α was often changed in response to cerebellar stimulation, as indicated by the responses of primary muscle spindle afferents. 7. The `tonic' γ neurones were as a rule more responsive to cerebellar stimulation than were the α and `rhythmic' γ neurones. Long-lasting post-tetanic effects were much more prominent in the `tonic' γ fibres than in the α or `rhythmic' γ fibres. 8. `Rhythmic' γ activity was abolished after cervical transections of the cord. `Tonic' γ activity remained in the spinal preparations although usually at a different discharge rate. 9. `Tonic' γ neurones were more responsive than the `rhythmic' γ neurones to the proprioceptive γ reflex elicited by passive movements of the chest wall as well as to other spinal and supraspinal reflexes. 10. Both `dynamic' and `static' γ fibres seem to be represented in the group of `tonic' intercostal γ neurones. 11

  11. Attenuator And Conditioner

    SciTech Connect

    Anderson, Gene R.; Armendariz, Marcelino G.; Carson, Richard F.; Bryan, Robert P.; Duckett, III, Edwin B.; Kemme, Shanalyn Adair; McCormick, Frederick B.; Peterson, David W.

    2006-04-04

    An apparatus and method of attenuating and/or conditioning optical energy for an optical transmitter, receiver or transceiver module is disclosed. An apparatus for attenuating the optical output of an optoelectronic connector including: a mounting surface; an array of optoelectronic devices having at least a first end; an array of optical elements having at least a first end; the first end of the array of optical elements optically aligned with the first end of the array of optoelectronic devices; an optical path extending from the first end of the array of optoelectronic devices and ending at a second end of the array of optical elements; and an attenuator in the optical path for attenuating the optical energy emitted from the array of optoelectronic devices. Alternatively, a conditioner may be adapted in the optical path for conditioning the optical energy emitted from the array of optoelectronic devices.

  12. Acute phosphate depletion inhibits the Na+/H+ antiporter in a cultured renal cell line.

    PubMed

    Green, J; Foellmer, O; Kleeman, C R; Basic, M M

    1993-09-01

    We studied the effect of acute Pi depletion on the regulation of intracellular pH (pHi) in the OK opossum kidney cell line by using the pH-sensitive dye 2'7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Cell recovery from an NH4Cl acid load in HCO3-free buffer disclosed an Na(+)-dependent component blocked by amiloride and a smaller Na(+)-independent component that increased on exposure of the cells to a high-K+ buffer. After 24-h incubation of the cells in phosphate-free medium, pHi recovery by the Na+/H+ exchanger was markedly inhibited, whereas the Na(+)-independent pHi recovery was not affected. The inhibition of Na+/H+ exchange was reversible on correction of cellular Pi deficit. A similar phenomenon was observed when cellular Pi depletion was induced by acute exposure (min) to fructose. Pi depletion shifted the pHi dependence of the exchanger and also reduced its maximal activity. Time-course studies revealed that the effect of Pi depletion could not be attributed to attenuation of Na(+)-K(+)-adenosinetriphosphatase activity and resultant diminution of the transmembrane gradient for the Na+ influx. We conclude that acute Pi depletion in cultured proximal tubular cells leads to reversible inhibition of the Na+/H+ exchanger. This in vitro finding may relate to the in vivo observation of impaired HCO3 reabsorption and bicarbonaturia in acute Pi depletion.

  13. Fiber Optic Attenuators

    NASA Technical Reports Server (NTRS)

    1995-01-01

    Mike Buzzetti designed a fiber optic attenuator while working at Jet Propulsion Laboratory, intended for use in NASA's Deep Space Network. Buzzetti subsequently patented and received an exclusive license to commercialize the device, and founded Nanometer Technologies to produce it. The attenuator functions without introducing measurable back-reflection or insertion loss, and is relatively insensitive to vibration and changes in temperature. Applications include cable television, telephone networks, other signal distribution networks, and laboratory instrumentation.

  14. Depleted uranium--the growing concern.

    PubMed

    Abu-Qare, Aqel W; Abou-Donia, Mohamed B

    2002-01-01

    Recently, several studies have reported on the health and environmental consequences of the use of depleted uranium. Depleted uranium is a heavy metal that is also radioactive. It is commonly used in missiles as a counterweight because of its very high density (1.6 times more than lead). Immediate health risks associated with exposure to depleted uranium include kidney and respiratory problems, with conditions such as kidney stones, chronic cough and severe dermatitis. Long-term risks include lung and bone cancer. Several published reports implicated exposure to depleted uranium in kidney damage, mutagenicity, cancer, inhibition of bone, neurological deficits, significant decrease in the pregnancy rate in mice and adverse effects on the reproductive and central nervous systems. Acute poisoning with depleted uranium elicited renal failure that could lead to death. The environmental consequences of its residue will be felt for thousands of years. It is inhaled and passed through the skin and eyes, transferred through the placenta into the fetus, distributed into tissues and eliminated in urine. The use of depleted uranium during the Gulf and Kosovo Wars and the crash of a Boeing airplane carrying depleted uranium in Amsterdam in 1992 were implicated in a health concern related to exposure to depleted uranium.

  15. Large discrepancies in cellular distribution of the tonicity-induced expression of osmoprotective genes and their regulatory transcription factor TonEBP in rat brain.

    PubMed

    Maallem, S; Berod, A; Mutin, M; Kwon, H M; Tappaz, M L

    2006-10-13

    Osmoprotective genes are tonicity-activated genes involved in cellular osmoadaptation to hypertonicity and considered to be regulated by a specific transcription factor called tonicity-responsive enhancer-binding protein (TonEBP). In the brain we had previously established that TonEBP was expressed and tonicity-induced in neurons only. Here we have compared in various brain regions of rats subjected to systemic hypertonicity, the cellular expression of TonEBP through immunocytochemistry and the cellular expression of osmoprotective genes, namely aldose reductase (AR), sodium-dependent myo-inositol transporter (SMIT), betaine/GABA transporter (BGT1) and taurine transporter (TauT), by in situ hybridization using non-radioactive digoxigenin-labeled riboprobes. In neurons where TonEBP was strongly tonicity-induced, AR-mRNA labeling was strongly increased in some subsets (e.g. hippocampus pyramidal cells, cerebellar Purkinje cells and neurons of the hypothalamic magnocellular nuclei) but remained undetectable in some other subsets (e.g. neurons in cerebral cortex). Tonicity-induced AR-mRNA labeling was observed only several hours after the tonicity-induced expression of TonEBP. SMIT-mRNA labeling was tonicity-induced as densely and evenly distributed dots in neuron poor regions (e.g. cerebral cortex layer I and hippocampus stratum lacunosum-moleculare). The tonicity-induced expression of SMIT-mRNA may thus occur in non-neuronal cells, presumably astrocytes, where TonEBP is neither significantly expressed, nor tonicity-induced. In neurons showing a strong tonicity-induced expression of TonEBP, no SMIT-mRNA labeling was observed. BGT1-mRNA and TauT-mRNA labeling could not be detected, even after systemic hypertonicity. The present work reveals large discrepancies between the cellular distribution of the tonicity-induced expression of osmoprotective genes and that of their regulatory transactivator TonEBP. Depending on the cell subsets and the osmoprotective genes, Ton

  16. Repeated exposure to MDMA provides neuroprotection against subsequent MDMA-induced serotonin depletion in brain

    PubMed Central

    Bhide, Nirmal S.; Lipton, Jack; Cunningham, Jacobi; Yamamoto, Bryan K.; Gudelsky, Gary A.

    2009-01-01

    Repeated exposure to sub-lethal insults has been reported to result in neuroprotection against a subsequent deleterious insult. The purpose of this study was to evaluate whether repeated exposure (preconditioning) to a non-5-HT depleting dose of MDMA in adult rats provides neuroprotection against subsequent MDMA induced 5-HT depletion. Treatment of rats with MDMA (10 mg/kg, ip every 2 hrs for 4 injections) resulted in a 50-65% depletion of 5-HT in the striatum, hippocampus and cortex, and these depletions were significantly attenuated in rats that received a preconditioning regimen of MDMA (10 mg/kg, ip daily for 4 days). The 5-HT depleting regimen of MDMA also resulted in a 40-80% reduction in 5-HT transporter immunoreactivity (SERTir), and the reduction in SERTir also was completely attenuated in MDMA preconditioned animals. Preconditioning with MDMA (10 mg/kg, i.p.) daily for 4 days provided neuroprotection against methamphetamine-induced 5-HT depletion, but not DA depletion, in the striatum. Additional studies were conducted to exclude the possibility that alterations in MDMA pharmacokinetics or MDMA induced hyperthermia in rats previously exposed to MDMA contributes towards neuroprotection. During the administration of the 5-HT depleting regimen of MDMA, there was no difference in the extracellular concentration of the drug in the striatum of rats that had received 4 prior, daily injections of vehicle or MDMA. Moreover, there was no difference in the hyperthermic response to the 5-HT depleting regimen of MDMA in rats that had earlier received 4 daily injections of vehicle or MDMA. Furthermore, hyperthermia induced by MDMA during preconditioning appears not to contribute toward neuroprotection, inasmuch as preconditioning with MDMA at a low ambient temperature at which hyperthermia was absent did not alter the neuroprotection provided by the preconditioning regimen. Thus, prior exposure to MDMA affords protection against the long-term depletion of brain 5-HT

  17. High homocysteine induces betaine depletion.

    PubMed

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J

    2015-04-28

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI-LC-MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte.

  18. High homocysteine induces betaine depletion

    PubMed Central

    Imbard, Apolline; Benoist, Jean-François; Esse, Ruben; Gupta, Sapna; Lebon, Sophie; de Vriese, An S; de Baulny, Helene Ogier; Kruger, Warren; Schiff, Manuel; Blom, Henk J.

    2015-01-01

    Betaine is the substrate of the liver- and kidney-specific betaine-homocysteine (Hcy) methyltransferase (BHMT), an alternate pathway for Hcy remethylation. We hypothesized that BHMT is a major pathway for homocysteine removal in cases of hyperhomocysteinaemia (HHcy). Therefore, we measured betaine in plasma and tissues from patients and animal models of HHcy of genetic and acquired cause. Plasma was collected from patients presenting HHcy without any Hcy interfering treatment. Plasma and tissues were collected from rat models of HHcy induced by diet and from a mouse model of cystathionine β-synthase (CBS) deficiency. S-adenosyl-methionine (AdoMet), S-adenosyl-homocysteine (AdoHcy), methionine, betaine and dimethylglycine (DMG) were quantified by ESI—LC–MS/MS. mRNA expression was quantified using quantitative real-time (QRT)-PCR. For all patients with diverse causes of HHcy, plasma betaine concentrations were below the normal values of our laboratory. In the diet-induced HHcy rat model, betaine was decreased in all tissues analysed (liver, brain, heart). In the mouse CBS deficiency model, betaine was decreased in plasma, liver, heart and brain, but was conserved in kidney. Surprisingly, BHMT expression and activity was decreased in liver. However, in kidney, BHMT and SLC6A12 expression was increased in CBS-deficient mice. Chronic HHcy, irrespective of its cause, induces betaine depletion in plasma and tissues (liver, brain and heart), indicating a global decrease in the body betaine pool. In kidney, betaine concentrations were not affected, possibly due to overexpression of the betaine transporter SLC6A12 where betaine may be conserved because of its crucial role as an osmolyte. PMID:26182429

  19. Gulf war depleted uranium risks.

    PubMed

    Marshall, Albert C

    2008-01-01

    US and British forces used depleted uranium (DU) in armor-piercing rounds to disable enemy tanks during the Gulf and Balkan Wars. Uranium particulate is generated by DU shell impact and particulate entrained in air may be inhaled or ingested by troops and nearby civilian populations. As uranium is slightly radioactive and chemically toxic, a number of critics have asserted that DU exposure has resulted in a variety of adverse health effects for exposed veterans and nearby civilian populations. The study described in this paper used mathematical modeling to estimate health risks from exposure to DU during the 1991 Gulf War for both US troops and nearby Iraqi civilians. The analysis found that the risks of DU-induced leukemia or birth defects are far too small to result in an observable increase in these health effects among exposed veterans or Iraqi civilians. The analysis indicated that only a few ( approximately 5) US veterans in vehicles accidentally targeted by US tanks received significant exposure levels, resulting in about a 1.4% lifetime risk of DU radiation-induced fatal cancer (compared with about a 24% risk of a fatal cancer from all other causes). These veterans may have also experienced temporary kidney damage. Iraqi children playing for 500 h in DU-destroyed vehicles are predicted to incur a cancer risk of about 0.4%. In vitro and animal tests suggest the possibility of chemically induced health effects from DU internalization, such as immune system impairment. Further study is needed to determine the applicability of these findings for Gulf War exposure to DU. Veterans and civilians who did not occupy DU-contaminated vehicles are unlikely to have internalized quantities of DU significantly in excess of normal internalization of natural uranium from the environment.

  20. Specification for the VERA Depletion Benchmark Suite

    SciTech Connect

    Kim, Kang Seog

    2015-12-17

    CASL-X-2015-1014-000 iii Consortium for Advanced Simulation of LWRs EXECUTIVE SUMMARY The CASL neutronics simulator MPACT is under development for the neutronics and T-H coupled simulation for the pressurized water reactor. MPACT includes the ORIGEN-API and internal depletion module to perform depletion calculations based upon neutron-material reaction and radioactive decay. It is a challenge to validate the depletion capability because of the insufficient measured data. One of the detoured methods to validate it is to perform a code-to-code comparison for benchmark problems. In this study a depletion benchmark suite has been developed and a detailed guideline has been provided to obtain meaningful computational outcomes which can be used in the validation of the MPACT depletion capability.

  1. Action orientation overcomes the ego depletion effect.

    PubMed

    Dang, Junhua; Xiao, Shanshan; Shi, Yucai; Mao, Lihua

    2015-04-01

    It has been consistently demonstrated that initial exertion of self-control had negative influence on people's performance on subsequent self-control tasks. This phenomenon is referred to as the ego depletion effect. Based on action control theory, the current research investigated whether the ego depletion effect could be moderated by individuals' action versus state orientation. Our results showed that only state-oriented individuals exhibited ego depletion. For individuals with action orientation, however, their performance was not influenced by initial exertion of self-control. The beneficial effect of action orientation against ego depletion in our experiment results from its facilitation for adapting to the depleting task. © 2014 Scandinavian Psychological Associations and John Wiley & Sons Ltd.

