Sample records for a-receptor blockade attenuates

  1. Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease. (United States)

    Kelsen, Silvia; Hall, John E; Chade, Alejandro R


    Endothelin (ET)-1, a potent renal vasoconstrictor with mitogenic properties, is upregulated by ischemia and has been shown to induce renal injury via the ET-A receptor. The potential role of ET-A blockade in chronic renovascular disease (RVD) has not, to our knowledge, been previously reported. We hypothesized that chronic ET-A receptor blockade would preserve renal hemodynamics and slow the progression of injury of the stenotic kidney in experimental RVD. Renal artery stenosis, a major cause of chronic RVD, was induced in 14 pigs and observed for 6 wk. In half of the pigs, chronic ET-A blockade was initiated (RVD+ET-A, 0.75 mg·kg(-1)·day(-1)) at the onset of RVD. Single-kidney renal blood flow, glomerular filtration rate, and perfusion were quantified in vivo after 6 wk using multidetector computer tomography. Renal microvascular density was quantified ex vivo using three-dimensional microcomputer tomography, and growth factors, inflammation, apoptosis, and fibrosis were determined in renal tissue. The degree of stenosis and increase in blood pressure were similar in RVD and RVD+ET-A pigs. Renal hemodynamics, function, and microvascular density were decreased in the stenotic kidney but preserved by ET-A blockade, accompanied by increased renal expression of vascular endothelial growth factor, hepatocyte growth factor, and downstream mediators such as phosphorilated-Akt, angiopoietins, and endothelial nitric oxide synthase. ET-A blockade also reduced renal apoptosis, inflammation, and glomerulosclerosis. This study shows that ET-A blockade slows the progression of renal injury in experimental RVD and preserves renal hemodynamics, function, and microvascular density in the stenotic kidney. These results support a role for ET-1/ET-A as a potential therapeutic target in chronic RVD.

  2. Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord (United States)

    Dai, Wen-Ling; Xiong, Feng; Yan, Bing; Cao, Zheng-Yu; Liu, Wen-Tao; Liu, Ji-Hua; Yu, Bo-Yang


    Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic. PMID:28004735

  3. Cannabidiol attenuates catalepsy induced by distinct pharmacological mechanisms via 5-HT1A receptor activation in mice. (United States)

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


    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.

  4. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Hidehiro Sawa; Takashi Ueda; Yoshifumi Takeyama; Takeo Yasuda; Makoto Shinzeki; Takahiro Nakajima; Yoshikazu Kuroda


    AIM: To examine the effects of anti-high mobility group box 1 (HMGB1) neutralizing antibody in experimental severe acute pancreatitis (SAP).METHODS: SAP was induced by creating closed duodenal loop in C3H/HeN mice. SAP was induced immediately after intraperitoneal injection of anti-HMGB1 neutralizing antibody (200 μg). Severity of pancreatitis, organ injury (liver, kidney and lung), and bacterial translocation to pancreas was examined 12 h after induction of SAP.RESULTS: Anti-HMGB1 neutralizing antibody significantly improved the elevation of the serum amylase level and the histological alterations of pancreas and lung in SAP.Anti-HMGB1 antibody also significantly ameliorated the elevations of serum alanine aminotransferase and creatinine in SAP. However, anti-HMGB1 antibody worsened the bacterial translocation to pancreas.CONCLUSION: Blockade of HMGB1 attenuated the development of SAP and associated organ dysfunction,suggesting that HMGB1 may act as a key mediator for inflammatory response and organ injury in SAP.

  5. Blockade of P2X7 receptors or pannexin-1 channels similarly attenuates postischemic damage. (United States)

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


    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.

  6. PVN Blockade of p44/42 MAPK Pathway Attenuates Salt-induced Hypertension through Modulating Neurotransmitters and Attenuating Oxidative Stress (United States)

    Gao, Hong-Li; Yu, Xiao-Jing; Liu, Kai-Li; Shi, Xiao-Lian; Qi, Jie; Chen, Yan-Mei; Zhang, Yan; Bai, Juan; Yi, Qiu-Yue; Feng, Zhi-Peng; Chen, Wen-Sheng; Cui, Wei; Liu, Jin-Jun; Zhu, Guo-Qing; Kang, Yu-Ming


    The imbalance of neurotransmitters and excessive oxidative stress responses contribute to the pathogenesis of hypertension. In this study, we determined whether blockade of p44/42 MAPK pathway in the hypothalamic paraventricular nucleus (PVN) ameliorates the development of hypertension through modulating neurotransmitters and attenuating oxidative stress. Dahl salt-sensitive (S) rats received a high-salt diet (HS, 8% NaCl) or a normal-salt diet (NS, 0.3% NaCl) for 6 weeks and were treated with bilateral PVN infusion of PD-98059 (0.025 μg/h), a p44/42 MAPK inhibitor, or vehicle via osmotic minipump. HS resulted in higher mean arterial pressure (MAP) and Fra-like (Fra-LI) activity, and plasma and PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. PD-98059 infusion reduced NE, TH, NOX2 and NOX4 in the PVN, and induced Cu/Zn-SOD and GAD67 in the PVN. It suggests that PVN blockade of p44/42 MAPK attenuates hypertension through modulating neurotransmitters and attenuating oxidative stress. PMID:28225041

  7. Blockade of Serotonin 5-HT2A Receptors Suppresses Behavioral Sensitization and Naloxone-Precipitated Withdrawal Symptoms in Morphine-Treated Mice (United States)

    Pang, Gang; Wu, Xian; Tao, Xinrong; Mao, Ruoying; Liu, Xueke; Zhang, Yong-Mei; Li, Guangwu; Stackman, Robert W.; Dong, Liuyi; Zhang, Gongliang


    The increasing prescription of opioids is fueling an epidemic of addiction and overdose deaths. Morphine is a highly addictive drug characterized by a high relapse rate – even after a long period of abstinence. Serotonin (5-HT) neurotransmission participates in the development of morphine dependence, as well as the expression of morphine withdrawal. In this study, we examined the effect of blockade of 5-HT2A receptors (5-HT2ARs) on morphine-induced behavioral sensitization and withdrawal in male mice. 5-HT2AR antagonist MDL 11,939 (0.5 mg/kg, i.p.) suppressed acute morphine (5.0 mg/kg, s.c.)-induced increase in locomotor activity. Mice received morphine (10 mg/kg, s.c.) twice a day for 3 days and then drug treatment was suspended for 5 days. On day 9, a challenge dose of morphine (10 mg/kg) was administered to induce the expression of behavioral sensitization. MDL 11,939 (0.5 mg/kg, i.p.) pretreatment suppressed the expression of morphine-induced behavioral sensitization. Another cohort of mice received increasing doses of morphine over a 7-day period to induce morphine-dependence. MDL 11,939 (0.5 mg/kg, i.p.) prevented naloxone-precipitated withdrawal in morphine-dependent mice on day 7. Moreover, chronic morphine treatment increased 5-HT2AR protein level and decreased the phosphorylation of extracellular signal-regulated kinases in the prefrontal cortex. Together, these results by the first time demonstrate that 5-HT2ARs modulate opioid dependence and blockade of 5-HT2AR may represent a novel strategy for the treatment of morphine use disorders. Highlights (i) Blockade of 5-HT2A receptors suppresses the expression of morphine-induced behavioral sensitization. (ii) Blockade of 5-HT2A receptors suppresses naloxone-precipitated withdrawal in morphine-treated mice. (iii) Chronic morphine exposure induces an increase in 5-HT2A receptor protein level and a decrease in ERK protein phosphorylation in prefrontal cortex. PMID:28082900

