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Sample records for a-receptor blockade attenuates

  1. Selective endothelin-A receptor blockade attenuates endotoxin-induced pulmonary hypertension and pulmonary vascular dysfunction

    PubMed Central

    2014-01-01

    Abstract Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ETAR) during endotoxemia remain unknown. We hypothesized that selective ETAR antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250–450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ETAR antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1β, IL-6, TNF-α, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dose-dependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ETAR blockade. We conclude that ETAR blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar

  2. Blockade of GABA(A) receptors within the extended amygdala attenuates D(2) regulation of alcohol-motivated behaviors in the ventral tegmental area of alcohol-preferring (P) rats.

    PubMed

    Eiler, William J A; June, Harry L

    2007-06-01

    The dopamine (DA) mesolimbic pathway, which originates from DA cell bodies within the ventral tegmental area (VTA), has been shown by various studies to play a role in the mediation of various drugs of abuse including alcohol (EtOH). It has been suggested that the VTA's control of EtOH reward is mediated in part by the D2 receptors within the VTA. These receptors may be under the regulation of reciprocal GABAergic inputs from forebrain components of the mesolimbic path such as the nucleus accumbens (NAcc), a classic EtOH reward substrate, and the bed nucleus of the stria terminalis, a substrate recently implicated in EtOH reinforcement, forming a self-regulating feedback loop. To test this hypothesis, D2 regulation of EtOH self-administration (SA) was evaluated by the microinfusion of the D2 antagonist eticlopride into the VTA of P rats, which produced profound reductions in EtOH SA in the highest (20.0 and 40.0microg) doses tested in both BST/VTA and NAcc/VTA implanted P rats. To determine the role of GABA in the mediation of EtOH SA, a 32.0ng dose the non-selective GABA antagonist SR 95531 was microinfused into the BST producing no effect on responding for EtOH and into the NAcc which lead to a reduction in EtOH responding. Finally, the hypothesis that GABA innervation of the VTA from the mesolimbic forebrain may influence EtOH SA was examined by the simultaneous infusion of eticlopride (40.0microg) into the VTA and SR 95531 (32.0ng) into either the BST or NAcc. This combination infusion completely attenuated the reduction in EtOH SA observed with the 40.0microg dose of eticlopride alone in both groups of animals. These results suggest that while the D2 receptors within the VTA regulate EtOH-motivated behaviors, this is modulated by GABAergic input from the mesolimbic forebrain, specifically from the BST and NAcc. PMID:17451754

  3. NEUROTROPHIN RECEPTOR BLOCKADE ATTENUATES DIESEL EXHAUST PARTICULATE MATTER (DEP) ENHANCEMENT OF ALLERGIC RESPONSES

    EPA Science Inventory

    ABSTRACT BODY:
    Recent investigations have linked neurotrophins including NGF, NT-3, and BDNF to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance associated with allergic airway responses in mice. Mice administered an antibody against the low aff...

  4. Attenuation of drinking sweetened water following calcium channel blockade.

    PubMed

    Calcagnetti, D J; Schechter, M D

    1992-06-01

    Recent reports cite results that both cocaine-induced conditioned place preference and activity stimulation are attenuated by pretreatment with the calcium channel blocker isradipine (ISR) in rats. By blocking voltage-dependent L-type calcium channels, ISR may regulate neural dopamine release that, in turn, decreases the putative rewarding effects mediated by dopaminergic mechanisms. It is known that nonfluid deprived rats avidly consume sweetened fluids; this suggests that the sweet taste is rewarding. Three experiments were conducted to determine the effects of ISR on drinking sweetened and nonflavored water. Experiment 1 was designed to test whether ISR would attenuate the intake of a palatable solution in a dose-dependent manner. To this end, ISR was administered both peripherally (3.0-30 mg/kg) and centrally (0.3-30 micrograms/rat) prior to a solution of saccharin and d-glucose (S + G) being made available to rats (15 min/day) and intake was recorded. ISR produced dose-dependent decreases (38%-81%) in S + G intake dependent on the route of administration. In Experiment 2, water intake was measured in 18 h water-deprived rats following ISR (10 mg/kg) administration as well as comparing S + G drinking. The effect of two ISR vehicles, dimethyl sulfoxide and Tween 80, upon fluid intake was also determined. ISR injection did not attenuate water intake in 18 h water-deprived rats and the choice of vehicle did not affect the ISR-induced attenuation of S + G drinking. In Experiment 3, a single dose (30 micrograms) of ICV administered ISR, that attenuated S + G intake by approximately 44%, did not attenuate water intake in 18 h water-deprived rats.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use

    PubMed Central

    McCaffrey, Gwen; Thompson, Michelle L.; Majuta, Lisa; Fealk, Michelle N.; Chartier, Stephane; Longo, Geraldine; Mantyh, Patrick W.

    2014-01-01

    Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and non-malignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in bone cancer patients. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40-70% depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight. PMID:25287160

  6. Blockade of adenosine A2A receptors prevents protein phosphorylation in the striatum induced by cortical stimulation.

    PubMed

    Quiroz, César; Gomes, Catarina; Pak, Arlene C; Ribeiro, Joaquim A; Goldberg, Steven R; Hope, Bruce T; Ferré, Sergi

    2006-10-18

    Previous studies have shown that cortical stimulation selectively activates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and immediate early gene expression in striatal GABAergic enkephalinergic neurons. In the present study, we demonstrate that blockade of adenosine A2A receptors with caffeine or a selective A2A receptor antagonist counteracts the striatal activation of cAMP-protein kinase A cascade (phosphorylation of the Ser845 residue of the glutamate receptor 1 subunit of the AMPA receptor) and mitogen-activated protein kinase (ERK1/2 phosphorylation) induced by the in vivo stimulation of corticostriatal afferents. The results indicate that A2A receptors strongly modulate the efficacy of glutamatergic synapses on striatal enkephalinergic neurons.

  7. Blockade of 5-HT2A receptors suppresses hyperthermic but not cardiovascular responses to psychosocial stress in rats.

    PubMed

    Beig, M I; Baumert, M; Walker, F R; Day, T A; Nalivaiko, E

    2009-03-31

    The aim of this study was to determine whether 5-HT2A receptors mediate cardiovascular and thermogenic responses to acute psychological stresses. For this purpose, adult male Wistar hooded rats instrumented for telemetric recordings of either electrocardiogram (ECG) (n=12) or arterial pressure (n=12) were subjected, on different days, to four 15-min episodes of social defeat. Prior to stress, animals received s.c. injection of the selective 5-HT2A receptor antagonist SR-46349B (trans-4-((3Z)3-[(2-dimethylaminoethyl)oxyimino]-3-(2-fluorophenyl)propen-1-yl)-phenol, hemifumarate) (at doses of 0.3, 1.0 and 3.0 mg/kg) or vehicle. The drug had no effect on basal heart rate or heart rate variability indexes, arterial pressure, and core body temperature. Social defeat elicited significant and substantial tachycardic (347+/-7 to 500+/-7 bpm), pressor (77+/-4 to 97+/-4 mm Hg) and hyperthermic (37.0+/-0.3 to 38.5+/-0.1 degrees C) responses. Blockade of 5-HT2A receptors, at all doses of the antagonist, completely prevented stress-induced hyperthermia. In contrast, stress-induced cardiovascular responses were not affected by the blockade (except small reduction of tachycardia by the highest dose of the drug). We conclude that in rats, 5-HT2A receptors mediate stress-induced hyperthermic responses, but are not involved in the genesis of stress-induced rises in heart rate or arterial pressure, and do not participate in cardiovascular control at rest. PMID:19356699

  8. Adenosine A(2A) receptor antagonists are broad facilitators of antinicotinic neuromuscular blockade monitored either with 2 Hz train-of-four or 50 Hz tetanic stimuli.

    PubMed

    Pereira, Monalisa W; Correia-de-Sá, Paulo; Alves-Do-Prado, Wilson

    2012-10-01

    1. The 2 Hz train-of-four ratio (TOF(ratio)) is used to monitor the degree of patient curarization. Using a rat phrenic nerve-hemidiaphragm preparation, we showed that antinicotinic agents, such as hexamethonium, d-tubocurarine and pancuronium, but not cisatracurium, decreased contractions produced by physiological nerve activity patterns (50 Hz) more efficiently than those caused by 2 Hz trains. Uncertainty about the usefulness of the TOF(ratio) to control safe recovery from curarization prompted us to investigate the muscarinic and adenosine neuromodulation of tetanic (50 Hz) fade induced by antinicotinic agents at concentrations that cause a 25% reduction in the TOF(ratio) (TOF(fade)). 2. Tetanic fade caused by d-tubocurarine (1.1 μmol/L), pancuronium (3 μmol/L) and hexamethonium (5.47 mmol/L) was attenuated by blocking presynaptic inhibitory muscarinic M(2) and adenosine A(1) receptors with methoctramine (1 μmol/L) and 1,3-dipropyl-8-cyclopentylxanthine (2.5 nmol/L), respectively. These compounds enhanced rather than decreased tetanic fade induced by cisatracurium (2.2 μmol/L), but they consistently attenuated cisatracurium-induced TOF(fade). The effect of the M(1) receptor antagonist pirenzepine (10 nmol/L) on fade produced by antinicotinic agents at 50 Hz was opposite to that observed with TOF stimulation. Blockade of adenosine A(2A) receptors with ZM 241385 (10 nmol/L) attenuated TOF(fade) caused by all antinicotinic drugs tested, with the exception of the 'pure' presynaptic nicotinic antagonist hexamethonium. ZM 241385 was the only compound tested in this series that facilitated recovery from tetanic fade produced by cisatracurium. 3. The data suggest that distinct antinicotinic relaxants interfere with fine-tuning neuromuscular adaptations to motor nerve stimulation patterns via activation of presynaptic muscarinic and adenosine receptors. These results support the use of A(2A) receptor antagonists together with atropine to facilitate recovery from

  9. Adenosine A2A Receptor Blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism

    PubMed Central

    Fathalla, Ahmed M.; Soliman, Amira M.; Ali, Mohamed H.; Moustafa, Ahmed A.

    2016-01-01

    Pharmacological studies implicate the blockade of adenosine receptorsas an effective strategy for reducing Parkinson’s disease (PD) symptoms. The objective of this study is to elucidate the possible protective effects of ZM241385 and 8-cyclopentyl-1, 3-dipropylxanthine, two selective A2A and A1 receptor antagonists, on a rotenone rat model of PD. Rats were split into four groups: vehicle control (1 ml/kg/48 h), rotenone (1.5 mg/kg/48 h, s.c.), ZM241385 (3.3 mg/kg/day, i.p) and 8-cyclopentyl-1, 3-dipropylxanthine (5 mg/kg/day, i.p). After that, animals were subjected to behavioral (stride length and grid walking) and biochemical (measuring concentration of dopamine levels using high performance liquid chromatography, HPLC). In the rotenone group, rats displayed a reduced motor activity and disturbed movement coordination in the behavioral tests and a decreased dopamine concentration as foundby HPLC. The effect of rotenone was partially prevented in the ZM241385 group, but not with 8-cyclopentyl-1,3-dipropylxanthine administration. The administration of ZM241385 improved motor function and movement coordination (partial increase of stride length and partial decrease in the number of foot slips) and an increase in dopamine concentration in the rotenone-injected rats. However, the 8-cyclopentyl-1,3-dipropylxanthine and rotenone groups were not significantly different. These results indicate that selective A2A receptor blockade by ZM241385, but not A1 receptor blockadeby 8-cyclopentyl-1,3-dipropylxanthine, may treat PD motor symptoms. This reinforces the potential use of A2A receptor antagonists as a treatment strategy for PD patients. PMID:26973484

  10. BLOCKADE OF NERVE GROWTH FACTOR (NGF) RECEPTOR TRKA ATTENUATES DIESEL EXHAUST PARTICULATE MATTER (DEP) ENHANCEMENT OF ALLERGIC INFLAMMATION

    EPA Science Inventory


    Recent studies have shown that asthmatics have increased levels of the neurotrophin, NGF, in their lungs. In addition, antibody blockade of NGF in mice attenuates airway resistance associated with allergic airway responses. DEP has been linked to asthma exacerbation in many c...

  11. NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia.

    PubMed

    Manning, Simon M; Talos, Delia M; Zhou, Chengwen; Selip, Debra B; Park, Hyun-Kyung; Park, Chang-Joo; Volpe, Joseph J; Jensen, Frances E

    2008-06-25

    Hypoxia-ischemia (H/I) in the premature infant leads to white matter injury termed periventricular leukomalacia (PVL), the leading cause of subsequent neurological deficits. Glutamatergic excitotoxicity in white matter oligodendrocytes (OLs) mediated by cell surface glutamate receptors (GluRs) of the AMPA subtype has been demonstrated as one factor in this injury. Recently, it has been shown that rodent OLs also express functional NMDA GluRs (NMDARs), and overactivation of these receptors can mediate excitotoxic OL injury. Here we show that preterm human developing OLs express NMDARs during the PVL period of susceptibility, presenting a potential therapeutic target. The expression pattern mirrors that seen in the immature rat. Furthermore, the uncompetitive NMDAR antagonist memantine attenuates NMDA-evoked currents in developing OLs in situ in cerebral white matter of immature rats. Using an H/I rat model of white matter injury, we show in vivo that post-H/I treatment with memantine attenuates acute loss of the developing OL cell surface marker O1 and the mature OL marker MBP (myelin basic protein), and also prevents the long-term reduction in cerebral mantle thickness seen at postnatal day 21 in this model. These protective doses of memantine do not affect normal myelination or cortical growth. Together, these data suggest that NMDAR blockade with memantine may provide an effective pharmacological prevention of PVL in the premature infant.

  12. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice.

    PubMed

    Gomes, Felipe V; Del Bel, Elaine A; Guimarães, Francisco S

    2013-10-01

    Cannabidiol (CBD) is a non-psychotomimetic compound from Cannabis sativa plant that produces antipsychotic effects in rodents and humans. It also reverses L-dopa-induced psychotic symptoms and improves motor function in Parkinson's patients. This latter effect raised the possibility that CBD could have beneficial effects on motor related striatal disorders. To investigate this possibility we evaluated if CBD would prevent catalepsy induced by drugs with distinct pharmacological mechanisms. The catalepsy test is largely used to investigate impairments of motor function caused by interference on striatal function. Male Swiss mice received acute pretreatment with CBD (5, 15, 30 or 60mg/kg, ip) 30min prior to the D2 receptor antagonist haloperidol (0.6mg/kg), the non-selective nitric oxide synthase (NOS) inhibitor L-nitro-N-arginine (L-NOARG, 80mg/kg) or the CB1 receptor agonist WIN55,212-2 (5mg/kg). The mice were tested 1, 2 or 4h after haloperidol, L-NOARG or WIN55,212-2 injection. These drugs significantly increased catalepsy time and this effect was attenuated dose-dependently by CBD. CBD, by itself, did not induce catalepsy. In a second set of experiments the mechanism of CBD effects was investigated. Thirty minutes before CBD (30mg/kg) the animals received the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). The anticataleptic effect of CBD was prevented by WAY100635. These findings indicate that CBD can attenuate catalepsy caused by different mechanisms (D2 blockade, NOS inhibition and CB1 agonism) via 5-HT1A receptor activation, suggesting that it could be useful in the treatment of striatal disorders.

  13. Improvement in lung diffusion by endothelin A receptor blockade at high altitude.

    PubMed

    de Bisschop, Claire; Martinot, Jean-Benoit; Leurquin-Sterk, Gil; Faoro, Vitalie; Guénard, Hervé; Naeije, Robert

    2012-01-01

    Lung diffusing capacity has been reported variably in high-altitude newcomers and may be in relation to different pulmonary vascular resistance (PVR). Twenty-two healthy volunteers were investigated at sea level and at 5,050 m before and after random double-blind intake of the endothelin A receptor blocker sitaxsentan (100 mg/day) vs. a placebo during 1 wk. PVR was estimated by Doppler echocardiography, and exercise capacity by maximal oxygen uptake (Vo(2 max)). The diffusing capacities for nitric oxide (DL(NO)) and carbon monoxide (DL(CO)) were measured using a single-breath method before and 30 min after maximal exercise. The membrane component of DL(CO) (Dm) and capillary volume (Vc) was calculated with corrections for hemoglobin, alveolar volume, and barometric pressure. Altitude exposure was associated with unchanged DL(CO), DL(NO), and Dm but a slight decrease in Vc. Exercise at altitude decreased DL(NO) and Dm. Sitaxsentan intake improved Vo(2 max) together with an increase in resting and postexercise DL(NO) and Dm. Sitaxsentan-induced decrease in PVR was inversely correlated to DL(NO). Both DL(CO) and DL(NO) were correlated to Vo(2 max) at sea level (r = 0.41-0.42, P < 0.1) and more so at altitude (r = 0.56-0.59, P < 0.05). Pharmacological pulmonary vasodilation improves the membrane component of lung diffusion in high-altitude newcomers, which may contribute to exercise capacity.

  14. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice.

    PubMed

    Podowski, Megan; Calvi, Carla; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath-Morrow, Sharon; Berger, Alan; Cheadle, Christopher; Tuder, Rubin; Dietz, Harry C; Mitzner, Wayne; Wise, Robert; Neptune, Enid

    2012-01-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

  15. Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria.

    PubMed

    Hayashi, Kaori; Sasamura, Hiroyuki; Nakamura, Mari; Sakamaki, Yusuke; Azegami, Tatsuhiko; Oguchi, Hideyo; Tokuyama, Hirobumi; Wakino, Shu; Hayashi, Koichi; Itoh, Hiroshi

    2015-10-01

    Proteinuria is a central component of chronic kidney disease and an independent risk factor for cardiovascular disease. Kidney podocytes have an essential role as a filtration barrier against proteinuria. Kruppel-like Factor 4 (KLF4) is expressed in podocytes and decreased in glomerular diseases leading to methylation of the nephrin promoter, decreased nephrin expression and proteinuria. Treatment with an angiotensin receptor blocker (ARB) reduced methylation of the nephrin promoter in murine glomeruli of an adriamycin nephropathy model with recovery of KLF4 expression and a decrease in albuminuria. In podocyte-specific KLF4 knockout mice, the effect of ARB on albuminuria and the nephrin promoter methylation was attenuated. In cultured human podocytes, angiotensin II reduced KLF4 expression and caused methylation of the nephrin promoter with decreased nephrin expression. In patients, nephrin promoter methylation was increased in proteinuric kidney diseases with decreased KLF4 and nephrin expression. KLF4 expression in ARB-treated patients was higher in patients with than without ARB treatment. Thus, angiotensin II can modulate epigenetic regulation in podocytes and ARB inhibits these actions in part via KLF4 in proteinuric kidney diseases. This study provides a new concept that renin-angiotensin system blockade can exert therapeutic effects through epigenetic modulation of the kidney gene expression. PMID:26108068

  16. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage

    PubMed Central

    Cisneros-Mejorado, Abraham; Gottlieb, Miroslav; Cavaliere, Fabio; Magnus, Tim; Koch-Nolte, Friederich; Scemes, Eliana; Pérez-Samartín, Alberto; Matute, Carlos

    2015-01-01

    The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to ~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise. PMID:25605289

  17. Role of adenosine A2A receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control.

    PubMed

    El-Mas, Mahmoud M; El-Gowilly, Sahar M; Fouda, Mohamed A; Saad, Evan I

    2011-08-01

    Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100μg/kg i.v.) dose-dependently reduced BRS(SNP) in contrast to no effect on BRS(PE). BRS(SNP) was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS(SNP) were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS(SNP) was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A(2A) antagonist), or VUF5574 (A(3) antagonist). In contrast, BRS(SNP) was preserved after blockade of A(1) (DPCPX) or A(2B) (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS(SNP) depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A(2A) receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms. PMID:21550361

  18. EXTRINSIC COAGULATION BLOCKADE ATTENUATES LUNG INJURY AND PROINFLAMMATORY CYTOKINE RELEASE AFTER INTRATRACHEAL LIPOPOLYSACCHARIDE

    EPA Science Inventory

    Initiation of coagulation by tissue factor (TF) is a potentially powerful regulator of local inflammatory responses. We hypothesized that blockade of TF-factor VIIa (FVIIa) complex would decrease lung inflammation and proinflammatory cytokine release after tracheal instillation o...

  19. Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

    PubMed

    Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

    2014-05-01

    Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

  20. Endothelin-A blockade attenuates systemic and renal hemodynamic effects of L-NAME in humans.

    PubMed

    Montanari, A; Biggi, A; Carra, N; Fasoli, E; Calzolari, M; Corsini, F; Perinotto, P; Novarini, A

    2000-01-01

    Eight Na-repleted volunteers underwent 3 separate 90-minute infusions of either N(G)-nitro-L-arginine methyl ester (L-NAME) 3.0 mg. kg(-1). min(-1) or endothelin-A receptor (ET-A) blocker BQ-123 (BQ) 0.125 nmol. kg(-1). min(-1) or both. Mean arterial pressure (MAP), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistances (RVR), and sodium excretion rate (UNaV) were measured at baseline (b) and from 0 to 45 minutes (period 1) and 45 to 90 minutes (period 2) of infusion. BQ alone had no effect. GFR declined by 4.9% (P<0.001 versus b) in period 1, to 9.9% (P<0. 001) in period 2 with L-NAME, and by 3.3% (P<0.01) to 6.6% (P<0.001) with L-NAME plus BQ (P=NS between L-NAME and L-NAME plus BQ). UNaV fell equally with L-NAME or L-NAME plus BQ. MAP rose significantly in period 2 with L-NAME (6.9%; P<0.001) but not with coinfused BQ (2. 1%; P=NA versus b, P=0.005 versus L-NAME alone). RBF declined by 12. 2% (P<0.001) to 18.3% (P<0.001) with L-NAME and by 4.6% (P<0.005) to 8.2% (P<0.001) with L-NAME plus BQ. These changes were smaller with L-NAME plus BQ (P<0.05 in period 1 and P<0.02 in period 2). Blunted changes were also seen for RVR (P<0.005 in period 1 and P<0.001 in period 2 between L-NAME alone and L-NAME plus BQ). These findings show that systemic and renal vasoconstriction due to L-NAME are attenuated by BQ, which suggests that an interaction between endogenous nitric oxide production and ET-A activity participates in the maintenance of baseline systemic and renal vascular tone in humans.

  1. Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles.

    PubMed

    Stone, Audrey J; Copp, Steven W; Kim, Joyce S; Kaufman, Marc P

    2015-12-01

    In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P < 0.019) and integrated (↓48%, P < 0.004) pressor components of the reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs.

  2. Combined, but not individual, blockade of ASIC3, P2X, and EP4 receptors attenuates the exercise pressor reflex in rats with freely perfused hindlimb muscles.

    PubMed

    Stone, Audrey J; Copp, Steven W; Kim, Joyce S; Kaufman, Marc P

    2015-12-01

    In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P < 0.019) and integrated (↓48%, P < 0.004) pressor components of the reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs. PMID:26472871

  3. ACTIVIN IIB RECEPTOR BLOCKADE ATTENUATES DYSTROPHIC PATHOLOGY IN A MOUSE MODEL OF DUCHENNE MUSCULAR DYSTROPHY

    PubMed Central

    Morine, Kevin J.; Bish, Lawrence T.; Selsby, Joshua T.; Gazzara, Jeffery A.; Pendrak, Klara; Sleeper, Meg M.; Barton, Elisabeth R.; Lee, Se-Jin; Sweeney, H. Lee

    2015-01-01

    Modulation of transforming growth factor-β (TGF-β) signaling to promote muscle growth holds tremendous promise for the muscular dystrophies and other disorders involving the loss of functional muscle mass. Previous studies have focused on the TGF-β family member myostatin and demonstrated that inhibition of myostatin leads to muscle growth in normal and dystrophic mice. We describe a unique method of systemic inhibition of activin IIB receptor signaling via adeno-associated virus (AAV)-mediated gene transfer of a soluble form of the extracellular domain of the activin IIB receptor to the liver. Treatment of mdx mice with activin IIB receptor blockade led to increased skeletal muscle mass, increased force production in the extensor digitorum longus (EDL), and reduced serum creatine kinase. No effect on heart mass or function was observed. Our results indicate that activin IIB receptor blockade represents a novel and effective therapeutic strategy for the muscular dystrophies. PMID:20730876

  4. The stimulant effects of caffeine on locomotor behaviour in mice are mediated through its blockade of adenosine A2A receptors

    PubMed Central

    Yacoubi, Malika El; Ledent, Catherine; Ménard, Jean-François; Parmentier, Marc; Costentin, Jean; Vaugeois, Jean-Marie

    2000-01-01

    The locomotor stimulatory effects induced by caffeine (1,3,7-trimethylxanthine) in rodents have been attributed to antagonism of adenosine A1 and A2A receptors. Little is known about its locomotor depressant effects seen when acutely administered at high doses. The roles of adenosine A1 and A2A receptors in these activities were investigated using a Digiscan actimeter in experiments carried out in mice. Besides caffeine, the A2A antagonist SCH 58261 (5-amino-7-(β-phenylethyl)-2-(8-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine), the A1 antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine), the A1 agonist CPA (N6-cyclopentyladenosine) and A2A receptor knockout mice were used.Caffeine had a biphasic effect on locomotion of wild-type mice not habituated to the open field, stimulating locomotion at 6.25–25 mg kg−1 i.p. doses, while depressing it at 100 mg kg−1. In sharp contrast, caffeine dose-dependently decreased locomotion in A2A receptor knockout mice over the whole range of tested doses.The depressant effects induced by high doses of caffeine were lost in control CD1 mice habituated to the open field.The A1 agonist CPA depressed locomotion at 0.3–1 mg kg−1 i.p. doses.The A1 antagonist DPCPX decreased locomotion of A2A receptor knockouts and CD1 mice at 5 mg kg−1 i.p. and 25 mg kg−1 i.p. respectively.DPCPX (0.2–1 mg kg−1 i.p.) left unaltered or even reduced the stimulant effect of SCH 58261 (1–3 mg kg−1 i.p.) on CD1 mice.These results suggest therefore that the stimulant effect of low doses of caffeine is mediated by A2A receptor blockade while the depressant effect seen at higher doses under some conditions is explained by A1 receptor blockade. PMID:10742303

  5. GABA(A) receptor blockade in dorsomedial and ventromedial nuclei of the hypothalamus evokes panic-like elaborated defensive behaviour followed by innate fear-induced antinociception.

    PubMed

    Freitas, Renato Leonardo; Uribe-Mariño, Andrés; Castiblanco-Urbina, Maria Angélica; Elias-Filho, Daoud Hibraim; Coimbra, Norberto Cysne

    2009-12-11

    Dysfunction in the hypothalamic GABAergic system has been implicated in panic syndrome in humans. Furthermore, several studies have implicated the hypothalamus in the elaboration of pain modulation. Panic-prone states are able to be experimentally induced in laboratory animals to study this phenomenon. The aim of the present work was to investigate the involvement of medial hypothalamic nuclei in the organization of panic-like behaviour and the innate fear-induced oscillations of nociceptive thresholds. The blockade of GABA(A) receptors in the neuronal substrates of the ventromedial or dorsomedial hypothalamus was followed by elaborated defensive panic-like reactions. Moreover, innate fear-induced antinociception was consistently elicited after the escape behaviour. The escape responses organized by the dorsomedial and ventromedial hypothalamic nuclei were characteristically more elaborated, and a remarkable exploratory behaviour was recorded during GABA(A) receptor blockade in the medial hypothalamus. The motor characteristic of the elaborated defensive escape behaviour and the patterns of defensive alertness and defensive immobility induced by microinjection of the bicuculline either into the dorsomedial or into the ventromedial hypothalamus were very similar. This was followed by the same pattern of innate fear-induced antinociceptive response that lasted approximately 40 min after the elaborated defensive escape reaction in both cases. These findings suggest that dysfunction of the GABA-mediated neuronal system in the medial hypothalamus causes panic-like responses in laboratory animals, and that the elaborated escape behaviour organized in both dorsomedial and ventromedial hypothalamic nuclei are followed by significant innate-fear-induced antinociception. Our findings indicate that the GABA(A) receptor of dorsomedial and ventromedial hypothalamic nuclei are critically involved in the modulation of panic-like behaviour.

  6. Selective blockade of TRPA1 channel attenuates pathological pain without altering noxious cold sensation or body temperature regulation.

    PubMed

    Chen, Jun; Joshi, Shailen K; DiDomenico, Stanley; Perner, Richard J; Mikusa, Joe P; Gauvin, Donna M; Segreti, Jason A; Han, Ping; Zhang, Xu-Feng; Niforatos, Wende; Bianchi, Bruce R; Baker, Scott J; Zhong, Chengmin; Simler, Gricelda H; McDonald, Heath A; Schmidt, Robert G; McGaraughty, Steve P; Chu, Katharine L; Faltynek, Connie R; Kort, Michael E; Reilly, Regina M; Kym, Philip R

    2011-05-01

    Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.

  7. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat.

    PubMed

    Dugovic, Christine; Shelton, Jonathan E; Aluisio, Leah E; Fraser, Ian C; Jiang, Xiaohui; Sutton, Steven W; Bonaventure, Pascal; Yun, Sujin; Li, Xiaorong; Lord, Brian; Dvorak, Curt A; Carruthers, Nicholas I; Lovenberg, Timothy W

    2009-07-01

    Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl]urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated

  8. Leptin blockade attenuates sodium excretion in saline-loaded normotensive rats.

    PubMed

    Villarreal, Daniel; Reams, Garry; Freeman, Ronald; Spear, Robert; Tchoukina, Inna; Samar, Huma

    2006-02-01

    Previous investigations in normotensive animals have demonstrated a marked natriuretic and diuretic response following the acute administration of supraphysiologic doses of synthetic leptin. However, the importance of endogenous leptin in the regulation of renal sodium and water balance is not yet defined. This study examined the hemodynamic and renal excretory effects of circulating leptin blockade with a specific polyclonal antibody in groups of normotensive, chronically saline-loaded Sprague-Dawley rats. In the experimental group (n = 10), leptin antibody significantly decreased urinary sodium excretion and urinary flow by approximately 30% compared to the control rats (n = 10). Mean arterial pressure remained unchanged. Collectively, these results are interpreted to suggest that leptin is an important renal sodium-regulating factor under conditions of mild sodium and volume expansion.

  9. Blockade of acid sensing ion channels attenuates the exercise pressor reflex in cats

    PubMed Central

    Hayes, Shawn G; Kindig, Angela E; Kaufman, Marc P

    2007-01-01

    Although thin fibre muscle afferents possess acid sensing ion channels (ASICs), their contribution to the exercise pressor reflex is not known. This lack of information is partly attributable to the fact that there is no known selective in vivo antagonist for ASICs. Although amiloride has been shown to antagonize ASICs, it also has been shown to antagonize voltage-gated sodium channels, thereby impairing impulse conduction in sensory nerves. Our aim was to test the hypothesis that lactic acid accumulation in exercising muscle acted on ASICs located on thin fibre muscle afferents to evoke the metabolic component of the exercise pressor reflex. To test this hypothesis, we determined in decerebrate cats if amiloride attenuated the pressor and cardioaccelerator responses to static contraction, to tendon stretch and to arterial injections of lactic acid and capsaicin. We found a dose of amiloride (0.5 μg kg−1; i.a.) that attenuated the pressor and cardioaccelerator responses to both contraction and lactic acid injection, but had no effect on the responses to stretch and capsaicin. A higher dose of amiloride (5 μg kg−1, i.a.) not only blocked the pressor and cardioaccelerator responses to lactic acid and contraction, but also attenuated the responses to stretch and to capsaicin, manoeuvers in which ASICs probably play no significant role. In addition, we found that the low dose of amiloride (0.5 μg kg−1) had no effect on the responses of muscle spindles to tendon stretch and to succinylcholine, whereas the high dose (5 μg kg−1) attenuated the responses to both. Our data suggest the low dose of amiloride used in our experiments selectively blocked ASICs, whereas the high dose blocked ASICs and impulse conduction in muscle afferents. We conclude that ASICs play a role in the metabolic component of the exercise pressor reflex. PMID:17395635

  10. Calcium channel blockade attenuates angiotensin II-induced drinking in rats.

    PubMed

    Calcagnetti, D J; Schechter, M D

    1993-01-01

    Lateral ventricular administration of angiotensin II (ANG II) produces potent dipsogenic effects in water-sated rats. ANG II seems to require functional voltage-gated calcium channels on neurons throughout circumventricular brain sites to exert its effects. Although there are at least three types of calcium channels, only L-type calcium channel-blocking drugs have been reported to decrease drinking. (4-(4-Benzofurazanyl)-1-4-dihydro-2,6-dimethyl-3,5-pyridine-dic arb oxylic acid methyl 1-methyl-ethyl ester) [PN 200-110; isradipine (ISR)], a selective L-type calcium channel blocker, has been shown to attenuate significantly the intake of sweetened water in water-sated rats following either peripheral or ICV administration, but ISR does not affect plain-water intake in water-deprived rats. The present experiment was designed to determine whether ISR would attenuate ANG II-induced drinking that is not either motivated by palatability or dependent on deprivation. Rats, each fitted with chronic indwelling ventricular cannulae, were pretreated with ISR (0.3, 3.0, and 30 micrograms/rat; ICV). ANG II (40 ng/rat; ICV) was administered 10 min later and rats were allowed free access to water for 15 min. Injections of ANG II plus saline and ANG II plus the ISR vehicle (dimethyl sulfoxide) did not attenuate ANG II-induced polydipsia, whereas ANG II+ISR (0.3 and 3.0 micrograms) attenuated ANG II-induced drinking to 62 and 22% of control, respectively. Results with the 30-micrograms dose were not different from the 3.0 dose.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Effects of activation and blockade of orexin A receptors in the medial preoptic area on food intake in male rats.

    PubMed

    Sarihi, Abdolrahman; Emam, Amir Hossein; Panah, Mohammad Hosseini; Komaki, Alireza; Seif, Sadegh; Vafaeirad, Majid; Alaii, Elham

    2015-09-14

    It has been shown that activation of type 1 orexinergic receptors (ORX1) in several parts of the hypothalamus stimulate food intake. Orexin A receptive sites for food intake exist primarily in a narrow band of the hypothalamus that is known to be involved in control of energy homeostasis. The present study aimed to investigate the role of orexin receptors in the medial preoptic area (MPOA) on food intake in rats. Twenty-four male rats weighing 200-250g were divided into three groups (n=8 in each group). Rats were cannulated using stereotaxic coordinates above the MPOA. Normal saline was microinjected into the MPOA in the control group. Another group received intra MPOA microinjection of SB334867, a selective antagonist for ORX1 receptors. In the other group, orexin A was microinjected (0.5μl of 1μmol) into the MPOA. Food intake was measured in metabolic cages. The statistical significance of differences between groups was detected by a one way ANOVA. A value of p<0.05 was considered significant. There was no significant difference in food consumption between saline and SB334867 treated groups. However, activation of the orexin receptor in the MPOA significantly increased food intake during the 2 and 8h after orexin A microinjection. Our results showed that during ad libitum access to food, activation but not blockade of the MPOA ORX1 receptor can increase food intake in a time-dependent manner. The role of these receptors in hunger and appetite stimulation requires further study.

  12. Adenosine A2A-receptor blockade abolishes the roll-off respiratory response to hypoxia in awake lambs.

    PubMed

    Koos, Brian J; Kawasaki, Yoshikazu; Kim, Young-Han; Bohorquez, Fanor

    2005-05-01

    Adenosine (ADO) receptor antagonists (aminophylline, caffeine) blunt the respiratory roll-off response to hypoxia in the newborn. This study was designed to determine the ADO receptor subtype involved in the respiratory depression. Chronically catheterized lambs of 7-16 days of age breathed via face mask a gas mixture with a fraction of inspired O2 of 0.21 (normoxia) or 0.07 (hypoxia), while being infused intravascularly with 9-cyclopentyl-1,3-dipropylxanthine (DPCPX; ADO A1-receptor antagonist, n=8), ZM-241385 (ADO A2A-receptor antagonist, n=7), or vehicle. Ventilation was measured at 20 degrees C by a turbine transducer flowmeter. In normoxia [arterial Po2 (PaO2) of approximately 83 Torr], infusion of vehicle did not alter cardiorespiratory measurements, whereas hypoxia (PaO2 of approximately 31 Torr, 15 min) elicited biphasic effects on mean arterial pressure (transient increase), heart rate (HR; diminishing tachycardia), and minute ventilation. In the latter, hypoxia increased ventilation to a peak value of approximately 2.5 times control within the first 3 min, which was followed by a significant (P<0.05) decline to approximately 50% of the maximum increment over the subsequent 7 min. ZM-241385 abolished the hypoxic ventilatory roll-off and blunted the rate of rise in HR without affecting mean arterial pressure or rectal temperature responses. In normoxia, DPCPX increased ventilation and mean arterial pressure but did not change HR. Compared with vehicle, DPCPX did not significantly affect cardiorespiratory responses to hypoxemia (PaO2 of approximately 31 Torr, 10 min). It is concluded that 1) ADO A2A receptors are critically involved in the ventilatory roll-off and HR responses to hypoxia, and 2) ADO A1 receptors, which are tonically active in cardiorespiratory control in normoxia, appear to have little impact on hypoxic ventilatory depression.

  13. Up-Regulation of Endothelin Type A Receptor in Human and Rat Radiation Proctitis: Preclinical Therapeutic Approach With Endothelin Receptor Blockade

    SciTech Connect

    Jullien, Nicolash; Blirando, Karl; Milliat, Fabien; Benderitter, Marc; Francois, Agnes

    2009-06-01

    Purpose: Rectum radiation damage and fibrosis are often associated with radiation therapy of pelvic tumors. The endothelin (ET) system has been implicated in several fibrotic diseases but never studied in the context of gastrointestinal radiation damage. This study assessed modifications in ET type 1 (ET-1), ET type A receptor (ET{sub A}), and ET type B receptor (ET{sub B}) localization and/or expression in irradiated human rectal tissue and in a rat model of delayed colorectal injury. We also evaluated the therapeutic potential of long-term ET receptor blockade. Methods and Materials: Routine histological studies of sections of healthy and radiation-injured human rectum tissue were done; the sections were also immunostained for ET{sub A} and ET{sub B} receptors. The rat model involved the delivery of 27 Gy in a single dose to the colons and rectums of the animals. The ET-1/ET{sub A}/ET{sub B} expression and ET{sub A}/ET{sub B} localization were studied at 10 weeks postexposure. The abilities of bosentan and atrasentan to protect against delayed rectal injury were also investigated. Results: The immunolocalization of ET{sub A} and ET{sub B} in healthy human rectums was similar to that in rat rectums. However, strong ET{sub A} immunostaining was seen in the presence of human radiation proctitis, and increased ET{sub A} mRNA levels were seen in the rat following colorectal irradiation. Immunostaining for ET{sub A} was also strongly positive in rats in areas of radiation-induced mucosal ulceration, atypia, and fibroproliferation. However, neither bosentan nor atrasentan prevented radiation damage to the rectum when given long term. The only effect seen for atrasentan was an increased number of sclerotic vessel sections in injured tissues. Conclusions: As the result of the overexpression of ET{sub A}, radiation exposure deregulates the endothelin system through an 'ET{sub A} profile' in the human and rodent rectum. However, therapeutic interventions involving mixed or

  14. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain.

    PubMed

    Ghilardi, Joseph R; Röhrich, Heidi; Lindsay, Theodore H; Sevcik, Molly A; Schwei, Matthew J; Kubota, Kazufumi; Halvorson, Kyle G; Poblete, Jeannie; Chaplan, Sandra R; Dubin, Adrienne E; Carruthers, Nicholas I; Swanson, Devin; Kuskowski, Michael; Flores, Christopher M; Julius, David; Mantyh, Patrick W

    2005-03-23

    Cancer colonization of bone leads to the activation of osteoclasts, thereby producing local tissue acidosis and bone resorption. This process may contribute to the generation of both ongoing and movement-evoked pain, resulting from the activation of sensory neurons that detect noxious stimuli (nociceptors). The capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1) is a cation channel expressed by nociceptors that detects multiple pain-producing stimuli, including noxious heat and extracellular protons, raising the possibility that it is an important mediator of bone cancer pain via its capacity to detect osteoclast- and tumor-mediated tissue acidosis. Here, we show that TRPV1 is present on sensory neuron fibers that innervate the mouse femur and that, in an in vivo model of bone cancer pain, acute or chronic administration of a TRPV1 antagonist or disruption of the TRPV1 gene results in a significant attenuation of both ongoing and movement-evoked nocifensive behaviors. Administration of the antagonist had similar efficacy in reducing early, moderate, and severe pain-related responses, suggesting that TRPV1 may be a novel target for pharmacological treatment of chronic pain states associated with bone cancer metastasis.

  15. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats

    PubMed Central

    Drummond, Shelley; Ramachandran, Shalini; Torres, Eneida; Huang, Jian; Hehre, Dorothy; Suguihara, Cleide; Young, Karen C.

    2015-01-01

    Background Lung inflammation is a key factor in the pathogenesis of bronchopulmonary dysplasia (BPD). Stromal derived factor-1 (SDF-1) and its receptor chemokine receptor 4 (CXCR4) modulate the inflammatory response. Whether antagonism of CXCR4 will alleviate lung inflammation in neonatal hyperoxia-induced lung injury is unknown. Objective To determine whether CXCR4 antagonism would attenuate lung injury in rodents with experimental BPD by decreasing pulmonary inflammation. Methods Newborn rats exposed to normoxia (RA) or hyperoxia (FiO2=0.9) from postnatal day 2 (P2)-P16 were randomized to receive the CXCR4 antagonist, AMD3100 or placebo (PL) from P5 to P15. Lung alveolarization, angiogenesis, and inflammation were evaluated at P16. Results As compared to RA, hyperoxic-PL pups had a decrease in alveolarization, reduced lung vascular density and increased lung inflammation. In contrast, AMD3100-treated hyperoxic pups had improved alveolarization and increased angiogenesis. This improvement in lung structure was accompanied by a decrease in bronchoalveolar lavage fluid macrophage and neutrophil count and reduced lung myeloperoxidase activity. Conclusion CXCR4 antagonism decreases lung inflammation and improves alveolar as well as vascular structure in neonatal rats with experimental BPD. These findings suggest a novel therapeutic strategy to alleviate lung injury in preterm infants with BPD. PMID:25825119

  16. TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling.

    PubMed

    Ye, Dongqing; Li, Yang; Zhang, Xiangrong; Guo, Fei; Geng, Leiyu; Zhang, Qi; Zhang, Zhijun

    2015-12-01

    Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction. PMID:26441141

  17. Effects of a Proprietary Standardized Orthosiphon stamineus Ethanolic Leaf Extract on Enhancing Memory in Sprague Dawley Rats Possibly via Blockade of Adenosine A 2A Receptors.

    PubMed

    George, Annie; Chinnappan, Sasikala; Choudhary, Yogendra; Choudhary, Vandana Kotak; Bommu, Praveen; Wong, Hoi Jin

    2015-01-01

    The aim of the study was to explore a propriety standardized ethanolic extract from leaves of Orthosiphon stamineus Benth in improving impairments in short-term social memory in vivo, possibly via blockade of adenosine A2A receptors (A2AR). The ethanolic extract of O. stamineus leaves showed significant in vitro binding activity of A2AR with 74% inhibition at 150 μg/ml and significant A2AR antagonist activity with 98% inhibition at 300 μg/mL. A significant adenosine A1 receptor (A1R) antagonist activity with 100% inhibition was observed at 300 μg/mL. Its effect on learning and memory was assessed via social recognition task using Sprague Dawley rats whereby the ethanolic extract of O. stamineus showed significant (p < 0.001) change in recognition index (RI) at 300 mg/kg and 600 mg/kg p.o and 120 mg/kg i.p., respectively, compared to the vehicle control. In comparison, the ethanolic extract of Polygonum minus aerial parts showed small change in inflexion; however, it remained insignificant in RI at 200 mg/kg p.o. Our findings suggest that the ethanolic extract of O. stamineus leaves improves memory by reversing age-related deficits in short-term social memory and the possible involvement of adenosine A1 and adenosine A2A as a target bioactivity site in the restoration of memory.

  18. Effects of a Proprietary Standardized Orthosiphon stamineus Ethanolic Leaf Extract on Enhancing Memory in Sprague Dawley Rats Possibly via Blockade of Adenosine A 2A Receptors.

    PubMed

    George, Annie; Chinnappan, Sasikala; Choudhary, Yogendra; Choudhary, Vandana Kotak; Bommu, Praveen; Wong, Hoi Jin

    2015-01-01

    The aim of the study was to explore a propriety standardized ethanolic extract from leaves of Orthosiphon stamineus Benth in improving impairments in short-term social memory in vivo, possibly via blockade of adenosine A2A receptors (A2AR). The ethanolic extract of O. stamineus leaves showed significant in vitro binding activity of A2AR with 74% inhibition at 150 μg/ml and significant A2AR antagonist activity with 98% inhibition at 300 μg/mL. A significant adenosine A1 receptor (A1R) antagonist activity with 100% inhibition was observed at 300 μg/mL. Its effect on learning and memory was assessed via social recognition task using Sprague Dawley rats whereby the ethanolic extract of O. stamineus showed significant (p < 0.001) change in recognition index (RI) at 300 mg/kg and 600 mg/kg p.o and 120 mg/kg i.p., respectively, compared to the vehicle control. In comparison, the ethanolic extract of Polygonum minus aerial parts showed small change in inflexion; however, it remained insignificant in RI at 200 mg/kg p.o. Our findings suggest that the ethanolic extract of O. stamineus leaves improves memory by reversing age-related deficits in short-term social memory and the possible involvement of adenosine A1 and adenosine A2A as a target bioactivity site in the restoration of memory. PMID:26649059

  19. Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.

    PubMed

    Mathes, Clare M; Spector, Alan C

    2014-09-01

    Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior.

  20. Effects of a Proprietary Standardized Orthosiphon stamineus Ethanolic Leaf Extract on Enhancing Memory in Sprague Dawley Rats Possibly via Blockade of Adenosine A2A Receptors

    PubMed Central

    Choudhary, Yogendra; Choudhary, Vandana Kotak; Bommu, Praveen; Wong, Hoi Jin

    2015-01-01

    The aim of the study was to explore a propriety standardized ethanolic extract from leaves of Orthosiphon stamineus Benth in improving impairments in short-term social memory in vivo, possibly via blockade of adenosine A2A receptors (A2AR). The ethanolic extract of O. stamineus leaves showed significant in vitro binding activity of A2AR with 74% inhibition at 150 μg/ml and significant A2AR antagonist activity with 98% inhibition at 300 μg/mL. A significant adenosine A1 receptor (A1R) antagonist activity with 100% inhibition was observed at 300 μg/mL. Its effect on learning and memory was assessed via social recognition task using Sprague Dawley rats whereby the ethanolic extract of O. stamineus showed significant (p < 0.001) change in recognition index (RI) at 300 mg/kg and 600 mg/kg p.o and 120 mg/kg i.p., respectively, compared to the vehicle control. In comparison, the ethanolic extract of Polygonum minus aerial parts showed small change in inflexion; however, it remained insignificant in RI at 200 mg/kg p.o. Our findings suggest that the ethanolic extract of O. stamineus leaves improves memory by reversing age-related deficits in short-term social memory and the possible involvement of adenosine A1 and adenosine A2A as a target bioactivity site in the restoration of memory. PMID:26649059

  1. The 5-hydroxytryptamine2A receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) attenuates impulsivity after both drug-induced disruption (dizocilpine) and enhancement (antidepressant drugs) of differential-reinforcement-of-low-rate 72-s behavior in the rat.

    PubMed

    Ardayfio, Paul A; Benvenga, Mark J; Chaney, Stephen F; Love, Patrick L; Catlow, John; Swanson, Steven P; Marek, Gerard J

    2008-12-01

    Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)(2A) receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic "antidepressant-like" effects of a 5-HT(2A) receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT(2A) receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT(2A) receptor blockade may exert effects on impulsivity, [R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT(2A) receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range. PMID:18772320

  2. Blockade of Extracellular High-Mobility Group Box 1 Attenuates Systemic Inflammation and Coagulation Abnormalities in Rats with Acute Traumatic Coagulopathy

    PubMed Central

    Xu, Lin; Zhao, Kun; Shen, Xiao; Fan, Xin-xin; Ding, Kai; Liu, Ren-min; Wang, Feng

    2016-01-01

    Background As an extracellularly released mediator, high-mobility group box 1 (HMGB1) initiates sterile inflammation following severe trauma. Serum HMGB1 levels correlate well with acute traumatic coagulopathy (ATC) in trauma patients, which is independently associated with higher mortality. We investigated the involvement of HMGB1 in ATC through blocking extracellular HMGB1. Material/Methods The ATC model was induced by polytrauma and hemorrhage in male Sprague-Dawley rats, which were randomly assigned to sham, ATC, and ATCH (ATC with HMGB1 blockade) groups. Thrombelastography (TEG) was performed to monitor changes in coagulation function. Serum levels of HMGB1, TNF-α, and IL-6 were measured, as well as lung levels of HMGB1 and nuclear factor (NF)-κB and expression of receptor for advanced glycation end-products (RAGE). Results Compared with the sham group, HMGB1 increased the serum levels of TNF-α and IL-6, whereas HMGB1 blockade inhibited the induction of TNF-α and IL-6. HMGB1 also induced elevated serum soluble P-selectin and fibrinolysis markers plasmin-antiplasmin complex, which both were reduced by HMGB1 blockade. Thrombelastography revealed the hypocoagulability status in the ATC group, which was attenuated by anti-HMGB1 antibody. Furthermore, the lung level of NF-κB and expression of RAGE were decreased by anti-HMGB1 antibody, suggesting the role of RAGE/NF-κB pathway in ATC. Conclusions HMGB1 blockade can attenuate inflammation and coagulopathy in ATC rats. Anti-HMGB1 antibody might exert protective effects partly through the RAGE/NF-κB pathway. Thus, HMGB1 has potential as a therapeutic target in ATC. PMID:27436061

  3. Role of adenosine A{sub 2A} receptor signaling in the nicotine-evoked attenuation of reflex cardiac sympathetic control

    SciTech Connect

    El-Mas, Mahmoud M. El-gowilly, Sahar M.; Fouda, Mohamed A.; Saad, Evan I.

    2011-08-01

    Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16 {mu}g/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100 {mu}g/kg i.v.) dose-dependently reduced BRS{sub SNP} in contrast to no effect on BRS{sub PE}. BRS{sub SNP} was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS{sub SNP} were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS{sub SNP} was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A{sub 2A} antagonist), or VUF5574 (A{sub 3} antagonist). In contrast, BRS{sub SNP} was preserved after blockade of A{sub 1} (DPCPX) or A{sub 2B} (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS{sub SNP} depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A{sub 2A} receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms

  4. Latent inhibition is attenuated by noise and partially restored by a 5-HT2A receptor antagonist.

    PubMed

    McDonald, L M; Moran, P M; Vythelingum, G N; Joseph, M H; Stephenson, J D; Gray, J A

    2002-12-01

    Latent inhibition (LI) is a model of attention, which is a cognitive process that can be modulated by stressors such as chronic intermittent broadband noise, e.g. caused by building work, which is particularly stressful to rats. The aim of this study was to analyse the effect of chronic noise stress, caused by a building project, on LI, and its interaction with SR 46,349B, a 5-HT2A receptor antagonist. Control groups from LI experiments conducted during periods of chronic intermittent noise were compared with control groups from LI experiments conducted in normal quiet conditions. The interaction of SR 46,349B with the effects of chronic noise stress was then tested. Chronic intermittent noise attenuated LI, an effect which was partially reversed by SR 46,349B, 2.4 mg/kg i.p. Attenuation of LI by chronic intermittent noise and reversal of this effect by SR 46,349B support suggestions that stress can modulate attention and that 5-HT2A receptors are involved in mediating the effects of chronic stress.

  5. Blockade of PARP activity attenuates poly(ADP-ribosyl)ation but offers only partial neuroprotection against NMDA-induced cell death in the rat retina.

    PubMed

    Goebel, Dennis J; Winkler, Barry S

    2006-09-01

    Recent reports have linked neuronal cell death by necrosis to poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation. It is believed that under stress, the activity of this enzyme is up-regulated, resulting in extensive poly(ADP-ribosyl)ation of nuclear proteins, using NAD(+) as its substrate, which, in turn, leads to the depletion of NAD(+). In efforts to restore the level of NAD(+), depletion of ATP occurs, resulting in the shutdown of ATP-dependent ionic pumps. This results in cell swelling and eventual loss of membrane selectivity, hallmarks of necrosis. Reports from in vitro and in vivo studies in the brain have shown that NMDA receptor activation stimulates PARP activity and that blockade of the enzyme provides substantial neuroprotection. The present study was undertaken to determine whether PARP activity is regulated by NMDA in the rat retina, and whether blockade of PARP activity provides protection against toxic effects of NMDA. Rat retinas exposed to intravitreal injections containing NMDA, with or without the PARP inhibitor N-(6-oxo-5, 6-dihydrophenanthridin-2-yl)-(N,-dimethylamino) acetamide hydrochloride (PJ-34), were assessed for changes in PARP-1 activity as evidenced by poly(ADP-ribosyl)ation (PAR), loss of membrane integrity, morphological indicators of apoptosis and necrosis, and ganglion cell loss. Results showed that: NMDA increased PAR formation in a concentration-dependent manner and caused a decline in retinal ATP levels; PJ-34 blockade attenuated the NMDA-induced formation of PAR and decline in ATP; NMDA induced the loss of membrane selectivity to ethidium bromide (EtBr) in inner retinal neurons, but loss of membrane selectivity was not prevented by blocking PARP activity; cells stained with EtBr, or reacted for TUNEL-labeling, displayed features characteristic of both apoptosis and necrosis. In the presence of PJ-34, greater numbers of cells exhibited apoptotic features; PJ-34 provided partial neuroprotection against NMDA-induced ganglion

  6. Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus.

    PubMed

    Liao, Xue-Mei; Yang, Xiao-Dun; Jia, Jiao; Li, Ji-Tao; Xie, Xiao-Meng; Su, Yun-Ai; Schmidt, Mathias V; Si, Tian-Mei; Wang, Xiao-Dong

    2014-05-01

    Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg g(-1) ) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg g(-1) ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment.

  7. Blockade of 5-HT1A receptors by (+/-)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: microdialysis and behavioral approaches in 5-HT1A receptor knockout mice.

    PubMed

    Guilloux, Jean-Philippe; David, Denis J P; Guiard, Bruno P; Chenu, Franck; Repérant, Christelle; Toth, Miklos; Bourin, Michel; Gardier, Alain M

    2006-10-01

    Selective serotonin reuptake inhibitors like paroxetine (Prx) often requires 4-6 weeks to achieve clinical benefits in depressed patients. Pindolol shortens this delay and it has been suggested that this effect is mediated by somatodendritic 5-hydroxytryptamine (5-HT) 1A autoreceptors. However clinical data on the beneficial effects of pindolol are conflicting. To study the effects of (+/-)-pindolol-paroxetine administration, we used genetical and pharmacological approaches in 5-HT1A knockout mice (5-HT1A-/-). Two assays, in vivo intracerebral microdialysis in awake mice and the forced swimming test (FST), were used to assess the antidepressant-like effects of this drug combination. Basal levels of extracellular serotonin, 5-HT ([5-HT]ext) in the frontal cortex (FCX) and the dorsal raphe nucleus (DRN) did not differ between the two strains of mice, suggesting a lack of tonic control of 5-HT1A autoreceptors on nerve terminal 5-HT release. Prx (1 and 4 mg/kg) dose-dependently increased cortical [5-HT]ext in both genotypes, but the effects were greater in mutants. The selective 5-HT1A receptor antagonist, WAY-100635 (0.5 mg/kg), or (+/-)-pindolol (5 and 10 mg/kg) potentiated the effects of Prx (4 mg/kg) on cortical [5-HT]ext in 5-HT1A+/+, but not in 5-HT1A-/- mice. Similar responses were obtained following local intra-raphe perfusion by reverse microdialysis of either WAY-100635 or (+/-)-pindolol (100 microM each). In the FST, Prx administration dose-dependently decreased the immobility time in both strains of mice, but the response was much greater in 5HT1A-/- mice. In contrast, (+/-)-pindolol blocked Prx-induced decreases in the immobility time while WAY-100635 had no effect in both genotypes. These findings using 5-HT1A-/- mice confirm that (+/-)-pindolol behaves as an antagonist of 5-HT1A autoreceptor in mice, but its blockade of paroxetine-induced antidepressant-like effects in the FST may be due to its binding to other neurotransmitter receptors.

  8. Blockade of CTLA-4 promotes the development of effector CD8+ T lymphocytes and the therapeutic effect of vaccination with an attenuated protozoan expressing NY-ESO-1.

    PubMed

    Dos Santos, Luara Isabela; Galvão-Filho, Bruno; de Faria, Paula Cristina; Junqueira, Caroline; Dutra, Miriam Santos; Teixeira, Santuza Maria Ribeiro; Rodrigues, Maurício Martins; Ritter, Gerd; Bannard, Oliver; Fearon, Douglas Thomas; Antonelli, Lis Ribeiro; Gazzinelli, Ricardo Tostes

    2015-03-01

    The development of cancer immunotherapy has long been a challenge. Here, we report that prophylactic vaccination with a highly attenuated Trypanosoma cruzi strain expressing NY-ESO-1 (CL-14-NY-ESO-1) induces both effector memory and effector CD8(+) T lymphocytes that efficiently prevent tumor development. However, the therapeutic effect of such a vaccine is limited. We also demonstrate that blockade of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) during vaccination enhances the frequency of NY-ESO-1-specific effector CD8(+) T cells producing IFN-γ and promotes lymphocyte migration to the tumor infiltrate. As a result, therapy with CL-14-NY-ESO-1 together with anti-CTLA-4 is highly effective in controlling the development of an established melanoma.

  9. The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats.

    PubMed

    Davoudi, Mahnaz; Azizi, Hossein; Mirnajafi-Zadeh, Javad; Semnanian, Saeed

    2016-03-23

    The aim of present study was to investigate the involvement of orexin-A neuropeptide in naloxone-induced morphine withdrawal syndrome via modulating neurons bearing GABAA receptors. The locus coeruleus (LC) is a sensitive site for expression of the somatic aspects of morphine withdrawal. Intra-LC microinjection of GABAA receptor agonist attenuates morphine withdrawal signs in rats. Here we studied the influence of LC orexin type 1 receptors blockade by SB-334867 in presence of bicuculline, a GABAA receptor antagonist, on naloxone-induced morphine withdrawal syndrome. Adult male Wistar rats, weighing 250-300 g, were rendered dependent on morphine by subcutaneous (s.c.) injection of increasing morphine doses (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. On 8th day, naloxone (3 mg/kg, s.c.) was injected and the somatic signs of morphine withdrawal were evaluated. Intra-LC microinjections (0.2 μl) of either bicuculline (15 μM) or SB-334867 (3 mM) or a combination of both chemicals were done immediately before naloxone injection. Intra-LC microinjection of bicuculline (15 μM) had no significant effect on morphine withdrawal signs, whereas intra-LC microinjection of SB-334867 considerably attenuated morphine withdrawal signs. However, the effect of SB-334867 in attenuating naloxone-induced morphine withdrawal signs was blocked in presence of bicuculline. This finding, for the first time, indicated that orexin-A may participate in expression of naloxone-induced morphine withdrawal syndrome partly through decreasing the activity of neurons bearing GABAA receptors.

  10. Angiotensin II type 1 receptor blockade partially attenuates hypoxia-induced pulmonary hypertension in newborn piglets: relationship with the nitrergic system

    PubMed Central

    Camelo, J.S.; Martins, A.R.; Rosa, E.; Ramos, S.G.; Hehre, D.; Bancalari, E.; Suguihara, C.

    2012-01-01

    The objective of this study was to observe possible interactions between the renin-angiotensin and nitrergic systems in chronic hypoxia-induced pulmonary hypertension in newborn piglets. Thirteen chronically instrumented newborn piglets (6.3 ± 0.9 days; 2369 ± 491 g) were randomly assigned to receive saline (placebo, P) or the AT1 receptor (AT1-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO2 = 0.12). During hypoxia, pulmonary arterial pressure (Ppa; P < 0.0001), pulmonary vascular resistance (PVR; P < 0.02) and the pulmonary to systemic vascular resistance ratio (PVR/SVR; P < 0.05) were significantly attenuated in the L (N = 7) group compared to the P group (N = 6). Western blot analysis of lung proteins showed a significant decrease of endothelial NOS (eNOS) in both P and L animals, and of AT1-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT1-R tended to decrease in L animals. Inducible NOS (iNOS) did not differ among P, L, and C animals and iNOS immunohistochemical staining in macrophages was significantly more intense in L than in P animals (P < 0.01). The vascular endothelium showed moderate or strong eNOS and AT1-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT1-R staining, but C animals showed weak iNOS and AT1-R staining. Macrophages of L and P animals showed moderate and weak AT2-R staining, respectively, but the endothelium of all groups only showed weak staining. In conclusion, pulmonary hypertension induced by chronic hypoxia in newborn piglets is partially attenuated by AT1-R blockade. We suggest that AT1-R blockade might act through AT2-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets. PMID:22310488

  11. PTEN overexpression attenuates angiogenic processes of endothelial cells by blockade of endothelin-1/endothelin B receptor signaling.

    PubMed

    Kuo, Hsiao-Mei; Lin, Chun-Yao; Lam, Hing-Chung; Lin, Pey-Ru; Chan, Hoi-Hung; Tseng, Jui-Cheng; Sun, Cheuk-Kwan; Hsu, Te-Fa; Wu, Chia-Ching; Yang, Chao-Yuh; Hsu, Ching-Mei; Tai, Ming-Hong

    2012-04-01

    Arteriovenous (AV) graft is frequently used as vascular access in hemodialysis patients. However, clotting or thrombosis of AV grafts often occurs and requires surgical removal. At present, the molecular pathogenesis underlying thrombosis of AV graft is not clear. The PTEN/Akt signaling has been implicated in the pathogenesis of vascular diseases. In this study, elevated PTEN expression and concomitant Akt inactivation was observed in endothelium of atherosclerotic brachial arteries from hemodialysis patients. To investigate whether PTEN upregulation affects endothelial function, adenovirus-mediated PTEN (Ad-PTEN) overexpression was performed in aorta rings and cultured endothelial cells. It was found that PTEN overexpression potently inhibited the microvessel sprouting in aorta rings and the angiogenic activities of endothelial cells including migration and tube formation. On the contrary, PTEN knockdown by RNA interference promoted the endothelial migration and reversed the Ad-PTEN-induced inhibition of endothelial migration. Expression analysis showed that PTEN overexpression attenuated the expression of endothelin-1 (ET-1) and endothelin B receptor (ETBR) in endothelial cells at transcriptional levels. However, exogenous ET-1 supply only partially reversed the PTEN-induced inhibition of migration and tube formation. This was delineated due to that PTEN overexpression also perturbed endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) release. In summary, PTEN upregulation induces endothelial dysfunction by attenuating the availability and signaling of multiple angiogenic pathways in endothelial cells, thereby may contribute to thrombosis of AV graft.

  12. Escitalopram attenuates β-amyloid-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway.

    PubMed

    Wang, Yan-Juan; Ren, Qing-Guo; Gong, Wei-Gang; Wu, Di; Tang, Xiang; Li, Xiao-Li; Wu, Fang-Fang; Bai, Feng; Xu, Lin; Zhang, Zhi-Jun

    2016-03-22

    Tau hyperphosphorylation is an important pathological feature of Alzheimer's disease (AD). To investigate whether escitalopram could inhibit amyloid-β (Aβ)-induced tau hyperphosphorylation and the underlying mechanisms, we treated the rat primary hippocampal neurons with Aβ1-42 and examined the effect of escitalopram on tau hyperphosphorylation. Results showed that escitalopram decreased Aβ1-42-induced tau hyperphosphorylation. In addition, escitalopram activated the Akt/GSK-3β pathway, and the PI3K inhibitor LY294002 blocked the attenuation of tau hyperphosphorylation induced by escitalopram. Moreover, the 5-HT1A receptor agonist 8-OH-DPAT also activated the Akt/GSK-3β pathway and decreased Aβ1-42-induced tau hyperphosphorylation. Furthermore, the 5-HT1A receptor antagonist WAY-100635 blocked the activation of Akt/GSK-3β pathway and the attenuation of tau hyperphosphorylation induced by escitalopram. Finally, escitalopram improved Aβ1-42 induced impairment of neurite outgrowth and spine density, and reversed Aβ1-42 induced reduction of synaptic proteins. Our results demonstrated that escitalopram attenuated Aβ1-42-induced tau hyperphosphorylation in primary hippocampal neurons through the 5-HT1A receptor mediated Akt/GSK-3β pathway. PMID:26950279

  13. Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model

    PubMed Central

    Jurga, Agnieszka M.; Rojewska, Ewelina; Makuch, Wioletta; Pilat, Dominika; Przewlocka, Barbara

    2016-01-01

    Accumulating evidence indicates that microglial TLR2 and TLR4 play a significant role in nociception. Experiments were conducted to evaluate the contribution of TLR2 and TLR4 and their adaptor molecules to neuropathy and their ability to amplify opioid effectiveness. Behavioral tests (von Frey's and cold plate) and biochemical (Western blot and qRT-PCR) analysis of spinal cord and DRG tissue were conducted after chronic constriction injury (CCI) to the sciatic nerve. Repeated intrathecal administration of LPS-RS (TLR2 and TLR4 antagonist) and LPS-RS Ultrapure (TLR4 antagonist) attenuated allodynia and hyperalgesia. Biochemical analysis revealed time-dependent upregulation of mRNA and/or protein levels of TLR2 and TLR4 and MyD88 and TRIF adaptor molecules, which was paralleled by an increase in IBA-1/CD40-positive cells under neuropathy. LPS-RS and LPS-RS Ultrapure similarly influenced opioid analgesia by enhancing the effectiveness of buprenorphine but not morphine. Summing up, in light of their upregulation over the course of pain, both TLR2 and TLR4 may indeed play a significant role in neuropathy, which could be linked to the observed activation of IBA-1/CD40-positive cells. Blockade of TLR2 and TLR4 produced analgesia and enhanced buprenorphine's effectiveness, which suggests that they may be a putative target for future pharmacological pain relief tools, especially for opioid rotation, when the effect of morphine is tolerated. PMID:26962463

  14. Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice.

    PubMed

    Chen, Bei-Yu; Zheng, Min-Hua; Chen, Yan; Du, Yan-Ling; Sun, Xiao-Long; Zhang, Xing; Duan, Li; Gao, Fang; Liang, Liang; Qin, Hong-Yan; Luo, Zhuo-Jing; Han, Hua

    2015-12-01

    The outcome of spinal cord injury (SCI) is determined by both neural cell-intrinsic survival pathways and tissue microenvironment-derived signals. Macrophages dominating the inflammatory responses in SCI possess both destructive and reparative potentials, according to their activation status. Notch signaling is involved in both cell survival and macrophage-mediated inflammation, but a comprehensive role of Notch signaling in SCI has been elusive. In this study, we compared the effects of general Notch blockade by a pharmaceutical γ-secretase inhibitor (GSI) and myeloid-specific Notch signal disruption by recombination signal binding protein Jκ (RBP-J) knockout on SCI. The administration of Notch signal inhibitor GSI resulted in worsened hind limb locomotion and exacerbated inflammation. However, mice lacking RBP-J, the critical transcription factor mediating signals from all four mammalian Notch receptors, in myeloid lineage displayed promoted functional recovery, attenuated glial scar formation, improved neuronal survival and axon regrowth, and mitigated inflammatory response after SCI. These benefits were accompanied by enhanced AKT activation in the lesion area after SCI. These findings demonstrate that abrogating Notch signal in myeloid cells ameliorates inflammation response post-SCI and promotes functional recovery, but general pharmaceutical Notch interception has opposite effects. Therefore, clinical intervention of Notch signaling in SCI needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition.