  2. Tonic and stimulus-evoked nitric oxide production in the mouse olfactory bulb

    PubMed Central

    Lowe, Graeme; Buerk, Donald G.; Ma, Jie; Gelperin, Alan

    2008-01-01

    Nitric oxide (NO) has been long assumed to play a key role in mammalian olfaction. This was based largely on circumstantial evidence, i.e. prominent staining for nitric oxide synthase (NOS) and cyclic GMP or soluble guanylyl cyclase, an effector enzyme activated by NO, in local interneurons of the olfactory bulb. Here we employ innovative custom-fabricated NO micro-sensors to obtain the first direct, time-resolved measurements of NO signaling in the olfactory bulb. In 400 μm thick mouse olfactory bulb slices, we detected a steady average basal level of 87 nM NO in the extracellular space of mitral or granule cell layers. This NO ‘tone’ was sensitive to NOS substrate manipulation (200 μM L-arginine, 2 mM L-NAME) and Mg2+ modulation of NMDA receptor conductance. Electrical stimulation of olfactory nerve fibers evoked transient (peak at 10 s) increments in NO levels 90 – 100 nM above baseline. In the anesthetized mouse, NO micro-sensors inserted into the granule cell layer detected NO transients averaging 55 nM in amplitude and peaking at 3.4 sec after onset of a 5 sec odorant stimulation. These findings suggest dual roles for NO signaling in the olfactory bulb – tonic inhibitory control of principal neurons, and regulation of circuit dynamics during odor information processing. PMID:18407420

  3. Quantitative evaluation of the tonic vibration reflex (TVR) in the masseter muscle.

    PubMed

    Takata, Y; Nakajima, T; Yamada, Y

    1996-11-01

    This study evaluated the efficacy of the tonic vibration reflex (TVR) elicited by high-frequency vibration in evaluating masticatory muscle excitability. The experiment was performed on 16 male adult volunteers, 20 to 45 years of age, without spontaneous pain or tenderness in the masticatory muscles. The subjects were seated in a chair in a fixed head position with the mouth kept open with a bite block. TVR was elicited by vibratory stimulation applied to the mandible (approximately 15 m/s2, 160 Hz). An electromyogram (EMG) was recorded bilaterally from the masseter muscles and analyzed quantitatively using an arbitrary index (TVR index) calculated from the response. Bite force was measured during clenching using a pressure-sensitive foil. Wide variations in the TVR index (maximum, 22.7%; minimum, 0.9%, average, 7.7%) were observed among individuals. The mean index for five subjects with a clenching habit was significantly higher than that for 11 subjects without a history of clenching. Tolperisone HCl (100 mg taken orally), a gamma-drive depressant, was found to reduce the response for 2 hours. There was a negative correlation (r = -.504, P < .05) between bite force and TVR index when the values on both sides were compared. The TVR may be of use in evaluating masseter muscle excitability.

  4. Spectral Analysis of Acceleration Data for Detection of Generalized Tonic-Clonic Seizures

    PubMed Central

    Joo, Hyo Sung; Han, Su-Hyun; Lee, Jongshill; Jang, Dong Pyo; Kang, Joong Koo; Woo, Jihwan

    2017-01-01

    Generalized tonic-clonic seizures (GTCSs) can be underestimated and can also increase mortality rates. The monitoring devices used to detect GTCS events in daily life are very helpful for early intervention and precise estimation of seizure events. Several studies have introduced methods for GTCS detection using an accelerometer (ACM), electromyography, or electroencephalography. However, these studies need to be improved with respect to accuracy and user convenience. This study proposes the use of an ACM banded to the wrist and spectral analysis of ACM data to detect GTCS in daily life. The spectral weight function dependent on GTCS was used to compute a GTCS-correlated score that can effectively discriminate between GTCS and normal movement. Compared to the performance of the previous temporal method, which used a standard deviation method, the spectral analysis method resulted in better sensitivity and fewer false positive alerts. Finally, the spectral analysis method can be implemented in a GTCS monitoring device using an ACM and can provide early alerts to caregivers to prevent risks associated with GTCS. PMID:28264522

  5. Synthesis of conolidine, a potent non-opioid analgesic for tonic and persistent pain

    NASA Astrophysics Data System (ADS)

    Tarselli, Michael A.; Raehal, Kirsten M.; Brasher, Alex K.; Streicher, John M.; Groer, Chad E.; Cameron, Michael D.; Bohn, Laura M.; Micalizio, Glenn C.

    2011-06-01

    Management of chronic pain continues to represent an area of great unmet biomedical need. Although opioid analgesics are typically embraced as the mainstay of pharmaceutical interventions in this area, they suffer from substantial liabilities that include addiction and tolerance, as well as depression of breathing, nausea and chronic constipation. Because of their suboptimal therapeutic profile, the search for non-opioid analgesics to replace these well-established therapeutics is an important pursuit. Conolidine is a rare C5-nor stemmadenine natural product recently isolated from the stem bark of Tabernaemontana divaricata (a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine). Although structurally related alkaloids have been described as opioid analgesics, no therapeutically relevant properties of conolidine have previously been reported. Here, we describe the first de novo synthetic pathway to this exceptionally rare C5-nor stemmadenine natural product, the first asymmetric synthesis of any member of this natural product class, and the discovery that (±)-, (+)- and (-)-conolidine are potent and efficacious non-opioid analgesics in an in vivo model of tonic and persistent pain.

  6. Critical tonicity determination of sperm using fluorescent staining and flow cytometry

    SciTech Connect

    Noiles, E.E.; Ruffing, N.A.; Kleinhans, F.W.; Mark, L.A.; Watson, P.F.; Critser, J.K. ); Horstman, L. . School of Veterinary Medicine); Mazur, P. )

    1990-01-01

    The use of cryopreserved, rather than fresh, mammalian semen for artificial insemination confers several important medical and/or economic advantages. However, current methods for cryopreservation of both human and bovine spermatozoa result in approximately only a 50% survival rate with thawing, obviously reducing the fertilizing capacity of the semen. A primary consideration during the cooling process is to avoid intracellular ice crystal formation with its lethal consequences to the cell. Current techniques achieve this by controlling the cooling rate. Computation of the time necessary for this dehydration, and hence, the cooling rate, is dependent upon knowledge of the water permeability coefficient (L{sub {rho}}) and its activation energy. The fluorophore, 6-carboxyfluoroscein diacetate (CFDA), which is nonfluorescent, readily crosses the intact plasma membrane. Intracellular esterases hydrolyze CFDA to 6-carboxyfluoroscein, a fluorescent, membrane-impermeable fluorophore. Consequently, spermatozoa with intact plasma membranes fluoresce bright green (Garner et. al., 1986), but those with disrupted membranes do not. Therefore, the purpose of this study was to use loss of CFDA fluorescence to determine the osmolality at which 50% of the spermatozoa will swell and lyse (critical tonicity, CT). These data will then be used to determine the L{sub {rho}} and its activation energy for sperm, thus increasing the knowledge available in cellular cryopreservation. 15 refs., 3 figs.

  7. Aralia elata prevents neuronal death by downregulating tonicity response element binding protein in diabetic retinopathy.

    PubMed

    Kim, Seong-Jae; Yoo, Woong-Sun; Kim, Hwajin; Kwon, Jeong Eun; Hong, Eun-Kyung; Choi, Meeyoung; Han, Yongseop; Chung, Inyoung; Seo, Seongwook; Park, Jongmoon; Yoo, Ji-Myong; Choi, Wan-Sung

    2015-01-01

    The present study addresses the role of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death in diabetic retinopathy and the impact of Aralia elata extract on the TonEBP/RGC interaction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). Control mice received phosphate-buffered saline. After five injections of STZ or saline buffer, A. elata extract was administered by daily oral tube feeding for 7 weeks. All mice were killed at 2 months after the last injection of STZ or saline and the extent of cell death together with the protein expression levels of TonEBP, aldose reductase (AR) and nuclear factor-kappa B (NF-κB) were examined. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive signals were colocalized with TonEBP-immunoreactive RGCs. The apoptotic cell death of RGCs and the expression levels of TonEBP, AR and NF-κB were significantly increased in the retinas of diabetic mice compared with controls at 2 months after the induction of diabetes. However, these changes were effectively blocked by the administration of A. elata extract. These results indicate that A. elata prevents diabetes-induced RGC apoptosis and downregulates TonEBP expression. Therefore, A. elata extract may have therapeutic potential to prevent diabetes-induced retinal neurodegeneration in diabetic retinopathy. © 2015 S. Karger AG, Basel.

  8. Tonicity response element binding protein associated with neuronal cell death in the experimental diabetic retinopathy

    PubMed Central

    Kim, Seong-Jae; Kim, Hwajin; Park, Jeongsook; Chung, Inyoung; Kwon, Hyug-Moo; Choi, Wan-Sung; Yoo, Ji-Myong

    2014-01-01

    AIM To study the contribution of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death of diabetic retinopathy (DR). METHODS Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Control mice received vehicle (phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of TonEBP and aldose reductase (AR) were examined. RESULTS The TonEBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive signals co-localized with TonEBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls. CONCLUSION The present data show that AR and TonEBP are upregulated in the DR and TonEBP may contribute to apoptosis of RGC in the DR. PMID:25540742

  9. Tonicity response element binding protein associated with neuronal cell death in the experimental diabetic retinopathy.

    PubMed

    Kim, Seong-Jae; Kim, Hwajin; Park, Jeongsook; Chung, Inyoung; Kwon, Hyug-Moo; Choi, Wan-Sung; Yoo, Ji-Myong

    2014-01-01

    To study the contribution of tonicity response element binding protein (TonEBP) in retinal ganglion cell (RGC) death of diabetic retinopathy (DR). Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin (STZ). Control mice received vehicle (phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of TonEBP and aldose reductase (AR) were examined. The TonEBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL)-positive signals co-localized with TonEBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls. The present data show that AR and TonEBP are upregulated in the DR and TonEBP may contribute to apoptosis of RGC in the DR.

  10. Tonically active protein kinase A regulates neurotransmitter release at the squid giant synapse.

    PubMed

    Hilfiker, S; Czernik, A J; Greengard, P; Augustine, G J

    2001-02-15

    1. Electrophysiological and microinjection methods were used to examine the role of cyclic AMP-dependent protein kinase A (PKA) in regulating transmitter release at the squid giant synapse. 2. Excitatory postsynaptic potentials (EPSPs) evoked by presynaptic action potentials were not affected by presynaptic injection of an exogenous active catalytic subunit of mammalian PKA. 3. In contrast, presynaptic injection of PKI-amide, a peptide that inhibits PKA with high potency and specificity, led to a reversible inhibition of EPSPs. 4. Injection of several other peptides that serve as substrates for PKA also reversibly inhibited neurotransmitter release. The ability of these peptides to inhibit release was correlated with their ability to serve as PKA substrates, suggesting that these peptides act by competing with endogenous substrates for phosphorylation by active endogenous PKA. 5. We suggest that the phosphorylation of PKA substrates is maintained at a relatively high state under basal conditions and that this tonic activity of PKA is to a large degree required for evoked neurotransmitter release at the squid giant presynaptic terminal.

  11. Influence of tonicity and chloramphenicol on hyperthermic cytotoxicity and cell permeability under various heating rates.

    PubMed

    Morozov, I I; Petin, V G; Dubovick, B V

    1997-01-01

    The cell lethality and permeability induced in Escherichia coli B/r, Escherichia coli Bs-1 and Zygosaccharomyces bailii cells by high temperature (52 degrees C) after heating at different rates (mean s 0.015, 0.25 and 1.50 degrees C per s) and in media of different tonicity and content (isotonic YEP broth versus 0.01 M phosphate buffer, pH 7.0 containing different concentrations of NaCl) and with versus without chloramphenicol (10 micrograms/ml) have been investigated. Hyperthermic treatment in YEP broth of isotonic 0.01 M phosphate buffer resulted in markedly reduced cytotoxicity with decreasing heat rate. The heating rate effect was larger when the cells were treated in YEP broth. Chloramphenicol, which is known to inhibit expression of heat shock proteins in bacteria, did not affect the viability of cells or the development of thermotolerance in cells heated at different heating rates in isotonic phosphate buffer but prevented the development of an additional degree of thermotolerance in cells heated slowly in YEP broth. In contrast, the differential effect of heating rate on cytotoxicity and cell permeability was not demonstrated when cells were heated in hypertonic solution (1M NaCl in phosphate buffer, pH 7.0). It is proposed that heat destabilization of the osmotic cell homeostasis, which is more profound after rapid heating, plays a major part in heat induced cellular lethality.

  12. Tonically Active α5GABAA Receptors Reduce Motoneuron Excitability and Decrease the Monosynaptic Reflex.

    PubMed

    Canto-Bustos, Martha; Loeza-Alcocer, Emanuel; Cuellar, Carlos A; Osuna, Paulina; Elias-Viñas, David; Granados-Soto, Vinicio; Manjarrez, Elías; Felix, Ricardo; Delgado-Lezama, Rodolfo

    2017-01-01

    Motoneurons, the final common path of the Central Nervous System (CNS), are under a complex control of its excitability in order to precisely translate the interneuronal pattern of activity into skeletal muscle contraction and relaxation. To fulfill this relevant function, motoneurons are provided with a vast repertoire of receptors and channels, including the extrasynaptic GABAA receptors which have been poorly investigated. Here, we confirmed that extrasynaptic α5 subunit-containing GABAA receptors localize with choline acetyltransferase (ChAT) positive cells, suggesting that these receptors are expressed in turtle motoneurons as previously reported in rodents. In these cells, α5GABAA receptors are activated by ambient GABA, producing a tonic shunt that reduces motoneurons' membrane resistance and affects their action potential firing properties. In addition, α5GABAA receptors shunted the synaptic excitatory inputs depressing the monosynaptic reflex (MSR) induced by activation of primary afferents. Therefore, our results suggest that α5GABAA receptors may play a relevant physiological role in motor control.