  8. Adenosine A2A receptor blockade or deletion diminishes fibrocyte accumulation in the skin in a murine model of scleroderma, bleomycin-induced fibrosis. (United States)

    Katebi, Majid; Fernandez, Patricia; Chan, Edwin S L; Cronstein, Bruce N


    Peripheral blood fibrocytes are a newly identified circulating leukocyte subpopulation that migrates into injured tissue where it may display fibroblast-like properties and participate in wound healing and fibrosis of skin and other organs. Previous studies in our lab demonstrated that A(2A) receptor-deficient and A(2A) antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis, thus the aim of this study was to determine whether the adenosine A(2A) receptor regulates recruitment of fibrocytes to the dermis in this bleomycin-induced model of dermal fibrosis. Sections of skin from normal mice and bleomycin-treated wild type, A(2A) knockout and A(2A) antagonist-treated mice were stained for Procollagen alpha2 Type I and CD34 and the double stained cells, fibrocytes, were counted in the tissue sections. There were more fibrocytes in the dermis of bleomycin-treated mice than normal mice and the increase was abrogated by deletion or blockade of adenosine A(2A) receptors. Because fibrocytes play a central role in tissue fibrosis these results suggest that diminished adenosine A(2A) receptor-mediated recruitment of fibrocytes into tissue may play a role in the pathogenesis of fibrosing diseases of the skin. Moreover, these results provide further evidence that adenosine A(2A) receptors may represent a new target for the treatment of such fibrosing diseases as scleroderma or nephrogenic fibrosing dermopathy.

  9. AT1 receptor blockade attenuates insulin resistance and myocardial remodeling in rats with diet-induced obesity.

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    Silvio A Oliveira-Junior

    Full Text Available BACKGROUND: Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. MATERIAL AND METHODS: Wistar-Kyoto (n = 40 rats were subjected to control (C; 3.2 kcal/g and hypercaloric diets (OB; 4.6 kcal/g for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE, and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP, echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2, c-Jun amino-terminal kinases (JNK, insulin receptor subunit β (βIR, and phosphatidylinositol 3-kinase (PI3K by Western Blot. RESULTS: Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated βIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr-βRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. CONCLUSION: Angiotensin II blockade with Losartan attenuates obesity-induced metabolic and cardiovascular changes.

  10. Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model.

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    Thomas J Brozoski

    Full Text Available Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(--2-amino-5-phosphonopentanoic acid (D-AP5 (0.5 mM, was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI. In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

  11. Aortic Remodeling Following Transverse Aortic Constriction in Mice is Attenuated with AT1 Receptor Blockade (United States)

    Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K.; Cao, Jiu-Mei; Guo, Steven; Villamizar, Carlos; Kwartler, Callie S.; Ju, Xiaoxi; Brasier, Allan R.; Milewicz, Dianna M.


    Objective Although hypertension is the most common risk factor for thoracic aortic diseases, it is not understood how increased pressures on the ascending aorta lead to aortic aneurysms. We investigated the role of Ang II type 1 (AT1) receptor activation in ascending aortic remodeling in response to increased biomechanical forces using a transverse aortic constriction (TAC) mouse model. Approach and Results Two weeks after TAC, the increased biomechanical pressures led to ascending aortic dilatation, aortic wall thickening and medial hypertrophy. Significant adventitial hyperplasia and inflammatory responses in TAC ascending aortas were accompanied by increased adventitial collagen, elevated inflammatory and proliferative markers, and increased cell density due to accumulation of myofibroblasts and macrophages. Treatment with losartan significantly blocked TAC induced vascular inflammation and macrophage accumulation. However, losartan only partially prevented TAC induced adventitial hyperplasia, collagen accumulation and ascending aortic dilatation. Increased Tgfb2 expression and phosphorylated-Smad2 staining in the medial layer of TAC ascending aortas was effectively blocked with losartan. In contrast, the increased Tgfb1 expression and adventitial phospho-Smad2 staining were only partially attenuated by losartan. In addition, losartan significantly blocked Erk activation and ROS production in the TAC ascending aorta. Conclusions Inhibition of the AT1 receptor using losartan significantly attenuated the vascular remodeling associated with TAC but did not completely block the increased TGF- β1 expression, adventitial Smad2 signaling and collagen accumulation. These results help to delineate the aortic TGF-β signaling that is dependent and independent of the AT1 receptor after TAC. PMID:23868934

  12. High extracellular potassium ion concentration attenuates the blockade action of ketanserin on Kvl.3 channels expressed in xenopus oocytes

    Institute of Scientific and Technical Information of China (English)


    Background Ketanserin (KT), a selective serotonin (5-HT) 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method was used to investigate the effect of KT and potassium ion on Kv1.3 potassium channels and explore the role of blocker KT in the alteration of channel kinetics contributing to the potassium ion imbalances. Methods Kvl.3 channels were expressed in xenopus oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. Results KCI made a left shift of activation and an inactivation curve of Kv1.3 current and accelerated the activation and inactivation time constant. High extracellular [K+] attenuated the blockade effect of KT on Kv1.3 channels. In the presence of KT and KCI the activation and inactivation time constants were not influenced significantly no matter what was administered first. KT did not significantly inhibit Kv1.3 current induced by tetraethylammonium (TEA). Conclusions KT is a weak blocker of Kv1.3 channels at different concentrations of extracellular potassium and binds to the intracellular side of the channel pore. The inhibitor KT of ion channels is not fully effective in clinical use because of high [K+]o and other electrolyte disorders.

  13. CXCR4 Blockade Attenuates Hyperoxia Induced Lung Injury in Neonatal Rats (United States)

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


    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

  14. Auraptenol attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors. (United States)

    Wang, Yunfei; Cao, Shu-e; Tian, Jianmin; Liu, Guozhe; Zhang, Xiaoran; Li, Pingfa


    Common chemotherapeutic agents such as vincristine often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is refractory to common analgesics and represents a challenging clinical issue. Angelicae dahuricae radix is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the active component(s) that attribute to the analgesic action have not been identified. This work described the anti-hyperalgesic effect of one coumarin component, auraptenol, in a mouse model of chemotherapeutic agent vincristine-induced neuropathic pain. We reported that auraptenol dose-dependently reverted the mechanical hyperalgesia in mice within the dose range of 0.05-0.8 mg/kg. In addition, the anti-hyperalgesic effect of auraptenol was significantly blocked by a selective serotonin 5-HT1A receptor antagonist WAY100635 (1 mg/kg). Within the dose range studied, auraptenol did not significantly alter the general locomotor activity in mice. Taken together, this study for the first time identified an active component from the herbal medicine angelicae dahuricae radix that possesses robust analgesic efficacy in mice. These data support further studies to assess the potential of auraptenol as a novel analgesic for the management of neuropathic pain.