  15. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor.

    PubMed

    Majuta, Lisa A; Longo, Geraldine; Fealk, Michelle N; McCaffrey, Gwen; Mantyh, Patrick W

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain-related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti-nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

  16. Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

    PubMed Central

    Majuta, Lisa A.; Longo, Geraldine; Fealk, Michelle N.; McCaffrey, Gwen; Mantyh, Patrick W.

    2015-01-01

    The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain–related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti–nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains. PMID:25599311

  17. Myeloid-Specific Blockade of Notch Signaling Attenuates Choroidal Neovascularization through Compromised Macrophage Infiltration and Polarization in Mice

    PubMed Central

    Dou, Guo-Rui; Li, Na; Chang, Tian-Fang; Zhang, Ping; Gao, Xiang; Yan, Xian-Chun; Liang, Liang; Han, Hua; Wang, Yu-Sheng

    2016-01-01

    Macrophages have been recognized as an important inflammatory component in choroidal neovascularization (CNV). However, it is unclear how these cells are activated and polarized, how they affect angiogenesis and what the underlining mechanisms are during CNV. Notch signaling has been implicated in macrophage activation. Previously we have shown that inducible disruption of RBP-J, the critical transcription factor of Notch signaling, in adult mice results in enhanced CNV, but it is unclear what is the role of macrophage-specific Notch signaling in the development of CNV. In the current study, by using the myeloid specific RBP-J knockout mouse model combined with the laser-induced CNV model, we show that disruption of Notch signaling in macrophages displayed attenuated CNV growth, reduced macrophage infiltration and activation, and alleviated angiogenic response after laser induction. The inhibition of CNV occurred with reduced expression of VEGF and TNF-α in infiltrating inflammatory macrophages in myeloid specific RBP-J knockout mice. These changes might result in direct inhibition of EC lumen formation, as shown in an in vitro study. Therefore, clinical intervention of Notch signaling in CNV needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition. PMID:27339903

  18. Blockade of Interplay between IL-17A and Endoplasmic Reticulum Stress Attenuates LPS-Induced Lung Injury

    PubMed Central

    Kim, So Ri; Kim, Hee Jung; Kim, Dong Im; Lee, Kyung Bae; Park, Hae Jin; Jeong, Jae Seok; Cho, Seong Ho; Lee, Yong Chul

    2015-01-01

    IL-17 is a cytokine mainly from IL-17-producing T cells, which are one of subsets of CD4+ T cells and play a role in adaptive immune system. Recent studies have demonstrated that IL-17A can act rapidly as an innate immune responder during infection before the onset of its classic adaptive immune response. This role of IL-17A in innate immune response is implicated in lipopolysaccharide (LPS)-induced lung inflammation. Very recently, we have reported that endoplasmic reticulum (ER) stress is involved in LPS-induced lung inflammation in vivo and in vitro. This study aimed to elucidate the role of IL-17A in LPS-induced lung injury, focusing on the link with ER stress. We treated a murine model of LPS-induced lung injury with IL-17A neutralizing antibody and 4-phenylbutyrate (4-PBA), a representative ER stress inhibitor. In addition, we evaluated the effects of IL-17A on ER stress in LPS-stimulated bronchial epithelial cells. Our results showed that inhibition of IL-17A decreased LPS-induced pulmonary neutrophilia, vascular leakage, nuclear translocation of nuclear factor-κB (NF-κB), infiltration of dendritic cells, increased expression of Toll-like receptor 4 (TLR4), activation of NLRP3 inflammasome, and increased ER stress in the lung. 4-PBA or TAK-242, a TLR4 inhibitor attenuated expression of IL-17A thereby improving LPS-induced lung inflammation. Intriguingly, we observed that stimulation with LPS increased expression of IL-17A in airway epithelial cells and co-stimulation with IL-17A further increased ER stress and NF-κB activation. This study indicates that the interrelationship between IL-17A and ER stress plays an important role in LPS-induced injury showing a positive feedback in airway epithelial cells and suggests that targeting their interaction can be a potential therapeutic approach to overcome one of severe refractory pulmonary disorders. PMID:26516372

  19. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature.

    PubMed

    Almeida, M Camila; Hew-Butler, Tamara; Soriano, Renato N; Rao, Sara; Wang, Weiya; Wang, Judy; Tamayo, Nuria; Oliveira, Daniela L; Nucci, Tatiane B; Aryal, Prafulla; Garami, Andras; Bautista, Diana; Gavva, Narender R; Romanovsky, Andrej A

    2012-02-01

    We studied N-(2-aminoethyl)-N-(4-(benzyloxy)-3-methoxybenzyl)thiophene-2-carboxamide hydrochloride (M8-B), a selective and potent antagonist of the transient receptor potential melastatin-8 (TRPM8) channel. In vitro, M8-B blocked cold-induced and TRPM8-agonist-induced activation of rat, human, and murine TRPM8 channels, including those on primary sensory neurons. In vivo, M8-B decreased deep body temperature (T(b)) in Trpm8(+/+) mice and rats, but not in Trpm8(-/-) mice, thus suggesting an on-target action. Intravenous administration of M8-B was more effective in decreasing T(b) in rats than intrathecal or intracerebroventricular administration, indicating a peripheral action. M8-B attenuated cold-induced c-Fos expression in the lateral parabrachial nucleus, thus indicating a site of action within the cutaneous cooling neural pathway to thermoeffectors, presumably on sensory neurons. A low intravenous dose of M8-B did not affect T(b) at either a constantly high or a constantly low ambient temperature (T(a)), but the same dose readily decreased T(b) if rats were kept at a high T(a) during the M8-B infusion and transferred to a low T(a) immediately thereafter. These data suggest that both a successful delivery of M8-B to the skin (high cutaneous perfusion) and the activation of cutaneous TRPM8 channels (by cold) are required for the hypothermic action of M8-B. At tail-skin temperatures <23°C, the magnitude of the M8-B-induced decrease in T(b) was inversely related to skin temperature, thus suggesting that M8-B blocks thermal (cold) activation of TRPM8. M8-B affected all thermoeffectors studied (thermopreferendum, tail-skin vasoconstriction, and brown fat thermogenesis), thus suggesting that TRPM8 is a universal cold receptor in the thermoregulation system.

  20. Selective pharmacological blockade of the 5-HT7 receptor attenuates light and 8-OH-DPAT induced phase shifts of mouse circadian wheel running activity.

    PubMed

    Shelton, Jonathan; Yun, Sujin; Losee Olson, Susan; Turek, Fred; Bonaventure, Pascal; Dvorak, Curt; Lovenberg, Timothy; Dugovic, Christine

    2014-01-01

    Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg) in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT) points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6) induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg). Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15) or advance (CT22) wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals.

  1. Cannabidiol attenuates haloperidol-induced catalepsy and c-Fos protein expression in the dorsolateral striatum via 5-HT1A receptors in mice.

    PubMed

    Sonego, Andreza B; Gomes, Felipe V; Del Bel, Elaine A; Guimaraes, Francisco S

    2016-08-01

    Cannabidiol (CBD) is a major non-psychoactive compound from Cannabis sativa plant. Given that CBD reduces psychotic symptoms without inducing extrapyramidal motor side-effects in animal models and schizophrenia patients, it has been proposed to act as an atypical antipsychotic. In addition, CBD reduced catalepsy induced by drugs with distinct pharmacological mechanisms, including the typical antipsychotic haloperidol. To further investigate this latter effect, we tested whether CBD (15-60mg/kg) would attenuate the catalepsy and c-Fos protein expression in the dorsal striatum induced by haloperidol (0.6mg/kg). We also evaluated if these effects occur through the facilitation of 5-HT1A receptor-mediated neurotransmission. For this, male Swiss mice were treated with CBD and haloperidol systemically and then subjected to the catalepsy test. Independent groups of animals were also treated with the 5-HT1A receptor antagonist WAY100635 (0.1mg/kg). As expected, haloperidol induced catalepsy throughout the experiments, an effect that was prevented by systemic CBD treatment 30min before haloperidol administration. Also, CBD, administered 2.5h after haloperidol, reversed haloperidol-induced catalepsy. Haloperidol also increased c-Fos protein expression in the dorsolateral striatum, an effect attenuated by previous CBD administration. CBD effects on catalepsy and c-Fos protein expression induced by haloperidol were blocked by the 5-HT1A receptor antagonist. We also evaluated the effects of CBD (60nmol) injection into the dorsal striatum on haloperidol-induced catalepsy. Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors. PMID:27131780

  2. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis

    PubMed Central

    Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M.; Meng, Fantao; Wu, Qi; Wemmie, John A.; Fisher, Rory A.

    2014-01-01

    Targeting serotonin (5-HT) bioavailability with selective 5-HT reuptake inhibitors (SSRIs) remains the most widely used treatment for mood disorders. However, their limited efficacy, delayed onset of action, and side effects restrict their clinical utility. Endogenous regulator of G-protein signaling (RGS) proteins have been implicated as key inhibitors of 5-HT1ARs, whose activation is believed to underlie the beneficial effects of SSRIs, but the identity of the specific RGS proteins involved remains unknown. We identify RGS6 as the critical negative regulator of 5-HT1AR-dependent antidepressant actions. RGS6 is enriched in hippocampal and cortical neurons, 5-HT1AR-expressing cells implicated in mood disorders. RGS6−/− mice exhibit spontaneous anxiolytic and antidepressant behavior rapidly and completely reversibly by 5-HT1AR blockade. Effects of the SSRI fluvoxamine and 5-HT1AR agonist 8-OH-DPAT were also potentiated in RGS6+/− mice. The phenotype of RGS6−/− mice was associated with decreased CREB phosphorylation in the hippocampus and cortex, implicating enhanced Gαi-dependent adenylyl cyclase inhibition as a possible causative factor in the behavior observed in RGS6−/− animals. Our results demonstrate that by inhibiting serotonergic innervation of the cortical-limbic neuronal circuit, RGS6 exerts powerful anxiogenic and prodepressant actions. These findings indicate that RGS6 inhibition may represent a viable means to treat mood disorders or enhance the efficacy of serotonergic agents.—Stewart, A., Maity, B., Wunsch, A. M., Meng, F., Wu, Q., Wemmie, J. A., Fisher, R. A. Regulator of G-protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin-mediated activation of the 5-HT1A receptor-adenylyl cyclase axis. PMID:24421401

  3. Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

    PubMed Central

    2013-01-01

    Background Brain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation. Methods Murine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia. Results LPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation. Conclusions We conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF. PMID:23363775

  4. The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain.

    PubMed

    Deseure, Kristof; Koek, Wouter; Colpaert, Francis C; Adriaensen, Hugo

    2002-12-01

    The effects of acute intraperitoneal injections of the 5-HT(1A) receptor agonists F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-[[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl]piperidin-1-yl]-methadone] and F 13714 [3-chloro-4-fluorophenyl-(4-fluoro-4-[[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl]-piperidin-1-yl-methanone] were studied in comparison with those of baclofen and morphine on responsiveness to von Frey hair stimulation after chronic constriction injury to the rat's infraorbital nerve (IoN-CCI). Following IoN-CCI, an ipsilateral hyperresponsiveness developed that remained stable in control rats throughout the period of drug testing. F 13640, F 13714, baclofen and morphine dose-dependently decreased the hyperresponsiveness; normalization of the response occurred at doses 0.63, 0.04, 5 and 10 mg/kg, respectively. Confirming earlier data, baclofen's effects further validate IoN-CCI as a model of trigeminal neuralgia. The effects of F 13640 and F 13714 are initial evidence that 5-HT(1A) receptor agonists produce profound analgesia in the IoN-CCI model. The present data extend recent evidence that high-efficacy 5-HT(1A) receptor activation constitutes a new mechanism of central analgesia the spectrum of which may also encompass trigeminal neuropathic pain. PMID:12450569

  5. Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats

    PubMed Central

    Bruijnzeel, Adrie W.; Ford, Jenna; Rogers, Jessica A.; Scheick, Stacey; Ji, Yue; Bishnoi, Mahendra; Alexander, Jon C.

    2012-01-01

    The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA. PMID:22182462

  6. NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism.

    PubMed

    Minic, Zeljka; O'Leary, Donal S; Scislo, Tadeusz J

    2015-07-01

    Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats (n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1-8 μg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism.

  7. NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism.

    PubMed

    Minic, Zeljka; O'Leary, Donal S; Scislo, Tadeusz J

    2015-07-01

    Adenosine is a powerful central neuromodulator acting via opposing A1 (inhibitor) and A2a (activator) receptors. However, in the nucleus of the solitary tract (NTS), both adenosine receptor subtypes attenuate cardiopulmonary chemoreflex (CCR) sympathoinhibition of renal, adrenal, and lumbar sympathetic nerve activity and attenuate reflex decreases in arterial pressure and heart rate. Adenosine A1 receptors inhibit glutamatergic transmission in the CCR pathway, whereas adenosine A2a receptors most likely facilitate release of an unknown inhibitory neurotransmitter, which, in turn, inhibits the CCR. We hypothesized that adenosine A2a receptors inhibit the CCR via facilitation of GABA release in the NTS. In urethane-chloralose-anesthetized rats (n = 51), we compared regional sympathetic responses evoked by stimulation of the CCR with right atrial injections of the 5-HT3 receptor agonist phenylbiguanide (1-8 μg/kg) before and after selective stimulation of NTS adenosine A2a receptors [microinjections into the NTS of CGS-21680 (20 pmol/50 nl)] preceded by blockade of GABAA or GABAB receptors in the NTS [bicuculline (10 pmol/100 nl) or SCH-50911 (1 nmol/100 nl)]. Blockade of GABAA receptors virtually abolished adenosine A2a receptor-mediated inhibition of the CCR. GABAB receptors had much weaker but significant effects. These effects were similar for the different sympathetic outputs. We conclude that stimulation of NTS adenosine A2a receptors inhibits CCR-evoked hemodynamic and regional sympathetic reflex responses via a GABA-ergic mechanism. PMID:25910812

  8. AT1 receptor blockade in the central nucleus of the amygdala attenuates the effects of muscimol on sodium and water intake.

    PubMed

    Hu, B; Qiao, H; Sun, B; Jia, R; Fan, Y; Wang, N; Lu, B; Yan, J Q

    2015-10-29

    The blockade of the central nucleus of the amygdala (CeA) with the GABAA receptor agonist muscimol significantly reduces hypertonic NaCl and water intake by sodium-depleted rats. In the present study we investigated the effects of previous injection of losartan, an angiotensin II type-1 (AT1) receptor antagonist, into the CeA on 0.3M NaCl and water intake reduced by muscimol bilaterally injected into the same areas in rats submitted to water deprivation-partial rehydration (WD-PR) and in rats treated with the diuretic furosemide (FURO). Male Sprague-Dawley rats with stainless steel cannulas bilaterally implanted into the CeA were used. Bilateral injections of muscimol (0.2 nmol/0.5 μl, n=8 rats/group) into the CeA in WD-PR-treated rats reduced 0.3M NaCl intake and water intake, and pre-treatment of the CeA with losartan (50 μg/0.5 μl) reversed the inhibitory effect of muscimol. The negative effect of muscimol on sodium and water intake could also be blocked by pretreatment with losartan microinjected into the CeA in rats given FURO (n=8 rats/group). However, bilateral injections of losartan (50 μg/0.5 μl) alone into the CeA did not affect the NaCl or water intake. These results suggest that the deactivation of CeA facilitatory mechanisms by muscimol injection into the CeA is promoted by endogenous angiotensin II acting on AT1 receptors in the CeA, which prevents rats from ingesting large amounts of hypertonic NaCl and water.

  9. Attenuation of autonomic reflexes by A803467 may not be solely caused by blockade of NaV 1.8 channels

    PubMed Central

    Stone, Audrey J.; Kim, Joyce S.; Yamauchi, Katsuya; Ruiz-Velasco, Victor; Kaufman, Marc P.

    2013-01-01

    In decerebrated rats, we determined the dose of A803467, a NaV 1.8 antagonist, needed to attenuate the reflex pressor responses to femoral arterial injections of lactic acid (24mM; ~0.1mL) and capsaicin (0.1μg), agents which stimulate thin fiber afferents having NaV 1.8 channels. We also determined whether the dose of A803467 needed to attenuate these reflex responses affected the responses of muscle spindle afferents to tendon stretch and succinylcholine (200μg). Spindle afferents are not supplied with NaV 1.8 channels, and consequently their responses to these stimuli should not be influenced by A803467. Pressor responses to lactic acid and capsaicin were not altered by 500μg of A803467 (n=6). A803467 in a dose of 1mg, however, significantly reduced (p< 0.05; n=12) the pressor responses to lactic acid (23±5 to 7±3ΔmmHg) and capsaicin (47±5 to 31±5ΔmmHg). Surprisingly, we also found that 1 mg of A803467 reduced the responses of 10 spindle afferents to succinylcholine (34±11 to 4±3 Δ imp/s p<0.05) and stretch (83±17 to 0.4±1 Δ imp/s; p<0.05). We conclude that A803467 reduces the reflex response to lactic acid and capsaicin; however, it may be working on multiple channels, including NaV 1.8, other NaVs as well as voltage-gated calcium channels. PMID:23523647

  10. Angiotensin-(1-7) blockade attenuates captopril- or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats treated with NG-nitro-L-arginine methyl ester.

    PubMed

    Benter, Ibrahim F; Yousif, Mariam H M; Al-Saleh, Fatemah M; Raghupathy, Raj; Chappell, Mark C; Diz, Debra I

    2011-05-01

    We assessed the contribution of angiotensin-(1-7) [Ang-(1-7)] to captopril-induced cardiovascular protection in spontaneously hypertensive rats (SHRs) chronically treated with the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (SHR-l). NG-nitro-L-arginine methyl ester (80 mg/L) administration for 3 weeks increased mean arterial pressure (MAP) from 196 ± 6 to 229 ± 3 mm Hg (P < 0.05). Treatment of SHR-l with Ang-(1-7) antagonist [d-Ala7]-Ang-(1-7) (A779; 744 μg·kg(-1)·d(-1) ip) further elevated MAP to 253 ± 6 mm Hg (P < 0.05 vs SHR-l or SHR). Moreover, A779 treatment attenuated the reduction in MAP and proteinuria by either captopril (300 mg/L in drinking water) or hydralazine (1.5 mg·kg(-1)·d(-1) ip). In isolated perfused hearts, the recovery of left ventricular function from global ischemia was enhanced by captopril or hydralazine treatment and was exacerbated with A779. The Ang-(1-7) antagonist attenuated the beneficial effects of captopril and hydralazine on cardiac function. Recovery from global ischemia was also improved in isolated SHR-l hearts acutely perfused with captopril during both the perfusion and reperfusion periods. The acute administration of A779 reduced the beneficial actions of captopril to improve recovery after ischemia. We conclude that during periods of reduced nitric oxide availability, endogenous Ang-(1-7) plays a protective role in effectively buffering the increase in blood pressure and renal injury and the recovery from cardiac ischemia. Moreover, Ang-(1-7) contributes to the blood pressure lowering and tissue protective actions of captopril and hydralazine in a model of severe hypertension and end-organ damage.

  11. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial

    PubMed Central

    Jimenez, Juan J; Iribarren, Jose L; Lorente, Leonardo; Rodriguez, Jose M; Hernandez, Domingo; Nassar, Ibrahim; Perez, Rosalia; Brouard, Maitane; Milena, Antonio; Martinez, Rafael; Mora, Maria L

    2007-01-01

    Introduction Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study. Methods A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes. Results In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB. Conclusion The use of TA attenuates the development of IR and VS after CPB. Trial registration number ISRCTN05718824. PMID:17988379

  12. Blockade of D1 dopamine receptors in the medial prefrontal cortex attenuates amphetamine- and methamphetamine-induced locomotor activity in the rat.

    PubMed

    Hall, Darien A; Powers, John P; Gulley, Joshua M

    2009-12-01

    The medial prefrontal cortex (mPFC) is a component of the mesolimbic dopamine (DA) system involved in psychostimulant-induced hyperactivity and previous studies have shown that altering DA transmission or D2 receptors within the mPFC can decrease this stimulant effect. The goal of this study was to investigate a potential modulatory role for D1 receptors in the mPFC in amphetamine (AMPH)- and methamphetamine (METH)-induced hyperactivity. Locomotor activity in an open-field arena was measured in male, Sprague-Dawley rats given an intra-mPFC infusion of vehicle or the D1 receptor antagonist SCH 23390 (0.25 or 1.0 microg) prior to systemic (i.p.) injection of saline, AMPH (1 mg/kg), or METH (1 mg/kg). We found that SCH 23390 produced a dose-dependent decrease in AMPH- and METH-induced locomotion and rearing but had no significant effect on spontaneous behavior that occurred following systemic saline injections. Because SCH 23390 has been shown to have agonist-like properties at 5-HT(2C) receptors, a follow-up experiment was performed to determine if this contributed to the attenuation of METH-induced activity that we observed. Rats were given intra-mPFC infusions of both SCH 23390 (1.0 microg) and the 5-HT(2C) antagonist RS 102221 (0.25 microg) prior to METH (1 mg/kg, i.p.). The addition of the 5-HT(2C) antagonist failed to alter SCH 23390-induced decreases in METH-induced locomotion and rearing; infusion of RS 102221 alone had no significant effects on locomotion and produced a non-significant decrease in rearing. The results of these studies suggest that D1 activation in the mPFC plays a significant role in AMPH- and METH-induced hyperactivity.

  13. Combined stimulation of the glycine and polyamine sites of the NMDA receptor attenuates NMDA blockade-induced learning deficits of rats in a 14-unit T-maze.

    PubMed

    Meyer, R C; Knox, J; Purwin, D A; Spangler, E L; Ingram, D K

    1998-02-01

    The present study examined the effects of multi-site activation of the glycine and polyamine sites of the NMDA receptor on memory formation in rats learning a 14-unit T-maze task. The competitive NMDA receptor antagonist, (+/-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP, 9 mg/kg), was used to impair learning. The objectives were two-fold: (1) to investigate the effects of independent stimulation of the strychnine-insensitive glycine site or the polyamine site; (2) to investigate the effects of simultaneous activation of these two sites. Male, Fischer-344 rats were pretrained to a criterion of 13 out of 15 shock avoidances in a straight runway, and 24 h later were trained in a 14-unit T-maze that also required shock avoidance. Prior to maze training, rats received intraperitoneal (i.p.) injections of saline, saline plus CPP, CPP plus the glycine agonist, D-cycloserine (DCS, 30 or 40 mg/kg), CPP plus the polyamine agonist, spermine (SPM, 2.5 or 5 mg/kg), or CPP plus a combination of DCS (7.5 mg/kg) and SPM (0.625 mg/kg). Individual administration of either DCS or SPM attenuated the CPP-induced maze learning impairment in a dose-dependent manner. However, the combined treatment with both DCS and SPM completely reversed the learning deficit at doses five-fold less than either drug given alone. These findings provide additional evidence that the glycine and polyamine modulatory sites of the NMDA receptor are involved in memory formation. Furthermore, the potent synergistic effect resulting from combined activation of the glycine and polyamine sites would suggest a stronger interaction between these two sites than previously considered, and might provide new therapeutic approaches for enhancing glutamatergic function. PMID:9498733

  14. Endothelin-a receptor antagonism after renal angioplasty enhances renal recovery in renovascular disease.

    PubMed

    Chade, Alejandro R; Tullos, Nathan; Stewart, Nicholas J; Surles, Bret

    2015-05-01

    Percutaneous transluminal renal angioplasty/stenting (PTRAS) is frequently used to treat renal artery stenosis and renovascular disease (RVD); however, renal function is restored in less than one half of the cases. This study was designed to test a novel intervention that could refine PTRAS and enhance renal recovery in RVD. Renal function was quantified in pigs after 6 weeks of chronic RVD (induced by unilateral renal artery stenosis), established renal damage, and hypertension. Pigs with RVD then underwent PTRAS and were randomized into three groups: placebo (RVD+PTRAS), chronic endothelin-A receptor (ET-A) blockade (RVD+PTRAS+ET-A), and chronic dual ET-A/B blockade (RVD+PTRAS+ET-A/B) for 4 weeks. Renal function was again evaluated after treatments, and then, ex vivo studies were performed on the stented kidney. PTRAS resolved renal stenosis, attenuated hypertension, and improved renal function but did not resolve renal microvascular rarefaction, remodeling, or renal fibrosis. ET-A blocker therapy after PTRAS significantly improved hypertension, microvascular rarefaction, and renal injury and led to greater recovery of renal function. Conversely, combined ET-A/B blockade therapy blunted the therapeutic effects of PTRAS alone or PTRAS followed by ET-A blockade. These data suggest that ET-A receptor blockade therapy could serve as a coadjuvant intervention to enhance the outcomes of PTRAS in RVD. These results also suggest that ET-B receptors are important for renal function in RVD and may contribute to recovery after PTRAS. Using clinically available compounds and techniques, our results could contribute to both refinement and design of new therapeutic strategies in chronic RVD.

  15. Memantine treatment reduces the expression of the K(+)/Cl(-) cotransporter KCC2 in the hippocampus and cerebral cortex, and attenuates behavioural responses mediated by GABA(A) receptor activation in mice.

    PubMed

    Molinaro, Gemma; Battaglia, Giuseppe; Riozzi, Barbara; Di Menna, Luisa; Rampello, Liborio; Bruno, Valeria; Nicoletti, Ferdinando

    2009-04-10

    A 7-day treatment with memantine (25 mg/kg, i.p.), a drug that is currently prescribed for the treatment of Alzheimer's disease, increased the levels of brain-derived neurotrophic factor (BDNF) and reduced the expression of the neuron-specific K(+)/Cl(-) co-transporter, KCC2, in the hippocampus and cerebral cortex of mice. Knowing that KCC2 maintains low intracellular Cl(-) concentrations, which drive Cl(-) influx in response to GABA(A) receptor activation, we monitored the behavioural response to the GABA(A) receptor enhancer, diazepam, in mice pre-treated for 7 days with saline or 25 mg/kg of memantine. Memantine treatment substantially attenuated motor impairment induced by an acute challenge with diazepam (6 mg/kg, i.p.), as assessed by the rotarod test and the horizontal wire test. We suggest that a prolonged treatment with memantine induces changes in the activity of GABA(A) receptors that might contribute to the therapeutic and/or toxic effects of the drug.

  16. Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats

    PubMed Central

    Muere, Clarissa; Neumueller, Suzanne; Olesiak, Samantha; Miller, Justin; Langer, Thomas; Hodges, Matthew R.; Pan, Lawrence

    2015-01-01

    Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing (P ≥ 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P (P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists. PMID:26023224

  17. Postsynaptic blockade of inhibitory postsynaptic currents by plasmin in CA1 pyramidal cells of rat hippocampus.

    PubMed

    Mizutani, A; Tanaka, T; Saito, H; Matsuki, N

    1997-06-27

    We have shown previously that plasmin facilitated the generation of long-term potentiation (LTP) in CA1 and dentate region of rat hippocampus. In the present study, we investigated the effects of plasmin on postsynaptic currents in CA1 pyramidal neurons of rat hippocampal slices. Plasmin (100 nM) had no effect on NMDA nor on non-NMDA receptor-mediated excitatory postsynaptic currents. However, plasmin significantly decreased GABA(A) receptor-mediated inhibitory postsynaptic currents. This effect of plasmin disappeared when intracellular Ca2+ was strongly chelated with BAPTA. Furthermore, plasmin attenuated the GABA-induced currents in CA1 pyramidal cells. These results suggest that the STP-enhancing effect of plasmin is due to a blockade of postsynaptic GABA(A) responses and that an increase in intracellular Ca2+ by plasmin may be involved in its mechanism.

  18. Intrathecal administration of a gap junction decoupler, an inhibitor of Na(+)-K(+)-2Cl(-) cotransporter 1, or a GABA(A) receptor agonist attenuates mechanical pain hypersensitivity induced by REM sleep deprivation in the rat.

    PubMed

    Wei, Hong; Hao, Bin; Huang, Jin-Lu; Ma, Ai-Niu; Li, Xin-Yan; Wang, Yong-Xiang; Pertovaara, Antti

    2010-12-01

    We studied the hypothesis that some of the spinal mechanisms that are involved in neuropathic hypersensitivity play a role in hypersensitivity induced by REM sleep deprivation (REMSD). Rats with a chronic intrathecal (i.t.) catheter had REMSD of 48h duration that induced hypersensitivity to mechanical stimulation. After REMSD, the animals were treated i.t. with carbenoxolone (a gap junction decoupler), bumetanide (a blocker of Na(+)-K(+)-2Cl(-) cotransporter 1 or NKCC1), muscimol (a GABA(A) receptor agonist), or pretreated intraperitoneally with minocycline (an inhibitor of microglia activation). Previously, all these treatments attenuated neuropathic hypersensitivity. Following REMSD, carbenoxolone, bumetanide and muscimol had a strong antihypersensitivity effect, whereas pretreatment with minocycline failed to prevent development of hypersensitivity. The results suggest that among spinal pain facilitatory mechanisms that are common to REMSD and neuropathy are NKCC1 blocker- and gap junction decoupler-reversible mechanisms. Moreover, there is a net pain inhibitory effect by spinal administration of an exogenous GABA(A) receptor agonist following REMSD as shown earlier in neuropathy. In contrast, activation of spinal microglia may not be as important for the development of hypersensitivity induced by REMSD as following nerve injury.

  19. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI.

    PubMed

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D; Hill-Smith, Tiffany E; Berg, Alexandra R; Lucki, Irwin; Mikkelsen, Jens D; Coyle, Joseph T

    2014-02-01

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly correlates to 5-HT2AR activation and is absent in 5-HT2AR knockout mice. The precise mechanism of this response remains unclear, but both an intrinsic cortico-cortical pathway and a thalamo-cortical pathway involving glutamate release have been proposed. Here, we used a genetic model of NMDAR hypofunction, the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos mRNA. These altered functional responses in SRKO mice were not associated with changes in cortical or hippocampal 5-HT levels or in 5-HT2AR and metabotropic glutamate-2 receptor (mGluR2) mRNA and protein expression. Together, these findings suggest that D-serine-dependent NMDAR activity is involved in mediating the cellular and behavioral effects of 5-HT2AR activation.

  20. 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.

    PubMed

    Voronova, Irina P; Khramova, Galina M; Kulikova, Elizabeth A; Petrovskii, Dmitrii V; Bazovkina, Daria V; Kulikov, Alexander V

    2016-01-01

    G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected. PMID:26621247

  1. 5-HT2A receptors control body temperature in mice during LPS-induced inflammation via regulation of NO production.

    PubMed

    Voronova, Irina P; Khramova, Galina M; Kulikova, Elizabeth A; Petrovskii, Dmitrii V; Bazovkina, Daria V; Kulikov, Alexander V

    2016-01-01

    G protein-coupled 5-HT2A receptors are involved in the regulation of numerous normal and pathological physiological functions. At the same time, its involvement in the regulation of body temperature (Tb) in normal conditions is obscure. Here we study the effect of the 5-HT2A receptor activation or blockade on Tb in sick animals. The experiments were carried out on adult C57BL/6 mouse males. Systemic inflammation and sickness were produced by lipopolysaccharide (LPS, 0.1mg/kg, ip), while the 5-HT2A receptor was stimulated or blocked through the administration of the receptor agonist DOI or antagonist ketanserin (1mg/kg), respectively. LPS, DOI or ketanserin alone produced no effect on Tb. However, administration of LPS together with a peripheral or central ketanserin injection reduced Tb (32.2°C). Ketanserin reversed the LPS-induced expression of inducible NO synthase in the brain. Consequently, an involvement of NO in the mechanism of the hypothermic effect of ketanserin in sick mice was hypothesized. Administration of LPS together with NO synthase inhibitor, l-nitro-arginine methyl ester (60mg/kg, ip) resulted in deep (28.5°C) and prolonged (8h) hypothermia, while administration of l-nitro-arginine methyl ester alone produced no effect on Tb. Thus, 5-HT2A receptors play a key role in Tb control in sick mice. Blockade of this GPCR produces hypothermia in mice with systemic inflammation via attenuation of LPS-induced NO production. These results indicate an unexpected role of 5-HT2A receptors in inflammation and NO production and have a considerable biological impact on understanding the mechanism of animal adaptation to pathogens and parasites. Moreover, adverse side effects of 5-HT2A receptor antagonists in patients with inflammation may be expected.

  2. Ultrasound for neuraxial blockade.

    PubMed

    Srinivasan, Karthikeyan Kallidaikurichi; Lee, Peter John; Iohom, Gabriella

    2014-12-01

    Neuraxial blockade is still largely performed as a blind procedure. Despite of developments in the type of needles used and drugs administered, the process of locating the epidural or intra-thecal space is still limited to identification of landmarks by palpation and reliance on tactile feedback of the operator. Ultrasound has provided the long needed "eye" to the procedure and has already shown promise of improving the safety and efficacy or neuraxial blocks. This review focuses on understanding the sonoanatomy of the neuraxial space, performing a systematic pre-procedural ultrasound scan, and reviewing the available evidence. PMID:25463890

  3. Deletion of adenosine A1 or A2A receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson’s disease

    PubMed Central

    Xiao, Danqing; Cassin, Jared J.; Healy, Brian; Burdett, Thomas C.; Chen, Jiang-Fan; Fredholm, Bertil B.; Schwarzschild, Michael A.

    2010-01-01

    Adenosine A2A receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson’s disease (PD). Clinical trials of A2A antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A1 receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A1 and/or A2A receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A1, A2A and double A1-A2A knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A1 and A2A receptors) or saline were treated daily for 18–21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A1 and A2A KOs, but not in A1-A2A KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A1 or A2A receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear. PMID:20828543

  4. M100907 attenuates elevated grooming behavior in the BTBR mouse.

    PubMed

    Amodeo, Dionisio A; Rivera, Elaine; Dunn, Jeffrey T; Ragozzino, Michael E

    2016-10-15

    Individuals with autism spectrum disorder (ASD) exhibit social-communication deficits along with restricted interests and repetitive behaviors (RRBs). To date, there is a lack of effective treatments to alleviate RRBs. A recent study found that treatment with the 5HT2A receptor antagonist M100907 attenuates a reversal learning deficit in the BTBR mouse model of autism. The BTBR mouse also exhibits elevated grooming behavior which may model stereotyped motor behaviors also observed in ASD. The present study examined whether 5HT2A receptor blockade with M100907 at either 0.01 or 0.1mg/kg can reduce repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR and C57BL6/J (B6) mice. M100907 at 0.1mg/kg, but not 0.01mg/kg, significantly attenuated repetitive grooming in BTBR mice compared to that of vehicle-treated BTBR mice. M100907 at either dose did not affect grooming behavior in B6 mice. To determine whether 0.1mg/kg M100907 had a more general effect on activity in BTBR mice, a second experiment determined whether M100907 at 0.1mg/kg affected locomotor activity in BTBR mice. M100907 treatment in BTBR and B6 mice did not alter locomotor activity compared to that of vehicle-treated BTBR and B6 mice. The present findings taken together with past results suggest that treatment with a 5HT2A receptor antagonist may be effective in ameliorating RRBs in ASD.

  5. Ionic Coulomb Blockade in Nanopores

    PubMed Central

    Krems, Matt; Di Ventra, Massimiliano

    2014-01-01

    Understanding the dynamics of ions in nanopores is essential for applications ranging from single-molecule detection to DNA sequencing. We show both analytically and by means of molecular dynamics simulations that under specific conditions ion-ion interactions in nanopores lead to the phenomenon of ionic Coulomb blockade, namely the build-up of ions inside a nanopore with specific capacitance impeding the flow of additional ions due to Coulomb repulsion. This is the counterpart of electronic Coulomb blockade observed in mesoscopic systems. We discuss the analogies and differences with the electronic case as well as experimental situations in which this phenomenon could be detected. PMID:23307655

  6. EFFECTOR CELL BLOCKADE

    PubMed Central

    Schrader, John W.; Nossal, G. J. V.

    1974-01-01

    of PFC. Consistent with this suggestion was the observation that the degree of inhibition of plaque formation could be increased by decreasing the sensitivity of the assay so that only AFC secreting at high rates were detected. A micromanipulation study, where single PFC were subjected to inhibition, and were then tested for the rate at which they could cause hemolysis, showed a 68% inhibition of mean secretory rate. Micromanipulation studies were performed to test the amount of cell surface-associated Ig on control and preinhibited PFC. For this, single PFC were held with [125I]antiglobulin and quantitative radioautography was performed. No significant difference emerged, suggesting that retention of secreted Ig on cell-attached antigen was not the cause of inhibition. The results are discussed in the framework of tolerance models and blocking effects at the T-cell level by antigen-antibody complexes. The name effector cell blockade is suggested in the belief that the phenomenon may be a general one applying to both T and B cells. PMID:4133616

  7. 5-HT2A receptor activation is necessary for CO2-induced arousal

    PubMed Central

    Smith, Haleigh R.; MacAskill, Amanda; Richerson, George B.

    2015-01-01

    Hypercapnia-induced arousal from sleep is an important protective mechanism pertinent to a number of diseases. Most notably among these are the sudden infant death syndrome, obstructive sleep apnea and sudden unexpected death in epilepsy. Serotonin (5-HT) plays a significant role in hypercapnia-induced arousal. The mechanism of 5-HT's role in this protective response is unknown. Here we sought to identify the specific 5-HT receptor subtype(s) involved in this response. Wild-type mice were pretreated with antagonists against 5-HT receptor subtypes, as well as antagonists against adrenergic, cholinergic, histaminergic, dopaminergic, and orexinergic receptors before challenge with inspired CO2 or hypoxia. Antagonists of 5-HT2A receptors dose-dependently blocked CO2-induced arousal. The 5-HT2C receptor antagonist, RS-102221, and the 5-HT1A receptor agonist, 8-OH-DPAT, attenuated but did not completely block CO2-induced arousal. Blockade of non-5-HT receptors did not affect CO2-induced arousal. None of these drugs had any effect on hypoxia-induced arousal. 5-HT2 receptor agonists were given to mice in which 5-HT neurons had been genetically eliminated during embryonic life (Lmx1bf/f/p) and which are known to lack CO2-induced arousal. Application of agonists to 5-HT2A, but not 5-HT2C, receptors, dose-dependently restored CO2-induced arousal in these mice. These data identify the 5-HT2A receptor as an important mediator of CO2-induced arousal and suggest that, while 5-HT neurons can be independently activated to drive CO2-induced arousal, in the absence of 5-HT neurons and endogenous 5-HT, 5-HT receptor activation can act in a permissive fashion to facilitate CO2-induced arousal via another as yet unidentified chemosensor system. PMID:25925320

  8. Thyroid storm during beta blockade.

    PubMed

    Strube, P J

    1984-04-01

    A thyrotoxic patient who had received beta-adrenoceptor blockers pre-operatively suffered an episode of severe heart failure immediately following thyroidectomy and required artificial ventilation of the lungs for six hours. The possible causes are discussed and the likelihood of thyroid storm unmitigated by beta adrenergic blockade suggested.

  9. Controllable attenuators

    NASA Astrophysics Data System (ADS)

    Krylov, G. M.; Khoniak, E. I.; Tynynyka, A. N.; Iliushenko, V. N.; Sikolenko, S. F.

    Methods for the synthesis of controllable attenuators and their implementations are examined. In particular, attention is given to the general properties of controllable attenuators, control elements, types of controllable attenuators and methods of their analysis, and synthesis of the control characteristic of attenuators. The discussion also covers the efficiency of attenuator control, the use of transmission line segments in wide-band controllable attenuators, and attenuators with a discretely controlled transmission coefficient.

  10. THE SEROTONIN (5-HT) 5-HT2A RECEPTOR: ASSOCIATION WITH INHERENT AND COCAINE-EVOKED BEHAVIORAL DISINHIBITION IN RATS

    PubMed Central

    Anastasio, Noelle C.; Stoffel, Erin C.; Fox, Robert G.; Bubar, Marcy J.; Rice, Kenner C.; Moeller, F. Gerard; Cunningham, Kathryn A.

    2011-01-01

    Alterations in the balance of functional activity within the serotonin (5-HT) system are hypothesized to underlie impulse control. Cocaine-dependent subjects consistently demonstrate greater impulsivity relative to non-drug using control subjects. Preclinical studies suggest that the 5-HT2A receptor (5-HT2AR) contributes to the regulation of impulsive behavior and also mediates some of the behavioral effects of cocaine. We hypothesized that the selective 5-HT2AR antagonist M100907 would reduce inherent levels of impulsivity and attenuate impulsive responding induced by cocaine in two animal models of impulsivity, the differential reinforcement of low rate (DRL) task and the one-choice serial reaction time (1-CSRT) task. M100907 reduced rates of responding in the DRL task and premature responding in the 1-CSRT task. Conversely, cocaine disrupted rates of responding in the DRL task and increased premature responding in the 1-CSRT task. M100907 attenuated cocaine-induced increases in specific markers of behavioral disinhibition in the DRL and 1-CSRT tasks. These results suggest that the 5-HT2AR regulates inherent impulsivity, and that blockade of the 5-HT2AR alleviates specific aspects of elevated levels of impulsivity induced by cocaine exposure. These data point to the 5-HT2AR as an important regulatory substrate in impulse control. PMID:21499079

  11. Brain temperature responses to salient stimuli persist during dopamine receptor blockade despite a blockade of locomotor responses.

    PubMed

    Kiyatkin, Eugene A

    2008-12-01

    We examined how an acute dopamine (DA) receptor blockade affects locomotor and brain (nucleus accumbens or NAcc), muscle and skin temperature responses to three arousing stimuli (procedure of sc injection, tail-pinch and social interaction with another male rat) and intravenous cocaine (1 mg/kg). DA receptor blockade was induced by mixture of D1- (SCH23390) and D-2 selective (eticlopride) DA antagonists at 0.2 mg/kg doses. Each arousing stimulus and cocaine caused locomotor activation, prolonged increase in NAcc and muscle temperature (0.6-1.0 degrees C for 20-50 min) and transient skin hypothermia (-0.6 degrees C for 1-3 min) in drug-naive conditions. DA receptor blockade strongly decreased basal locomotor activity, but moderately increased brain, muscle and skin temperatures. Therefore, selective interruption of DA transmission does not inhibit the brain, making it more metabolically active and warmer despite skin vasodilatation and the enhanced heat loss to the body and the external environment. DA antagonists strongly decreased locomotor responses to all stimuli and cocaine, had no effects on acute skin vasoconstriction, but differentially affected stimuli- and drug-induced changes in NAcc and muscle temperatures. While brain and muscle temperatures induced by cocaine were fully blocked and both temperatures slightly decreased, temperature increases induced by tail-pinch and social interaction, despite a significant attenuation, persisted during DA receptor blockade. These data are discussed to define the role of the DA system in regulating the central activation processes and behavioral responsiveness to natural arousing and drug stimuli. PMID:18727935

  12. Chronic blockade of endothelin A and B receptors using macitentan in experimental renovascular disease

    PubMed Central

    Tullos, Nathan A.; Stewart, Nicholas J.; Davidovich, Ryan; Chade, Alejandro R.

    2015-01-01

    Background Emerging research has identified the endothelin (ET)-1 pathway as a potential target for novel renoprotective therapies. We recently showed that selective ET-A receptor antagonism in chronic renovascular disease (RVD) improves renal function and reduces renal injury. Although ET-A and -B have opposing roles, in some clinical situations they may induce similar effects. Thus, we hypothesized that simultaneous blockade of the ET-A and -B receptors would protect the kidney during RVD. Methods Unilateral RVD was induced in pigs. After 6 weeks, single-kidney function was quantified in vivo using multi-detector computer tomography. Pigs were subsequently divided into untreated (RVD, n = 7) or daily-treated with the dual ET-A/B receptor antagonist macitentan (RVD + macitentan, n = 6) for 4 weeks. At 10 weeks, in vivo studies were repeated, then pigs were euthanized and ex vivo studies performed in the stenotic kidney to quantify inflammation, fibrosis, microvascular density and remodeling. Results Four weeks of macitentan therapy modestly improved renal blood flow (29%, P = 0.06 versus pre-treatment) and showed protective effects on the renal parenchyma by attenuating inflammation and glomerulosclerosis, reducing apoptosis and tubular casts and improving albuminuria and cortical microvessel density. No overt adverse effects were observed. Conclusion Possibly by inducing a pro-survival renal microenvironment, macitentan increased renal microvascular density, promoted cell survival and decreased injury, which in turn improved stenotic kidney hemodynamics in our model. Our results further support the safety of using macitentan in patients with concomitant chronic renal disease and supported the feasibility of a new strategy that may preserve the stenotic kidney in RVD. PMID:25438341

  13. Plasmon blockade in nanostructured graphene.

    PubMed

    Manjavacas, Alejandro; Nordlander, Peter; García de Abajo, F Javier

    2012-02-28

    Among the many extraordinary properties of graphene, its optical response allows one to easily tune its interaction with nearby molecules via electrostatic doping. The large confinement displayed by plasmons in graphene nanodisks makes it possible to reach the strong-coupling regime with a nearby quantum emitter, such as a quantum dot or a molecule. In this limit, the quantum emitter can introduce a significant plasmon-plasmon interaction, which gives rise to a plasmon blockade effect. This produces, in turn, strongly nonlinear absorption cross sections and modified statistics of the bosonic plasmon mode. We characterize these phenomena by studying the equal-time second-order correlation function g((2))(0), which plunges below a value of 1, thus revealing the existence of nonclassical plasmon states. The plasmon-emitter coupling, and therefore the plasmon blockade, can be efficiently controlled by tuning the doping level of the graphene nanodisks. The proposed system emerges as a new promising platform to realize quantum plasmonic devices capable of commuting optical signals at the single-photon/plasmon level.

  14. Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity.

    PubMed

    Bornia, Elaine Cs; Correia-de-Sá, Paulo; Alves-Do-Prado, Wilson

    2011-03-01

    1. Pancuronium, cisatracurium and vecuronium are antinicotinic agents that, in contrast with d-tubocurarine and hexamethonium, exhibit anticholinesterase activity. Pancuronium-, cisatracurium- and vecuronium-induced fade results from blockade of facilitatory nicotinic receptors on motor nerves, but fade produced by such agents also depends on the presynaptic activation of inhibitory muscarinic M2 receptors by acetylcholine released from motor nerve terminals and activation of inhibitory adenosine A1 receptors by adenosine released from motor nerves and muscles. The participation of presynaptic facilitatory A2A receptors in fade caused by pancuronium, cisatracurium and vecuronium has not yet been investigated. In the present study, we determined the effects of ZM241385, an antagonist of presynaptic facilitatory A2A receptors, on fade produced by these neuromuscular relaxants in the rat phrenic nerve-diaphragm (PND) preparation. 2. The muscles were stimulated indirectly at 75±3Hz to induce a sustained tetanizing muscular contraction. The lowest concentration at which each antinicotinic agent produced fade without modifying initial tetanic tension (presynaptic action) was determined. 3. d-Tubocurarine-induced fade occurred only at 55 nmol/L, a concentration that also reduced maximal tetanic tension (post-synaptic action). At 10 nmol/L, ZM 241385 alone did not produce fade, but it did attenuate pancuronium (0.32 μmol/L)-, cisatracurium (0.32 μmol/L)- and vecuronium (0.36 μmol/L)-induced fade. 4. The fade induced by the 'pure' antinicotinic agents d-tubocurarine (55 nmol/L) and hexamethonium (413 μmol/L) was not altered by 10 nmol/L ZM 241385, indicating that presynaptic adenosine A2A receptors play a significant role in the fade produced by antinicotinic agents when such agents have anticholinesterase activity.

  15. Astrocytic adenosine A2A receptors control the amyloid-β peptide-induced decrease of glutamate uptake.

    PubMed

    Matos, Marco; Augusto, Elisabete; Machado, Nuno J; dos Santos-Rodrigues, Alexandre; Cunha, Rodrigo A; Agostinho, Paula

    2012-01-01

    Alzheimer's disease (AD) is characterized by a progressive cognitive impairment tightly correlated with the accumulation of amyloid-β (Aβ) peptides (mainly Aβ(1-42)). There is a precocious disruption of glutamatergic synapses in AD, in line with an ability of Aβ to decrease astrocytic glutamate uptake. Accumulating evidence indicates that caffeine prevents the burden of AD, likely through the antagonism of A(2A) receptors (A(2A)R) which attenuates Aβ-induced memory impairment and synaptotoxicity. Since A(2A)R also modulate astrocytic glutamate uptake, we now tested if A(2A)R blockade could prevent the decrease of astrocytic glutamate uptake caused by Aβ. In cultured astrocytes, Aβ(1-42). (1 μM for 24 hours) triggered an astrogliosis typified by an increased density of GFAP, which was mimicked by the A(2A)R agonist, CGS 26180 (30 nM), and prevented by the A(2A)R antagonist, SCH 58261 (100 nM). Aβ1-42 also decreased D-aspartate uptake by 28 ± 4%, an effect abrogated upon genetic inactivation or pharmacological blockade of A(2A)R. In accordance with the long term control of glutamate transporter expression by A(2A)R, Aβ(1-42). enhanced the expression and density of astrocytic A(2A)R and decreased GLAST and GLT-I expression in astrocytes from wild type, but not from A(2A)R knockout mice. This impact of Aβ(1-42). on glutamate transporters and uptake, dependent on A(2A)R function, was also confirmed in an ex vivo astrocyte preparation (gliosomes) from rats intracerebroventricularly (icv) injected with Aβ(1-42). . These results provide the first demonstration for a direct key role of astrocytic A(2A)R in the ability of Aβ-induced impairment of glutamate uptake, which may underlie glutamatergic synaptic dysfunction and excitotoxicity in AD.

  16. Pro-neurogenesis and anti-dementia properties of tetradecyl 2,3-dihydroxybenzoate through TrkA receptor-mediated signalling pathways.

    PubMed

    Zhou, Libin; Lu, Zihong; Li, Lin; Chen, Lei; Qi, Jianhua; Chen, Ling

    2014-11-01

    Tetradecyl 2,3-dihydroxybenzoate, termed ABG001, has been reported to enhance neurite outgrowth of PC12 cells. Herein, we report that oral administration of ABG001 for five days to adult male mice could dose-dependently enhance survival and neurite growth of newborn cells in hippocampal dentate gyrus (DG) without changes in cell proliferation and differentiation of progenitor cells. The ABG001 administration (0.5 mg/kg) enhanced the phosphorylation of tyrosine kinase A (TrkA) receptor, which induced increases in the levels of ERK, Akt and mTOR phosphorylation in hippocampus. The pro-neurogenesis of ABG001 was blocked by the TrkA receptor inhibitor K252a. By contrast, the ERK inhibitor U0126 attenuated only the ABG001-increased number of newborn cells, while the PI3K inhibitor LY294002 prevented mainly the ABG001-enhanced neurite growth. In comparison with control mice, the mice treated with ABG001 showed a more preferential spatial cognitive function as assessed by Morris water maze and Y maze tests, which was sensitive to the blockade of TrkA receptor. In addition, a single injection (i.c.v.) of 'aggregated' Aβ 25-35 in adult male mice (Aβ 25-35-mice) impaired spatial memory, survival and neurite growth of newborn cells in the DG with reduced phosphorylation of Akt and mTOR. The treatment of Aβ 25-35-mice with ABG001 could protect the survival and neurite growth of newborn cells through increasing TrkA receptor-induced phosphorylation of Akt and mTOR, which was accompanied by the improvement of spatial cognitive performance.

  17. Valley blockade quantum switching in Silicon nanostructures.

    PubMed

    Prati, Enrico

    2011-10-01

    In analogy to the Coulomb and the Pauli spin blockade, based on the electrostatic repulsion and the Pauli exclusion principle respectively, the concept of valley blockade in Silicon nanostructures is explored. The valley parity operator is defined. Valley blockade is determined by the parity conservation of valley composition eigenvectors in quantum transport. A Silicon quantum changeover switch based on a triple of donor quantum dots capable to separate electrons having opposite valley parity by virtue of the valley parity conservation is proposed. The quantum changeover switch represents a novel kind of hybrid quantum based classical logic device.

  18. Role of alpha1-blockade in congenital long QT syndrome: investigation by exercise stress test.

    PubMed

    Furushima, H; Chinushi, M; Washizuka, T; Aizawa, Y

    2001-07-01

    before exercise and in the early recovery phase after exercise (131+/-36 to 105+/-37ms (p<0.05), and 132+/-29 to 102+/-31 ms (p<0.01), respectively). The slopes of the QT interval-heart rate relation by linear regression became significantly steeper from -2.23+/-0.38 to -2.93+/-0.76 (p<0.01) with the addition of alpha1-blockade. The findings suggest that the addition of alpha1-blockade attenuated the exercise-induced prolongation of the QT interval and that the rate adaptation of the QT interval to heart rate during exercise was improved. This indicates that additional treatment with alpha1-blockade may be beneficial to prevent cardiac events in LQTS patients in whom ventricular arrhythmia is resistant to beta-blockade.

  19. Sugammadex: A Review of Neuromuscular Blockade Reversal.

    PubMed

    Keating, Gillian M

    2016-07-01

    Sugammadex (Bridion(®)) is a modified γ-cyclodextrin that reverses the effect of the steroidal nondepolarizing neuromuscular blocking agents rocuronium and vecuronium. Intravenous sugammadex resulted in rapid, predictable recovery from moderate and deep neuromuscular blockade in patients undergoing surgery who received rocuronium or vecuronium. Recovery from moderate neuromuscular blockade was significantly faster with sugammadex 2 mg/kg than with neostigmine, and recovery from deep neuromuscular blockade was significantly faster with sugammadex 4 mg/kg than with neostigmine or spontaneous recovery. In addition, recovery from neuromuscular blockade was significantly faster when sugammadex 16 mg/kg was administered 3 min after rocuronium than when patients spontaneously recovered from succinylcholine. Sugammadex also demonstrated efficacy in various special patient populations, including patients with pulmonary disease, cardiac disease, hepatic dysfunction or myasthenia gravis and morbidly obese patients. Intravenous sugammadex was generally well tolerated. In conclusion, sugammadex is an important option for the rapid reversal of rocuronium- or vecuronium-induced neuromuscular blockade. PMID:27324403

  20. Adenosine A2A receptor antagonists: blockade of adenosinergic effects and T regulatory cells

    PubMed Central

    Sitkovsky, M; Lukashev, D; Deaglio, S; Dwyer, K; Robson, S C; Ohta, A

    2008-01-01

    The intensity and duration of host responses are determined by protective mechanisms that control tissue injury by dampening down inflammation. Adenosine generation and consequent effects, mediated via A2A adenosine receptors (A2AR) on effector cells, play a critical role in the pathophysiological modulation of these responses in vivo. Adenosine is both released by hypoxic cells/tissues and is also generated from extracellular nucleotides by ecto-enzymes e.g. CD39 (ENTPD1) and CD73 that are expressed by the vasculature and immune cells, in particular by T regulatory cell. In general, these adenosinergic mechanisms minimize the extent of collateral damage to host tissues during the course of inflammatory reactions. However, induction of suppressive pathways might also cause escape of pathogens and permit dissemination. In addition, adenosinergic responses may inhibit immune responses while enhancing vascular angiogenic responses to malignant cells that promote tumor growth. Novel drugs that block A2AR-adenosinergic effects and/or adenosine generation have the potential to boost pathogen destruction and to selectively destroy malignant tissues. In the latter instance, future treatment modalities might include novel ‘anti-adenosinergic' approaches that augment immune clearance of malignant cells and block permissive angiogenesis. This review addresses several possible pharmacological modalities to block adenosinergic pathways and speculates on their future application together with impacts on human disease. PMID:18311159

  1. Inhibition of SNL-induced upregulation of CGRP and NPY in the spinal cord and dorsal root ganglia by the 5-HT(2A) receptor antagonist ketanserin in rats.

    PubMed

    Wang, Dongmei; Chen, Tingjun; Gao, Yun; Quirion, Rémi; Hong, Yanguo

    2012-05-01

    Our previous study has demonstrated that topical and systemic administration of the 5-HT(2A) receptor antagonist ketanserin attenuates neuropathic pain. To explore the mechanisms involved, we examined whether ketanserin reversed the plasticity changes associated with calcitonin gene-related peptides (CGRP) and neuropeptide Y (NPY) which may reflect distinct mechanisms: involvement and compensatory protection. Behavioral responses to thermal and tactile stimuli after spinal nerve ligation (SNL) at L5 demonstrated neuropathic pain and its attenuation in the vehicle- and ketanserin-treated groups, respectively. SNL surgery induced an increase in CGRP and NPY immunoreactivity (IR) in laminae I-II of the spinal cord. L5 SNL produced an expression of NPY-IR in large, medium and small diameter neurons in dorsal root ganglion (DRG) only at L5, but not adjacent L4 and L6. Daily injection of ketanserin (0.3 mg/kg, s.c.) for two weeks suppressed the increase in CGRP-IR and NPY-IR in the spinal cord or DRG. The present study demonstrated that: (1) the expression of CGRP was enhanced in the spinal dorsal horn and NPY was expressed in the DRG containing injured neurons, but not in the adjacent DRG containing intact neurons, following L5 SNL; (2) the maladaptive changes in CGRP and NPY expression in the spinal cord and DRG mediated the bioactivity of 5-HT/5-HT(2A) receptors in neuropathic pain and (3) the blockade of 5-HT(2A) receptors by ketanserin reversed the evoked upregulation of both CGRP and NPY in the spinal cord and DRG contributing to the inhibition of neuropathic pain.

  2. Observation of ionic Coulomb blockade in nanopores

    NASA Astrophysics Data System (ADS)

    Feng, Jiandong; Liu, Ke; Graf, Michael; Dumcenco, Dumitru; Kis, Andras; di Ventra, Massimiliano; Radenovic, Aleksandra

    2016-08-01

    Emergent behaviour from electron-transport properties is routinely observed in systems with dimensions approaching the nanoscale. However, analogous mesoscopic behaviour resulting from ionic transport has so far not been observed, most probably because of bottlenecks in the controlled fabrication of subnanometre nanopores for use in nanofluidics. Here, we report measurements of ionic transport through a single subnanometre pore junction, and the observation of ionic Coulomb blockade: the ionic counterpart of the electronic Coulomb blockade observed for quantum dots. Our findings demonstrate that nanoscopic, atomically thin pores allow for the exploration of phenomena in ionic transport, and suggest that nanopores may also further our understanding of transport through biological ion channels.

  3. Atomic Fock state preparation using Rydberg blockade.

    PubMed

    Ebert, Matthew; Gill, Alexander; Gibbons, Michael; Zhang, Xianli; Saffman, Mark; Walker, Thad G

    2014-01-31

    We use coherent excitation of 3-16 atom ensembles to demonstrate collective Rabi flopping mediated by Rydberg blockade. Using calibrated atom number measurements, we quantitatively confirm the expected √N Rabi frequency enhancement to within 4%. The resulting atom number distributions are consistent with an essentially perfect blockade. We then use collective Rabi π pulses to produce N=1, 2 atom number Fock states with fidelities of 62% and 48%, respectively. The N=2 Fock state shows the collective Rabi frequency enhancement without corruption from atom number fluctuations.

  4. Depressed GABA and glutamate synaptic signaling by 5-HT1A receptors in the nucleus tractus solitarii and their role in cardiorespiratory function

    PubMed Central

    Ostrowski, Tim D.; Ostrowski, Daniela; Hasser, Eileen M.

    2014-01-01

    Serotonin (5-HT), and its 5-HT1A receptor (5-HT1AR) subtype, is a powerful modulator of the cardiorespiratory system and its sensory reflexes. The nucleus tractus solitarii (nTS) serves as the first central station for visceral afferent integration and is critical for cardiorespiratory reflex responses. However, the physiological and synaptic role of 5-HT1ARs in the nTS is relatively unknown. In the present study, we examined the distribution and modulation of 5-HT1ARs on cardiorespiratory and synaptic parameters in the nTS. 5-HT1ARs were widely distributed to cell bodies within the nTS but not synaptic terminals. In anesthetized rats, activation of 5-HT1ARs by microinjection of the 5-HT1AR agonist 8-OH-DPAT into the caudal nTS decreased minute phrenic neural activity via a reduction in phrenic amplitude. In brain stem slices, 8-OH-DPAT decreased the amplitude of glutamatergic tractus solitarii-evoked excitatory postsynaptic currents, and reduced overall spontaneous excitatory nTS network activity. These effects persisted in the presence of GABAA receptor blockade and were antagonized by coapplication of 5-HT1AR blocker WAY-100135. 5-HT1AR blockade alone had no effect on tractus solitarii-evoked excitatory postsynaptic currents, but increased excitatory network activity. On the other hand, GABAergic nTS-evoked inhibitory postsynaptic currents did not change by activation of the 5-HT1ARs, but spontaneous inhibitory nTS network activity decreased. Blocking 5-HT1ARs tended to increase nTS-evoked inhibitory postsynaptic currents and inhibitory network activity. Taken together, 5-HT1ARs in the caudal nTS decrease breathing, likely via attenuation of afferent transmission, as well as overall nTS network activity. PMID:24671532

  5. Neuromuscular blockade in the elderly patient

    PubMed Central

    Lee, Luis A; Athanassoglou, Vassilis; Pandit, Jaideep J

    2016-01-01

    Neuromuscular blockade is a desirable or even essential component of general anesthesia for major surgical operations. As the population continues to age, and more operations are conducted in the elderly, due consideration must be given to neuromuscular blockade in these patients to avoid possible complications. This review considers the pharmacokinetics and pharmacodynamics of neuromuscular blockade that may be altered in the elderly. Compartment distribution, metabolism, and excretion of drugs may vary due to age-related changes in physiology, altering the duration of action with a need for reduced dosage (eg, aminosteroids). Other drugs (atracurium, cisatracurium) have more reliable duration of action and should perhaps be considered for use in the elderly. The range of interpatient variability that neuromuscular blocking drugs may exhibit is then considered and drugs with a narrower range, such as cisatracurium, may produce more predictable, and inherently safer, outcomes. Ultimately, appropriate neuromuscular monitoring should be used to guide the administration of muscle relaxants so that the risk of residual neuromuscular blockade postoperatively can be minimized. The reliability of various monitoring is considered. This paper concludes with a review of the various reversal agents, namely, anticholinesterase drugs and sugammadex, and the alterations in dosing of these that should be considered for the elderly patient. PMID:27382330

  6. Nonequilibrium dephasing in Coulomb blockaded quantum dots.

    PubMed

    Altland, Alexander; Egger, Reinhold

    2009-01-16

    We present a theory of zero-bias anomalies and dephasing rates for a Coulomb-blockaded quantum dot, driven out of equilibrium by coupling to voltage biased source and drain leads. We interpret our results in terms of the statistics of voltage fluctuations in the system.

  7. Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock.

    PubMed

    DeLano, Frank A; Schmid-Schönbein, Geert W

    2014-01-01

    Hemorrhagic shock is associated with metabolic defects, including hyperglycemia and insulin resistance, but the mechanisms are unknown. We recently demonstrated that reduction of the extracellular domain of the insulin receptor by degrading proteases may lead to a reduced ability to maintain normal plasma glucose values. In shock, transfer of digestive enzymes from the lumen of the intestine into the systemic circulation after breakdown of the intestinal mucosal barrier causes inflammation and organ dysfunction. Suppression of the digestive enzymes in the lumen of the intestine with protease inhibitors is effective in reducing the level of the inflammatory reactions. To determine the degree to which blockade of digestive enzymes affects insulin resistance in shock, rats were exposed to acute hemorrhagic shock (mean arterial pressure of 30 mmHg for 2 h) at which time all shed blood volume was returned. Digestive proteases in the intestine were blocked with a serine protease inhibitor (tranexamic acid in polyethylene glycol and physiological electrolyte solution), and the density of the insulin receptor was measured with immunohistochemistry in the mesentery microcirculation. The untreated rat without enzyme blockade had significantly attenuated levels of insulin receptor density as compared with control and treated rats. Blockade of the digestive proteases after 60 min of hypotension in the lumen of the small intestine led to a lesser decrease in insulin receptor density compared with controls without protease blockade. Glucose tolerance test indicates a significant increase in plasma glucose levels 2 h after hemorrhagic shock, which are reduced to control values in the presence of protease inhibition in the lumen of the intestine. The transient reduction of the plasma glucose levels after an insulin bolus is significantly attenuated after shock but is restored when digestive enzymes in the lumen of the intestine are blocked. These results suggest that in

  8. INHIBITION OF PAN NEUROTROPHIN RECEPTOR P75 ATTENUATES DIESEL PARTICULATE-INDUCED ENHANCEMENT OF ALLERGIC AIRWAY RESPONSES IN C57/BL6J MICE

    EPA Science Inventory

    Recent investigations have linked neurotrophins including nerve growth factor (NGF), neurotrophin-3 (NT-3), and brain-derived neurotrophic factor (BDNF) to allergic airways diseases. Antibody blockade of NGF attenuates airway resistance in allergic mice. Diesel exhaust particle...

  9. 5-Hydroxytryptamine 2A receptor signaling cascade modulates adiponectin and plasminogen activator inhibitor 1 expression in adipose tissue.

    PubMed

    Uchida-Kitajima, Shoko; Yamauchi, Toshimasa; Takashina, Youko; Okada-Iwabu, Miki; Iwabu, Masato; Ueki, Kohjiro; Kadowaki, Takashi

    2008-09-01

    Knowledge of the regulatory factors associated with down-regulation of adiponectin gene expression and up-regulation of PAI-1 gene expression is crucial to understand the pathophysiological basis of obesity and metabolic diseases, and could establish new treatment strategies for these conditions. We showed that expression of 5-HT(2A) receptors was up-regulated in hypertrophic 3T3-L1 adipocytes, which exhibited decreased expression of adiponectin and increased expression of PAI-1. 5-HT(2A) receptor antagonists and suppression of 5-HT(2A) receptor gene expression enhanced adiponectin expression. Activation of Gq negatively regulated adiponectin expression, and inhibition of mitogen-activated protein kinase reversed the Gq-induced effect. Moreover, the 5-HT(2A) receptor blockade reduced PAI-1 expression. These findings indicate that antagonism of 5-HT(2A) receptors in adipocytes could improve the obesity-linked decreases in adiponectin expression and increases in PAI-1 expression.