  13. Phasic and Tonic mGlu7 Receptor Activity Modulates the Thalamocortical Network

    PubMed Central

    Tassin, Valériane; Girard, Benoît; Chotte, Apolline; Fontanaud, Pierre; Rigault, Delphine; Kalinichev, Mikhail; Perroy, Julie; Acher, Francine; Fagni, Laurent; Bertaso, Federica

    2016-01-01

    Mutation of the metabotropic glutamate receptor type 7 (mGlu7) induces absence-like epileptic seizures, but its precise role in the somatosensory thalamocortical network remains unknown. By combining electrophysiological recordings, optogenetics, and pharmacology, we dissected the contribution of the mGlu7 receptor at mouse thalamic synapses. We found that mGlu7 is functionally expressed at both glutamatergic and GABAergic synapses, where it can inhibit neurotransmission and regulate short-term plasticity. These effects depend on the PDZ-ligand of the receptor, as they are lost in mutant mice. Interestingly, the very low affinity of mGlu7 receptors for glutamate raises the question of how it can be activated, namely at GABAergic synapses and in basal conditions. Inactivation of the receptor activity with the mGlu7 negative allosteric modulator (NAM), ADX71743, enhances thalamic synaptic transmission. In vivo administration of the NAM induces a lethargic state with spindle and/or spike-and-wave discharges accompanied by a behavioral arrest typical of absence epileptic seizures. This provides evidence for mGlu7 receptor-mediated tonic modulation of a physiological function in vivo preventing synchronous and potentially pathological oscillations. PMID:27199672

  14. Tonic efferent-induced cochlear damping in roosting and echolocating mustached bats.

    PubMed

    Xie, D H; Henson, O W

    1998-10-01

    The activity of the medial olivocochlear (MOC) efferent system in mustached bats, Pteronotus p. parnellii, was studied by monitoring changes in the mechanical properties of the cochlea. The changing properties were expressed by the decay time (DT) of cochlear microphonic potentials produced by transient-induced ringing (Henson et al., 1995). Tape-recorded roost noise (biosonar and communication sounds) produced sudden, marked decreases in DT when presented to the contralateral ear of animals adapted to the quiet. When the animals were first removed from their roosts the DT was relatively short (1.2-1.5 ms) but this gradually lengthened by about 0.5-1.0 ms as they rested in a quiet chamber. The time required to reach a stable, quiet-adapted state after noise exposure varied with SPL and exposure time; in many experiments recovery was in the range of 90-120 min. When quiet-adapted bats were isolated and allowed to fly and echolocate for 20 min, the DTs measured within a few minutes after the end of the flight were also short and only slowly returned to longer preflight values. The administration of a single dose of gentamicin, which blocks MOC effects, greatly reduced the amount of suppression (damping) observed after periods of noise and echolocation sound exposure. We conclude that tonic MOC activity is induced by the natural vocalizations and roost noise and this activity probably regulates and protects the highly resonant cochlear partition.

  15. Muscle group dependent responses to stimuli in a grasshopper model for tonic immobility

    PubMed Central

    Miriyala, Ashwin; Dutta-Gupta, Aparna; Joseph, Joby

    2013-01-01

    Summary Tonic Immobility (TI) is a prolonged immobile condition exhibited by a variety of animals when exposed to certain stimuli, and is thought to be associated with a specific state of arousal. In our study, we characterize this state by using the reliably inducible TI state of the grasshopper (Hieroglyphus banian) and by monitoring abdominal pulsations and body movements in response to visual and auditory stimuli. These pulsations are present during the TI and ‘awake’, standing states, but not in the CO2 anesthetized state. In response to the stimuli, animals exhibited a suppression in pulsation and a startle response. The suppression of pulsation lasted longer than the duration of stimulus application. During TI, the suppression of pulsation does not habituate over time, whereas the startle response does. In response to the translating visual stimulus, the pulsations are suppressed at a certain phase independent of the time of stimulus application. Thus, we describe TI in Hieroglyphus banian as a state more similar to an ‘awake’ state than to an anesthetized state. During TI, the circuitry to the muscle outputs controlling the abdomen pulsation and the startle response are, at least in some part, different. The central pattern generators that maintain the abdomen pulsation receive inputs from visual and auditory pathways. PMID:24244858

  16. Differential physiological effects during tonic painful hand immersion tests using hot and ice water.

    PubMed

    Streff, Anouk; Kuehl, Linn K; Michaux, Gilles; Anton, Fernand

    2010-03-01

    The cold pressor test (CPT) is an empirically validated test commonly used in research on stress, pain and cardiovascular reactivity. Surprisingly, the equivalent test with water heated to noxious temperatures (hot water immersion test, HIT) has not been thoroughly investigated. The aim of the present study was to characterize the physiological effects and psychophysics of both tests and to analyze whether the autonomic responses are mainly induced by baroreflexes or a consequence of the pain experience itself. The study consisted of a single session including one CPT (4+/-0.2 degrees C) and one HIT (47+/-0.5 degrees C; cut-off point 5 min) trial performed on 30 healthy drug free volunteers aged 19-57 (median 24) yrs. The sequence of both trials was alternated and participants were randomly assigned to sequence order and parallelized with respect to gender. Physiological parameters (cardiovascular, respiratory and electrodermal activity) and subjective pain intensity were continuously monitored. In addition, pain detection and tolerance thresholds as well as pain unpleasantness were assessed. Both tests were comparable with regard to the time course and intensity of subjective pain. However, a significantly higher increase of blood pressure could be observed during the CPT when compared to the HIT. The HIT appears less confounded with thermoregulatory baroreflex activity and therefore seems to be a more appropriate model for tonic pain.

  17. Responses of tonically active neurons in the monkey striatum discriminate between motivationally opposing stimuli.

    PubMed

    Ravel, Sabrina; Legallet, Eric; Apicella, Paul

    2003-09-17

    The striatum is involved in the control of appetitively motivated behavior. We found previously that tonically active neurons (TANs) in the monkey striatum show discriminative responses to different stimuli that are appetitive or aversive. However, these differential responses may reflect the sensory qualities of the stimulus rather than its motivational value. In the present study, we sought to define more precisely the relationship between the particular aspect of the response of TANs and the motivational value of stimuli. For this purpose, three monkeys were presented with two types of aversive stimuli (loud sound and air puff) and one appetitive stimulus (fruit juice). In most instances, the TAN responses to the loud sound and the air puff were similar, in terms of response pattern and duration, whereas responses to the liquid reward showed distinct features. Using classical appetitive conditioning, we reversed the motivational value of a stimulus so that a previously aversive stimulus was now associatively paired with a reward and found that this manipulation selectively modifies the expression of TAN responses to the stimulus. These data indicate that the characteristics of neuronal responses undergo modifications when the valence of the stimulus is changed from aversive to appetitive during associative learning, suggesting that TANs may contribute to a form of stimulus encoding that is dependent on motivational attributes. The adaptation of TAN responses such as observed in the present study likewise reflects a neuronal system that adjusts to the motivational information about environmental events.

  18. Activation of Gi-coupled receptors releases a tonic state of inhibited platelet aggregation.

    PubMed

    Maayani, S; Schwarz, T; Martinez, R; Tagliente, T M

    2001-03-01

    Single-receptor pharmacology does not satisfactorily explain the physiology of the ADP-induced platelet aggregation response. It has been shown that, in addition to Gq-coupled receptor activation, one Gi-coupled receptor, either the ADP P2T or the alpha2-adrenoceptor, is required for elicitation of aggregation. The underlying mechanism of this action, however, has not been elucidated. By systematically assaying the entire time course of the aggregation and its fade using two methods of aggregometry, we have investigated the role of graded activation of these two Gi-coupled receptors. We demonstrate that constant activation of either of two Gq-coupled receptors, the ADP P2Y1 or the 5-HT2A, and incremental activation of either of the two Gi-coupled receptors, tightly regulates the aggregation response in vitro, through the apparent release of a tonic inhibition of platelet aggregation. This tightly regulated release of inhibition, which appears analogous to the phenomena of disinhibition observed in the central nervous system, may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions.

  19. HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling.

    PubMed

    Walter, Roland; Pan, Kuan-Ting; Doebele, Carmen; Comoglio, Federico; Tomska, Katarzyna; Bohnenberger, Hanibal; Young, Ryan M; Jacobs, Laura; Keller, Ulrich; Bönig, Halvard; Engelke, Michael; Rosenwald, Andreas; Urlaub, Henning; Staudt, Louis M; Serve, Hubert; Zenz, Thorsten; Oellerich, Thomas

    2017-02-02

    Burkitt lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we show that, in BL, HSP90 inhibition compromises the activity of the pivotal B-cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL.

  20. Erythrocyte adhesion is modified by alterations in cellular tonicity and volume.

    PubMed

    Wandersee, Nancy J; Punzalan, Rowena C; Rettig, Michael P; Kennedy, Michael D; Pajewski, Nicholas M; Sabina, Richard L; Paul Scott, J; Low, Philip S; Hillery, Cheryl A

    2005-11-01

    We tested the hypothesis that dehydration-induced alterations in red blood cell (RBC) membrane organisation or composition contribute to sickle cell adhesion in sickle cell disease (SCD). To examine the role of RBC hydration in adhesion to the subendothelial matrix protein thrombospondin-1 (TSP), normal and sickle RBCs were incubated in buffers of varying tonicity and tested for adhesion to immobilised TSP under flow conditions. Sickle RBCs exhibited a decrease in TSP binding with increasing cell hydration (P<0.005), suggesting that cellular dehydration may contribute to TSP adhesion. Consistent with this hypothesis, normal RBCs showed an increase in TSP adhesion with increasing dehydration (P<0.01). Furthermore, increased TSP adhesion of normal RBCs could also be induced by isotonic dehydration using nystatin-sucrose buffers. Finally, TSP adhesion of both sickle RBCs and dehydrated normal RBCs was inhibited by the anionic polysaccharides, chondroitin sulphate A and high molecular weight dextran sulphate, but not by competitors of CD47-, band 3-, or RBC phosphatidylserine-mediated adhesion. More importantly, we found increased adhesion of nystatin-sucrose dehydrated normal mouse RBCs to kidney capillaries following re-infusion in vivo. In summary, these findings demonstrate that changes in hydration can significantly impact adhesion, causing normal erythrocytes to display adhesive properties similar to those of sickle cells and vice versa.

  1. Biophysical modeling of tonic cortical electrical activity in attention deficit hyperactivity disorder.

    PubMed

    Rowe, D L; Robinson, P A; Lazzaro, I L; Powles, R C; Gordon, E; Williams, L M

    2005-09-01

    Psychophysiological theories characterize Attention Deficit Hyperactivity Disorder (ADHD) in terms of cortical hypoarousal and a lack of inhibition of irrelevant sensory input, drawing on evidence of abnormal electroencephalographic (EEG) delta-theta activity. To investigate the mechanisms underlying this disorder a biophysical model of the cortex was used to fit and replicate the EEGs from 54 ADHD adolescents and their control subjects. The EEG abnormalities in ADHD were accounted for by the model's neurophysiological parameters as follows: (i) dendritic response times were increased, (ii) intrathalamic activity involving the thalamic reticular nucleus (TRN) was increased, consistent with enhanced delta-theta activity, and (iii) intracortical activity was increased, consistent with slow wave (<1 Hz) abnormalities. The longer dendritic response time is consistent with the increase in the activity of inhibitory cells types, particularly in the TRN, and therefore reduced arousal. The increase in intracortical activity may also reflect an increase in background activity or cortical noise within neocortical circuits. In terms of neurochemistry, these findings may be accounted for by disturbances in the cholinergic and/or noradrenergic systems. To the knowledge of the authors, this is the first study to use a detailed biophysical model of the brain to elucidate the neurophysiological mechanisms underlying tonic abnormalities in ADHD.

  2. Tonic glutamatergic input in the rostral ventrolateral medulla is increased in rats with chronic heart failure.

    PubMed

    Wang, Wei-Zhong; Gao, Lie; Wang, Han-Jun; Zucker, Irving H; Wang, Wei

    2009-02-01

    Chronic heart failure (CHF) is characterized by increased sympathetic tone. The glutamatergic input in the rostral ventrolateral medulla (RVLM), which is a key region involved in sympathetic outflow, seems not to be involved in the generation of sympathetic tone in the normal state. The aim of this study was to determine the role of the RVLM glutamate receptors in the generation of sympathetic tone in CHF. CHF was produced by coronary artery ligation. Bilateral microinjection of the glutamate receptor antagonist kynurenic acid, the N-methyl-d-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoate, or the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione into the RVLM dose-dependently reduced resting blood pressure and renal sympathetic nerve activity in CHF but not in sham rats. Picoinjection of kynurenic acid (100 pmol in 5 nL) significantly decreased the basal discharge by 47% in 25 RVLM presympathetic neurons in CHF rats. In contrast, kynurenic acid had no effect on the discharge in all 22 of the RVLM presympathetic neurons tested in sham rats. These data suggest that upregulated glutamate receptors, including NMDA and non-NMDA, in the RVLM are involved in tonic control of elevated sympathetic tone in CHF.

  3. The FcμR Limits Tonic BCR Signaling by Regulating IgM-BCR Expression

    PubMed Central

    Nguyen, Trang T. T.; Kläsener, Kathrin; Zürn, Christa; Castillo, Patricia A.; Brust-Mascher, Ingrid; Imai, Denise M.; Bevins, Charles L.; Reardon, Colin; Reth, Michael; Baumgarth, Nicole

    2017-01-01

    The IgM Fc receptor (FcμR), originally cloned as “Fas-apoptosis inhibitory molecule (FAIM3/TOSO)” can function as a cell surface receptor for secreted IgM on a variety of cell types. We report that FcμR also is expressed in the trans-Golgi network of developing B cells, where it constrains IgM- but not IgD-BCR transport. In FcμR absence, IgM-BCR surface expression was increased, resulting in enhanced tonic BCR signaling. B cell-specific FcμR-deficiency enhanced spontaneous differentiation of B-1 cells, resulting in increases in natural IgM levels, and dysregulated B-2 cell homeostasis, causing spontaneous germinal center formation, increased serum autoantibody titers, and excessive B cell accumulation. Thus, FcμR/FAIM3 is a critical regulator of B cell biology by constraining IgM-BCR transport and cell surface expression. PMID:28135254

  4. Limited Expression of Slow Tonic Myosin Heavy Chain in Human Cranial Muscles

    PubMed Central

    Sokoloff, Alan J.; Li, Haiyan; Burkholder, Thomas J.

    2013-01-01

    Recent reports of slow tonic myosin heavy chain (MHCst) in human masticatory and laryngeal muscles suggest that MHCst may have a wider distribution in humans than previously thought. Because of the novelty of this finding, we sought to confirm the presence of MHCst in human masticatory and laryngeal muscles by reacting tissue from these muscles and controls from extraocular, intrafusal, cardiac, appendicular and developmental muscle with antibodies (Abs) ALD-58 and S46 considered highly specific for MHCst. At Ab dilutions producing minimal reaction to muscle fibers positive for MHCI, only extraocular, intrafusal and fetal tongue tissue reacted with Ab S46 had strong immunoreaction in an appreciable number of muscle fibers. In immunoblots Ab S46, but not Ab ALD-58, labeled adult extraocular muscles; no other muscles were labeled with either Ab. We conclude that, in humans, Ab S46 has greater specificity for MHCst than does Ab ALD-58. We suggest that reports of MHCst in human masticatory and laryngeal muscles reflect false-positive identification of MHCst due to cross-reactivity of Ab ALD-58 with another MHC isoform. PMID:17486578

  5. [Arginine, octopine and alanine during the tonic and phasic contraction of the anterior byssus retractor muscle of Mytilus edulis].