  15. 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. (United States)

    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


    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.

  16. The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats. (United States)

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


    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.

  17. Lithium attenuated the behavioral despair induced by acute neurogenic stress through blockade of opioid receptors in mice. (United States)

    Khaloo, Pegah; Sadeghi, Banafshe; Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Haj-Mirzaian, Arya; Zolfagharie, Samira; Dehpour, Ahmad-Reza


    Major depressive disorder is disease with high rate of morbidity and mortality. Stressful events lead to depression and they can be used as a model of depression in rodents. In this study we aimed to investigate whether lithium modifies the stressed-induced depression through blockade of opioid receptors in mice. We used foot shock stress as stressor and forced swimming test (FST), tail suspension test (TST) and open field test (OFT) to evaluation the behavioral responses in mice. We also used naltrexone hydrochloride (as opioid receptor antagonist), and morphine (as opioid receptor agonist). Our results displayed that foot-shock stress significantly increased the immobility time in TST and FST but it could not change the locomotor behavior in OFT. When we combined the low concentrations of lithium and naltrexone a significant reduction in immobility time was seen in the FST and TST in comparison with control foot-shock stressed group administered saline only. Despite the fact that our data showed low concentrations of lithium, when administered independently did not significantly affect the immobility time. Also our data indicated that concurrent administration of lithium and naltrexone had no effect on open field test. Further we demonstrated that simultaneous administration of morphine and lithium reverses the antidepressant like effect of active doses of lithium. Our data acclaimed that we lithium can augment stressed-induced depression and opioid pathways are involved in this action.

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

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    Camelo, J.S. Jr. [Departamento de Puericultura e Pediatria, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Martins, A.R. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Instituto de Ciências Biológicas, Universidade Federal do Triângulo Mineiro, Uberaba, MG (Brazil); Rosa, E. [Departamento de Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Ramos, S.G. [Departamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SPBrasil (Brazil); Hehre, D.; Bancalari, E.; Suguihara, C. [Department of Pediatrics, Division of Neonatology, Neonatal Developmental Biology Laboratory, University of Miami Miller School of Medicine, Miami, FL (United States)


    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 AT{sub 1} receptor (AT{sub 1}-R) blocker L-158,809 (L) during 6 days of hypoxia (FiO{sub 2} = 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 AT{sub 1}-R in P animals during hypoxia compared to normoxic animals (C group, N = 5; P < 0.01 for all groups). AT{sub 1}-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 AT{sub 1}-R staining. Macrophages and pneumocytes showed moderate or strong iNOS and AT{sub 1}-R staining, but C animals showed weak iNOS and AT{sub 1}-R staining. Macrophages of L and P animals showed moderate and weak AT{sub 2}-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 AT{sub 1}-R blockade. We suggest that AT{sub 1}-R blockade might act through AT{sub 2}-R and/or Mas receptors and the nitrergic system in the lungs of hypoxemic newborn piglets.

  19. Attenuation of Myocardial Injury by HMGB1 Blockade during Ischemia/Reperfusion Is Toll-Like Receptor 2-Dependent

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    Jan Mersmann


    Full Text Available Genetic or pharmacological ablation of toll-like receptor 2 (TLR2 protects against myocardial ischemia/reperfusion injury (MI/R. However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT or TLR2−/−-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min and reperfusion (24 hrs. Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2−/−-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2−/−-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2−/−-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln. We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.

  20. Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice. (United States)

    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


    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.

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

    Directory of Open Access Journals (Sweden)

    Agnieszka M. Jurga


    Full Text Available 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.

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

    Jurga, Agnieszka M; Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Pilat, Dominika; Przewlocka, Barbara; Mika, Joanna


    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.

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

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


    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

  4. Blockade of GABA, type A, receptors in the rat pontine reticular formation induces rapid eye movement sleep that is dependent upon the cholinergic system. (United States)

    Marks, G A; Sachs, O W; Birabil, C G


    The brainstem reticular formation is an area important to the control of rapid eye movement (REM) sleep. The antagonist of GABA-type A (GABA(A)) receptors, bicuculline methiodide (BMI), injected into the rat nucleus pontis oralis (PnO) of the reticular formation resulted in a long-lasting increase in REM sleep. Thus, one factor controlling REM sleep appears to be the number of functional GABA(A) receptors in the PnO. The long-lasting effect produced by BMI may result from secondary influences on other neurotransmitter systems known to have long-lasting effects. To study this question, rats were surgically prepared for chronic sleep recording and additionally implanted with guide cannulas aimed at sites in the PnO. Multiple, 60 nl, unilateral injections were made either singly or in combination. GABA(A) receptor antagonists, BMI and gabazine (GBZ), produced dose-dependent increases in REM sleep with GBZ being approximately 35 times more potent than BMI. GBZ and the cholinergic agonist, carbachol, produced very similar results, both increasing REM sleep for about 8 h, mainly through increased period frequency, with little reduction in REM latency. Pre-injection of the muscarinic antagonist, atropine, completely blocked the REM sleep-increase by GBZ. GABAergic control of REM sleep in the PnO requires the cholinergic system and may be acting through presynaptic modulation of acetylcholine release.

  5. K(Ca3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma.

    Directory of Open Access Journals (Sweden)

    Joanne Van Der Velden

    Full Text Available BACKGROUND: The Ca(2+-activated K(+ channel K(Ca3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca3.1 modifies experimental asthma in sheep. METHODOLOGY AND PRINCIPAL FINDINGS: Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073, a selective inhibitor of the K(Ca3.1-channel, or vehicle alone (0.5% methylcellulose twice daily (orally. Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; n = 10, P = 0.0147. The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; n = 10, P = 0.0288. Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; n = 10, P = 0.0340. Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling. CONCLUSIONS: These findings suggest that K(Ca3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of K(Ca3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans.

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

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


    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.

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

    Directory of Open Access Journals (Sweden)

    Jonathan eShelton


    Full Text Available 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.

  8. Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus. (United States)

    Zhang, Jianbo; Wang, Na; Chen, Bo; Wang, Yi'nan; He, Jing; Cai, Xintong; Zhang, Hongbo; Wei, Shuguang; Li, Shengbin


    Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse. Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction. However, the downstream signaling of CB1R is not fully elucidated. In the present study, we investigated the relationship between CB1R and the extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF) signaling in the nucleus accumbens (NAc) and hippocampus in morphine-induced conditioned place preference (CPP), which is used to assess the morphine-induced reward memory. The protein level of CB1R, ERK, CREB, and BDNF were detected by western blotting. Additionally, a CB1R antagonist, AM251, was used to study whether blockade of CB1R altered the CPP and above-mentioned molecules. We found an increase of CB1R expression in the NAc and hippocampus of the mice following morphine CPP, but not those after repeated morphine in home cage without context exposure (NO-CPP). Both morphine CPP and NO-CPP induced an upregulation of ERK, CREB phosphorylation and BDNF expression. Furthermore, pretreatment with AM251 before morphine attenuated the CPP acquisition and CB1R expression as well as the activation of ERK-CREB-BDNF cascade. Collectively, these findings demonstrate that (1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. (2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP.