  10. Identification and specific blockade of two receptors for histamine in the cardiovascular system.

    PubMed

    Powell, J R; Brody, M J

    1976-01-01

    Histamine caused a fall in blood pressure in anesthetized dogs and cats which was only partially attenuated by mepyramine (pyrilamine), a histamine type H1-receptor antagonist. Further treatment with burimide or metiamide, type H2-receptor antagonists, caused nearly complete attenuation of the response to histamine. Burimamide alone had no effect on vasodilatation produced by histamine in the dog gracilis muscle whereas mepyramine alone caused a partial attenuation. An H2-receptor agonist, 4-methylhistamine and an H1-receptor agonist, 2-(2-pyridyl)ethylamine, both produced vasodilatation which was blocked by metiamide and mepyramine, respectively. Constriction of the saphenous vein produced by histamine was found to involve interaction with H1-receptors only. In the intact dog, histamine increased heart rate and decreased left ventricular dp/dt through direct effects. Mepyramine prevented the increase in heart rate but did not affect the chronotropic actions of isoproterenol and glyceryl trinitrate. H1-receptor blockade did not alter inotropic effects whereas subsequent H2-receptor blockade prevented the negative inotropic effect of histamine. It is concluded that both peripheral vascular and cardiac responses to histamine are mediated through activation of H1- and H2-histamine receptors.

  11. Hippocampal 5-HT1A Receptor and Spatial Learning and Memory

    PubMed Central

    Glikmann-Johnston, Yifat; Saling, Michael M.; Reutens, David C.; Stout, Julie C.

    2015-01-01

    Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory. PMID:26696889

  12. [Cancer immunotherapy by immuno-checkpoint blockade].

    PubMed

    Kawakami, Yutaka

    2015-10-01

    As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

  13. Efficient Multiparticle Entanglement via Asymmetric Rydberg Blockade

    SciTech Connect

    Saffman, M.; Moelmer, K.

    2009-06-19

    We present an efficient method for producing N particle entangled states using Rydberg blockade interactions. Optical excitation of Rydberg states that interact weakly, yet have a strong coupling to a second control state is used to achieve state dependent qubit rotations in small ensembles. On the basis of quantitative calculations, we predict that an entangled quantum superposition state of eight atoms can be produced with a fidelity of 84% in cold Rb atoms.

  14. Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males.

    PubMed

    Doh, Hyung-Woo; Stebbins, Charles L; Choi, Hyun-Min; Park, Joonsung; Nho, Hosung; Kim, Jong-Kyung

    2016-06-01

    Histamine is a potent vasodilator that has been found to increase during exercise. We tested the hypothesis that histamine would attenuate blood pressure (BP), cardiac output (CO), and vascular resistance responses to short-term, submaximal dynamic exercise during H2 receptor blockade. Fourteen healthy men (20-29 years of age) were studied. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) BP and heart rate (HR) were assessed at rest and during the last minute of 10 min of submaximal cycling exercise (60% of peak oxygen consumption) in the absence and presence of histamine H2 receptor blockade (ranitidine, 300 mg). Stroke volume (SV) (impedance cardiography) and plasma norepinephrine (NE) were measured, and CO, rate × pressure product (RPP), and total peripheral resistance (TPR) were calculated. Plasma levels of histamine were also measured. H2 blockade had no effects on any variables at rest. During exercise, SBP (184 ± 3 mm Hg vs. 166 ± 2 mm Hg), MAP (121 ± 2 mm Hg vs. 112 ± 5 mm Hg), and RPP (25.9 ± 0.8 × 10(3) mm Hg·beats/min vs. 23.5 ± 0.8 × 10(3) mm Hg/beats·min) were greater during blocked conditions (P < 0.05), and an interaction was observed for TPR. SV, DBP, HR, and NE levels were unaffected by blockade. Plasma histamine increased from 1.83 ± 0.14 ng/mL at rest to 2.33 ± 0.23 ng/mL during exercise (P < 0.05) and was not affected by H2 blockade (1.56 ± 0.23 ng/mL vs. 1.70 ± 0.24 ng/mL). These findings suggest that, during submaximal exercise, histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and that these effects occurred primarily in the vasculature and not in the myocardium.

  15. Histamine H2 receptor blockade augments blood pressure responses to acute submaximal exercise in males.

    PubMed

    Doh, Hyung-Woo; Stebbins, Charles L; Choi, Hyun-Min; Park, Joonsung; Nho, Hosung; Kim, Jong-Kyung

    2016-06-01

    Histamine is a potent vasodilator that has been found to increase during exercise. We tested the hypothesis that histamine would attenuate blood pressure (BP), cardiac output (CO), and vascular resistance responses to short-term, submaximal dynamic exercise during H2 receptor blockade. Fourteen healthy men (20-29 years of age) were studied. Systolic (SBP), diastolic (DBP), and mean arterial (MAP) BP and heart rate (HR) were assessed at rest and during the last minute of 10 min of submaximal cycling exercise (60% of peak oxygen consumption) in the absence and presence of histamine H2 receptor blockade (ranitidine, 300 mg). Stroke volume (SV) (impedance cardiography) and plasma norepinephrine (NE) were measured, and CO, rate × pressure product (RPP), and total peripheral resistance (TPR) were calculated. Plasma levels of histamine were also measured. H2 blockade had no effects on any variables at rest. During exercise, SBP (184 ± 3 mm Hg vs. 166 ± 2 mm Hg), MAP (121 ± 2 mm Hg vs. 112 ± 5 mm Hg), and RPP (25.9 ± 0.8 × 10(3) mm Hg·beats/min vs. 23.5 ± 0.8 × 10(3) mm Hg/beats·min) were greater during blocked conditions (P < 0.05), and an interaction was observed for TPR. SV, DBP, HR, and NE levels were unaffected by blockade. Plasma histamine increased from 1.83 ± 0.14 ng/mL at rest to 2.33 ± 0.23 ng/mL during exercise (P < 0.05) and was not affected by H2 blockade (1.56 ± 0.23 ng/mL vs. 1.70 ± 0.24 ng/mL). These findings suggest that, during submaximal exercise, histamine attenuates BP, vascular resistance, and the work of the heart via activation of H2 receptors and that these effects occurred primarily in the vasculature and not in the myocardium. PMID:27191340

  16. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    SciTech Connect

    Cui, Ruibing; Yan, Lihui; Luo, Zheng; Guo, Xiaolan; Yan, Ming

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.

  17. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases.

    PubMed

    Boia, Raquel; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-01-01

    Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

  18. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases.

    PubMed

    Boia, Raquel; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-01-01

    Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation. PMID:26959995

  19. Photonic nonlinearities via quantum Zeno blockade.

    PubMed

    Sun, Yu-Zhu; Huang, Yu-Ping; Kumar, Prem

    2013-05-31

    Realizing optical-nonlinear effects at a single-photon level is a highly desirable but also extremely challenging task, because of both fundamental and practical difficulties. We present an avenue to surmounting these difficulties by exploiting quantum Zeno blockade in nonlinear optical systems. Considering specifically a lithium-niobate microresonator, we find that a deterministic phase gate can be realized between single photons with near-unity fidelity. Supported by established techniques for fabricating and operating such devices, our approach can provide an enabling tool for all-optical applications in both classical and quantum domains.

  20. Immune checkpoint blockade in lung cancer.

    PubMed

    Somasundaram, Aswin; Socinski, Mark A; Villaruz, Liza C

    2016-08-01

    Immunotherapy has revolutionized the therapeutic landscape of advanced lung cancer. The adaptive immune system has developed a sophisticated method of tumor growth control, but T-cell activation is regulated by various checkpoints. Blockade of the immune checkpoints with therapies targeting the PD-1 pathway, such as nivolumab and pembrolizumab, has been validated as a therapeutic approach in non-small cell lung cancer. Newer therapies and novel combinations are also being evaluated, and the use of biomarkers in conjunction with these drugs is an area of active investigation. This review summarizes the current evidence for the efficacy and safety of the above approaches in the treatment of lung cancer. PMID:27585231

  1. Pyramidal Neurons in Rat Prefrontal Cortex Projecting to Ventral Tegmental Area and Dorsal Raphe Nucleus Express 5-HT2A Receptors

    PubMed Central

    Vázquez-Borsetti, Pablo; Cortés, Roser

    2009-01-01

    The prefrontal cortex (PFC) is involved in higher brain functions altered in schizophrenia. Classical antipsychotics modulate cortico-limbic circuits mainly through subcortical D2 receptor blockade, whereas second generation (atypical) antipsychotics preferentially target cortical 5-HT receptors. Anatomical and functional evidence supports a PFC-based control of the brainstem monoaminergic nuclei. Using a combination of retrograde tracing experiments and in situ hybridization we report that a substantial proportion of PFC pyramidal neurons projecting to the dorsal raphe (DR) and/or ventral tegmental area (VTA) express 5-HT2A receptors. Cholera-toxin B application into the DR and the VTA retrogradely labeled projection neurons in the medial PFC (mPFC) and in orbitofrontal cortex (OFC). In situ hybridization of 5-HT2A receptor mRNA in the same tissue sections labeled a large neuronal population in mPFC and OFC. The percentage of DR-projecting neurons expressing 5-HT2A receptor mRNA was ∼60% in mPFC and ∼75% in OFC (n = 3). Equivalent values for VTA-projecting neurons were ∼55% in both mPFC and ventral OFC. Thus, 5-HT2A receptor activation/blockade in PFC may have downstream effects on dopaminergic and serotonergic systems via direct descending pathways. Atypical antipsychotics may distally modulate monoaminergic cells through PFC 5-HT2A receptor blockade, presumably decreasing the activity of neurons receiving direct cortical inputs. PMID:19029064

  2. Effects of sustained proNGF blockade on attentional capacities in aged rats with compromised cholinergic system.

    PubMed

    Yegla, B; Parikh, V

    2014-03-01

    Disruption in nerve growth factor (NGF) signaling via tropomyosin-related kinase A (trkA) receptors compromises the integrity of the basal forebrain (BF) cholinergic system, yielding cognitive, specifically attentional, impairments in Alzheimer's disease (AD). Although normal aging is considered a risk factor for AD, the mechanisms underlying the selective vulnerability of the aging cholinergic system to trkA disruption is not clear. The levels of proNGF, a proneurotrophin that possesses higher affinity for p75 receptors, increase in aging. The present study was designed to test the hypothesis that cholinergic and attentional dysfunction in aged rats with reduced BF trkA receptors occurs due to the overactivation of endogenous proNGF signaling. We employed a viral vector that produced trkA shRNA to suppress trkA receptors in the corticopetal cholinergic neurons of aged rats. BF trkA suppression impaired animals' performance on signal trials in both the sustained attention task (SAT) and the cognitively taxing distractor version of SAT (dSAT) and these deficits were normalized by chronic intracerebroventricular administration of proNGF antibody. Moreover, depolarization-evoked acetylcholine (ACh) release and the density of cortical cholinergic fibers were partially restored in these animals. However, SAT/dSAT scores reflecting overall performance did not improve following proNGF blockade in trkA knockdown rats due to impaired performance in non-signal trials. Sustained proNGF blockade alone did not alter baseline attentional performance but produced moderate impairments during challenging conditions. Collectively, our findings indicate that barring proNGF-p75 signaling may exert some beneficial effects on attentional capacities specifically when BF trkA signaling is abrogated. However, endogenous proNGF may also possess neurotrophic effects and blockade of this proneurotrophin may not completely ameliorate attentional impairments in AD and potentially hinder

  3. Electromagnetically induced transparency and fluorescence in blockaded Rydberg atomic system

    SciTech Connect

    Li, Cheng; Zheng, Huaibin; Zhang, Zhaoyang; Yao, Xin; Zhang, Yunzhe; Zhang, Yiqi; Zhang, Yanpeng

    2013-10-28

    We investigate the interaction between dark states and Rydberg excitation blockade by using electromagnetically induced transparency (EIT), fluorescence, and four-wave mixing (FWM) signals both theoretically and experimentally. By scanning the frequency detunings of the probe and dressing fields, respectively, we first observe these signals (three coexisting EIT windows, two fluorescence signals, and two FWM signals) under Rydberg excitation blockade. Next, frequency detuning dependences of these signals are obtained, in which the modulated results are well explained by introducing the dressing effects (leading to the dark states) with the corrected factor of the Rydberg excitation blockade. In addition, the variations by changing the principal quantum number n of Rydberg state shown some interesting phenomena resulting from Rydberg blockade are observed. The unique nature of such blockaded signals can have potential application in the demonstration of quantum computing.

  4. On Disruption of Fear Memory by Reconsolidation Blockade: Evidence from Cannabidiol Treatment

    PubMed Central

    Stern, Cristina A J; Gazarini, Lucas; Takahashi, Reinaldo N; Guimarães, Francisco S; Bertoglio, Leandro J

    2012-01-01

    The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3–30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6 h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions. PMID:22549120

  5. The Effect of Therapeutic Blockades of Dust Particles-Induced Ca2+ Signaling and Proinflammatory Cytokine IL-8 in Human Bronchial Epithelial Cells

    PubMed Central

    Yoon, Ju Hee; Jeong, Sung Hwan; Hong, Jeong Hee

    2015-01-01

    Bronchial epithelial cells are the first barrier of defense against respiratory pathogens. Dust particles as extracellular stimuli are associated with inflammatory reactions after inhalation. It has been reported that dust particles induce intracellular Ca2+ signal, which subsequently increases cytokines production such as interleukin- (IL-) 8. However, the study of therapeutic blockades of Ca2+ signaling induced by dust particles in human bronchial epithelial cells is poorly understood. We investigated how to modulate dust particles-induced Ca2+ signaling and proinflammatory cytokine IL-8 expression. Bronchial epithelial BEAS-2B cells were exposed to PM10 dust particles and subsequent mediated intracellular Ca2+ signaling and reactive oxygen species signal. Our results show that exposure to several inhibitors of Ca2+ pathway attenuated the PM10-induced Ca2+ response and subsequent IL-8 mRNA expression. PM10-mediated Ca2+ signal and IL-8 expression were attenuated by several pharmacological blockades such as antioxidants, IP3-PLC blockers, and TRPM2 inhibitors. Our results show that blockades of PLC or TRPM2 reduced both of PM10-mediated Ca2+ signal and IL-8 expression, suggesting that treatment with these blockades should be considered for potential therapeutic trials in pulmonary epithelium for inflammation caused by environmental events such as seasonal dust storm. PMID:26640326

  6. The Effect of Therapeutic Blockades of Dust Particles-Induced Ca²⁺ Signaling and Proinflammatory Cytokine IL-8 in Human Bronchial Epithelial Cells.

    PubMed

    Yoon, Ju Hee; Jeong, Sung Hwan; Hong, Jeong Hee

    2015-01-01

    Bronchial epithelial cells are the first barrier of defense against respiratory pathogens. Dust particles as extracellular stimuli are associated with inflammatory reactions after inhalation. It has been reported that dust particles induce intracellular Ca(2+) signal, which subsequently increases cytokines production such as interleukin- (IL-) 8. However, the study of therapeutic blockades of Ca(2+) signaling induced by dust particles in human bronchial epithelial cells is poorly understood. We investigated how to modulate dust particles-induced Ca(2+) signaling and proinflammatory cytokine IL-8 expression. Bronchial epithelial BEAS-2B cells were exposed to PM10 dust particles and subsequent mediated intracellular Ca(2+) signaling and reactive oxygen species signal. Our results show that exposure to several inhibitors of Ca(2+) pathway attenuated the PM10-induced Ca(2+) response and subsequent IL-8 mRNA expression. PM10-mediated Ca(2+) signal and IL-8 expression were attenuated by several pharmacological blockades such as antioxidants, IP3-PLC blockers, and TRPM2 inhibitors. Our results show that blockades of PLC or TRPM2 reduced both of PM10-mediated Ca(2+) signal and IL-8 expression, suggesting that treatment with these blockades should be considered for potential therapeutic trials in pulmonary epithelium for inflammation caused by environmental events such as seasonal dust storm. PMID:26640326

  7. Pauli spin blockade in double molecular magnets

    NASA Astrophysics Data System (ADS)

    Płomińska, Anna; Weymann, Ireneusz

    2016-07-01

    The Pauli spin blockade effect in transport through two, coupled in series, single molecular magnets weakly attached to external leads is considered theoretically. By using the real-time diagrammatic technique in the lowest-order perturbation theory with respect to the coupling strength, the behavior of the current and the shot noise is studied in the nonlinear response regime. It is shown that the current suppression occurs due to the occupation of highest-weight spin states of the system. Moreover, transport properties are found to strongly depend on parameters of the double molecular magnet, such as the magnitude of spin, internal exchange interaction and the hopping between the molecules. It is also demonstrated that the current suppression may be accompanied by negative differential conductance and a large super-Poissonian shot noise. The mechanisms leading to those effects are discussed.

  8. Novel drug development for neuromuscular blockade

    PubMed Central

    Prabhakar, Amit; Kaye, Alan D; Wyche, Melville Q; Salinas, Orlando J; Mancuso, Kenneth; Urman, Richard D

    2016-01-01

    Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review. With regard to nondepolarizer neuromuscular blocker agents, the enantiomers Gantacurium and CW002, which are olefinic isoquinolinium diester fumarates, have shown potential for clinical application. Advantages include ultra rapid reversal of neuromuscular blockade via cysteine adduction and minimal systemic hemodynamic effects with administration. PMID:27625489

  9. Novel drug development for neuromuscular blockade

    PubMed Central

    Prabhakar, Amit; Kaye, Alan D; Wyche, Melville Q; Salinas, Orlando J; Mancuso, Kenneth; Urman, Richard D

    2016-01-01

    Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review. With regard to nondepolarizer neuromuscular blocker agents, the enantiomers Gantacurium and CW002, which are olefinic isoquinolinium diester fumarates, have shown potential for clinical application. Advantages include ultra rapid reversal of neuromuscular blockade via cysteine adduction and minimal systemic hemodynamic effects with administration.

  10. Novel drug development for neuromuscular blockade.

    PubMed

    Prabhakar, Amit; Kaye, Alan D; Wyche, Melville Q; Salinas, Orlando J; Mancuso, Kenneth; Urman, Richard D

    2016-01-01

    Pharmacological advances in anesthesia in recent decades have resulted in safer practice and better outcomes. These advances include improvement in anesthesia drugs with regard to efficacy and safety profiles. Although neuromuscular blockers were first introduced over a half century ago, few new neuromuscular blockers and reversal agents have come to market and even fewer have remained as common clinically employed medications. In recent years, newer agents have been studied and are presented in this review. With regard to nondepolarizer neuromuscular blocker agents, the enantiomers Gantacurium and CW002, which are olefinic isoquinolinium diester fumarates, have shown potential for clinical application. Advantages include ultra rapid reversal of neuromuscular blockade via cysteine adduction and minimal systemic hemodynamic effects with administration. PMID:27625489

  11. Energy Gaps and Interaction Blockade in Confined Quantum Systems

    SciTech Connect

    Capelle, K.; Borgh, M.; Kaerkkaeinen, K.; Reimann, S. M.

    2007-07-06

    We investigate universal properties of strongly confined particles that turn out to be dramatically different from what is observed for electrons in atoms and molecules. For a large class of harmonically confined systems, such as small quantum dots and optically trapped atoms, many-body particle addition and removal energies, and energy gaps, are accurately obtained from single-particle eigenvalues. Transport blockade phenomena are related to the derivative discontinuity of the exchange-correlation functional. This implies that they occur very generally, with Coulomb blockade being a particular realization of a more general phenomenon. In particular, we predict a van der Waals blockade in cold atom gases in traps.

  12. Activity blockade and GABAA receptor blockade produce synaptic scaling through chloride accumulation in embryonic spinal motoneurons and interneurons.

    PubMed

    Lindsly, Casie; Gonzalez-Islas, Carlos; Wenner, Peter

    2014-01-01

    Synaptic scaling represents a process whereby the distribution of a cell's synaptic strengths are altered by a multiplicative scaling factor. Scaling is thought to be a compensatory response that homeostatically controls spiking activity levels in the cell or network. Previously, we observed GABAergic synaptic scaling in embryonic spinal motoneurons following in vivo blockade of either spiking activity or GABAA receptors (GABAARs). We had determined that activity blockade triggered upward GABAergic scaling through chloride accumulation, thus increasing the driving force for these currents. To determine whether chloride accumulation also underlies GABAergic scaling following GABAAR blockade we have developed a new technique. We expressed a genetically encoded chloride-indicator, Clomeleon, in the embryonic chick spinal cord, which provides a non-invasive fast measure of intracellular chloride. Using this technique we now show that chloride accumulation underlies GABAergic scaling following blockade of either spiking activity or the GABAAR. The finding that GABAAR blockade and activity blockade trigger scaling via a common mechanism supports our hypothesis that activity blockade reduces GABAAR activation, which triggers synaptic scaling. In addition, Clomeleon imaging demonstrated the time course and widespread nature of GABAergic scaling through chloride accumulation, as it was also observed in spinal interneurons. This suggests that homeostatic scaling via chloride accumulation is a common feature in many neuronal classes within the embryonic spinal cord and opens the possibility that this process may occur throughout the nervous system at early stages of development.

  13. 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.

  14. Kinetics of cycle length dependence of ventricular repolarization: effect of autonomic blockade

    NASA Technical Reports Server (NTRS)

    Raeder, E. A.; Albrecht, P.; Perrott, M.; Cohen, R. J.

    1995-01-01

    INTRODUCTION: Beat-to-beat adaptation of ventricular repolarization duration to cardiac cycle length and autonomic activity has not been previously characterized in the spontaneously beating human heart. METHODS AND RESULTS: The ECG of 14 healthy subjects was recorded from the supine and upright positions. Autonomic blockade was accomplished by atropine and propranolol. RR and RT intervals were measured by a computer algorithm, and the impulse response (h) from RR to RT computed. In the supine position the maximal adjustment of the RT interval occurred in the first beat following a change in cycle length (hpeak = 17.8 +/- 1.6 msec/sec), but continued to be detectable for 3.8 seconds (2.9-4.7 sec). Propranolol attenuated the peak impulse response to 15.8 +/- 4.0 msec/sec (P = NS). In the standing position the peak impulse response was increased to 25.2 +/- 5.0 msec/sec (P = 0.004 vs supine), and the impulse response duration (hdur) shortened to 1.4 seconds (1.3-1.6). This was reversed by beta blockade (hpeak = 10.7 +/- 3.6 [P = 0.005 vs standing]; hdur = 5.5 sec [4.8-6.1]). Parasympathetic and combined autonomic blockade resulted in too little residual heart rate variability to estimate the impulse response accurately. The slope of the regression of delta RT and delta RR in the supine position was 0.0177 +/- 0.0016, which was closely correlated with the peak impulse response (r = 0.91). CONCLUSIONS: System identification techniques can assist in characterizing the cycle dependence of ventricular repolarization and may provide new insights into conditions associated with abnormal repolarization.

  15. Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock.

    PubMed

    DeLano, Frank A; Hoyt, David B; Schmid-Schönbein, Geert W

    2013-01-23

    Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors--6-amidino-2-naphtyl p-guanidinobenzoate dimethanesulfate, tranexamic acid, or aprotinin--into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multiorgan failure, which can be treated with protease inhibitors that are currently available for use in the clinic.

  16. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis.

    PubMed

    Cui, Ruibing; Yan, Lihui; Luo, Zheng; Guo, Xiaolan; Yan, Ming

    2015-08-15

    Extracellular Ca(2+) influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca(2+) entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague-Dawley rats. Our data demonstrated that ethanol (0-400mM) dose-dependently increased hepatocyte injury and 100mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72h in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca(2+) overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases.

  17. Blockade involving high- n, n ~ 300 , strontium Rydberg atoms

    NASA Astrophysics Data System (ADS)

    Yoshida, Shuhei; Burgdörfer, Joachim; Zhang, Xinyue; Dunning, F. Barry

    2016-05-01

    The blockade of high- n strontium n1F3 Rydberg states contained in a hot atomic beam is investigated both theoretically and experimentally. One difficulty in such experiments is that, once created, Rydberg atoms move out of the excitation volume reducing blockade effects. While the effects of such motion are apparent, the data provide strong evidence of blockade, consistent with theoretical predictions. Because of their relatively high angular momentum (L = 3) , a pair of n1F3 Rydberg atoms have many degenerate states whose degeneracy is removed by Rydberg-Rydberg interactions yielding a high density of states near the target energy. To evaluate the effect of blockade not only the energy shifts but also the modification of the oscillator strengths for excitation have to be taken into account. The n-scaling of the interactions and the importance of high-order multipoles will also be discussed. Research supported by the NSF and Robert A. Welch Foundation.

  18. Duration of opioid receptor blockade determines biotherapeutic response.

    PubMed

    McLaughlin, Patricia J; Zagon, Ian S

    2015-10-01

    Historically, studies on endogenous and exogenous opioids and their receptors focused on the mediation of pain, with excess opiate consumption leading to addiction. Opioid antagonists such as naloxone and naltrexone blocked these interactions, and still are widely used to reverse drug and alcohol overdose. Although specific opioid antagonists have been designed for mu, delta, and kappa opioid receptors, the general antagonists remain the most effective. With the discovery of the opioid growth factor (OGF)-OGF receptor (OGFr) axis as a novel biological pathway involved in homeostasis of replicating cells and tissues, the role of opioid receptor antagonists was expanded. An intermittent OGFr blockade by low dosages of naltrexone resulted in depressed cell replication, whereas high (or sustained) dosages of naltrexone that conferred a continuous OGFr blockade resulted in enhanced growth. More than 3 decades of research have confirmed that the duration of opioid receptor blockade, not specifically the dosage, by general opioid antagonists determines the biotherapeutic outcome. Dysregulation of the OGF-OGFr pathway is apparent in a number of human disorders including diabetes, multiple sclerosis, and cancer, and thus opioid antagonist disruption of interaction prevails as a therapeutic intervention. We review evidence that the duration of opioid receptor blockade is correlated with the magnitude and direction of response, and discuss the potential therapeutic effectiveness of continuous receptor blockade for treatment of diabetic complications such as corneal defects and skin wounds, and of intermittent receptor blockade by low dosages of naltrexone for treatment of autoimmune diseases and cancer. PMID:26119823

  19. Valley-spin blockade and spin resonance in carbon nanotubes.

    PubMed

    Pei, Fei; Laird, Edward A; Steele, Gary A; Kouwenhoven, Leo P

    2012-10-01

    The manipulation and readout of spin qubits in quantum dots have been successfully achieved using Pauli blockade, which forbids transitions between spin-triplet and spin-singlet states. Compared with spin qubits realized in III-V materials, group IV materials such as silicon and carbon are attractive for this application because of their low decoherence rates (nuclei with zero spins). However, valley degeneracies in the electronic band structure of these materials combined with Coulomb interactions reduce the energy difference between the blocked and unblocked states, significantly weakening the selection rules for Pauli blockade. Recent demonstrations of spin qubits in silicon devices have required strain and spatial confinement to lift the valley degeneracy. In carbon nanotubes, Pauli blockade can be observed by lifting valley degeneracy through disorder, but this makes the confinement potential difficult to control. To achieve Pauli blockade in low-disorder nanotubes, quantum dots have to be made ultrasmall, which is incompatible with conventional fabrication methods. Here, we exploit the bandgap of low-disorder nanotubes to demonstrate robust Pauli blockade based on both valley and spin selection rules. We use a novel stamping technique to create a bent nanotube, in which single-electron spin resonance is detected using the blockade. Our results indicate the feasibility of valley-spin qubits in carbon nanotubes.

  20. Transport Through a Coulomb Blockaded Majorana Nanowire

    NASA Astrophysics Data System (ADS)

    Zazunov, Alex; Egger, Reinhold; Yeyati, Alfredo Levy; Hützen, Roland; Braunecker, Bernd

    In one-dimensional (1D) quantum wires with strong spin-orbit coupling and a Zeeman field, a superconducting substrate can induce zero-energy Majorana bound states located near the ends of the wire. We study electronic properties when such a wire is contacted by normal metallic or superconducting electrodes. A special attention is devoted to Coulomb blockade effects. We analyze the "Majorana single-charge transistor" (MSCT), i.e., a floating Majorana wire contacted by normal metallic source and drain contacts, where charging effects are important. We describe Coulomb oscillations in this system and predict that Majorana fermions could be unambiguously detected by the emergence of sideband peaks in the nonlinear differential conductance. We also study a superconducting variant of the MSCT setup with s-wave superconducting (instead of normal-conducting) leads. In the noninteracting case, we derive the exact current-phase relation (CPR) and find π-periodic behavior with negative critical current for weak tunnel couplings. Charging effects then cause the anomalous CPR I(\\varphi ) = Ic\\cos \\varphi, where the parity-sensitive critical current I c provides a signature for Majorana states.

  1. Interleukin-6 blockade in ocular inflammatory diseases

    PubMed Central

    Mesquida, M; Leszczynska, A; Llorenç, V; Adán, A

    2014-01-01

    Interleukin-6 (IL-6) is a key cytokine featuring redundancy and pleiotropic activity. It plays a central role in host defence against environmental stress such as infection and injury. Dysregulated, persistent interleukin (IL)-6 production has been implicated in the development of various autoimmune, chronic inflammatory diseases and even cancers. Significant elevation of IL-6 has been found in ocular fluids derived from refractory/chronic uveitis patients. In experimental autoimmune uveitis models with IL-6 knock-out mice, IL-6 has shown to be essential for inducing inflammation. IL-6 blockade can suppress acute T helper type 17 (Th17) responses via its differentiation and, importantly, can ameliorate chronic inflammation. Tocilizumab, a recombinant humanized anti-IL-6 receptor antibody, has been shown to be effective in several autoimmune diseases, including uveitis. Herein, we discuss the basic biology of IL-6 and its role in development of autoimmune conditions, focusing particularly on non-infectious uveitis. It also provides an overview of efficacy and safety of tocilizumab therapy for ocular inflammatory diseases. PMID:24528300

  2. Effect of global and regional sympathetic blockade on arterial pressure during water deprivation in conscious rats

    PubMed Central

    Veitenheimer, Britta J.; Engeland, William C.; Guzman, Pilar A.; Fink, Gregory D.

    2012-01-01

    Forty-eight hours of water deprivation (WD) in conscious rats results in a paradoxical increase in mean arterial pressure (MAP). Previous studies suggest this may be due to increased sympathetic nerve activity (SNA). However, this remains to be investigated in conscious, freely behaving animals. The purpose of this study was to determine, in conscious rats, the role of the sympathetic nervous system (SNS) in mediating WD-induced increases in MAP and to identify which vascular beds are targeted by increased SNA. Each rat was chronically instrumented with a radiotelemetry transmitter to measure MAP and heart rate (HR) and an indwelling venous catheter for plasma sampling and/or drug delivery. MAP and HR were continuously measured during a 2-day baseline period followed by 48 h of WD and then a recovery period. By the end of the WD period, MAP increased by ∼15 mmHg in control groups, whereas HR did not change significantly. Chronic blockade of α1/β1-adrenergic receptors significantly attenuated the WD-induced increase in MAP, suggesting a role for global activation of the SNS. However, the MAP response to WD was unaffected by selective denervations of the hindlimb, renal, or splanchnic vascular beds, or by adrenal demedullation. In contrast, complete adrenalectomy (with corticosterone and aldosterone replaced) significantly attenuated the MAP response to WD in the same time frame as α1/β1-adrenergic receptor blockade. These results suggest that, in conscious water-deprived rats, the SNS contributes to the MAP response and may be linked to release of adrenocortical hormones. Finally, this sympathetically mediated response is not dependent on increased SNA to one specific vascular bed. PMID:22904160

  3. Muscarinic M(3) facilitation of acetylcholine release from rat myenteric neurons depends on adenosine outflow leading to activation of excitatory A(2A) receptors.

    PubMed

    Vieira, C; Duarte-Araújo, M; Adães, S; Magalhães-Cardoso, T; Correia-de-Sá, P

    2009-10-01

    Acetylcholine (ACh) is a major excitatory neurotransmitter in the myenteric plexus, and it regulates its own release acting via muscarinic autoreceptors. Adenosine released from stimulated myenteric neurons modulates ACh release preferentially via facilitatory A(2A) receptors. In this study, we investigated how muscarinic and adenosine receptors interplay to regulate ACh from the longitudinal muscle-myenteric plexus of the rat ileum. Blockade of the muscarinic M(2) receptor with 11-[[2-1[(diethylamino) methyl-1-piperidinyl]- acetyl

  4. Calcium channel blockade attenuates abnormal synaptic transmission in the dentate gyrus elicited by entorhinal amyloidopathy.

    PubMed

    Gholami Pourbadie, Hamid; Naderi, Nima; Janahmadi, Mahyar; Mehranfard, Nasrin; Motamedi, Fereshteh

    2016-10-01

    Entorhinal-hippocampal network is one of the earliest circuits which is affected by Alzheimer's disease (AD). There are numerous data providing the evidence of synaptic deficit in the dentate gyrus (DG) of AD animal model. However, there is little known about how entorhinal cortex (EC) amyloidophaty affects each excitatory and/or inhibitory transmission in the early stage of AD. On the other hand, it is believed that calcium dyshomeostasis has a critical role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on excitatory or inhibitory post synaptic currents (EPSC and IPSC, respectively) in the DG granule cells and then the possible neuroprotective action of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were examined. The amyloid beta (Aβ) 1-42 was injected bilaterally into the EC of male rats and one week later, synaptic currents in the DG granule cells were assessed by whole cell patch clamp. EPSCs were evoked by stimulating the perforant pathway. Voltage clamp recording showed profound decrease of evoked EPSC amplitude and paired pulse facilitation in the DG granule cells of Aβ treated rats. Furthermore, AMPA/NMDA ratio was significantly decreased in the Aβ treated animals. On the other hand, amplitude of IPSC currents was significantly increased in the DG granule cells of these animals. These modifications of synaptic currents were partially reversed by daily intracerebroventricular administration of isradipine or nimodipine. In conclusion, our results suggest that Aβ in the EC triggers decreased excitatory transmission in the DG with substantial decrement in AMPA currents, leading to a prominent activity of inhibitory circuits and increased inhibition of granule cells which may contribute to the development of AD-related neurological deficits in AD and treatment by CCBs could preserve normal synaptic transmission against Aβ toxicity. PMID:27240164

  5. 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.

  6. Genetic blockade of adenosine A2A receptors induces cognitive impairments and anatomical changes related to psychotic symptoms in mice.

    PubMed

    Moscoso-Castro, Maria; Gracia-Rubio, Irene; Ciruela, Francisco; Valverde, Olga

    2016-07-01

    Schizophrenia is a chronic severe mental disorder with a presumed neurodevelopmental origin, and no effective treatment. Schizophrenia is a multifactorial disease with genetic, environmental and neurochemical etiology. The main theories on the pathophysiology of this disorder include alterations in dopaminergic and glutamatergic neurotransmission in limbic and cortical areas of the brain. Early hypotheses also suggested that nucleoside adenosine is a putative affected neurotransmitter system, and clinical evidence suggests that adenosine adjuvants improve treatment outcomes, especially in poorly responsive patients. Hence, it is important to elucidate the role of the neuromodulator adenosine in the pathophysiology of schizophrenia. A2A adenosine receptor (A2AR) subtypes are expressed in brain areas controlling motivational responses and cognition, including striatum, and in lower levels in hippocampus and cerebral cortex. The aim of this study was to characterize A2AR knockout (KO) mice with complete and specific inactivation of A2AR, as an animal model for schizophrenia. We performed behavioral, anatomical and neurochemical studies to assess psychotic-like symptoms in adult male and female KO and wild-type (WT) littermates. Our results show impairments in inhibitory responses and sensory gating in A2AR KO animals. Hyperlocomotion induced by d-amphetamine and MK-801 was reduced in KO animals when compared to WT littermates. Moreover, A2AR KO animals show motor disturbances, social and cognitive alterations. Finally, behavioral impairments were associated with enlargement of brain lateral ventricles and decreased BDNF levels in the hippocampus. These data highlight the role of adenosine in the pathophysiology of schizophrenia and provide new possibilities for the therapeutic management of schizophrenia. PMID:27133030

  7. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception.

    PubMed

    Biagioni, Audrey Franceschi; de Oliveira, Rithiele Cristina; de Oliveira, Ricardo; da Silva, Juliana Almeida; dos Anjos-Garcia, Tayllon; Roncon, Camila Marroni; Corrado, Alexandre Pinto; Zangrossi, Hélio; Coimbra, Norberto Cysne

    2016-03-01

    The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH. PMID:26749090

  8. Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats

    PubMed Central

    2015-01-01

    Abnormal blood pressure (BP) elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R) causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB), oral administration of hydralazine (HYD), or ICV of vehicle (VEH). Telemetric averaged mean BP (MBP) was measured at early morning (EM), after morning (AM), and night (NT). At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats. PMID:25918643

  9. Brain Angiotensin II Type 1 Receptor Blockade Improves Dairy Blood Pressure Variability via Sympathoinhibition in Hypertensive Rats.

    PubMed

    Kishi, Takuya; Hirooka, Yoshitaka; Sunagawa, Kenji

    2015-01-01

    Abnormal blood pressure (BP) elevation in early morning is known to cause cardiovascular events. Previous studies have suggested that one of the reasons in abnormal dairy BP variability is sympathoexcitation. We have demonstrated that brain angiotensin II type 1 receptor (AT1R) causes sympathoexcitation. The aim of the present study was to investigate whether central AT1R blockade attenuates the excess BP elevation in rest-to-active phase in hypertensive rats or not. Stroke-prone spontaneously hypertensive rats (SHRSP) were treated with intracerebroventricular infusion (ICV) of AT1R receptor blocker (ARB), oral administration of hydralazine (HYD), or ICV of vehicle (VEH). Telemetric averaged mean BP (MBP) was measured at early morning (EM), after morning (AM), and night (NT). At EM, MBP was significantly lower in ARB to a greater extent than in HYD compared to VEH, though MBP at AM was the same in ARB and HYD. At NT, MBP was also significantly lower in ARB than in HYD. These results in MBP were compatible to those in sympathoexcitation and suggest that central AT1R blockade attenuates excess BP elevation in early active phase and continuous BP elevation during rest phase independent of depressor response in hypertensive rats.

  10. Renin-angiotensin system blockade: Its contribution and controversy.

    PubMed

    Miyajima, Akira; Kosaka, Takeo; Kikuchi, Eiji; Oya, Mototsugu

    2015-08-01

    Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin-angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin-angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time.

  11. 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.

  12. The effect of adrenergic blockade on blushing and facial flushing.

    PubMed

    Drummond, P D

    1997-03-01

    The effect of adrenergic blockade on vascular responses in the forehead was assessed during stressful mental arithmetic, singing, and moderate exercise in 21 frequent blushers and 21 infrequent blushers. Adrenergic antagonists were introduced into a small site on the forehead by iontophoresis, and vascular responses were monitored bilaterally with laser Doppler flowmetry. Beta blockade prevented increases in blood flow in infrequent blushers during mental arithmetic and partially inhibited vasodilatation during singing, indicating minor participation of beta-adrenoceptors in blushing. Alpha blockade did not affect blushing but augmented vasodilatation during exercise. Despite higher ratings of self-consciousness in frequent than in infrequent blushers, vascular responses were similar in both groups. Thus, blushing propensity does not appear to be related to the density of alpha- or beta-adrenoceptors in facial vessels and may have a psychological basis. PMID:9090265

  13. Gene expression and function of adenosine A(2A) receptor in the rat carotid body.

    PubMed

    Kobayashi, S; Conforti, L; Millhorn, D E

    2000-08-01

    The present study was undertaken to determine whether rat carotid bodies express adenosine (Ado) A(2A) receptors and whether this receptor is involved in the cellular response to hypoxia. Our results demonstrate that rat carotid bodies express the A(2A) and A(2B) Ado receptor mRNAs but not the A(1) or A(3) receptor mRNAs as determined by reverse transcriptase-polymerase chain reaction. In situ hybridization confirmed the expression of the A(2A) receptor mRNA. Immunohistochemical studies further showed that the A(2A) receptor is expressed in the carotid body and that it is colocalized with tyrosine hydroxylase in type I cells. Whole cell voltage-clamp studies using isolated type I cells showed that Ado inhibited the voltage-dependent Ca(2+) currents and that this inhibition was abolished by the selective A(2A) receptor antagonist ZM-241385. Ca(2+) imaging studies using fura 2 revealed that exposure to severe hypoxia induced elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) in type I cells and that extracellularly applied Ado significantly attenuated the hypoxia-induced elevation of [Ca(2+)](i). Taken together, our findings indicate that A(2A) receptors are present in type I cells and that activation of A(2A) receptors modulates Ca(2+) accumulation during hypoxia. This mechanism may play a role in regulating intracellular Ca(2+) homeostasis and cellular excitability during hypoxia. PMID:10926550

  14. Primary Thermometry in the Intermediate Coulomb Blockade Regime

    NASA Astrophysics Data System (ADS)

    Feshchenko, A. V.; Meschke, M.; Gunnarsson, D.; Prunnila, M.; Roschier, L.; Penttilä, J. S.; Pekola, J. P.

    2013-10-01

    We investigate Coulomb blockade thermometers (CBT) in an intermediate temperature regime, where measurements with enhanced accuracy are possible due to the increased magnitude of the differential conductance dip. Previous theoretical results show that corrections to the half width and to the depth of the measured conductance dip of a sensor are needed, when leaving the regime of weak Coulomb blockade towards lower temperatures. In the present work, we demonstrate experimentally that the temperature range of a CBT sensor can be extended by employing these corrections without compromising the primary nature or the accuracy of the thermometer.

  15. Mechanical vibrations induced resonant breakdown of the Coulomb blockade

    NASA Astrophysics Data System (ADS)

    Pogosov, A. G.; Budantsev, M. V.; Shevyrin, A. A.; Plotnikov, A. E.; Bakarov, A. K.; Toropov, A. I.

    2011-12-01

    Influence of forced mechanical vibrations of a suspended single-electron transistor on electron tunneling through the quantum dot limited by the Coulomb blockade is investigated. It is shown that mechanical oscillations of the quantum dot lead to the Coulomb blockade breakdown, shown in sharp resonant peaks in the transistor conductance dependence on the excitation frequency at values corresponding to the mechanical oscillations eigen modes. The observed effect is presumably connected with oscillations of the mutual electrical capacitances between the quantum dot and surrounding electrodes.

  16. INSIGHTS INTO THE REGULATION OF 5-HT2A RECEPTORS BY SCAFFOLDING PROTEINS AND KINASES

    PubMed Central

    Allen, John A.; Yadav, Prem N.

    2008-01-01

    SUMMARY 5-HT2A serotonin receptors are essential molecular targets for the actions of LSD-like hallucinogens and atypical antipsychotic drugs. 5-HT2A serotonin receptors also mediate a variety of physiological processes in peripheral and central nervous systems including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. Scaffolding proteins have emerged as important regulators of 5-HT2A receptors and our recent studies suggest multiple scaffolds exist for 5-HT2A receptors including PSD95, arrestin, and caveolin. In addition, a novel interaction has emerged between p90 ribosomal S6 kinase and 5-HT2A receptors which attenuates receptor signaling. This article reviews our recent studies and emphasizes the role of scaffolding proteins and kinases in the regulation of 5-HT2A trafficking, targeting and signaling. PMID:18640136

  17. Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

    PubMed

    Lesch, K P; Poten, B; Söhnle, K; Schulte, H M

    1990-01-01

    The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs. PMID:1980461

  18. Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans.

    PubMed

    Lesch, K P; Poten, B; Söhnle, K; Schulte, H M

    1990-01-01

    The selective 5-HT1A receptor ligand ipsapirone (IPS) caused dose-related hypothermia in humans. The response was attenuated by the nonselective 5-HT1/2 receptor antagonist metergoline and was completely antagonized by the nonselective beta-adrenoceptor antagonist pindolol, which interacts stereoselectively with the 5-HT1A receptor. The selective beta 1-adrenergic antagonist betaxolol had no effect. The findings indicate that IPS-induced hypothermia specifically involves activation of (presynaptic) 5-HT1A receptors. Therefore, the hypothermic response to IPS may provide a convenient in vivo paradigma to assess the function of the presynaptic 5-HT receptor in affective disorders and its involvement in the effects of psychotropic drugs.

  19. [Alfa-blockade with doxazosin vs tamsulozin in combination of intermittent androgen blockade in patients with prostate cancer].

    PubMed

    Muradian, A A

    2005-03-01

    We have studied the efficacy of Alfa-blockade with Doxazosin vs Tamsulozin in combination with Intermittent Androgen Blockade (IAB) in patients with low grade prostate cancer. Our clinical trial included: I group (n=15) of patients who received doxazosin with IAB and flutamide; II group (n=13) of patients who received tamsulozin in combination with IAB and flutamide and III (n=33) group with flutamid monotherapy alone. Our results have shown that the combination of doxasozin and IAB with the flutamide leads to the better improvement of uroflowmetry and IPSS parameters, whereas the tamsulozin and IAB with flutamide combination induce those improvements for the longer period during the disease remission.

  20. 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.

  1. 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.

  2. The Union Blockade and Demoralization of the South: Relative Prices in the Confederacy.

    ERIC Educational Resources Information Center

    Ekelund, Robert B., Jr.; Thornton, Mark

    1992-01-01

    Applies the economic concept of relative prices to the blockaded Confederacy during the U.S. Civil War. Describes how the Union blockade encouraged blockade runners to supply luxury items while soldiers lacked food, clothing, and ammunition. Contends that the resultant demoralization was a factor in the demise of the Confederacy. (CFR)

  3. Coronary responses to cold air inhalation following afferent and efferent blockade

    PubMed Central

    Gao, Zhaohui; McQuillan, Patrick M.; Leuenberger, Urs A.; Sinoway, Lawrence I.

    2014-01-01

    Cardiac ischemia and angina pectoris are commonly experienced during exertion in a cold environment. In the current study we tested the hypotheses that oropharyngeal afferent blockade (i.e., local anesthesia of the upper airway with lidocaine) as well as systemic β-adrenergic receptor blockade (i.e., intravenous propranolol) would improve the balance between myocardial oxygen supply and demand in response to the combined stimulus of cold air inhalation (−15 to −30°C) and isometric handgrip exercise (Cold + Grip). Young healthy subjects underwent Cold + Grip following lidocaine, propranolol, and control (no drug). Heart rate, blood pressure, and coronary blood flow velocity (CBV, from Doppler echocardiography) were continuously measured. Rate-pressure product (RPP) was calculated, and changes from baseline were compared between treatments. The change in RPP at the end of Cold + Grip was not different between lidocaine (2,441 ± 376) and control conditions (3,159 ± 626); CBV responses were also not different between treatments. With propranolol, heart rate (8 ± 1 vs. 14 ± 3 beats/min) and RPP responses to Cold + Grip were significantly attenuated. However, at peak exercise propranolol also resulted in a smaller ΔCBV (1.4 ± 0.8 vs. 5.3 ± 1.4 cm/s, P = 0.035), such that the relationship between coronary flow and cardiac metabolism was impaired under propranolol (0.43 ± 0.37 vs. 2.1 ± 0.63 arbitrary units). These data suggest that cold air breathing and isometric exercise significantly influence efferent control of coronary blood flow. Additionally, β-adrenergic vasodilation may play a significant role in coronary regulation during exercise. PMID:24816257

  4. Accurate Coulomb blockade thermometry up to 60 kelvin.

    PubMed

    Meschke, M; Kemppinen, A; Pekola, J P

    2016-03-28

    We demonstrate experimentally a precise realization of Coulomb blockade thermometry working at temperatures up to 60 K. Advances in nano-fabrication methods using electron beam lithography allow us to fabricate uniform arrays of sufficiently small tunnel junctions to guarantee an overall temperature reading precision of about 1%. PMID:26903107

  5. A new regime of Pauli-spin blockade

    NASA Astrophysics Data System (ADS)

    Perron, Justin K.; Stewart, M. D.; Zimmerman, Neil M.

    2016-04-01

    Pauli-spin blockade (PSB) is a transport phenomenon in double quantum dots that allows for a type of spin to charge conversion often used to probe fundamental physics such as spin relaxation and singlet-triplet coupling. In this paper, we theoretically explore Pauli-spin blockade as a function of magnetic field B applied parallel to the substrate. In the well-studied low magnetic field regime, where PSB occurs in the forward (1, 1) → (0, 2) tunneling direction, we highlight some aspects of PSB that are not discussed in detail in existing literature, including the change in size of both bias triangles measured in the forward and reverse biasing directions as a function of B. At higher fields, we predict a crossover to "reverse PSB" in which current is blockaded in the reverse direction due to the occupation of a spin singlet as opposed to the traditional triplet blockade that occurs at low fields. The onset of reverse PSB coincides with the development of a tail like feature in the measured bias triangles and occurs when the Zeeman energy of the polarized triplet equals the exchange energy in the (0, 2) charge configuration. In Si quantum dots, these fields are experimentally accessible; thus, this work suggests a way to observe a crossover in magnetic field to qualitatively different behavior.

  6. Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

    ERIC Educational Resources Information Center

    Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

    1997-01-01

    Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

  7. Non-linear HRV indices under autonomic nervous system blockade.

    PubMed

    Bolea, Juan; Pueyo, Esther; Laguna, Pablo; Bailón, Raquel

    2014-01-01

    Heart rate variability (HRV) has been studied as a non-invasive technique to characterize the autonomic nervous system (ANS) regulation of the heart. Non-linear methods based on chaos theory have been used during the last decades as markers for risk stratification. However, interpretation of these nonlinear methods in terms of sympathetic and parasympathetic activity is not fully established. In this work we study linear and non-linear HRV indices during ANS blockades in order to assess their relation with sympathetic and parasympathetic activities. Power spectral content in low frequency (0.04-0.15 Hz) and high frequency (0.15-0.4 Hz) bands of HRV, as well as correlation dimension, sample and approximate entropies were computed in a database of subjects during single and dual ANS blockade with atropine and/or propranolol. Parasympathetic blockade caused a significant decrease in the low and high frequency power of HRV, as well as in correlation dimension and sample and approximate entropies. Sympathetic blockade caused a significant increase in approximate entropy. Sympathetic activation due to postural change from supine to standing caused a significant decrease in all the investigated non-linear indices and a significant increase in the normalized power in the low frequency band. The other investigated linear indices did not show significant changes. Results suggest that parasympathetic activity has a direct relation with sample and approximate entropies.

  8. P2X7 receptor blockade protects against cisplatin-induced nephrotoxicity in mice by decreasing the activities of inflammasome components, oxidative stress and caspase-3

    SciTech Connect

    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao; Zhai, Zhifang; Gang Huang; Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong; Hou, Weiping

    2014-11-15

    Nephrotoxicity is a common complication of cisplatin chemotherapy and thus limits the use of cisplatin in clinic. The purinergic 2X7 receptor (P2X7R) plays important roles in inflammation and apoptosis in some inflammatory diseases; however, its roles in cisplatin-induced nephrotoxicity remain unclear. In this study, we first assessed the expression of P2X7R in cisplatin-induced nephrotoxicity in C57BL/6 mice, and then we investigated the changes of renal function, histological injury, inflammatory response, and apoptosis in renal tissues after P2X7R blockade in vivo using an antagonist A-438079. Moreover, we measured the changes of nod-like receptor family, pyrin domain containing proteins (NLRP3) inflammasome components, oxidative stress, and proapoptotic genes in renal tissues in cisplatin-induced nephrotoxicity after treatment with A-438079. We found that the expression of P2X7R was significantly upregulated in the renal tubular epithelial cells in cisplatin-induced nephrotoxicity compared with that of the normal control group. Furthermore, pretreatment with A-438079 markedly attenuated the cisplatin-induced renal injury while lightening the histological damage, inflammatory response and apoptosis in renal tissue, and improved the renal function. These effects were associated with the significantly reduced levels of NLRP3 inflammasome components, oxidative stress, p53 and caspase-3 in renal tissues in cisplatin-induced nephrotoxicity. In conclusions, our studies suggest that the upregulated activity of P2X7R might play important roles in the development of cisplatin-induced nephrotoxicity, and P2X7R blockade might become an effective therapeutic strategy for this disease. - Highlights: • The P2X7R expression was markedly upregulated in cisplatin-induced nephrotoxicity. • P2X7R blockade significantly attenuated the cisplatin-induced renal injury. • P2X7R blockade reduced activities of NLRP3 inflammasome components in renal tissue. • P2X7R blockade

  9. Ethanol Attenuates Peripheral NMDAR-Mediated Vascular Oxidative Stress and Pressor Response

    PubMed Central

    McGee, Marie A.; Abdel-Rahman, Abdel A.

    2015-01-01

    There are no studies on the acute effect of ethanol on peripheral N-methyl-D-aspartate receptor (NMDAR)-mediated increases in reactive oxygen species (ROS) and blood pressure (BP). We tested the hypothesis that ethanol antagonism of peripheral NMDAR dampens systemic NMDA-evoked increases in vascular ROS and BP. We investigated the effect of ethanol (1 g/kg) on BP and heart rate (HR) responses elicited by systemic bolus (125–1000 μg/kg, intra-venous [i.v.]) or infused (180 μg/kg/min) NMDA in conscious male Sprague-Dawley rats. We also hypothesized that peripheral NMDAR blockade with DL-2-Amino-5-phosphonopentanoic acid (AP-5; 5 mg/kg, i.v.) uncovers an ethanol- (1 or 1.5 g/kg) evoked hypotensive response. Ethanol attenuated the peripheral NMDAR-mediated pressor and bradycardic responses caused by NMDA infusion, and ex vivo studies revealed parallel ethanol attenuation of peripheral NMDAR-mediated increases in vascular ROS. While ethanol (1 or 1.5 g/kg) alone had no effect on BP, the higher dose caused a hypotensive response in the presence of NMDAR blockade (AP-5). Blood ethanol concentrations were not statistically different in the groups that received ethanol alone or along with NMDA or AP-5. These findings are the first to demonstrate ethanol attenuation of peripheral NMDAR-mediated pressor response, and the uncovering of ethanol-evoked hypotension in the presence of peripheral NMDAR blockade. PMID:25986731

  10. Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs.

    PubMed Central

    Verheggen, R.; Freudenthaler, S.; Meyer-Dulheuer, F.; Kaumann, A. J.

    1996-01-01

    1. We investigated the hypothesis that, as in some other large human arteries, 5-HT-induced contraction of the temporal artery is mediated through two co-existing receptor populations, 5-HT1-like- and 5-HT2A. Temporal arterial segments were obtained from patients undergoing brain surgery and rings prepared set up to contract with 5-HT and related agents. Fractions of maximal 5-HT responses mediated through 5-HT1-like and 5-HT2A receptors, f1 and f2 = 1-f1, were estimated by use of the 5-HT2A-selective antagonist ketanserin. 2. In rings with intact endothelium 5-HT evoked contractions with a -log EC50, M of 7.0. Ketanserin (10-1000 nM) antagonized part of the 5-HT-induced contractions. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M of 6.9 and f1 of 0.17 (100 nM ketanserin) and -log EC50, M of 6.4 and f1 of 0.20 (1000 nM ketanserin). 3. In rings with endothelial function attenuated by enzymatic treatment, 5-HT caused contractions with a -log EC50, M of 7.2 that were partially blocked by ketanserin. Ketanserin-resistant components of 5-HT-induced contractions were found with -log EC50, M 7.4 and f1 of 0.16 (100 nM ketanserin) and -log EC50, M of 7.5 and f1 of 0.14 (1000 nM ketanserin). 4. The ketanserin-resistant component of 5-HT-evoked contraction was blocked by methiothepin (100-1000 nM) consistent with mediation through 5-HT1-like receptors. 5. In rings with intact endothelium the 5-HT1-like-selective agonist, sumatriptan, caused small contractions with a -log EC50, M of 6.5 and intrinsic activity of 0.21 with respect to 5-HT that were resistant to blockade by 1000 nM ketanserin but antagonized by 100 nM methiothepin. 6. In rings with intact endothelium the 5-HT2A receptor partial agonist SK&F 103829 (2,3,4,5-tetrahydro-8[methyl sulphonyl]-1H3-benzazepin-7-ol methensulphonate) contracted rings with a -log EC50, M of 5.0 and an intrinsic activity of 0.49 with respect to 5-HT; the effects were antagonized by ketanserin 1000

  11. Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit.

    PubMed

    Wohlfarth, Kai M; Bianchi, Matt T; Macdonald, Robert L

    2002-03-01

    Attenuated behavioral sensitivity to neurosteroids has been reported for mice deficient in the GABA(A) receptor delta subunit. We therefore investigated potential subunit-specific neurosteroid pharmacology of the following GABA(A) receptor isoforms in a transient expression system: alpha1beta3gamma2L, alpha1beta3delta, alpha6beta3gamma2L, and alpha6beta3delta. Potentiation of submaximal GABA(A) receptor currents by the neurosteroid tetrahydrodeoxycorticosterone (THDOC) was greatest for the alpha1beta3delta isoform. Whole-cell GABA concentration--response curves performed with and without low concentrations (30 nm) of THDOC revealed enhanced peak GABA(A) receptor currents for isoforms tested without affecting the GABA EC50. Alpha1beta3delta currents were enhanced the most (>150%), whereas the other isoform currents were enhanced 15-50%. At a higher concentration (1 microm), THDOC decreased peak alpha1beta3gamma2L receptor current amplitude evoked by GABA (1 mm) concentration jumps and prolonged deactivation but had little effect on the rate or extent of apparent desensitization. Thus the polarity of THDOC modulation depended on GABA concentration for alpha1beta3gamma2L GABA(A) receptors. However, the same protocol applied to alpha1beta3delta receptors resulted in peak current enhancement by THDOC of >800% and prolonged deactivation. Interestingly, THDOC induced pronounced desensitization in the minimally desensitizing alpha1beta3delta receptors. Single channel recordings obtained from alpha1beta3delta receptors indicated that THDOC increased the channel opening duration, including the introduction of an additional longer duration open state. Our results suggest that the GABA(A) receptor delta subunit confers increased sensitivity to neurosteroid modulation and that the intrinsic gating and desensitization kinetics of alpha1beta3delta GABA(A) receptors are altered by THDOC.

  12. 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.

  13. 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)

  14. Blockade of Wnt/β-Catenin Pathway Aggravated Silica-Induced Lung Inflammation through Tregs Regulation on Th Immune Responses

    PubMed Central

    Dai, Wujing; Liu, Fangwei; Li, Chao; Lu, Yiping; Lu, Xiaowei; Du, Sitong; Chen, Ying; Weng, Dong; Chen, Jie

    2016-01-01

    CD4+ T cells play an important role in regulating silica-induced inflammation and fibrosis. Recent studies showed that Wnt/β-catenin pathway could modulate the function and the differentiation of CD4+ T cells. Therefore, Wnt/β-catenin pathway may participate in the development and progress of silicosis. To investigate the role of Wnt/β-catenin pathway, we used lentivirus expressing β-catenin shRNA to block the Wnt/β-catenin pathway by intratracheal instillation to the mice model of silicosis. Treatment of lentivirus could significantly aggravate the silica-induced lung inflammation and attenuated the fibrosis at the late stage. By analyzing CD4+ T cells, we found that blockade of Wnt/β-catenin pathway suppressed regulatory T cells (Tregs). Reciprocally, enhanced Th17 response was responsible for the further accumulation of neutrophils and production of proinflammatory cytokines. In addition, blockade of Wnt/β-catenin pathway delayed the Th1/Th2 polarization by inhibiting Tregs and Th2 response. These results indicated that Wnt/β-catenin pathway could regulate Tregs to modulate Th immune response, which finally altered the pathological character of silicosis. Our study suggested that Wnt/β-catenin pathway might be a potential target to treat the silica-induced inflammation and fibrosis. PMID:27069316

  15. Immunotherapeutic implications of IL-6 blockade for cytokine storm.

    PubMed

    Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

    2016-07-01

    IL-6 contributes to host defense against infections and tissue injuries. However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as 'cytokine storm', since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function. Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with cytokine release syndrome complicated by T-cell engaged therapy. In this review we propose the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis. PMID:27381687

  16. Counting Atoms Using Interaction Blockade in an Optical Superlattice

    SciTech Connect

    Cheinet, P.; Trotzky, S.; Schnorrberger, U.; Moreno-Cardoner, M.; Foelling, S.; Bloch, I.; Feld, M.

    2008-08-29

    We report on the observation of an interaction blockade effect for ultracold atoms in optical lattices, analogous to the Coulomb blockade observed in mesoscopic solid state systems. When the lattice sites are converted into biased double wells, we detect a discrete set of steps in the well population for increasing bias potentials. These correspond to tunneling resonances where the atom number on each side of the barrier changes one by one. This allows us to count and control the number of atoms within a given well. By evaluating the amplitude of the different plateaus, we can fully determine the number distribution of the atoms in the lattice, which we demonstrate for the case of a superfluid and Mott insulating regime of {sup 87}Rb.

  17. Immunotherapeutic implications of IL-6 blockade for cytokine storm.

    PubMed

    Tanaka, Toshio; Narazaki, Masashi; Kishimoto, Tadamitsu

    2016-07-01

    IL-6 contributes to host defense against infections and tissue injuries. However, exaggerated, excessive synthesis of IL-6 while fighting environmental stress leads to an acute severe systemic inflammatory response known as 'cytokine storm', since high levels of IL-6 can activate the coagulation pathway and vascular endothelial cells but inhibit myocardial function. Remarkable beneficial effects of IL-6 blockade therapy using a humanized anti-IL-6 receptor antibody, tocilizumab were recently observed in patients with cytokine release syndrome complicated by T-cell engaged therapy. In this review we propose the possibility that IL-6 blockade may constitute a novel therapeutic strategy for other types of cytokine storm, such as the systemic inflammatory response syndrome including sepsis, macrophage activation syndrome and hemophagocytic lymphohistiocytosis.

  18. Silicon-based Coulomb blockade thermometer with Schottky barriers

    NASA Astrophysics Data System (ADS)

    Tuboltsev, V.; Savin, A.; Rogozin, V. D.; Räisänen, J.

    2014-04-01

    A hybrid Coulomb blockade thermometer (CBT) in form of an array of intermittent aluminum and silicon islands connected in series via tunnel junctions was fabricated on a thin silicon-on-insulator (SOI) film. Tunnel barriers in the micrometer size junctions were formed by metal-semiconductor Schottky contacts between aluminium electrodes and heavily doped silicon. Differential conductance through the array vs. bias voltage was found to exhibit characteristic features of competing thermal and charging effects enabling absolute temperature measurements over the range of ˜65 to ˜500 mK. The CBT performance implying the primary nature of the thermometer demonstrated for rather trivial architecture attempted in this work paves a route for introduction of Coulomb blockade thermometry into well-developed contemporary SOI technology.

  19. Conductance of a proximitized nanowire in the Coulomb blockade regime

    NASA Astrophysics Data System (ADS)

    van Heck, B.; Lutchyn, R. M.; Glazman, L. I.

    2016-06-01

    We identify the leading processes of electron transport across finite-length segments of proximitized nanowires and build a quantitative theory of their two-terminal conductance. In the presence of spin-orbit interaction, a nanowire can be tuned across the topological transition point by an applied magnetic field. Due to a finite segment length, electron transport is controlled by the Coulomb blockade. Upon increasing of the field, the shape and magnitude of the Coulomb blockade peaks in the linear conductance are defined, respectively, by Andreev reflection, single-electron tunneling, and resonant tunneling through the Majorana modes emerging after the topological transition. Our theory provides the framework for the analysis of experiments with proximitized nanowires [such as reported in S. M. Albrecht et al., Nature (London) 531, 206 (2016), 10.1038/nature17162] and identifies the signatures of the topological transition in the two-terminal conductance.

  20. Vasopressin V1 receptors contribute to hemodynamic and sympathoinhibitory responses evoked by stimulation of adenosine A2a receptors in NTS.

    PubMed

    Scislo, Tadeusz J; O'Leary, Donal S

    2006-05-01

    Activation of adenosine A2a receptors in the nucleus of the solitary tract (NTS) decreases mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas increases in preganglionic adrenal sympathetic nerve activity (pre-ASNA) occur, a pattern similar to that observed during hypotensive hemorrhage. Central vasopressin V1 receptors may contribute to posthemorrhagic hypotension and bradycardia. Both V1 and A2a receptors are densely expressed in the NTS, and both of these receptors are involved in cardiovascular control; thus they may interact. The responses elicited by NTS A2a receptors are mediated mostly via nonglutamatergic mechanisms, possibly via release of vasopressin. Therefore, we investigated whether blockade of NTS V1 receptors alters the autonomic response patterns evoked by stimulation of NTS A2a receptors (CGS-21680, 20 pmol/50 nl) in alpha-chloralose-urethane anesthetized male Sprague-Dawley rats. In addition, we compared the regional sympathetic responses to microinjections of vasopressin (0.1-100 ng/50 nl) into the NTS. Blockade of V1 receptors reversed the normal decreases in MAP into increases (-95.6 +/- 28.3 vs. 51.4 +/- 15.7 integralDelta%), virtually abolished the decreases in HR (-258.3 +/- 54.0 vs. 18.9 +/- 57.8 integralDeltabeats/min) and RSNA (-239.3 +/- 47.4 vs. 15.9 +/- 36.1 integralDelta%), and did not affect the increases in pre-ASNA (279.7 +/- 48.3 vs. 233.1 +/- 54.1 integralDelta%) evoked by A2a receptor stimulation. The responses partially returned toward normal values approximately 90 min after the blockade. Microinjections of vasopressin into the NTS evoked dose-dependent decreases in HR and RSNA and variable MAP and pre-ASNA responses with a tendency toward increases. We conclude that the decreases in MAP, HR, and RSNA in response to NTS A2a receptor stimulation may be mediated via release of vasopressin from neural terminals in the NTS. The differential effects of NTS V1 and A2a receptors on

  1. Touch Perception Altered by Chronic Pain and by Opioid Blockade.

    PubMed

    Case, Laura K; Čeko, Marta; Gracely, John L; Richards, Emily A; Olausson, Håkan; Bushnell, M Catherine

    2016-01-01

    Touch plays a significant role in human social behavior and social communication, and its rewarding nature has been suggested to involve opioids. Opioid blockade in monkeys leads to increased solicitation and receipt of grooming, suggesting heightened enjoyment of touch. We sought to study the role of endogenous opioids in perception of affective touch in healthy adults and in patients with fibromyalgia, a chronic pain condition shown to involve reduced opioid receptor availability. The pleasantness of touch has been linked to the activation of C-tactile fibers, which respond maximally to slow gentle touch and correlate with ratings of pleasantness. We administered naloxone to patients and healthy controls to directly observe the consequences of µ-opioid blockade on the perceived pleasantness and intensity of touch. We found that at baseline chronic pain patients showed a blunted distinction between slow and fast brushing for both intensity and pleasantness, suggesting reduced C-tactile touch processing. In addition, we found a differential effect of opioid blockade on touch perception in healthy subjects and pain patients. In healthy individuals, opioid blockade showed a trend toward increased ratings of touch pleasantness, while in chronic pain patients it significantly decreased ratings of touch intensity. Further, in healthy individuals, naloxone-induced increase in touch pleasantness was associated with naloxone-induced decreased preference for slow touch, suggesting a possible effect of opioid levels on processing of C-tactile fiber input. These findings suggest a role for endogenous opioids in touch processing, and provide further evidence for altered opioid functioning in chronic pain patients. PMID:27022625

  2. Deterministic entanglement of two neutral atoms via Rydberg blockade

    SciTech Connect

    Zhang, X. L.; Isenhower, L.; Gill, A. T.; Walker, T. G.; Saffman, M.