    PubMed

    Devroede, J; Baguet, F

    1982-01-01

    In this work, we compare the energetic cost of tonic and phasic contractions of the anterior byssus retractor muscle (ABRM) of Mytilus edulis. The muscle is stimulated by six different stimulation methods and frozen when it reaches its maximal isometric response. Tonic and phasic tension developments are of similar amplitude and cause a hydrolysis of the same amount of phosphoarginine corresponding to 0.64 mumole per g of muscle and per kg/cm2 of tension (Fig. 1). As compared with the results reported in the literature the values are in good agreement with the biochemical and respiratory measurements, but they are 10 times higher than those measured by the heat production. The total arginine, octopine and alanine contents of those muscles frozen at the peak of contraction are not significantly different from those measured on the resting muscle. On the other hand, these metabolites may show seasonal variations.

  6. Effect of Zena F-III, a liquid nutritive and tonic drug, on the neurochemical changes elicited by physical fatigue in mice.

    PubMed

    Hanawa, M; Asano, T; Akiyama, K; Yabe, K; Tsunoda, K; Tadano, T; Sutoo, D

    2000-08-01

    The effects of a liquid nutritive and tonic drug (NTD) on the neurochemical changes elicited by physical fatigue in mice were investigated in terms of the calcium-dependent dopamine synthesizing function of the brain. In this study, Zena F-III (Taisho Pharmaceutical Co., Ltd., Japan), one of the most popular NTDs in Japan, containing 15 crude drug extracts together with taurine, caffeine, and vitamins, and formulated based on the precepts of traditional Chinese medicine, was used. Male mice were forced to walk for 0-6 h at a speed of 3 m/min using a programmed motor-driven wheel cage. The serum and brain calcium levels in the mice were significantly increased following forced walking. The increase in brain calcium level began later and was more gradual than that in the serum calcium level, and reached its maximum value following forced walking for 3 h. The neostriatal dopamine level was also significantly increased, and locomotor activity significantly decreased following forced walking for 3 h. Prior oral administration of F-III (10 ml/kg) attenuated the increases in the serum and brain calcium levels, the increase in the brain dopamine levels, and the decrease in locomotor activity induced by forced walking. Taking into consideration these findings with our previous reports, it is suggested that physical fatigue leads to an increase in dopamine synthesis in the brain through a calcium/calmodulin-dependent system, thereby inducing behavioral changes, and that F-III inhibits this pathway and may alleviate overwork-induced physical fatigue.

  7. Influence of caffeine on the protective activity of gabapentin and topiramate in a mouse model of generalized tonic-clonic seizures.

    PubMed

    Chrościńska-Krawczyk, Magdalena; Jargiełło-Baszak, Małgorzata; Andres-Mach, Marta; Łuszczki, Jarogniew J; Czuczwar, Stanisław J

    2016-08-01

    Caffeine may interact with classical antiepileptic drugs (AEDs), reducing their anticonvulsant effects in basic seizure models. The aim of the present study was to ascertain whether intraperitoneal caffeine (acute or chronic for 15 days) could attenuate the anticonvulsant effect of some newer AEDs: gabapentin (GBP) and topiramate (TPM) against electroconvulsions in mice. Maximal electroshock (MES)-induced mouse seizure model was used for the estimation of the anticonvulsant activity of TPM whilst the protective activity of GBP was evaluated in the threshold test for maximal (tonic) convulsions. Adverse effects were evaluated by measurement of long-term memory (the step-through passive avoidance task) and motor coordination (chimney test). Plasma AED concentrations were also measured to determinate any pharmacokinetic contribution to the observed effects. Caffeine (both acute and chronic at 23.1 and 46.2mg/kg) significantly reduced the protective effects of TPM against MES. As regards GBP, caffeine (acutely at 46.2mg/kg and chronically at 23.1 or 46.2mg/kg) significantly diminished the GBP-induced increases in the electroconvulsive threshold. In addition, caffeine did not affect the free plasma concentrations of TPM or GBP. Acute and chronic caffeine (23.1 and 46.2mg/kg) enhanced the impairment of motor coordination in mice pretreated with GBP whilst an opposite effect was observed in TPM injected mice and pretreated with chronic caffeine at 46.2mg/kg. The results indicate that newer AEDs, GBP or TPM behave in the exactly same way as classical antiepileptics in mice challenged with caffeine. This hazardous effect of caffeine is not subject to tolerance. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  8. Effects of Macrophage Depletion on Sleep in Mice.

    PubMed

    Ames, Conner; Boland, Erin; Szentirmai, Éva

    2016-01-01

    The reciprocal interaction between the immune system and sleep regulation has been widely acknowledged but the cellular mechanisms that underpin this interaction are not completely understood. In the present study, we investigated the role of macrophages in sleep loss- and cold exposure-induced sleep and body temperature responses. Macrophage apoptosis was induced in mice by systemic injection of clodronate-containing liposomes (CCL). We report that CCL treatment induced an immediate and transient increase in non-rapid-eye movement sleep (NREMS) and fever accompanied by decrease in rapid-eye movement sleep, motor activity and NREMS delta power. Chronically macrophage-depleted mice had attenuated NREMS rebound after sleep deprivation compared to normal mice. Cold-induced increase in wakefulness and decrease in NREMS, rapid-eye movement sleep and body temperature were significantly enhanced in macrophage-depleted mice indicating increased cold sensitivity. These findings provide further evidence for the reciprocal interaction among the immune system, sleep and metabolism, and identify macrophages as one of the key cellular elements in this interplay.

  9. Effects of Macrophage Depletion on Sleep in Mice

    PubMed Central

    Ames, Conner; Boland, Erin; Szentirmai, Éva

    2016-01-01

    The reciprocal interaction between the immune system and sleep regulation has been widely acknowledged but the cellular mechanisms that underpin this interaction are not completely understood. In the present study, we investigated the role of macrophages in sleep loss- and cold exposure-induced sleep and body temperature responses. Macrophage apoptosis was induced in mice by systemic injection of clodronate-containing liposomes (CCL). We report that CCL treatment induced an immediate and transient increase in non-rapid-eye movement sleep (NREMS) and fever accompanied by decrease in rapid-eye movement sleep, motor activity and NREMS delta power. Chronically macrophage-depleted mice had attenuated NREMS rebound after sleep deprivation compared to normal mice. Cold-induced increase in wakefulness and decrease in NREMS, rapid-eye movement sleep and body temperature were significantly enhanced in macrophage-depleted mice indicating increased cold sensitivity. These findings provide further evidence for the reciprocal interaction among the immune system, sleep and metabolism, and identify macrophages as one of the key cellular elements in this interplay. PMID:27442442

  10. Exercise training attenuates chemoreflex-mediated reductions of renal blood flow in heart failure.

    PubMed

    Marcus, Noah J; Pügge, Carolin; Mediratta, Jai; Schiller, Alicia M; Del Rio, Rodrigo; Zucker, Irving H; Schultz, Harold D

    2015-07-15

    In chronic heart failure (CHF), carotid body chemoreceptor (CBC) activity is increased and contributes to increased tonic and hypoxia-evoked elevation in renal sympathetic nerve activity (RSNA). Elevated RSNA and reduced renal perfusion may contribute to development of the cardio-renal syndrome in CHF. Exercise training (EXT) has been shown to abrogate CBC-mediated increases in RSNA in experimental heart failure; however, the effect of EXT on CBC control of renal blood flow (RBF) is undetermined. We hypothesized that CBCs contribute to tonic reductions in RBF in CHF, that stimulation of the CBC with hypoxia would result in exaggerated reductions in RBF, and that these responses would be attenuated with EXT. RBF was measured in CHF-sedentary (SED), CHF-EXT, CHF-carotid body denervation (CBD), and CHF-renal denervation (RDNX) groups. We measured RBF at rest and in response to hypoxia (FiO2 10%). All animals exhibited similar reductions in ejection fraction and fractional shortening as well as increases in ventricular systolic and diastolic volumes. Resting RBF was lower in CHF-SED (29 ± 2 ml/min) than in CHF-EXT animals (46 ± 2 ml/min, P < 0.05) or in CHF-CBD animals (42 ± 6 ml/min, P < 0.05). In CHF-SED, RBF decreased during hypoxia, and this was prevented in CHF-EXT animals. Both CBD and RDNX abolished the RBF response to hypoxia in CHF. Mean arterial pressure increased in response to hypoxia in CHF-SED, but was prevented by EXT, CBD, and RDNX. EXT is effective in attenuating chemoreflex-mediated tonic and hypoxia-evoked reductions in RBF in CHF. Copyright © 2015 the American Physiological Society.

  11. Essiac? and Flor-Essence? herbal tonics stimulate the in vitro growth of human breast cancer cells

    SciTech Connect

    Kulp, K S; Montgomery, J L; McLimans, B; Latham, E R; Shattuck, D L; Klotz, D M; Bennett, L M

    2005-10-07

    People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence{reg_sign} and Essiac{reg_sign} Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence{reg_sign} and Essiac{reg_sign} for their effects on the growth of human tumor cells in culture. The effect of Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. Flor-Essence{reg_sign} and Essiac{reg_sign} herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls and activated ER dependent luciferase activity in MCF-7 cells. A 10{sup -7} M concentration of ICI 870,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence{reg_sign} and Essiac{reg_sign}, but did not affect cell proliferation. Flor-Essence{reg_sign} and Essiac{reg_sign} Herbal Tonics can stimulate the growth of human breast cancer cells through ER mediated as well as ER independent mechanisms of action. Cancer patients and health care providers can use this information to make informed decisions about the use of these CAMs.

  12. Influence of the environmental tonicity perturbations on the release of model compounds from large unilamellar vesicles (LUVs): A mechanistic investigation.

    PubMed

    Wu, Iren Yeeling; Škalko-Basnet, Nataša; di Cagno, Massimiliano Pio

    2017-09-01

    In this work, the influence of environmental tonicity perturbations on the size and release kinetics of model markers from liposomes (calcein and rhodamine) was investigated. Large unilamellar vesicles (LUVs) were prepared from a mixture composed of organic solvents containing dissolved phosphatidylcholine and phosphate buffered saline (PBS, pH 7.4). Organic phase was removed by rotary evaporation and the obtained liposomal dispersions were extruded to reduce the liposomal sizes to approx. 400 nm. The LUVs were exposed to PBS of different tonicity to induce water migration, and consequently, generate an osmotic pressure on the vesicle membranes. The markers release kinetics were studied by the dialysis method employing Franz diffusion cells. LUVs appeared to be more susceptible to the osmotic swelling than the shrinking and the size changes were significantly more pronounced for calcein-loaded LUVs in comparison to rhodamine-loaded LUVs. The calcein release from LUVs was highly affected by the water influx/efflux, whereas rhodamine release was less affected by the tonicity perturbations. Mechanistically, it appeared that hydrophilic molecules (calcein) followed the water flux, whereas lipophilic molecules (rhodamine) seemed to be more affected by the changes in LUVs size and consequent alteration of the tightness of the phospholipid bilayer (where the lipophilic marker was imbedded in). These results demonstrate that the different tonicity (within the inner core and external environment of vesicles) can enhance/hamper the diffusion of a marker from LUVs and that osmotically active liposomes could be used as a novel controlled drug delivery system. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Delta-subunit-containing GABAA-receptors mediate tonic inhibition in paracapsular cells of the mouse amygdala

    PubMed Central

    Marowsky, Anne; Vogt, Kaspar E.

    2014-01-01

    The intercalated paracapsular cells (pcs) are small GABAergic interneurons that form densely populated clusters surrounding the basolateral (BLA) complex of the amygdala. Their main task in the amygdala circuitry appears to be the control of information flow, as they act as an inhibitory interface between input and output nuclei. Modulation of their activity is thus thought to affect amygdala output and the generation of fear and anxiety. Recent evidence indicates that pcs express benzodiazepine (BZ)-sensitive GABAA receptor (GABAAR) variants containing the α2- and α3-subunit for transmission of post-synaptic currents, yet little is known about the expression of extrasynaptic GABAARs, mediating tonic inhibition and regulating neuronal excitability. Here, we show that pcs from the lateral and medial intercalated cell cluster (l- and mITC, respectively) express a tonic GABAergic conductance that could be significantly increased in a concentration-dependent manner by the δ-preferring GABAAR agonist THIP (0.5–10 μM), but not by the BZ diazepam (1 μM). The neurosteroid THDOC (300 nM) also increased tonic currents in pcs significantly, but only in the presence of additional GABA (5 μM). Immunohistochemical stainings revealed that both the δ-GABAAR and the α4-GABAAR subunit are expressed throughout all ITCs, while no staining for the α5-GABAAR subunit could be detected. Moreover, 1 μM THIP dampened excitability in pcs most likely by increasing shunting inhibition. In line with this, THIP significantly decreased lITC-generated inhibition in target cells residing in the BLA nucleus by 30%. Taken together these results demonstrate for the first time that pcs express a tonic inhibitory conductance mediated most likely by α4/δ-containing GABAARs. This data also suggest that δ-GABAAR targeting compounds might possibly interfere with pcs-related neuronal processes such as fear extinction. PMID:24723854

  14. Tonicity balance, and not electrolyte-free water calculations, more accurately guides therapy for acute changes in natremia.

    PubMed

    Carlotti, A P; Bohn, D; Mallie, J P; Halperin, M L

    2001-05-01

    The usual way to decide why hyponatremia or hypernatremia has developed and to plan goals for its therapy is to analyze events in electrolyte-free water (EFW) terms. We shall demonstrate that an EFW balance does not supply this information. Rather, one must calculate mass balances for water and sodium plus potassium separately (a tonicity balance) to understand the basis for the change in natremia and the proper goals for its therapy. These points are illustrated with a clinical example.

  15. Absence of tonic supraspinal control of substance P release in the substantia gelatinosa of the anaesthetized cat.

    PubMed

    Duggan, A W; Morton, C R; Hutchison, W D; Hendry, I A

    1988-01-01

    Antibody microprobes were used to measure immunoreactive substance P (irSP) release in the substantia gelatinosa of the lower lumbar spinal cord of barbiturate-anaesthetized cats. Release of irSP was produced by noxious peripheral stimuli. Such release was not altered by blocking spinal conduction at the first lumbar segment by cooling or transecting the spinal cord. The results suggest that the release of irSP from the central terminals of nociceptors is not subject to tonic supraspinal inhibition.