  9. Blockade of CRF1 receptors in the central nucleus of the amygdala attenuates the dysphoria associated with nicotine withdrawal in rats. (United States)

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


    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.

  10. NTS adenosine A2a receptors inhibit the cardiopulmonary chemoreflex control of regional sympathetic outputs via a GABAergic mechanism. (United States)

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


    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.

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

    DEFF Research Database (Denmark)

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D


    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 c...

  12. 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. (United States)

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


    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.

  13. Postsynaptic blockade of inhibitory postsynaptic currents by plasmin in CA1 pyramidal cells of rat hippocampus. (United States)

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


    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.

  14. Rosuvastatin attenuates mucus secretion in a murine model of chronic asthma by inhibiting the gamma-aminobutyric acid type A receptor

    Institute of Scientific and Technical Information of China (English)

    ZHU Tao; ZHANG Wei; WANG Dao-xin; HUANG Ni-wen; BO Hong; DENG Wang; DENG Jia


    Background Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction,pulmonary inflammation and airway remodeling.Current standard therapies for asthma provide symptomatic control,but fail to target the underlying disease pathology.Furthermore,no therapeutic agent is effective in preventing airway remodeling.A substantial amount of evidence suggests that statins have anti-inflammatory properties and immunomodulatory activity.In this study,we investigated the effect of rosuvastatin on airway inflammation and its inhibitory mechanism in mucus hypersecretion in a murine model of chronic asthma.Methods BALB/c mice were sensitized and challenged by ovalbumin to induce asthma.The recruitment of inflammatory cells into bronchoalveolar lavage fluid (BALF) and the lung tissues were measured by Diff-Quik staining and hematoxylin and eosin (H&E) staining.ELISA was used for measuring the levels of IL-4,IL-5,IL-13 and TNF-α in BALF.Periodic acid-Schiff (PAS) staining was used for mucus secretion.Gamma-aminobutyric acid type A receptor (GABAAR)32 expression was measured by means of immunohistochemistry,reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.Results Rosuvastatin reduced the number of total inflammatory cells,lymphocytes,macrophages,neutrophils,and eosinophils recruited into BALF,the levels of IL-4,IL-5,IL-13 and TNF-α in BALF,along with the histological mucus index (HMI) and GABAAR β2 expression.Changes occurred in a dose-dependent manner.Conclusions Based on its ability to reduce the inflammatory response and mucus hypersecretion by regulating GABAAR activity in a murine model of chronic asthma,rosuvastatin may be a useful therapeutic agent for treatment of asthma.

  15. Traceable Coulomb Blockade Thermometry

    CERN Document Server

    Hahtela, Ossi; Kemppinen, Antti; Meschke, Matthias; Prunnila, Mika; Gunnarsson, David; Roschier, Leif; Penttila, Jari; Pekola, Jukka


    We present a measurement and analysis scheme for determining traceable thermodynamic temperature at cryogenic temperatures using Coulomb blockade thermometry. The uncertainty of the electrical measurement is improved by utilizing two sampling digital voltmeters instead of the traditional lock-in technique. The remaining uncertainty is dominated by that of the numerical analysis of the measurement data. Two analysis methods, the numerical fitting of the full conductance curve and measuring the height of the conductance dip yield almost identical results. The complete uncertainty analysis shows that the relative expanded uncertainty (k = 2) in determining the thermodynamic temperature in the temperature range from 20 mK to 200 mK is below 1 %. A good agreement within the measurement uncertainty is experimentally demonstrated between the Coulomb blockade thermometer and a superconducting reference point device that has been directly calibrated against the Provisional Low Temperature Scale of 2000.

  16. Role of 5-HT5A receptors in the consolidation of memory. (United States)

    Gonzalez, Roberto; Chávez-Pascacio, Karla; Meneses, Alfredo


    5-HT5 receptor occurs in brain areas implicated in learning and memory. Hence, the effects (0.01-3.0 mg/kg) of SB-6995516 (a 5-HT5A receptor antagonist) in the associative learning task of autoshaping were studied. The results showed that post-training injection of SB-699551 decreased conditioned responses (CR) during short-term (STM; 1.5h; at 0.1mg/kg) and long-term memory (LTM; 24 h; at 3.0 mg/kg) relative to the vehicle animals. Moreover, considering that there are no selective 5-HT5A receptor agonists, next, diverse doses of the serotonin precursor l-tryptophan were studied during STM and LTM, showing that l-tryptophan (5-100mg/kg) facilitated performance, particularly at 50mg/kg. In interactions experiments, l-tryptophan (50 mg/kg) attenuated the impairment effect induced by SB-699551 (either 0.3 or 3.0 mg/kg). All together this evidence suggests that the blockade of 5-HT5A receptor appear to be able to impair STM and LTM (24 h), while its stimulation might facilitate it. Of course further investigation is necessary, meanly with selective 5-HT5A compounds are necessary.

  17. Traceable Coulomb blockade thermometry (United States)

    Hahtela, O.; Mykkänen, E.; Kemppinen, A.; Meschke, M.; Prunnila, M.; Gunnarsson, D.; Roschier, L.; Penttilä, J.; Pekola, J.


    We present a measurement and analysis scheme for determining traceable thermodynamic temperature at cryogenic temperatures using Coulomb blockade thermometry. The uncertainty of the electrical measurement is improved by utilizing two sampling digital voltmeters instead of the traditional lock-in technique. The remaining uncertainty is dominated by that of the numerical analysis of the measurement data. Two analysis methods are demonstrated: numerical fitting of the full conductance curve and measuring the height of the conductance dip. The complete uncertainty analysis shows that using either analysis method the relative combined standard uncertainty (k  =  1) in determining the thermodynamic temperature in the temperature range from 20 mK to 200 mK is below 0.5%. In this temperature range, both analysis methods produced temperature estimates that deviated from 0.39% to 0.67% from the reference temperatures provided by a superconducting reference point device calibrated against the Provisional Low Temperature Scale of 2000.

  18. Acute serotonin 2A receptor blocking alters the processing of fearful faces in the orbitofrontal cortex and amygdala

    DEFF Research Database (Denmark)

    Hornboll, Bettina; Macoveanu, Julian; Rowe, James;


    blockade reduced the neural response to fearful faces in the medial orbitofrontal cortex (OFC), independently of 5-HT2A receptor occupancy or neocortical 5-HT2A receptor BPp . The medial OFC also showed increased functional coupling with the left amygdala during processing of fearful faces depending...

  19. Checkpoint Blockade in Cancer Immunotherapy (United States)

    Korman, Alan J.; Peggs, Karl S.; Allison, James P.


    The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade. PMID:16730267

  20. Presynaptic facilitatory adenosine A2A receptors mediate fade induced by neuromuscular relaxants that exhibit anticholinesterase activity. (United States)

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


    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.