    2010-09-15

    We demonstrate the deterministic entanglement of two individually addressed neutral atoms using a Rydberg blockade mediated controlled-not gate. Parity oscillation measurements reveal a Bell state fidelity of F=0.58{+-}0.04, which is above the entanglement threshold of F=0.5, without any correction for atom loss, and F=0.71{+-}0.05 after correcting for background collisional losses. The fidelity results are shown to be in good agreement with a detailed error model.

  3. Dynamical Coulomb blockade of tunnel junctions driven by alternating voltages

    NASA Astrophysics Data System (ADS)

    Grabert, Hermann

    2015-12-01

    The theory of the dynamical Coulomb blockade is extended to tunneling elements driven by a time-dependent voltage. It is shown that, for standard setups where an external voltage is applied to a tunnel junction via an impedance, time-dependent driving entails an excitation of the modes of the electromagnetic environment by the applied voltage. Previous approaches for ac driven circuits need to be extended to account for the driven bath modes. A unitary transformation involving also the variables of the electromagnetic environment is introduced which allows us to split off the time dependence from the Hamiltonian in the absence of tunneling. This greatly simplifies perturbation-theoretical calculations based on treating the tunneling Hamiltonian as a perturbation. In particular, the average current flowing in the leads of the tunnel junction is studied. Explicit results are given for the case of an applied voltage with a constant dc part and a sinusoidal ac part. The connection with standard dynamical Coulomb blockade theory for constant applied voltage is established. It is shown that an alternating voltage source reveals significant additional effects caused by the electromagnetic environment. The hallmark of the dynamical Coulomb blockade in ac driven devices is a suppression of higher harmonics of the current by the electromagnetic environment. The theory presented basically applies to all tunneling devices driven by alternating voltages.

  4. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Wang, Jieh-Neng; Wang, Jhi-Joung; Chen, Yu-Wen; Hung, Ching-Hsia

    2016-04-01

    The purpose of the experiment was to evaluate the local anesthetic effect of rimantadine in spinal anesthesia. Rimantadine in a dose-dependent fashion was constructed after intrathecally injecting the rats with four different doses. The potency and duration of rimantadine were compared with that of the local anesthetic lidocaine at producing spinal motor, nociceptive, and proprioceptive blockades. We demonstrated that intrathecal rimantadine dose-dependently produced spinal motor, nociceptive, and proprioceptive blockades. On the 50% effective dose (ED50) basis, the ranks of potencies at inducing spinal motor, nociceptive, and proprioceptive blockades was lidocaine>rimantadine (P<0.01). Rimantadine exhibited more nociceptive block (ED50) than motor block (P<0.05). At equi-anesthetic doses (ED25, ED50, and ED75), the spinal block duration produced by rimantadine was longer than that produced by lidocaine (P<0.01). Furthermore, rimantadine (26.52μmol/kg) prolonged the nociceptive nerve block more than the motor block (P<0.001). Our preclinical data showed that rimantadine, with a more sensory-selective action over motor block, was less potent than lidocaine. Rimantadine produced longer duration in spinal anesthesia when compared with lidocaine.

  5. Sequential RAAS blockade: is it worth the risk?

    PubMed

    Persson, Frederik; Rossing, Peter

    2014-03-01

    Soon after the emergence of the renin-angiotensin-aldosterone system (RAAS) blocking treatment as the cornerstone of renoprotective treatment in the prevention and treatment of diabetic and nondiabetic CKD, it was investigated if a higher degree of achievable RAAS blockade by combining more than one compound is feasible and advantageous. Regardless of the benefits from using monotherapy for diabetic kidney disease, there is still much improvement to wish for in terms of kidney prognosis in these populations. A great deal of research has gone into evaluating combinations of the RAAS blocking treatments in different populations and with different drugs and doses. Studies have mostly been short-term and use surrogate endpoints such as albuminuria. Side effects have been well known and expected in terms of increasing potassium levels and hypotension, but to an acceptable extent. With recent disappointing results from major hard endpoint trials using dual RAAS blockade the concept is now under scrutiny. In this review we will discuss the pros and cons of dual RAAS blockade, with facts and findings from smaller studies, endpoint trials, and meta-analyses. PMID:24602465

  6. Shape-sensitive Pauli blockade in a bent carbon nanotube

    NASA Astrophysics Data System (ADS)

    Széchenyi, Gábor; Pályi, András

    2015-01-01

    Motivated by a recent experiment [F. Pei et al., Nat. Nanotechnol. 7, 630 (2012), 10.1038/nnano.2012.160], we theoretically study the Pauli blockade transport effect in a double quantum dot embedded in a bent carbon nanotube. We establish a model for the Pauli blockade, taking into account the strong g -factor anisotropy that is linked to the local orientation of the nanotube axis in each quantum dot. We provide a set of conditions under which our model is approximately mapped to the spin-blockade model of Jouravlev and Nazarov [O. N. Jouravlev and Y. V. Nazarov, Phys. Rev. Lett. 96, 176804 (2006), 10.1103/PhysRevLett.96.176804]. The results we obtain for the magnetic anisotropy of the leakage current, together with their qualitative geometrical explanation, provide a possible interpretation of previously unexplained experimental results. Furthermore, we find that in a certain parameter range, the leakage current becomes highly sensitive to the shape of the tube, and this sensitivity increases with increasing g -factor anisotropy. This mutual dependence of the electron transport and the tube shape allows for mechanical control of the leakage current, and for characterization of the tube shape via measuring the leakage current.

  7. Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta 2-adrenoceptor blockade.

    PubMed Central

    Lipworth, B J; Brown, R A; McDevitt, D G

    1989-01-01

    1. The purpose of the study was to assess and compare the effects of inhaled salbutamol on heart rate (HR), finger tremor (Tr) and specific airways conductance (sGaw) in the measurement of beta 2-adrenoceptor blockade in normal subjects. 2. Five healthy volunteers were given oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40) or identical placebo (P1) in a single-blind crossover design. 3. Three hours after drug ingestion, dose-response curves were constructed using cumulative doses of inhaled salbutamol: 200 micrograms, 700 micrograms, 1700 micrograms, 3200 micrograms, 6200 micrograms. HR, Tr and sGaw were measured at each dose increment, made every 20 min. 4. Increasing doses of atenolol were associated with progressive reduction in salbutamol induced beta-adrenoceptor responses. The greatest attenuation occurred with propranolol. These effects on beta-adrenoceptor responses were similar for HR, Tr and sGaw. Geometric mean dose ratios (compared with placebo) for A50, A100, A200 and P40 were as follows HR: 1.98, 2.75, 4.29; Tr: 1.60, 3.78, 6.34, 80.50; sGaw: 1.08, 4.35, 12.30, 66.0 (no dose ratio was obtained for HR with P40). 5. These results showed that atenolol and propranolol attenuated the effects of salbutamol on HR to a similar degree as Tr and sGaw. Furthermore, the variability was least in the measurement of chronotropic responses, suggesting that this may be used to quantify beta 2-adrenoceptor antagonism. The beta 1-adrenoceptor selectivity of atenolol was a dose-dependent phenomenon, although the beta 2-adrenoceptor blockade of A200 was much less than with P40. PMID:2570601

  8. Tetrandrine induces lipid accumulation through blockade of autophagy in a hepatic stellate cell line.

    PubMed

    Miyamae, Yusaku; Nishito, Yukina; Nakai, Naomi; Nagumo, Yoko; Usui, Takeo; Masuda, Seiji; Kambe, Taiho; Nagao, Masaya

    2016-08-12

    Macroautophagy, or autophagy, is a cellular response in which unnecessary cytoplasmic components, including lipids and organelles, are self-degraded. Recent studies closely related autophagy to activation of hepatic stellate cells (HSCs), a process critical in the pathogenesis of liver fibrosis. During HSC activation, cytoplasmic lipid droplets (LDs) are degraded as autophagic cargo, and then cells express fibrogenic genes. Thus, inhibition of autophagy in HSCs is a potential therapeutic approach for attenuating liver fibrosis. We found that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra, induced lipid accumulation, a phenotype associated with quiescent HSCs, through blockade of autophagy in the rat-derived HSC line HSC-T6. Tetrandrine inhibited autophagic flux without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes (e.g., syntaxin 17). Moreover, perilipin 1, an LD-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated HSC-T6 cells. This suggests a potential role for perilipin 1 in autophagy-mediated LD degradation in HSCs. Our results identified tetrandrine as a potential tool for prevention and treatment of HSC activation. PMID:27270032

  9. Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders.

    PubMed

    Zhong, Chunlong; Luo, Qizhong; Jiang, Jiyao

    2014-12-01

    The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.

  10. Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.

    PubMed

    Pilat, Dominika; Piotrowska, Anna; Rojewska, Ewelina; Jurga, Agnieszka; Ślusarczyk, Joanna; Makuch, Wioletta; Basta-Kaim, Agnieszka; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.

  11. Checkpoint Blockade Cancer Immunotherapy Targets Tumour-Specific Mutant Antigens

    PubMed Central

    Gubin, Matthew M.; Zhang, Xiuli; Schuster, Heiko; Caron, Etienne; Ward, Jeffrey P.; Noguchi, Takuro; Ivanova, Yulia; Hundal, Jasreet; Arthur, Cora D.; Krebber, Willem-Jan; Mulder, Gwenn E.; Toebes, Mireille; Vesely, Matthew D.; Lam, Samuel S.K.; Korman, Alan J.; Allison, James P.; Freeman, Gordon J.; Sharpe, Arlene H.; Pearce, Erika L.; Schumacher, Ton N.; Aebersold, Ruedi; Rammensee, Hans-Georg; Melief, Cornelis J. M.; Mardis, Elaine R.; Gillanders, William E.; Artyomov, Maxim N.; Schreiber, Robert D.

    2014-01-01

    The immune system plays key roles in determining the fate of developing cancers by not only functioning as a tumour promoter facilitating cellular transformation, promoting tumour growth and sculpting tumour cell immunogenicity1–6, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion1,2,7. Yet clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer induced immunosuppression. In many individuals, immunosuppression is mediated by Cytotoxic T-Lymphocyte Associated Antigen-4 (CTLA-4) and Programmed Death-1 (PD-1), two immunomodulatory receptors expressed on T cells8,9. Monoclonal antibody (mAb) based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies10–13. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Herein, we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T cell rejection antigens following αPD-1 and/or αCTLA-4 therapy of mice bearing progressively growing sarcomas and show that therapeutic synthetic long peptide (SLP) vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Whereas, mutant tumour antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with αPD-1- and/or αCTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens (TSMA) are not only important targets of checkpoint blockade therapy but also can be

  12. Differential effects of dopamine and opioid receptor blockade on motivated Coca-Cola drinking behavior and associated changes in brain, skin and muscle temperatures.

    PubMed

    Kiyatkin, E A

    2010-05-01

    metabolic activity. This treatment (approximately 60 min) had minimal effects on the latencies of drinking, but increased its total duration, with licking interrupted by pauses and retreats. This behavioral attenuation was coupled with weaker than in control locomotor activation and diminished temperature fluctuations in each recording location. Therefore, attenuation of normal behavioral and physiological responses to appetitive stimuli appears to underlie modest inhibiting effects of opiate receptor blockade on motivated behavior and consumption.

  13. Planetary Ices Attenuation Properties

    NASA Astrophysics Data System (ADS)

    McCarthy, Christine; Castillo-Rogez, Julie C.

    In this chapter, we review the topic of energy dissipation in the context of icy satellites experiencing tidal forcing. We describe the physics of mechanical dissipation, also known as attenuation, in polycrystalline ice and discuss the history of laboratory methods used to measure and understand it. Because many factors - such as microstructure, composition and defect state - can influence rheological behavior, we review what is known about the mechanisms responsible for attenuation in ice and what can be inferred from the properties of rocks, metals and ceramics. Since attenuation measured in the laboratory must be carefully scaled to geologic time and to planetary conditions in order to provide realistic extrapolation, we discuss various mechanical models that have been used, with varying degrees of success, to describe attenuation as a function of forcing frequency and temperature. We review the literature in which these models have been used to describe dissipation in the moons of Jupiter and Saturn. Finally, we address gaps in our present knowledge of planetary ice attenuation and provide suggestions for future inquiry.

  14. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors.

    PubMed

    Duraiswamy, Jaikumar; Kaluza, Karen M; Freeman, Gordon J; Coukos, George

    2013-06-15

    Tumor progression is facilitated by regulatory T cells (Treg) and restricted by effector T cells. In this study, we document parallel regulation of CD8(+) T cells and Foxp3(+) Tregs by programmed death-1 (PD-1, PDCD1). In addition, we identify an additional role of CTL antigen-4 (CTLA-4) inhibitory receptor in further promoting dysfunction of CD8(+) T effector cells in tumor models (CT26 colon carcinoma and ID8-VEGF ovarian carcinoma). Two thirds of CD8(+) tumor-infiltrating lymphocytes (TIL) expressed PD-1, whereas one third to half of CD8(+) TIL coexpressed PD-1 and CTLA-4. Double-positive (PD-1(+)CTLA-4(+)) CD8(+) TIL had characteristics of more severe dysfunction than single-positive (PD-1(+) or CTLA-4(+)) TIL, including an inability to proliferate and secrete effector cytokines. Blockade of both PD-1 and CTLA-4 resulted in reversal of CD8(+) TIL dysfunction and led to tumor rejection in two thirds of mice. Double blockade was associated with increased proliferation of antigen-specific effector CD8(+) and CD4(+) T cells, antigen-specific cytokine release, inhibition of suppressive functions of Tregs, and upregulation of key signaling molecules critical for T-cell function. When used in combination with GVAX vaccination (consisting of granulocyte macrophage colony-stimulating factor-expressing irradiated tumor cells), inhibitory pathway blockade induced rejection of CT26 tumors in 100% of mice and ID8-VEGF tumors in 75% of mice. Our study indicates that PD-1 signaling in tumors is required for both suppressing effector T cells and maintaining tumor Tregs, and that PD-1/PD-L1 pathway (CD274) blockade augments tumor inhibition by increasing effector T-cell activity, thereby attenuating Treg suppression.

  15. 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.

  16. Radiofrequency attenuator and method

    SciTech Connect

    Warner, Benjamin P.; McCleskey, T. Mark; Burrell, Anthony K.; Agrawal, Anoop; Hall, Simon B.

    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.

  17. 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.

  18. 5-HT-1A receptor-mediated modulation of medullary expiratory neurones in the cat.

    PubMed Central

    Lalley, P M; Bischoff, A M; Richter, D W

    1994-01-01

    The involvement of the 5-HT-1A receptor in serotoninergic responses of stage 2 expiratory (E-2) neurones was investigated in pentobarbitone-anaesthetized, mechanically ventilated cats. The specific agonist of the 5-HT-1A receptor, 8-hydroxy-diproplaminotetralin (8-OH-DPAT), administered systemically or by ionophoresis directly on to the neurones, had a clear depressant effect. Administration of 8-OH-DPAT at doses of 10-50 micrograms kg-1 (I.V.) increased the membrane hyperpolarizations of E-2 neurones during the inspiratory and postinspiratory phases, and shortened their duration of activity in association with shortening of phrenic nerve activity. Discharges of E-2 neurones were also less intense. At doses of 50-90 micrograms kg-1, 8-OH-DPAT reduced or abolished inspiratory hyperpolarizations, and reduced expiratory depolarizations of membrane potential and discharge in parallel with inhibition of phrenic nerve discharges. The effects of the larger doses were reversed by I.V. injection of NAN-190, an antagonist at the 5-HT-1A receptor. Dose-dependent effects on the membrane potential and discharge of E-2 neurones, but not on phrenic nerve activity, were also seen by ionophoretic administration of 8-OH-DPAT on to E-2 neurones. At low currents, ejection of 8-OH-DPAT hyperpolarized the neurones without affecting the duration of inspiratory hyperpolarization and expiratory depolarization. This hyperpolarization depressed the intensity and the duration of expiratory discharges. Ejection with larger currents hyperpolarized the E-2 neurones further, and depressed expiratory depolarization leading to blockade of expiratory discharges. The effects on membrane potential were accompanied by decreased neuronal input resistance. This depressed the excitability of E-2 neurones as tested by discharge evoked by intracellular current injection. The amplitudes of action potentials decreased in parallel with the changes in input resistance. The effects were attributed to a

  19. Neuromuscular blockade: what was, is and will be.

    PubMed

    Schepens, Tom; Cammu, Guy

    2014-01-01

    Non-depolarizing neuromuscular blocking agents (NMBAs) produce neuromuscular blockade by competing with acetylcholine at the neuromuscular junction, whereas depolarizing NMBAs open receptor channels in a manner similar to that of acetylcholine. Problems with NMBAs include malignant hyperthermia caused by succinylcholine, anaphylaxis with the highest incidence for succinylcholine and rocuronium, and residual neuromuscular blockade. To reverse these blocks, anticholinesterases can act indirectly by increasing the amount of acetylcholine in the neuromuscular junction; sugammadex is the only selective relaxant binding agent (SRBA) in clinical use. At all levels of blockade, recovery after sugammadex is faster than after neostigmine. Sugammadex potentially also has some other advantages over neostigmine that are related to neostigmine's increase in the amount of acetylcholine and the necessity of co-administering anticholinergics. However, hypersensitivity reactions, including anaphylaxis, have occurred in some patients and healthy volunteers after sugammadex and remain an issue for the FDA. In the near future, we may see the emergence of new SRBAs and of easier-to-use technologies that can routinely monitor neuromuscular transmissions in daily practice. The nature of the effect of sugammadex on freeing nicotinic acetylcholine receptors located outside the neuromuscular junction from NMBAs is unknown. Moreover, it is uncertain whether the full removal of the competing antagonists (by SRBAs) at the neuromuscular junction impacts the efficiency of acetylcholine transmission. In a recent pilot study in healthy volunteers, we demonstrated increased electromyographic diaphragm activity after sugammadex, compared to neostigmine. Further research is needed to elucidate the role of NMBAs and their reversal agents in the central control of breathing, respiratory muscle activity, and respiratory outcomes. PMID:25622380

  20. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium

    PubMed Central

    Fan, Xiujun; Krieg, Sacha; Kuo, Calvin J.; Wiegand, Stanley J.; Rabinovitch, Marlene; Druzin, Maurice L.; Brenner, Robert M.; Giudice, Linda C.; Nayak, Nihar R.

    2008-01-01

    Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that blockade of VEGF action with VEGF Trap, a potent VEGF blocker, completely inhibited neovascularization during endometrial regeneration in both models but had no marked effect on preexisting or newly formed vessels, suggesting that VEGF is essential for neoangiogenesis but not survival of mature vessels in this vascular bed. Blockade of VEGF also blocked reepithelialization in both the postmenstrual endometrium and the mouse uterus after decidual breakdown, evidence that VEGF has pleiotropic effects in the endometrium. In vitro studies with a scratch wound assay showed that the migration of luminal epithelial cells during repair involved signaling through VEGF receptor 2–neuropilin 1 (VEGFR2-NP1) receptors on endometrial stromal cells. The leading front of tissue growth during endometrial repair was strongly hypoxic, and this hypoxia was the local stimulus for VEGF expression and angiogenesis in this tissue. In summary, we provide novel experimental data indicating that VEGF is essential for endometrial neoangiogenesis during postmenstrual/postpartum repair.—Fan, X., Krieg, S., Kuo, C. J., Wiegand, S. J., Rabinovitch, M., Druzin, M. L., Brenner, R. M., Giudice, L. C., Nayak, N. R. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. PMID:18606863

  1. GP IIb/IIIa Blockade During Peripheral Artery Interventions

    SciTech Connect

    Tepe, Gunnar Wiskirchen, Jakub; Pereira, Philippe; Claussen, Claus D.; Miller, Stephen; Duda, Stephan H.

    2008-01-15

    The activation of the platelet GP IIb/IIIa receptor is the final and common pathway in platelet aggregation. By blocking this receptor, platelet aggregation can be inhibited independently of the stimulus prompted the targeting of this receptor. Several years ago, three drugs have been approved for coronary artery indications. Since that time, there is increasing evidence that GP IIb/IIIa receptor blockade might have also an important role in peripheral arterial intervention. This article summarizes the action and differences of GP Ilb/IIIa receptor inhibitors and its possible indication in peripheral arteries.

  2. Coulomb blockade and superuniversality of the theta angle.

    PubMed

    Burmistrov, I S; Pruisken, A M M

    2008-08-01

    Based on the Ambegaokar-Eckern-Schön approach to the Coulomb blockade, we develop a complete quantum theory of the single electron transistor. We identify a previously unrecognized physical observable in the problem that, unlike the usual average charge on the island, is robustly quantized for any finite value of the tunneling conductance as the temperature goes to absolute zero. This novel quantity is fundamentally related to the nonsymmetrized current noise of the system. Our results display all of the superuniversal topological features of the theta angle concept that previously arose in the theory of the quantum Hall effect.

  3. Angiotensin II type 1a receptor signalling directly contributes to the increased arrhythmogenicity in cardiac hypertrophy

    PubMed Central

    Yasuno, Shinji; Kuwahara, Koichiro; Kinoshita, Hideyuki; Yamada, Chinatsu; Nakagawa, Yasuaki; Usami, Satoru; Kuwabara, Yoshihiro; Ueshima, Kenji; Harada, Masaki; Nishikimi, Toshio; Nakao, Kazuwa

    2013-01-01

    BACKGROUND AND PURPOSE Angiotensin II has been implicated in the development of various cardiovascular ailments, including cardiac hypertrophy and heart failure. The fact that inhibiting its signalling reduced the incidences of both sudden cardiac death and heart failure in several large-scale clinical trials suggests that angiotensin II is involved in increased cardiac arrhythmogenicity during the development of heart failure. However, because angiotensin II also promotes structural remodelling, including cardiomyocyte hypertrophy and cardiac fibrosis, it has been difficult to assess its direct contribution to cardiac arrhythmogenicity independently of the structural effects. EXPERIMENTAL APPROACH We induced cardiac hypertrophy in wild-type (WT) and angiotensin II type 1a receptor knockout (AT1aR-KO) mice by transverse aortic constriction (TAC). The susceptibility to ventricular tachycardia (VT) assessed in an in vivo electrophysiological study was compared in the two genotypes. The effect of acute pharmacological blockade of AT1R on the incidences of arrhythmias was also assessed. KEY RESULTS As described previously, WT and AT1aR-KO mice with TAC developed cardiac hypertrophy to the same degree, but the incidence of VT was much lower in the latter. Moreover, although TAC induced an increase in tyrosine phosphorylation of connexin 43, a critical component of gap junctional channels, and a reduction in ventricular levels of connexin 43 protein in both genotypes, the effect was significantly ameliorated in AT1aR-KO mice. Acute pharmacological blockade of AT1R also reduced the incidence of arrhythmias. CONCLUSIONS AND IMPLICATIONS Our findings demonstrate that AT1aR-mediated signalling makes a direct contribution to the increase in arrhythmogenicity in hypertrophied hearts independently of structural remodelling. PMID:23937445

  4. 5-HT1a receptor antagonists block perforant path-dentate LTP induced in novel, but not familiar, environments

    PubMed Central

    Sanberg, Cyndy Davis; Jones, Floretta L.; Do, Viet H.; Dieguez, Dario; Derrick, Brian E.

    2006-01-01

    Numerous studies suggest roles for monoamines in modulating long-term potentiation (LTP). Previously, we reported that both induction and maintenance of perforant path-dentate gyrus LTP is enhanced when induced while animals explore novel environments. Here we investigate the contribution of serotonin and 5-HT1a receptors to the novelty-mediated enhancement of LTP. In freely moving animals, systemic administration of the selective 5-HT1a antagonist WAY-100635 (WAY) attenuated LTP in a dose-dependent manner when LTP was induced while animals explored novel cages. In contrast, LTP was completely unaffected by WAY when induced in familiar environments. LTP was also blocked in anesthetized animals by direct application of WAY to the dentate gyrus, but not to the median raphe nucleus (MRN), suggesting the effect of systemic WAY is mediated by a block of dentate 5-HT1a receptors. Paradoxically, systemic administration of the 5-HT1a agonist 8-OH-DPAT also attenuated LTP. This attenuation was mimicked in anesthetized animals following application of 8-OH-DPAT to the MRN, but not the dentate gyrus. In addition, application of a 5-HT1a agonist to the dentate gyrus reduced somatic GABAergic inhibition. Because serotonergic projections from the MRN terminate on dentate inhibitory interneurons, these data suggest 5-HT1a receptors contribute to LTP induction via inhibition of GABAergic interneurons. Moreover, activation of raphe 5-HT1a autoreceptors, which inhibits serotonin release, attenuated LTP induction even in familiar environments. This suggests that serotonin normally contributes to dentate LTP induction in a variety of behavioral states. Together, these data suggest that serotonin and dentate 5-HT1a receptors play a permissive role in dentate LTP induction, particularly in novel conditions, and presumably, during the encoding of novel, hippocampus-relevant information. PMID:16452654

  5. Tritium Attenuation by Distillation

    SciTech Connect

    Wittman, N.E.

    2001-07-31

    The objective of this study was to determine how a 100 Area distillation system could be used to reduce to a satisfactory low value the tritium content of the dilute moderator produced in the 100 Area stills, and whether such a tritium attenuator would have sufficient capacity to process all this material before it is sent to the 400 Area for reprocessing.

  6. Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients

    PubMed Central

    Salciccioli, Justin D.; Cocchi, Michael N.; Rittenberger, Jon C.; Peberdy, Mary Ann; Ornato, Joseph P.; Abella, Benjamin S.; Gaieski, David F.; Clore, John; Gautam, Shiva; Giberson, Tyler; Callaway, Clifton W.; Donnino, Michael W.

    2013-01-01

    Aim Neuromuscular blockade may improve outcome in patients with acute respiratory distress syndrome. In post-cardiac arrest patients receiving therapeutic hypothermia, neuromuscular blockade is often used to prevent shivering. Our objective was to determine whether neuromuscular blockade is associated with improved outcomes after out-of-hospital cardiac arrest. Methods A post-hoc analysis of a prospective observational study of comatose adult (> 18 years) out-of-hospital cardiac arrest at 4 tertiary cardiac arrest centers. The primary exposure of interest was neuromuscular blockade for 24 hours following return of spontaneous circulation and primary outcomes were in-hospital survival and neurologically intact survival. Secondary outcomes were evolution of oxygenation (PaO2:FiO2), and change in lactate. We tested the primary outcomes of in-hospital survival and neurologically intact survival with multivariable logistic regression. Secondary outcomes were tested with multivariable linear mixed-models. Results A total of 111 patients were analyzed. In patients with 24 hours of sustained neuromuscular blockade, the crude survival rate was 14/18 (78%) compared to 38/93 (41%) in patients without sustained neuromuscular blockade (p = 0.004). After multivariable adjustment, neuromuscular blockade was associated with survival (adjusted OR: 7.23, 95% CI: 1.56 –33.38). There was a trend toward improved functional outcome with neuromuscular blockade (50% vs. 28%; p = 0.07). Sustained neuromuscular blockade was associated with improved lactate clearance (adjusted p = 0.01). Conclusions We found that early neuromuscular blockade for a 24-hour period is associated with an increased probability of survival. Secondarily, we found that early, sustained neuromuscular blockade is associated with improved lactate clearance. PMID:23796602

  7. Antidepressant, Antipsychotic, and Hallucinogen Drugs for the Treatment of Psychiatric Disorders: A Convergence at the Serotonin-2A Receptor.

    PubMed

    Howland, Robert H

    2016-07-01

    Antidepressant, atypical antipsychotic, and hallucinogen drugs mediate their actions in part by interactions with the serotonin-2A (5HT2A) receptor. Serotonergic hallucinogen drugs, such as psilocybin, bind most potently as agonists at the 5HT2A receptor, producing profound changes in perception, mood, and cognition. Some of these drugs have been or are currently being investigated in small Phase 2 studies for depression, alcoholism, smoking cessation, anxiety, and posttraumatic stress disorder. However, unlike the synergistic effects of combining antidepressant and atypical antipsychotic drugs, the potential therapeutic effects of hallucinogen drugs may be attenuated by the concurrent use of these medications because antidepressant and atypical antipsychotic drugs desensitize and/or down-regulate 5HT2A receptors. This finding has important implications for optimizing the potential therapeutic use of hallucinogen drugs in psychiatry. [Journal of Psychosocial Nursing and Mental Health Services, 54(7), 21-24.]. PMID:27362381

  8. Postsynaptic Adenosine A2A Receptors Modulate Intrinsic Excitability of Pyramidal Cells in the Rat Basolateral Amygdala

    PubMed Central

    Rau, Andrew R.; Ariwodola, Olusegun J.

    2015-01-01

    Background: The basolateral amygdala plays a critical role in the etiology of anxiety disorders and addiction. Pyramidal neurons, the primary output cells of this region, display increased firing following exposure to stressors, and it is thought that this increase in excitability contributes to stress responsivity and the expression of anxiety-like behaviors. However, much remains unknown about the underlying mechanisms that regulate the intrinsic excitability of basolateral amygdala pyramidal neurons. Methods: Ex vivo gramicidin perforated patch recordings were conducted in current clamp mode where hyper- and depolarizing current steps were applied to basolateral amygdala pyramidal neurons to assess the effects of adenosine A2A receptor modulation on intrinsic excitability. Results: Activation of adenosine A2A receptors with the selective A2A receptor agonist CGS-21680 significantly increased the firing rate of basolateral amygdala pyramidal neurons in rat amygdala brain slices, likely via inhibition of the slow afterhyperpolarization potential. Both of these A2A receptor-mediated effects were blocked by preapplication of a selective A2A receptor antagonist (ZM-241385) or by intra-pipette infusion of a protein kinase A inhibitor, suggesting a postsynaptic locus of A2A receptors on basolateral amygdala pyramidal neurons. Interestingly, bath application of the A2A receptor antagonist alone significantly attenuated basolateral amygdala pyramidal cell firing, consistent with a role for tonic adenosine in the regulation of the intrinsic excitability of these neurons. Conclusions: Collectively, these data suggest that adenosine, via activation of A2A receptors, may directly facilitate basolateral amygdala pyramidal cell output, providing a possible balance for the recently described inhibitory effects of adenosine A1 receptor activation on glutamatergic excitation of basolateral amygdala pyramidal cells. PMID:25716780

  9. Assessment of bronchial beta blockade after oral bevantolol.

    PubMed

    Mackay, A D; Gribbin, H R; Baldwin, C J; Tattersfield, A E

    1981-01-01

    We have applied a new method for quantitative measurement of bronchial beta adrenoceptor blockade to a new beta adrenoceptor antagonist, bevantolol. Dose-response curves to a beta agonist, albuterol, were obtained in six normal subjects by measuring specific airway conductance (sGaw) after increasing doses of inhaled albuterol. These were repeated on three separate occasions 2 hr after subjects had taken oral placebo or bevantolol (75 or 150 mg), double-blind in random order. The dose-response curves after bevantolol 75 mg were displaced in the right of placebo in four subjects and after 150 mg were displaced to the right of placebo in all subjects. The mean dose ratios for bevantolol 75 or 150 mg were 1.02 and 2.77, much the same as those obtained in the same subjects after practolol 100 and 200 mg and considerably less than that after propranolol 40 mg. The mean reductions in exercise heart rate were 25% and 29% after bevantolol 75 and 150 mg. Our data show that bronchial beta blockade after a beta blocking drug can be assessed quantitatively in many by a double-blind technique.

  10. Effects of VLA-1 Blockade on Experimental Inflammation in Mice.

    PubMed

    Totsuka, Ryuichi; Kondo, Takaaki; Matsubara, Shigeki; Hirai, Midori; Kurebayashi, Yoichi

    2016-01-01

    VLA-1 (very late antigen-1) is implicated in recruitment, retention and activation of leukocytes and its blockade has been referred as a potential target of new drug discovery to address unmet medical needs in inflammatory disease area. In the present study, we investigate the effects of an anti-murine CD49a (integrin α subunit of VLA-1) monoclonal antibody (Ha31/8) on various experimental models of inflammatory diseases in mice. Pretreatment with Ha31/8 at an intraperitoneal dose of 250 µg significantly (P<0.01) reduced arthritic symptoms and joint tissue damage in mice with type II collagen-induced arthritis. In addition, Ha31/8 at an intraperitoneal dose of 100 µg significantly (P<0.01) inhibited airway inflammatory cell infiltration induced by repeated exposure to cigarette smoke. In contrast, Ha31/8 failed to inhibit oxazolone-induced chronic dermatitis and OVA-induced airway hyperresponsiveness at an intraperitoneal dose of 100 µg. These results show that VLA-1 is involved, at least partly, in the pathogenesis of type II collagen-induced arthritis and cigarette smoke-induced airway inflammatory cell infiltration in mice, indicating the therapeutic potential of VLA-1 blockade against rheumatoid arthritis and chronic occlusive pulmonary disease. PMID:27578034

  11. OX40L blockade protects against inflammation-driven fibrosis.

    PubMed

    Elhai, Muriel; Avouac, Jérôme; Hoffmann-Vold, Anna Maria; Ruzehaji, Nadira; Amiar, Olivia; Ruiz, Barbara; Brahiti, Hassina; Ponsoye, Matthieu; Fréchet, Maxime; Burgevin, Anne; Pezet, Sonia; Sadoine, Jérémy; Guilbert, Thomas; Nicco, Carole; Akiba, Hisaya; Heissmeyer, Vigo; Subramaniam, Arun; Resnick, Robert; Molberg, Øyvind; Kahan, André; Chiocchia, Gilles; Allanore, Yannick

    2016-07-01

    Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.

  12. Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats.

    PubMed

    Tzeng, Jann-Inn; Lin, Heng-Teng; Chen, Yu-Wen; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-04-01

    This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine.

  13. Assessment of Methods for the Intracellular Blockade of GABAA Receptors.

    PubMed

    Atherton, Laura A; Burnell, Erica S; Mellor, Jack R

    2016-01-01

    Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4'-dinitro-stilbene-2,2'-disulphonic acid (DNDS) and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility. PMID:27501143

  14. Philosophical Intelligence: Letters, Print, and Experiment during Napoleon's Continental Blockade.

    PubMed

    Watts, Iain P

    2015-12-01

    This essay investigates scientific exchanges between Britain and France from 1806 to 1814, at the height of the Napoleonic Wars. It argues for a picture of scientific communication that sees letters and printed texts not as separate media worlds, but as interconnected bearers of time-critical information within a single system of intelligence gathering and experimental practice. During this period, Napoleon Bonaparte's Continental System blockade severed most links between Britain and continental Europe, yet scientific communications continued--particularly on electrochemistry, a subject of fierce rivalry between Britain and France. The essay traces these exchanges using the archive of a key go-between, the English man of science Sir Charles Blagden. The first two sections look at Blagden's letter-writing operation, reconstructing how he harnessed connections with neutral American diplomats, merchants, and the State to get scientific intelligence between London and Paris. The third section, following Blagden's words from Britain to France to America, looks at how information in letters cross-fertilized with information in print. The final section considers how letters and print were used together to solve the difficult practical problem of replicating experiments across the blockade.

  15. [Recent Development of Therapies for Melanoma Using Immune Checkpoint Blockades].

    PubMed

    Okuyama, Ryuhei

    2016-06-01

    Melanoma is a highly immune tumor, and tumor-specific T lymphocytes are occasionally induced. Recent progress in tumor immunology has made it possible to clinically develop new medicines targeting immune checkpoint molecules, such as cytotoxic T lymphocyte antigen 4(CTLA-4), programmed cell death 1(PD-1), and programmed cell death 1 ligand 1(PD-L1). CTLA-4 is expressed on naïve T cells and regulatory T cells. Ipilimumab, an anti-CTLA-4 antibody, shows a distinct durable clinical benefit by inhibiting the immunosuppressive function of CTLA-4. PD-1, which is expressed on activated T cells, inhibits T cell responses against tumor cells. The antibodies against PD-1, nivolumab and pembrolizumab, produce anti-tumor responses in melanoma and other cancers due to T cell reactivation. Furthermore, clinical trials of combination therapies using immune checkpoint blockades with molecularly targeted therapies and other chemotherapeutic agents are being conducted. However, immune checkpoint blockades frequently cause immune-related adverse events. Targeted therapies to immune checkpoint molecules are expected to be promising strategies for treatment of melanoma and other cancers. PMID:27306802

  16. OX40L blockade protects against inflammation-driven fibrosis.

    PubMed

    Elhai, Muriel; Avouac, Jérôme; Hoffmann-Vold, Anna Maria; Ruzehaji, Nadira; Amiar, Olivia; Ruiz, Barbara; Brahiti, Hassina; Ponsoye, Matthieu; Fréchet, Maxime; Burgevin, Anne; Pezet, Sonia; Sadoine, Jérémy; Guilbert, Thomas; Nicco, Carole; Akiba, Hisaya; Heissmeyer, Vigo; Subramaniam, Arun; Resnick, Robert; Molberg, Øyvind; Kahan, André; Chiocchia, Gilles; Allanore, Yannick

    2016-07-01

    Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40-OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease, we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation. PMID:27298374

  17. Philosophical Intelligence: Letters, Print, and Experiment during Napoleon's Continental Blockade.

    PubMed

    Watts, Iain P

    2015-12-01

    This essay investigates scientific exchanges between Britain and France from 1806 to 1814, at the height of the Napoleonic Wars. It argues for a picture of scientific communication that sees letters and printed texts not as separate media worlds, but as interconnected bearers of time-critical information within a single system of intelligence gathering and experimental practice. During this period, Napoleon Bonaparte's Continental System blockade severed most links between Britain and continental Europe, yet scientific communications continued--particularly on electrochemistry, a subject of fierce rivalry between Britain and France. The essay traces these exchanges using the archive of a key go-between, the English man of science Sir Charles Blagden. The first two sections look at Blagden's letter-writing operation, reconstructing how he harnessed connections with neutral American diplomats, merchants, and the State to get scientific intelligence between London and Paris. The third section, following Blagden's words from Britain to France to America, looks at how information in letters cross-fertilized with information in print. The final section considers how letters and print were used together to solve the difficult practical problem of replicating experiments across the blockade. PMID:27024935

  18. The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

    PubMed Central

    Arzt, Michael E.; Weinmann, Oliver; Obermair, Franz J.; Pernet, Vincent; Zagrebelsky, Marta; Delekate, Andrea; Iobbi, Cristina; Zemmar, Ajmal; Ristic, Zorica; Gullo, Miriam; Spies, Peter; Dodd, Dana; Gygax, Daniel; Korte, Martin; Schwab, Martin E.

    2014-01-01

    Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A−/− mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity. PMID:24453941

  19. Monitored natural attenuation.

    PubMed

    Jørgensen, Kirsten S; Salminen, Jani M; Björklöf, Katarina

    2010-01-01

    Monitored natural attenuation (MNA) is an in situ remediation technology that relies on naturally occurring and demonstrable processes in soil and groundwater which reduce the mass and concentration of the contaminants. Natural attenuation (NA) involves both aerobic and anaerobic degradation of the contaminants due to the fact that oxygen is used up near the core of the contaminant plume. The aerobic and anaerobic microbial processes can be assessed by microbial activity measurements and molecular biology methods in combination with chemical analyses. The sampling and knowledge on the site conditions are of major importance for the linkage of the results obtained to the conditions in situ. Rates obtained from activity measurements can, with certain limitations, be used in modeling of the fate of contaminants whereas most molecular methods mainly give qualitative information on the microbial community and gene abundances. However, molecular biology methods are fast and describe the in situ communities and avoid the biases inherent to activity assays requiring laboratory incubations.

  20. Fluid dynamic bowtie attenuators

    NASA Astrophysics Data System (ADS)

    Szczykutowicz, Timothy P.; Hermus, James

    2015-03-01

    Fluence field modulated CT allows for improvements in image quality and dose reduction. To date, only 1-D modulators have been proposed, the extension to 2-D modulation is difficult with solid-metal attenuation-based modulators. This work proposes to use liquids and gas to attenuate the x-ray beam which can be arrayed allowing for 2-D fluence modulation. The thickness of liquid and the pressure for a given path length of gas were determined that provided the same attenuation as 30 cm of soft tissue at 80, 100, 120, and 140 kV. Gaseous Xenon and liquid Iodine, Zinc Chloride, and Cerium Chloride were studied. Additionally, we performed some proof-of-concept experiments in which (1) a single cell of liquid was connected to a reservoir which allowed the liquid thickness to be modulated and (2) a 96 cell array was constructed in which the liquid thickness in each cell was adjusted manually. Liquid thickness varied as a function of kV and chemical composition, with Zinc Chloride allowing for the smallest thickness; 1.8, 2.25, 3, and 3.6 cm compensated for 30 cm of soft tissue at 80, 100, 120, and 140 kV respectively. The 96 cell Iodine attenuator allowed for a reduction in both dynamic range to the detector and scatter to primary ratio. Successful modulation of a single cell was performed at 0, 90, and 130 degrees using a simple piston/actuator. The thickness of liquids and the Xenon gas pressure seem logistically implementable within the constraints of CBCT and diagnostic CT systems.

  1. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2

    PubMed Central

    Mediero, Aránzazu; Wilder, Tuere; Perez-Aso, Miguel; Cronstein, Bruce N.

    2015-01-01

    Promoting bone regeneration and repair of bone defects is a need that has not been well met to date. We have previously found that adenosine, acting via A2A receptors (A2AR) promotes wound healing and inhibits inflammatory osteolysis and hypothesized that A2AR might be a novel target to promote bone regeneration. Therefore, we determined whether direct A2AR stimulation or increasing endogenous adenosine concentrations via purine transport blockade with dipyridamole regulates bone formation. We determined whether coverage of a 3 mm trephine defect in a mouse skull with a collagen scaffold soaked in saline, bone morphogenetic protein-2 (BMP-2; 200 ng), 1 μM CGS21680 (A2AR agonist, EC50 = 160 nM), or 1 μM dipyridamole (EC50 = 32 nM) promoted bone regeneration. Microcomputed tomography examination demonstrated that CGS21680 and dipyridamole markedly enhanced bone regeneration as well as BMP-2 8 wk after surgery (60 ± 2%, 79 ± 2%, and 75 ± 1% bone regeneration, respectively, vs. 32 ± 2% in control, P < 0.001). Blockade by a selective A2AR antagonist (ZM241385, 1 μM) or deletion of A2AR abrogated the effect of CGS21680 and dipyridamole on bone regeneration. Both CGS21680 and dipyridamole treatment increased alkaline phosphatase-positive osteoblasts and diminished tartrate resistance acid phosphatase-positive osteoclasts in the defects. In vivo imaging with a fluorescent dye for new bone formation revealed a strong fluorescent signal in treated animals that was equivalent to BMP-2. In conclusion, stimulation of A2AR by specific agonists or by increasing endogenous adenosine levels stimulates new bone formation as well as BMP-2 and represents a novel approach to stimulating bone regeneration.—Mediero, A., Wilder, T., Perez-Aso, M., Cronstein, B. N. Direct or indirect stimulation of adenosine A2A receptors enhances bone regeneration as well as bone morphogenetic protein-2. PMID:25573752

  2. Ventral hippocampal α7 and α4β2 nicotinic receptor blockade and clozapine effects on memory in female rats

    PubMed Central

    Pocivavsek, Ana; Icenogle, Laura; Levin, Edward D.

    2007-01-01

    Rationale Nicotinic systems in the hippocampus play important roles in memory function. Decreased hippocampal nicotinic receptor concentration is associated with cognitive impairment in schizophrenia and Alzheimer's disease. Methods We modeled in rats the cognitive effects of chronic decrease in hippocampal α7 or α4β2 receptors with 4-week continuous bilateral local infusions of the α7 nicotinic antagonist methyllycaconitine (MLA) or the α4β2 antagonist dihydro-β-erythroidine (DHβE). The working memory effects of these infusions were assessed by performance on the radial-arm maze. To test the effect of antipsychotic medication, we gave acute injections of clozapine and to determine the impact of nicotine, which is widely used by people with schizophrenia approximately half of the rats received chronic systemic infusions of nicotine. Results Chronic ventral hippocampal DHβE infusion caused a significant (p<0.001) working memory impairment. Acute systemic clozapine (2.5 mg/kg) caused a significant (p<0.005) working memory impairment in rats given control aCSF hippocampal infusions. Clozapine significantly (p<0.025) attenuated the memory deficit caused by chronic hippocampal DHβE infusions. Chronic ventral hippocampal infusions with MLA did not significantly affect the working memory performance in the radial-arm maze, but it did significantly (p<0.05) potentiate the memory impairment caused by 1.25 mg/kg of clozapine. Chronic systemic nicotine did not significantly interact with these effects. Conclusions The state of nicotinic receptor activation in the ventral hippocampus significantly affected the impact of clozapine on working memory with blockade of α7 nicotinic receptors potentiating clozapine-induced memory impairment and blockade of α4β2 receptors reversing the clozapine effect from impairing to improving memory. PMID:16715255

  3. Blockade of the N-Methyl-D-Aspartate Glutamate Receptor Ameliorates Lipopolysaccharide-Induced Renal Insufficiency

    PubMed Central

    Huang, Ho-Shiang; Ma, Ming-Chieh

    2015-01-01

    N-methyl-D-aspartate (NMDA) receptor activation in rat kidney reduces renal perfusion and ultrafiltration. Hypoperfusion-induced ischemia is the most frequent cause of functional insufficiency in the endotoxemic kidney. Here, we used non-hypotensive rat model of lipopolysaccharide-induced endotoxemia to examine whether NMDA receptor hyperfunction contributes to acute kidney injury. Lipopolysaccharide-induced renal damage via increased enzymuria and hemodynamic impairments were ameliorated by co-treatment with the NMDA receptor blocker, MK-801. The NMDA receptor NR1 subunit in the rat kidney mainly co-localized with serine racemase, an enzyme responsible for synthesizing the NMDA receptor co-agonist, D-serine. The NMDA receptor hyperfunction in lipopolysaccharide-treated kidneys was demonstrated by NR1 and serine racemase upregulation, particularly in renal tubules, and by increased D-serine levels. Lipopolysaccharide also induced cell damage in cultured tubular cell lines and primary rat proximal tubular cells. This damage was mitigated by MK-801 and by small interfering RNA targeting NR1. Lipopolysaccharide increased cytokine release in tubular cell lines via toll-like receptor 4. The release of interleukin-1β from these cells are the most abundant. An interleukin-1 receptor antagonist not only attenuated cell death but also abolished lipopolysaccharide-induced NR1 and serine racemase upregulation and increases in D-serine secretion, suggesting that interleukin-1β-mediated NMDA receptor hyperfunction participates in lipopolysaccharide-induced tubular damage. The results of this study indicate NMDA receptor hyperfunction via cytokine effect participates in lipopolysaccharide-induced renal insufficiency. Blockade of NMDA receptors may represent a promising therapeutic strategy for the treatment of sepsis-associated renal failure. PMID:26133372

  4. Fast and slow blockade of sodium channels by flecainide in rabbit cardiac Purkinje fibres.

    PubMed

    Konzen, G; Reichardt, B; Hauswirth, O

    1990-06-01

    The electrophysiological effects of flecainide were tested using the two-microelectrode voltage-clamp technique and Vmax-measurements in isolated rabbit cardiac Purkinje fibres. Flecainide predominantly unfolds its sodium-channel blocking action during the upstroke phase of the cardiac action potential, because its Vmax-depressant effects are independent of the duration of the depolarizing interval. Very long lasting depolarizations caused a second, very slow blocking activity. Starting from a steady-state block, recovery from block was tested and yielded a time constant of 7.3 s for a membrane potential of -105 mV. The strong blockade of sodium-channels combined with a delayed recovery behaviour of the drug-associated channels gives reasons for the observation of a marked use-dependent block. This block increased when the cycle length was shortened or the holding potential was less negative. Additional application of lidocaine in several concentrations did not significantly increase or attenuate the phasic block caused by flecainide alone. Under special conditions we investigated flecainide's depression and shift of the Vmax/Vm-relation and we observed that the concentration dependence of both parameters could be described by simple 1:1 binding reaction. The effects of flecainide are largely reversible often greater than or equal to 15 min. Flecainide could be characterized as an open channel blocker with a very slow inactivated channel blocking activity. For the qualitative description of the sodium-channel block by flecainide we used the "modulated-receptor hypothesis", whereas for reconstructions of the use-dependent action we applied the "guarded-receptor hypothesis", which enables computations of phasic block with the knowledge of only one forward and one reverse rate constant.

  5. Renin Inhibition and AT1R blockade improve metabolic signaling, oxidant stress and myocardial tissue remodeling

    PubMed Central

    Whaley-Connell, Adam; Habibi, Javad; Rehmer, Nathan; Ardhanari, Sivakumar; Hayden, Melvin R; Pulakat, Lakshmi; Krueger, Caroline; M Ferrario, Carlos; DeMarco, Vincent G; Sowers, James R

    2013-01-01

    Objective Strategies that block angiotensin II actions on its angiotensin type 1 receptor or inhibit actions of aldosterone have been shown to reduce myocardial hypertrophy and interstitial fibrosis in states of insulin resistance. Thereby, we sought to determine if combination of direct renin inhibition with angiotensin type 1 receptor blockade in vivo, through greater reductions in systolic blood pressure (SBP) and aldosterone would attenuate left ventricular hypertrophy and interstitial fibrosis to a greater extent than either intervention alone. Materials/Methods We utilized the transgenic Ren2 rat which manifests increased tissue expression of murine renin which, in turn, results in increased renin-angiotensin system activity, aldosterone secretion and insulin resistance. Ren2 rats were treated with aliskiren, valsartan, the combination (aliskiren+valsartan), or vehicle for 21 days. Results Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic blood pressure, elevated serum aldosterone levels, cardiac tissue hypertrophy, interstitial fibrosis and ultrastructural remodeling. These biochemical and functional alterations were accompanied by increases in the NADPH oxidase subunit Nox2 and 3-nitrotyrosine content along with increases in mammalian target of rapamycin and reductions in protein kinase B phosphorylation. Combination therapy contributed to greater reductions in systolic blood pressure and serum aldosterone but did not result in greater improvement in metabolic signaling or markers of oxidative stress, fibrosis or hypertrophy beyond either intervention alone. Conclusions Thereby, our data suggest that the greater impact of combination therapy on reductions in aldosterone does not translate into greater reductions in myocardial fibrosis or hypertrophy in this transgenic model of tissue renin overexpression. PMID:23352204

  6. Blockade of chronic high glucose-induced endothelial apoptosis by Sasa borealis bamboo extract.

    PubMed

    Choi, Yean-Jung; Lim, Hyeon-Sook; Choi, Jung-Suk; Shin, Seung-Yong; Bae, Ji-Young; Kang, Sang-Wook; Kang, Il-Jun; Kang, Young-Hee

    2008-05-01

    Hyperglycemia is a causal factor in the development of diabetic vascular complications including impaired vascular smooth muscle contractility and increased cell proliferation. The present study was designed to investigate the effects of Sasa borealis water-extract (SBwE) on chronic hyperglycemia-induced oxidative stress and apoptosis in human umbilical endothelial cells (HUVEC). HUVEC were cultured in 5.5 mM low glucose, 5.5 mM glucose plus 27.5 mM mannitol as an osmotic control, or 33 mM high glucose for 5 days in the absence and presence of 1-30 microg/ ml SBwE. Caspase-3 activation and Annexin V staining revealed chronic high glucose-induced endothelial apoptotic toxicity with a generation of oxidants detected by DCF-fluorescence, and these effects were reversed by SBwE at > or =1 microg/ml in a dose-dependent manner. Cytoprotective SBwE substantially reduced the sustained high glucose-induced expression of endothelial nitric oxide synthase and attenuated the formation of peroxynitrite radicals. The suppressive effects of SBwE were most likely mediated through blunting activation of PKC beta 2 and NADPH oxidase promoted by high glucose. In addition, this bamboo extract modulated the high glucose-triggered mitogen-activated protein kinase-dependent upregulation of heat-shock proteins. Our results suggest that SBwE suppressed these detrimental effects caused by PKC-dependent peroxynitrite formation via activation of NADPH oxidase and induction of nitric oxide synthase and heat-shock protein family that may be essential mechanisms responsible for increased apoptotic oxidative stress in diabetic vascular complications. Moreover, the blockade of high glucose-elicited heat-shock protein induction appeared to be responsible for SBwE-alleviated endothelial apoptosis. Therefore, SBwE may be a therapeutic agent for the prevention and treatment of diabetic endothelial dysfunction and related complications. PMID:18375828

  7. Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

    PubMed Central

    Essandoh, Kobina; Yang, Liwang; Wang, Xiaohong; Huang, Wei; Qin, Dongze; Hao, Jiukuan; Wang, Yigang; Zingarelli, Basilia; Peng, Tianqing; Fan, Guo-Chang

    2015-01-01

    Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival. PMID:26300484

  8. Ethanol attenuates peripheral NMDAR-mediated vascular oxidative stress and pressor response.

    PubMed

    McGee, Marie A; Abdel-Rahman, Abdel A

    2015-08-01

    There are no studies on the acute effect of ethanol on peripheral N-methyl-d-aspartate receptor (NMDAR)-mediated increases in reactive oxygen species (ROS) and blood pressure (BP). We tested the hypothesis that ethanol antagonism of peripheral NMDAR dampens systemic NMDA-evoked increases in vascular ROS and BP. We investigated the effect of ethanol (1 g/kg) on BP and heart rate (HR) responses elicited by systemic bolus (125-1000 μg/kg, intra-venous [i.v.]) or infused (180 μg/kg/min) NMDA in conscious male Sprague-Dawley rats. We also hypothesized that peripheral NMDAR blockade with DL-2-Amino-5-phosphonopentanoic acid (AP-5; 5 mg/kg, i.v.) uncovers an ethanol- (1 or 1.5 g/kg) evoked hypotensive response. Ethanol attenuated the peripheral NMDAR-mediated pressor and bradycardic responses caused by NMDA infusion, and ex vivo studies revealed parallel ethanol attenuation of peripheral NMDAR-mediated increases in vascular ROS. While ethanol (1 or 1.5 g/kg) alone had no effect on BP, the higher dose caused a hypotensive response in the presence of NMDAR blockade (AP-5). Blood ethanol concentrations were not statistically different in the groups that received ethanol alone or along with NMDA or AP-5. These findings are the first to demonstrate ethanol attenuation of peripheral NMDAR-mediated pressor response, and the uncovering of ethanol-evoked hypotension in the presence of peripheral NMDAR blockade.

  9. Control algorithms for dynamic attenuators

    SciTech Connect

    Hsieh, Scott S.; Pelc, Norbert J.

    2014-06-15

    Purpose: The authors describe algorithms to control dynamic attenuators in CT and compare their performance using simulated scans. Dynamic attenuators are prepatient beam shaping filters that modulate the distribution of x-ray fluence incident on the patient on a view-by-view basis. These attenuators can reduce dose while improving key image quality metrics such as peak or mean variance. In each view, the attenuator presents several degrees of freedom which may be individually adjusted. The total number of degrees of freedom across all views is very large, making many optimization techniques impractical. The authors develop a theory for optimally controlling these attenuators. Special attention is paid to a theoretically perfect attenuator which controls the fluence for each ray individually, but the authors also investigate and compare three other, practical attenuator designs which have been previously proposed: the piecewise-linear attenuator, the translating attenuator, and the double wedge attenuator. Methods: The authors pose and solve the optimization problems of minimizing the mean and peak variance subject to a fixed dose limit. For a perfect attenuator and mean variance minimization, this problem can be solved in simple, closed form. For other attenuator designs, the problem can be decomposed into separate problems for each view to greatly reduce the computational complexity. Peak variance minimization can be approximately solved using iterated, weighted mean variance (WMV) minimization. Also, the authors develop heuristics for the perfect and piecewise-linear attenuators which do not requirea priori knowledge of the patient anatomy. The authors compare these control algorithms on different types of dynamic attenuators using simulated raw data from forward projected DICOM files of a thorax and an abdomen. Results: The translating and double wedge attenuators reduce dose by an average of 30% relative to current techniques (bowtie filter with tube current

  10. Selective α1-adrenergic blockade disturbs the regional distribution of cerebral blood flow during static handgrip exercise.

    PubMed

    Fernandes, Igor A; Mattos, João D; Campos, Monique O; Machado, Alessandro C; Rocha, Marcos P; Rocha, Natalia G; Vianna, Lauro C; Nobrega, Antonio C L

    2016-06-01

    Handgrip-induced increases in blood flow through the contralateral artery that supplies the cortical representation of the arm have been hypothesized as a consequence of neurovascular coupling and a resultant metabolic attenuation of sympathetic cerebral vasoconstriction. In contrast, sympathetic restraint, in theory, inhibits changes in perfusion of the cerebral ipsilateral blood vessels. To confirm whether sympathetic nerve activity modulates cerebral blood flow distribution during static handgrip (SHG) exercise, beat-to-beat contra- and ipsilateral internal carotid artery blood flow (ICA; Doppler) and mean arterial pressure (MAP; Finometer) were simultaneously assessed in nine healthy men (27 ± 5 yr), both at rest and during a 2-min SHG bout (30% maximal voluntary contraction), under two experimental conditions: 1) control and 2) α1-adrenergic receptor blockade. End-tidal carbon dioxide (rebreathing system) was clamped throughout the study. SHG induced increases in MAP (+31.4 ± 10.7 mmHg, P < 0.05) and contralateral ICA blood flow (+80.9 ± 62.5 ml/min, P < 0.05), while no changes were observed in the ipsilateral vessel (-9.8 ± 39.3 ml/min, P > 0.05). The reduction in ipsilateral ICA vascular conductance (VC) was greater compared with contralateral ICA (contralateral: -0.8 ± 0.8 vs. ipsilateral: -2.6 ± 1.3 ml·min(-1)·mmHg(-1), P < 0.05). Prazosin was effective to induce α1-blockade since phenylephrine-induced increases in MAP were greatly reduced (P < 0.05). Under α1-adrenergic receptor blockade, SHG evoked smaller MAP responses (+19.4 ± 9.2, P < 0.05) but similar increases in ICAs blood flow (contralateral: +58.4 ± 21.5 vs. ipsilateral: +54.3 ± 46.2 ml/min, P > 0.05) and decreases in VC (contralateral: -0.4 ± 0.7 vs. ipsilateral: -0.4 ± 1.0 ml·min(-1)·mmHg(-1), P > 0.05). These findings indicate a role of sympathetic nerve activity in the regulation of cerebral blood flow distribution during SHG.

  11. Ultrasonic attenuation in pearlitic steel.

    PubMed

    Du, Hualong; Turner, Joseph A

    2014-03-01

    Expressions for the attenuation coefficients of longitudinal and transverse ultrasonic waves are developed for steel with pearlitic microstructure. This type of lamellar duplex microstructure influences attenuation because of the lamellar spacing. In addition, longitudinal attenuation measurements were conducted using an unfocused transducer with 10 MHz central frequency on the cross section of a quenched railroad wheel sample. The dependence of longitudinal attenuation on the pearlite microstructure is observed from the changes of longitudinal attenuation from the quenched tread surface to deeper locations. The results show that the attenuation value is lowest and relatively constant within the quench depth, then increases linearly. The experimental results demonstrate a reasonable agreement with results from the theoretical model. Ultrasonic attenuation provides an important non-destructive method to evaluate duplex microstructure within grains which can be implemented for quality control in conjunction with other manufacturing processes.

  12. Coulomb blockade and BLOCH oscillations in superconducting Ti nanowires.

    PubMed

    Lehtinen, J S; Zakharov, K; Arutyunov, K Yu

    2012-11-01

    Quantum fluctuations in quasi-one-dimensional superconducting channels leading to spontaneous changes of the phase of the order parameter by 2π, alternatively called quantum phase slips (QPS), manifest themselves as the finite resistance well below the critical temperature of thin superconducting nanowires and the suppression of persistent currents in tiny superconducting nanorings. Here we report the experimental evidence that in a current-biased superconducting nanowire the same QPS process is responsible for the insulating state--the Coulomb blockade. When exposed to rf radiation, the internal Bloch oscillations can be synchronized with the external rf drive leading to formation of quantized current steps on the I-V characteristic. The effects originate from the fundamental quantum duality of a Josephson junction and a superconducting nanowire governed by QPS--the QPS junction.

  13. Interleukin-1 blockade in refractory giant cell arteritis.

    PubMed

    Ly, Kim-Heang; Stirnemann, Jérôme; Liozon, Eric; Michel, Marc; Fain, Olivier; Fauchais, Anne-Laure

    2014-01-01

    Giant cell arteritis is a primary large-vessel vasculitis characterized by an arterial wall inflammation associated with intimal hyperplasia leading to arterial occlusion. Glucocorticoids remain the mainstay of giant cell arteritis treatment. However, relapses and glucocorticoid-related complications are frequent and therapeutic options for refractory giant cell arteritis are quite limited. Like tumor necrosis factor-α and interleukin-6, interleukin-1β is also highly expressed in inflamed arterial walls of patients with giant cell arteritis and may contribute in the pathogenesis of this disease. We report treatment of three cases of refractory giant cell arteritis successfully treated with anakinra, an interleukin-1 blockade therapy. Anakinra was effective for all patients, yielding improvement in their inflammation biomarkers and/or in their symptoms, as well as a disappearance of arterial inflammation in PET/CT for two of them.

  14. Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway.

    PubMed

    Adams, Andrew B; Ford, Mandy L; Larsen, Christian P

    2016-09-15

    T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology. Abatacept and belatacept are clinically approved agents for the treatment of rheumatoid arthritis and renal transplantation, respectively. Future interventions may include selective CD28 blockade to block the costimulatory potential of CD28 while exploiting the coinhibitory effects of CTLA-4. PMID:27591335

  15. Cavity polaritons with Rydberg blockade and long-range interactions

    NASA Astrophysics Data System (ADS)

    Litinskaya, Marina; Tignone, Edoardo; Pupillo, Guido

    2016-08-01

    We study interactions between polaritons, arising when photons strongly couple to collective excitations in an array of two-level atoms trapped in an optical lattice inside a cavity. We consider two types of interactions between atoms: dipolar forces and atomic saturability, which range from hard-core repulsion to Rydberg blockade. We show that, in spite of the underlying repulsion in the subsystem of atomic excitations, saturability induces a broadband bunching of photons for two-polariton scattering states. We interpret this bunching as a result of interference, and trace it back to the mismatch of the quantization volumes for atomic excitations and photons. We also examine bound bipolaritonic states: these include states created by dipolar forces, as well as a gap bipolariton, which forms solely due to saturability effects in the atomic transition. Both types of bound states exhibit strong bunching in the photonic component. We discuss the dependence of bunching on experimentally relevant parameters.

  16. Weber Blockade Theory of Magnetoresistance Oscillations in Superconducting Strips

    NASA Astrophysics Data System (ADS)

    Pekker, David; Refael, Gil; Goldbart, Paul M.

    2011-07-01

    Recent experiments on the conductance of thin, narrow superconducting strips have found periodic fluctuations, as a function of the perpendicular magnetic field, with a period corresponding to approximately two flux quanta per strip area [A. Johansson , Phys. Rev. Lett. 95, 116805 (2005)PRLTAO0031-900710.1103/PhysRevLett.95.116805]. We argue that the low-energy degrees of freedom responsible for dissipation correspond to vortex motion. Using vortex-charge duality, we show that the superconducting strip behaves as the dual of a quantum dot, with the vortices, magnetic field, and bias current respectively playing the roles of the electrons, gate voltage, and source-drain voltage. In the bias-current versus magnetic-field plane, the strip conductance displays regions of small vortex conductance (i.e., small electrical resistance) that we term “Weber blockade” diamonds, which are dual to Coulomb blockade diamonds in quantum dots.

  17. Investigation of uncertainty components in Coulomb blockade thermometry

    SciTech Connect

    Hahtela, O. M.; Heinonen, M.; Manninen, A.; Meschke, M.; Savin, A.; Pekola, J. P.; Gunnarsson, D.; Prunnila, M.; Penttilä, J. S.; Roschier, L.

    2013-09-11

    Coulomb blockade thermometry (CBT) has proven to be a feasible method for primary thermometry in every day laboratory use at cryogenic temperatures from ca. 10 mK to a few tens of kelvins. The operation of CBT is based on single electron charging effects in normal metal tunnel junctions. In this paper, we discuss the typical error sources and uncertainty components that limit the present absolute accuracy of the CBT measurements to the level of about 1 % in the optimum temperature range. Identifying the influence of different uncertainty sources is a good starting point for improving the measurement accuracy to the level that would allow the CBT to be more widely used in high-precision low temperature metrological applications and for realizing thermodynamic temperature in accordance to the upcoming new definition of kelvin.

  18. Deterministic spin-wave interferometer based on the Rydberg blockade

    SciTech Connect

    Wei Ran; Deng Youjin; Pan Jianwei; Zhao Bo; Chen Yuao

    2011-06-15

    The spin-wave (SW) N-particle path-entangled |N,0>+|0,N> (NOON) state is an N-particle Fock state with two atomic spin-wave modes maximally entangled. Attributed to the property that the phase is sensitive to collective atomic motion, the SW NOON state can be utilized as an atomic interferometer and has promising application in quantum enhanced measurement. In this paper we propose an efficient protocol to deterministically produce the atomic SW NOON state by employing the Rydberg blockade. Possible errors in practical manipulations are analyzed. A feasible experimental scheme is suggested. Our scheme is far more efficient than the recent experimentally demonstrated one, which only creates a heralded second-order SW NOON state.

  19. Effect of on-chip filter on Coulomb blockade thermometer

    NASA Astrophysics Data System (ADS)

    Roschier, L.; Gunnarsson, D.; Meschke, M.; Savin, A.; Penttilä, J. S.; Prunnila, M.

    2012-12-01

    Coulomb Blockade Thermometer (CBT) is a primary thermometer based on electric conductance of normal tunnel junction arrays. One limitation for CBT use at the lowest temperatures has been due to environmental noise heating. To improve on this limitation, we have done measurements on CBT sensors fabricated with different on-chip filtering structures in a dilution refrigerator with a base temperature of 10 mK. The CBT sensors were produced with a wafer scale tunnel junction process. We present how the different on-chip filtering schemes affect the limiting saturation temperatures and show that CBT sensors with proper on-chip filtering work at temperatures below 20 mK and are tolerant to noisy environment.

  20. Investigation of uncertainty components in Coulomb blockade thermometry

    NASA Astrophysics Data System (ADS)

    Hahtela, O. M.; Meschke, M.; Savin, A.; Gunnarsson, D.; Prunnila, M.; Penttilä, J. S.; Roschier, L.; Heinonen, M.; Manninen, A.; Pekola, J. P.

    2013-09-01

    Coulomb blockade thermometry (CBT) has proven to be a feasible method for primary thermometry in every day laboratory use at cryogenic temperatures from ca. 10 mK to a few tens of kelvins. The operation of CBT is based on single electron charging effects in normal metal tunnel junctions. In this paper, we discuss the typical error sources and uncertainty components that limit the present absolute accuracy of the CBT measurements to the level of about 1 % in the optimum temperature range. Identifying the influence of different uncertainty sources is a good starting point for improving the measurement accuracy to the level that would allow the CBT to be more widely used in high-precision low temperature metrological applications and for realizing thermodynamic temperature in accordance to the upcoming new definition of kelvin.

  1. Anisotropic Pauli spin blockade in hole quantum dots

    NASA Astrophysics Data System (ADS)

    Brauns, Matthias; Ridderbos, Joost; Li, Ang; Bakkers, Erik P. A. M.; van der Wiel, Wilfred G.; Zwanenburg, Floris A.