  16. Review of the efficacy of rectal paraldehyde in the management of acute and prolonged tonic-clonic convulsions.

    PubMed

    Rowland, A G; Gill, A M; Stewart, A B; Appleton, R E; Al Kharusi, A; Cramp, C; Yeung, L-K

    2009-09-01

    The aim of this prospective audit was to assess the effectiveness and safety of rectal paraldehyde in the management of acute, including prolonged, tonic-clonic convulsions. There are very limited published data on its effectiveness and safety, and previous data have focused on its intramuscular route of administration. Four hospitals participated in the study. Information was collected on each dose of paraldehyde used for the treatment of a tonic-clonic convulsion over 1 year. Data were not included on patients treated with rectal paraldehyde for other seizure types or non-convulsive status epilepticus. Data analysis was undertaken regarding 53 episodes in 30 patients. Patient's ages ranged from 5 months to 16 years (mean 6.12 years, median 5.91 years). A pre-existing diagnosis of epilepsy was recorded in 35 episodes (66%). The mean dose of paraldehyde was 0.65 ml/kg (SD 0.22, 95% CI 0.59 to 0.71) and median dose 0.79 ml/kg. Rectal paraldehyde terminated the convulsion in 33 (62.3%) of the 53 episodes. In the 35 episodes where a pre-existing diagnosis of epilepsy was recorded, paraldehyde stopped the convulsion on 26 (74.3%) occasions. There was no difference in the dose of paraldehyde between the episodes where the convulsion was or was not terminated. There was no recorded respiratory depression in any episode. This study provides unique evidence that rectal paraldehyde is effective and safe in treating acute prolonged tonic-clonic convulsions. This would appear to confirm that paraldehyde should remain a treatment for the management of prolonged tonic-clonic convulsions, including convulsive status epilepticus.

  17. Phasic and Tonic Patterns of Locus Coeruleus Output Differentially Modulate Sensory Network Function in the Awake Rat

    PubMed Central

    Waterhouse, Barry D.

    2011-01-01

    Neurons of the nucleus locus coeruleus (LC) discharge with phasic bursts of activity superimposed on highly regular tonic discharge rates. Phasic bursts are elicited by bottom-up input mechanisms involving novel/salient sensory stimuli and top-down decision making processes; whereas tonic rates largely fluctuate according to arousal levels and behavioral states. Although it is generally believed that these two modes of activity differentially modulate information processing in LC targets, the unique role of phasic versus tonic LC output on signal processing in cells, circuits, and neural networks of waking animals is not well understood. In the current study, simultaneous recordings of individual neurons within ventral posterior medial thalamus and barrel field cortex of conscious rats provided evidence that each mode of LC output produces a unique modulatory impact on single neuron responsiveness to sensory-driven synaptic input and representations of sensory information across ensembles of simultaneously recorded cells. Each mode of LC activation specifically modulated the relationship between sensory-stimulus intensity and the subsequent responses of individual neurons and neural ensembles. Overall these results indicate that phasic versus tonic modes of LC discharge exert fundamentally different modulatory effects on target neuronal circuits within the rodent trigeminal somatosensory system. As such, each mode of LC output may differentially influence signal processing as a means of optimizing behaviorally relevant neural computations within this sensory network. Likely the ability of the LC system to differentially regulate neural responses and local circuit operations according to behavioral demands extends to other brain regions including those involved in higher cognitive functions. PMID:20980542

  18. No effects of ingesting or rinsing sucrose on depleted self-control performance.

    PubMed

    Boyle, N B; Lawton, C L; Allen, R; Croden, F; Smith, K; Dye, L

    2016-02-01

    Self-control tasks appear to deplete a limited resource resulting in reduced subsequent self-control performance; a state of ego depletion. Evidence of reduced peripheral glucose by exertion of self-control, and attenuation of ego depletion by carbohydrate metabolism underpins the proposition that this macronutrient provides the energetic source of self-control. However, the demonstration of positive, non-metabolic effects on ego depletion when merely sensing carbohydrates orally contradicts this hypothesis. Recent studies have also failed to support both metabolic and non-metabolic accounts. The effects of ingesting or rinsing a carbohydrate (sucrose) and an artificially sweetened (sucralose) solution on capillary blood and interstitial glucose, and depleted self-control performance were examined in older adults. Forty, healthy, adults (50-65years) ingested and rinsed sucrose and sucralose solutions in a 2 (method)×2 (source), fully counterbalanced, repeated measures, crossover design. Capillary blood and interstitial glucose responses were assayed. Depleted self-control performance (induced by the Bakan visual processing task) on an attention switch task was assessed under each study condition. Ego depletion had no consistent effects on peripheral glucose levels and no significant effects of ingesting or rinsing sucrose on self-control were observed. The act of rinsing the solutions, independent of energetic content, resulted in a small, non-significant enhancement of performance on the attention switch task relative to ingesting the same solutions (RT: p=.05; accuracy: p=.09). In conclusion, a metabolic account of self-control was not supported. Whilst a positive effect of rinsing on depleted self-control performance was demonstrated, this was independent of energetic content. Findings suggest glucose is an unlikely physiological analogue for self-control resources. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Determination of tonicity effects of ketoacids and lactate by use of two canine red blood cell assays.

    PubMed

    Reinhart, Jennifer M; Yancey, Misty R; Girard-Denton, Jennifer D; Schermerhorn, Thomas

    2015-01-01

    To determine the tonicity effects of β-hydroxybutyrate, acetoacetate, and lactate in canine RBCs. RBCs from approximately 40 dogs. 2 in vitro methods were used to conduct 4 experiments. The modified osmotic fragility assay was used to measure the ability of ketoacid salts added to serial sucrose dilutions to protect RBCs from osmotic hemolysis. In a second assay, a handheld cell counting device was used to measure changes in RBC diameter to assess the tonicity effect of solutions of ketoacid and lactate salts. For the modified osmotic fragility assay, all ketoacid salts had an osmoprotective effect, but the effect was determined to be completely attributable to the tonicity effect of added cations (sodium and lithium) and not the ketoacid moieties. However, both the sodium and lithium lactate salts provided osmoprotection attributable to both the cation and lactate anion. For the second assay, RBC diameter was significantly increased with the addition of urea (an ineffective osmole) but did not change with the addition of glucose (an effective osmole), which established the behaviors of ineffective and effective osmoles in this assay. The RBC diameter was significantly increased over that of control samples by the addition of sodium β-hydroxybutyrate, lithium acetoacetate, and lithium lactate but was decreased by the addition of sodium lactate. For both assays, β-hydroxybutyrate and acetoacetate acted as ineffective osmoles, whereas lactate acted as an effective osmole in 3 of 4 experiments.

  20. The effects of physical therapy on exaggerated muscle tonicity, balance and quality of life on hemiparetic patients due to stroke.

    PubMed

    Hoseinabadi, Mohammad Reza; Taheri, Hamid Reza; Keavanloo, Fahimeh; Seyedahmadi, Mohammad; Mohamadinia, Mehdi; Pejhan, Akbar

    2013-06-01

    To determine the effects of physical therapy on balance, exaggerated muscle tonicity and quality of life on patients with hemiparesis. This quasi-experimental study was conducted in 2011 among male hemiparetic patients secondary to stroke, at a physiotherapy centre in Neyshabur, Iran. Twenty-four patients were randomly assigned to two equal groups representing the cases and the controls.The cases were assigned to do the practical protocol for 4 weeks.To collect the data, Berg Balance Scaling, Modified Ashworth Scale, Barthel Activities of Daily Living Index and demographic questionnaires were used. Paired and un-paired t-tests were used to analyse data. All analyses were done on SPSS 16. The two groups were similar before intervention. Post-test analysis showed that the average balance and quality of life significantly improved (p<0.001) among the cases, and the quadriceps muscle tonicity decreased (p<0.001). Among the controls, there was no significant change between pre-test and post-test readings. Physical therapy can enhance balance and quality of life of hemiparetic patients and reduces their exaggerated muscle tonicity.

  1. Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.

    PubMed

    Egawa, Kiyoshi; Kitagawa, Kyoko; Inoue, Koichi; Takayama, Masakazu; Takayama, Chitoshi; Saitoh, Shinji; Kishino, Tatsuya; Kitagawa, Masatoshi; Fukuda, Atsuo

    2012-12-05

    Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of γ-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome.

  2. Adenosine A1 Receptor Suppresses Tonic GABAA Receptor Currents in Hippocampal Pyramidal Cells and in a Defined Subpopulation of Interneurons.

    PubMed

    Rombo, Diogo M; Dias, Raquel B; Duarte, Sofia T; Ribeiro, Joaquim A; Lamsa, Karri P; Sebastião, Ana M

    2016-03-01

    Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naïve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR δ-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.

  3. Comparative Efficacy of Silymarin and Choline Chloride (Liver Tonics) in Preventing the Effects of Aflatoxin B1 in Bovine Calves.

    PubMed

    Naseer, O; Khan, J A; Khan, M S; Omer, M O; Chishti, G A; Sohail, M L; Saleem, M U

    2016-09-01

    Aflatoxins are secondary metabolites produced by Aspergillus spp. which are injurious to animals and humans The aim of this study was to determine the effects of aflatoxin B1 (AFB1) on Average Daily Feed Intake (ADFI), Average Daily Weight Gain (ADWG), haematological and serum biochemical responses of Bovine Calves and to determine the comparative efficacy of two different liver tonics against AFB1. Twenty seven calves were selected from herd and divided into 3 groups. All calves were fed with 1.0 mg/kg AFB1 for a period of 10 days. After that they were fed with liver tonics: Silymarin fed at a rate of 600 mg/kg and Choline chloride 500 mg/kg for 7 days. The results indicate that the ADFI and ADWG of AFB1 treated calves decreased significantly. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN) and creatinine significantly increased due to AFB1. In haematology the total erythrocyte count (TEC), total leukocyte count (TLC), haemoglobin concentration (HGB), haematocrit levels (HCT), mean corpuscular haemoglobin (MCH), mean corpuscular volume (MCV) and mean corpuscular haemoglobin concentration (MCHC), lymphocyte %, neutrophil % and monocyte % significantly decreased in AFB1 treated calves after 10 days of feeding. Both liver tonics significantly (p<0.05) improved all the parameters, including ADFI, ADWG, hematologial and serum biochemical test. However, Silymarin comparatively more efficiently ameliorate the effects induced by AFB1 than choline chloride.

  4. Salvia miltiorrhiza Induces Tonic Contraction of the Lower Esophageal Sphincter in Rats via Activation of Extracellular Ca2+ Influx.

    PubMed

    Tsai, Ching-Chung; Chang, Li-Ching; Huang, Shih-Che; Tey, Shu-Leei; Hsu, Wen-Li; Su, Yu-Tsun; Liu, Ching-Wen; Tsai, Tong-Rong

    2015-08-11

    Up to 40% of patients with gastroesophageal reflux disease (GERD) suffer from proton pump inhibitor refractory GERD but clinically the medications to strengthen the lower esophageal sphincter (LES) to avoid irritating reflux are few in number. This study aimed to examine whether Salvia miltiorrhiza (SM) extracts induce tonic contraction of rat LES ex vivo and elucidate the underlying mechanisms. To investigate the mechanism underlying the SM extract-induced contractile effects, rats were pretreated with atropine (a muscarinic receptor antagonist), tetrodotoxin (a sodium channel blocker), nifedipine (a calcium channel blocker), and Ca(2+)-free Krebs-Henseleit solution with ethylene glycol tetraacetic acid (EGTA), followed by administration of cumulative dosages of SM extracts. SM extracts induced dose-related tonic contraction of the LES, which was unaffected by tetrodotoxin, atropine, or nifedipine. However, the SM extract-induced LES contraction was significantly inhibited by Ca(2+)-free Krebs-Henseleit solution with EGTA. Next, SM extracts significantly induce extracellular Ca(2+) entry into primary LES cells in addition to intracellular Ca(2+) release and in a dose-response manner. Confocal fluorescence microscopy showed that the SM extracts consistently induced significant extracellular Ca(2+) influx into primary LES cells in a time-dependent manner. In conclusion, SM extracts could induce tonic contraction of LES mainly through the extracellular Ca(2+) influx pathway.

  5. Orienting, emotion, and memory: phasic and tonic variation in heart rate predicts memory for emotional pictures in men.

    PubMed

    Abercrombie, Heather C; Chambers, Andrea S; Greischar, Lawrence; Monticelli, Roxanne M

    2008-11-01

    Arousal-related processes associated with heightened heart rate (HR) predict memory enhancement, especially for emotionally arousing stimuli. In addition, phasic HR deceleration reflects "orienting" and sensory receptivity during perception of stimuli. We hypothesized that both tonic elevations in HR as well as phasic HR deceleration during viewing of pictures would be associated with deeper encoding and better subsequent memory for stimuli. Emotional pictures are more memorable and cause greater HR deceleration than neutral pictures. Thus, we predicted that the relations between cardiac activity and memory enhancement would be most pronounced for emotionally-laden compared to neutral pictures. We measured HR in 53 males during viewing of unpleasant, neutral, and pleasant pictures, and tested memory for the pictures two days later. Phasic HR deceleration during viewing of individual pictures was greater for subsequently remembered than forgotten pictures across all three emotion categories. Elevated mean HR across the entire encoding epoch also predicted better memory performance, but only for emotionally arousing pictures. Elevated mean HR and phasic HR deceleration were associated, such that individuals with greater tonic HR also showed greater HR decelerations during picture viewing, but only for emotionally arousing pictures. Results suggest that tonic elevations in HR are associated both with greater orienting and heightened memory for emotionally arousing stimuli.

  6. Fixed eruption due to quinine in tonic water: a case report with high-performance liquid chromatography and ultraviolet A analyses.

    PubMed

    Ohira, Aoi; Yamaguchi, Sayaka; Miyagi, Takuya; Yamamoto, Yu-Ichi; Yamada, Satoshi; Shiohira, Hideo; Hagiwara, Keisuke; Uno, Tsukasa; Uezato, Hiroshi; Takahashi, Kenzo

    2013-08-01

    Fixed drug eruption is a common cutaneous adverse reaction in young patients with a characteristic clinical appearance. However, the diagnosis and identification of the substance may be difficult if food or food additives provoke the fixed eruption. A 26-year-old man had a history of two episodes of cutaneous erythema with residual pigmentation. Close examination of the history including his diet in addition to an oral challenge test and patch testing led to the diagnosis of fixed eruption secondary to quinine in tonic water. We examined for the presence of quinine in commercially available brands of tonic water using ultraviolet A and irradiation and high-performance liquid chromatography. Both Schweppes and CANADA DRY brands of tonic water emitted fluorescent light upon ultraviolet A irradiation, and contained quinine at concentrations of 67.9 and 61.3 mg/L, respectively. Quinine contained in some tonic waters may trigger fixed eruption.