  1. Valley blockade quantum switching in Silicon nanostructures. (United States)

    Prati, Enrico


    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.

  2. Blockade of Ethanol Reward by the Kappa Opioid Receptor Agonist U50,488h


    Logrip, Marian L.; Janak, Patricia H; Ron, Dorit


    Alcoholism is a pervasive social problem, and thus understanding factors which regulate alcohol (ethanol) reward is important for designing effective therapies. One putative regulatory system includes the kappa opioid receptor (KOR) and its endogenous ligand, dynorphin. Previously we demonstrated that acute ethanol increased preprodynorphin expression via brain-derived neurotrophic factor (BDNF) in striatal neurons, and that blockade of the KOR attenuated decreases in ethanol intake observed ...

  3. Axillary brachial plexus blockade in moyamoya disease?

    Directory of Open Access Journals (Sweden)

    Saban Yalcin


    Full Text Available Moyamoya disease is characterized by steno-occlusive changes of the intracranial internal carotid arteries. Cerebral blood flow and metabolism are strictly impaired. The goal in perioperative anaesthetic management is to preserve the stability between oxygen supply and demand in the brain. Peripheral nerve blockade allows excellent neurological status monitoring and maintains haemodynamic stability which is very important in this patient group. Herein, we present an axillary brachial plexus blockade in a moyamoya patient operated for radius fracture.

  4. Serotonin 2A receptors contribute to the regulation of risk-averse decisions

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Rowe, James B; Hornboll, Bettina


    -averse choice behavior was abolished by 5-HT2A receptor blockade. The results provide the first evidence for a critical role of 5-HT2A receptor function in regulating risk-averse behavior. We suggest that the 5-HT2A receptor system facilitates risk-taking behavior by modulating the outcome evaluation of "missed......Pharmacological studies point to a role of the neurotransmitter serotonin (5-HT) in regulating the preference for risky decisions, yet the functional contribution of specific 5-HT receptors remains to be clarified. We used pharmacological fMRI to investigate the role of the 5-HT2A receptors...... in processing negative outcomes and regulating risk-averse behavior. During fMRI, twenty healthy volunteers performed a gambling task under two conditions: with or without blocking the 5-HT2A receptors. The volunteers repeatedly chose between small, likely rewards and large, unlikely rewards. Choices were...

  5. Combined LFA-1 and costimulatory blockade prevents transplant rejection mediated by heterologous immune memory alloresponses (United States)

    Kitchens, William H.; Haridas, Divya; Wagener, Maylene E.; Song, Mingqing; Ford, Mandy L.


    Background Recent evidence suggests that alloreactive memory T cells are generated by the process of heterologous immunity, whereby memory T cells arising in response to pathogen infection cross-react with donor antigens. Due to their diminished requirements for costimulation during recall, these pathogen-elicited allo-crossreactive memory T cells are of particular clinical importance, especially given the emergence of costimulatory blockade as a transplant immunosuppression strategy. Methods We utilized an established model of heterologous immunity involving sequential infection of a naïve C57BL/6 recipient with lymphocytic choriomeningitis virus and vaccinia virus, followed by combined skin and bone marrow transplant from a BALB/c donor. Results We demonstrate that coupling the integrin antagonist anti-LFA-1 with costimulatory blockade could surmount the barrier posed by heterologous immunity in a fully allogeneic murine transplant system. The combined costimulatory and integrin blockade regimen suppressed proliferation of alloreactive memory T cells and attenuated their cytokine effector responses. This combined blockade regimen also promoted the retention of FoxP3+ Tregs in draining lymph nodes. Finally, we show that in an in vitro mixed lymphocyte reaction system using human T cells, the combination of belatacept and anti-LFA-1 was able to suppress cytokine production by alloreactive memory T cells that was resistant to belatacept alone. Conclusions As an antagonist against human LFA-1 exists and has been used clinically to treat psoriasis, these findings have significant translational potential for future clinical transplant trials. PMID:22475765

  6. Observation of ionic Coulomb blockade in nanopores (United States)

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


    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.

  7. Atomic Fock State Preparation Using Rydberg Blockade

    CERN Document Server

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


    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 $\\sqrt{N}$ Rabi frequency enhancement to within 4%. The resulting atom number distributions are consistent with essentially perfect blockade. We then use collective Rabi $\\pi$ pulses to produce ${\\cal N}=1,2$ atom number Fock states with fidelities of 62% and 48% respectively. The ${\\cal N}=2$ Fock state shows the collective Rabi frequency enhancement without corruption from atom number fluctuations.

  8. 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. (United States)

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


    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.

  9. Efficient Grover search with Rydberg blockade

    DEFF Research Database (Denmark)

    Mølmer, Klaus; Isenhower, Larry; Saffman, Mark


    We present efficient methods to implement the quantum computing Grover search algorithm using the Rydberg blockade interaction. We show that simple π-pulse excitation sequences between ground and Rydberg excited states readily produce the key conditional phase shift and inversion...

  10. Pancreatic digestive enzyme blockade in the small intestine prevents insulin resistance in hemorrhagic shock. (United States)

    DeLano, Frank A; Schmid-Schönbein, Geert W


    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

  11. Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

    Directory of Open Access Journals (Sweden)

    Fisher Jason C


    Full Text Available Abstract Vascular endothelial growth factor (VEGF blockade is an effective therapy for human cancer, yet virtually all neoplasms resume primary tumor growth or metastasize during therapy. Mechanisms of progression have been proposed to include genes that control vascular remodeling and are elicited by hypoperfusion, such as the inducible enzyme cyclooxygenase-2 (COX-2. We have previously shown that COX-2 inhibition by the celecoxib analog SC236 attenuates perivascular stromal cell recruitment and tumor growth. We therefore examined the effect of combined SC236 and VEGF blockade, using the metastasizing orthotopic SKNEP1 model of pediatric cancer. Combined treatment perturbed tumor vessel remodeling and macrophage recruitment, but did not further limit primary tumor growth as compared to VEGF blockade alone. However, combining SC236 and VEGF inhibition significantly reduced the incidence of lung metastasis, suggesting a distinct effect on prometastatic mechanisms. We found that SC236 limited tumor cell viability and migration in vitro, with effects enhanced by hypoxia, but did not change tumor proliferation or matrix metalloproteinase expression in vivo. Gene set expression analysis (GSEA indicated that the addition of SC236 to VEGF inhibition significantly reduced expression of gene sets linked to macrophage mobilization. Perivascular recruitment of macrophages induced by VEGF blockade was disrupted in tumors treated with combined VEGF- and COX-2-inhibition. Collectively, these findings suggest that during VEGF blockade COX-2 may restrict metastasis by limiting both prometastatic behaviors in individual tumor cells and mobilization of macrophages to the tumor vasculature.

  12. Identification and specific blockade of two receptors for histamine in the cardiovascular system. (United States)

    Powell, J R; Brody, M J


    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.