    2016-07-01

    We present measurements on gate-defined double quantum dots in Ge-Si core-shell nanowires, which we tune to a regime with visible shell filling in both dots. We observe a Pauli spin blockade and can assign the measured leakage current at low magnetic fields to spin-flip cotunneling, for which we measure a strong anisotropy related to an anisotropic g factor. At higher magnetic fields we see signatures for leakage current caused by spin-orbit coupling between (1,1) singlet and (2,0) triplet states. Taking into account these anisotropic spin-flip mechanisms, we can choose the magnetic field direction with the longest spin lifetime for improved spin-orbit qubits.

  2. Assessment of Methods for the Intracellular Blockade of GABAA Receptors

    PubMed Central

    Atherton, Laura A.; Burnell, Erica S.; Mellor, Jack R.

    2016-01-01

    Selective blockade of inhibitory synaptic transmission onto specific neurons is a useful tool for dissecting the excitatory and inhibitory synaptic components of ongoing network activity. To achieve this, intracellular recording with a patch solution capable of blocking GABAA receptors has advantages over other manipulations, such as pharmacological application of GABAergic antagonists or optogenetic inhibition of populations of interneurones, in that the majority of inhibitory transmission is unaffected and hence the remaining network activity preserved. Here, we assess three previously described methods to block inhibition: intracellular application of the molecules picrotoxin, 4,4’-dinitro-stilbene-2,2’-disulphonic acid (DNDS) and 4,4’-diisothiocyanostilbene-2,2’-disulphonic acid (DIDS). DNDS and picrotoxin were both found to be ineffective at blocking evoked, monosynaptic inhibitory postsynaptic currents (IPSCs) onto mouse CA1 pyramidal cells. An intracellular solution containing DIDS and caesium fluoride, but lacking nucleotides ATP and GTP, was effective at decreasing the amplitude of IPSCs. However, this effect was found to be independent of DIDS, and the absence of intracellular nucleotides, and was instead due to the presence of fluoride ions in this intracellular solution, which also blocked spontaneously occurring IPSCs during hippocampal sharp waves. Critically, intracellular fluoride ions also caused a decrease in both spontaneous and evoked excitatory synaptic currents and precluded the inclusion of nucleotides in the intracellular solution. Therefore, of the methods tested, only fluoride ions were effective for intracellular blockade of IPSCs but this approach has additional cellular effects reducing its selectivity and utility. PMID:27501143

  3. Influence of antiseptics on microcirculation after neuronal and receptor blockade.

    PubMed

    Goertz, Ole; Hirsch, Tobias; Ring, Andrej; Muehlberger, Thomas; Steinau, Hans U; Tilkorn, Daniel; Lehnhardt, Marcus; Homann, Heinz H

    2011-08-01

    The topical application of the antiseptics octenidine and polyhexanide on wounds seems to improve microcirculation. These two antiseptics were tested in combination with neuronal inhibition and sympathethic receptor blockade to verify these findings, explore the influence of β blockers on these microcirculative effects, and find out the principle of operation. Investigations were carried out on a standardised cremaster muscle model in rats (n = 66). The tested antiseptics, octenidine and polyhexanide were investigated alone (n = 12) and in combination with bupivacaine (n = 12), metoprolol (n = 12), phentolamine (n = 12) and surgical denervation (n = 12). Physiological saline was used for control (n = 6). The arteriolar diameter and functional capillary density (FCD) were investigated via trans-illumination microscopy before, as well as 60 and 120 minutes after application. Polyhexanide caused a significant increase in arteriolar diameter (86·5 ± 3·8 µm versus 100·0 ± 3·6 µm) and, like octenidine (7·2 ± 0·7 n/0·22 mm(2) versus 11·6 ± 0·6 n/0·22 mm(2) ), in FCD (9·2 ± 0·5 versus 12·6 ± 0·9) as well. When the antiseptics are used in combination with bupivacaine, metoprolol, phentolamine or surgical sympathectomy, these effects were eliminated or inverted. Assessing the results of the different blockades in combination with polyhexanide, we surmise that the antiseptic polyhexanide acts on the microcirculation mainly by blocking α receptors. This study shows that polyhexanide and octenidine improve muscular perfusion. Interestingly, the benefit of polyhexanide and octenidine on muscular perfusion is eliminated when the antiseptics are combined with other vasoactive agents, especially β blockers.

  4. Blockade of tolerance to morphine analgesia by cocaine.

    PubMed

    Misra, A L; Pontani, R B; Vadlamani, N L

    1989-07-01

    Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system. PMID:2780065

  5. Oleanolic acid acrylate elicits antidepressant-like effect mediated by 5-HT1A receptor.

    PubMed

    Fajemiroye, James O; Polepally, Prabhakar R; Chaurasiya, Narayan D; Tekwani, Babu L; Zjawiony, Jordan K; Costa, Elson A

    2015-01-01

    The development of new drugs for the treatment of depression is strategic to achieving clinical needs of patients. This study evaluates antidepressant-like effect and neural mechanisms of four oleanolic acid derivatives i.e. acrylate (D1), methacrylate (D2), methyl fumarate (D3) and ethyl fumarate (D4). All derivatives were obtained by simple one-step esterification of oleanolic acid prior to pharmacological screening in the forced swimming (FS) and open field (OF) tests. Pharmacological tools like α-methyl-p-tyrosine (AMPT, catecholamine depletor), p-chlorophenylalanine (serotonin depletor), prazosin (PRAZ, selective α1-receptor antagonist), WAY-100635 (selective serotonin 5-HT1A receptor antagonist) as well as monoamine oxidase (MAO) and functional binding assays were conducted to investigate possible neural mechanisms. In the FS test, D1 showed the most promising antidepressant-like effect without eliciting locomotor incoordination. Unlike group of mice pretreated with AMPT 100 mg/kg, PCPA 100 mg/kg or PRAZ 1 mg/kg, the effect of D1 was attenuated by WAY-100635 0.3 mg/kg pretreatment. D1 demonstrated moderate inhibition of MAO-A (IC50 = 48.848 ± 1.935 μM), potency (pEC50 = 6.1 ± 0.1) and intrinsic activity (E max = 26 ± 2.0%) on 5-HT1A receptor. In conclusion, our findings showed antidepressant-like effect of D1 and possible involvement of 5-HT1A receptor.

  6. Diminished trkA receptor signaling reveals cholinergic-attentional vulnerability of aging

    PubMed Central

    Parikh, Vinay; Howe, William M.; Welchko, Ryan M.; Naughton, Sean X.; D'Amore, Drew E.; Han, Daniel H.; Deo, Monika; Turner, David L.; Sarter, Martin

    2012-01-01

    The cellular mechanisms underlying the exceptional vulnerability of the basal forebrain (BF) cholinergic neurons during pathological aging have remained elusive. Here we employed an adeno-associated viral vector-based RNA interference (AAV-RNAi) strategy to suppress the expression of trkA receptors by cholinergic neurons in the nucleus basalis of Meynert/ substantia innominata (nMB/SI) of adult and aged rats. Suppression of trkA receptor expression impaired attentional performance selectively in aged rats. Performance correlated with trkA levels in the nMB/SI. TrkA knockdown neither affected nMB/SI cholinergic cell counts nor the decrease in cholinergic cell size observed in aged rats. However, trkA suppression augmented an age-related decrease in the density of cortical cholinergic processes and attenuated the capacity of cholinergic neurons to release ACh. The capacity of cortical synapses to release acetylcholine (ACh) in vivo was also lower in aged/trkA-AAV-infused rats than in aged or young controls, and it correlated with their attentional performance. Furthermore, age-related increases in cortical proNGF and p75 receptor levels interacted with the vector-induced loss of trkA receptors to shift NGF signaling toward p75-mediated suppression of the cholinergic phenotype, thereby attenuating cholinergic function and impairing attentional performance. These effects model the abnormal trophic regulation of cholinergic neurons and cognitive impairments in patients with early Alzheimer's disease. This rat model is useful for identifying the mechanisms rendering aging cholinergic neurons vulnerable as well as for studying the neuropathological mechanisms that are triggered by disrupted trophic signaling. PMID:23228124

  7. 5-HT1A receptors of the nucleus tractus solitarii facilitate sympathetic recovery following hypotensive hemorrhage in rats

    PubMed Central

    Vantrease, Jaime E.; Dudek, Nichole; DonCarlos, Lydia L.

    2015-01-01

    The role of serotonin in the hemodynamic response to blood loss remains controversial. Caudal raphe serotonin neurons are activated during hypotensive hemorrhage, and their destruction attenuates sympathetic increases following blood loss in unanesthetized rats. Caudal raphe neurons provide serotonin-positive projections to the nucleus tractus solitarii (NTS), and disruption of serotonin-positive nerve terminals in the NTS attenuates sympathetic recovery following hemorrhage. Administration of 5-HT1A-receptor agonists following hemorrhage augments sympathetic-mediated increases in venous tone and tissue hypoxia. These findings led us to hypothesize that severe blood loss promotes activation of 5-HT1A receptors in the NTS, which facilitates sympathetic recovery and peripheral tissue perfusion. Here, we developed an adeno-associated viral vector encoding an efficacious small hairpin RNA sequence targeting the rat 5-HT1A receptor. Unanesthetized rats subjected to NTS injection of the anti-rat 5-HT1A small hairpin RNA-encoding vector 4 wk prior showed normal blood pressure recovery, but an attenuated recovery of renal sympathetic nerve activity (−6.4 ± 12.9 vs. 42.6 ± 15.6% baseline, P < 0.05) 50 min after 21% estimated blood volume withdrawal. The same rats developed increased tissue hypoxia after hemorrhage, as indicated by prolonged elevations in lactate (2.77 ± 0.5 vs. 1.34 ± 0.2 mmol/l, 60 min after start of hemorrhage, P < 0.05). 5-HT1A mRNA levels in the commissural NTS were directly correlated with renal sympathetic nerve activity (P < 0.01) and inversely correlated with lactate (P < 0.05) 60 min after start of hemorrhage. The data suggest that 5-HT1A receptors in the commissural NTS facilitate tissue perfusion after blood loss likely by increasing sympathetic-mediated venous return. PMID:25980022

  8. Digitally Controlled Beam Attenuator

    NASA Astrophysics Data System (ADS)

    Peppler, W. W.; Kudva, B.; Dobbins, J. T.; Lee, C. S.; Van Lysel, M. S.; Hasegawa, B. H.; Mistretta, C. A.

    1982-12-01

    In digital fluorographic techniques the video camera must accommodate a wide dynamic range due to the large variation in the subject thickness within the field of view. Typically exposure factors and the optical aperture are selected such that the maximum video signal is obtained in the most transmissive region of the subject. Consequently, it has been shown that the signal-to-noise ratio is severely reduced in the dark regions. We have developed a prototype digital beam attenuator (DBA) which will alleviate this and some related problems in digital fluorography. The prototype DBA consists of a 6x6 array of pistons which are individually controlled. A membrane containing an attenuating solu-tion of (CeC13) in water and the piston matrix are placed between the x-ray tube and the subject. Under digital control the pistons are moved into the attenuating material in order to adjust the beam intensity over each of the 36 cells. The DBA control unit which digitizes the image during patient positioning will direct the pistons under hydraulic control to produce a uniform x-ray field exiting the subject. The pistons were designed to produce very little structural background in the image. In subtraction studies any structure would be cancelled. For non-subtraction studies such as cine-cardiology we are considering higher cell densities (eg. 64x64). Due to the narrow range of transmission provided by the DBA, in such studies ultra-high contrast films could be used to produce a high resolution quasi-subtraction display. Additional benefits of the DBA are: 1) reduced dose to the bright image areas when the dark areas are properly exposed. 2) improved scatter and glare to primary ratios, leading to improved contrast in the dark areas.

  9. Chloride dysregulation and inhibitory receptor blockade yield equivalent disinhibition of spinal neurons yet are differentially reversed by carbonic anhydrase blockade.

    PubMed

    Lee, Kwan Yeop; Prescott, Steven A

    2015-12-01

    Synaptic inhibition plays a key role in processing somatosensory information. Blocking inhibition at the spinal level is sufficient to produce mechanical allodynia, and many neuropathic pain conditions are associated with reduced inhibition. Disinhibition of spinal neurons can arise through decreased GABAA/glycine receptor activation or through dysregulation of intracellular chloride. We hypothesized that these distinct disinhibitory mechanisms, despite all causing allodynia, are differentially susceptible to therapeutic intervention. Specifically, we predicted that reducing bicarbonate efflux by blocking carbonic anhydrase with acetazolamide (ACTZ) would counteract disinhibition caused by chloride dysregulation without affecting normal inhibition or disinhibition caused by GABAA/glycine receptor blockade. To test this, responses to innocuous tactile stimulation were recorded in vivo from rat superficial dorsal horn neurons before and after different forms of pharmacological disinhibition and again after application of ACTZ. Blocking GABAA or glycine receptors caused hyperresponsiveness equivalent to that caused by blocking the potassium chloride cotransporter KCC2, but, consistent with our predictions, only disinhibition caused by KCC2 blockade was counteracted by ACTZ. ACTZ did not alter responses of neurons with intact inhibition. As pathological downregulation of KCC2 is triggered by brain-derived neurotrophic factor, we also confirmed that ACTZ was effective against brain-derived neurotrophic factor-induced hyperresponsiveness. Our results argue that intrathecal ACTZ has antiallodynic effects only if allodynia arises through chloride dysregulation; therefore, behavioral evidence that ACTZ is antiallodynic in nerve-injured animals affirms the contribution of chloride dysregulation as a key pathological mechanism. Although different disinhibitory mechanisms are not mutually exclusive, these results demonstrate that their relative contribution dictates which

  10. Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells.

    PubMed

    Rao, Velidi H; Rai, Vikrant; Stoupa, Samantha; Agrawal, Devendra K

    2015-09-15

    Although degradation of extracellular matrix by matrix metalloproteinases (MMPs) is thought to be involved in symptomatic (S) carotid plaques in atherosclerosis, the mechanisms of MMP expression are poorly understood. Here, we demonstrate that collagen loss in vascular smooth vessel cells (VSMCs) isolated from S plaques was induced by epidermal growth factor (EGF) through the activation of p38-MAPK and JNK-MAPK pathways. Inhibitors of p38-MAPK and JNK-MAPK signaling pathways downregulated the expression of MMP-1 and MMP-9. In addition, we examined whether v-ets erythroblastosis virus E26 oncogene homologue 1 (Ets-1), an important regulator of different genes, is involved in destabilizing S plaques in patients with carotid stenosis. We demonstrate that EGF induces Ets-1 expression and decreases interstitial and basement membrane collagen in vascular smooth muscle cells (VSMCs) from patients with carotid stenosis. Increased expression of MMP-1 and -9 and decreased collagen mRNA transcripts were also found in Ets-1-overexpressed VSMCs. Transfection with both dominant-negative form of Ets-1 and small interfering RNA blocked EGF-induced MMP-1 and -9 expressions and increased the mRNA transcripts for collagen I (α1) and collagen III (α1) in S compared with asymptomatic (AS) carotid plaques. Inhibitors of p38-MAPK (SB202190) and JNK-MAPK (SP600125) signaling pathways decreased the expression of Ets-1, MMP-1, and MMP-9 and increased collagen type I and III expression in EGF-treated VSMCs. This study provides a mechanistic insight into the role of Ets-1 in the plaque destabilization in patients with carotid stenosis involving p38-MAPK and JNK signaling pathways.

  11. Propranolol, a β-adrenergic antagonist, attenuates the decrease in trabecular bone mass in high calorie diet fed growing mice.

    PubMed

    Baek, Kyunghwa; Hwang, Hyo Rin; Park, Hyun-Jung; Kwon, Arang; Qadir, Abdul S; Baek, Jeong-Hwa

    2014-09-01

    We investigated the effects of high calorie and low calorie diets on skeletal integrity, and whether β-adrenergic blockade (BB) attenuates bone loss induced by dietary calorie alteration. Male 6-week-old C57BL/6 mice were assigned to either an ad-lib fed control diet (CON), a high calorie diet (HIGH), or a low calorie diet (LOW) group. In each diet group, mice were treated with either vehicle (VEH) or propranolol, a β-adrenergic antagonist. Over 12-weeks, β-blockade mitigated body weight and fat mass increases induced by the high calorie diet. Femoral trabecular bone mineral density and the expression levels of osteogenic marker genes in bone marrow cells were reduced in HIGHVEH and LOWVEH mice, and BB significantly attenuated this decline only in HIGH mice. In summary, the magnitude of bone loss induced by low calorie diet was greater than that caused by high calorie diet in growing mice, and β-blockade mitigated high calorie diet-induced bone loss.

  12. Ultrasonic Attenuation in Zircaloy-4

    SciTech Connect

    Gomez, M.P.; Banchik, A.D.; Lopez Pumarega, M.I.; Ruzzante, J.E.

    2005-04-09

    In this work the relationship between Zircaloy-4 grain size and ultrasonic attenuation behavior was studied for longitudinal waves in the frequency range of 10-90 MHz. The attenuation was analyzed as a function of frequency for samples with different mechanical and heat treatments having recrystallized and Widmanstatten structures with different grain size. The attenuation behavior was analyzed by different scattering models, depending on grain size, wavelength and frequency.

  13. Chopping-Wheel Optical Attenuator

    NASA Technical Reports Server (NTRS)

    Leviton, Douglas B.

    1988-01-01

    Star-shaped rotating chopping wheel provides adjustable time-averaged attenuation of narrow beam of light without changing length of optical path or spectral distribution of light. Duty cycle or attenuation factor of chopped beam controlled by adjusting radius at which beam intersects wheel. Attenuation factor independent of wavelength. Useful in systems in which chopping frequency above frequency-response limits of photodetectors receiving chopped light. Used in systems using synchronous detection with lock-in amplifiers.

  14. Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting

    PubMed Central

    Files, D. Clark; Liu, Chun; Pereyra, Andrea; Wang, Zhong-Min; Aggarwal, Neil R.; D’Alessio, Franco R.; Garibaldi, Brian T.; Mock, Jason R.; Singer, Benjamin D.; Feng, Xin; Yammani, Raghunatha R.; Zhang, Tan; Lee, Amy L.; Philpott, Sydney; Lussier, Stephanie; Purcell, Lina; Chou, Jeff; Seeds, Michael; King, Landon S.; Morris, Peter E.; Delbono, Osvaldo

    2016-01-01

    Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)–mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans. PMID:25761888

  15. Therapeutic exercise attenuates neutrophilic lung injury and skeletal muscle wasting.

    PubMed

    Files, D Clark; Liu, Chun; Pereyra, Andrea; Wang, Zhong-Min; Aggarwal, Neil R; D'Alessio, Franco R; Garibaldi, Brian T; Mock, Jason R; Singer, Benjamin D; Feng, Xin; Yammani, Raghunatha R; Zhang, Tan; Lee, Amy L; Philpott, Sydney; Lussier, Stephanie; Purcell, Lina; Chou, Jeff; Seeds, Michael; King, Landon S; Morris, Peter E; Delbono, Osvaldo

    2015-03-11

    Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)-mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans. PMID:25761888

  16. Natural attenuation of contaminated soils.

    PubMed

    Mulligan, Catherine N; Yong, Raymond N

    2004-06-01

    Natural attenuation is increasing in use as a low cost means of remediating contaminated soil and groundwater. Modelling of contaminant migration plays a key role in evaluating natural attenuation as a remediation option and in ensuring that there will be no adverse impact on humans and the environment. During natural attenuation, the contamination must be characterized thoroughly and monitored through the process. In this paper, attenuation mechanisms for both organic and inorganic contaminants, use of models and protocols, role of monitoring and field case studies will be reviewed.

  17. Electronic ground state properties of Coulomb blockaded quantum dots

    NASA Astrophysics Data System (ADS)

    Patel, Satyadev Rajesh

    Conductance through quantum dots at low temperature exhibits random but repeatable fluctuations arising from quantum interference of electrons. The observed fluctuations follow universal statistics arising from the underlying universality of quantum chaos. Random matrix theory (RMT) has provided an accurate description of the observed universal conductance fluctuations (UCF) in "open" quantum dots (device conductance ≥e 2/h). The focus of this thesis is to search for and decipher the underlying origin of similar universal properties in "closed" quantum dots (device conductance ≤e2/ h). A series of experiments is presented on electronic ground state properties measured via conductance measurements in Coulomb blockaded quantum dots. The statistics of Coulomb blockade (CB) peak heights with zero and non-zero magnetic field measured in various devices agree qualitatively with predictions from Random Matrix Theory (RMT). The standard deviation of the peak height fluctuations for non-zero magnetic field is lower than predicted by RMT; the temperature dependence of the standard deviation of the peak height for non-zero magnetic field is also measured. The second experiment summarizes the statistics of CB peak spacings. The peak spacing distribution width is observed to be on the order of the single particle level spacing, Delta, for both zero and non-zero magnetic field. The ratio of the zero field peak spacing distribution width to the non-zero field peak spacing distribution width is ˜1.2; this is good agreement with predictions from spin-resolved RMT predictions. The standard deviation of the non-zero magnetic field peak spacing distribution width shows a T-1/2 dependence in agreement with a thermal averaging model. The final experiment summarizes the measurement of the peak height correlation length versus temperature for various quantum dots. The peak height correlation length versus temperature saturates in small quantum dots, suggesting spectral scrambling

  18. Chronic treatment with LY341495 decreases 5-HT(2A) receptor binding and hallucinogenic effects of LSD in mice.

    PubMed

    Moreno, José L; Holloway, Terrell; Rayannavar, Vinayak; Sealfon, Stuart C; González-Maeso, Javier

    2013-03-01

    Hallucinogenic drugs, such as lysergic acid diethylamide (LSD), mescaline and psilocybin, alter perception and cognitive processes. All hallucinogenic drugs have in common a high affinity for the serotonin 5-HT(2A) receptor. Metabotropic glutamate 2/3 (mGlu2/3) receptor ligands show efficacy in modulating the cellular and behavioral responses induced by hallucinogenic drugs. Here, we explored the effect of chronic treatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)-propionic acid (LY341495) on the hallucinogenic-like effects induced by LSD (0.24mg/kg). Mice were chronically (21 days) treated with LY341495 (1.5mg/kg), or vehicle, and experiments were carried out one day after the last injection. Chronic treatment with LY341495 down-regulated [(3)H]ketanserin binding in somatosensory cortex of wild-type, but not mGlu2 knockout (KO), mice. Head-twitch behavior, and expression of c-fos, egr-1 and egr-2, which are responses induced by hallucinogenic 5-HT(2A) agonists, were found to be significantly decreased by chronic treatment with LY341495. These findings suggest that repeated blockade of the mGlu2 receptor by LY341495 results in reduced 5-HT(2A) receptor-dependent hallucinogenic effects of LSD.

  19. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota

    PubMed Central

    Vétizou, Marie; Pitt, Jonathan M.; Daillère, Romain; Lepage, Patricia; Waldschmitt, Nadine; Flament, Caroline; Rusakiewicz, Sylvie; Routy, Bertrand; Roberti, Maria P.; Duong, Connie P. M.; Poirier-Colame, Vichnou; Roux, Antoine; Becharef, Sonia; Formenti, Silvia; Golden, Encouse; Cording, Sascha; Eberl, Gerard; Schlitzer, Andreas; Ginhoux, Florent; Mani, Sridhar; Yamazaki, Takahiro; Jacquelot, Nicolas; Enot, David P.; Bérard, Marion; Nigou, Jérôme; Opolon, Paule; Eggermont, Alexander; Woerther, Paul-Louis; Chachaty, Elisabeth; Chaput, Nathalie; Robert, Caroline; Mateus, Christina; Kroemer, Guido; Raoult, Didier; Boneca, Ivo Gomperts; Carbonnel, Franck; Chamaillard, Mathias; Zitvogel, Laurence

    2016-01-01

    Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4 blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade. PMID:26541610

  20. Fano effect dominance over Coulomb blockade in transport properties of parallel coupled quantum dot system

    SciTech Connect

    Brogi, Bharat Bhushan Ahluwalia, P. K.; Chand, Shyam

    2015-06-24

    Theoretical study of the Coulomb blockade effect on transport properties (Transmission Probability and I-V characteristics) for varied configuration of coupled quantum dot system has been studied by using Non Equilibrium Green Function(NEGF) formalism and Equation of Motion(EOM) method in the presence of magnetic flux. The self consistent approach and intra-dot Coulomb interaction is being taken into account. As the key parameters of the coupled quantum dot system such as dot-lead coupling, inter-dot tunneling and magnetic flux threading through the system can be tuned, the effect of asymmetry parameter and magnetic flux on this tuning is being explored in Coulomb blockade regime. The presence of the Coulomb blockade due to on-dot Coulomb interaction decreases the width of transmission peak at energy level ε + U and by adjusting the magnetic flux the swapping effect in the Fano peaks in asymmetric and symmetric parallel configuration sustains despite strong Coulomb blockade effect.

  1. [Genetic Mutation Accumulation and Clinical Outcome of Immune Checkpoint Blockade Therapy].

    PubMed

    Takahashi, Masanobu

    2016-06-01

    Immune checkpoint blockade therapy has recently attracted great attention in the area of oncology. In Japan, since 2014, an anti-PD-1 antibody nivolumab and anti-CTLA-4 antibody ipilimumab have been available for the treatment of patients with malignant melanoma, and nivolumab has been available for patients with non-small cell lung cancer. Clinical trials using these drugs and other immune checkpoint inhibitors are currently in progress worldwide. The immune checkpoint blockade therapy is a promising new cancer therapy; however, not all patients with cancer can benefit from this therapy. Recent evidence shows that markers reflecting the extent of genetic mutation accumulation, including mutation burden, non-synonymous mutation that produces neoantigen, and microsatellite instability, possibly serve as promising marker to predict who can benefit from the immune checkpoint blockade therapy. Here, I introduce the recent evidence and discuss the correlation between genetic mutation accumulation and clinical outcome of immune checkpoint blockade therapy. PMID:27306805

  2. Growth Attenuation Therapy.

    PubMed

    Kerruish, Nikki

    2016-01-01

    The "Ashley treatment" has provoked much debate and remains ethically controversial. Given that more children are being referred for such treatment, there remains a need to provide advice to clinicians and ethics committees regarding how to respond to such requests. This article contends that there is one particularly important gap in the existing literature about growth attenuation therapy (GAT) (one aspect of the Ashley treatment): the views of parents of children with profound cognitive impairment (PCI) remain significantly underrepresented. The article attempts to redress this balance by analyzing published accounts both from parents of children who have received GAT and from parents who oppose treatment. Using these accounts, important points are illuminated regarding how parents characterize benefits and harms, and their responsibilities as surrogate decisionmakers. This analysis could contribute to decisionmaking about future requests for GAT and might also have wider relevance to healthcare decisionmaking for children with PCI. PMID:26788948

  3. Fiber optic attenuator

    NASA Technical Reports Server (NTRS)

    Buzzetti, Mike F. (Inventor)

    1994-01-01

    A fiber optic attenuator of the invention is a mandrel structure through which a bundle of optical fibers is wrapped around in a complete circle. The mandrel structure includes a flexible cylindrical sheath through which the bundle passes. A set screw on the mandrel structure impacts one side of the sheath against two posts on the opposite side of the sheath. By rotating the screw, the sheath is deformed to extend partially between the two posts, bending the fiber optic bundle to a small radius controlled by rotating the set screw. Bending the fiber optic bundle to a small radius causes light in each optical fiber to be lost in the cladding, the amount depending upon the radius about which the bundle is bent.

  4. Efficacy of methods of intercostal nerve blockade for pain relief after thoracotomy.

    PubMed

    Detterbeck, Frank C

    2005-10-01

    Intercostal nerve blockade for postthoracotomy pain relief can be accomplished by continuous infusion of local anesthetics through a catheter in the subpleural space or through an interpleural catheter, by cryoanalgesia, and by a direct intercostal nerve block. A systematic review of randomized studies indicates that an extrapleural infusion is at least as effective as an epidural and significantly better than narcotics alone. The other techniques of intercostal blockade do not offer an advantage over narcotics alone. PMID:16181921

  5. Dynamic properties of a Josephson junction balanced comparator with Coulomb blockade

    NASA Astrophysics Data System (ADS)

    Askerzade, I. N.

    2016-09-01

    The dynamics of a Josephson junction balanced comparator with Coulomb blockade has been analyzed. An expression for the time resolution in the case of a linearly increasing gating voltage pulse has been derived with regard to the Bloch inductance. It has been shown that the time resolution depends on the Bloch inductance of small Josephson junctions. Estimates have confirmed the feasibility of a subpicosecond time resolution for balance Josephson comparators with Coulomb blockade.

  6. Transfer of entangled state, entanglement swapping and quantum information processing via the Rydberg blockade

    NASA Astrophysics Data System (ADS)

    Deng, Li; Chen, Ai-Xi; Zhang, Jian-Song

    2011-11-01

    We provide a scheme with which the transfer of the entangled state and the entanglement swapping can be realized in a system of neutral atoms via the Rydberg blockade. Our idea can be extended to teleport an unknown atomic state. According to the latest theoretical research of the Rydberg excitation and experimental reports of the Rydberg blockade effect in quantum information processing, we discuss the experimental feasibility of our scheme.

  7. Bidirectional Crosstalk between C5a Receptors and the NLRP3 Inflammasome in Macrophages and Monocytes

    PubMed Central

    Haggadone, Mikel D.; Grailer, Jamison J.; Fattahi, Fatemeh; Zetoune, Firas S.; Ward, Peter A.

    2016-01-01

    C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1β during endotoxemia was reduced in C5aR1−/− mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1β in bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1β expression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a's suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1β response to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses. PMID:27382187

  8. Coulomb Blockade Oscillations in Coupled Single-Electron Transistors

    NASA Astrophysics Data System (ADS)

    Shin, Mincheol; Lee, Seongjae; Park, Kyoung Wan

    2000-03-01

    The system we consider in this work is parallel coupled single-electron transistors (SETs) at strong coupling. For weak coupling, the transport characteristics of our coupled SETs are the same as those of the single SET, with the stability diagram exhibiting usual Coulomb diamonds. When the coupling becomes sufficiently strong, however, electron-hole binding and transport become important. In contrast to the previous works carried out in the cotunneling-dominating Coulomb blockade regime [1,2], we study e-h binding in the sequential-tunneling-dominating conducting regime. The major findings in this work are that the Coulomb diamonds in the conducting regime break up into fine internal structures at strong coupling, and that, although the cotunneling processes are much less frequent, they nonetheless play a crucial role. [1] D. V. Averin, A. N. Korotkov, and Yu. V. Nazarov, Phys. Rev. Lett. 66, 2818 (1991). [2] M. Matters, J. J. Versluys, and J. E. Mooij, Phys. Rev. Lett. 78, 2469 (1997).

  9. Novel pharmacological approaches for the antagonism of neuromuscular blockade.

    PubMed

    Pic, Lisa C

    2005-02-01

    Gamma cyclodextrin and purified plasma cholinesterase are 2 novel pharmacological agents being investigated as to their suitability for antagonism of neuromuscular blockade. Both of these agents are devoid of cholinergic stimulation and the accompanying side effects because their action is independent of acetylcholinesterase inhibition. Gamma cyclodextrin antagonizes the steroidal neuromuscular blocker rocuronium via the chemical encapsulation of the molecule forming a "host-guest" complex through van der Waals and hydrophobic interactions in the plasma. Encapsulation decreases plasma drug concentrations, shifting the neuromuscular blocking drug molecules from the neuromuscular junction back to the plasma compartment resulting in a rapid recovery of the neuromuscular function. Org 25969, a modified gamma cyclodextrin, will antagonize profound neuromuscular block induced by rocuronium in approximately 2 minutes. A commercial preparation of purified human plasma cholinesterase has been shown to be effective in reversing succinylcholine or mivacurium-induced block. Administration of exogenous plasma cholinesterase also has been shown to be effective in antagonizing mivacurium-induced neuromuscular block, cocaine toxicity, and organophosphate poisoning.

  10. Reversal of aging by NFkappaB blockade.

    PubMed

    Adler, Adam S; Kawahara, Tiara L A; Segal, Eran; Chang, Howard Y

    2008-03-01

    Genetic studies in model organisms such as yeast, worms, flies, and mice leading to lifespan extension suggest that longevity is subject to regulation. In addition, various system-wide interventions in old animals can reverse features of aging. To better understand these processes, much effort has been put into the study of aging on a molecular level. In particular, genome-wide microarray analysis of differently aged individual organisms or tissues has been used to track the global expression changes that occur during normal aging. Although these studies consistently implicate specific pathways in aging processes, there is little conservation between the individual genes that change. To circumvent this problem, we have recently developed a novel computational approach to discover transcription factors that may be responsible for driving global expression changes with age. We identified the transcription factor NFkappaB as a candidate activator of aging-related transcriptional changes in multiple human and mouse tissues. Genetic blockade of NFkappaB in the skin of chronologically aged mice reversed the global gene expression program and tissue characteristics to those of young mice, demonstrating for the first time that disruption of a single gene is sufficient to reverse features of aging, at least for the short-term.

  11. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    PubMed Central

    Ahn, Brian J.; Pollack, Ian F.; Okada, Hideho

    2013-01-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas. PMID:24202450

  12. Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: possible involvement of 5HT1A receptors.

    PubMed

    Campos, Alline Cristina; Ferreira, Frederico Rogério; Guimarães, Francisco Silveira

    2012-11-01

    Posttraumatic stress disorder (PTSD) is an incapacitating syndrome that follows a traumatic experience. Predator exposure promotes long-lasting anxiogenic effect in rodents, an effect related to symptoms found in PTSD patients. Cannabidiol (CBD) is a non-psychotomimetic component of Cannabis sativa with anxiolytic effects. The present study investigated the anti-anxiety actions of CBD administration in a model of PTSD. Male Wistar rats exposed to a predator (cat) received, 1 h later, singled or repeated i.p. administration of vehicle or CBD. Seven days after the stress animals were submitted to the elevated plus maze. To investigate the involvement of 5HT1A receptors in CBD effects animals were pre-treated with WAY100635, a 5HT1A receptor antagonist. To explore possible neurobiological mechanisms involved in these effects, 5HT1A receptor mRNA and BDNF protein expression were measured in the hippocampus, frontal cortex, amygdaloid complex and dorsal periaqueductal gray. Repeated administration of CBD prevented long-lasting anxiogenic effects promoted by a single predator exposure. Pretreatment with WAY100635 attenuated CBD effects. Seven days after predator exposure 5HT1A mRNA expression was up regulated in the frontal cortex and hippocampus. CBD and paroxetine failed to prevent this effect. No change in BDNF expression was found. In conclusion, predator exposure promotes long-lasting up-regulation of 5HT1A receptor gene expression in the hippocampus and frontal cortex. Repeated CBD administration prevents the long-lasting anxiogenic effects observed after predator exposure probably by facilitating 5HT1A receptors neurotransmission. Our results suggest that CBD has beneficial potential for PTSD treatment and that 5HT1A receptors could be a therapeutic target in this disorder.

  13. Endothelin Receptor-A Antagonist Attenuates Retinal Vascular and Neuroretinal Pathology in Diabetic Mice

    PubMed Central

    Chou, Jonathan C.; Rollins, Stuart D.; Ye, Minghao; Batlle, Daniel; Fawzi, Amani A.

    2014-01-01

    Purpose. We sought to determine the effects of atrasentan, a selective endothelin-A receptor antagonist, on the retinal vascular and structural integrity in a db/db mouse, an animal model of type 2 diabetes and diabetic retinopathy. Methods. Diabetic mice, 23 weeks old, were given either atrasentan or vehicle treatment in drinking water for 8 weeks. At the end of the treatment period, eyes underwent trypsin digest to assess the retinal vascular pathology focusing on capillary degeneration, endothelial cell, and pericyte loss. Paraffin-embedded retinal cross sections were used to evaluate retinal sublayer thickness both near the optic nerve and in the retinal periphery. Immunohistochemistry and TUNEL assay were done to evaluate retinal cellular and vascular apoptosis. Results. Compared with untreated db/db mice, atrasentan treatment was able to ameliorate the retinal vascular pathology by reducing pericyte loss (29.2% ± 0.4% vs. 44.4% ± 2.0%, respectively, P < 0.05) and capillary degeneration as determined by the percentage of acellular capillaries (8.6% ± 0.3% vs. 3.3% ± 0.41%, respectively, P < 0.05). A reduction in inner retinal thinning both at the optic nerve and at the periphery in treated diabetic mice was also observed in db/db mice treated with atrasentan as compared with untreated db/db mice (P < 0.05). TUNEL assay suggested that atrasentan may decrease enhanced apoptosis in neuroretinal layers and vascular pericytes in the db/db mice. Conclusions. Endothelin-A receptor blockade using atrasentan significantly reduces the vascular and neuroretinal complications in diabetic mice. Endothelin-A receptor blockade is a promising therapeutic target in diabetic retinopathy. PMID:24644048

  14. Suicide Risk: Amplifiers and Attenuators.

    ERIC Educational Resources Information Center

    Plutchik, Robert; Van Praag, Herman M.

    1994-01-01

    Attempts to integrate findings on correlates of suicide and violent risk in terms of a theory called a two-stage model of countervailing forces, which assumes that the strength of aggressive impulses is modified by amplifiers and attenuators. The vectorial interaction of amplifiers and attenuators creates an unstable equilibrium making prediction…

  15. CD28 family of receptors on T cells in chronic HBV infection: Expression characteristics, clinical significance and correlations with PD-1 blockade

    PubMed Central

    Tang, Zong-Sheng; Hao, You-Hua; Zhang, E-Juan; Xu, Chun-Li; Zhou, Yun; Zheng, Xin; Yang, Dong-Liang

    2016-01-01

    The aim of the present study was to investigate the overall clinical expression characteristics of the cluster of differentiation (CD)28 family receptors [CD28, inducible T-cell co-stimulator, programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 and B- and T-lymphocyte attenuator] on T cells in patients with chronic hepatitis B (CHB), analyze the correlations among these receptors and the clinical parameters, and to investigate the effects of PD-1 blockade on the receptor expression profiles, T-cell function and other biological effects. The expression characteristics of the CD28 family of receptors, the effects of PD-1 blockade on the receptor expression profiles and the levels of interferon (IFN)-γ were investigated in the T cells of patients with CHB. In addition, the transcription factor, T-box 21 (T-bet) and GATA binding protein 3 (GATA-3) mRNA expression levels were investigated in the peripheral blood mononuclear cells (PBMCs) of patients with CHB. The expression levels of the CD28 family receptors in the T cells of patients with CHB demonstrated distinct characteristics, for example levels of PD-1 and CTLA-4 on CD4 T cells and ICOS, PD-1, and BTLA on CD8 T cells were increased in cells from patients with CHB compared with those from the healthy individuals. A significant positive correlation was demonstrated among the serum HBV DNA titers and the levels of PD-1 on CD8+ T cells with the highest expression of PD-1 corresponding to viral levels >106 IU/ml. A significant positive correlation was observed between the serum HBV DNA titers and the expression levels of BTLA on CD8+ T cells with the highest expression of BTLA corresponding to viral levels >106 IU/ml. PD-1 blockade altered the expression profiles of CD28 family receptors in the T cells of patients with CHB, partly enhanced T cell function and increased the ratio of T-bet/GATA-3 mRNA in PBMCs. Thus, CD28 family receptors are potential clinical indicators for the rapid

  16. Attenuation of Vaccinia Virus.

    PubMed

    Yakubitskiy, S N; Kolosova, I V; Maksyutov, R A; Shchelkunov, S N

    2015-01-01

    Since 1980, in the post-smallpox vaccination era the human population has become increasingly susceptible compared to a generation ago to not only the variola (smallpox) virus, but also other zoonotic orthopoxviruses. The need for safer vaccines against orthopoxviruses is even greater now. The Lister vaccine strain (LIVP) of vaccinia virus was used as a parental virus for generating a recombinant 1421ABJCN clone defective in five virulence genes encoding hemagglutinin (A56R), the IFN-γ-binding protein (B8R), thymidine kinase (J2R), the complement-binding protein (C3L), and the Bcl-2-like inhibitor of apoptosis (N1L). We found that disruption of these loci does not affect replication in mammalian cell cultures. The isogenic recombinant strain 1421ABJCN exhibits a reduced inflammatory response and attenuated neurovirulence relative to LIVP. Virus titers of 1421ABJCN were 3 lg lower versus the parent VACV LIVP when administered by the intracerebral route in new-born mice. In a subcutaneous mouse model, 1421ABJCN displayed levels of VACV-neutralizing antibodies comparable to those of LIVP and conferred protective immunity against lethal challenge by the ectromelia virus. The VACV mutant holds promise as a safe live vaccine strain for preventing smallpox and other orthopoxvirus infections. PMID:26798498

  17. GHRH excess and blockade in X-LAG syndrome.

    PubMed

    Daly, Adrian F; Lysy, Philippe A; Desfilles, Céline; Rostomyan, Liliya; Mohamed, Amira; Caberg, Jean-Hubert; Raverot, Veronique; Castermans, Emilie; Marbaix, Etienne; Maiter, Dominique; Brunelle, Chloe; Trivellin, Giampaolo; Stratakis, Constantine A; Bours, Vincent; Raftopoulos, Christian; Beauloye, Veronique; Barlier, Anne; Beckers, Albert

    2016-03-01

    X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome. PMID:26671997

  18. Blockade of mast cell activation reduces cutaneous scar formation.

    PubMed

    Chen, Lin; Schrementi, Megan E; Ranzer, Matthew J; Wilgus, Traci A; DiPietro, Luisa A

    2014-01-01

    Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1α, IL-1β, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re-organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase β1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound.

  19. Selective blockade of CaMKII-alpha inhibits NMDA-induced caspase-3-dependent cell death but does not arrest PARP-1 activation or loss of plasma membrane selectivity in rat retinal neurons.

    PubMed

    Goebel, Dennis J

    2009-02-23

    Calcium/calmodulin-dependent protein kinase II-alpha (CaMKII-alpha) has been implicated in a number of receptor mediated events in neurons. Pharmacological blockade of CaMKII-alpha has been shown to prevent phosphorylation of NMDA-R2A and R2B receptor subunits, suggesting that this enzyme may be linked to receptor trafficking of glutamate receptors and serve as a regulatory protein for neuronal cell death. In the retina, inhibition of CaMKII-alpha has been reported to be neuroprotective against NMDA-induced cell death by preventing the activation of the caspase-3 dependent pathway. However, the effects of CaMKII-alpha blockade on the caspase-3 independent, PARP-1 dependent and the non-programmed cell death pathways have not previously been investigated. In the present study, blockade of CaMKII-alpha with the highly specific antagonist myristoylated autocamtide-2-related inhibitory peptide (AIP) was used in a rat in vivo model of retinal toxicity to compare the effects of on NMDA-induced caspase-3-dependent, PARP-1 dependent and the non-programmed (necrosis) cell death pathways. Results confirmed that AIP fully attenuates caspase-3 activation for at least 8 h following NMDA insult and also significantly improves retinal ganglion cell survival. However, this blockade had little effect on reducing the loss of plasma membrane selectivity (LPMS, e.g. necrosis) in cells located in the ganglion cell and inner nuclear layers and did not alter NMDA-induced PARP-1 hyperactivation, or prevent TUNEL labeling following a moderate NMDA-insult. These findings support a specific role for CaMKII-alpha in mediating the caspase-3 dependent cell death pathway and provide evidence that it is not directly linked to the signaling of either the PARP-1 dependent or the non-programmed cell death pathways.

  20. Disordered food intake and obesity in rats lacking cholecystokinin A receptors.

    PubMed

    Moran, T H; Katz, L F; Plata-Salaman, C R; Schwartz, G J

    1998-03-01

    Otsuka Long-Evans Tokushima Fatty (OLETF) rats develop obesity, hyperglycemia, and non-insulin-dependent diabetes mellitus and do not express cholecystokinin A (CCK-A) receptors, the receptor subtype mediating the satiety actions of CCK. In short-term feeding tests, male OLETF rats were completely resistant to exogenous CCK, and their response to bombesin was attenuated. Comparisons of liquid meal consumption in OLETF and control Long-Evans Tokushima (LETO) rats demonstrated that 1) OLETF rats had greater intakes during 30-min scheduled daytime meals and significantly larger and fewer spontaneous night-time meals and 2) although the initial rates of licking were the same, OLETF rats maintained the initial rate longer and the rate at which their licking declined was slower. In 24-h solid food access tests, OLETF rats consumed significantly more pellets than LETO controls, and this increase was attributable to significant increases in meal size. Together, these data are consistent with the interpretation that the lack of CCK-A receptors in OLETF rats results in a satiety deficit leading to increases in meal size, overall hyperphagia, and obesity.

  1. Oleanolic acid acrylate elicits antidepressant-like effect mediated by 5-HT1A receptor

    PubMed Central

    Fajemiroye, James O.; Polepally, Prabhakar R.; Chaurasiya, Narayan D.; Tekwani, Babu L.; Zjawiony, Jordan K.; Costa, Elson A.

    2015-01-01

    The development of new drugs for the treatment of depression is strategic to achieving clinical needs of patients. This study evaluates antidepressant-like effect and neural mechanisms of four oleanolic acid derivatives i.e. acrylate (D1), methacrylate (D2), methyl fumarate (D3) and ethyl fumarate (D4). All derivatives were obtained by simple one-step esterification of oleanolic acid prior to pharmacological screening in the forced swimming (FS) and open field (OF) tests. Pharmacological tools like α-methyl-p-tyrosine (AMPT, catecholamine depletor), p-chlorophenylalanine (serotonin depletor), prazosin (PRAZ, selective α1-receptor antagonist), WAY-100635 (selective serotonin 5-HT1A receptor antagonist) as well as monoamine oxidase (MAO) and functional binding assays were conducted to investigate possible neural mechanisms. In the FS test, D1 showed the most promising antidepressant-like effect without eliciting locomotor incoordination. Unlike group of mice pretreated with AMPT 100 mg/kg, PCPA 100 mg/kg or PRAZ 1 mg/kg, the effect of D1 was attenuated by WAY-100635 0.3 mg/kg pretreatment. D1 demonstrated moderate inhibition of MAO-A (IC50 = 48.848 ± 1.935 μM), potency (pEC50 = 6.1 ± 0.1) and intrinsic activity (Emax = 26 ± 2.0%) on 5-HT1A receptor. In conclusion, our findings showed antidepressant-like effect of D1 and possible involvement of 5-HT1A receptor. PMID:26199018

  2. Serotonin blockade delays learning performance in a cooperative fish.

    PubMed

    Soares, Marta C; Paula, José R; Bshary, Redouan

    2016-09-01

    Animals use learning and memorizing to gather information that will help them to make ecologically relevant decisions. Neuro-modulatory adjustments enable them to make associations between stimuli and appropriate behavior. A key candidate for the modulation of cooperative behavior is serotonin. Previous research has shown that modulation of the serotonergic system spontaneously affects the behavior of the cleaner wrasse Labroides dimidiatus during interactions with so-called 'client' reef fish. Here, we asked whether shifts in serotonin function affect the cleaners' associative learning abilities when faced with the task to distinguish two artificial clients that differ in their value as a food source. We found that the administration of serotonin 1A receptor antagonist significantly slowed learning speed in comparison with saline treated fish. As reduced serotonergic signaling typically enhances fear, we discuss the possibility that serotonin may affect how cleaners appraise, acquire information and respond to client-derived stimuli via manipulation of the perception of danger. PMID:27107861

  3. Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure.

    PubMed

    Holzem, Katherine M; Gomez, Juan F; Glukhov, Alexey V; Madden, Eli J; Koppel, Aaron C; Ewald, Gregory A; Trenor, Beatriz; Efimov, Igor R

    2016-07-01

    Heart failure (HF) claims 250,000 lives per year in the US, and nearly half of these deaths are sudden and presumably due to ventricular tachyarrhythmias. QT interval and action potential (AP) prolongation are hallmark proarrhythmic changes in the failing myocardium, which potentially result from alterations in repolarizing potassium currents. Thus, we aimed to examine whether decreased expression of the rapid delayed rectifier potassium current, IKr, contributes to repolarization abnormalities in human HF. To map functional IKr expression across the left ventricle (LV), we optically imaged coronary-perfused LV free wall from donor and end-stage failing human hearts. The LV wedge preparation was used to examine transmural AP durations at 80% repolarization (APD80), and treatment with the IKr-blocking drug, E-4031, was utilized to interrogate functional expression. We assessed the percent change in APD80 post-IKr blockade relative to baseline APD80 (∆APD80) and found that ∆APD80s are reduced in failing versus donor hearts in each transmural region, with 0.35-, 0.43-, and 0.41-fold reductions in endo-, mid-, and epicardium, respectively (p=0.008, 0.037, and 0.022). We then assessed hERG1 isoform gene and protein expression levels using qPCR and Western blot. While we did not observe differences in hERG1a or hERG1b gene expression between donor and failing hearts, we found a shift in the hERG1a:hERG1b isoform stoichiometry at the protein level. Computer simulations were then conducted to assess IKr block under E-4031 influence in failing and nonfailing conditions. Our results confirmed the experimental observations and E-4031-induced relative APD80 prolongation was greater in normal conditions than in failing conditions, provided that the cellular model of HF included a significant downregulation of IKr. In human HF, the response to IKr blockade is reduced, suggesting decreased functional IKr expression. This attenuated functional response is associated with

  4. Effect of magnesium sulphate on sugammadex reversal time for neuromuscular blockade: a randomised controlled study.

    PubMed

    Germano Filho, P A; Cavalcanti, I L; Barrucand, L; Verçosa, N

    2015-08-01

    Magnesium potentiates neuromuscular blockade. Sugammadex reverses rocuronium-induced blockade. The aim of this study was to determine the effect of pre-treatment with magnesium sulphate on sugammadex reversal time for neuromuscular blockade. Seventy-three patients were randomly assigned to receive magnesium sulphate (40 mg.kg(-1) ) or saline intravenously. After anaesthetic induction, continuous train-of-four monitoring was performed and rocuronium was administered (0.6 mg.kg(-1) ). When a second twitch appeared, the patients received sugammadex (2 mg.kg(-1) ). The median (IQR [range]) reversal time of moderate neuromuscular blockade to a train-of-four ratio of 0.9 facilitated by sugammadex was 115 (93-177.5 [68-315]) s in the magnesium group and 120 (105-140 [70-298]) s in the saline group (p = 0.79). The median (IQR [range]) clinical duration was 45 (35.5-53 [22-102]) min in the magnesium group and 37 (31-43 [19-73]) min in the saline group (p = 0.031). Pre-treatment with magnesium did not significantly affect sugammadex reversal time of moderate neuromuscular blockade induced by rocuronium.

  5. Bronchial and cardiac beta-adrenoceptor blockade--a comparison of atenolol, acebutolol and labetalol.

    PubMed Central

    Gribbin, H R; Mackay, A D; Baldwin, C J; Tattersfield, A E

    1981-01-01

    Bronchial and cardiac beta-adrenoceptor blockade have been compared in six normal subjects after three beta-adrenoceptor antagonists. Single and double doses of atenolol (50 and 100 mg), acebutolol (100 and 200 mg) and labetalolol (150 and 300 mg) were studied on separate occasions. 2 Salbutamol airway dose-response curves were obtained by measuring the airway response as the change in specific airway conductance (sGaw) after increasing doses of inhaled salbutamol. Bronchial beta-adrenoceptor blockade was assessed after each drug as the dose of salbutamol needed to cause a 50% increase in sGaw (sGaw D50). 3 Cardiac beta-adrenoceptor blockade was assessed after the same doses of each beta-adrenoceptor antagonist, by measuring the percentage reduction in exercise heart rate from control, after exercise for 5 min at 70% of the subject's maximum work rate. 4 Atenolol 50 and 100 mg caused least bronchial beta-adrenoceptor blockade and the greatest reduction in exercise heart rate. 5 Acebutolol 100 and 200 mg and labetalol 150 and 300 mg produced more bronchial beta-adrenoceptor blockade than atenolol. 6 With this approach new beta-adrenoceptor antagonists can be assessed without putting asthmatic patients at risk. PMID:6264936

  6. Spinal blockades of class I antiarrythmic drugs with bupivacaine by isobolographic analysis in rats.

    PubMed

    Chen, Yu-Wen; Chu, Chin-Chen; Chen, Yu-Chung; Leung, Yuk-Man; Wang, Jhi-Joung

    2012-10-18

    Flecainide, quinidine, and mexiletine have been shown to be sodium channel blockers and local anesthetics. The purpose of this study was to examine the interaction of the traditional local anesthetic bupivacaine with flecainide, quinidine, or mexiletine on spinal blockades. To obtain the 50% effective dose (ED(50)) of drugs, dose-dependent responses of spinal blockades of motor and sensory functions with intrathecal flecainide, quinidine, mexiletine, and bupivacaine in rats were constructed. Using a continuum of different fixed drug dose ratios, the interactions of bupivacaine with drugs (flecainide, quinidine, or mexiletine) were evaluated by an isobolographic analysis. Our resulting data showed that flecainide, quinidine, and mexiletine, as well as local anesthetic bupivacaine produced dose-dependent spinal blockades in motor function and nociception. Flecainide had the most potent spinal antinociceptive effect (P<0.01) among these three class I antiarrhythmic drugs. Co-administration of bupivacaine with flecainide, quinidine, or mexiletine displayed an additive effect on spinal blockades of motor function and nociception. We concluded that bupivacaine combined with flecainide, quinidine, or mexiletine exhibited an additive effect on spinal blockades of motor function and nociception. Using such a combination strategy to produce antinociception may potentially provide an improved therapeutic separation from myocardial toxicity occurred after spinal bupivacaine. PMID:22985507

  7. [Pulmonary hemodynamics following experimental myocardial ischemia after the blockade of adrenergic receptors].

    PubMed

    Evlakhov, V I; Poiasov, I Z

    2015-01-01

    In acute experiments in anesthetized rabbits the changes of the pulmonary hemodynamics following 60 s myocardial ischemia in the region of the descendent left coronary artery were studied in control animals and after the blockade of α-adrenoreceptors by phentolamine or β-adrenoreceptors by propranolol. Following myocardial ischemia in control animals the pulmonary artery pressure and flow decreased, the pulmonary vascular resistance did not change, the left atrial pressure elevated; the cardiac output decreased more than pulmonary artery flow. Following myocardial ischemia after the blockade of β-adrenoreceptors the pulmonary artery pressure decreased more than in control animals, the pulmonary artery flow was decreased in the same level as in the last case. The pulmonary vascular resistance was diminished, the left atrial pressure increased; the pulmonary artery flow and cardiac output decreased in the same level. Following myocardial ischemia after the blockade of β-adrenoreceptors the pulmonary artery pressure and pulmonary vascular resistance decreased more than after the blockade of α-adrenoreceptors, the left atrial pressure did not change. In both cases the pulmonary artery flow decreased in the same level and its changes were correlated with venous return shifts. The differences of the pulmonary artery changes following myocardial ischemia after the blockade of α- and β-adrenoreceptors are caused not only the different pulmonary vascular resistance changes, but also the left atrial pressure.

  8. Effects of beta-adrenergic blockade on ventilation and gas exchange during incremental exercise.

    PubMed

    Dodd, S; Powers, S; O'Malley, N; Brooks, E; Sommers, H

    1988-08-01

    Controversy exists concerning the effects of acute beta-adrenergic blockade on ventilation during exercise. Hence, the purpose of this study was to determine the effects of acute beta blockade on ventilation and gas exchange during incremental exercise. Nine male subjects underwent incremental exercise on a cycle ergometer (30 W.min-1) to exhaustion, with one trial being performed 60 min after the subject ingested propranolol hydrochloride (Inderal 1 mg.kg-1 BW) while the second test served as control. The treatment order was counterbalanced to preclude any ordering effect on the results, and 1 week separated the tests. Ventilation and gas exchange were monitored by open circuit techniques. No difference (p greater than 0.05) existed in VE, % Hb sat, VCO2, ventilatory threshold, and VE/VCO2 between treatments at the same exercise stage. VO2max was lowered from 3.82 to 3.26 l.min-1 (p less than 0.05) and HRmax was reduced from 190 to 150 bpm (p less than 0.05) as a result of beta blockade. These data suggested that acute beta blockade had no effect on exercise ventilation, but decreased HRmax at comparable work rates. In addition, VO2max and exercise time to exhaustion were hindered, probably due to beta blockade limitation of HRmax, and, thus, oxygen transport. PMID:3178619

  9. Dll4 Blockade in Stromal Cells Mediates Antitumor Effects in Preclinical Models of Ovarian Cancer.

    PubMed

    Kuhnert, Frank; Chen, Guoying; Coetzee, Sandra; Thambi, Nithya; Hickey, Carlos; Shan, Jing; Kovalenko, Pavel; Noguera-Troise, Irene; Smith, Eric; Fairhurst, Jeanette; Andreev, Julian; Kirshner, Jessica R; Papadopoulos, Nicholas; Thurston, Gavin

    2015-10-01

    The Notch ligand delta-like 4 (Dll4) has been identified as a promising target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. In this study, we report the development of REGN421 (enoticumab), a fully human IgG1 monoclonal antibody that binds human Dll4 with sub-nanomolar affinity and inhibits Notch signaling. Administering REGN421 to immunodeficient mice engineered to express human Dll4 inhibited the growth of several human tumor xenografts in association with the formation of nonfunctional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by the tumor endothelium, and Dll4 blockade by human-specific or mouse-specific Dll4 antibodies exerted potent antitumor activity, which relied entirely on targeting Dll4 expressed by tumor stromal cells but not by the tumor cells themselves. However, Dll4 blockade reduced Notch signaling in both blood vessels and tumor cells surrounding the blood vessels, suggesting that endothelial-expressed Dll4 might induce Notch signaling in adjacent ovarian tumor cells. The antitumor effects of targeting Dll4 were augmented significantly by simultaneous inhibition of VEGF signaling, whereas this combined blockade reversed normal organ vascular changes induced by Dll4 blockade alone. Overall, our findings deepen the rationale for antibody-based strategies to target Dll4 in ovarian cancers, especially in combination with VEGF blockade.

  10. PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques.

    PubMed

    Dyavar Shetty, Ravi; Velu, Vijayakumar; Titanji, Kehmia; Bosinger, Steven E; Freeman, Gordon J; Silvestri, Guido; Amara, Rama Rao

    2012-05-01

    Hyperimmune activation is a strong predictor of disease progression during pathogenic immunodeficiency virus infections and is mediated in part by sustained type I IFN signaling in response to adventitious microbial infection. The immune inhibitory receptor programmed death-1 (PD-1) regulates functional exhaustion of virus-specific CD8(+) T cells during chronic infections, and in vivo PD-1 blockade has been shown to improve viral control of SIV. Here, we show that PD-1 blockade during chronic SIV infection markedly reduced the expression of transcripts associated with type I IFN signaling in the blood and colorectal tissue of rhesus macaques (RMs). The effect of PD-1 blockade on type I IFN signaling was durable and persisted even under conditions of high viremia. Reduced type I IFN signaling was associated with enhanced expression of some of the junction-associated genes in colorectal tissue and with a profound decrease in plasma LPS levels, suggesting a possible repair of gut-associated junctions and decreased microbial translocation into the blood. PD-1 blockade enhanced immunity to gut-resident pathogenic bacteria, control of gut-associated opportunistic infections, and survival of SIV-infected RMs. Our results suggest PD-1 blockade as a potential novel therapeutic approach to enhance combination antiretroviral therapy by suppressing hyperimmune activation in HIV-infected individuals. PMID:22523065

  11. Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion.

    PubMed

    Duan, Wei; Ran, Hong; Zhou, Zhujuan; He, Qifen; Zheng, Jian

    2012-01-01

    In previous studies, we have shown that the inactivation of the adenosine A2A receptor exacerbates chronic cerebral hypoperfusion-induced white matter lesions (WMLs) by enhancing neuroinflammatory responses. However, the molecular mechanism underlying the effect of the adenosine A2A receptor remains unknown. Recent studies have demonstrated that cystatin F, a potent endogenous cysteine protease inhibitor, is selectively expressed in immune cells in association with inflammatory demyelination in central nervous system diseases. To understand the expression of cystatin F and its potential role in the effect of A2A receptor on WMLs induced through chronic cerebral hypoperfusion, we investigated cystatin F expression in the WMLs of A2A receptor gene knockout mice, the littermate wild-type mice and wild-type mice treated daily with the A2A receptor agonist CGS21680 or both CGS21680 and A2A receptor antagonist SCH58261 after chronic cerebral hypoperfusion. The results of quantitative-PCR and western blot analysis revealed that cystatin F mRNA and protein expression were significantly up-regulated in the WMLs after chronic cerebral hypoperfusion. In addition, cystatin F expression in the corpus callosum was significantly increased in A2A receptor gene knockout mice and markedly decreased in mice treated with CGS21680 on both the mRNA and protein levels. Additionally, SCH58261 counteracted the attenuation of cystatin F expression produced by CGS21680 after chronic cerebral hypoperfusion. Moreover, double immunofluorescence staining revealed that cystatin F was co-localized with the activated microglia marker CD11b. In conclusion, the cystatin F expression in the activated microglia is closely associated with the effect of the A2A receptors, which may be related to the neuroinflammatory responses occurring during the pathological process.

  12. Mononuclear cell complement receptor blockade in primary biliary cirrhosis.

    PubMed Central

    Al-Aghbar, M N; Neuberger, J; Williams, R; Eddleston, A L

    1985-01-01

    Peripheral blood monocyte and lymphocyte receptors for Fc and C3b fragments were examined in vitro in patients with primary biliary cirrhosis and other chronic liver diseases using sheep red blood cells coated with anti-SRBC IgG1 (to detect Fc receptors) and with anti-SRBC IgM and complement (to detect C3b receptors). The number of C3b receptors detected on 100 monocytes was significantly lower in patients with primary biliary cirrhosis (23.0 +/- 12.0, mean +/- 1 SD) compared with normal controls (57.4 +/- 16.9) and other chronic liver disease (HBsAg negative chronic active hepatitis 62.0 +/- 17.0, alcoholic cirrhosis 50.9 +/- 4.0), while the number of Fc receptors detected on 100 monocytes was not significantly different in all the groups (primary biliary cirrhosis 72.8 +/- 28.6, chronic active hepatitis 74.7 +/- 14.0, alcoholic cirrhosis 58.0 +/- 13.5 and normal controls 69.6 +/- 19.9). When mononuclear cells isolated from normal individuals were pre-incubated with serum from patients with primary biliary cirrhosis before testing their receptor function there was a significant reduction in the number of C3b receptors detected per 100 monocytes (27.6 +/- 10.8) compared with pre-incubation with normal serum (72.0 +/- 18.0). This reduction in C3b-receptor function was again observed when the serum used for pre-incubation was depleted of circulating immune complexes; but when complement was further depleted from these sera, the number of C3b-receptors detected after pre-incubation was similar to normal values (64.0 +/- 11.8). Lymphocyte receptors showed a similar pattern of results. This implies a specific C3b receptor blockade on monocytes and lymphocytes from patients with primary biliary cirrhosis which appears to be because of blocking by serum factor(s) including complement fragments. PMID:3155513

  13. [Antidepressants, stressors and the serotonin 1A receptor].

    PubMed

    Kirilly, Eszter; Gonda, Xénia; Bagdy, György

    2015-06-01

    5-HT(1A) receptor is a receptor of surprises. Buspirone, an anxiolytic drug with a then yet unidentified mechanism of action had been marketed for years when it was discovered that it is a 5-HT(1A) partial agonist. Several more years had to pass before it was accepted that this receptor plays the key role in the action mechanism of buspirone. This was followed by further surprises. It was discovered that in spite of its anxiolytic effect buspirone activates the hypothalamic-pituitary-adrenal (HPA) stress axis, furthermore, it increases peripheral noradrenaline and adrenaline concentration via a central mechanism. Thus activation of this receptor leads to ACTH/corticosterone and catecholamine release and also increases beta-endorphine, oxytocin and prolactin secretion while decreasing body temperature, increasing food uptake, eliciting characteristic behavioural responses in rodents and also playing a role in the development of certain types of epilepsy. Human genetic studies revealed the role of 5-HT(1A) receptors in cognitive processes playing a role in the development of depression such as impulsiveness or response to environmental stress. This exceptionally wide spectrum of effects is attributable to the presence of 5-HT1A receptors in serotonergic as well as other, for example glutamatergic, cholinergic, dopaminergic and noradrenergic neurons. The majority of the effects of 5-HT(1A) receptors is manifested via the mediation of Gi proteins through the hyperpolarisation or inhibition of the neuron carrying the receptor. 5-HT(1A) receptors on serotonergic neurons can be found in the somatodendritic area and play a significant role in delaying the effects of antidepressants which is an obvious disadvantage. Therefore the newest serotonergic antidepressants including vilazodone and vortioxetine have been designed to possess 5-HT(1A) receptor partial agonist properties. In the present paper we focus primarily on the role of 5-HT(1A) receptors in stress and

  14. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    PubMed

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists.

  15. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

    PubMed

    Minic, Zeljka; Li, Cailian; O'Leary, Donal S; Scislo, Tadeusz J

    2014-09-15

    Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists. PMID:25063794

  16. Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models.

    PubMed

    Silva, M M; Lemos, J M; Coito, A; Costa, B A; Wigren, T; Mendonça, T

    2014-01-01

    This paper addresses the local identifiability and sensitivity properties of two classes of Wiener models for the neuromuscular blockade and depth of hypnosis, when drug dose profiles like the ones commonly administered in the clinical practice are used as model inputs. The local parameter identifiability was assessed based on the singular value decomposition of the normalized sensitivity matrix. For the given input signal excitation, the results show an over-parameterization of the standard pharmacokinetic/pharmacodynamic models. The same identifiability assessment was performed on recently proposed minimally parameterized parsimonious models for both the neuromuscular blockade and the depth of hypnosis. The results show that the majority of the model parameters are identifiable from the available input-output data. This indicates that any identification strategy based on the minimally parameterized parsimonious Wiener models for the neuromuscular blockade and for the depth of hypnosis is likely to be more successful than if standard models are used.

  17. Analgesia, sedation, and neuromuscular blockade during targeted temperature management after cardiac arrest.

    PubMed

    Riker, Richard R; Gagnon, David J; May, Teresa; Seder, David B; Fraser, Gilles L

    2015-12-01

    The approach to sedation, analgesia, and neuromuscular blockade during targeted temperature management (TTM) remains largely unstudied, forcing clinicians to adapt previous research from other patient environments. During TTM, very little data guide drug selection, doses, and specific therapeutic goals. Sedation should be deep enough to prevent awareness during neuromuscular blockade, but titration is complex as metabolism and clearance are delayed for almost all drugs during hypothermia. Deeper sedation is associated with prolonged intensive care unit (ICU) and ventilator therapy, increased delirium and infection, and delayed wakening which can confound early critical neurological assessments, potentially resulting in erroneous prognostication and inappropriate withdrawal of life support. We review the potential therapeutic goals for sedation, analgesia, and neuromuscular blockade during TTM; the adverse events associated with that treatment; data suggesting that TTM and organ dysfunction impair drug metabolism; and controversies and potential benefits of specific monitoring. We also highlight the areas needing better research to guide our therapy. PMID:26670815

  18. Rydberg-blockaded medium inside a high-finesse optical cavity

    NASA Astrophysics Data System (ADS)

    Sheng, Jiteng; Kumar, Santosh; Whiteneck, William; Sedlacek, Jonathon; Shaffer, James

    2015-05-01

    We present experimental and theoretical progress on a Rydberg-blockaded atomic ensemble coupled to a high-finesse optical cavity. Theoretically, we analyze the role that the Rydberg blockade mechanism can play in synthesizing collective quantum states and non-classical states of light in this system. We study the correlation of two photon emission in the case of two Rydberg excitations within the cavity. Experimentally, we show that a cold atomic cloud can be transported into a high-finesse optical cavity by using a focus-tunable lens and that a collective state can be created inside the cavity using Rydberg atom blockade. Future work to realize collective quantum states in the atom-cavity experiment and study the interesting dynamics of the correlated photon emission will be presented.