  7. Amygdala central nucleus lesions attenuate acoustic startle stimulus-evoked heart rate changes in rats.

    PubMed

    Young, B J; Leaton, R N

    1996-04-01

    Amygdala central nucleus (CNA) lesions were used to test the hypothesis that stimulus-evoked heart rate changes can reflect the development of fear during acoustic startle testing. A 120-dB white noise startle stimulus produced freezing as well as phasic heart rate accelerations and decelerations, and an abrupt decrease in tonic heart rate, in sham-operated rats. These responses were all significantly reduced in CNA-lesioned rats. In contrast, an 87-dB stimulus elicited only significant phasic decelerations that were similarly attenuated by the CNA lesions. In a follow-up experiment, the CNA lesions also attenuated phasic cardiac decelerations evoked by a conditioned stimulus-like, 85-dB pure tone. The results support the contention (B. J. Young & R.N. Leaton, 1994) that heart rate changes can reflect fear conditioned during acoustic startle testing and, in addition, suggest that the amygdala mediates responses to nonsignal acoustic stimuli.

  8. Possible ozone depletions following nuclear explosions

    NASA Technical Reports Server (NTRS)

    Whitten, R. C.; Borucki, W. J.; Turco, R. P.

    1975-01-01

    The degree of depletion of the ozone layer ensuing after delivery of strategic nuclear warheads (5000 and 10,000 Mton) due to production of nitrogen oxides is theoretically assessed. Strong depletions are calculated for 16-km and 26-km altitudes, peaking 1-2 months after detonation and lasting for three years, while a significant depletion at 36 km would peak after one year. Assuming the explosions occur between 30 and 70 deg N, these effects should be much more pronounced in this region than over the Northern Hemisphere as a whole. It is concluded that Hampson's concern on this matter (1974) is well-founded.-

  9. Fully Depleted Charge-Coupled Devices

    SciTech Connect

    Holland, Stephen E.

    2006-05-15

    We have developed fully depleted, back-illuminated CCDs thatbuild upon earlier research and development efforts directed towardstechnology development of silicon-strip detectors used inhigh-energy-physics experiments. The CCDs are fabricated on the same typeof high-resistivity, float-zone-refined silicon that is used for stripdetectors. The use of high-resistivity substrates allows for thickdepletion regions, on the order of 200-300 um, with corresponding highdetection efficiency for near-infrared andsoft x-ray photons. We comparethe fully depleted CCD to thep-i-n diode upon which it is based, anddescribe the use of fully depleted CCDs in astronomical and x-ray imagingapplications.

  10. Possible ozone depletions following nuclear explosions

    NASA Technical Reports Server (NTRS)

    Whitten, R. C.; Borucki, W. J.; Turco, R. P.

    1975-01-01

    The degree of depletion of the ozone layer ensuing after delivery of strategic nuclear warheads (5000 and 10,000 Mton) due to production of nitrogen oxides is theoretically assessed. Strong depletions are calculated for 16-km and 26-km altitudes, peaking 1-2 months after detonation and lasting for three years, while a significant depletion at 36 km would peak after one year. Assuming the explosions occur between 30 and 70 deg N, these effects should be much more pronounced in this region than over the Northern Hemisphere as a whole. It is concluded that Hampson's concern on this matter (1974) is well-founded.-

  11. Thyrotropin-releasing hormone causes a tonic excitatory postsynaptic current and inhibits the phasic inspiratory inhibitory inputs in inspiratory-inhibited airway vagal preganglionic neurons.

    PubMed

    Hou, L; Zhou, X; Chen, Y; Qiu, D; Zhu, L; Wang, J

    2012-01-27

    The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA), which include the inspiratory-activated AVPNs (IA-AVPNs) and inspiratory-inhibited AVPNs (II-AVPNs), predominate in the control of the trachea and bronchia. The AVPNs receive particularly dense inputs from terminals containing thyrotropin-releasing hormone (TRH). TRH microinjection into the nucleus ambiguus (NA) caused constriction of the tracheal smooth muscles. However, it is unknown whether TRH affects all subtypes of the AVPNs in the eNA, and as a result affects the control of all types of target tissues in the airway (smooth muscles, submucosal glands, and blood vessels). It is also unknown how TRH affects the AVPNs at neuronal and synaptic levels. In this study, the AVPNs in the eNA were retrogradely labeled from the extrathoracic trachea, the II-AVPNs were identified in rhythmically firing brainstem slices, and the effects of TRH were examined using patch-clamp. TRH (100 nmol L(-1)) enhanced both the rhythm and the intensity of the hypoglossal bursts, and caused a tonic excitatory inward current in the II-AVPNs at a holding voltage of -80 mV. The frequency of the spontaneous excitatory postsynaptic currents (EPSCs) in the II-AVPNs, which showed no respiratory-related change in a respiratory cycle, was not significantly changed by TRH. At a holding voltage of -50 mV, the II-AVPNs showed both spontaneous and phasic inspiratory (outward) inhibitory postsynaptic currents (IPSCs). TRH had no effect on the spontaneous IPSCs but significantly attenuated the phasic inspiratory outward currents, in both the amplitude and area. After focal application of strychnine, an antagonist of glycine receptors, to the II-AVPNs, the spontaneous IPSCs were extremely scarce and the phasic inspiratory inhibitory currents were abolished; and further application of TRH had no effect on these currents. Under current clamp configuration, TRH caused a depolarization and increased the

  12. Differential effects of rapamycin treatment on tonic and phasic GABAergic inhibition in dentate granule cells after focal brain injury in mice.

    PubMed

    Butler, Corwin R; Boychuk, Jeffery A; Smith, Bret N

    2016-06-01

    The cascade of events leading to post-traumatic epilepsy (PTE) after traumatic brain injury (TBI) remains unclear. Altered inhibition in the hippocampal formation and dentate gyrus is a hallmark of several neurological disorders, including TBI and PTE. Inhibitory synaptic signaling in the hippocampus is predominately driven by γ-aminobutyric acid (GABA) neurotransmission, and is prominently mediated by postsynaptic type A GABA receptors (GABAAR's). Subsets of these receptors involved in tonic inhibition of neuronal membranes serve a fundamental role in maintenance of inhibitory state, and GABAAR-mediated tonic inhibition is altered functionally in animal models of both TBI and epilepsy. In this study, we assessed the effect of mTOR inhibition on hippocampal hilar inhibitory interneuron loss and synaptic and tonic GABAergic inhibition of dentate gyrus granule cells (DGCs) after controlled cortical impact (CCI) to determine if mTOR activation after TBI modulates GABAAR function. Hilar inhibitory interneuron density was significantly reduced 72h after CCI injury in the dorsal two-thirds of the hemisphere ipsilateral to injury compared with the contralateral hemisphere and sham controls. Rapamycin treatment did not alter this reduction in cell density. Synaptic and tonic current measurements made in DGCs at both 1-2 and 8-13weeks post-injury indicated reduced synaptic inhibition and THIP-induced tonic current density in DGCs ipsilateral to CCI injury at both time points post-injury, with no change in resting tonic GABAAR-mediated currents. Rapamycin treatment did not alter the reduced synaptic inhibition observed in ipsilateral DGCs 1-2weeks post-CCI injury, but further reduced synaptic inhibition of ipsilateral DGCs at 8-13weeks post-injury. The reduction in THIP-induced tonic current after injury, however, was prevented by rapamycin treatment at both time points. Rapamycin treatment thus differentially modifies CCI-induced changes in synaptic and tonic GABAAR

  13. Vortex attenuation flight experiments

    NASA Technical Reports Server (NTRS)

    Barber, M. R.; Hastings, E. C., Jr.; Champine, R. A.; Tymczyszyn, J. J.

    1977-01-01

    Flight tests evaluating the effects of altered span loading, turbulence ingestion, combinations of mass and turbulence ingestion, and combinations of altered span loading turbulance ingestion on trailed wake vortex attenuation were conducted. Span loadings were altered in flight by varying the deflections of the inboard and outboard flaps on a B-747 aircraft. Turbulence ingestion was achieved in flight by mounting splines on a C-54G aircraft. Mass and turbulence ingestion was achieved in flight by varying the thrust on the B-747 aircraft. Combinations of altered span loading and turbulence ingestion were achieved in flight by installing a spoiler on a CV-990 aircraft and by deflecting the existing spoilers on a B-747 aircraft. The characteristics of the attenuated and unattenuated vortexes were determined by probing them with smaller aircraft. Acceptable separation distances for encounters with the attenuated and unattenuated vortexes are presented.

  14. Radiofrequency attenuator and method

    DOEpatents

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    2009-11-10

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3 C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  15. Radiofrequency attenuator and method

    DOEpatents

    Warner, Benjamin P [Los Alamos, NM; McCleskey, T Mark [Los Alamos, NM; Burrell, Anthony K [Los Alamos, NM; Agrawal, Anoop [Tucson, AZ; Hall, Simon B [Palmerston North, NZ

    2009-01-20

    Radiofrequency attenuator and method. The attenuator includes a pair of transparent windows. A chamber between the windows is filled with molten salt. Preferred molten salts include quarternary ammonium cations and fluorine-containing anions such as tetrafluoroborate (BF.sub.4.sup.-), hexafluorophosphate (PF.sub.6.sup.-), hexafluoroarsenate (AsF.sub.6.sup.-), trifluoromethylsulfonate (CF.sub.3SO.sub.3.sup.-), bis(trifluoromethylsulfonyl)imide ((CF.sub.3SO.sub.2).sub.2N.sup.-), bis(perfluoroethylsulfonyl)imide ((CF.sub.3CF.sub.2SO.sub.2).sub.2N.sup.-) and tris(trifluoromethylsulfonyl)methide ((CF.sub.3SO.sub.2).sub.3C.sup.-). Radicals or radical cations may be added to or electrochemically generated in the molten salt to enhance the RF attenuation.

  16. In the rat, chronic intermittent ethanol exposure during adolescence alters the ethanol sensitivity of tonic inhibition in adulthood.

    PubMed

    Fleming, Rebekah L; Acheson, Shawn K; Moore, Scott D; Wilson, Wilkie A; Swartzwelder, H Scott

    2012-02-01

    Alcohol drinking by adolescents is a major public health concern. Adolescents tend to drink in a chronic, intermittent, that is, "binge," pattern, and such patterns of ethanol exposure are associated with increased risk of neurotoxicity and the development of alcohol use disorders (Crews et al., 2000; Hunt, 1993). Both adolescent humans and rats are more sensitive to acute ethanol-induced memory impairment than adults (Acheson et al., 1998; Markwiese et al., 1998). Furthermore, in rats, chronic intermittent ethanol (CIE) exposure during adolescence produces a long-lasting, perhaps permanent, maintenance of the adolescent high sensitivity to ethanol's amnestic effects (White et al., 2000a). We have previously shown that acute ethanol increases tonic inhibitory current mediated by extrasynaptic GABA(A) receptors more efficaciously in dentate granule cells (DGCs) from adolescent than adult rats (Fleming et al., 2007). In this study, we determined if CIE during adolescence produced long-lasting changes in this tonic current. Adolescent rats were subjected to a CIE exposure regimen and allowed to mature to full adulthood. Whole-cell voltage-clamp measurements of tonic inhibitory current and mean phasic current were made in vitro in hippocampal brain slices. CIE exposure during adolescence increased the ethanol sensitivity of tonic inhibitory current mediated by extrasynaptic GABA(A) receptors and decreased the ethanol sensitivity of phasic, synaptic GABA(A) receptor-mediated current in adult DGCs. CIE exposure during adolescence produces long-lasting changes in the function and ethanol sensitivity of extrasynaptic GABA(A) receptors in DGCs. These changes appear to "lock-in" and maintain the high adolescent sensitivity to ethanol in these cells. Furthermore, greater ethanol enhancement of tonic inhibition in the hippocampal formation after CIE is consistent with the greater sensitivity to ethanol-induced memory impairment after adolescent CIE. This finding represents the

  17. Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic-clonic seizure.

    PubMed

    Liu, Feng; Wang, Yifeng; Li, Meiling; Wang, Wenqin; Li, Rong; Zhang, Zhiqiang; Lu, Guangming; Chen, Huafu

    2017-02-01

    Idiopathic generalized epilepsy (IGE) has been linked with disrupted intra-network connectivity of multiple resting-state networks (RSNs); however, whether impairment is present in inter-network interactions between RSNs, remains largely unclear. Here, 50 patients with IGE characterized by generalized tonic-clonic seizures (GTCS) and 50 demographically matched healthy controls underwent resting-state fMRI scans. A dynamic method was implemented to investigate functional network connectivity (FNC) in patients with IGE-GTCS. Specifically, independent component analysis was first carried out to extract RSNs, and then sliding window correlation approach was employed to obtain dynamic FNC patterns. Finally, k-mean clustering was performed to characterize six discrete functional connectivity states, and state analysis was conducted to explore the potential alterations in FNC and other dynamic metrics. Our results revealed that state-specific FNC disruptions were observed in IGE-GTCS and the majority of aberrant functional connectivity manifested itself in default mode network. In addition, temporal metrics derived from state transition vectors were altered in patients including the total number of transitions across states and the mean dwell time, the fraction of time spent and the number of subjects in specific FNC state. Furthermore, the alterations were significantly correlated with disease duration and seizure frequency. It was also found that dynamic FNC could distinguish patients with IGE-GTCS from controls with an accuracy of 77.91% (P < 0.001). Taken together, this study not only provided novel insights into the pathophysiological mechanisms of IGE-GTCS but also suggested that the dynamic FNC analysis was a promising avenue to deepen our understanding of this disease. Hum Brain Mapp 38:957-973, 2017. © 2016 Wiley Periodicals, Inc.

  18. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial.

    PubMed

    French, Jacqueline A; Krauss, Gregory L; Wechsler, Robert T; Wang, Xue-Feng; DiVentura, Bree; Brandt, Christian; Trinka, Eugen; O'Brien, Terence J; Laurenza, Antonio; Patten, Anna; Bibbiani, Francesco

    2015-09-15

    To assess efficacy and safety of adjunctive perampanel in patients with drug-resistant, primary generalized tonic-clonic (PGTC) seizures in idiopathic generalized epilepsy (IGE). In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743; funded by Eisai Inc.), patients 12 years or older with PGTC seizures and IGE were randomized to placebo or perampanel during a 4-week titration period (perampanel up titrated from 2 to 8 mg/d, or highest tolerated dose) and 13-week maintenance period. The primary endpoint was percent change in PGTC seizure frequency per 28 days (titration plus maintenance vs baseline). The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving $50% reduction in PGTC seizure frequency; maintenance vs baseline). Treatment-emergent adverse events were monitored. Of 164 randomized patients, 162 comprised the full analysis set (placebo, 81; perampanel, 81). Compared with placebo, perampanel conferred a greater median percent change in PGTC seizure frequency per 28 days (238.4%vs 276.5%; p , 0.0001) and greater 50%PGTC seizure responder rate (39.5% vs 64.2%; p 5 0.0019). During maintenance, 12.3% of placebo treated patients and 30.9%of perampanel-treated patients achieved PGTC seizure freedom. For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%). Adjunctive perampanel was well tolerated and improved control of drug-resistant PGTC seizures in patients with IGE. This study provides Class I evidence that adjunctive perampanel reduces PGTC seizure frequency, compared with placebo, in patients with drug-resistant PGTC seizures in IGE.