  13. Neuromuscular blockade during laparoscopic ventral herniotomy

    DEFF Research Database (Denmark)

    Medici, Roar; Madsen, Matias V; Asadzadeh, Sami;


    INTRODUCTION: Laparoscopic herniotomy is the preferred technique for some ventral hernias. Several factors may influence the surgical conditions, one being the depth of neuromuscular blockade (NMB) applied. We hypothesised that deep neuromuscular blockade defined as a post-tetanic count below eight...... would provide a better surgical workspace. METHODS: This was an investigator-initiated, assessor- and patient-blinded randomised cross-over study. A total of 34 patients with planned laparoscopic umbilical, incisional and linea alba herniotomy were studied. Patients would be randomised to receive deep......'s rating of surgical conditions during suturing, duration of surgery and duration of the suturing of the hernia. CONCLUSION: This randomised cross-over study investigated a potential effect on the surgical workspace in laparoscopic ventral herniotomy using deep NMB compared with no NMB. The study may...

  14. [Cancer immunotherapy by immuno-checkpoint blockade]. (United States)

    Kawakami, Yutaka


    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.

  15. Efficient Multiparticle Entanglement via Asymmetric Rydberg Blockade

    DEFF Research Database (Denmark)

    Saffman, Mark; Mølmer, Klaus


    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....

  16. hERG Blockade by Iboga Alkaloids. (United States)

    Alper, Kenneth; Bai, Rong; Liu, Nian; Fowler, Steven J; Huang, Xi-Ping; Priori, Silvia G; Ruan, Yanfei


    The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

  17. Rydberg-interaction-based quantum gates free from blockade error

    CERN Document Server

    Shi, Xiao-Feng


    Accurate quantum gates are basic elements for building quantum computers. There has been great interest in designing quantum gates by using blockade effect of Rydberg atoms recently. The fidelity and operation speed of these gates, however, are fundamentally limited by the blockade error. Here we propose another type of quantum gates, which are based on Rydberg blockade effect, yet free from any blockade error. In contrast to the `blocking' method in previous schemes, we use Rydberg energy shift to realise a rational generalised Rabi frequency so that a novel $\\pi$ phase for one input state of the gate emerges. This leads to an accurate Rydberg-blockade based two-qubit quantum gate that can operate in a $0.1\\mu s$ timescale or faster thanks to that it operates by a Rabi frequency which is comparable to the blockade shift.

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

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Ruibing [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Lihui [Shandong Normal University, Jinan, Shandong Province 250012 (China); Luo, Zheng; Guo, Xiaolan [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China); Yan, Ming, E-mail: [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)


    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.

  19. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Schaub, M; Issazadeh-Navikas, Shohreh; Stadlbauer, T H;


    Blockade of the CD28-B7 or CD40L-CD40 T cell costimulatory signals prevents induction of experimental autoimmune encephalomyelitis (EAE). However, the effect of simultaneous blockade of these signals in EAE is unknown. We show that administration of either MR1 (to block CD40L) or CTLA4Ig (to block...... cells in the periphery. Selective B7-1 blockade did not protect from EAE. These observations have implications for therapy of autoimmune diseases....

  20. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade

    DEFF Research Database (Denmark)

    Brueckmann, B; Sasaki, N; Grobara, P;


    by randomized allocation to sugammadex (2 or 4 mg kg(-1)) or usual care (neostigmine/glycopyrrolate, dosing per usual care practice) for reversal of neuromuscular blockade. Timing of reversal agent administration was based on the providers' clinical judgement. Primary endpoint was the presence of residual......BACKGROUND: This study aimed to investigate whether reversal of rocuronium-induced neuromuscular blockade with sugammadex reduced the incidence of residual blockade and facilitated operating room discharge readiness. METHODS: Adult patients undergoing abdominal surgery received rocuronium, followed...... neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio

  1. Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, D.M.; Bagby, G.J.; Lang, C.H.; Spitzer, J.J. (Louisiana State Univ., New Orleans (USA))


    Infusions of adrenergic antagonists were used to investigate the role of catecholamines in infection-induced elevations of glucose kinetics. Infection was produced in conscious catheterized rats by repeated subcutaneous injections of live Escherichia coli over 24 h. Glucose kinetics were measured by the constant intravenous infusion of (6-{sup 3}H)- and (U-{sup 14}C)glucose. Compared with noninfected rats, infected animals were hyperthermic and showed increased rates of glucose appearance, clearance, and recycling as well as mild hyperlacticacidemia. Plasma catecholamine concentrations were increased by 50-70% in the infected rats, but there were no differences in plasma glucagon, corticosterone, and insulin levels. Adrenergic blockade was produced by primed constant infusion of both propranolol ({beta}-blocker) and phentolamine ({alpha}-blocker). A 2-h administration of adrenergic antagonists did not attenuate the elevated glucose kinetics or plasma lactate concentration in the infected rats, although it abolished the hyperthermia. In a second experiment, animals were infused with propranolol and phentolamine beginning 1 h before the first injection of E. coli and throughout the course of infection. Continuous adrenergic blockade failed to attenuate infection-induced elevations in glucose kinetics and plasma lactate. These results indicate that the adrenergic system does not mediate the elevated glucose metabolism observed in this mild model of infection.

  2. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases. (United States)

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


    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.

  3. Antilocalization of Coulomb Blockade in a Ge-Si Nanowire

    DEFF Research Database (Denmark)

    Higginbotham, Andrew P.; Kuemmeth, Ferdinand; Larsen, Thorvald Wadum


    The distribution of Coulomb blockade peak heights as a function of magnetic field is investigated experimentally in a Ge-Si nanowire quantum dot. Strong spin-orbit coupling in this hole-gas system leads to antilocalization of Coulomb blockade peaks, consistent with theory. In particular, the peak...

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

    Directory of Open Access Journals (Sweden)

    Ju Hee Yoon


    Full Text Available 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.

  5. GABA(A) receptor subtype selective cognition enhancers. (United States)

    Maubach, Karen


    Currently the treatment of Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI) is largely unrealised, with no preventive or curative therapies. The marketed acetylcholinesterase inhibitors (eg. donepezil, Aricept) are directed toward temporary symptomatic relief from impaired cognition, but have prominent adverse effects with minimal efficacy. In pursuit of novel cognition enhancers, the observation that classical benzodiazepines (BZ, eg. diazepam) are amnesic, coupled with the preservation of GABA(A) receptors in brain areas most affected by AD, highlighted the GABA(A) receptor as a potential therapeutic target. In contrast to the amnesic BZ agonists, the BZ inverse agonists (eg. DMCM) which attenuate GABA(A) receptor function, have been shown to improve performance in animal models of learning and memory. Unfortunately, such non-selective ligands also induce anxiety and convulsions. More recently, novel ligands have been developed (eg. 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one) that demonstrate binding selectivity and high inverse agonism for the alpha5 GABA(A) receptor subtype, which is preferentially located in the hippocampus, a region of the brain associated with learning and memory. Pre-clinical results are encouraging, since these alpha5 selective inverse agonists enhance memory in animal models, such as spatial learning in the Morris water-maze, but are devoid of the adverse effects associated with activity at other GABA(A) receptor subtypes in other brain regions. If the efficacy and safety profiles of alpha5 inverse agonists in humans prove to be similar to those seen in pre-clinical studies, these compounds would offer significant benefit to AD and MCI patients.