  19. Current hot spot in the spin-valley blockade in carbon nanotubes

    NASA Astrophysics Data System (ADS)

    Széchenyi, Gábor; Pályi, András

    2013-12-01

    We present a theoretical study of the spin-valley blockade transport effect in a double quantum dot defined in a straight carbon nanotube. We find that intervalley scattering due to short-range impurities completely lifts the spin-valley blockade and induces a large leakage current in a certain confined range of the external magnetic field vector. This current hot spot emerges due to different effective magnetic fields acting on the spin-valley qubit states of the two quantum dots. Our predictions are compared to a recent measurement [F. Pei , Nat. Nanotech.1748-338710.1038/nnano.2012.160 7, 630 (2012)]. We discuss the implications for blockade-based schemes for qubit initialization/readout and motion sensing of nanotube-based mechanical resonators.

  20. High-fidelity Rydberg-blockade entangling gate using shaped, analytic pulses

    NASA Astrophysics Data System (ADS)

    Theis, L. S.; Motzoi, F.; Wilhelm, F. K.; Saffman, M.

    2016-09-01

    We show that the use of shaped pulses improves the fidelity of a Rydberg-blockade two-qubit entangling gate by several orders of magnitude compared to previous protocols based on square pulses or optimal control pulses. Using analytical derivative removal by adiabatic gate (DRAG) pulses that reduce excitation of primary leakage states and an analytical method of finding the optimal Rydberg blockade, we generate Bell states with a fidelity of F >0.9999 in a 300 K environment for a gate time of only 50 ns , which is an order of magnitude faster than previous protocols. These results establish the potential of neutral atom qubits with Rydberg-blockade gates for scalable quantum computation.

  1. CD4-Blockade Can Induce Protection from Peanut-Induced Anaphylaxis

    PubMed Central

    Duarte, Joana; Caridade, Marta; Graca, Luis

    2011-01-01

    Monoclonal antibodies (mAb) have been shown effective in inducing immune tolerance in a range of animal models of autoimmunity, allergy, and transplantation. We investigated whether CD4-blockade, effective in inducing transplantation tolerance, could prevent systemic immune responses leading to anaphylaxis. We found that treatment with a non-depleting anti-CD4 mAb could prevent peanut-induced anaphylaxis following subsequent systemic exposure to crude peanut extract (CPE). Furthermore, the effect of CD4-blockade did not interfere with overall immune competence, as anti-CD4 treated mice remained fully competent to respond to unrelated antigens. Protection from anaphylaxis correlated with increased frequency of Foxp3+ regulatory T cells (Treg), and was abrogated following Treg depletion. Taken together our data suggest that activation of T cells by CPE in presence of CD4-blockade leads to Treg expansion that can prevent peanut-induced anaphylaxis. PMID:22566846

  2. Valley blockade and multielectron spin-valley Kondo effect in silicon

    NASA Astrophysics Data System (ADS)

    Crippa, A.; Tagliaferri, M. L. V.; Rotta, D.; De Michielis, M.; Mazzeo, G.; Fanciulli, M.; Wacquez, R.; Vinet, M.; Prati, E.

    2015-07-01

    We report on the valley blockade and the multielectron Kondo effect generated by an impurity atom in a silicon nanofield effect device. According to the spin-valley nature of tunneling processes, and consistently with those allowed by the valley blockade regime, the manifestation of Kondo effect at occupation N =1 ,2 ,3 has the periodicity 4 of the electron filling sequence typical of silicon. The spin-valley Kondo effect emerges under different kinds of screening depending on the electron filling. By exploiting the valley blockade regime, valley index conservation in the Kondo SU(4) is deduced with no need of an external magnetic field. Microwave irradiation suppresses the Kondo effect at occupancies up to three electrons.

  3. Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling

    PubMed Central

    Fernandez-Sauze, Samantha; Berenguer-Daizé, Caroline; Sigaud, Romain; Delfino, Christine; Cayol, Mylène; Metellus, Philippe; Chinot, Olivier; Mabrouk, Kamel; Martin, Pierre-Marie; Ouafik, L'Houcine

    2015-01-01

    The cellular and molecular mechanisms by which adrenomedullin (AM) blockade suppresses tumor neovessels are not well defined. Herein, we show that AM blockade using anti-AM and anti-AM receptors antibodies targets vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and induces regression of unstable nascent tumor neovessels. The underlying mechanism involved, and shown in vitro and in vivo in mice, is the disruption of the molecular engagement of the endothelial cell-specific junctional molecules vascular endothelial-cadherin (VE-cadherin)/β-catenin complex. AM blockade increases endothelial cell permeability by inhibiting cell-cell contacts predominantly through disruption of VE-cadherin/β-catenin/Akt signalling pathway, thereby leading to vascular collapse and regression of tumor neovessels. At a molecular level, we show that AM blockade induces tyrosine phosphorylation of VE-cadherin at a critical tyrosine, Tyr731, which is sufficient to prevent the binding of β-catenin to the cytoplasmic tail of VE-cadherin leading to the inhibition of cell barrier function. Furthermore, we demonstrate activation of Src kinase by phosphorylation on Tyr416, supporting a role of Src to phosphorylate Tyr731-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr731-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr731-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser33/Ser37/Thr41 sites in both ECs and VSMCs both in vitro and in vivo in mice. These data suggest that AM blockade selectively induces regression of unstable tumor neovessels, through disruption of VE-cadherin signalling. Targeting AM system may present a novel therapeutic target to selectively disrupt assembly and induce regression of nascent tumor neovessels, without affecting normal stabilized vasculature. PMID:25924235

  4. Adrenomedullin blockade induces regression of tumor neovessels through interference with vascular endothelial-cadherin signalling.

    PubMed

    Khalfaoui-Bendriss, Ghizlane; Dussault, Nadège; Fernandez-Sauze, Samantha; Berenguer-Daizé, Caroline; Sigaud, Romain; Delfino, Christine; Cayol, Mylène; Metellus, Philippe; Chinot, Olivier; Mabrouk, Kamel; Martin, Pierre-Marie; Ouafik, L'Houcine

    2015-04-10

    The cellular and molecular mechanisms by which adrenomedullin (AM) blockade suppresses tumor neovessels are not well defined. Herein, we show that AM blockade using anti-AM and anti-AM receptors antibodies targets vascular endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), and induces regression of unstable nascent tumor neovessels. The underlying mechanism involved, and shown in vitro and in vivo in mice, is the disruption of the molecular engagement of the endothelial cell-specific junctional molecules vascular endothelial-cadherin (VE-cadherin)/β-catenin complex. AM blockade increases endothelial cell permeability by inhibiting cell-cell contacts predominantly through disruption of VE-cadherin/β-catenin/Akt signalling pathway, thereby leading to vascular collapse and regression of tumor neovessels. At a molecular level, we show that AM blockade induces tyrosine phosphorylation of VE-cadherin at a critical tyrosine, Tyr731, which is sufficient to prevent the binding of β-catenin to the cytoplasmic tail of VE-cadherin leading to the inhibition of cell barrier function. Furthermore, we demonstrate activation of Src kinase by phosphorylation on Tyr416, supporting a role of Src to phosphorylate Tyr731-VE-cadherin. In this model, Src inhibition impairs αAM and αAMR-induced Tyr731-VE-cadherin phosphorylation in a dose-dependent manner, indicating that Tyr731-VE-cadherin phosphorylation state is dependent on Src activation. We found that AM blockade induces β-catenin phosphorylation on Ser33/Ser37/Thr41 sites in both ECs and VSMCs both in vitro and in vivo in mice. These data suggest that AM blockade selectively induces regression of unstable tumor neovessels, through disruption of VE-cadherin signalling. Targeting AM system may present a novel therapeutic target to selectively disrupt assembly and induce regression of nascent tumor neovessels, without affecting normal stabilized vasculature. PMID:25924235

  5. Unconventional photon blockade in doubly resonant microcavities with second-order nonlinearity

    NASA Astrophysics Data System (ADS)

    Gerace, Dario; Savona, Vincenzo

    2014-03-01

    It is shown that noncentrosymmetric materials with bulk second-order nonlinear susceptibility can be used to generate strongly antibunched radiation at an arbitrary wavelength, solely determined by the resonant behavior of suitably engineered coupled microcavities. The proposed scheme exploits the unconventional photon blockade of a coherent driving field at the input of a coupled cavity system, where one of the two cavities is engineered to resonate at both fundamental and second harmonic frequencies, respectively. Remarkably, the unconventional blockade mechanism occurs with reasonably low quality factors at both harmonics, and does not require a sharp doubly resonant condition for the second cavity, thus proving its feasibility with current semiconductor technology.

  6. Increasing the Brightness of Cold Ion Beams by Suppressing Disorder-Induced Heating with Rydberg Blockade

    NASA Astrophysics Data System (ADS)

    Murphy, D.; Scholten, R. E.; Sparkes, B. M.

    2015-11-01

    A model for the equilibrium coupling of an ion system with varying initial hard-sphere Rydberg blockade correlations is used to quantify the suppression of disorder-induced heating in Coulomb-expanding cold ion bunches. We show that bunches with experimentally achievable blockade parameters have an emittance reduced by a factor of 2.6 and increased focusability and brightness compared to a disordered bunch. Demonstrating suppression of disorder-induced heating is an important step in the development of techniques for the creation of beam sources with sufficient phase-space density for ultrafast, single-shot coherent diffractive imaging.

  7. Effects of cervical-lymphatic blockade on brain edema and infarction volume in cerebral ischemic rats.

    PubMed

    Si, Jinchao; Chen, Lianbi; Xia, Zuoli

    2006-10-31

    To observe the effects of cervical-lymphatic blockade (CLB) on brain edema and infarction volume of ischemic (MCAO) rat, we examined changes in cerebral water content, Ca2+ and glutamate concentrations, cerebral infarction volume and mRNA expression levels of N-methyl-D-aspartame receptor 1 (NMDA receptor 1) in the ischemic (left) hemisphere. The present results demonstrated that all the above indices in rats with middle cerebral artery occlusion plus cervical lymphatic blockade (MCAO+CLB) were markedly higher than those with only middle cerebral artery occlusion (MCAO) at different time points. These results indicated [corrected] that CLB can aggravate cerebral ischemia by increasing brain edema and infarction volume.

  8. Prevention of induced atherosclerosis by diversion of bile or blockade of intestinal lymphatics in dogs.

    PubMed Central

    Wilk, P J; Karipineni, R C; Pertsemlidis, D; Danese, C A

    1976-01-01

    The prevention of induced hypercholesterolemia and atherosclerosis was studied by means of intestinal lymphatic blockade and of bile diversion in the dog. Hypercholesterolemia and atherosclerosis were produced by high cholesterol feeding after induction of hypothyroidism with radio-iodine plus thiouracil. Complete diversion of bile, by shunting all bile into the urinary bladder, effectively prevented hypercholesterolemia and atherosclerosis; in contrast, blockade of the intestinal lymphatics failed to prevent the consequences of the atherogenic regimen, because of the development of collateral lymphatic channels. Images Fig. 3. Fig. 4. Fig. 5. PMID:817679

  9. Cardiac baroreflex facilitation evoked by hypothalamus and prefrontal cortex stimulation: role of the nucleus tractus solitarius 5-HT2A receptors.

    PubMed

    Sévoz-Couche, C; Comet, M A; Bernard, J F; Hamon, M; Laguzzi, R

    2006-10-01

    We previously showed that serotonin (5-HT2) receptor activation in the nucleus of the tractus solitarius (NTS) produced hypotension, bradycardia, and facilitation of the baroreflex bradycardia. Activation of the preoptic area (POA) of the hypothalamus, which is involved in shock-evoked passive behaviors, induces similar modifications. In addition, previous studies showed that blockade of the infralimbic (IL) part of the medial prefrontal cortex, which sends projections to POA, produced an inhibitory influence on the baroreflex cardiac response. Thus, to assess the possible implication of NTS 5-HT2 receptors in passive cardiovascular responses, we analyzed in anesthetized rats the effects of NTS inhibition and NTS 5-HT2 receptor blockade on the cardiovascular modifications induced by chemical (0.3 M D,L-homocysteic acid) and electrical (50 Hz, 150-200 microA) stimulation of IL or POA. Intra-NTS microinjections of muscimol, a GABAA receptor agonist, prevented the decreases in blood pressure and heart rate normally evoked by IL or POA activation. In addition, we found that intra-NTS microinjection of R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol, a specific 5-HT2A receptor antagonist, did not affect the decreases in cardiovascular baseline parameters induced by IL or POA stimulation but prevented the facilitation of the aortic baroreflex bradycardia normally observed during IL (+65 and +60%) or POA (+70 and +69%) electrical and chemical stimulation, respectively. These results show that NTS 5-HT2A receptors play a key role in the enhancement of the cardiac response of the baroreflex but not in the changes in basal heart rate and blood pressure induced by IL or POA stimulation. PMID:16763082

  10. Method for observing robust and tunable phonon blockade in a nanomechanical resonator coupled to a charge qubit

    NASA Astrophysics Data System (ADS)

    Wang, Xin; Miranowicz, Adam; Li, Hong-Rong; Nori, Franco

    2016-06-01

    Phonon blockade is a purely quantum phenomenon, analogous to Coulomb and photon blockades, in which a single phonon in an anharmonic mechanical resonator can impede the excitation of a second phonon. We propose an experimental method to realize phonon blockade in a driven harmonic nanomechanical resonator coupled to a qubit, where the coupling is proportional to the second-order nonlinear susceptibility χ(2 ). This is in contrast to the standard realizations of phonon and photon blockade effects in Kerr-type χ(3 ) nonlinear systems. The nonlinear coupling strength can be adjusted conveniently by changing the coherent drive field. As an example, we apply this model to predict and describe phonon blockade in a nanomechanical resonator coupled to a Cooper-pair box (i.e., a charge qubit) with a linear longitudinal coupling. By obtaining the solutions of the steady state for this composite system, we give the conditions for observing strong antibunching and sub-Poissonian phonon-number statistics in this induced second-order nonlinear system. Besides using the qubit to produce phonon blockade states, the qubit itself can also be employed to detect blockade effects by measuring its states. Numerical simulations indicate that the robustness of the phonon blockade, and the sensitivity of detecting it, will benefit from this strong induced nonlinear coupling.

  11. Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

    PubMed

    Evonuk, Kirsten S; Baker, Brandi J; Doyle, Ryan E; Moseley, Carson E; Sestero, Christine M; Johnston, Bryce P; De Sarno, Patrizia; Tang, Andrew; Gembitsky, Igor; Hewett, Sandra J; Weaver, Casey T; Raman, Chander; DeSilva, Tara M

    2015-07-15

    T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system Xc(-) attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc(-) 7 d after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc(-) were resistant to EAE, corroborating a central role for system Xc(-) in mediating immune cell infiltration. We next examined the role of the system Xc(-) transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system Xc(-) transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release glutamate via the system Xc(-) transporter, causing excitotoxic death to mature myelin-producing oligodendrocytes. Taken together, these studies support a novel role for the system Xc(-) transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE.

  12. Inhibition of system xc− transporter attenuates autoimmune inflammatory demyelination1

    PubMed Central

    Doyle, Ryan E.; Moseley, Carson E.; Sestero, Christine M.; Johnston, Bryce P.; De Sarno, Patrizia; Tang, Andrew; Gembitsky, Igor; Hewett, Sandra J.; Weaver, Casey T.; Raman, Chander; DeSilva, Tara M.

    2015-01-01

    T cell infiltration into the central nervous system (CNS) is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system xc− transporter, however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system xc− attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system xc− seven days after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system xc− were resistant to EAE, corroborating a central role for system xc− in mediating immune cell infiltration. We next examined the role of the system xc− transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system xc− transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary co-culture studies demonstrate that myelin-specific CD4+ T helper type 1 (Th1) cells provoke microglia to release glutamate via the system xc− transporter causing excitotoxic death to mature myelin-producing OLs. Taken together these studies support a novel role for the system xc− transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE. PMID:26071560

  13. Sound attenuation in magnetorheological fluids

    NASA Astrophysics Data System (ADS)

    Rodríguez-López, J.; Elvira, L.; Resa, P.; Montero de Espinosa, F.

    2013-02-01

    In this work, the attenuation of ultrasonic elastic waves propagating through magnetorheological (MR) fluids is analysed as a function of the particle volume fraction and the magnetic field intensity. Non-commercial MR fluids made with iron ferromagnetic particles and two different solvents (an olive oil based solution and an Araldite-epoxy) were used. Particle volume fractions of up to 0.25 were analysed. It is shown that the attenuation of sound depends strongly on the solvent used and the volume fraction. The influence of a magnetic field up to 212 mT was studied and it was found that the sound attenuation increases with the magnetic intensity until saturation is reached. A hysteretic effect is evident once the magnetic field is removed.

  14. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors.

    PubMed

    Linge, Raquel; Jiménez-Sánchez, Laura; Campa, Leticia; Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Pazos, Angel; Adell, Albert; Díaz, Álvaro

    2016-04-01

    Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.

  15. Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling*

    PubMed Central

    Schellekens, Harriët; van Oeffelen, Wesley E. P. A.; Dinan, Timothy G.; Cryan, John F.

    2013-01-01

    G protein-coupled receptors (GPCRs), such as the ghrelin receptor (GHS-R1a), the melanocortin 3 receptor (MC3), and the serotonin 2C receptor (5-HT2C), are well known for their key role in the homeostatic control of food intake and energy balance. Ghrelin is the only known gut peptide exerting an orexigenic effect and has thus received much attention as an anti-obesity drug target. In addition, recent data have revealed a critical role for ghrelin in dopaminergic mesolimbic circuits involved in food reward signaling. This study investigates the downstream signaling consequences and ligand-mediated co-internalization following heterodimerization of the GHS-R1a receptor with the dopamine 1 receptor, as well as that of the GHS-R1a-MC3 heterodimer. In addition, a novel heterodimer between the GHS-R1a receptor and the 5-HT2C receptor was identified. Interestingly, dimerization of the GHS-R1a receptor with the unedited 5-HT2C-INI receptor, but not with the partially edited 5-HT2C-VSV isoform, significantly reduced GHS-R1a agonist-mediated calcium influx, which was completely restored following pharmacological blockade of the 5-HT2C receptor. These results combined suggest a potential novel mechanism for fine-tuning GHS-R1a receptor-mediated activity via promiscuous dimerization of the GHS-R1a receptor with other G protein-coupled receptors involved in appetite regulation and food reward. These findings may uncover novel mechanisms of significant relevance for the future pharmacological targeting of the GHS-R1a receptor in the homeostatic regulation of energy balance and in hedonic appetite signaling, both of which play a significant role in the development of obesity. PMID:23161547

  16. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-04-01

    In this report we will show results of seismic and well log derived attenuation attributes from a deep water Gulf of Mexico data set. This data was contributed by Burlington Resources and Seitel Inc. The data consists of ten square kilometers of 3D seismic data and three well penetrations. We have computed anomalous seismic absorption attributes on the seismic data and have computed Q from the well log curves. The results show a good correlation between the anomalous absorption (attenuation) attributes and the presence of gas as indicated by well logs.

  17. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage

    PubMed Central

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-01-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4 (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.—Sasso, O., Migliore, M., Habrant, D., Armirotti, A., Albani, C., Summa, M., Moreno-Sanz, G., Scarpelli, R., Piomelli, D. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. PMID:25757568

  18. Blockade of interleukin-6 receptor enhances the anti-arthritic effect of glucocorticoids without decreasing bone mineral density in mice with collagen-induced arthritis.

    PubMed

    Suzuki, M; Yoshida, H; Hashizume, M; Tanaka, K; Matsumoto, Y

    2015-11-01

    In a mouse arthritis model, we investigated whether interleukin-6 receptor (IL-6R) blockade would enhance the anti-arthritic effect of glucocorticoids (GCs). DBA/1J mice were immunized with type II collagen (CII), and were treated with prednisolone (PSL) and/or anti-mouse IL-6R antibody (MR16-1). Also, the effects of IL-6 on gene expression and the nuclear translocation of glucocorticoid receptors (GRs) were examined in cultured cells treated with dexamethasone (DEX). PSL reduced the arthritis score dose-dependently in the collagen-induced arthritis (CIA) mouse model. The arthritis score in the PSL (3 mg/kg) + MR16-1 group was lower than in the PSL (3 mg/kg) group, and at the same level as in the PSL (6 mg/kg) group. Lumbar vertebra bone mineral density (BMD) was decreased significantly in CIA mice and was higher in the PSL (3 mg/kg) + MR16-1 group than in the PSL (6 mg/kg) group. In the in-vitro synovial cells, IL-6 pretreatment attenuated the inhibitory effect of DEX on cyclooxygenase (COX)-2 expression and inhibited the nuclear translocation of GR induced by DEX. In contrast, in MC3T3-E1 osteoblastic cells, IL-6 pretreatment exacerbated the decrease in expression of osteocalcin and the increase in expression of receptor activator of nuclear factor kappa-B ligand (RANKL) by DEX. We demonstrated that IL-6 signalling blockade by an anti-IL-6R antibody can augment the anti-arthritic effect of GCs and inhibit the bone loss they cause. PMID:26201536

  19. Blockade of the Renin-Angiotensin system improves insulin receptor signaling and insulin-stimulated skeletal muscle glucose transport in burn injury.

    PubMed

    Kasper, Sherry O; Phillips, Erin E; Castle, Scott M; Daley, Brian J; Enderson, Blaine L; Karlstad, Michael D

    2011-01-01

    Burn injury is associated with a decline in glucose utilization and insulin sensitivity due to alterations in postreceptor insulin signaling pathways. We have reported that blockade of the renin-angiotensin system with losartan, an angiotensin II type 1 (AT1) receptor blocker, improves whole body insulin sensitivity and glucose metabolism after burn injury. This study examines whether losartan improves insulin signaling pathways and insulin-stimulated glucose transport in skeletal muscle in burn-injured rats. Rats were injured by a 30% full-skin-thickness scalding burn and treated with losartan or placebo for 3 days after burn. Insulin signaling pathways were investigated in rectus abdominus muscle taken before and 90 s after intraportal insulin injection (10 U·kg). Insulin-stimulated insulin receptor substrate 1-associated phosphatidylinositol 3-kinase and plasma membrane-associated GLUT4 transporter were substantially increased with losartan treatment in burn-injured animals (59% above sham). Serine phosphorylated AKT/PKB was decreased with burn injury, and this decrease was attenuated with losartan treatment. In a separate group of rats, the effect of insulin on 2-deoxyglucose transport was significantly impaired in burned as compared with sham soleus muscles, in vitro; however, treatment of burned rats with losartan completely abolished the reduction of insulin-stimulated 2-deoxyglucose transport. These findings demonstrate a cross talk between the AT1 and insulin receptor that negatively modulates insulin receptor signaling and suggest a potential role of renin-angiotensin system blockade as a therapeutic strategy for enhancing insulin sensitivity in skeletal muscle and improving whole-body glucose homeostasis in burn injury.

  20. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

    PubMed

    Kashyap, Sonu; Warner, Gina M; Hartono, Stella P; Boyilla, Rajendra; Knudsen, Bruce E; Zubair, Adeel S; Lien, Karen; Nath, Karl A; Textor, Stephen C; Lerman, Lilach O; Grande, Joseph P

    2016-03-01

    Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH. PMID:26661648

  1. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension.

    PubMed

    Kashyap, Sonu; Warner, Gina M; Hartono, Stella P; Boyilla, Rajendra; Knudsen, Bruce E; Zubair, Adeel S; Lien, Karen; Nath, Karl A; Textor, Stephen C; Lerman, Lilach O; Grande, Joseph P

    2016-03-01

    Renovascular hypertension (RVH) is a common cause of both cardiovascular and renal morbidity and mortality. In renal artery stenosis (RAS), atrophy in the stenotic kidney is associated with an influx of macrophages and other mononuclear cells. We tested the hypothesis that chemokine receptor 2 (CCR2) inhibition would reduce chronic renal injury by reducing macrophage influx in the stenotic kidney of mice with RAS. We employed a well-established murine model of RVH to define the relationship between macrophage infiltration and development of renal atrophy in the stenotic kidney. To determine the role of chemokine ligand 2 (CCL2)/CCR2 signaling in the development of renal atrophy, mice were treated with the CCR2 inhibitor RS-102895 at the time of RAS surgery and followed for 4 wk. Renal tubular epithelial cells expressed CCL2 by 3 days following surgery, a time at which no significant light microscopic alterations, including interstitial inflammation, were identified. Macrophage influx increased with time following surgery. At 4 wk, the development of severe renal atrophy was accompanied by an influx of inducible nitric oxide synthase (iNOS)+ and CD206+ macrophages that coexpressed F4/80, with a modest increase in macrophages coexpressing arginase 1 and F4/80. The CCR2 inhibitor RS-102895 attenuated renal atrophy and significantly reduced the number of dual-stained F4/80+ iNOS+ and F4/80+ CD206+ but not F4/80+ arginase 1+ macrophages. CCR2 inhibition reduces iNOS+ and CD206+ macrophage accumulation that coexpress F4/80 and renal atrophy in experimental renal artery stenosis. CCR2 blockade may provide a novel therapeutic approach to humans with RVH.

  2. VAP-1 blockade prevents subarachnoid hemorrhage-associated cerebrovascular dilating dysfunction via repression of a neutrophil recruitment-related mechanism.

    PubMed

    Xu, Haoliang; Testai, Fernando D; Valyi-Nagy, Tibor; N Pavuluri, Mani; Zhai, Fengguo; Nanegrungsunk, Danop; Paisansathan, Chanannait; Pelligrino, Dale A

    2015-04-01

    Our previous findings indicated that in rats subjected to subarachnoid hemorrhage (SAH), suppression of post-SAH neuroinflammation via vascular adhesion protein-1 (VAP-1) blockade provides significant neuroprotection. We and others have reported that neuroinflammation contributes to cerebral microvascular impairment. Thus, in the present study, we tested the hypotheses that: (1) treatment with LJP-1586, a selective VAP-1 blocker, prevents SAH-associated pial arteriolar dilating dysfunction; and (2) the vasculoprotective effect of LJP-1586 arises from inhibiting SAH-elicited neutrophil recruitment. We utilized an endovascular perforation model of SAH. Rats subjected to SAH were either treated with LJP-1586 or rendered neutropenic via anti-neutrophil-antibody treatment. Findings from these groups were compared to their respective control groups. At 48 h post-SAH, rats were evaluated for neurobehavioral function, pial venular leukocyte trafficking, and pial arteriolar reactivity to topically-applied acetylcholine (ACh) and S-nitroso-N-acetyl penicillamine (SNAP). Pial arteriolar responses decreased at 48 h post-SAH. However, in the presence of LJP-1586, those responses were significantly preserved. Neutrophil-depletion yielded a substantial suppression of SAH-associated leukocyte adhesion and infiltration. This was accompanied by a significant preservation of pial arteriolar dilating function, suggesting a direct link between neutrophil recruitment and the loss of cerebral microvascular reactivity. Moreover, neutrophil depletion also was associated with significant protection of neurobehavioral function. The present findings suggest that attenuating SAH-linked elevation in neutrophil trafficking will protect against the development of microvascular dysfunction and subsequent neurological impairment.

  3. Effect of P2 receptor blockade with pyridoxine on sympathetic response to exercise pressor reflex in humans

    PubMed Central

    Cui, Jian; Leuenberger, Urs A; Blaha, Cheryl; King, Nicholas C; Sinoway, Lawrence I

    2011-01-01

    Animal studies suggest that ATP plays a role in evoking the muscle reflex via stimulating purinergic P2 receptors on sensory neurons. However, there are no human data regarding the role ATP and P2 receptors may play in evoking the exercise pressor reflex. We hypothesized that P2 receptor blockade in humans would attenuate the exercise pressor response. Blood pressure (Finometer), heart rate and muscle sympathetic nerve activity (MSNA; peroneal nerve) were assessed during fatiguing isometric handgrip, post-exercise circulatory occlusion (PECO), and passive muscle stretch during PECO in 10 young healthy volunteers. The protocol was performed before and after local infusion of pyridoxine hydrochloride (i.e. vitamin B6) in saline via Bier block. Pyridoxine is converted into pyridoxal-5-phosphate, a P2-purinoceptor antagonist. In the second experiment, the same amount of saline was infused via the same procedure. After pyridoxine, the MSNA responses to fatiguing handgrip (Δ349 ± 70 vs.Δ556 ± 92), PECO (Δ285 ± 37 vs.Δ532 ± 115) and PECO + passive stretch (Δ368 ± 66 vs.Δ641 ± 128 units min−1, all P < 0.05) were all significantly less than those before pyridoxine. The blood pressure responses were also significantly (all P < 0.05) less than those before pyridoxine. Infusion of saline (as opposed to pyridoxine) had no effect on the MSNA and blood pressure responses. These data are consistent with the concept that P2 receptors contribute to the exercise pressor reflex in humans. PMID:21078590

  4. Blockade of Urotensin II Receptor Prevents Vascular Dysfunction

    PubMed Central

    Kim, Young-Ae; Lee, Dong Gil; Yi, Kyu Yang; Lee, Byung Ho; Jung, Yi-Sook

    2016-01-01

    Urotensin II (UII) is a potent vasoactive peptide and mitogenic agent to induce proliferation of various cells including vascular smooth muscle cells (VSMCs). In this study, we examined the effects of a novel UII receptor (UT) antagonist, KR-36676, on vasoconstriction of aorta and proliferation of aortic SMCs. In rat aorta, UII-induced vasoconstriction was significantly inhibited by KR-36676 in a concentration-dependent manner. In primary human aortic SMCs (hAoSMCs), UII-induced cell proliferation was significantly inhibited by KR-36676 in a concentration-dependent manner. In addition, KR-36676 decreased UII-induced phosphorylation of ERK, and UII-induced cell proliferation was also significantly inhibited by a known ERK inhibitor U0126. In mouse carotid ligation model, intimal thickening of carotid artery was dramatically suppressed by oral treatment with KR-36676 (30 mg/ kg/day) for 4 weeks compared to vehicle-treated group. From these results, it is indicated that KR-36676 suppress UII-induced proliferation of VSMCs at least partially through inhibition of ERK activation, and that it also attenuates UII-induced vasoconstriction and vascular neointima formation. Our study suggest that KR-36676 may be an attractive candidate for the pharmacological management of vascular dysfunction. PMID:27582556

  5. Blockade of Urotensin II Receptor Prevents Vascular Dysfunction.

    PubMed

    Kim, Young-Ae; Lee, Dong Gil; Yi, Kyu Yang; Lee, Byung Ho; Jung, Yi-Sook

    2016-09-01

    Urotensin II (UII) is a potent vasoactive peptide and mitogenic agent to induce proliferation of various cells including vascular smooth muscle cells (VSMCs). In this study, we examined the effects of a novel UII receptor (UT) antagonist, KR-36676, on vasoconstriction of aorta and proliferation of aortic SMCs. In rat aorta, UII-induced vasoconstriction was significantly inhibited by KR-36676 in a concentration-dependent manner. In primary human aortic SMCs (hAoSMCs), UII-induced cell proliferation was significantly inhibited by KR-36676 in a concentration-dependent manner. In addition, KR-36676 decreased UII-induced phosphorylation of ERK, and UII-induced cell proliferation was also significantly inhibited by a known ERK inhibitor U0126. In mouse carotid ligation model, intimal thickening of carotid artery was dramatically suppressed by oral treatment with KR-36676 (30 mg/ kg/day) for 4 weeks compared to vehicle-treated group. From these results, it is indicated that KR-36676 suppress UII-induced proliferation of VSMCs at least partially through inhibition of ERK activation, and that it also attenuates UII-induced vasoconstriction and vascular neointima formation. Our study suggest that KR-36676 may be an attractive candidate for the pharmacological management of vascular dysfunction. PMID:27582556

  6. Blockade of processing/activation of caspase-3 by hypoxia

    SciTech Connect

    Han, Sang Hee; Kim, Moonil; Park, Kyoungsook; Kim, Tae-Hyoung; Seol, Dai-Wu

    2008-10-31

    Tumor hypoxia, which is caused by the rapid proliferation of tumor cells and aberrant vasculature in tumors, results in inadequate supplies of oxygen and nutrients to tumor cells. Paradoxically, these unfavorable growth conditions benefit tumor cell survival, although the mechanism is poorly understood. We have demonstrated for the first time that hypoxia inhibits TRAIL-induced apoptosis by blocking translocation of Bax from cytosol to the mitochondria in tumor cells. However, it is largely unknown how hypoxia-inhibited Bax translocation attenuates TRAIL-induced apoptosis. Here, we demonstrate that despite its inhibitory activity in TRAIL-induced apoptosis, hypoxia does not affect TRAIL-triggered proximal apoptotic signaling events, including caspase-8 activation and Bid cleavage. Instead, hypoxia inhibited processing of caspase-3, leading to incomplete activation of the caspase. Importantly, hypoxia-blocked translocation of Bax to the mitochondria significantly inhibited releasing the mitochondrial factors, such as cytochrome c and Smac/DIABLO, to the cytosol in response to TRAIL. It is well-known that complete processing/activation of caspase-3 requires Smac/DIABLO released from mitochondria. Therefore, our data indicate that an engagement of the apoptotic mitochondrial events leading to caspase-3 activation is blocked by hypoxia. Our data shed new light on understanding of the apoptotic signal transduction and targets regulated by tumor hypoxia.

  7. Sinus node function after autonomic blockade in normals and in sick sinus syndrome.

    PubMed

    Sethi, K K; Jaishankar, S; Balachander, J; Bahl, V K; Gupta, M P

    1984-06-01

    Electrophysiologic studies were performed in 10 normals and 33 patients with sick sinus syndrome before and after total autonomic blockade with propranolol and atropine. In normals both corrected sinus node recovery time (SNRT) and sinoatrial conduction time (SACT) decreased significantly after autonomic blockade. In patients with sick sinus syndrome the corrected SNRT was abnormal (greater than 450 msec) in 16 (48.5%) cases before and 25 (76%) cases (greater than 285 msec) after autonomic ablation (P less than 0.02). Thirteen of 21 patients (62%) with normal intrinsic heart rate and all 12 cases with abnormally low intrinsic rate after autonomic blockade had abnormal corrected SNRT (greater than 285 msec). Mean SACT measured in 19 patients also shortened significantly following pharmacologic denervation. During control it was prolonged (greater than 226 msec) in 8 patients (44%). After autonomic blockade 2 of 13 patients with normal intrinsic heart rate and 3 of 6 with low intrinsic rate showed abnormal SACT (greater than 151 msec). The data suggest that the majority (76%) of patients with sick sinus syndrome have intrinsic abnormality of sinus node automaticity while in a minority (24%) disturbed autonomic regulation is the pathogenetic mechanism. Patients with normal intrinsic heart rate usually have normal intrinsic SACT, while a significant proportion of those with low intrinsic rate have abnormal perinodal conduction. Subjects with abnormal intrinsic heart rate have more severe disturbances of sinus node function than those with normal intrinsic rate.

  8. CD47 Blockade Triggers T cell-mediated Destruction of Immunogenic Tumors

    PubMed Central

    Liu, Xiaojuan; Pu, Yang; Cron, Kyle; Deng, Liufu; Kline, Justin; Frazier, William A.; Xu, Hairong; Peng, Hua; Fu, Yang-Xin; Xu, Meng Michelle

    2015-01-01

    Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Using syngeneic immunocompetent tumor models, we reveal that in the therapeutic effects of CD47 blockade depend on dendritic cell (DC) but not macrophage cross-priming of T cell responses in immunocompetent mice. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the anti-tumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of anti-tumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors. PMID:26322579

  9. Effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans.

    PubMed

    Lorenzoni, R; Rosen, S D; Camici, P G

    1996-10-01

    In the present study we aimed to assess the effect of alpha 1-adrenoceptor blockade on resting and hyperemic myocardial blood flow in normal humans. Myocardial blood flow, at baseline and after dipyridamole, was measured with positron emission tomography and 15O-labeled water in 11 normal volunteers at control and during alpha 1-blockade with doxazosin. Baseline myocardial blood flow during alpha 1-blockade was not different from control, whereas coronary resistance was significantly lower (73.48 +/- 18.31 vs. 89.84 +/- 27.96 mmHg.min.ml-1.g-1; P < 0.05). After dipyridamole, myocardial blood flow during alpha 1-blockade was significantly higher (3.50 +/- 0.75 vs. 2.58 +/- 0.54 ml.min-1.g-1; P < 0.01) and coronary resistance lower (25.30 +/- 7.37 vs. 33.89 +/- 7.04 mmHg.min.ml-1.g-1; P < 0.01) compared with control. In conclusion, in normal humans, dipyridamole-induced increase in myocardial blood flow is limited by alpha 1-mediated coronary vasoconstriction.

  10. Coulomb blockade model of permeation and selectivity in biological ion channels

    NASA Astrophysics Data System (ADS)

    Kaufman, I. Kh; McClintock, P. V. E.; Eisenberg, R. S.

    2015-08-01

    Biological ion channels are protein nanotubes embedded in, and passing through, the bilipid membranes of cells. Physiologically, they are of crucial importance in that they allow ions to pass into and out of cells, fast and efficiently, though in a highly selective way. Here we show that the conduction and selectivity of calcium/sodium ion channels can be described in terms of ionic Coulomb blockade in a simplified electrostatic and Brownian dynamics model of the channel. The Coulomb blockade phenomenon arises from the discreteness of electrical charge, the strong electrostatic interaction, and an electrostatic exclusion principle. The model predicts a periodic pattern of Ca2+ conduction versus the fixed charge Qf at the selectivity filter (conduction bands) with a period equal to the ionic charge. It thus provides provisional explanations of some observed and modelled conduction and valence selectivity phenomena, including the anomalous mole fraction effect and the calcium conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The same considerations may also be applicable to other kinds of channel, as well as to charged artificial nanopores.

  11. Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes.

    PubMed

    Zhang, Heng; Ji, Hui; Liu, Zhirui; Ji, Yonghua; You, Xinmin; Ding, Gang; Cheng, Zhijun

    2014-08-01

    Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels (VGSCs), how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Nav1.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine-triggered arrhythmia. Here, we investigated the effect of bupivacaine on Nav1.5 within the clinical concentration range. The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.

  12. Blockade of ActRIIB Signaling Triggers Muscle Fatigability and Metabolic Myopathy

    PubMed Central

    Relizani, Karima; Mouisel, Etienne; Giannesini, Benoit; Hourdé, Christophe; Patel, Ketan; Morales Gonzalez, Susanne; Jülich, Kristina; Vignaud, Alban; Piétri-Rouxel, France; Fortin, Dominique; Garcia, Luis; Blot, Stéphane; Ritvos, Olli; Bendahan, David; Ferry, Arnaud; Ventura-Clapier, Renée; Schuelke, Markus; Amthor, Helge

    2014-01-01

    Myostatin regulates skeletal muscle size via the activin receptor IIB (ActRIIB). However, its effect on muscle energy metabolism and energy-dependent muscle function remains largely unexplored. This question needs to be solved urgently since various therapies for neuromuscular diseases based on blockade of ActRIIB signaling are being developed. Here, we show in mice, that 4-month pharmacological abrogation of ActRIIB signaling by treatment with soluble ActRIIB-Fc triggers extreme muscle fatigability. This is associated with elevated serum lactate levels and a severe metabolic myopathy in the mdx mouse, an animal model of Duchenne muscular dystrophy. Blockade of ActRIIB signaling downregulates porin, a crucial ADP/ATP shuttle between cytosol and mitochondrial matrix leading to a consecutive deficiency of oxidative phosphorylation as measured by in vivo Phophorus Magnetic Resonance Spectroscopy (31P-MRS). Further, ActRIIB blockade reduces muscle capillarization, which further compounds the metabolic stress. We show that ActRIIB regulates key determinants of muscle metabolism, such as Pparβ, Pgc1α, and Pdk4 thereby optimizing different components of muscle energy metabolism. In conclusion, ActRIIB signaling endows skeletal muscle with high oxidative capacity and low fatigability. The severe metabolic side effects following ActRIIB blockade caution against deploying this strategy, at least in isolation, for treatment of neuromuscular disorders. PMID:24861054

  13. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

    PubMed Central

    Ginestier, Christophe; Liu, Suling; Diebel, Mark E.; Korkaya, Hasan; Luo, Ming; Brown, Marty; Wicinski, Julien; Cabaud, Olivier; Charafe-Jauffret, Emmanuelle; Birnbaum, Daniel; Guan, Jun-Lin; Dontu, Gabriela; Wicha, Max S.

    2010-01-01

    Recent evidence suggests that breast cancer and other solid tumors possess a rare population of cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. We report here the development of a strategy to target these breast cancer stem cells (CSCs) through blockade of the IL-8 receptor CXCR1. CXCR1 blockade using either a CXCR1-specific blocking antibody or repertaxin, a small-molecule CXCR1 inhibitor, selectively depleted the CSC population in 2 human breast cancer cell lines in vitro. Furthermore, this was followed by the induction of massive apoptosis in the bulk tumor population via FASL/FAS signaling. The effects of CXCR1 blockade on CSC viability and on FASL production were mediated by the FAK/AKT/FOXO3A pathway. In addition, repertaxin was able to specifically target the CSC population in human breast cancer xenografts, retarding tumor growth and reducing metastasis. Our data therefore suggest that CXCR1 blockade may provide a novel means of targeting and eliminating breast CSCs. PMID:20051626

  14. Anomalous voltage dependence of channel blockade at a crustacean glutamate-mediated synapse.

    PubMed Central

    Lingle, C J

    1989-01-01

    1. The voltage dependence and concentration dependence of blockade of glutamate-activated currents by the diquaternary amine, chlorisondamine, were examined in a marine crustacean muscle. 2. Chlorisondamine results in the splitting of focally recorded synaptic current decays into two exponential components. The fast component becomes faster with increases in drug concentration and with hyperpolarization. The slow decay rate is unchanged or faster with hyperpolarization and the relative amplitude of the slow component is increased with hyperpolarization. 3. The alteration of synaptic current decay rates by chlorisondamine over the range of 5 to 100 microM and -80 to -140 mV is quantitatively consistent with a simple channel blockade model with a zero-voltage blocking rate of 6 x 10(5) M-1 s-1 at 12 degrees C with a voltage dependence of about 40 mV per e-fold change. The unblocking rate is about 5 s-1 at 0 mV and increases with hyperpolarization with a voltage dependence of about 30 mV per e-fold change. 4. The dose dependence and voltage dependence of blockade of ionophoretically activated glutamate currents by chlorisondamine are qualitatively consistent with the kinetic estimates. 5. The anomalous voltage dependence of the unblocking process is considered in terms of the possibility that the relief from blockade by chlorisondamine occurs by transit of chlorisondamine through the ion channel opened by glutamate. PMID:2479739

  15. Reversal of profound neuromuscular blockade with sugammadex in an infant after bronchial foreign body removal.

    PubMed

    Azizoglu, Mustafa; Birbicer, Handan; Memis, Suleyman; Taşkınlar, Hakan

    2016-09-01

    Sugammadex is a selective chemical agent that can reverse neuromuscular blockade induced by vecuronium and rocuronium. The aim of this report is to discuss the effectiveness of sugammadex in the reversal of neuromuscular blockade in children younger than 2 years. A 16-month-old boy, weighing 10 kg, was admitted to the pediatric emergency department due to choking, cyanosis, and severe respiratory distress that occurred while he was eating peanuts. In the emergency department, the patient's condition deteriorated, and he went into respiratory arrest. He was immediately intubated and taken to the operating room. A rigid bronchoscopy was performed under general anesthesia, with administration of intravenous pentothal (5 mg/kg), rocuronium (0.6 mg/kg), and fentanyl (0.5 μg/kg) in the operating room. The foreign body was removed within 6 minutes, and the profound neuromuscular blockade was reversed with a dose of 2 mg/kg sugammadex. He was extubated successfully after obtaining the spontaneous respiratory activity, and adequate breathing was restored. Clinical use of sugammadex in children younger than 2 years is not recommended because of the lack of clinical studies. In this case report, the profound neuromuscular blockade was successfully reversed with a dose of 2 mg/kg sugammadex in a 16-month-old boy. However, more prospective clinical studies are required for the safe use of this agent in children. PMID:27555184

  16. Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences

    PubMed Central

    Lozano-Maneiro, Luz; Puente-García, Adriana

    2015-01-01

    Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID:26569322

  17. Niacin stimulates adiponectin secretion through the GPR109A receptor.

    PubMed

    Plaisance, Eric P; Lukasova, Martina; Offermanns, Stefan; Zhang, Youyan; Cao, Guoqing; Judd, Robert L

    2009-03-01

    Niacin (nicotinic acid) has recently been shown to increase serum adiponectin concentrations in men with the metabolic syndrome. However, little is known about the mechanism(s) by which niacin regulates the intracellular trafficking and secretion of adiponectin. Since niacin appears to exert its effects on lipolysis through receptor (GPR109A)-dependent and -independent pathways, the purpose of this investigation was to examine the role of the recently identified GPR109A receptor in adiponectin secretion. Initial in vivo studies in rats demonstrated that niacin (30 mg/kg po) acutely increases serum adiponectin concentrations, whereas it decreases NEFAs. Further in vitro studies demonstrated an increase in adiponectin secretion and a decrease in lipolysis in primary adipocytes following treatment with niacin or beta-hydroxybutyrate (an endogenous ligand of the GPR109A receptor), but these effects were blocked when adipocytes were pretreated with pertussis toxin. Niacin had no effect on adiponectin secretion or lipolysis in 3T3-L1 adipocytes, which have limited cell surface expression of the GPR109A receptor. To further substantiate these in vitro findings, wild-type and GPR109A receptor knockout mice were administered a single dose of niacin or placebo, and serum was obtained for the determination of adiponectin and NEFA concentrations. Serum adiponectin concentrations increased and serum NEFAs decreased in the wild-type mice within 10 min following niacin administration. However, niacin administration had no effect on adiponectin and NEFA concentrations in the GPR109A receptor knockout mice. These results demonstrate that the GPR109A receptor plays an important role in the dual regulation of adiponectin secretion and lipolysis.

  18. Critical role of activation-inducible lymphocyte immunomediatory molecule/inducible costimulator in the effector function of human T cells: a comparative in vitro study of effects of its blockade and CD28 blockade in human beings and monkeys.

    PubMed

    Tajima, Nobuyuki; Tezuka, Katsunari; Tanaka, Masaru; Tanimoto, Minako; Miyai, Atsuko; Takeshima, Hiroaki; Watanabe, Yoshihiro

    2008-07-01

    Activation-inducible lymphocyte immunomediatory molecule (AILIM; also referred to as inducible costimulator, ICOS) is the third homolog of the "professional" costimulatory molecule, CD28. To date, the characteristics and role of AILIM/ICOS, especially in effector function of T cells, have been determined through numerous studies in vitro and in vivo using mice. Considering potential differences among species, whether the AILIM/ICOS blockade acts as an efficacious immunomodulator for human diseases remains to be elucidated. In the present study, ability of AILIM/ICOS blockade to modulate immune responses of human and monkey cells was investigated using a fully human antibody (JTA-009), comparing the effect of CD28 blockade. JTA-009 blocked the response of human and monkey T cells co-stimulated with anti-CD3 and AILIM/ICOS ligand, B7h. AILIM/ICOS and CD28 blockade both inhibited human mixed lymphocyte reaction in different fashions, as well as cytokine production in T helper (Th) 1-/Th2-type recall responses. In monkeys however, CD28 blockade by CTLA4-Ig effectively prevented mixed lymphocyte reaction to a greater extent than AILIM/ICOS blockade. These results suggest that AILIM/ICOS blockade is valuable for suppressing both primary allogenic response and recall responses of T cell in human beings, and that there are differences between human and monkey use preferences for costimulatory molecules.

  19. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

    PubMed Central

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M.; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia. PMID:27536240

  20. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.

    PubMed

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia. PMID:27536240

  1. TIM-4, a Receptor for Phosphatidylserine, Controls Adaptive Immunity by Regulating the Removal of Antigen-Specific T Cells

    PubMed Central

    Albacker, Lee A.; Karisola, Piia; Chang, Ya-Jen; Umetsu, Sarah E.; Zhou, Meixia; Akbari, Omid; Kobayashi, Norimoto; Baumgarth, Nicole; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

    2010-01-01

    Adaptive immunity is characterized by the expansion of an Ag-specific T cell population following Ag exposure. The precise mechanisms, however, that control the expansion and subsequent contraction in the number of Ag-specific T cells are not fully understood. We show that T cell/transmembrane, Ig, and mucin (TIM)-4, a receptor for phosphatidylserine, a marker of apoptotic cells, regulates adaptive immunity in part by mediating the removal of Ag-specific T cells during the contraction phase of the response. During Ag immunization or during infection with influenza A virus, blockade of TIM-4 on APCs increased the expansion of Ag-specific T cells, resulting in an increase in secondary immune responses. Conversely, overexpression of TIM-4 on APCs in transgenic mice reduced the number of Ag-specific T cells that remained after immunization, resulting in reduced secondary T cell responses. There was no change in the total number of cell divisions that T cells completed, no change in the per cell proliferative capacity of the remaining Ag-specific T cells, and no increase in the development of Ag-specific regulatory T cells in TIM-4 transgenic mice. Thus, TIM-4–expressing cells regulate adaptive immunity by mediating the removal of phosphatidylserine-expressing apoptotic, Ag-specific T cells, thereby controlling the number of Ag-specific T cells that remain after the clearance of Ag or infection. PMID:21037090

  2. Flagella Overexpression Attenuates Salmonella Pathogenesis

    PubMed Central

    Yang, Xinghong; Thornburg, Theresa; Suo, Zhiyong; Jun, SangMu; Robison, Amanda; Li, Jinquan; Lim, Timothy; Cao, Ling; Hoyt, Teri; Avci, Recep; Pascual, David W.

    2012-01-01

    Flagella are cell surface appendages involved in a number of bacterial behaviors, such as motility, biofilm formation, and chemotaxis. Despite these important functions, flagella can pose a liability to a bacterium when serving as potent immunogens resulting in the stimulation of the innate and adaptive immune systems. Previous work showing appendage overexpression, referred to as attenuating gene expression (AGE), was found to enfeeble wild-type Salmonella. Thus, this approach was adapted to discern whether flagella overexpression could induce similar attenuation. To test its feasibility, flagellar filament subunit FliC and flagellar regulon master regulator FlhDC were overexpressed in Salmonella enterica serovar Typhimurium wild-type strain H71. The results show that the expression of either FliC or FlhDC alone, and co-expression of the two, significantly attenuates Salmonella. The flagellated bacilli were unable to replicate within macrophages and thus were not lethal to mice. In-depth investigation suggests that flagellum-mediated AGE was due to the disruptive effects of flagella on the bacterial membrane, resulting in heightened susceptibilities to hydrogen peroxide and bile. Furthermore, flagellum-attenuated Salmonella elicited elevated immune responses to Salmonella presumably via FliC’s adjuvant effect and conferred robust protection against wild-type Salmonella challenge. PMID:23056473

  3. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-07-01

    In fully-saturated rock and at ultrasonic frequencies, the microscopic squirt flow induced between the stiff and soft parts of the pore space by an elastic wave is responsible for velocity-frequency dispersion and attenuation. In the seismic frequency range, it is the macroscopic cross-flow between the stiffer and softer parts of the rock. We use the latter hypothesis to introduce simple approximate equations for velocity-frequency dispersion and attenuation in a fully water saturated reservoir. The equations are based on the assumption that in heterogeneous rock and at a very low frequency, the effective elastic modulus of the fully-saturated rock can be estimated by applying a fluid substitution procedure to the averaged (upscaled) dry frame whose effective porosity is the mean porosity and the effective elastic modulus is the Backus-average (geometric mean) of the individual dry-frame elastic moduli of parts of the rock. At a higher frequency, the effective elastic modulus of the saturated rock is the Backus-average of the individual fully-saturated-rock elastic moduli of parts of the rock. The difference between the effective elastic modulus calculated separately by these two methods determines the velocity-frequency dispersion. The corresponding attenuation is calculated from this dispersion by using (e.g.) the standard linear solid attenuation model.

  4. Emergence of a Norovirus GII.4 Strain Correlates with Changes in Evolving Blockade Epitopes

    PubMed Central

    Lindesmith, Lisa C.; Costantini, Verónica; Swanstrom, Jesica; Debbink, Kari; Donaldson, Eric F.; Vinjé, Jan

    2013-01-01

    The major capsid protein of norovirus GII.4 strains is evolving rapidly, resulting in epidemic strains with altered antigenicity. GII.4.2006 Minerva strains circulated at pandemic levels in 2006 and persisted at lower levels until 2009. In 2009, a new GII.4 variant, GII.4.2009 New Orleans, emerged and since then has become the predominant strain circulating in human populations. To determine whether changes in evolving blockade epitopes correlate with the emergence of the GII.4.2009 New Orleans strains, we compared the antibody reactivity of a panel of mouse monoclonal antibodies (MAbs) against GII.4.2006 and GII.4.2009 virus-like particles (VLPs). Both anti-GII.4.2006 and GII.4.2009 MAbs effectively differentiated the two strains by VLP-carbohydrate ligand blockade assay. Most of the GII.4.2006 MAbs preferentially blocked GII.4.2006, while all of the GII.4.2009 MAbs preferentially blocked GII.4.2009, although 8 of 12 tested blockade MAbs blocked both VLPs. Using mutant VLPs designed to alter predicted antigenic epitopes, binding of seven of the blockade MAbs was impacted by alterations in epitope A, identifying residues 294, 296, 297, 298, 368, and 372 as important antigenic sites in these strains. Convalescent-phase serum collected from a GII.4.2009 outbreak confirmed the immunodominance of epitope A, since alterations of epitope A affected serum reactivity by 40%. These data indicate that the GII.4.2009 New Orleans variant has evolved a key blockade epitope, possibly allowing for at least partial escape from protective herd immunity and provide epidemiological support for the utility of monitoring changes in epitope A in emergent strain surveillance. PMID:23269783

  5. Inflammatory cytokine receptor blockade in a rodent model of mild traumatic brain injury.

    PubMed

    Perez-Polo, J R; Rea, H C; Johnson, K M; Parsley, M A; Unabia, G C; Xu, G-Y; Prough, D; DeWitt, D S; Paulucci-Holthauzen, A A; Werrbach-Perez, K; Hulsebosch, C E

    2016-01-01

    In rodent models of traumatic brain injury (TBI), both Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels increase early after injury to return later to basal levels. We have developed and characterized a rat mild fluid percussion model of TBI (mLFP injury) that results in righting reflex response times (RRRTs) that are less than those characteristic of moderate to severe LFP injury and yet increase IL-1α/β and TNFα levels. Here we report that blockade of IL-1α/β and TNFα binding to IL-1R and TNFR1, respectively, reduced neuropathology in parietal cortex, hippocampus, and thalamus and improved outcome. IL-1β binding to the type I IL-1 receptor (IL-1R1) can be blocked by a recombinant form of the endogenous IL-1R antagonist IL-1Ra (Kineret). TNFα binding to the TNF receptor (TNFR) can be blocked by the recombinant fusion protein etanercept, made up of a TNFR2 peptide fused to an Fc portion of human IgG1. There was no benefit from the combined blockades compared with individual blockades or after repeated treatments for 11 days after injury compared with one treatment at 1 hr after injury, when measured at 6 hr or 18 days, based on changes in neuropathology. There was also no further enhancement of blockade benefits after 18 days. Given that both Kineret and etanercept given singly or in combination showed similar beneficial effects and that TNFα also has a gliotransmitter role regulating AMPA receptor traffic, thus confounding effects of a TNFα blockade, we chose to focus on a single treatment with Kineret. PMID:26172557

  6. Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

    PubMed Central

    Xu, Zhen-Zhong; Kim, Yong Ho; Bang, Sangsu; Zhang, Yi; Berta, Temugin; Wang, Fan; Oh, Seog Bae; Ji, Ru-Rong

    2016-01-01

    SUMMARY Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold small-diameter unmyelinated C-fibers has limited effects on mechanical allodynia1–4. While large myelinated A-fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia5–7, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppressed mechanical allodynia following chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that flagellin/QX-314 co-application selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ blockade but not capsaicin-mediated C-fiber blockade also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment. PMID:26479925

  7. Blockade of maitotoxin-induced oncotic cell death reveals zeiosis

    PubMed Central

    Estacion, Mark; Schilling, William P

    2002-01-01

    Background Maitotoxin (MTX) initiates cell death by sequentially activating 1) Ca2+ influx via non-selective cation channels, 2) uptake of vital dyes via formation of large pores, and 3) release of lactate dehydrogenase, an indication of cell lysis. MTX also causes formation of membrane blebs, which dramatically dilate during the cytolysis phase. To determine the role of phospholipase C (PLC) in the cell death cascade, U73122, a specific inhibitor of PLC, and U73343, an inactive analog, were examined on MTX-induced responses in bovine aortic endothelial cells. Results Addition of either U73122 or U73343, prior to MTX, produced a concentration-dependent inhibition of the cell death cascade (IC50 ≈ 1.9 and 0.66 μM, respectively) suggesting that the effect of these agents was independent of PLC. Addition of U73343 shortly after MTX, prevented or attenuated the effects of the toxin, but addition at later times had little or no effect. Time-lapse videomicroscopy showed that U73343 dramatically altered the blebbing profile of MTX-treated cells. Specifically, U73343 blocked bleb dilation and converted the initial blebbing event into "zeiosis", a type of membrane blebbing commonly associated with apoptosis. Cells challenged with MTX and rescued by subsequent addition of U73343, showed enhanced caspase-3 activity 48 hr after the initial insult, consistent with activation of the apoptotic program. Conclusions Within minutes of MTX addition, endothelial cells die by oncosis. Rescue by addition of U73343 shortly after MTX showed that a small percentage of cells are destined to die by oncosis, but that a larger percentage survive; cells that survive the initial insult exhibit zeiosis and may ultimately die by apoptotic mechanisms. PMID:11825342

  8. Stormwater Attenuation by Green Roofs

    NASA Astrophysics Data System (ADS)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.

    2014-12-01

    Innovative municipal stormwater management technologies are urgently required in urban centers. Inadequate stormwater management can lead to excessive flooding, channel erosion, decreased stream baseflows, and degraded water quality. A major source of urban stormwater is unused roof space. Green roofs can be used as a stormwater management tool to reduce roof generated stormwater and generally improve the quality of runoff. With recent legislation in some North American cities, including Toronto, requiring the installation of green roofs on large buildings, research on the effectiveness of green roofs for stormwater management is important. This study aims to assess the hydrologic response of an extensive sedum green roof in London, Ontario, with emphasis on the response to large precipitation events that stress municipal stormwater infrastructure. A green roof rapidly reaches field capacity during large storm events and can show significantly different behavior before and after field capacity. At field capacity a green roof has no capillary storage left for retention of stormwater, but may still be an effective tool to attenuate peak runoff rates by transport through the green roof substrate. The attenuation of green roofs after field capacity is linked to gravity storage, where gravity storage is the water that is temporarily stored and can drain freely over time after field capacity has been established. Stormwater attenuation of a modular experimental green roof is determined from water balance calculations at 1-minute intervals. Data is used to evaluate green roof attenuation and the impact of field capacity on peak flow rates and gravity storage. In addition, a numerical model is used to simulate event based stormwater attenuation. This model is based off of the Richards equation and supporting theory of multiphase flow through porous media.

  9. Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

    PubMed

    Davidson, Joanne O; Rout, Alexandra L; Wassink, Guido; Yuill, Caroline A; Zhang, Frank G; Green, Colin R; Bennet, Laura; Gunn, Alistair J

    2015-12-01

    Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.

  10. Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

    PubMed

    Davidson, Joanne O; Rout, Alexandra L; Wassink, Guido; Yuill, Caroline A; Zhang, Frank G; Green, Colin R; Bennet, Laura; Gunn, Alistair J

    2015-12-01

    Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep. PMID:26174327

  11. Antipsychotics differ in their ability to internalise human dopamine D2S and human serotonin 5-HT1A receptors in HEK293 cells.

    PubMed

    Heusler, Peter; Newman-Tancredi, Adrian; Loock, Timothé; Cussac, Didier

    2008-02-26

    Antipsychotic drugs act preferentially via dopamine D(2) receptor blockade, but interaction with serotonin 5-HT(1A) receptors has attracted interest as additional target for antipsychotic treatment. As receptor internalisation is considered crucial for drug action, we tested the propensity of antipsychotics to internalise human (h)D(2S) receptors and h5-HT(1A) receptors. Agonist-induced internalisation of hemaglutinin (HA)-tagged hD(2S) and HA-h5-HT(1A) receptors expressed in HEK293 cells was increased by coexpression of G-protein coupled receptor kinase 2 and beta-arrestin2. At the HA-hD(2S) receptor, dopamine, quinpirole and bromocriptine behaved as full agonists, while S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(-)-3PPP] and sarizotan were partial agonists. The typical antipsychotic, haloperidol, and the atypical compounds, olanzapine, nemonapride, ziprasidone and clozapine did not internalise HA-hD(2S) receptors, whereas aripiprazole potently internalised these receptors (>50% relative efficacy). Among antipsychotics with combined D(2)/5-HT(1A) properties, bifeprunox and (3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo-[3.2.1]octane-3-methanamine (SSR181507) partially internalised HA-hD(2S) receptors, piperazine, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)-4-[[5-(4-fluorophenyl)-3-pyridinyl]methyl (SLV313) and N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063) were inactive. At the HA-h5-HT(1A) receptor, serotonin, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] and sarizotan were full agonists, buspirone acted as partial agonist. (-)-Pindolol showed little activity and no internalising properties were manifested for the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635). Most antipsychotics induced HA-h5-HT(1A) receptor internalisation, with an efficacy rank order: nemonapride>F15063>SSR181507

  12. Conserved site for neurosteroid modulation of GABA A receptors.

    PubMed

    Hosie, Alastair M; Clarke, Laura; da Silva, Helena; Smart, Trevor G

    2009-01-01

    This study addresses whether the potentiation site for neurosteroids on GABA(A) receptors is conserved amongst different GABA(A) receptor isoforms. The neurosteroid potentiation site was previously identified in the alpha1beta2gamma2S receptor by mutation of Q241 to methionine or leucine, which reduced the potentiation of GABA currents by the naturally occurring neurosteroids, allopregnanolone or tetrahydrodeoxycorticosterone (THDOC). By using heterologous expression of GABA(A) receptors in HEK cells, in combination with whole-cell patch clamp recording methods, a relatively consistent potentiation by allopregnanolone of GABA-activated currents was evident for receptors composed of one alpha subunit isoform (alpha2-5) assembled with beta3 and gamma2S subunits. Using mutant alphabetagamma receptors, the neurosteroid potentiation was universally dependent on the conserved glutamine residue in M1 of the respective alpha subunit. Studying wild-type and mutant receptors composed of alpha4beta3delta subunits revealed that the delta subunit is unlikely to contribute to the neurosteroid potentiation binding site and probably affects the efficacy of potentiation. Thus, in keeping with the ability of neurosteroids to potentiate GABA currents via a broad variety of GABA(A) receptor isoforms in neurons, the potentiation site is structurally highly conserved on this important neurotransmitter receptor family.

  13. Action of tremorgenic mycotoxins on GABA/sub A/ receptor

    SciTech Connect

    Gant, D.B.; Cole, R.J.; Valdes, J.J.; Eldefrawi, M.E.; Eldefrawi, A.T.

    1987-11-09

    The effects of four tremorgenic and one nontremorgenic mycotoxins were studied on ..gamma..-aminobutyric acid (GABA/sub A/) receptor binding and function in rat brain and on binding of a voltage-operated Cl/sup -/ channel in Torpedo electric organ. None of the mycotoxins had significant effect on (/sup 3/H)muscimol or (/sup 3/H)flunitrazepam binding to the GAMA/sup A/ receptor. However, only the four tremorgenic mycotoxins inhibited GABA-induced /sup 36/Cl/sup -/ influx and (/sup 35/S)t-butylbicyclophosphorothionate ((/sup 35/S)TBPS) binding in rate brain membranes, while the nontremorgenic verruculotoxin had no effect. Inhibition of (/sup 35/S)TBPS binding by paspalinine was non-competitive. This suggests that tremorgenic mycotoxins inhibit GABA/sub A/ receptor function by binding close to the receptor's Cl/sup -/ channel. On the voltage-operated Cl/sup -/ channel, only high concentrations of verruculogen and verruculotoxin caused significant inhibition of the channel's binding of (/sup 35/S)TBPS. The data suggest that the tremorgenic action of these mycotoxins may be due in part to their inhibition of GABA/sub A/ receptor function. 21 references, 4 figures, 2 tables.

  14. Altered photic and non-photic phase shifts in 5-HT(1A) receptor knockout mice.

    PubMed

    Smith, V M; Sterniczuk, R; Phillips, C I; Antle, M C

    2008-12-01

    The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) is thought to be modulated by 5-HT. 5-HT is though to inhibit photic phase shifts by inhibiting the release of glutamate from retinal terminals, as well as by decreasing the responsiveness of retinorecipient cells in the SCN. Furthermore, there is also evidence that 5-HT may underlie, in part, non-photic phase shifts of the circadian system. Understanding the mechanism by which 5-HT accomplishes these goals is complicated by the wide variety of 5-HT receptors found in the SCN, the heterogeneous organization of both the circadian clock and the location of 5-HT receptors, and by a lack of sufficiently selective pharmacological agents for the 5-HT receptors of interest. Genetically modified animals engineered to lack a specific 5-HT receptor present an alternative avenue of investigation to understand how 5-HT regulates the circadian system. Here we examine behavioral and molecular responses to both photic and non-photic stimuli in mice lacking the 5-HT(1A) receptor. When compared with wild-type controls, these mice exhibit larger phase advances to a short late-night light pulse and larger delays to long 12 h light pulses that span the whole subjective night. Fos and mPer1 expression in the retinorecipient SCN is significantly attenuated following late-night light pulses in the 5-HT(1A) knockout animals. Finally, non-photic phase shifts to (+/-)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) are lost in the knockout animals, while attenuation of the phase shift to the long light pulse due to rebound activity following a wheel lock is unaffected. These findings suggest that the 5-HT(1A) receptor plays an inhibitory role in behavioral phase shifts, a facilitatory role in light-induced gene expression, a necessary role in phase shifts to 8-OH-DPAT, and is not necessary for activity-induced phase advances that oppose photic phase shifts to long light pulses.

  15. Blockade of dopamine D1-like receptor signalling protects mice against OVA-induced acute asthma by inhibiting B-cell activating transcription factor signalling and Th17 function.