  19. Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial.

    PubMed

    Shinnar, Shlomo; Cnaan, Avital; Hu, Fengming; Clark, Peggy; Dlugos, Dennis; Hirtz, Deborah G; Masur, David; Mizrahi, Eli M; Moshé, Solomon L; Glauser, Tracy A

    2015-09-29

    To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE). Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE. As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs (p=-0.0009), as was the duration of the shortest burst on the baseline EEG (p=0.037). Failure to respond to initial treatment (p<0.001) but not treatment assignment was associated with a higher rate of GTCs. Among patients initially assigned to ethosuximide, 94% (15/16) with GTCs experienced initial therapy failure (p<0.0001). A similar but more modest effect was noted in those initially treated with valproate (p=0.017) and not seen in those initially treated with lamotrigine. The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs. © 2015 American Academy of Neurology.

  20. GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum.

    PubMed

    Chiu, Chi-Sung; Brickley, Stephen; Jensen, Kimmo; Southwell, Amber; Mckinney, Sheri; Cull-Candy, Stuart; Mody, Istvan; Lester, Henry A

    2005-03-23

    GABA transporter subtype 1 (GAT1) knock-out (KO) mice display normal reproduction and life span but have reduced body weight (female, -10%; male, -20%) and higher body temperature fluctuations in the 0.2-1.5/h frequency range. Mouse GAT1 (mGAT1) KO mice exhibit motor disorders, including gait abnormality, constant 25-32 Hz tremor, which is aggravated by flunitrazepam, reduced rotarod performance, and reduced locomotor activity in the home cage. Open-field tests show delayed exploratory activity, reduced rearing, and reduced visits to the central area, with no change in the total distance traveled. The mGAT1 KO mice display no difference in acoustic startle response but exhibit a deficiency in prepulse inhibition. These open-field and prepulse inhibition results suggest that the mGAT1 KO mice display mild anxiety or nervousness. The compromised GABA uptake in mGAT1 KO mice results in an increased GABA(A) receptor-mediated tonic conductance in both cerebellar granule and Purkinje cells. The reduced rate of GABA clearance from the synaptic cleft is probably responsible for the slower decay of spontaneous IPSCs in cerebellar granule cells. There is little or no compensatory change in other proteins or structures related to GABA transmission in the mGAT1 KO mice, including GAT1-independent GABA uptake, number of GABAergic interneurons, and GABA(A)-, vesicular GABA transporter-, GAD65-, and GAT3-immunoreactive structures in cerebellum or hippocampus. Therefore, the excessive extracellular GABA present in mGAT1 KO mice results in behaviors that partially phenocopy the clinical side effects of tiagabine, suggesting that these side effects are inherent to a therapeutic strategy that targets the widely expressed GAT1 transporter system.

  1. Mechanosensitivity of mouse tracheal ciliary beat frequency: roles for Ca2+, purinergic signaling, tonicity, and viscosity.

    PubMed

    Winters, Scot L; Davis, C William; Boucher, Richard C

    2007-03-01

    Mechanosensitivity is hypothesized to participate in the regulation of ciliary beat frequency (CBF) in airway epithelia. To investigate this hypothesis, CBF in excised mouse trachea was monitored (microscopy image analysis) while varying mucosal shear (perfusate velocity and/or viscosity; planar flow). CBF increased within minutes of step increase to steady shear stress as small as 10(-3) Pa and decreased within minutes of shear reduction (tonicity, viscosity, and metabolism/exposure of ATP, and thus reflective of a complex interplay of physical and biochemical actions.

  2. How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

    PubMed Central

    Zhou, Xiaoming

    2016-01-01

    NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to, activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifically signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to

  3. How do kinases contribute to tonicity-dependent regulation of the transcription factor NFAT5?

    PubMed

    Zhou, Xiaoming

    2016-01-06

    NFAT5 plays a critical role in maintaining the renal functions. Its dis-regulation in the kidney leads to or is associated with certain renal diseases or disorders, most notably the urinary concentration defect. Hypertonicity, which the kidney medulla is normally exposed to, activates NFAT5 through phosphorylation of a signaling molecule or NFAT5 itself. Hypotonicity inhibits NFAT5 through a similar mechanism. More than a dozen of protein and lipid kinases have been identified to contribute to tonicity-dependent regulation of NFAT5. Hypertonicity activates NFAT5 by increasing its nuclear localization and transactivating activity in the early phase and protein abundance in the late phase. The known mechanism for inhibition of NFAT5 by hypotonicity is a decrease of nuclear NFAT5. The present article reviews the effect of each kinase on NFAT5 nuclear localization, transactivation and protein abundance, and the relationship among these kinases, if known. Cyclosporine A and tacrolimus suppress immune reactions by inhibiting the phosphatase calcineurin-dependent activation of NFAT1. It is hoped that this review would stimulate the interest to seek explanations from the NFAT5 regulatory pathways for certain clinical presentations and to explore novel therapeutic approaches based on the pathways. On the basic science front, this review raises two interesting questions. The first one is how these kinases can specifically signal to NFAT5 in the context of hypertonicity or hypotonicity, because they also regulate other cellular activities and even opposite activities in some cases. The second one is why these many kinases, some of which might have redundant functions, are needed to regulate NFAT5 activity. This review reiterates the concept of signaling through cooperation. Cells need these kinases working in a coordinated way to provide the signaling specificity that is lacking in the individual one. Redundancy in regulation of NFAT5 is a critical strategy for cells to

  4. Effect of neuromuscular electrical stimulation on motor cortex excitability upon release of tonic muscle contraction.

    PubMed

    Sugawara, Kenichi; Tanabe, Shigeo; Suzuki, Tomotaka; Higashi, Toshio

    The aim of the present study was to investigate the neurophysiological triggers underlying muscle relaxation from the contracted state, and to examine the mechanisms involved in this process and their subsequent modification by neuromuscular electrical stimulation (NMES). Single-pulse transcranial magnetic stimulation (TMS) was used to produce motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) in 23 healthy participants, wherein motor cortex excitability was examined at the onset of voluntary muscle relaxation following a period of voluntary tonic muscle contraction. In addition, the effects of afferent input on motor cortex excitability, as produced by NMES during muscle contraction, were examined. In particular, two NMES intensities were used for analysis: 1.2 times the sensory threshold and 1.2 times the motor threshold (MT). Participants were directed to execute constant wrist extensions and to release muscle contraction in response to an auditory "GO" signal. MEPs were recorded from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles, and TMS was applied at three different time intervals (30, 60, and 90 ms) after the "GO" signal. Motor cortex excitability was greater during voluntary ECR and FCR relaxation using high-intensity NMES, and relaxation time was decreased. Each parameter differed significantly between 30 and 60 ms. Moreover, in both muscles, SICI was larger in the presence than in the absence of NMES. Therefore, the present findings suggest that terminating a muscle contraction triggers transient neurophysiological mechanisms that facilitate the NMES-induced modulation of cortical motor excitability in the period prior to muscle relaxation. High-intensity NMES might facilitate motor cortical excitability as a function of increased inhibitory intracortical activity, and therefore serve as a transient trigger for the relaxation of prime mover muscles in a therapeutic context.

  5. Pulmonary edema following generalized tonic clonic seizures is directly associated with seizure duration

    PubMed Central

    Kennedy, Jeffrey D.; Hardin, Kimberly A.; Parikh, Palak; Li, Chin-Shang; Seyal, Masud

    2015-01-01

    Purpose Postictal pulmonary edema (PPE) is almost invariably present in human and animal cases of sudden unexpected death in epilepsy (SUDEP) coming to autopsy. PPE may be a contributing factor in SUDEP. The incidence of postictal PPE is unknown. We retrospectively investigated PPE following generalized tonic clonic seizures (GTCS) in the epilepsy monitoring unit. Methods Chest X-Rays (CXR) following each GTCS were obtained in 24 consecutive patients. Relationship of CXR abnormality to seizure duration, ictal/postictal oxygen desaturation (SpO2), apnea and presence of postictal generalized EEG suppression (PGES) was investigated using logistic regression. Results Eleven of 24 patients had CXR abnormalities following a GTCS. In these 11 patients, 22 CXR were obtained and abnormalities were present in 15 CXR. Abnormalities included PPE in 7 patients, of which 2 also had focal infiltrates. In 4 patients focal infiltrates were present without PPE. There was no significant difference in mean time to CXR (225 min) following GTCS in the abnormal CXR group versus the normal group of patients (196 min). Mean preceding seizure duration was longer (p=0.002) in GTCS with abnormal CXR (259.7 sec) versus GTCS with normal CXR (101.2 sec). Odds-ratio for CXR abnormality was 20.46 (p=0.006) with seizure duration greater than 100 sec versus less than 100 sec. On multivariable analysis, only the seizure duration was a significant predictor of CXR abnormality (p=0.015). Conclusions Radiographic abnormalities are not uncommon following GTCS. The presence of CXR abnormality is significantly associated with the duration of the preceding GTCS. Severe, untreated PPE may be relevant to the pathophysiology of SUDEP. PMID:25844030

  6. Tracking generalized tonic-clonic seizures with a wrist accelerometer linked to an online database.

    PubMed

    Velez, Mariel; Fisher, Robert S; Bartlett, Victoria; Le, Scheherazade

    2016-07-01

    Clinical management of epilepsy and current epilepsy therapy trials rely on paper or electronic diaries often with inaccurate self-reported seizure frequency as the primary outcome. This is the first study addressing the feasibility of detecting and recording generalized tonic-clonic seizures (GTCS) through a biosensor linked to an online seizure database. A prospective trial was conducted with video-EEG (vEEG) in an epilepsy monitoring unit. Patients wore a wristwatch accelerometer that detected shaking and transmitted events via Bluetooth® to a bedside electronic tablet and then via Wi-Fi to an online portal. The watch recorded the date, time, audio, duration, frequency and amplitude of events. Events logged by the watch and recorded in a bedside paper diary were measured against vEEG, the "gold standard." Thirty patients were enrolled and 62 seizures were recorded on vEEG: 31 convulsive and 31 non-convulsive. Twelve patients had a total of 31 convulsive seizures, and of those, 10 patients had 13 GTCS. The watch captured 12/13 (92.3%) GTCS. Watch audio recordings were consistent with seizures in 11/12 (91.6%). Data were successfully transferred to the bedside tablet in 11/12 (91.6%), and to the online database in 10/12 (83.3%) GTCS. The watch recorded 81 false positives, of which 42/81 (51%) were cancelled by the patients. Patients and caregivers verbally reported 15/62 seizures (24.2% sensitivity) but no seizures were recorded on paper logs. Automatic detection and recording of GTCS to an online database is feasible and may be more informative than seizure logging in a paper diary. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  7. Tonic tensor tympani syndrome in tinnitus and hyperacusis patients: a multi-clinic prevalence study.

    PubMed

    Westcott, Myriam; Sanchez, Tanit Ganz; Diges, Isabel; Saba, Clarice; Dineen, Ross; McNeill, Celene; Chiam, Alison; O'Keefe, Mary; Sharples, Tricia

    2013-01-01

    Tonic tensor tympani syndrome (TTTS) is an involuntary, anxiety-based condition where the reflex threshold for tensor tympani muscle activity is reduced, causing a frequent spasm. This can trigger aural symptoms from tympanic membrane tension, middle ear ventilation alterations and trigeminal nerve irritability. TTTS is considered to cause the distinctive symptoms of acoustic shock (AS), which can develop after exposure to an unexpected loud sound perceived as highly threatening. Hyperacusis is a dominant AS symptom. Aural pain/blockage without underlying pathology has been noted in tinnitus and hyperacusis patients, without wide acknowledgment. This multiclinic study investigated the prevalence of TTTS symptoms and AS in tinnitus and hyperacusis patients. This study included consecutive patients with tinnitus and/or hyperacusis seen in multiple clinics. Symptoms consistent with TTTS (pain/numbness/burning in and around the ear; aural "blockage"; mild vertigo/nausea; "muffled" hearing; tympanic flutter; headache); onset or exacerbation from exposure to loud/intolerable sounds; tinnitus/hyperacusis severity. All patients were medically cleared of underlying pathology, which could cause these symptoms. 60.0% of the total sample (345 patients), 40.6% of tinnitus only patients, 81.1% of hyperacusis patients had ≥ 1 symptoms (P < 0.001). 68% of severe tinnitus patients, 91.3% of severe hyperacusis patients had ≥ 1 symptoms (P < 0.001). 19.7% (68/345) of patients in the total sample had AS. 83.8% of AS patients had hyperacusis, 41.2% of non-AS patients had hyperacusis (P < 0.001). The high prevalence of TTTS symptoms suggests they readily develop in tinnitus patients, more particularly with hyperacusis. Along with AS, they should be routinely investigated in history-taking.

  8. Interictal electrocardiographic and echocardiographic changes in patients with generalized tonic-clonic seizures.

    PubMed

    M Ramadan, Mahmoud; El-Shahat, Nader; A Omar, Ashraf; Gomaa, Mohamed; Belal, Tamer; A Sakr, Sherif; Abu-Hegazy, Mohammad; Hakim, Hazem; A Selim, Heba; Omar, Sabry; A Omar, Sabry

    2013-01-01

    Partial and generalized seizures often affect autonomic functions during seizures, and interictal and postictal periods. We investigated possible interictal electrocardiographic abnormalities in patients with generalized tonic-clonic seizures (GTCS), together with evaluating any structural heart changes by echocardiography in these patients in comparison with healthy controls. We studied 120 definite GTCS patients (76 males and 44 females) who are neither diabetic nor under any medical treatment, and 60 healthy controls with a mean age of 25.2 ± 9.3 and 27.3 ± 7.5 years; respectively. Resting systolic and diastolic arterial blood pressures were measured, and standard 12-lead electrocardiograms and a 2-dimensional echocardiographic examination were performed. In univariate analysis, GTCS patients (compared to controls) had significantly lower means of PR interval (147.2 ± 18.6 versus 153.8 ± 22.6 msec; P = 0.037), QT interval (362.8 ± 22.9 versus 379.9 ± 29.3 msec; P < 0.001), and QTc interval (425.5 ± 20.7 versus 441.6 ± 19.9 msec; P < 0.001) but significantly higher mean left atrial diameter (3.49 ± 0.64 versus 3.09 ± 0.45 cm; P < 0.001). After adjusting for age, gender, and body mass index in a multivariate adjusted logistic regression model, left atrial diameter (OR = 3.941 [1.739 - 8.932]) and QTc (OR = 0.924 [0.895 - 0.954]) were significantly and independently associated with GTCS. In conclusion, patients with epilepsy may be predisposed to disturbances of autonomic functions with subsequent cardiac arrhythmias due to the effects of recurrent seizures on cardiac microstructure. Further work is needed to stratify the risk of sudden unexplained cardiac death (SUDEP) on the basis of interictal autonomic parameters to improve prognosis.