  6. Ionic Coulomb Blockade and Resonant Conduction in Biological Ion Channels

    CERN Document Server

    Kaufman, I Kh; Eisenberg, R S


    The conduction and selectivity of calcium/sodium ion channels are described in terms of ionic Coulomb blockade, a phenomenon based on charge discreteness and an electrostatic model of an ion channel. This novel approach provides a unified explanation of numerous observed and modelled conductance and selectivity phenomena, including the anomalous mole fraction effect and discrete conduction bands. Ionic Coulomb blockade and resonant conduction are similar to electronic Coulomb blockade and resonant tunnelling in quantum dots. The model is equally applicable to other nanopores.

  7. Pauli Spin Blockade and the Ultrasmall Magnetic Field Effect

    KAUST Repository

    Danon, Jeroen


    Based on the spin-blockade model for organic magnetoresistance, we present an analytic expression for the polaron-bipolaron transition rate, taking into account the effective nuclear fields on the two sites. We reveal the physics behind the qualitatively different magnetoconductance line shapes observed in experiment, as well as the ultrasmall magnetic field effect (USFE). Since our findings agree in detail with recent experiments, they also indirectly provide support for the spin-blockade interpretation of organic magnetoresistance. In addition, we predict the existence of a similar USFE in semiconductor double quantum dots tuned to the spin-blockade regime.

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

    Directory of Open Access Journals (Sweden)

    Casie Lindsly

    Full Text Available 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.

  9. Alpha-adrenergic receptor blockade by phentolamine increases the efficacy of vasodilators in penile corpus cavernosum. (United States)

    Kim, N N; Goldstein, I; Moreland, R B; Traish, A M


    Penile trabecular smooth muscle tone, a major determinant of erectile function, is highly regulated by numerous inter- and intracellular pathways. The interaction between pathways mediating contraction and relaxation has not been studied in detail. To this end, we investigated the functional effects of alpha adrenergic receptor blockade with phentolamine and its interaction with vasodilators (sildenafil, vasoactive intestinal polypeptide (VIP) and PGE1) that elevate cyclic nucleotides on penile cavernosal smooth muscle contractility. In organ bath preparations of cavernosal tissue strips contracted with phenylephrine, phentolamine significantly enhanced relaxation induced by sildenafil, VIP and PGE1. Sildenafil, VIP or PGE1 also significantly enhanced relaxation induced by phentolamine in cavernosal tissue strips contracted with phenylephrine. To study the effects of alpha adrenergic receptor blockade and modification of cyclic nucleotide metabolism during active neurogenic input, cavernosal tissue strips in organ bath preparations were contracted with the non-adrenergic agonist endothelin-1 and subjected to electrical field stimulation (EFS) in the absence or presence of phentolamine and/or sildenafil. EFS (5-40Hz) typically caused biphasic relaxation and contraction responses. Phentolamine alone enhanced relaxation and reduced or prevented contraction to EFS. Sildenafil enhanced relaxation to EFS at lower frequencies (phentolamine and sildenafil enhanced EFS-induced relaxation at all frequencies tested. EFS, in the presence of 10 nM phentolamine and 30 nM sildenafil, produced enhanced relaxation responses which were quantitatively similar to those obtained in the presence of 50 nM sildenafil alone. Thus, blockade of alpha-adrenergic receptors with phentolamine increases the efficacy of cyclic nucleotide-dependent vasodilators. Furthermore, phentolamine potentiates relaxation and attenuates contraction in response to endogenous neurotransmitters which are released

  10. The effects of calcium channel blockade on agouti-induced obesity

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Jung Han; Moustaid, N.; Zemel, M.B. [Univ. of Tennessee, Knoxville, TN (United States)] [and others


    We have previously observed that obese viable yellow (A{sup vy}/a) mice exhibit increased intracellular Ca{sup 2+} ([Ca{sup 2+}]i) and fatty acid synthase (FAS) gene expression; further, recombinant agouti protein increases in cultured adipocytes and these effects are inhibited by Ca{sup 2+} channel blockade. Accordingly, we determined the effect of Ca{sup 2+} channel blockade (nifedipine for 4 wk) on FAS and obesity in transgenic mice expressing the agouti gene in a ubiquitous manner. The transgenic mice initially were significantly heavier (30.5 {+-} 0.6 vs. 27.3 {+-} 0.3 g; P<0.001) and exhibited a 0.81{degrees}C lower initial core temperature (P<0.0005), an approximately twofold increase in fat pad weights (P=0.002), a sevenfold increase in adipose FAS activity (P=0.009), and a twofold increase in plasma insulin level (P<0.05) compared to control mice. Nifedipine treatment resulted in an 18% decrease in fat pad weights (P<0.007) and a 74% decrease in adipose FAS activity (P=0.03), normalized circulating insulin levels and insulin sensitivity (P,0.05), and transiently elevated core temperature in the transgenic mice, but was without effect in the control mice. These data suggest that agouti regulates FAS, fat storage, and possibly thermogenesis, at least partially, via a [Ca{sup 2+}]{sub i}-dependent mechanism, and that Ca{sup 2+} channel blockade may partially attenuate agouti-induced obesity. 42 refs., 4 figs., 1 tab.

  11. 5-HT1A receptor blockade reverses GABA(A) receptor alpha(3) subunit-mediated anxiolytic effects on stress-induced hyperthermia

    NARCIS (Netherlands)

    Vinkers, Christiaan H.; van Oorschot, Ruud; Korte, S. Mechiel; Olivier, Berend; Groenink, Lucianne


    Stress-related disorders are associated with dysfunction of both serotonergic and GABAergic pathways, and clinically effective anxiolytics act via both neurotransmitter systems. As there is evidence that the GABA(A) and the serotonin receptor system interact, a serotonergic component in the anxiolyt

  12. Checkpoint Blockade in Cancer Immunotherapy: Squaring the Circle

    Directory of Open Access Journals (Sweden)

    Maria A.V. Marzolini


    Full Text Available Manipulating the complex interaction between the immune system and tumour cells has been the focus of cancer research for many years, but it is only in the past decade that significant progress has been made in the field of cancer immunotherapy resulting in clinically effective treatments. The blockade of co-inhibitory immune checkpoints, essential for maintaining lymphocyte homeostasis and self-tolerance, by immunomodulatory monoclonal antibodies has resulted in the augmentation of anti-tumour responses. The greatest successes so far have been seen with the blockade of cytotoxic T lymphocyte associated antigen-4, which has resulted in the first Phase III clinical trial showing an overall survival benefit in metastatic melanoma, and in the blockade of the programmed cell death protein-1 axis. This concise review will focus on the clinical advances made by the blockade of these two pathways and their role in current cancer treatment strategies.