    PubMed

    Gong, Subo; Li, Jinxiu; Ma, Libing; Li, Keng; Zhang, Li; Wang, Guyi; Liu, Yi; Ji, Xiaoying; Liu, Xiaokun; Chen, Ping; Ouyang, Ruoyun; Zhang, Shu; Zhou, Zhiguang; Wang, Cong-Yi; Xiang, Xudong; Yang, Yu

    2013-12-01

    Previous studies have consistently demonstrated that dopamine D1-like receptor (D1-like-R) signalling is implicated in the pathogenesis of experimental autoimmune encephalomyelitis and type I diabetes. Given that allergic asthma shares certain disease aetiology similarities with autoimmune diseases, we conducted studies in OVA-induced mice aiming to address the impact of D1-like-R signalling on the pathogenesis of allergic asthma. It was noted that blockade of D1-like-R signalling provided protection for mice against OVA-induced acute asthma. Particularly, treatment of OVA-induced mice with SCH23390, a D1-like-R antagonist, significantly attenuated inflammatory infiltration in the airways along with repressed goblet cell hyperplasia and mucus production, as well as airway resistance. By contrast, administration of SKF83959, a D1-like-R agonist, displayed the opposite effect. Blockade of D1-like-R signalling impaired Th17 function, as manifested by a significant reduction of Th17 cells in the spleen and bronchoalveolar lavage fluid. Mechanistic studies revealed that D1-like-R signalling enhances B-cell activating transcription factor activity, which then transcribes the expression of RORγt, a Th17 transcription factor; accordingly, D1-like-R signalling regulates Th17 differentiation to promote the development of allergic asthma. Taken together, the data obtained in the present suggest that blockade of D1-like-R signalling could be an effective therapeutic strategy for the prevention and treatment of allergic asthma in clinical practice.

  16. ENHANCEMENTS TO NATURAL ATTENUATION: SELECTED CASE STUDIES

    SciTech Connect

    Vangelas, K; W. H. Albright, W; E. S. Becvar, E; C. H. Benson, C; T. O. Early, T; E. Hood, E; P. M. Jardine, P; M. Lorah, M; E. Majche, E; D. Major, D; W. J. Waugh, W; G. Wein, G; O. R. West, O

    2007-05-15

    In 2003 the US Department of Energy (DOE) embarked on a project to explore an innovative approach to remediation of subsurface contaminant plumes that focused on introducing mechanisms for augmenting natural attenuation to achieve site closure. Termed enhanced attenuation (EA), this approach has drawn its inspiration from the concept of monitored natural attenuation (MNA).

  17. Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors.

    PubMed

    Kumar, Manish; Dillon, Glenn H

    2016-03-15

    Meprobamate is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (γ-aminobutyric acid Type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In αxβzγ2 GABAA receptors (where x=1-6 and z=1-3), the ability to enhance GABA-mediated current was evident for all α subunit isoforms, with the largest effect observed in α5-expressing receptors. Direct gating was present with all α subunits, although attenuated in α3-expressing receptors. Allosteric and direct effects were comparable in α1β1γ2 and α1β2γ2 receptors, whereas allosteric effects were enhanced in α1β2 compared to α1β2γ2 receptors. In "extrasynaptic" (α1β3δ and α4β3δ) receptors, meprobamate enhanced EC20 and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of meprobamate. Whereas pentobarbital directly gated homomeric β3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ρ1 receptors, pentobarbital and meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to meprobamate. Our results provide insight into the actions of meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of meprobamate were comparable to those of carisoprodol, differential effects of meprobamate at some receptor subtypes suggest potential advantages of meprobamate may be exploited. A re-assessment of previously synthesized meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted. PMID:26872987

  18. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Gary Mavko; Jack Dvorkin

    2002-01-01

    In Section 1 of this first report we will describe the work we are doing to collect and analyze rock physics data for the purpose of modeling seismic attenuation from other measurable quantities such as porosity, water saturation, clay content and net stress. This work and other empirical methods to be presented later, will form the basis for ''Q pseudo-well modeling'' that is a key part of this project. In Section 2 of this report, we will show the fundamentals of a new method to extract Q, dispersion, and attenuation from field seismic data. The method is called Gabor-Morlet time-frequency decomposition. This technique has a number of advantages including greater stability and better time resolution than spectral ratio methods.

  19. Chlorine signal attenuation in concrete.

    PubMed

    Naqvi, A A; Maslehuddin, M; ur-Rehman, Khateeb; Al-Amoudi, O S B

    2015-11-01

    The intensity of prompt gamma-ray was measured at various depths from chlorine-contaminated silica fume (SF) concrete slab concrete specimens using portable neutron generator-based prompt gamma-ray setup. The intensity of 6.11MeV chloride gamma-rays was measured from the chloride contaminated slab at distance of 15.25, 20.25, 25.25, 30.25 and 35.25cm from neutron target in a SF cement concrete slab specimens. Due to attenuation of thermal neutron flux and emitted gamma-ray intensity in SF cement concrete at various depths, the measured intensity of chlorine gamma-rays decreases non-linearly with increasing depth in concrete. A good agreement was noted between the experimental results and the results of Monte Carlo simulation. This study has provided useful experimental data for evaluating the chloride contamination in the SF concrete utilizing gamma-ray attenuation method.

  20. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis

    PubMed Central

    Dubin, Krista; Callahan, Margaret K.; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G.; Wolchok, Jedd D.

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  1. Modification by Beta-Adrenergic Blockade of the Circulatory Responses to Acute Hypoxia in Man*

    PubMed Central

    Richardson, David W.; Kontos, Hermes A.; Raper, A. Jarrell; Patterson, John L.

    1967-01-01

    In 17 healthy men, beta-adrenergic blockade reduced significantly the tachycardia and the elevation of cardiac output associated with inhalation of 7.5% oxygen for 7 to 10 minutes. Hypoxia did not increase plasma concentrations of epinephrine or norepinephrine in six subjects. Furthermore, blockade of alpha and beta receptors in the forearm did not modify the vasodilation in the forearm induced by hypoxia, providing pharmacologic evidence that hypoxia of the degree and duration used was not associated with an increase in the concentrations of circulating catecholamines in man. Part of the increase in cardiac output and heart rate during acute hypoxia in man is produced by stimulation of beta-adrenergic receptors, probably by cardiac sympathetic nerves. The mechanism of the vasodilation in the forearm during hypoxia remains uncertain. PMID:4381183

  2. Quantum transport through a Coulomb blockaded quantum emitter coupled to a plasmonic dimer.

    PubMed

    Goker, A; Aksu, H

    2016-01-21

    We study the electron transmission through a Coulomb blockaded quantum emitter coupled to metal nanoparticles possessing plasmon resonances by employing the time-dependent non-crossing approximation. We find that the coupling of the nanoparticle plasmons with the excitons results in a significant enhancement of the conductance through the discrete state with higher energy beyond the unitarity limit while the other discrete state with lower energy remains Coulomb blockaded. We show that boosting the plasmon-exciton coupling well below the Kondo temperature increases the enhancement adding another quantum of counductance upon saturation. Finite bias and increasing emitter resonance energy tend to reduce this enhancement. We attribute these observations to the opening of an additional transport channel via the plasmon-exciton coupling. PMID:26686761

  3. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

    PubMed

    Sykes, David B; Kfoury, Youmna S; Mercier, François E; Wawer, Mathias J; Law, Jason M; Haynes, Mark K; Lewis, Timothy A; Schajnovitz, Amir; Jain, Esha; Lee, Dongjun; Meyer, Hanna; Pierce, Kerry A; Tolliday, Nicola J; Waller, Anna; Ferrara, Steven J; Eheim, Ashley L; Stoeckigt, Detlef; Maxcy, Katrina L; Cobert, Julien M; Bachand, Jacqueline; Szekely, Brian A; Mukherjee, Siddhartha; Sklar, Larry A; Kotz, Joanne D; Clish, Clary B; Sadreyev, Ruslan I; Clemons, Paul A; Janzer, Andreas; Schreiber, Stuart L; Scadden, David T

    2016-09-22

    While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.

  4. Erythromelalgia in the pediatric patient: role of computed-tomography-guided lumbar sympathetic blockade

    PubMed Central

    Kundu, Anjana; Rafiq, Mahmood; Warren, Patrick S; Tobias, Joseph D

    2016-01-01

    Erythromelalgia (EM) is an uncommon condition characterized by erythema, increased skin temperature, and burning pain, most frequently occurring in the lower extremities. The pain is generally very severe and treatment can be extremely challenging, especially in the pediatric and adolescent population. We report a series of three cases of primary EM in pediatric patients involving the lower extremities, refractory to medical treatment that responded favorably to computed-tomography-guided lumbar sympathetic blockade. There was a significant improvement in pain scores, quality of life, and overall function as well as decreased analgesic requirements. Lumbar sympathetic blockade should be considered as a therapeutic modality in pediatric and adolescent patients with EM who are refractory to other treatments. PMID:27799815

  5. Coherent Generation of Nonclassical Light on Chip via Detuned Photon Blockade.

    PubMed

    Müller, Kai; Rundquist, Armand; Fischer, Kevin A; Sarmiento, Tomas; Lagoudakis, Konstantinos G; Kelaita, Yousif A; Sánchez Muñoz, Carlos; del Valle, Elena; Laussy, Fabrice P; Vučković, Jelena

    2015-06-12

    The on-chip generation of nonclassical states of light is a key requirement for future optical quantum hardware. In solid-state cavity quantum electrodynamics, such nonclassical light can be generated from self-assembled quantum dots strongly coupled to photonic crystal cavities. Their anharmonic strong light-matter interaction results in large optical nonlinearities at the single photon level, where the admission of a single photon into the cavity may enhance (photon tunneling) or diminish (photon blockade) the probability for a second photon to enter the cavity. Here, we demonstrate that detuning the cavity and quantum-dot resonances enables the generation of high-purity nonclassical light from strongly coupled systems. For specific detunings we show that not only the purity but also the efficiency of single-photon generation increases significantly, making high-quality single-photon generation by photon blockade possible with current state-of-the-art samples. PMID:26196801

  6. Double-island Coulomb blockade in (Ga,Mn)As nanoconstrictions

    NASA Astrophysics Data System (ADS)

    Geißler, S.; Pfaller, S.; Utz, M.; Bougeard, D.; Donarini, A.; Grifoni, M.; Weiss, D.

    2015-05-01

    We report on a systematic study of the Coulomb-blockade effects in nanofabricated narrow constrictions in thin (Ga,Mn)As films. Different low-temperature transport regimes have been observed for decreasing constriction sizes: the Ohmic, the single-electron tunneling (SET), and a completely insulating regime. In the SET, complex stability diagrams with nested Coulomb diamonds and anomalous conductance suppression in the vicinity of charge degeneracy points have been observed. We rationalize these observations in the SET with a double ferromagnetic island model coupled to ferromagnetic leads. Its transport characteristics are analyzed in terms of a modified orthodox theory of Coulomb blockade which takes into account the energy dependence of the density of states in the metallic islands.

  7. [Organization of medical support for troops, defending Leningrad and the people of the blockaded city].

    PubMed

    Shelepov, A M; Kryuchkov, O A

    2015-03-01

    The data on the composition of forces of medical services and organization of medical-evacuation support for troops defending the blockaded Leningrad are presented. The information about the health losses among the population of Leningrad as a result of bombing, shelling and disease is given. Extremely high rates of morbidity and mortality in residents were associated with hunger, hypothermia and emotional stress. The clinical picture of some diseases has different peculiarities because of alimentary dystrophy background. The city health service suffered huge losses: 482 medical institutions were destroyed, only about 300 people from 1.5 thousand of medical personnel in 1942 saved working capability. The health care service of the local air defense played an essential role in delivery of medical aid. The contribution of civil and military health workers in saving residents lives in the blockaded Leningrad was appreciated. PMID:26454930

  8. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis.

    PubMed

    Dubin, Krista; Callahan, Margaret K; Ren, Boyu; Khanin, Raya; Viale, Agnes; Ling, Lilan; No, Daniel; Gobourne, Asia; Littmann, Eric; Huttenhower, Curtis; Pamer, Eric G; Wolchok, Jedd D

    2016-01-01

    The composition of the intestinal microbiota influences the development of inflammatory disorders. However, associating inflammatory diseases with specific microbial members of the microbiota is challenging, because clinically detectable inflammation and its treatment can alter the microbiota's composition. Immunologic checkpoint blockade with ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) signalling, is associated with new-onset, immune-mediated colitis. Here we conduct a prospective study of patients with metastatic melanoma undergoing ipilimumab treatment and correlate the pre-inflammation faecal microbiota and microbiome composition with subsequent colitis development. We demonstrate that increased representation of bacteria belonging to the Bacteroidetes phylum is correlated with resistance to the development of checkpoint-blockade-induced colitis. Furthermore, a paucity of genetic pathways involved in polyamine transport and B vitamin biosynthesis is associated with an increased risk of colitis. Identification of these biomarkers may enable interventions to reduce the risk of inflammatory complications following cancer immunotherapy. PMID:26837003

  9. Dissociation between renin and arterial pressure responses to beta-adrenergic blockade in human essential hypertension.

    PubMed

    Bravo, E L; Tarazi, R C; Dustan, H P; Lewis, J W

    1975-06-01

    Studies were carried out in 69 patients with essential hypertension to examine the relationship between changes in plasma renin activity (PRA) and arterial pressure (BP) in response to a beta-adrenergic blocking agent, propranolol. PRA had no consistent relationship with BP during treatment, either in patients receiving propranolol alone (r = 0.12) or in those receiving a combination of diuretics and propranolol (r = 0.18). Furthermore, long-term beta-adrenergic blockade failed to inhibit increases of PRA induced by diuretics or rapid sodium depletion. These results indicate that (1) beta-adrenergic blockade can reduce BP by mechanisms other than PRA suppression; and (2) the beta-adrenergic nervous system is important, but not essential, for renin release. PMID:236841

  10. [Organization of medical support for troops, defending Leningrad and the people of the blockaded city].

    PubMed

    Shelepov, A M; Kryuchkov, O A

    2015-03-01

    The data on the composition of forces of medical services and organization of medical-evacuation support for troops defending the blockaded Leningrad are presented. The information about the health losses among the population of Leningrad as a result of bombing, shelling and disease is given. Extremely high rates of morbidity and mortality in residents were associated with hunger, hypothermia and emotional stress. The clinical picture of some diseases has different peculiarities because of alimentary dystrophy background. The city health service suffered huge losses: 482 medical institutions were destroyed, only about 300 people from 1.5 thousand of medical personnel in 1942 saved working capability. The health care service of the local air defense played an essential role in delivery of medical aid. The contribution of civil and military health workers in saving residents lives in the blockaded Leningrad was appreciated.

  11. Expression of α(1)-adrenergic receptors in rat prefrontal cortex: cellular co-localization with 5-HT(2A) receptors.

    PubMed

    Santana, Noemí; Mengod, Guadalupe; Artigas, Francesc

    2013-06-01

    The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α(1)-adrenergic receptors (α(1)ARs) and 5-HT(2A) receptors (5-HT(2A)Rs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α(1)ARs while having preferential affinity for D(2) and 5-HT(2A)Rs, respectively. Using double in situ hybridization we examined the cellular expression of α(1)ARs in pyramidal (vGluT1-positive) and GABAergic (GAD(65/67)-positive) neurons in rat PFC and their co-localization with 5-HT(2A)Rs. α(1)ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α(1)AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α(1A), α(1B) and α(1D) adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT(2A)Rs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α(1)ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α(1)AR blockade. The high co-expression with 5-HT(2A)Rs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α(1)ARs and 5-HT(2A)Rs.

  12. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience.

    PubMed

    Fogaça, M V; Reis, F M C V; Campos, A C; Guimarães, F S

    2014-03-01

    The prelimbic medial prefrontal cortex (PL) is an important encephalic structure involved in the expression of emotional states. In a previous study, intra-PL injection of cannabidiol (CBD), a major non-psychotomimetic cannabinoid present in the Cannabis sativa plant, reduced the expression of fear conditioning response. Although its mechanism remains unclear, CBD can facilitate 5HT1A receptor-mediated neurotransmission when injected into several brain structures. This study was aimed at verifying if intra-PL CBD could also induce anxiolytic-like effect in a conceptually distinct animal model, the elevated plus maze (EPM). We also verified if CBD effects in the EPM and contextual fear conditioning test (CFC) depend on 5HT1A receptors and previous stressful experience. CBD induced opposite effects in the CFC and EPM, being anxiolytic and anxiogenic, respectively. Both responses were prevented by WAY100,635, a 5HT1A receptor antagonist. In animals that had been previously (24h) submitted to a stressful event (2h-restraint) CBD caused an anxiolytic, rather than anxiogenic, effect in the EPM. This anxiolytic response was abolished by previous injection of metyrapone, a glucocorticoid synthesis blocker. Moreover, restraint stress increased 5HT1A receptors expression in the dorsal raphe nucleus, an effect that was attenuated by injection of metyrapone before the restraint procedure. Taken together, these results suggest that CBD modulation of anxiety in the PL depend on 5HT1A-mediated neurotransmission and previous stressful experience.

  13. Natural and enhanced attenuation of metals

    SciTech Connect

    Rouse, J.V.; Pyrih, R.Z.

    1996-12-31

    The ability of natural earthen materials to attenuate the movement of contamination can be quantified in relatively simple geochemical experiments. In addition, the ability of subsurface material to attenuate potential contaminants can be enhanced through modifications to geochemical parameters such as pH or redox conditions. Such enhanced geochemical attenuation has been demonstrated at a number of sites to be a cost-effective alternative to conventional pump and treat operations. This paper describes the natural attenuation reactions which occur in the subsurface, and the way to quantify such attenuation. It also introduces the concept of enhanced geochemical attenuation, wherein naturally-occurring geochemical reactions can be used to achieve in situ fixation. The paper presents examples where such natural and enhanced attenuation have been implemented as a part of an overall remedy.

  14. PD-1 blockade enhances the vaccination-induced immune response in glioma

    PubMed Central

    Antonios, Joseph P.; Soto, Horacio; Everson, Richard G.; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H.; Li, Gang; Cloughesy, Timothy F.; Liau, Linda M.; Prins, Robert M.

    2016-01-01

    DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor–bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID:27453950

  15. Generation of nonclassical states of light via photon blockade in optical nanocavities

    SciTech Connect

    Faraon, Andrei; Majumdar, Arka; Vuckovic, Jelena

    2010-03-15

    The generation of nonclassical states of light via photon blockade with time-modulated input is analyzed. We show that improved single-photon statistics can be obtained by adequately choosing the parameters of the driving laser pulses. An alternative method, where the system is driven via a continuous-wave laser and the frequency of the dipole is controlled (e.g., electrically) at very fast time scales is presented.

  16. N(N)-nicotinic blockade as an acute human model of autonomic failure

    NASA Technical Reports Server (NTRS)

    Jordan, J.; Shannon, J. R.; Black, B. K.; Lance, R. H.; Squillante, M. D.; Costa, F.; Robertson, D.

    1998-01-01

    Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.

  17. Touch Perception Altered by Chronic Pain and by Opioid Blockade1,2,3

    PubMed Central

    Gracely, John L.; Richards, Emily A.; Olausson, Håkan

    2016-01-01

    Abstract Touch plays a significant role in human social behavior and social communication, and its rewarding nature has been suggested to involve opioids. Opioid blockade in monkeys leads to increased solicitation and receipt of grooming, suggesting heightened enjoyment of touch. We sought to study the role of endogenous opioids in perception of affective touch in healthy adults and in patients with fibromyalgia, a chronic pain condition shown to involve reduced opioid receptor availability. The pleasantness of touch has been linked to the activation of C-tactile fibers, which respond maximally to slow gentle touch and correlate with ratings of pleasantness. We administered naloxone to patients and healthy controls to directly observe the consequences of µ-opioid blockade on the perceived pleasantness and intensity of touch. We found that at baseline chronic pain patients showed a blunted distinction between slow and fast brushing for both intensity and pleasantness, suggesting reduced C-tactile touch processing. In addition, we found a differential effect of opioid blockade on touch perception in healthy subjects and pain patients. In healthy individuals, opioid blockade showed a trend toward increased ratings of touch pleasantness, while in chronic pain patients it significantly decreased ratings of touch intensity. Further, in healthy individuals, naloxone-induced increase in touch pleasantness was associated with naloxone-induced decreased preference for slow touch, suggesting a possible effect of opioid levels on processing of C-tactile fiber input. These findings suggest a role for endogenous opioids in touch processing, and provide further evidence for altered opioid functioning in chronic pain patients. PMID:27022625

  18. Low-dose alpha/beta blockade in the treatment of essential hypertension.

    PubMed

    Mann, S J; Gerber, L M

    2001-06-01

    Despite the recent emphasis on combination drug therapy for hypertension, little attention has been given to alpha/beta blockade using agents other than labetalol. The purpose of this study was to 1) compare the efficacy of low-dose alpha/beta blockade using doxazosin + betaxolol, versus monotherapy with an angiotensin converting enzyme inhibitor (quinapril) and a diuretic (hydrochlorothiazide [HCTZ]), and 2) assess the efficacy of low-dose doxazosin. In a crossover study, 21 hypertensive subjects were treated for 3 weeks each with HCTZ, 12.5 to 25 mg/day, quinapril, 10 to 40 mg/day, and a combination of doxazosin, 1 to 4 mg + betaxolol, 5 to 10 mg daily. Doses were titrated to achieve a systolic pressure <130 mm Hg, as assessed by self-recorded home measurements. Home blood pressure decreased 11.5/7.5 mm Hg after HCTZ, 12.9/8.8 mm Hg after quinapril, and 21.2/16.5 mm Hg after doxazosin + betaxolol (P < .001/< .001 v HCTZ and P < .002/< .001 v quinapril). The target systolic pressure was achieved by 33%, 43%, and 71% of subjects, respectively (P = .04 v HCTZ, and .03 v quinapril). Among the 8 subjects in whom doxazosin dosage was increased to the maximum of 4 mg, the mean blood pressure achieved at 4 mg did not differ from that achieved at 2 mg (136/87 v 136/88 mm Hg). We conclude that oral alpha/beta blockade is superior to monotherapy with an angiotensin converting enzyme inhibitor or a diuretic and that maximal or near maximal efficacy can be achieved at a 2-mg dose of doxazosin. Low-dose oral alpha/beta blockade merits greater consideration in the drug therapy of essential hypertension.

  19. Therapeutic blockade of TNF in patients with SLE-promising or crazy?

    PubMed

    Aringer, Martin; Smolen, Josef S

    2012-03-01

    TNF is an important mediator of inflammation, but is also involved in the control of autoimmunity. The latter has been demonstrated in a murine model of SLE (NZB/W) and by the occurrence of autoantibodies to nuclear antigens as well as occasional, transient lupus-like syndromes in patients under TNF blockade. In contrast, data on increased TNF levels in serum, kidney and skin samples of SLE patients as well as results in other mouse models of the disease point to an inflammatory role of TNF in SLE organ disease. Despite all due caution, given these two sides of the cytokine, TNF blockade has by now been employed for several years in single cases and open label studies; data on more than fifty patients have meanwhile been published, for the vast majority of which infliximab was employed. These clinical data have to be very cautiously interpreted, as always with data on single cases or open label trials. However, some consistent pieces of information emerge and may inform controlled clinical trials: (i) While antibodies to double-stranded DNA commonly showed transient increases, lupus flares have not been seen so far and thus apparently are at least not the rule; (ii) in contrast, increases in anti-phospholipid antibodies may be associated with vascular adverse events; (iii) bacterial infections, pneumonia and urinary tract infections in particular, have been observed; (iv) short term induction therapy appears relatively safe, while long-term TNF blockade may confer significant risks in SLE; (v) TNF blocker induction therapy may lead to long-term remission in patients with lupus nephritis, hemophagocytic syndrome, and interstitial lung disease; (vi) patients with lupus arthritis often respond to TNF-blockade but symptoms recur after cessation of therapy, necessitating longer term therapy, which is more risky than short term treatment.

  20. Channel blockade in a two-path triple-quantum-dot system

    NASA Astrophysics Data System (ADS)

    Kotzian, M.; Gallego-Marcos, F.; Platero, G.; Haug, R. J.

    2016-07-01

    Electronic transport through a two-path triple-quantum-dot system with two source leads and one drain is studied and the interaction between the two paths is analyzed. We observe a channel blockade as a result of interchannel Coulombic interaction. The experimental results are understood with the help of a theoretical model which allows one to obtain the parameters of the system, the stability regions of each state, and the full dynamical transport in the triple-dot resonances.

  1. Continuous blockade of brain glucocorticoid receptors facilitates spatial learning and memory in rats.

    PubMed

    Oitzl, M S; Fluttert, M; Sutanto, W; de Kloet, E R

    1998-12-01

    Previously, a corticosterone surge associated with a learning task was shown to facilitate cognitive processes through brain glucocorticoid receptors (GR) while chronic overexposure to this stress hormone impaired cognition. In the present study we tested the hypothesis that opposing effects on learning and memory might also occur after either phasic or continuous blockade of brain GR by intracerebroventricular (i.c.v.) administration of the GR antagonist RU38486 (aGR). We used a Morris water maze procedure to assess spatial learning and memory abilities in male Wistar rats. The effect of phasic brain GR blockade was studied following daily pretraining administration of 10 and 100 ng/microL aGR i.c.v. on 3 consecutive days. This repetitive aGR treatment impaired spatial learning and memory dose-dependently in comparison with vehicle controls. For continuous brain GR blockade, animals received an i.c.v., infusion of aGR (10 and 100 ng/0.5 microL per h or vehicle) over 10 days. Infusion of 100 ng aGR per hour resulted in a long-lasting facilitation of spatial performance. The 10 ng aGR infusion also caused initially a facilitating effect, which was, however, transient and performance became impaired during retest. Possible anxiolytic properties of the drugs were excluded in view of the animals' behaviour in the elevated plus maze. Both doses of aGR infusion reduced the number of mineralocorticoid receptors in the hippocampus, but only the high dose of aGR resulted in a significant reduction of available GR sites. In conclusion, continuous administration of GR antagonist improves cognitive function, while phasic blockade of brain GR function causes a cognitive deficit.

  2. Blockade of central delta-opioid receptors inhibits salt appetite in sodium-depleted rats.

    PubMed

    Nascimento, A I R; Ferreira, H S; Cerqueira, D R; Fregoneze, J B

    2014-05-01

    Various studies have investigated the role of central opioid peptides in feeding behavior; however, only a few have addressed the participation of opioids in the control of salt appetite. The present study investigated the effect of intracerebroventricular injections of the δ-opioid antagonist, naltrindole (5, 10 and 20 nmol/rat) and the agonist, deltorphin II (2.5, 5, 10 and 20 nmol/rat) on salt intake. Two protocols for inducing salt intake were used: sodium-depletion and the central injection of angiotensin II. In addition, the effect of a central δ-opioid receptor blockade on locomotor activity, on palatable solution intake (0.1% saccharin) and on blood pressure was also studied. The blockade of central δ-opioid receptors inhibits salt intake in sodium-depleted rats, while the pharmacological stimulation of these receptors increases salt intake in sodium-replete animals. Furthermore, the blockade of central δ-opioid receptors inhibits salt intake induced by central angiotensinergic stimulation. These data suggest that during sodium-depletion activation of the δ-opioid receptors regulates salt appetite to correct the sodium imbalance and it is possible that an interaction between opioidergic and angiotensinergic brain system participates in this control. Under normonatremic conditions, δ-opioid receptors may be necessary to modulate sodium intake, a response that could be mediated by angiotensin II. The decrease in salt intake following central δ-opioid receptors blockade does not appear to be due to a general inhibition of locomotor activity, changes in palatability or in blood pressure.

  3. PD-1 blockade enhances the vaccination-induced immune response in glioma

    PubMed Central

    Antonios, Joseph P.; Soto, Horacio; Everson, Richard G.; Orpilla, Joey; Moughon, Diana; Shin, Namjo; Sedighim, Shaina; Yong, William H.; Li, Gang; Cloughesy, Timothy F.; Liau, Linda M.; Prins, Robert M.

    2016-01-01

    DC vaccination with autologous tumor lysate has demonstrated promising results for the treatment of glioblastoma (GBM) in preclinical and clinical studies. While the vaccine appears capable of inducing T cell infiltration into tumors, the effectiveness of active vaccination in progressively growing tumors is less profound. In parallel, a number of studies have identified negative costimulatory pathways, such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1), as relevant mediators of the intratumoral immune responses. Clinical responses to PD-1 pathway inhibition, however, have also been varied. To evaluate the relevance to established glioma, the effects of PD-1 blockade following DC vaccination were tested in intracranial (i.c.) glioma tumor– bearing mice. Treatment with both DC vaccination and PD-1 mAb blockade resulted in long-term survival, while neither agent alone induced a survival benefit in animals with larger, established tumors. This survival benefit was completely dependent on CD8+ T cells. Additionally, DC vaccine plus PD-1 mAb blockade resulted in the upregulation of integrin homing and immunologic memory markers on tumor-infiltrating lymphocytes (TILs). In clinical samples, DC vaccination in GBM patients was associated with upregulation of PD-1 expression in vivo, while ex vivo blockade of PD-1 on freshly isolated TILs dramatically enhanced autologous tumor cell cytolysis. These findings strongly suggest that the PD-1/PD-L1 pathway plays an important role in the adaptive immune resistance of established GBM in response to antitumor active vaccination and provide us with a rationale for the clinical translation of this combination therapy. PMID:27453950

  4. Benefits of Renin-Angiotensin Blockade on Retinopathy in Type 1 Diabetes Vary With Glycemic Control

    PubMed Central

    Harindhanavudhi, Tasma; Mauer, Michael; Klein, Ronald; Zinman, Bernard; Sinaiko, Alan; Caramori, M. Luiza

    2011-01-01

    OBJECTIVE Optimal glycemic control slows diabetic retinopathy (DR) development and progression and is the standard of care for type 1 diabetes. However, these glycemic goals are difficult to achieve and sustain in clinical practice. The Renin Angiotensin System Study (RASS) showed that renin-angiotensin system (RAS) blockade can slow DR progression. In the current study, we evaluate whether glycemic control influenced the benefit of RAS blockade on DR progression in type 1 diabetic patients. RESEARCH DESIGN AND METHODS We used RASS data to analyze the relationships between two-steps or more DR progression and baseline glycemic levels in 223 normotensive, normoalbuminuric type 1 diabetic patients randomized to receive 5 years of enalapril or losartan compared with placebo. RESULTS A total of 147 of 223 patients (65.9%) had DR at baseline (47 of 74 patients [63.5%] in placebo and 100 of 149 patients [67.1%] in the combined treatment groups [P = 0.67]). Patients with two-steps or more DR progression had higher baseline A1C than those without progression (9.4 vs. 8.2%, P < 0.001). There was no beneficial effect of RAS blockade (P = 0.92) in patients with baseline A1C ≤7.5%. In contrast, 30 of 112 (27%) patients on the active treatment arms with A1C >7.5% had two-steps or more DR progression compared with 26 of 56 patients (46%) in the placebo group (P = 0.03). CONCLUSIONS RAS blockade reduces DR progression in normotensive, normoalbuminuric type 1 diabetic patients with A1C >7.5%. Whether this therapy could benefit patients with A1C ≤7.5% will require long-term studies of much larger cohorts. PMID:21715517

  5. The role of adenosine A1 and A2A receptors in the caffeine effect on MDMA-induced DA and 5-HT release in the mouse striatum.

    PubMed

    Górska, A M; Gołembiowska, K

    2015-04-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") popular as a designer drug is often used with caffeine to gain a stronger stimulant effect. MDMA induces 5-HT and DA release by interaction with monoamine transporters. Co-administration of caffeine and MDMA may aggravate MDMA-induced toxic effects on DA and 5-HT terminals. In the present study, we determined whether caffeine influences DA and 5-HT release induced by MDMA. We also tried to find out if adenosine A1 and A2A receptors play a role in the effect of caffeine by investigating the effect of the selective adenosine A1 and A2A receptor antagonists, DPCPX and KW 6002 on DA and 5-HT release induced by MDMA. Mice were treated with caffeine (10 mg/kg) and MDMA (20 or 40 mg/kg) alone or in combination. DA and 5-HT release in the mouse striatum was measured using in vivo microdialysis. Caffeine exacerbated the effect of MDMA on DA and 5-HT release. DPCPX or KW 6002 co-administered with MDMA had similar influence as caffeine, but KW 6002 was more potent than caffeine or DPCPX. To exclude the contribution of MAO inhibition by caffeine in the caffeine effect on MDMA-induced increase in DA and 5-HT, we also tested the effect of the nonxanthine adenosine receptor antagonist CGS 15943A lacking properties of MAO activity modification. Our findings indicate that adenosine A1 and A2A receptor blockade may account for the caffeine-induced exacerbation of the MDMA effect on DA and 5-HT release and may aggravate MDMA toxicity.

  6. Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors.

    PubMed

    Espejo-Porras, Francisco; Fernández-Ruiz, Javier; Pertwee, Roger G; Mechoulam, Raphael; García, Concepción

    2013-12-01

    The broad presence of CB1 receptors in the basal ganglia, mainly in GABA- or glutamate-containing neurons, as well as the presence of TRPV1 receptors in dopaminergic neurons and the identification of CB2 receptors in some neuronal subpopulations within the basal ganglia, explain the powerful motor effects exerted by those cannabinoids that can activate/block these receptors. By contrast, cannabidiol (CBD), a phytocannabinoid with a broad therapeutic profile, is generally presented as an example of a cannabinoid compound with no motor effects due to its poor affinity for the CB1 and the CB2 receptor, despite its activity at the TRPV1 receptor. However, recent evidence suggests that CBD may interact with the serotonin 5-HT1A receptor to produce some of its beneficial effects. This may enable CBD to directly influence motor activity through the well-demonstrated role of serotonergic transmission in the basal ganglia. We have investigated this issue in rats using three different pharmacological and neurochemical approaches. First, we compared the motor effects of various i.p. doses of CBD with the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; i.p.). Second, we investigated whether the motor effects of CBD are sensitive to 5-HT1A receptor blockade in comparison with CB1 receptor antagonism. Finally, we investigated whether CBD was able to potentiate the effect of a sub-effective dose of 8-OH-DPAT. Our results demonstrated that: (i) only high doses of CBD (>10 mg/kg) altered motor behavior measured in a computer-aided actimeter; (ii) these alterations were restricted to vertical activity (rearing) with only modest changes in other parameters; (iii) similar effects were produced by 8-OH-DPAT (1 mg/kg), although this agonist affected exclusively vertical activity, with no effects on other motor parameters, and it showed always more potency than CBD; (iv) the effects of 8-OH-DPAT (1 mg/kg) and CBD (20 mg/kg) on vertical activity

  7. Robust and High Fidelity Quantum Logic with the Rydberg-Dressed Blockade

    NASA Astrophysics Data System (ADS)

    Keating, Tyler; Cook, Robert; Deutsch, Ivan; Hankin, Aaron; Jau, Yuan-Yu; Biedermann, Grant

    2015-05-01

    We study a scheme for implementing a controlled-Z (CZ) gate between two neutral-atom qubits based on the Rydberg blockade mechanism in a manner that is robust to errors caused by atomic motion. By adiabatically dressing the ground electronic state, we can protect the gate from decoherence due to random phase errors that typically arise from atomic thermal motion. The adiabatic protocol also allows for a Doppler-free configuration with counterpropagating lasers in a σ+ /σ- orthogonal polarization geometry that further reduces motional errors due to Doppler shifts. The residual error is dominated by dipole-dipole forces acting on doubly-excited Rydberg atoms when the blockade is imperfect. For reasonable parameters, with qubits encoded into the clock states of 133Cs, we predict that our protocol could produce a CZ gate in <10 μs with error probability of order 10-3. We generalize this protocol to exploit the multi-body nature of the Rydberg blockade and go beyond two qubits. We show how one can implement a three-qubit Toffoli gate in a single-step. Finally, we consider encoding in collective states of small ensembles of atoms, and show how such a scheme can allow for scalable, robust, quantum logic.

  8. Negative differential photoconductance in gold nanoparticle arrays in the Coulomb blockade regime.

    PubMed

    Mangold, Markus A; Calame, Michel; Mayor, Marcel; Holleitner, Alexander W

    2012-05-22

    We investigate the photoconductance of gold nanoparticle arrays in the Coulomb blockade regime. Two-dimensional, hexagonal crystals of nanoparticles are produced by self-assembly. The nanoparticles are weakly coupled to their neighbors by a tunneling conductance. At low temperatures, the single electron charging energy of the nanoparticles dominates the conductance properties of the array. The Coulomb blockade of the nanoparticles can be lifted by optical excitation with a laser beam. The optical excitation leads to a localized heating of the arrays, which in turn gives rise to a local change in conductance and a redistribution of the overall electrical potential in the arrays. We introduce a dual-beam optical excitation technique to probe the distribution of the electrical potential in the nanoparticle array. A negative differential photoconductance is the direct consequence of the redistribution of the electrical potential upon lifting of the Coulomb blockade. On the basis of our model, we calculate the optically induced current from the dark current-voltage characteristics of the nanoparticle array. The calculations closely reproduce the experimental observations.

  9. Postoperative sciatic and femoral or saphenous nerve blockade for lower extremity surgery in anesthetized adults

    PubMed Central

    Lollo, Loreto; Bhananker, Sanjay; Stogicza, Agnes

    2015-01-01

    Background: Guidelines warn of increased risks of injury when placing regional nerve blocks in the anesthetized adult but complications occurred in patients that received neither sedation nor local anesthetic. This restriction of nerve block administration places vulnerable categories of patients at risk of severe opioid induced side effects. Patient and operative technical factors can preclude use of preoperative regional anesthesia. The purpose of this study was to assess complications following sciatic popliteal and femoral or saphenous nerve blockade administered to anesthetized adult patients following foot and ankle surgery. Materials and Methods: Postoperative patients administered general anesthesia received popliteal sciatic nerve blockade and either femoral or saphenous nerve blockade if operative procedures included medial incisions. Nerve blocks were placed with nerve stimulator or ultrasound guidance. A continuous nerve catheter was inserted if hospital admission was over 24 hours. Opioid analgesic supplementation was administered for inadequate pain relief. Postoperative pain scores and total analgesic requirements for 24 hours were recorded. Nerve block related complications were monitored for during the hospital admission and at follow up surgical clinic evaluation. Results: 190 anesthetized adult patients were administered 357 nerve blocks. No major nerve injury or deficit was reported. One patient had numbness in the toes not ascribed to a specific nerve of the lower extremity. Perioperative opioid dose differences were noted between male and female and between opioid naïve and tolerant patients. PMID:26807391

  10. Pauli spin blockade in a highly tunable silicon double quantum dot.

    PubMed

    Lai, N S; Lim, W H; Yang, C H; Zwanenburg, F A; Coish, W A; Qassemi, F; Morello, A; Dzurak, A S

    2011-01-01

    Double quantum dots are convenient solid-state platforms to encode quantum information. Two-electron spin states can be detected and manipulated using quantum selection rules based on the Pauli exclusion principle, leading to Pauli spin blockade of electron transport for triplet states. Coherent spin states would be optimally preserved in an environment free of nuclear spins, which is achievable in silicon by isotopic purification. Here we report on a deliberately engineered, gate-defined silicon metal-oxide-semiconductor double quantum dot system. The electron occupancy of each dot and the inter-dot tunnel coupling are independently tunable by electrostatic gates. At weak inter-dot coupling we clearly observe Pauli spin blockade and measure a large intra-dot singlet-triplet splitting > 1 meV. The leakage current in spin blockade has a peculiar magnetic field dependence, unrelated to electron-nuclear effects and consistent with the effect of spin-flip cotunneling processes. The results obtained here provide excellent prospects for realising singlet-triplet qubits. PMID:22355627

  11. System identification of closed-loop cardiovascular control: effects of posture and autonomic blockade

    NASA Technical Reports Server (NTRS)

    Mullen, T. J.; Appel, M. L.; Mukkamala, R.; Mathias, J. M.; Cohen, R. J.

    1997-01-01

    We applied system identification to the analysis of fluctuations in heart rate (HR), arterial blood pressure (ABP), and instantaneous lung volume (ILV) to characterize quantitatively the physiological mechanisms responsible for the couplings between these variables. We characterized two autonomically mediated coupling mechanisms [the heart rate baroreflex (HR baroreflex) and respiratory sinus arrhythmia (ILV-HR)] and two mechanically mediated coupling mechanisms [the blood pressure wavelet generated with each cardiac contraction (circulatory mechanics) and the direct mechanical effects of respiration on blood pressure (ILV-->ABP)]. We evaluated the method in humans studied in the supine and standing postures under control conditions and under conditions of beta-sympathetic and parasympathetic pharmacological blockades. Combined beta-sympathetic and parasympathetic blockade abolished the autonomically mediated couplings while preserving the mechanically mediated coupling. Selective autonomic blockade and postural changes also altered the couplings in a manner consistent with known physiological mechanisms. System identification is an "inverse-modeling" technique that provides a means for creating a closed-loop model of cardiovascular regulation for an individual subject without altering the underlying physiological control mechanisms.

  12. Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

    PubMed Central

    Zhou, Shutang; Potts, Erin N.; Cuttitta, Frank; Foster, W. Michael; Sunday, Mary E.

    2011-01-01

    Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans. PMID:21252304

  13. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.

    PubMed

    Siravegna, Giulia; Mussolin, Benedetta; Buscarino, Michela; Corti, Giorgio; Cassingena, Andrea; Crisafulli, Giovanni; Ponzetti, Agostino; Cremolini, Chiara; Amatu, Alessio; Lauricella, Calogero; Lamba, Simona; Hobor, Sebastijan; Avallone, Antonio; Valtorta, Emanuele; Rospo, Giuseppe; Medico, Enzo; Motta, Valentina; Antoniotti, Carlotta; Tatangelo, Fabiana; Bellosillo, Beatriz; Veronese, Silvio; Budillon, Alfredo; Montagut, Clara; Racca, Patrizia; Marsoni, Silvia; Falcone, Alfredo; Corcoran, Ryan B; Di Nicolantonio, Federica; Loupakis, Fotios; Siena, Salvatore; Sartore-Bianchi, Andrea; Bardelli, Alberto

    2015-07-01

    Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

  14. Van der Waals Interactions and Dipole Blockade in a Cold Rydberg Gas Probed by Microwave Spectroscopy

    NASA Astrophysics Data System (ADS)

    Nguyen, Thanh Long; Celistrino Teixeira, Raul; Hermann Avigliano, Carla; Cantat Moltrecht, Tigrane; Raimond, Jean Michel; Haroche, Serge; Gleyzes, Sebastiens; Brune, Michel

    2016-05-01

    Dipole-dipole interactions between Rydberg atoms are a flourishing tool for quantum information processing and for quantum simulation of complex many-body problems. Microwave spectroscopy of a dense Rydberg gas trapped close to a superconducting atom chip in the strong dipole blockade regime reveals directly the many-body atomic interaction spectrum. We present here a direct measurement of the interaction energy distribution in the strong dipole blockade regime, based on microwave spectroscopy. We first apply this method to the observation of the excitation dynamics of the Rydberg gas, conditioned by dipole-dipole interactions, in either the strong blockade regime or the so-called facilitation regime. We also observe with this method the atomic cloud expansion driven by the repulsive Van der Waals interaction after excitation. This measurement, in good agreement with Monte Carlo simulations of the excitation process and of the cloud dynamics, reveals the limits of the frozen gas approximation. This method can help investigate self-organization and dynamical phase transitions in Rydberg-atom based quantum simulators. This study thus opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atom.

  15. Some effects of vagal blockade on abdominal muscle activation and shortening in awake dogs.

    PubMed Central

    Leevers, A M; Road, J D

    1995-01-01

    1. The mechanisms of abdominal muscle activation are thought to be different during expiratory threshold loading (ETL) compared with hypercapnia. Our objectives in the present study were to determine the effects of removing excitatory vagal feedback on abdominal muscle activation, shortening and pattern of recruitment during ETL and hypercapnia. Six tracheotomized dogs were chronically implanted with sonomicrometer transducers and fine wire EMG electrodes in each of the four abdominal muscles. Muscle length changes and EMG activity were studied in the awake dog during ETL (6 dogs) and CO2 rebreathing (3 dogs), before and after vagal blockade. 2. Following vagal blockade, the change in volume (increase in functional residual capacity, FRC) during ETL was greater and active phasic shortening of all the abdominal muscles was reduced, when shortening was compared with a similar change in lung volume. Similarly, at comparable minute ventilation, abdominal muscle active shortening was also reduced during hypercapnia. The internal muscle layer was recruited preferentially in both control and vagally blocked dogs during both ETL and hypercapnia. 3. The degree of recruitment of the abdominal muscles during ETL and hypercapnia in awake dogs is influenced by vagal feedback, but less so than in anaesthetized dogs. These results illustrate the importance of the vagi and abdominal muscle activation in load compensation. However, vagal reflexes are apparently not contributing to the preferential recruitment of the internal muscle layer. In awake dogs during vagal blockade abdominal muscle recruitment still occurs by extravagal mechanisms. PMID:8568685

  16. Spin blockade in a triple silicon quantum dot in CMOS technology

    NASA Astrophysics Data System (ADS)

    Prati, E.; Petretto, G.; Belli, M.; Mazzeo, G.; Cocco, S.; de Michielis, M.; Fanciulli, M.; Guagliardo, F.; Vinet, M.; Wacquez, R.

    2012-02-01

    We study the spin blockade (SB) phenomenon by quantum transport in a triple quantum dot made of two single electron transistors (SET) on a CMOS platform separated by an implanted multiple donor quantum dot [1]. Spin blockade condition [2] has been used in the past to realize single spin localization and manipulation in GaAs quantum dots [3]. Here, we reproduce the same physics in a CMOS preindustrial silicon quantum device. Single electron quantum dots are connected via an implanted quantum dot and exhibit SB in one current direction. We break the spin blockade by applying a magnetic field of few tesla. Our experimental results are explained by a theoretical microscopic scheme supported by simulations in which only some of the possible processes through the triple quantum dot are spin blocked, according to the asymmetry of the coupling capacitances with the control gates and the central dot. Depending on the spin state, the SB may be both lifted and induced. Spin control in CMOS quantum dots is a necessary condition to realize large fabrication of spin qubits in some solid state silicon quantum device architectures.[0pt] [1] Pierre et al., Appl. Phys. Lett., 95, 24, 242107 (2009); [2] Liu et al., Phys. Rev. B 77, 073310 (2008); [3] Koppens et al., Nature 442, 766-771 (2006)

  17. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy.

    PubMed

    Sharabi, Andrew B; Lim, Michael; DeWeese, Theodore L; Drake, Charles G

    2015-10-01

    Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.

  18. The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement

    PubMed Central

    Lee, Seung-Jun; Oh, Jaewon; Ko, Young-Guk; Lee, Sak; Chang, Byung-Chul; Lee, Do Yun; Kwak, Young-Ran

    2016-01-01

    Purpose In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. Materials and Methods We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed β-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. Results There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). Conclusion In MFS patients who underwent ARR, the addition of RAAS blockade to β-blocker was associated with reduction of aortic dilatation and clinical events. PMID:26632386

  19. Persistence of pain induced by startle and forehead cooling after sympathetic blockade in patients with complex regional pain syndrome

    PubMed Central

    Drummond, P; Finch, P

    2004-01-01

    Background: Stimuli arousing sympathetic activity can increase ratings of clinical pain in patients with complex regional pain syndrome (CRPS). Objective: To determine whether the increase in pain is mediated by peripheral sympathetic activity. Methods: The effect of sympathetic ganglion blockade on pain evoked by a startle stimulus and cooling the forehead was investigated in 36 CRPS patients. Results: Loss of vasoconstrictor reflexes and warming of the limb indicated that sympathetic blockade was effective in 26 cases. Before sympathetic blockade, pain increased in 12 of these 26 patients when they were startled. Pain increased in seven of the 12 patients and in another five cases when their forehead was cooled. As expected, pain that increased during sympathetic arousal generally subsided in patients with signs of sympathetic blockade. However, pain still increased in three of 12 of patients after the startle stimulus and in six of 12 of patients during forehead cooling, despite indisputable sympathetic blockade. Conclusions: These findings suggest that stimuli arousing sympathetic activity act by a central process to exacerbate pain in some patients, independent of the peripheral sympathetic nervous system. This may account for the lack of effect of peripheral sympathetic blockade on pain in some CRPS patients. PMID:14707316

  20. Serotonin 2A Receptors Differentially Contribute to Abuse-Related Effects of Cocaine and Cocaine-Induced Nigrostriatal and Mesolimbic Dopamine Overflow in Nonhuman Primates

    PubMed Central

    Murnane, Kevin S.; Winschel, Jake; Schmidt, Karl T.; Stewart, LaShaya M.; Rose, Samuel J.; Cheng, Kejun; Rice, Kenner C.

    2013-01-01

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  1. Serotonin 2A receptors differentially contribute to abuse-related effects of cocaine and cocaine-induced nigrostriatal and mesolimbic dopamine overflow in nonhuman primates.

    PubMed

    Murnane, Kevin S; Winschel, Jake; Schmidt, Karl T; Stewart, LaShaya M; Rose, Samuel J; Cheng, Kejun; Rice, Kenner C; Howell, Leonard L

    2013-08-14

    Two of the most commonly used procedures to study the abuse-related effects of drugs in laboratory animals are intravenous drug self-administration and reinstatement of extinguished behavior previously maintained by drug delivery. Intravenous self-administration is widely accepted to model ongoing drug-taking behavior, whereas reinstatement procedures are accepted to model relapse to drug taking following abstinence. Previous studies indicate that 5-HT2A receptor antagonists attenuate the reinstatement of cocaine-maintained behavior but not cocaine self-administration in rodents. Although the abuse-related effects of cocaine have been closely linked to brain dopamine systems, no previous study has determined whether this dissociation is related to differential regulation of dopamine neurotransmission. To elucidate the neuropharmacological and neuroanatomical mechanisms underlying this phenomenon, we evaluated the effects of the selective 5-HT2A receptor antagonist M100907 on intravenous cocaine self-administration and drug- and cue-primed reinstatement in rhesus macaques (Macaca mulatta). In separate subjects, we evaluated the role of 5-HT2A receptors in cocaine-induced dopamine overflow in the nucleus accumbens (n = 4) and the caudate nucleus (n = 5) using in vivo microdialysis. Consistent with previous studies, M100907 (0.3 mg/kg, i.m.) significantly attenuated drug- and cue-induced reinstatement but had no significant effects on cocaine self-administration across a range of maintenance doses. Importantly, M100907 (0.3 mg/kg, i.m.) attenuated cocaine-induced (1.0 mg/kg, i.v.) dopamine overflow in the caudate nucleus but not in the nucleus accumbens. These data suggest that important abuse-related effects of cocaine are mediated by distinct striatal dopamine projection pathways. PMID:23946394

  2. Lecozotan (SRA-333): a selective serotonin 1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.

    PubMed

    Schechter, L E; Smith, D L; Rosenzweig-Lipson, S; Sukoff, S J; Dawson, L A; Marquis, K; Jones, D; Piesla, M; Andree, T; Nawoschik, S; Harder, J A; Womack, M D; Buccafusco, J; Terry, A V; Hoebel, B; Rada, P; Kelly, M; Abou-Gharbia, M; Barrett, J E; Childers, W

    2005-09-01

    Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.

  3. Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder.

    PubMed

    Kawaura, Kazuaki; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko

    2014-08-15

    A 5-trial inhibitory avoidance test using spontaneously hypertensive rat (SHR) pups has been used as an animal model of attention deficit hyperactivity disorder (ADHD). However, the roles of noradrenergic systems, which are involved in the pathophysiology of ADHD, have not been investigated in this model. In the present study, the effects of adrenergic α2 receptor stimulation, which has been an effective treatment for ADHD, on attention/cognition performance were investigated in this model. Moreover, neuronal mechanisms mediated through adrenergic α2 receptors were investigated. We evaluated the effects of both clonidine, a non-selective adrenergic α2 receptor agonist, and guanfacine, a selective adrenergic α2A receptor agonist, using a 5-trial inhibitory avoidance test with SHR pups. Juvenile SHR exhibited a shorter transfer latency, compared with juvenile Wistar Kyoto (WKY) rats. Both clonidine and guanfacine significantly prolonged the transfer latency of juvenile SHR. The effects of clonidine and guanfacine were significantly blocked by pretreatment with an adrenergic α2A receptor antagonist. In contrast, the effect of clonidine was not attenuated by pretreatment with an adrenergic α2B receptor antagonist, or an adrenergic α2C receptor antagonist, while it was attenuated by a non-selective adrenergic α2 receptor antagonist. Furthermore, the effects of neither clonidine nor guanfacine were blocked by pretreatment with a selective noradrenergic neurotoxin. These results suggest that the stimulation of the adrenergic α2A receptor improves the attention/cognition performance of juvenile SHR in the 5-trial inhibitory avoidance test and that postsynaptic, rather than presynaptic, adrenergic α2A receptor is involved in this effect.

  4. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-04-01

    In this report we will show some new Q related seismic attributes on the Burlington-Seitel data set. One example will be called Energy Absorption Attribute (EAA) and is based on a spectral analysis. The EAA algorithm is designed to detect a sudden increase in the rate of exponential decay in the relatively higher frequency portion of the spectrum. In addition we will show results from a hybrid attribute that combines attenuation with relative acoustic impedance to give a better indication of commercial gas saturation.

  5. Circadian rhythm of heart rate in the rabbit: prolongation of action potential duration by sustained beta adrenoceptor blockade is not due to associated bradycardia.

    PubMed

    Vaughan Williams, E M; Dennis, P D; Garnham, C

    1986-07-01

    Six litters of six young rabbits were injected intraperitoneally, two per litter, with saline, alinidine, or nadolol once or twice daily for two weeks. In four litters successful radiotransmissions of electrocardiograms were recorded once hourly for four days before and during treatment. Alinidine and nadolol produced an overall mean bradycardia in comparison with saline treated animals, the effect of alinidine exceeding that of nadolol. At 48-70 hours after the end of treatment the hearts were used for in vitro electrophysiological study. Nadolol, but not alinidine, induced a prolongation of action potential duration compared with that of saline treated littermates in both atrial and ventricular muscle. An incidental observation was that heart rate in the rabbit followed a circadian rhythm, heart rates being slower in the morning and faster in late afternoon and evening. The circadian rhythm was attenuated but not abolished by alinidine and nadolol. These results suggest that if prolongation of action potential duration by sustained beta blockade in patients after myocardial infarction contributes to protection against sudden death (by a class III antiarrhythmic action) then alinidine would not be expected to provide a comparable prophylaxis.

  6. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice.

    PubMed

    Yin, Xinru; Gong, Xia; Jiang, Rong; Kuang, Ge; Wang, Bin; Zhang, Li; Xu, Ge; Wan, Jingyuan

    2014-11-01

    Emodin has been reported to possess anti-inflammatory and anti-oxidant activities. The aim of this study was to explore the effect and mechanism of emodin on lipopolysaccharide (LPS)-induced fulminant hepatic failure (FHF) in D-galactosamine (D-GalN)-sensitized mice. Our results showed that pretreatment with emodin inhibited the elevation of plasma aminotransferases, alleviated the hepatic histopathological abnormalities and improved the survival rate of LPS/D-GalN-primed mice. Moreover, emodin markedly attenuated the increased serum and hepatic tumor necrosis factor-α (TNF-α) production, and activated hepatic p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) signal pathways in LPS/D-GalN-challenged mice. Furthermore, using an in vitro experiment, we found that emodin dose-dependently suppressed TNF-α production, dampened AP-1 and NF-κB activation, and blocked toll-like receptor (TLR) 4/myeloid differentiation factor (MD) 2 complex expression in LPS-elicited RAW264.7 mouse macrophage cells. Taken together, these data suggested that emodin could effectively prevent LPS-induced FHF, which might be mediated by inhibition of TNF-α production, deactivation of MAPKs and NF-κB, and blockade of TLR4/MD2 complex expression.

  7. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage.

    PubMed

    Sasso, Oscar; Migliore, Marco; Habrant, Damien; Armirotti, Andrea; Albani, Clara; Summa, Maria; Moreno-Sanz, Guillermo; Scarpelli, Rita; Piomelli, Daniele

    2015-06-01

    The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.

  8. Disulfiram Attenuates Osteoclast Differentiation In Vitro: A Potential Antiresorptive Agent

    PubMed Central

    Cheng, Tak S.; Pavlos, Nathan J.; Rea, Sarah; Dai, Kerong; Zheng, Ming H.

    2015-01-01

    Disulfiram (DSF), a cysteine modifying compound, has long been clinically employed for the treatment of alcohol addiction. Mechanistically, DSF acts as a modulator of MAPK and NF-κB pathways signaling pathways. While these pathways are crucial for osteoclast (OC) differentiation, the potential influence of DSF on OC formation and function has not been directly assessed. Here, we explore the pharmacological effects of DSF on OC differentiation, activity and the modulation of osteoclastogenic signaling cascades. We first analyzed cytotoxicity of DSF on bone marrow monocytes isolated from C57BL/6J mice. Upon the establishment of optimal dosage, we conducted osteoclastogenesis and bone resorption assays in the presence or absence of DSF treatment. Luciferase assays in RAW264.7 cells were used to examine the effects of DSF on major transcription factors activation. Western blot, reverse transcription polymerase chain reaction, intracellular acidification and proton influx assays were employed to further dissect the underlying mechanism. DSF treatment dose-dependently inhibited both mouse and human osteoclastogenesis, especially at early stages of differentiation. This inhibition correlated with a decrease in the expression of key osteoclastic marker genes including CtsK, TRAP, DC-STAMP and Atp6v0d2 as well as a reduction in bone resorption in vitro. Suppression of OC differentiation was found to be due, at least in part, to the blockade of several key receptor activators of nuclear factor kappa-B ligand (RANKL)-signaling pathways including ERK, NF-κB and NFATc1. On the other hand, DSF failed to suppress intracellular acidification and proton influx in mouse and human osteoclasts using acridine orange quenching and microsome-based proton transport assays. Our findings indicate that DSF attenuates OC differentiation via the collective suppression of several key RANKL-mediated signaling cascades, thus making it an attractive agent for the treatment of OC

  9. Imaging Rayleigh wave attenuation with USArray

    NASA Astrophysics Data System (ADS)

    Bao, Xueyang; Dalton, Colleen A.; Jin, Ge; Gaherty, James B.; Shen, Yang

    2016-07-01

    The EarthScope USArray provides an opportunity to obtain detailed images of the continental upper mantle at an unprecedented scale. The majority of mantle models derived from USArray data to date contain spatial variations in seismic-wave speed; however, in many cases these data sets do not by themselves allow a non-unique interpretation. Joint interpretation of seismic attenuation and velocity models can improve upon the interpretations based only on velocity and provide important constraints on the temperature, composition, melt content, and volatile content of the mantle. The surface wave amplitudes that constrain upper-mantle attenuation are sensitive to factors in addition to attenuation, including the earthquake source excitation, focusing and defocusing by elastic structure, and local site amplification. Because of the difficulty of isolating attenuation from these other factors, little is known about the attenuation structure of the North American upper mantle. In this study, Rayleigh wave traveltime and amplitude in the period range 25-100 s are measured using an interstation cross-correlation technique, which takes advantage of waveform similarity at nearby stations. Several estimates of Rayleigh wave attenuation and site amplification are generated at each period, using different approaches to separate the effects of attenuation and local site amplification on amplitude. It is assumed that focusing and defocusing effects can be described by the Laplacian of the traveltime field. All approaches identify the same large-scale patterns in attenuation, including areas where the attenuation values are likely contaminated by unmodelled focusing and defocusing effects. Regionally averaged attenuation maps are constructed after removal of the contaminated attenuation values, and the variations in intrinsic shear attenuation that are suggested by these Rayleigh wave attenuation maps are explored.

  10. A question of balance--positive versus negative allosteric modulation of GABA(A) receptor subtypes as a driver of analgesic efficacy in rat models of inflammatory and neuropathic pain.

    PubMed

    Munro, Gordon; Erichsen, Helle K; Rae, Mark G; Mirza, Naheed R

    2011-01-01

    After injury GABA(A) receptor positive allosteric modulators (PAMs) mediate robust analgesia in animals via putative restoration of post-synaptic GABA(A)-α2 and -α3 receptor function within the spinal cord. GABA can also act at GABA(A) receptors localized on primary afferent neurones to inhibit presynaptic neurotransmitter release and produce analgesia via a process called primary afferent depolarization (PAD). Some forms of injury might sufficiently enhance PAD to shift it into a net excitatory process. Thus, negative allosteric modulators (NAMs) might also possess analgesic activity. We have compared compounds capable of either positively or negatively modulating GABA(A) receptors in rat models associated with injury-induced central sensitization. The subtype-selective PAMs NS11394 (1-10 mg/kg) and TPA023 (3-30 mg/kg) attenuated formalin-induced nocifensive behaviours. Similarly, both compounds reversed hindpaw mechanical hypersensitivity and weight bearing deficits in carrageenan-inflamed and nerve-injured rats. The non-selective PAM diazepam (1-5 mg/kg) was ineffective in all models. Surprisingly, both the non-selective NAM FG-7142 (3-30 mg/kg) and the α5-selective NAM α5IA-II (10-60 mg/kg) also attenuated formalin-induced nocifensive behaviours. In carrageenan-inflamed rats α5IA-II reversed mechanical hypersensitivity and weight bearing deficits whilst FG-7142 only attenuated weight bearing deficits. This picture was essentially reversed in nerve-injured rats for these two NAMs. With the exception of NS11394, all compounds attenuated exploratory motility behaviour in rats, either as a consequence of sedative or anxiogenic-like side-effects. These data indicate that the preferred selectivity and activity profiles for mediating analgesia upon activation of GABA(A) receptors might be more complex than previously anticipated, and is worthy of further exploration.

  11. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors.

    PubMed

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X

    2005-10-01

    Increasing evidence suggests a link between attention, working memory, serotonin (5-HT), and prefrontal cortex activity. In an attempt to tease out the relationship between these elements, this study tested the effects of the hallucinogenic mixed 5-HT1A/2A receptor agonist psilocybin alone and after pretreatment with the 5-HT2A antagonist ketanserin. Eight healthy human volunteers were tested on a multiple-object tracking task and spatial working memory task under the four conditions: placebo, psilocybin (215 microg/kg), ketanserin (50 mg), and psilocybin and ketanserin. Psilocybin significantly reduced attentional tracking ability, but had no significant effect on spatial working memory, suggesting a functional dissociation between the two tasks. Pretreatment with ketanserin did not attenuate the effect of psilocybin on attentional performance, suggesting a primary involvement of the 5-HT1A receptor in the observed deficit. Based on physiological and pharmacological data, we speculate that this impaired attentional performance may reflect a reduced ability to suppress or ignore distracting stimuli rather than reduced attentional capacity. The clinical relevance of these results is also discussed.

  12. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2003-12-01

    We have developed and tested technology for a new type of direct hydrocarbon detection. The method uses inelastic rock properties to greatly enhance the sensitivity of surface seismic methods to the presence of oil and gas saturation. These methods include use of energy absorption, dispersion, and attenuation (Q) along with traditional seismic attributes like velocity, impedance, and AVO. Our approach is to combine three elements: (1) a synthesis of the latest rock physics understanding of how rock inelasticity is related to rock type, pore fluid types, and pore microstructure, (2) synthetic seismic modeling that will help identify the relative contributions of scattering and intrinsic inelasticity to apparent Q attributes, and (3) robust algorithms that extract relative wave attenuation attributes from seismic data. This project provides: (1) Additional petrophysical insight from acquired data; (2) Increased understanding of rock and fluid properties; (3) New techniques to measure reservoir properties that are not currently available; and (4) Provide tools to more accurately describe the reservoir and predict oil location and volumes. These methodologies will improve the industry's ability to predict and quantify oil and gas saturation distribution, and to apply this information through geologic models to enhance reservoir simulation. We have applied for two separate patents relating to work that was completed as part of this project.

  13. Magnetoelectric Composite Based Microwave Attenuator

    NASA Astrophysics Data System (ADS)

    Tatarenko, A. S.; Srinivasan, G.

    2005-03-01

    Ferrite-ferroelectric composites are magnetoelectric (ME) due to their response to elastic and electromagnetic force fields. The ME composites are characterized by tensor permittivity, permeability and ME susceptibility. The unique combination of magnetic, electrical, and ME interactions, therefore, opens up the possibility of electric field tunable ferromagnetic resonance (FMR) based devices [1]. Here we discuss an ME attenuator operating at 9.3 GHz based on FMR in a layered sample consisting of lead magnesium niobate-lead titanate bonded to yttrium iron garnet (YIG) film on a gadolinium gallium garnet substrate. Electrical tuning is realized with the application of a control voltage due to ME effect; the shift is 0-15 Oe as E is increased from 0 to 3 kV/cm. If the attenuator is operated at FMR, the corresponding insertion loss will range from 25 dB to 2 dB. 1. S. Shastry and G. Srinivasan, M.I. Bichurin, V.M. Petrov, A.S. Tatarenko. Phys. Rev. B, 70 064416 (2004). - supported by grants the grants from the National Science Foundation (DMR-0302254), from Russian Ministry of Education (Å02-3.4-278) and from Universities of Russia Foundation (UNR 01.01.026).

  14. Global Attenuation Model of the Upper Mantle

    NASA Astrophysics Data System (ADS)

    Adenis, A.; Debayle, E.; Ricard, Y. R.

    2015-12-01

    We present a three-dimensional shear attenuation model based on a massive surface wave data-set (372,629 Rayleigh waveforms analysed in the period range 50-300s by Debayle and Ricard, 2012). For each seismogram, this approach yields depth-dependent path average models of shear velocity and quality factor, and a set of fundamental and higher-mode dispersion and attenuation curves. We combine these attenuation measurements in a tomographic inversion after a careful rejection of the noisy data. We first remove data likely to be biased by a poor knowledge of the source. Then we assume that waves corresponding to events having close epicenters and recorded at the same station sample the same elastic and anelastic structure, we cluster the corresponding rays and average the attenuation measurements. Logarithms of the attenuations are regionalized using the non-linear east square formalism of Tarantola and Valette (1982), resulting in attenuation tomographic maps between 50s and 300s. After a first inversion, outlyers are rejected and a second inversion yields a moderate variance reduction of about 20%. We correct the attenuation curves for focusing effect using the linearized ray theory of Woodhouse and Wong (1986). Accounting for focussing effects allows building tomographic maps with variance reductions reaching 40%. In the period range 120-200s, the root mean square of the model perturbations increases from about 5% to 20%. Our 3-D attenuation models present strong agreement with surface tectonics at period lower than 200s. Areas of low attenuation are located under continents and areas of high attenuation are associated with oceans. Surprisingly, although mid oceanic ridges are located in attenuating regions, their signature, even if enhanced by focusing corrections, remains weaker than in the shear velocity models. Synthetic tests suggests that regularisation contributes to damp the attenuation signature of ridges, which could therefore be underestimated.

  15. General relationships between ultrasonic attenuation and dispersion

    NASA Technical Reports Server (NTRS)

    Odonnell, M.; Jaynes, E. T.; Miller, J. G.