  9. Oral toxicity studies of a Nigerian polyherbal health tonic tea extract in rats.

    PubMed

    Adeneye, A A; Agbaje, E O; Elias, S O; Amole, O O

    2008-03-01

    In the present study, acute and subchronic oral toxicity studies of an aqueous extract of a Nigerian Polyherbal Health Tonic (PHT) were investigated in adult Wistar rats of both sexes and weighing between 110-200 g. Acute toxicity study was conducted using limit dose test of Up and Down Procedure under computer guided statistical software program (AOT 425 StatPgm). The subchronic toxicity was evaluated in 4 groups of rats made up of six rats/group, administered single, daily oral doses of 10 ml/kg distilled water (DW), 125, 500 and 1500 mg/kg of PHT, respectively, for 90 days. On the 91st day, blood samples for haematological and biochemical assays were collected through cardiac puncture and selected vital organs harvested en bloc for histopathological examination under inhaled anaesthesia. Results showed PHT to be relatively safe on acute toxicity with an estimated LD50 value greater than 5000 mg/kg/oral route. On prolonged exposure, PHT induced initial weight gain in the 1st 6 weeks followed by significant (P < 0.05) dose related weight loss in the latter 6 weeks. The extract also caused significant (P < 0.05) dose related elevation of the full blood count parameters, dose unrelated elevation of serum urea, liver enzymes, serum proteins, albumin, total and conjugated bilirubin. On histology, PHT induced dose dependent gastric mucosal denudation, bile ductal lining distortion, diffuse pulmonary interstitial fibrous proliferation and diffuse splenic lymphocytic proliferation. Thus, our results showed that PHT use may be relatively safe on acute exposure but toxic on chronic exposure to high doses, although reversibility of these toxic effects was not studied in the present study.

  10. Detection of generalized tonic-clonic seizures using surface electromyographic monitoring.

    PubMed

    Halford, Jonathan J; Sperling, Michael R; Nair, Dileep R; Dlugos, Dennis J; Tatum, William O; Harvey, Jay; French, Jacqueline A; Pollard, John R; Faught, Edward; Noe, Katherine H; Henry, Thomas R; Jetter, Gina M; Lie, Octavian V; Morgan, Lola C; Girouard, Michael R; Cardenas, Damon P; Whitmire, Luke E; Cavazos, Jose E

    2017-10-05

    A prospective multicenter phase III trial was undertaken to evaluate the performance and tolerability in the epilepsy monitoring unit (EMU) of an investigational wearable surface electromyographic (sEMG) monitoring system for the detection of generalized tonic-clonic seizures (GTCSs). One hundred ninety-nine patients with a history of GTCSs who were admitted to the EMU in 11 level IV epilepsy centers for clinically indicated video-electroencephalographic monitoring also received sEMG monitoring with a wearable device that was worn on the arm over the biceps muscle. All recorded sEMG data were processed at a central site using a previously developed detection algorithm. Detected GTCSs were compared to events verified by a majority of three expert reviewers. For all subjects, the detection algorithm detected 35 of 46 (76%, 95% confidence interval [CI] = 0.61-0.87) of the GTCSs, with a positive predictive value (PPV) of 0.03 and a mean false alarm rate (FAR) of 2.52 per 24 h. For data recorded while the device was placed over the midline of the biceps muscle, the system detected 29 of 29 GTCSs (100%, 95% CI = 0.88-1.00), with a detection delay averaging 7.70 s, a PPV of 6.2%, and a mean FAR of 1.44 per 24 h. Mild to moderate adverse events were reported in 28% (55 of 199) of subjects and led to study withdrawal in 9% (17 of 199). These adverse events consisted mostly of skin irritation caused by the electrode patch that resolved without treatment. No serious adverse events were reported. Detection of GTCSs using an sEMG monitoring device on the biceps is feasible. Proper positioning of this device is important for accuracy, and for some patients, minimizing the number of false positives may be challenging. © 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

  11. Feeling psychologically restrained: the effect of social exclusion on tonic immobility

    PubMed Central

    Mooren, Nora; van Minnen, Agnes

    2014-01-01

    Background A variety of studies have demonstrated posttraumatic stress disorder (PTSD) symptoms in victims of bullying. Because bullying with only relational aggression, such as social exclusion, does not involve physical aggression that could explain PTSD symptoms, it remains unclear why these relational aggression situations are also linked to PTSD symptoms. Objective The aim of the present study was to investigate whether the fear-response tonic immobility (Ti) can occur during social exclusion. Since Ti, as an indicator of peritraumatic dissociation, is an important predictor of PTSD symptoms, we expected that the presence of Ti during social exclusion might contribute to possible explanations of PTSD symptoms in victims of relational aggression. Method Social exclusion was manipulated by a virtual Cyberball game in which participants were excluded and included by virtual confederates. During the game, Ti was measured, both physiologically (heart rate) and psychologically (subjective symptoms). Also, the underlying concepts of Ti, high levels of fear and psychological restraint (threatened sense of control), were measured. Results Excluded participants experienced higher levels of subjective and physiological Ti symptoms (lower heart rates) in comparison to social inclusion. Also, as expected, social exclusion resulted in higher levels of fear and psychological restraint in comparison to social inclusion. Conclusion Social exclusion can evoke symptoms of Ti, fear, and psychological restraint, which might be important mechanisms to consider in explaining PTSD symptoms after relational forms of bullying in the absence of physical aggression. Limitations The sample only contains healthy, female participants. Whether our results translate to bullying victims of relational aggression is therefore not known. Also, the physiological measurement of Ti (average heart rate) was rather limited and could be expanded in future studies. PMID:24765247

  12. Experimental tonic hand pain modulates the corticospinal plasticity induced by a subsequent hand deafferentation.

    PubMed

    Mavromatis, N; Gagné, M; Voisin, J I A V; Reilly, K T; Mercier, C

    2016-08-25

    Sensorimotor reorganization is believed to play an important role in the development and maintenance of phantom limb pain, but pain itself might modulate sensorimotor plasticity induced by deafferentation. Clinical and basic research support this idea, as pain prior to amputation increases the risk of developing post-amputation pain. The aim of this study was to examine the influence of experimental tonic cutaneous hand pain on the plasticity induced by temporary ischemic hand deafferentation. Sixteen healthy subjects participated in two experimental sessions (Pain, No Pain) in which transcranial magnetic stimulation was used to assess corticospinal excitability in two forearm muscles (flexor carpi radialis and flexor digitorum superficialis) before (T0, T10, T20, and T40) and after (T60 and T75) inflation of a cuff around the wrist. The cuff was inflated at T45 in both sessions and in the Pain session capsaicin cream was applied on the dorsum of the hand at T5. Corticospinal excitability was significantly greater during the Post-inflation phase (p=0.002) and increased similarly in both muscles (p=0.861). Importantly, the excitability increase in the Post-inflation phase was greater for the Pain than the No-Pain condition (p=0.006). Post-hoc analyses revealed a significant difference between the two conditions during the Post-inflation phase (p=0.030) but no difference during the Pre-inflation phase (p=0.601). In other words, the corticospinal facilitation was greater when pain was present prior to cuff inflation. These results indicate that pain can modulate the plasticity induced by another event, and could partially explain the sensorimotor reorganization often reported in chronic pain populations. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Effects of external calcium on potassium contractures in tonic muscle fibers of the frog (Rana pipiens).

    PubMed Central

    Huerta, M; Muñiz, J; Stefani, E

    1986-01-01

    K+ contractures of tonic bundles from cruralis muscle of the frog were studied with different K+ concentrations (10-120 mM). K+ contractures had an initial transient phase followed by a sustained tension. The amplitude of the sustained tension diminished with high K+ concentration (80-120 mM). However, in all cases, tension was maintained for several minutes. External Ca2+ reduction practically abolished the sustained phase of the K+ contractures. The initial phase was also reduced and tension spontaneously relaxed. The curve relating the peak tension with log [K+]o, showed that the threshold was not affected but the peak tension was reduced to about 70% in low-Ca2+ saline (0 Ca2+ + 3 mM-Mg2+) and 50% in Ca2+-free saline (1 mM-EGTA + 3 mM-Mg2+). The dependence of the sustained tension on external Ca2+ was further confirmed by Ca2+ withdrawal and re-establishment and/or by Ni2+ substitution for Ca2+ before or during K+ contractures. These results indicate that external Ca2+ had to be continuously present to maintain the tension during K+ contractures and that Ni2+ was not able to restore the normal temporal course of K+ contracture. The sustained phase was diminished by blocking agents of Ca2+ channels, such as nifedipine (1 microM) and diltiazem (1-10 microM). The present results can be explained by a direct control of the Ca2+ currents on K+ contracture or by specific interactions between external Ca2+ and Ca2+-binding sites in the membrane. PMID:3491902

  14. Long-term outcomes of generalized tonic-clonic seizures in a childhood absence epilepsy trial

    PubMed Central

    Cnaan, Avital; Hu, Fengming; Clark, Peggy; Dlugos, Dennis; Hirtz, Deborah G.; Masur, David; Mizrahi, Eli M.; Moshé, Solomon L.; Glauser, Tracy A.

    2015-01-01

    Objective: To determine incidence and early predictors of generalized tonic-clonic seizures (GTCs) in children with childhood absence epilepsy (CAE). Methods: Occurrence of GTCs was determined in 446 children with CAE who participated in a randomized clinical trial comparing ethosuximide, lamotrigine, and valproate as initial therapy for CAE. Results: As of June 2014, the cohort had been followed for a median of 7.0 years since enrollment and 12% (53) have experienced at least one GTC. The median time to develop GTCs from initial therapy was 4.7 years. The median age at first GTC was 13.1 years. Fifteen (28%) were not on medications at the time of their first GTC. On univariate analysis, older age at enrollment was associated with a higher risk of GTCs (p = −0.0009), as was the duration of the shortest burst on the baseline EEG (p = 0.037). Failure to respond to initial treatment (p < 0.001) but not treatment assignment was associated with a higher rate of GTCs. Among patients initially assigned to ethosuximide, 94% (15/16) with GTCs experienced initial therapy failure (p < 0.0001). A similar but more modest effect was noted in those initially treated with valproate (p = 0.017) and not seen in those initially treated with lamotrigine. Conclusions: The occurrence of GTCs in a well-characterized cohort of children with CAE appears lower than previously reported. GTCs tend to occur late in the course of the disorder. Children initially treated with ethosuximide who are responders have a particularly low risk of developing subsequent GTCs. PMID:26311751

  15. Impairment of the proximal to distal tonic gradient in the human diabetic stomach.

    PubMed

    Min, Y W; Hong, Y S; Ko, E-J; Lee, J Y; Min, B-H; Sohn, T S; Kim, J J; Rhee, P-L

    2014-02-01

    Little has been known about the contractile characteristics of diabetic stomach. We investigated spontaneous contractions and responses to acetylcholine in the gastric muscle in diabetic patients and non-diabetic control subjects according to the region of stomach. Gastric specimens were obtained from 26 diabetics and 55 controls who underwent gastrectomy at Samsung Medical Center between February 2008 and November 2011. Isometric force measurements were performed using circular muscle strips from the different regions of stomach under basal condition and in response to acetylcholine. Basal tone of control was higher in the proximal stomach than in the distal (0.63 g vs 0.46 g, p = 0.027). However, in diabetics, basal tone was not significantly different between the proximal and distal stomach (0.75 g vs 0.62 g, p = 0.32). The distal stomach of diabetics had higher basal tone and lower frequency than that of control (0.62 g vs 0.46 g, p = 0.049 and 4.0/min vs 4.9/min, p = 0.049, respectively). After exposure to acetylcholine, dose-dependent increases of basal tone, peak, and area under the curve (AUC) were noticed in both proximal and distal stomach of the two groups. In the proximal stomach, however, the dose-dependent increase of basal tone and AUC was less prominent in diabetics than in control. On the contrary to control, the proximal to distal tonic gradient was not observed in diabetic stomach. Diabetic stomach also had lower frequency of spontaneous contraction in the distal stomach and less acetylcholine-induced positive inotropic effect in the proximal stomach than control. © 2013 John Wiley & Sons Ltd.

  16. Resting blood pressure differentially predicts time course in a tonic pain experiment.

    PubMed

    Horing, Bjoern; McCubbin, James A; Moore, Dewayne; Muth, Eric R

    2016-10-01

    Resting blood pressure (BP) shows a negative relationship with pain sensitivity (BP-related hypoalgesia). In chronic pain conditions, this relationship is inverted. The precise mechanisms responsible for the inversion are unknown. Using a tonic pain protocol, we report findings closely resembling this inversion in healthy participants. Resting BP and state measures of anxiety and mood were assessed from 33 participants (21 female). Participants then immersed their dominant hand in painfully hot water (47 °C) for five trials of 1-min duration, with 30-s intertrial intervals. Throughout the trials, participants continually registered their pain. After a 35-min intermission, the trial sequence was repeated. A disassociation of the negative relationship of resting systolic BP (as per Trial 1) was found using hierarchical linear modeling (p < .001, R(2)  = .07). The disassociation unfolds over each consecutive trial, with an increasingly positive relationship. In Sequence 2, the initially negative relationship is almost completely absent. Furthermore, the association of BP and pain was found to be moderated by anxiety, such that only persons with low anxiety exhibited BP hypoalgesia. Our findings expand the existing literature by incorporating anxiety as a moderator of BP hypoalgesia. Furthermore, the protocol emulates the changing relationship between BP and pain observed in chronic pain patients. The protocol has potential as a model for chronic pain; however, future research should determine if similar physiological systems are involved. The finding holds potential diagnostic or prognostic relevance for certain clinical pain conditions, especially those involving dysfunction of the descending modulation of pain. © 2016 Society for Psychophysiological Research.

  17. THE TONICITY-VOLUME RELATIONS