    1978-01-01

    General relationships between the ultrasonic attenuation and dispersion are presented. The validity of these nonlocal relationships hinges only on the properties of causality and linearity, and does not depend upon details of the mechanism responsible for the attenuation and dispersion. Approximate, nearly local relationships are presented and are demonstrated to predict accurately the ultrasonic dispersion in solutions of hemoglobin from the results of attenuation measurements.

  16. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1 receptor blockade

    PubMed Central

    Bellocchio, Luigi; Soria-Gómez, Edgar; Quarta, Carmelo; Metna-Laurent, Mathilde; Cardinal, Pierre; Binder, Elke; Cannich, Astrid; Delamarre, Anna; Häring, Martin; Martín-Fontecha, Mar; Vega, David; Leste-Lasserre, Thierry; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat; Chaouloff, Francis; Pagotto, Uberto; Guzman, Manuel; Cota, Daniela; Marsicano, Giovanni

    2013-01-01

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors. PMID:23487769

  17. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.

    PubMed

    Bellocchio, Luigi; Soria-Gómez, Edgar; Quarta, Carmelo; Metna-Laurent, Mathilde; Cardinal, Pierre; Binder, Elke; Cannich, Astrid; Delamarre, Anna; Häring, Martin; Martín-Fontecha, Mar; Vega, David; Leste-Lasserre, Thierry; Bartsch, Dusan; Monory, Krisztina; Lutz, Beat; Chaouloff, Francis; Pagotto, Uberto; Guzman, Manuel; Cota, Daniela; Marsicano, Giovanni

    2013-03-19

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.

  18. Dopamine D3 Receptor Inactivation Attenuates Cocaine-Induced Conditioned Place Preference in Mice

    PubMed Central

    Song, Rui; Zhang, Hai-Ying; Peng, Xiao-Qing; Su, Rui-Bin; Yang, Ri-Fang; Li, Jin; Xi, Zheng-Xiong; Gardner, Eliot L.

    2013-01-01

    The dopamine (DA) D3 receptor (D3R) has received much attention in medication development for treatment of addiction. However, the functional role of the D3R in drug reward and addiction has been a matter of debate. We recently reported that D3 receptor-knockout (D3−/−) mice display increased vulnerability to cocaine self-administration, which we interpret as a compensatory response to attenuated cocaine reward after D3R deletion. Here we report that D3−/− mice displayed attenuated cocaine-induced conditioned place response (CPP) compared to wild-type mice. Similarly, blockade of brain D3Rs by YQA-14, a novel DA D3 receptor antagonist, significantly and dose-dependently inhibits acquisition and expression of cocaine-induced CPP in WT mice, but not in D3−/− mice. These findings suggest that: 1) D3Rs play an important role in mediating cocaine’s rewarding effects; and 2) YQA-14 is a highly potent and selective D3R antagonist in vivo, which deserves further study as a candidate for treatment of cocaine addiction. PMID:23643749

  19. The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade

    PubMed Central

    Pamenter, Matthew E.; Nguyen, Jetson; Carr, John A.; Powell, Frank L.

    2014-01-01

    Abstract Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839–1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7–9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a “cocktail” of the GluR antagonists MK‐801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15‐min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P <0.05). CSH increased ventilation in hypoxia and acute normoxia. In CSH‐conditioned rats, GluR antagonists in the NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats. PMID:25107985

  20. The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade.

    PubMed

    Pamenter, Matthew E; Nguyen, Jetson; Carr, John A; Powell, Frank L

    2014-08-01

    Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839-1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7-9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a "cocktail" of the GluR antagonists MK-801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15-min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P < 0.05). CSH increased ventilation in hypoxia and acute normoxia. In CSH-conditioned rats, GluR antagonists in the NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats.

  1. The effect of combined glutamate receptor blockade in the NTS on the hypoxic ventilatory response in awake rats differs from the effect of individual glutamate receptor blockade.

    PubMed

    Pamenter, Matthew E; Nguyen, Jetson; Carr, John A; Powell, Frank L

    2014-08-01

    Ventilatory acclimatization to hypoxia (VAH) increases the hypoxic ventilatory response (HVR) and causes persistent hyperventilation when normoxia is restored, which is consistent with the occurrence of synaptic plasticity in acclimatized animals. Recently, we demonstrated that antagonism of individual glutamate receptor types (GluRs) within the nucleus tractus solitarii (NTS) modifies this plasticity and VAH (J. Physiol. 592(8):1839-1856); however, the effects of combined GluR antagonism remain unknown in awake rats. To evaluate this, we exposed rats to room air or chronic sustained hypobaric hypoxia (CSH, PiO2 = 70 Torr) for 7-9 days. On the experimental day, we microinjected artificial cerebrospinal fluid (ACSF: sham) and then a "cocktail" of the GluR antagonists MK-801 and DNQX into the NTS. The location of injection sites in the NTS was confirmed by glutamate injections on a day before the experiment and with histology following the experiment. Ventilation was measured in awake, unrestrained rats breathing normoxia or acute hypoxia (10% O2) in 15-min intervals using barometric pressure plethysmography. In control (CON) rats, acute hypoxia increased ventilation; NTS microinjections of GluR antagonists, but not ACSF, significantly decreased ventilation and breathing frequency in acute hypoxia but not normoxia (P < 0.05). CSH increased ventilation in hypoxia and acute normoxia. In CSH-conditioned rats, GluR antagonists in the NTS significantly decreased ventilation in normoxia and breathing frequency in hypoxia. A persistent HVR after combined GluR blockade in the NTS contrasts with the effect of individual GluR blockade and also with results in anesthetized rats. Our findings support the hypotheses that GluRs in the NTS contribute to, but cannot completely explain, VAH in awake rats. PMID:25107985

  2. Differential dust attenuation in CALIFA galaxies

    NASA Astrophysics Data System (ADS)

    Vale Asari, N.; Cid Fernandes, R.; Amorim, A. L.; Lacerda, E. A. D.; Schlickmann, M.; Wild, V.; Kennicutt, R. C.

    2016-06-01

    Dust attenuation has long been treated as a simple parameter in SED fitting. Real galaxies are, however, much more complicated: The measured dust attenuation is not a simple function of the dust optical depth, but depends strongly on galaxy inclination and the relative distribution of stars and dust. We study the nebular and stellar dust attenuation in CALIFA galaxies, and propose some empirical recipes to make the dust treatment more realistic in spectral synthesis codes. By adding optical recombination emission lines, we find better constraints for differential attenuation. Those recipes can be applied to unresolved galaxy spectra, and lead to better recovered star formation rates.

  3. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

    PubMed

    Kaster, Manuella P; Machado, Nuno J; Silva, Henrique B; Nunes, Ana; Ardais, Ana Paula; Santana, Magda; Baqi, Younis; Müller, Christa E; Rodrigues, Ana Lúcia S; Porciúncula, Lisiane O; Chen, Jiang Fan; Tomé, Ângelo R; Agostinho, Paula; Canas, Paula M; Cunha, Rodrigo A

    2015-06-23

    The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function.

  4. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress.

    PubMed

    Kaster, Manuella P; Machado, Nuno J; Silva, Henrique B; Nunes, Ana; Ardais, Ana Paula; Santana, Magda; Baqi, Younis; Müller, Christa E; Rodrigues, Ana Lúcia S; Porciúncula, Lisiane O; Chen, Jiang Fan; Tomé, Ângelo R; Agostinho, Paula; Canas, Paula M; Cunha, Rodrigo A

    2015-06-23

    The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function. PMID:26056314

  5. CD40 Blockade Combines with CTLA4Ig and Sirolimus To Produce Mixed Chimerism in an MHC-defined Rhesus Macaque Transplant Model

    PubMed Central

    Page, Andrew; Srinivasan, Swetha; Singh, Karnail; Russell, Maria; Hamby, Kelly; Deane, Taylor; Sen, Sharon; Stempora, Linda; Leopardi, Frank; Price, Andrew A.; Strobert, Elizabeth; Reimann, Keith A.; Kirk, Allan D.; Larsen, Christian P.; Kean, Leslie S.

    2011-01-01

    In murine models, T-cell costimulation blockade of the CD28:B7 and CD154:CD40 pathways synergistically promotes immune tolerance after transplantation. While CD28 blockade has been successfully translated to the clinic, translation of blockade of the CD154:CD40 pathway has been less successful, in large part due to thromboembolic complications associated with anti-CD154 antibodies. Translation of CD40 blockade has also been slow, in part due to the fact that synergy between CD40 blockade and CD28 blockade had not yet been demonstrated in either primate models or humans. Here we show that a novel, non-depleting CD40 monoclonal antibody, 3A8, can combine with combined CTLA4Ig and sirolimus in a well-established primate bone marrow chimerism-induction model. Prolonged engraftment required the presence of all three agents during maintenance therapy, and resulted in graft acceptance for the duration of immunosuppressive treatment, with rejection resulting upon immunosuppression withdrawal. Flow cytometric analysis revealed that upregulation of CD95 expression on both CD4+ and CD8+ T-cells correlated with rejection, suggesting that CD95 may be a robust biomarker of graft loss. These results are the first to demonstrate prolonged chimerism in primates treated with CD28/mTOR blockade and non-depletional CD40 blockade, and support further investigation of combined costimulation blockade targeting the CD28 and CD40 pathways. PMID:21929643

  6. SEISMIC ATTENUATION FOR RESERVOIR CHARACTERIZATION

    SciTech Connect

    Joel Walls; M.T. Taner; Naum Derzhi; Gary Mavko; Jack Dvorkin

    2002-10-01

    RSI has access to two synthetic seismic programs: Osiris seismic modeling system provided by Odegaard (Osiris) and synthetic seismic program, developed by SRB, implementing the Kennett method for normal incidence. Achieving virtually identical synthetic seismic traces from these different programs serves as cross-validation for both. The subsequent experiments have been performed with the Kennett normal incidence code because: We have access to the source code, which allowed us to easily control computational parameters and integrate the synthetics computations with our graphical and I/O systems. This code allows to perform computations and displays on a PC in MatLab or Octave environment, which is faster and more convenient. The normal incidence model allows us to exclude from the synthetic traces some of the physical effects that take place in 3-D models (like inhomogeneous waves) but have no relevance to the topic of our investigation, which is attenuation effects on seismic reflection and transmission.

  7. Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation

    PubMed Central

    Hernandez, Giovanni; Cossette, Marie-Pierre; Shizgal, Peter; Rompré, Pierre-Paul

    2016-01-01

    Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward. Blockade of VM NMDAR, however, enhances brain stimulation reward (BSR), the results can be explained by a reduction in the inhibitory drive on DA neurons that is also under the control of glutamate. In this study, we used fast-scan cyclic voltammetry (FSCV) in anesthetized animals to determine whether this enhancement is associated with a change in phasic DA release in the nucleus accumbens. Rats were implanted with a stimulation electrode in the dorsal-raphe (DR) and bilateral cannulae above the VM and trained to self-administer trains of electrical stimulation. The curve-shift method was used to evaluate the effect of a single dose (0.825 nmol/0.5 μl/side) of the NMDAR antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA), on reward. These animals were then anesthetized and DA release was measured during delivery of electrical stimulation before and after VM microinjection of the vehicle followed by PPPA. As expected, phasic DA release and operant responding depended similarly on the frequency of rewarding electrical stimulation. As anticipated, PPPA produced a significant reward enhancement. Unexpectedly, PPPA produced a decrease in the magnitude of DA transients at all tested frequencies. To test whether this decrease resulted from excessive activation of DA neurons, we injected apomorphine 20 min after PPPA microinjection. At a dose (100 μg s.c.) sufficient to reduce DA firing under control conditions, apomorphine restored electrical stimulation-induced DA transients. These findings show that combined electrical stimulation and VM NMDARs blockade induce DA inactivation, an effect that indirectly demonstrates that VM NMDARs blockade enhances reward by potentiating stimulation-induced excitation in the mesoaccumbens DA pathway. PMID:27616984

  8. Mechanism of blood pressure and R-R variability: insights from ganglion blockade in humans

    NASA Technical Reports Server (NTRS)

    Zhang, Rong; Iwasaki, Kenichi; Zuckerman, Julie H.; Behbehani, Khosrow; Crandall, Craig G.; Levine, Benjamin D.; Blomqvist, C. G. (Principal Investigator)

    2002-01-01

    Spontaneous blood pressure (BP) and R-R variability are used frequently as 'windows' into cardiovascular control mechanisms. However, the origin of these rhythmic fluctuations is not completely understood. In this study, with ganglion blockade, we evaluated the role of autonomic neural activity versus other 'non-neural' factors in the origin of BP and R-R variability in humans. Beat-to-beat BP, R-R interval and respiratory excursions were recorded in ten healthy subjects (aged 30 +/- 6 years) before and after ganglion blockade with trimethaphan. The spectral power of these variables was calculated in the very low (0.0078-0.05 Hz), low (0.05-0.15 Hz) and high (0.15-0.35 Hz) frequency ranges. The relationship between systolic BP and R-R variability was examined by cross-spectral analysis. After blockade, R-R variability was virtually abolished at all frequencies; however, respiration and high frequency BP variability remained unchanged. Very low and low frequency BP variability was reduced substantially by 84 and 69 %, respectively, but still persisted. Transfer function gain between systolic BP and R-R interval variability decreased by 92 and 88 % at low and high frequencies, respectively, while the phase changed from negative to positive values at the high frequencies. These data suggest that under supine resting conditions with spontaneous breathing: (1) R-R variability at all measured frequencies is predominantly controlled by autonomic neural activity; (2) BP variability at high frequencies (> 0.15 Hz) is mediated largely, if not exclusively, by mechanical effects of respiration on intrathoracic pressure and/or cardiac filling; (3) BP variability at very low and low frequencies (< 0.15 Hz) is probably mediated by both sympathetic nerve activity and intrinsic vasomotor rhythmicity; and (4) the dynamic relationship between BP and R-R variability as quantified by transfer function analysis is determined predominantly by autonomic neural activity rather than other

  9. Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation.

    PubMed

    Hernandez, Giovanni; Cossette, Marie-Pierre; Shizgal, Peter; Rompré, Pierre-Paul

    2016-01-01

    Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward. Blockade of VM NMDAR, however, enhances brain stimulation reward (BSR), the results can be explained by a reduction in the inhibitory drive on DA neurons that is also under the control of glutamate. In this study, we used fast-scan cyclic voltammetry (FSCV) in anesthetized animals to determine whether this enhancement is associated with a change in phasic DA release in the nucleus accumbens. Rats were implanted with a stimulation electrode in the dorsal-raphe (DR) and bilateral cannulae above the VM and trained to self-administer trains of electrical stimulation. The curve-shift method was used to evaluate the effect of a single dose (0.825 nmol/0.5 μl/side) of the NMDAR antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA), on reward. These animals were then anesthetized and DA release was measured during delivery of electrical stimulation before and after VM microinjection of the vehicle followed by PPPA. As expected, phasic DA release and operant responding depended similarly on the frequency of rewarding electrical stimulation. As anticipated, PPPA produced a significant reward enhancement. Unexpectedly, PPPA produced a decrease in the magnitude of DA transients at all tested frequencies. To test whether this decrease resulted from excessive activation of DA neurons, we injected apomorphine 20 min after PPPA microinjection. At a dose (100 μg s.c.) sufficient to reduce DA firing under control conditions, apomorphine restored electrical stimulation-induced DA transients. These findings show that combined electrical stimulation and VM NMDARs blockade induce DA inactivation, an effect that indirectly demonstrates that VM NMDARs blockade enhances reward by potentiating stimulation-induced excitation in the mesoaccumbens DA pathway. PMID:27616984

  10. Ventral Midbrain NMDA Receptor Blockade: From Enhanced Reward and Dopamine Inactivation

    PubMed Central

    Hernandez, Giovanni; Cossette, Marie-Pierre; Shizgal, Peter; Rompré, Pierre-Paul

    2016-01-01

    Glutamate stimulates ventral midbrain (VM) N-Methyl-D-Aspartate receptors (NMDAR) to initiate dopamine (DA) burst firing activity, a mode of discharge associated with enhanced DA release and reward. Blockade of VM NMDAR, however, enhances brain stimulation reward (BSR), the results can be explained by a reduction in the inhibitory drive on DA neurons that is also under the control of glutamate. In this study, we used fast-scan cyclic voltammetry (FSCV) in anesthetized animals to determine whether this enhancement is associated with a change in phasic DA release in the nucleus accumbens. Rats were implanted with a stimulation electrode in the dorsal-raphe (DR) and bilateral cannulae above the VM and trained to self-administer trains of electrical stimulation. The curve-shift method was used to evaluate the effect of a single dose (0.825 nmol/0.5 μl/side) of the NMDAR antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA), on reward. These animals were then anesthetized and DA release was measured during delivery of electrical stimulation before and after VM microinjection of the vehicle followed by PPPA. As expected, phasic DA release and operant responding depended similarly on the frequency of rewarding electrical stimulation. As anticipated, PPPA produced a significant reward enhancement. Unexpectedly, PPPA produced a decrease in the magnitude of DA transients at all tested frequencies. To test whether this decrease resulted from excessive activation of DA neurons, we injected apomorphine 20 min after PPPA microinjection. At a dose (100 μg s.c.) sufficient to reduce DA firing under control conditions, apomorphine restored electrical stimulation-induced DA transients. These findings show that combined electrical stimulation and VM NMDARs blockade induce DA inactivation, an effect that indirectly demonstrates that VM NMDARs blockade enhances reward by potentiating stimulation-induced excitation in the mesoaccumbens DA pathway.

  11. Similarities and differences between selective and nonselective BAFF blockade in murine SLE

    PubMed Central

    Ramanujam, Meera; Wang, Xiaobo; Huang, Weiqing; Liu, Zheng; Schiffer, Lena; Tao, Haiou; Frank, Daniel; Rice, Jeffrey; Diamond, Betty; Yu, Karl O.A.; Porcelli, Steven; Davidson, Anne

    2006-01-01

    B cells have multiple roles in immune activation and inflammation separate from their capacity to produce antibodies. B cell depletion is currently under intense investigation as a therapeutic strategy for autoimmune diseases. The TNF family members B cell–activating factor of the TNF family (BAFF) and its homolog A proliferation-inducing ligand (APRIL) are B cell survival and differentiation factors and are therefore rational therapeutic targets. We compared the effects of BAFF receptor–Ig, which blocks only BAFF, with those of transmembrane activator and calcium modulator ligand interactor–Ig, which blocks both BAFF and APRIL, in a murine SLE model. Both reagents prolonged the life of NZB/W F1 mice when given either before or after disease onset. Many immunologic effects of the 2 reagents were similar, including B cell and B cell subset depletion and prevention of the progressive T cell activation and dendritic cell accumulation that occurs with age in NZB/W mice without substantial effects on the emergence of the IgG anti–double-stranded DNA response. Furthermore, both reagents inhibited the T cell–independent marginal zone B cell response to particulate antigen delivered i.v., but not the B1 B cell response to the same antigen delivered i.p. In contrast, blockade of both BAFF and APRIL, but not blockade of BAFF alone, reduced the serum levels of IgM antibodies, decreased the frequency of plasma cells in the spleen, and inhibited the IgM response to a T cell–dependent antigen. The differences between selective and nonselective BAFF blockade are relevant to the choice of a BAFF blocking agent for the treatment of autoimmune and malignant diseases. PMID:16485042

  12. Effect of alpha1-adrenoceptor blockade on coronary vasodilator reserve in cardiac syndrome X.

    PubMed

    Rosen, S D; Lorenzoni, R; Kaski, J C; Foale, R A; Camici, P G

    1999-10-01

    We sought to test the response of the coronary microcirculation to alpha-adrenoceptor blockade in patients with syndrome X (angina, ischemia-like stress electrocardiogram, and a normal coronary arteriogram). The response of the microcirculation was assessed by quantification of coronary vasodilator reserve (the ratio of hyperemic to resting myocardial blood flow). We investigated 28 patients with syndrome X [18 women, age 54.4 (7.6) years]. Myocardial blood flow was measured at rest and after dipyridamole by using positron emission tomography with H(2)15O. The measurements were made before and after treatment for 10 days with doxazosin (1 mg o.d. for 3 days, followed by 2 mg o.d. for 7 days) or a matched placebo, similarly administered. Patients were randomized to alpha1-blockade or to placebo in double-blind fashion. No significant differences were demonstrable between syndrome X patients treated with doxazosin and those receiving placebo, with respect to resting myocardial blood flow, myocardial blood flow after dipyridamole, or coronary vasodilator reserve (the ratio of the latter two). In addition, no relations were demonstrable among myocardial blood flow, coronary vasodilator reserve, development of chest pain after dipyridamole, or development of ischemia-like ECG changes. Doxazosin had no effect on the perception of chest pain after dipyridamole. No differences were found between the effects of alpha1-blockade with doxazosin or those of placebo with respect to myocardial blood flow in syndrome X. The values obtained for myocardial blood flow and coronary vasodilator reserve for the patients were within the normal range. The data do not support the case for alpha1-mediated vasoconstriction having an etiologic role in the chest pain of syndrome X.

  13. Androgen receptor blockade using flutamide skewed sex ratio of litters in mice.

    PubMed

    Gharagozlou, Faramarz; Youssefi, Reza; Vojgani, Mehdi; Akbarinejad, Vahid; Rafiee, Ghazaleh

    2016-01-01

    Maternal testosterone has been indicated to affect sex ratio of offspring. The present study was conducted to elucidate the role of androgen receptor in this regard by blockade of androgen receptor using flutamide in female mice. Mice were randomly assigned to two experimental groups. Mice in the control (n = 20) and treatment (n = 20) groups received 8 IU equine chorionic gonadotropin (eCG) followed by human chorionic gonadotropin (hCG) injection (8 IU) 47 hr later. In addition, mice in the control and treatment groups received four injections of ethanol-saline vehicle and flutamide solution (2.50 mg), respectively, started from 1 hr before eCG injection until hCG injection at 12-hr intervals. Conception rate was not different between the treatment (18/20: 90.00%) and control (19/20: 95.00%) groups (p > 0.05). Litter size was higher in the treatment (8.22 ± 0.26) than control (7.21 ± 0.28) group (p < 0.05). Male sex ratio was lower in the flutamide-treated mice (67/148: 45.30%) as compared with the untreated ones (80/137: 58.40%; odds ratio = 1.69; p < 0.05). In conclusion, the results showed that androgen receptor blockade could skew sex ratio of offspring toward females implying that the effect of testosterone on sex ratio might be through binding to androgen receptor. In addition, the blockade of androgen receptor using flutamide appeared to enhance litter size. PMID:27482363

  14. Macroscopic quantum tunneling in Josephson tunnel junctions and Coulomb blockade in single small tunnel junctions

    SciTech Connect

    Cleland, A.N.

    1991-04-01

    Experiments investigating the process of macroscopic quantum tunneling in a moderately-damped, resistively shunted, Josephson junction are described, followed by a discussion of experiments performed on very small capacitance normal-metal tunnel junctions. The experiments on the resistively-shunted Josephson junction were designed to investigate a quantum process, that of the tunneling of the Josephson phase variable under a potential barrier, in a system in which dissipation plays a major role in the dynamics of motion. All the parameters of the junction were measured using the classical phenomena of thermal activation and resonant activation. Theoretical predictions are compared with the experimental results, showing good agreement with no adjustable parameters; the tunneling rate in the moderately damped (Q {approx} 1) junction is seen to be reduced by a factor of 300 from that predicted for an undamped junction. The phase is seen to be a good quantum-mechanical variable. The experiments on small capacitance tunnel junctions extend the measurements on the larger-area Josephson junctions from the region in which the phase variable has a fairly well-defined value, i.e. its wavefunction has a narrow width, to the region where its value is almost completely unknown. The charge on the junction becomes well-defined and is predicted to quantize the current through the junction, giving rise to the Coulomb blockade at low bias. I present the first clear observation of the Coulomb blockade in single junctions. The electrical environment of the tunnel junction, however, strongly affects the behavior of the junction: higher resistance leads are observed to greatly sharpen the Coulomb blockade over that seen with lower resistance leads. I present theoretical descriptions of how the environment influences the junctions; comparisons with the experimental results are in reasonable agreement.

  15. Androgen receptor blockade using flutamide skewed sex ratio of litters in mice

    PubMed Central

    Gharagozlou, Faramarz; Youssefi, Reza; Vojgani, Mehdi; Akbarinejad, Vahid; Rafiee, Ghazaleh

    2016-01-01

    Maternal testosterone has been indicated to affect sex ratio of offspring. The present study was conducted to elucidate the role of androgen receptor in this regard by blockade of androgen receptor using flutamide in female mice. Mice were randomly assigned to two experimental groups. Mice in the control (n = 20) and treatment (n = 20) groups received 8 IU equine chorionic gonadotropin (eCG) followed by human chorionic gonadotropin (hCG) injection (8 IU) 47 hr later. In addition, mice in the control and treatment groups received four injections of ethanol-saline vehicle and flutamide solution (2.50 mg), respectively, started from 1 hr before eCG injection until hCG injection at 12-hr intervals. Conception rate was not different between the treatment (18/20: 90.00%) and control (19/20: 95.00%) groups (p > 0.05). Litter size was higher in the treatment (8.22 ± 0.26) than control (7.21 ± 0.28) group (p < 0.05). Male sex ratio was lower in the flutamide-treated mice (67/148: 45.30%) as compared with the untreated ones (80/137: 58.40%; odds ratio = 1.69; p < 0.05). In conclusion, the results showed that androgen receptor blockade could skew sex ratio of offspring toward females implying that the effect of testosterone on sex ratio might be through binding to androgen receptor. In addition, the blockade of androgen receptor using flutamide appeared to enhance litter size. PMID:27482363

  16. P2X1 receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

    PubMed Central

    Osmond, David A.

    2010-01-01

    In vitro experiments demonstrate that P2X1 receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X1 receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X1 receptor blockade with IP5I, or A1 receptor blockade with DPCPX. Both P2X1 and A1 receptor stimulation with α,β-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X1 receptor stimulation. Likewise, administration of DPCPX significantly blocked A1 receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100–120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80–100 mmHg, suggesting that A1 receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X1 receptor activation is important for whole kidney autoregulation in vivo. PMID:20335318

  17. Zolpidem modulates GABA(A) receptor function in subthalamic nucleus.

    PubMed

    Chen, Lei; Xie, Jun-Xia; Fung, Kam-Shuen; Yung, Wing-Ho

    2007-05-01

    The subthalamic nucleus occupies a position in the indirect pathway of basal ganglia circuit, which plays an important role in the movement regulation. Zolpidem is an imidazopyridine agonist with a high affinity on the benzodiazepine site of GABA(A) receptors containing alpha 1 subunit. Recently, zolpidem has been reported to be useful in treating subgroups of parkinsonian patients. A high density of zolpidem binding sites has been shown in rat subthalamic nucleus. To further investigate the modulation of zolpidem on GABA(A) receptor-mediated inhibitory synaptic current in subthalamic nucleus, whole-cell patch clamp recordings were used in the present study. Zolpidem at 100nM significantly prolonged the decay time and rise time of miniature inhibitory postsynaptic currents, with no effect on the amplitude and frequency. The benzodiazepine antagonist flumazenil could completely block the potentiation induced by zolpidem, confirming the specificity on the benzodiazepine site. At a high concentration of 1 microM, zolpidem significantly increased the decay time, rise time, amplitude and frequency of miniature inhibitory postsynaptic currents. In the behaving rats, unilateral microinjection of zolpidem into subthalamic nucleus induced a significant contralateral rotation. The present findings on the effect of zolpidem in subthalamic nucleus provide a rationale for further investigations into its potential in the treatment of Parkinson's disease. PMID:17337310

  18. Microwaves Probe Dipole Blockade and van der Waals Forces in a Cold Rydberg Gas.

    PubMed

    Teixeira, R Celistrino; Hermann-Avigliano, C; Nguyen, T L; Cantat-Moltrecht, T; Raimond, J M; Haroche, S; Gleyzes, S; Brune, M

    2015-07-01

    We show that microwave spectroscopy of a dense Rydberg gas trapped on a superconducting atom chip in the dipole blockade regime reveals directly the dipole-dipole many-body interaction energy spectrum. We use this method to investigate the expansion of the Rydberg cloud under the effect of repulsive van der Waals forces and the breakdown of the frozen gas approximation. This study opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atoms.

  19. Iodine-induced thyroid blockade: role of selenium and iodine in the thyroid and pituitary glands.

    PubMed

    Basalaeva, Nadezdha L

    2013-08-01

    The purpose of this study was to determine the content of iodine and selenium in the thyroid and pituitary glands of rats under iodine-induced blockade of the thyroid gland. Electron probe microanalysis, wavelength-dispersive spectrometry, and point analysis were used in this investigation. We also determined the expression of sodium iodide symporter and caspase 32 in the thyroid and pituitary glands and the expression of thyroid-stimulating hormone in the pituitary. The samples for iodine analysis must be thoroughly dehydrated, and for this purpose, we developed a method that produced samples of constant mass with minimal loss of substrate (human thyroid gland was used for the investigation). Normal levels of iodine and selenium were found in the thyroid, pituitary, ovaries, testes hypothalamus, and pancreas of healthy rats. The levels of iodine and selenium in I- or Se-positive points and the percentage of positive points in most of these organs were similar to those of controls (basal level), except for the level of iodine in the thyroid gland and testes. Blockade of the thyroid gland changed the iodine level in iodine-positive points of the thyroid and the pituitary glands. On the sixth day of blockage, the iodine level in iodine-positive points of the thyroid gradually decreased to the basal level followed by an abrupt increase on the seventh day, implying a rebound effect. The opposite was found in the pituitary, in which the level of iodine in iodine-positive points increased during the first 6 days and then abruptly decreased on the seventh day. Expression of the thyroid-stimulating hormone in the pituitary decreased during the first 5 days but sharply increased on the sixth day, with a minimum level of iodine in the thyroid and maximum in the pituitary, before normalization of the iodine level in both glands preceding the rebound effect. The expression of sodium iodide symporter increased during the first 4 days of blockage and then decreased in both

  20. Dopamine blockade and clinical response: Evidence for two biological subgroups of schizophrenia

    SciTech Connect

    Wolkin, A.; Barouche, F.; Wolf, A.P.; Rotrosen, J.; Fowler, J.S.; Shiue, C.Y.; Cooper, T.B.; Brodie, J.D. )

    1989-07-01

    Because CNS neuroleptic concentration cannot be directly measured in patients, the relation between clinical response and extent of dopamine receptor blockade is unknown. This relationship is critical in ascertaining whether nonresponse to neuroleptics is the result merely of inadequate CNS drug levels or of more basic biological differences in pathophysiology. Using ({sup 18}F)N-methylspiroperidol and positron emission tomography, the authors assessed dopamine receptor occupancy in 10 schizophrenic patients before and after treatment with haloperidol. Responders and nonresponders had virtually identical indices of ({sup 18}F)N-methylspiroperidol uptake after treatment, indicating that failure to respond clinically was not a function of neuroleptic uptake or binding in the CNS.

  1. Density functional theory of the Seebeck coefficient in the Coulomb blockade regime

    NASA Astrophysics Data System (ADS)

    Yang, Kaike; Perfetto, Enrico; Kurth, Stefan; Stefanucci, Gianluca; D'Agosta, Roberto

    2016-08-01

    The Seebeck coefficient plays a fundamental role in identifying the efficiency of a thermoelectric device. Its theoretical evaluation for atomistic models is routinely based on density functional theory calculations combined with the Landauer-Büttiker approach to quantum transport. This combination, however, suffers from serious drawbacks for devices in the Coulomb blockade regime. We show how to cure the theory through a simple correction in terms of the temperature derivative of the exchange correlation potential. Our results compare well with both rate equations and experimental findings on carbon nanotubes.

  2. Microwaves Probe Dipole Blockade and van der Waals Forces in a Cold Rydberg Gas.

    PubMed

    Teixeira, R Celistrino; Hermann-Avigliano, C; Nguyen, T L; Cantat-Moltrecht, T; Raimond, J M; Haroche, S; Gleyzes, S; Brune, M

    2015-07-01

    We show that microwave spectroscopy of a dense Rydberg gas trapped on a superconducting atom chip in the dipole blockade regime reveals directly the dipole-dipole many-body interaction energy spectrum. We use this method to investigate the expansion of the Rydberg cloud under the effect of repulsive van der Waals forces and the breakdown of the frozen gas approximation. This study opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atoms. PMID:26182093

  3. Microwaves Probe Dipole Blockade and van der Waals Forces in a Cold Rydberg Gas

    NASA Astrophysics Data System (ADS)

    Teixeira, R. Celistrino; Hermann-Avigliano, C.; Nguyen, T. L.; Cantat-Moltrecht, T.; Raimond, J. M.; Haroche, S.; Gleyzes, S.; Brune, M.

    2015-07-01

    We show that microwave spectroscopy of a dense Rydberg gas trapped on a superconducting atom chip in the dipole blockade regime reveals directly the dipole-dipole many-body interaction energy spectrum. We use this method to investigate the expansion of the Rydberg cloud under the effect of repulsive van der Waals forces and the breakdown of the frozen gas approximation. This study opens a promising route for quantum simulation of many-body systems and quantum information transport in chains of strongly interacting Rydberg atoms.

  4. Nonlithographic nanowire-array tunnel device: Fabrication, zero-bias anomalies, and Coulomb blockade

    NASA Astrophysics Data System (ADS)

    Davydov, D. N.; Haruyama, J.; Routkevitch, D.; Statt, B. W.; Ellis, D.; Moskovits, M.; Xu, J. M.

    1998-06-01

    Coulomb blockade (CB) was observed in Al/aluminum oxide/Ni nanowire single-junction arrays fabricated by electrochemical deposition of Ni into porous aluminum oxide nanotemplates. The bias dependence of the tunneling current and the temperature dependence of the zero-bias anomalies observed in the tunneling spectra are shown to accord well with the theory of Nazarov for CB in systems where the leads play a significant role. Direct scanning tunneling microscopy measurements of the nanowire leads resistance confirms it to be the regime required by the theory.

  5. Cardiovascular and endocrine response to hemorrhage after. cap alpha. /sub 1/-blockade in lambs and ewes

    SciTech Connect

    Block, S.M.; Rose, J.C.; Ernest, J.M.; Flowe, K.; South, S.; Zimmerman, C.

    1987-02-01

    To evaluate the role of the ..cap alpha../sub 1/-adrenergic system in the response to hemorrhage during development, lambs and adult sheep were chronically catheterized and hemorrhaged after pretreatment with prazosin or vehicle. The adults became markedly more hypotensive after ..cap alpha../sub 1/-blockade and hemorrhage than after vehicle and hemorrhage, whereas the lambs were no more hypotensive when hemorrhaged after prazosin. In the adults and the lambs hemorrhage produced elevations in plasma renin activity and arginine vasopressin measured by radioimmunoassay. However, after prazosin, the adults had a far greater increase in arginine vasopressin levels than after vehicle treatment.

  6. LONG TERM MONITORING FOR NATURAL ATTENUATION

    EPA Science Inventory

    We have good statistical methods to: (1) determine whether concentrations of a contaminant are attenuating over time, (2) determine the rate of attenuation and confidence interval on the rate, and (3) determine whether concentrations have met a particular clean up goal. We do no...

  7. The thromboxane receptor antagonist S18886 attenuates renal oxidant stress and proteinuria in diabetic apolipoprotein E-deficient mice.

    PubMed

    Xu, Shanqin; Jiang, Bingbing; Maitland, Karlene A; Bayat, Hossein; Gu, Jiali; Nadler, Jerry L; Corda, Stefano; Lavielle, Gilbert; Verbeuren, Tony J; Zuccollo, Adriana; Cohen, Richard A

    2006-01-01

    Arachidonic acid metabolites, some of which may activate thromboxane A(2) receptors (TPr) and contribute to the development of diabetes complications, including nephropathy, are elevated in diabetes. This study determined the effect of blocking TPr with S18886 or inhibiting cyclooxygenase with aspirin on oxidative stress and the early stages of nephropathy in streptozotocin-induced diabetic apolipoprotein E(-/-) mice. Diabetic mice were treated with S18886 (5 mg . kg(-1) . day(-1)) or aspirin (30 mg . kg(-1) . day(-1)) for 6 weeks. Neither S18886 nor aspirin affected hyperglycemia or hypercholesterolemia. There was intense immunohistochemical staining for nitrotyrosine in diabetic mouse kidney. In addition, a decrease in manganese superoxide dismutase (MnSOD) activity was associated with an increase in MnSOD tyrosine-34 nitration. Tyrosine nitration was significantly reduced by S18886 but not by aspirin. Staining for the NADPH oxidase subunit p47(phox), inducible nitric oxide synthase, and 12-lipoxygenase was increased in diabetic mouse kidney, as were urine levels of 12-hydroxyeicosatetraenoic acid and 8-iso-prostaglandin F(2alpha). S18886 attenuated all of these markers of oxidant stress and inflammation. Furthermore, S18886 significantly attenuated microalbuminuria in diabetic mice and ameliorated histological evidence of diabetic nephropathy, including transforming growth factor-beta and extracellular matrix expression. Thus, in contrast to inhibiting cyclooxygenase, blockade of TPr may have therapeutic potential in diabetic nephropathy, in part by attenuating oxidative stress. PMID:16380483

  8. Genetic ablation of interleukin-18 does not attenuate hypobaric hypoxia-induced right ventricular hypertrophy.

    PubMed

    Bruns, Danielle R; Buttrick, Peter M; Walker, Lori A

    2016-03-15

    Interleukin-18 (IL-18), a proinflammatory cytokine, has been implicated in pathologic left ventricular hypertrophy and is elevated in plasma of heart failure patients. However, IL-18 blockade strategies have been conflicting. The purpose of these experiments was to determine whether genetic ablation of IL-18 would protect mice against hypobaric hypoxia (HH)-induced right ventricular (RV) hypertrophy, a condition in which chamber-specific inflammation is prominent. We hypothesized that IL-18 knockout (KO) mice would be protected while wild-type (WT) mice would demonstrate RV hypertrophy in response to HH exposure. KO and WT mice were exposed to HH for 7 wk, and control mice were exposed to normoxic ambient air. Following echocardiography, the RV was dissected and flash-frozen for biochemical analyses. HH exposure increased IL-18 mRNA (P = 0.08) in RV from WT mice. Genetic ablation of IL-18 mildly attenuated RV hypertrophy as assessed by myocyte size. However, IL-18 KO mice were not protected against HH-induced organ-level remodeling, as evidenced by higher RV weights, elevated RV systolic pressure, and increased RV anterior wall thickness compared with normoxic KO mice. These RV changes were similar to those seen in HH-exposed WT mice. Compensatory upregulation of other proinflammatory cytokines IL-2 and stromal cell-derived factor-1 was seen in the HH-KO animals, suggesting that activation of parallel inflammatory pathways might mitigate the effect of IL-18 KO. These data suggest targeted blockade of IL-18 alone is not a viable therapeutic strategy in this model.

  9. Yokukansan Increases 5-HT1A Receptors in the Prefrontal Cortex and Enhances 5-HT1A Receptor Agonist-Induced Behavioral Responses in Socially Isolated Mice

    PubMed Central

    Ueki, Toshiyuki; Mizoguchi, Kazushige; Yamaguchi, Takuji; Nishi, Akinori; Ikarashi, Yasushi; Hattori, Tomohisa; Kase, Yoshio

    2015-01-01

    The traditional Japanese medicine yokukansan has an anxiolytic effect, which occurs after repeated administration. In this study, to investigate the underlying mechanisms, we examined the effects of repeated yokukansan administration on serotonin 1A (5-HT1A) receptor density and affinity and its expression at both mRNA and protein levels in the prefrontal cortex (PFC) of socially isolated mice. Moreover, we examined the effects of yokukansan on a 5-HT1A receptor-mediated behavioral response. Male mice were subjected to social isolation stress for 6 weeks and simultaneously treated with yokukansan. Thereafter, the density and affinity of 5-HT1A receptors were analyzed by a receptor-binding assay. Levels of 5-HT1A receptor protein and mRNA were also measured. Furthermore, (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT; a 5-HT1A receptor agonist) was injected intraperitoneally, and rearing behavior was examined. Social isolation stress alone did not affect 5-HT1A receptor density or affinity. However, yokukansan significantly increased receptor density and decreased affinity concomitant with unchanged protein and mRNA levels. Yokukansan also enhanced the 8-OH-DPAT-induced decrease in rearing behavior. These results suggest that yokukansan increases 5-HT1A receptors in the PFC of socially isolated mice and enhances their function, which might underlie its anxiolytic effects. PMID:26681968

  10. A Rare Case of C2 Sensory Blockade with Preserved Phrenic Nerve Function in an Obstetric Patient

    PubMed Central

    Fiorini, Kasey; Cook, Meghan

    2016-01-01

    High neuraxial blockade is a serious complication in obstetric patients and requires prompt recognition and management in order to optimize patient outcomes. In cases of high neuroblockade, patients may present with significant hypotension, dyspnea, agitation, difficulty speaking or inability to speak, or even loss of consciousness. We report the unusual presentation of an obstetric patient that remained hemodynamically stable and had the preserved ability to initiate breaths despite sensory blockade up to C2. The presence of differential motor and sensory block documented in this case helped enable the patient to be managed with noninvasive ventilatory support until the high blockade regressed and we are not aware of any other similar reports in literature. PMID:27559484

  11. A Rare Case of C2 Sensory Blockade with Preserved Phrenic Nerve Function in an Obstetric Patient.

    PubMed

    Coffman, John C; Fiorini, Kasey; Cook, Meghan; Small, Robert H

    2016-01-01

    High neuraxial blockade is a serious complication in obstetric patients and requires prompt recognition and management in order to optimize patient outcomes. In cases of high neuroblockade, patients may present with significant hypotension, dyspnea, agitation, difficulty speaking or inability to speak, or even loss of consciousness. We report the unusual presentation of an obstetric patient that remained hemodynamically stable and had the preserved ability to initiate breaths despite sensory blockade up to C2. The presence of differential motor and sensory block documented in this case helped enable the patient to be managed with noninvasive ventilatory support until the high blockade regressed and we are not aware of any other similar reports in literature. PMID:27559484

  12. Dual human epidermal growth factor receptor 2 blockade for the treatment of HER2-positive breast cancer

    PubMed Central

    Hortobagyi, Gabriel N.

    2014-01-01

    The introduction of trastuzumab into clinical practice changed the natural course of HER2-positive breast cancer. Currently, treatment with trastuzumab represents the standard of care for HER2-positive breast cancer and this treatment has been approved in the adjuvant, neoadjuvant, and metastatic settings. Besides trastuzumab, two other anti-HER2 agents—lapatinib and pertuzumab—have been approved for the treatment of HER2-positive advanced breast cancer. Strong biologic data support the concept of dual HER2 blockade, with different anti-HER2 agents demonstrating complementary mechanisms of action. Several neoadjuvant and metastatic studies performed in HER2-positive breast cancer using dual HER2 blockade have been proven to outperform anti-HER2 monotherapies. These dual combinations of agents represent a promising therapeutic strategy that is now reaching clinical practice. In this review we describe the results of studies utilizing dual blockade in patients with HER2-positive breast cancer. PMID:23377763

  13. Distortions of the coulomb blockade conductance line in scanning gate measurements of inas nanowire based quantum dots

    SciTech Connect

    Zhukov, A. A.; Volk, Ch.; Winden, A.; Hardtdegen, H.; Schaepers, Th.

    2013-01-15

    We performed measurements at helium temperatures of the electronic transport in the linear regime in an InAs quantum wire in the presence of a charged tip of an atomic force microscope (AFM) at low electron concentration. We show that at certain concentration of electrons, only two closely placed quantum dots, both in the Coulomb blockade regime, govern conductance of the whole wire. Under this condition, two types of peculiarities-wobbling and splitting-arise in the behavior of the lines of the conductance peaks of Coulomb blockade. These peculiarities are measured in quantum-wire-based structures for the first time. We explain both peculiarities as an interplay of the conductance of two quantum dots present in the wire. Detailed modeling of wobbling behavior made in the framework of the orthodox theory of Coulomb blockade demonstrates good agreement with the obtained experimental data.

  14. Role of the complement anaphylatoxin C5a-receptor pathway in atopic dermatitis in mice

    PubMed Central

    DANG, LIN; HE, LEI; WANG, YAN; XIONG, JIKUI; BAI, BINGXUE; LI, YUZHEN

    2015-01-01

    Atopic dermatitis (AD) is a chronic inflammatory skin disease with a genetic background. The C5a-receptor (C5aR) pathway has been reported to be involved in AD; however, the precise pathogenesis remains to be elucidated. In the present study, the contribution of the C5aR pathway to AD in mice was investigated. A BALB/c mouse model of AD was induced by application of 2,4-dinitrochlorobenzene (DNCB) onto hairless dorsal skin. Following DNCB application for 2 weeks, C5aR expression in skin tissue was assessed by reverse transcription quantitative polymerase chain reaction. C5aR expression in skin tissue was significantly increased in mice with AD. In an additional experiment, C5aR antagonist (C5aRA) intracutaneously injected in combination with DNCB treatment. The skin-fold thickness, number of total infiltrating leukocytes and mast cells infiltrating in skin tissue were measured. Interleukin-4 (IL-4) and interferon-γ (IFN-γ) levels in skin tissue and IL-4, IFN-γ, histamine and immunoglobulin E (IgE) levels in serum were measured using ELISA. The skin-fold thickness, numbers of total infiltrating leukocytes and mast cells in skin tissue, as well as levels of IL-4, IFN-γ, histamine and IgE were significantly increased in mice with AD. However, simultaneous treatment with C5aRA significantly attenuated increases in skin fold thickness and the numbers of total infiltrating leukocytes and mast cells in skin tissue. Treatment with C5aRA also decreased IL-4 and IFN-γ levels in skin tissue, as well as the levels of IL-4, IFN-γ, histamine and IgE in the serum. In conclusion, C5aRA inhibited AD in mice, possibly through suppression of the C5aR-mediated cascade action of mast cells. PMID:25650554

  15. The inhibitory effect of Camellia sinensis extracts against the neuromuscular blockade of Crotalus durissus terrificus venom

    PubMed Central

    de Jesus Reis Rosa, Luana; Silva, Gleidy Ana Araujo; Filho, Jorge Amaral; Silva, Magali Glauzer; Groppo, Francisco Carlos; Oshima-Franco, Yoko

    2010-01-01

    In geographically isolated populations where intensive medical care or serum therapy is not easily accessible snake envenomation is a major cause for concern. The aim of the present study was to test Camellia sinensis extracts, theaflavin and epigallocatechin (two of the main C. sinensis components) against the irreversible neuromuscular blockade induced by Crotalus durissus terrificus venom in mouse phrenic-nerve diaphragm preparations. A quantitative histological study was also performed. The venom (20µg/ml) completely decreased twitch tension after 70min and 5µg/ml venom abolished 50% of twitch amplitude after 60min. C. sinensis extract induced intense facilitatory effect in the preparation activity at 0.2mg/ml and slightly facilitatory effect at 0.05mg/ml. Both 0.05mg/ml C. sinensis extract and 0.05mg/ml commercial theaflavin maintained partial muscular activity in presence of 5µg/ml venom. The histological data confirms that Cs is able to protect the muscle from the myotoxic activity of the venom. Commercial epigallocatechin gallate did not show pre-synaptic nor post-synaptic activities. C. sinensis extract was able to protect the mouse phrenic-nerve diaphragm against the irreversible neuromuscular blockade induced by C. durissus terrificus venom. PMID:21544176

  16. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    PubMed Central

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia. PMID:24865217

  17. Cavity-Free Photon Blockade Induced by Many-Body Bound States

    NASA Astrophysics Data System (ADS)

    Zheng, Huaixiu; Gauthier, Daniel; Baranger, Harold

    2012-02-01

    We show theoretically that a variety of strong quantum nonlinear phenomena occur in a completely open one-dimensional waveguide coupled to an N-type four-level system. This system could be realized, for example, in experiments using superconducting circuits. We focus on photon blockade, photon-induced tunneling, bunching or anti-bunching, and the creation of single-photon states, all in the absence of a cavity. Many-body bound states appear due to the strong photon-photon correlation mediated by the four-level system. These bound states cause photon blockade, generating a sub-Poissonian single-photon source [1]. Such a source is crucial for quantum cryptography and distributed quantum networking; our work thus supports the notion that open quantum systems can play a critical role in the manipulation of individual, mobile quanta, a key goal of quantum communication. [1] H. Zheng, D. J. Gauthier, and H. U. Baranger, Phys. Rev. Lett. in press (2011), arXiv:1107.0309.

  18. Efficacy of Immediate Switching from Bicalutamide to Flutamide as Second-Line Combined Androgen Blockade.

    PubMed

    Yokomizo, Yumiko; Kawahara, Takashi; Miyoshi, Yasuhide; Otani, Masako; Yamanaka, Shoji; Teranishi, Jun-Ichi; Noguchi, Kazumi; Yao, Masahiro; Uemura, Hiroji

    2016-01-01

    We determined whether prostate specific antigen (PSA) would decrease with immediate antiandrogen switching from bicalutamide (BCL) to flutamide (FLT) in patients receiving combined androgen blockade for advanced prostate cancer. From 2002 to 2006, 20 patients who showed PSA failure after first-line hormonal therapy with a luteinizing hormone-release hormone (LH-RH) agonist and BCL were enrolled. All patients were immediately switched from BCL to FLT, administered with an LH-RH agonist, as second-line combined androgen blockade (CAB). We evaluated the PSA response to second-line CAB. Eight patients (40%) were responsive, showing PSA decreases of at least 50%. The median (range) duration of the PSA response was 18.4 (3-26) months. Second-line CAB using FLT was effective in 40% of patients who received first-line CAB using BCL. The lower Gleason scores at the initial prostate biopsy probably reflect the response to second-line CAB. Responders showed significantly better OS and CSS in the determination of any PSA decline and 40% PSA decline. The median OS duration in nonresponders and responders (40% PSA decline) was 1433 days versus 3617 days. It is concluded that an immediate switch from BCL to FLT is effective for some CRPC patients after first-line CAB using BCL. PMID:27493956

  19. CXCR3 Blockade Inhibits T Cell Migration into the Skin and Prevents Development of Alopecia Areata.

    PubMed

    Dai, Zhenpeng; Xing, Luzhou; Cerise, Jane; Wang, Eddy Hsi Chun; Jabbari, Ali; de Jong, Annemieke; Petukhova, Lynn; Christiano, Angela M; Clynes, Raphael

    2016-08-15

    Alopecia areata (AA) is an autoimmune disease of the hair follicle that results in hair loss of varying severity. Recently, we showed that IFN-γ-producing NKG2D(+)CD8(+) T cells actively infiltrate the hair follicle and are responsible for its destruction in C3H/HeJ AA mice. Our transcriptional profiling of human and mouse alopecic skin showed that the IFN pathway is the dominant signaling pathway involved in AA. We showed that IFN-inducible chemokines (CXCL9/10/11) are markedly upregulated in the skin of AA lesions, and further, that the IFN-inducible chemokine receptor, CXCR3, is upregulated on alopecic effector T cells. To demonstrate whether CXCL9/10/11 chemokines were required for development of AA, we treated mice with blocking Abs to CXCR3, which prevented the development of AA in the graft model, inhibiting the accumulation of NKG2D(+)CD8(+) T cells in the skin and cutaneous lymph nodes. These data demonstrate proof of concept that interfering with the Tc1 response in AA via blockade of IFN-inducible chemokines can prevent the onset of AA. CXCR3 blockade could be approached clinically in human AA with either biologic or small-molecule inhibition, the latter being particularly intriguing as a topical therapeutic. PMID:27412416

  20. Ablation of type I hypersensitivity in experimental allergic conjunctivitis by eotaxin-1/CCR3 blockade

    PubMed Central

    Nakamura, Takao; Ohbayashi, Masaharu; Kuo, Chuan Hui; Komatsu, Naoki; Yakura, Keiko; Tominaga, Takeshi; Inoue, Yoshitsugu; Higashi, Hidemitsu; Murata, Meguru; Takeda, Shuzo; Fukushima, Atsuki; Liu, Fu-Tong; Rothenberg, Marc E.; Ono, Santa Jeremy

    2009-01-01

    The immune response is regulated, in part, by effector cells whose activation requires multiple signals. For example, T cells require signals emanating from the T cell antigen receptor and co-stimulatory molecules for full activation. Here, we present evidence indicating that IgE-mediated hypersensitivity reactions in vivo also require cognate signals to activate mast cells. Immediate hypersensitivity reactions in the conjunctiva are ablated in mice deficient in eotaxin-1, despite normal numbers of tissue mast cells and levels of IgE. To further define the co-stimulatory signals mediated by chemokine receptor 3 (CCR3), an eotaxin-1 receptor, effects of CCR3 blockade were tested with an allergic conjunctivitis model and in ex vivo isolated connective tissue-type mast cells. Our results show that CCR3 blockade significantly suppresses allergen-mediated hypersensitivity reactions as well as IgE-mediated mast cell degranulation. We propose that a co-stimulatory axis by CCR3, mainly stimulated by eotaxin-1, is pivotal in mast cell-mediated hypersensitivity reactions. PMID:19147836

  1. Blockade of Glutamatergic Transmission in Perirhinal Cortex Impairs Object Recognition Memory in Macaques

    PubMed Central

    Forcelli, Patrick A.; Wellman, Laurie L.; Dybdal, David; Dubach, Mark F.; Gale, Karen

    2015-01-01

    The perirhinal cortex (PRc) is essential for visual recognition memory, as shown by electrophysiological recordings and lesion studies in a variety of species. However, relatively little is known about the functional contributions of perirhinal subregions. Here we used a systematic mapping approach to identify the critical subregions of PRc through transient, focal blockade of glutamate receptors by intracerebral infusion of kynurenic acid. Nine macaques were tested for visual recognition memory using the delayed nonmatch-to-sample task. We found that inactivation of medial PRc (consisting of Area 35 together with the medial portion of Area 36), but not lateral PRc (the lateral portion of Area 36), resulted in a significant delay-dependent impairment. Significant impairment was observed with 30 and 60 s delays but not with 10 s delays. The magnitude of impairment fell within the range previously reported after PRc lesions. Furthermore, we identified a restricted area located within the most anterior part of medial PRc as critical for this effect. Moreover, we found that focal blockade of either NMDA receptors by the receptor-specific antagonist AP-7 or AMPA receptors by the receptor-specific antagonist NBQX was sufficient to disrupt object recognition memory. The present study expands the knowledge of the role of PRc in recognition memory by identifying a subregion within this area that is critical for this function. Our results also indicate that, like in the rodent, both NMDA and AMPA-mediated transmission contributes to object recognition memory. PMID:25810533

  2. Glutamate receptor blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex.

    PubMed Central

    Fox, K; Schlaggar, B L; Glazewski, S; O'Leary, D D

    1996-01-01

    The segregation of thalamocortical inputs into eye-specific stripes in the developing cat or monkey visual cortex is prevented by manipulations that perturb or abolish neural activity in the visual pathway. Such findings show that proper development of the functional organization of visual cortex is dependent on normal patterns of neural activity. The generalisation of this conclusion to other sensory cortices has been questioned by findings that the segregation of thalamocortical afferents into a somatotopic barrel pattern in developing rodent primary somatosensory cortex (S1) is not prevented by activity blockade. We show that a temporary block of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in rat S1 during the critical period for barrel development disrupts the topographic refinement of thalamocortical connectivity and columnar organization. These effects are evident well after the blockade is ineffective and thus may be permanent. Our findings show that neural activity and specifically the activation of postsynaptic cortical neurons has a prominent role in establishing the primary sensory map in S1, as well as the topographic organization of higher order synaptic connections. Images Fig. 1 PMID:8643619

  3. The effect of androgen blockade on pulsatile gonadotrophin release and LH response to naloxone.

    PubMed

    Balzano, S; Migliari, R; Sica, V; Scarpa, R M; Pintus, C; Loviselli, A; Usai, E; Balestrieri, A

    1987-10-01

    In order to clarify the effects of androgen blockade on the hypothalamic-pituitary-testicular axis in man, four patients with advanced prostate cancer, not previously treated, were given oral flutamide, 250 mg three times daily for 9 days. Before, and 7, 8 and 9 days after starting flutamide treatment, on separate days, the following tests were performed: a gonadotrophin pulsatility study, with 20 min interval blood sampling for 12 h, a naloxone test and a GnRH test. Flutamide induced a significant increase in both LH and FSH pulse frequency, while pulse amplitudes and plasma integrated concentrations (IC) of LH and FSH were unaffected. Plasma integrated concentrations of testosterone and oestradiol rose significantly, while that of prolactin was unaffected. The increase in plasma LH concentration induced by naloxone injection was abolished by flutamide treatment. On the other hand, the small FSH response to naloxone was unaffected by flutamide treatment. Response to GnRH was unaffected by flutamide. These results suggest that flutamide exerts effective androgen blockade at the hypothalamic level, since, despite increased plasma testosterone concentrations, gonadotrophin pulse frequency increased and the LH response to naloxone was abolished.

  4. The role of adrenergic receptor blockade in serotonin-induced changes in the pulmonary circulation.

    PubMed Central

    Rapaport, E; Rolston, W A; Stern, S

    1977-01-01

    1. In dogs i.v. injection of serotonin caused a rise in pulmonary artery pressure and pulmonary arteriocapillary resistance that persisted even after alpha- and beta-adrenergic receptor blockade; pulmonary venous resistance also increased, but this was abolished by pretreatment with either propranolol or phenoxybenzamine. 2. The injection of serotonin into the ascending aorta produced an immediate rise in systemic, pulmonary arterial and pulmonary venous pressures and pulmonary venous resistance. After phenoxybenzmine, the rise in systemic and pulmonary arterial pressures remained unchanged, but previously observed increases in pulmonary venous pressure and resistance were blocked. In contrast, propranolol failed to abolish the rise in pulmonary venous resistance after serotonin injection into the ascending aorta. 3. These results confirm the observation that the vasoconstrictor effect attributed to intravenously injected serotonin on the arterial side of the pulmonary circulation is independent of the known sympathetic pathways. The data suggest that the pulmonary venoconstriction induced by intravenous serotonin is of reflex origin, abolished by alpha and beta receptor blockade, whereas the efferent arm of the reflex pulmonary venoconstriction following injection of serotonin into the ascending aorta is mediated via alpha-adrenergic receptors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:599427

  5. Dispersively Detected Pauli Spin-Blockade in a Silicon Nanowire Field-Effect Transistor.

    PubMed

    Betz, A C; Wacquez, R; Vinet, M; Jehl, X; Saraiva, A L; Sanquer, M; Ferguson, A J; Gonzalez-Zalba, M F

    2015-07-01

    We report the dispersive readout of the spin state of a double quantum dot formed at the corner states of a silicon nanowire field-effect transistor. Two face-to-face top-gate electrodes allow us to independently tune the charge occupation of the quantum dot system down to the few-electron limit. We measure the charge stability of the double quantum dot in DC transport as well as dispersively via in situ gate-based radio frequency reflectometry, where one top-gate electrode is connected to a resonator. The latter removes the need for external charge sensors in quantum computing architectures and provides a compact way to readout the dispersive shift caused by changes in the quantum capacitance during inter-dot charge transitions. Here, we observe Pauli spin-blockade in the high-frequency response of the circuit at finite magnetic fields between singlet and triplet states. The blockade is lifted at higher magnetic fields when intra-dot triplet states become the ground state configuration. A line shape analysis of the dispersive phase shift reveals furthermore an intra-dot valley-orbit splitting Δvo of 145 μeV. Our results open up the possibility to operate compact complementary metal-oxide semiconductor (CMOS) technology as a singlet-triplet qubit and make split-gate silicon nanowire architectures an ideal candidate for the study of spin dynamics. PMID:26047255

  6. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension.

    PubMed

    Martínez-Martínez, Ernesto; Calvier, Laurent; Fernández-Celis, Amaya; Rousseau, Elodie; Jurado-López, Raquel; Rossoni, Luciana V; Jaisser, Frederic; Zannad, Faiez; Rossignol, Patrick; Cachofeiro, Victoria; López-Andrés, Natalia

    2015-10-01

    Hypertensive cardiac remodeling is accompanied by molecular inflammation and fibrosis, 2 mechanisms that finally affect cardiac function. At cardiac level, aldosterone promotes inflammation and fibrosis, although the precise mechanisms are still unclear. Galectin-3 (Gal-3), a β-galactoside-binding lectin, is associated with inflammation and fibrosis in the cardiovascular system. We herein investigated whether Gal-3 inhibition could block aldosterone-induced cardiac inflammation and fibrosis and its potential role in cardiac damage associated with hypertension. Aldosterone-salt-treated rats presented hypertension, cardiac inflammation, and fibrosis that were prevented by the pharmacological inhibition of Gal-3 with modified citrus pectin. Cardiac inflammation and fibrosis presented in spontaneously hypertensive rats were prevented by modified citrus pectin treatment, whereas Gal-3 blockade did not modify blood pressure levels. In the absence of blood pressure modifications, Gal-3 knockout mice were resistant to aldosterone-induced cardiac inflammation. In human cardiac fibroblasts, aldosterone increased Gal-3 expression via its mineralocorticoid receptor. Gal-3 and aldosterone enhanced proinflammatory and profibrotic markers, as well as metalloproteinase activities in human cardiac fibroblasts, effects that were not observed in Gal-3-silenced cells treated with aldosterone. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac inflammation and fibrosis, alterations that were prevented by Gal-3 blockade independently of blood pressure levels. These data suggest that Gal-3 could be a new molecular mechanism linking cardiac inflammation and fibrosis in situations with high-aldosterone levels, such as hypertension.

  7. Theory of charge transport in molecular junctions: From Coulomb blockade to coherent tunneling

    SciTech Connect

    Chang, Yao-Wen; Jin, Bih-Yaw

    2014-08-14

    We study charge transport through molecular junctions in the presence of electron-electron interaction using the nonequilibrium Green's function techniques and the renormalized perturbation theory. In the perturbation treatment, the zeroth-order Hamiltonian of the molecular junction is composed of independent single-impurity Anderson's models, which act as the channels where charges come through or occupy, and the interactions between different channels are treated as the perturbation. Using this scheme, the effects of molecule-lead, electron-electron, and hopping interactions are included nonperturbatively, and the charge transport processes can thus be studied in the intermediate parameter range from the Coulomb blockade to the coherent tunneling regimes. The concept of quasi-particles is introduced to describe the kinetic process of charge transport, and then the electric current can be studied and calculated. As a test study, the Hubbard model is used as the molecular Hamiltonian to simulate dimeric and trimeric molecular junctions. Various nonlinear current-voltage characteristics, including Coulomb blockade, negative differential resistance, rectification, and current hysteresis, are shown in the calculations, and the mechanisms are elucidated.

  8. Stroke, mTBI, infection, antibiotics and beta blockade: Connecting the dots.

    PubMed

    Griffin, Gerald Dieter

    2015-08-01

    Several themes supported by a robust literature are addressed in this clinical translational review and research paper: (1) the inadequate standard of care for minimal traumatic brain injury (mTBI)/concussion when compared to stroke because diagnosis and care for mTBI/concussion are based primarily on a symptom only framework; (2) the treatment of stroke (brain injury) infection with select antibiotics; (3) the use of beta blockade in stroke (brain injury). The various etiologies of brain injury appear to coalesce to common endpoints: potential neuronal demise, cognitive and functional losses, immune suppression and infection. The use of principles patterned after 'Koch's Postulates' (show/prove the presence of infection/illness/disease, treat until resolved, and prove objectively that the disease/illness is gone/healed/cured) appears to be marginalized in establishing a diagnosis and recovery from mTBI/TBI. The pathways of immune system interactions in stroke (brain injury) and infection are briefly discussed. The suggestion of combined specific antibiotic and beta blockade for ischemic stroke (brain injury) and mTBI is advanced for treatment and expeditious further study. Stroke is considered a brain injury in this paper. Stroke is also considered and recommended as a study model for mTBI therapy because of their common end points from brain damage. It is suggested that potential transfer or translation of therapy for stroke may be useful in mTBI.

  9. Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans.

    PubMed

    Kahnt, Thorsten; Weber, Susanna C; Haker, Helene; Robbins, Trevor W; Tobler, Philippe N

    2015-03-01

    The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs.

  10. Renin–angiotensin–aldosterone system blockade for cardiovascular diseases: current status

    PubMed Central

    Ma, Terry KW; Kam, Kevin KH; Yan, Bryan P; Lam, Yat-Yin

    2010-01-01

    Activation of the renin–angiotensin–aldosterone system (RAAS) results in vasoconstriction, muscular (vascular and cardiac) hypertrophy and fibrosis. Established arterial stiffness and cardiac dysfunction are key factors contributing to subsequent cardiovascular and renal complications. Blockade of RAAS has been shown to be beneficial in patients with hypertension, acute myocardial infarction, chronic systolic heart failure, stroke and diabetic renal disease. An aggressive approach for more extensive RAAS blockade with combination of two commonly used RAAS blockers [ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)] yielded conflicting results in different patient populations. Combination therapy is also associated with more side effects, in particular hypotension, hyperkalaemia and renal impairment. Recently published ONTARGET study showed ACEI/ARB combination therapy was associated with more adverse effects without any increase in benefit. The Canadian Hypertension Education Program responded with a new warning: ‘Do not use ACEI and ARB in combination’. However, the European Society of Cardiology in their updated heart failure treatment guidelines still recommended ACEI/ARB combo as a viable option. This apparent inconsistency among guidelines generates debate as to which approach of RAAS inhibition is the best. The current paper reviews the latest evidence of isolated ACEI or ARB use and their combination in cardiovascular diseases, and makes recommendations for their prescriptions in specific patient populations. PMID:20590619

  11. Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.

    PubMed

    Sykes, David B; Kfoury, Youmna S; Mercier, François E; Wawer, Mathias J; Law, Jason M; Haynes, Mark K; Lewis, Timothy A; Schajnovitz, Amir; Jain, Esha; Lee, Dongjun; Meyer, Hanna; Pierce, Kerry A; Tolliday, Nicola J; Waller, Anna; Ferrara, Steven J; Eheim, Ashley L; Stoeckigt, Detlef; Maxcy, Katrina L; Cobert, Julien M; Bachand, Jacqueline; Szekely, Brian A; Mukherjee, Siddhartha; Sklar, Larry A; Kotz, Joanne D; Clish, Clary B; Sadreyev, Ruslan I; Clemons, Paul A; Janzer, Andreas; Schreiber, Stuart L; Scadden, David T

    2016-09-22

    While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML. PMID:27641501

  12. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

    PubMed

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

    2015-12-01

    Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade. PMID:26301611

  13. Blockade of Vascular Adhesion Protein-1 Inhibits Lymphocyte Infiltration in Rat Liver Allograft Rejection

    PubMed Central

    Martelius, Timi; Salaspuro, Ville; Salmi, Marko; Krogerus, Leena; Höckerstedt, Krister; Jalkanen, Sirpa; Lautenschlager, Irmeli

    2004-01-01

    Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174–5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 ± 1.0 and 2.4 ± 1.0 corrected increment units, respectively) compared to control (6.6 ± 1.0) (P < 0.05). In histology, the intensity of portal inflammation was significantly decreased (P < 0.05). The amount of T cells expressing activation markers diminished. This is the first demonstration in any prolonged in vivo model that VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection. PMID:15579442