  13. Dipole blockade in a cold Rydberg atomic sample

    CERN Document Server

    Comparat, Daniel; 10.1364/JOSAB.27.00A208


    We review here the studies performed about interactions in an assembly of cold Rydberg atoms. We focus more specially the review on the dipole-dipole interactions and on the effect of the dipole blockade in the laser Rydberg excitation, which offers attractive possibilities for quantum engineering. We present first the various interactions between Rydberg atoms. The laser Rydberg excitation of such an assembly is then described with the introduction of the dipole blockade phenomenon. We report recent experiments performed in this subject by starting with the case of a pair of atoms allowing the entanglement of the wave-functions of the atoms and opening a fascinating way for the realization of quantum bits and quantum gates. We consider then several works on the blockade effect in a large assembly of atoms for three different configurations: blockade through electric-field induced dipole, through F\\"orster resonance and in van der Waals interaction. The properties of coherence and cooperativity are analyzed. ...

  14. Rydberg blockade effects at n ˜300 in strontium (United States)

    Zhang, X.; Dunning, F. B.; Yoshida, S.; Burgdörfer, J.


    Rydberg blockade at n ˜300 , is examined using strontium n F13 Rydberg atoms excited in an atomic beam in a small volume defined by two tightly focused crossed laser beams. The observation of blockade for such states is challenging due to their extreme sensitivity to stray fields and the many magnetic sublevels associated with F states which results in a high local density of states. Nonetheless, with a careful choice of laser polarization to selectively excite only a limited number of these sublevels, sizable blockade effects are observed on an ˜0.1 mm length scale extending blockade measurements into the near-macroscopic regime and enabling study of the dynamics of strongly coupled many-body high-n Rydberg systems under carefully controlled conditions.

  15. Blockade involving high- n, n ~ 300 , strontium Rydberg atoms (United States)

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


    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.

  16. Aldosterone blockade in post-acute myocardial infarction heart failure

    NARCIS (Netherlands)

    Pitt, Bertram; Ferrari, Roberto; Gheorghiade, Mihai; van Veldhuisen, Dirk J.; Krum, Henry; McMurray, John; Lopez-Sendon, Jose


    Development of heart failure (HF) or left ventricular systolic dysfunction (LVSD) significantly increases mortality post acute myocardial infarction (AMI). Aldosterone contributes to the development and progression of HF post AMI, and major guidelines now recommend aldosterone blockade in this setti

  17. Transport Through a Coulomb Blockaded Majorana Nanowire (United States)

    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.


    Institute of Scientific and Technical Information of China (English)

    王太宏; 李宏伟; 周均铭


    Coulomb blockade oscillations of Si single-electron transistors, which are fabricated completely by the conventional photolithography technique, have been investigated. Most of the single-electron transistors clearly show Coulomb blockade oscillations and these oscillations can be periodic by applying negative voltages to the in-plane gates. A shift of the peak positions is observed at high temperatures. It is also found that the fluctuation of the peak spacing cannot be neglected.

  19. Parasympathetic blockade attenuates augmented pancreatic polypeptide but not insulin secretion in Pima Indians

    DEFF Research Database (Denmark)

    de Courten, Barbora; Weyer, Christian; Stefan, Norbert


    There is evidence from animal models of obesity and type 2 diabetes that increased parasympathetic vagal input to the pancreas contributes to hyperinsulinemia. Compared with Caucasians, Pima Indians have a high risk of type 2 diabetes and exhibit marked hyperinsulinemia and elevated plasma levels...

  20. Photonic Crystal Fiber Attenuator

    Institute of Scientific and Technical Information of China (English)

    Joo; Beom; Eom; Hokyung; Kim; Jinchae; Kim; Un-Chul; Paek; Byeong; Ha; Lee


    We propose a novel fiber attenuator based on photonic crystal fibers. The difference in the modal field diameters of a conventional single mode fiber and a photonic crystal fiber was used. A variable optical attenuator was also achieved by applying macro-bending on the PCF part of the proposed attenuator

  1. Tracer attenuation in groundwater (United States)

    Cvetkovic, Vladimir


    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.

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

    Directory of Open Access Journals (Sweden)

    Takuya Kishi


    Full Text Available 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.

  3. Enhancement of Adipocyte Browning by Angiotensin II Type 1 Receptor Blockade (United States)

    Tsukuda, Kana; Mogi, Masaki; Iwanami, Jun; Kanno, Harumi; Nakaoka, Hirotomo; Wang, Xiao-Li; Bai, Hui-Yu; Shan, Bao-Shuai; Kukida, Masayoshi; Higaki, Akinori; Yamauchi, Toshifumi; Min, Li-Juan; Horiuchi, Masatsugu


    Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named ‘beige’ or ‘brite’ adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders. PMID:27992452

  4. Exploring dipole blockade using high- n strontium Rydberg atoms (United States)

    Zhang, Xinyue; Ye, Shuzhen; Dunning, F. Barry; Hiller, Moritz; Yoshida, Shuhei; Burgdörfer, Joachim


    Studies of the production of strongly-polarized quasi-1D high- n, n ~ 300 , strontium `` nF'' Rydberg states in an atomic beam by three-photon excitation in a weak dc field suggest that (in the absence of blockade effects) densities of ~106 cm-3 might be achieved. At such densities the interparticle separation, ~ 100 μm , becomes comparable to that at which dipole blockade effects are expected to become important. Apparatus modifications are underway to allow the exploration of blockade at very high- n and the effects of the high energy level density. Blockade is also being examined through calculations of the energy spectrum for two interaction atoms. Access to the blockade regime promises creation of Rydberg atoms at well-defined separations whose interactions can be coherently controlled using electric field pulses thereby enabling study of the dynamics of strongly-coupled Rydberg systems. Research supported by the NSF, the Robert A. Welch Foundation, and the FWF (Austria).

  5. Renin-angiotensin system blockade: Its contribution and controversy. (United States)

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


    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.

  6. 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception. (United States)

    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


    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.

  7. Blockade of glutamatergic transmission in the primate basolateral amygdala suppresses active behavior without altering social interaction. (United States)

    Forcelli, Patrick A; Wellman, Laurie L; Malkova, Ludise


    The amygdala is an integrator of affective processing, and a key component of a network regulating social behavior. While decades of lesion studies in nonhuman primates have shown alterations in social interactions after amygdala damage, acute manipulations of the amygdala in primates have been underexplored. We recently reported (Wellman, Forcelli, Aguilar, & Malkova, 2016) that acute pharmacological inhibition of the basolateral complex of the amygdala (BLA) or the central nucleus of the amygdala increased affiliative social interactions in experimental dyads of macaques; this was achieved through microinjection of a GABA-A receptor agonist. Prior studies in rodents have shown similar effects achieved by blocking NMDA receptors or AMPA receptors within the BLA. Here, we sought to determine the role of these receptor systems in the primate BLA in the context of social behavior. In familiar dyads, we microinjected the NMDA receptor antagonist 2-amino-7-phosphonoheptanoic acid (AP7) or the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) and observed behaviors and social interactions in the immediate postinjection period. In striking contrast with our prior report using GABA agonists, and in contrast with prior reports in rodents using glutamate antagonists, we found that neither NMDA nor AMPA blockade increase social interaction. Both treatments, however, were associated with decreases in locomotion and manipulation and increases in passive behavior. These data suggest that local blockade of glutamatergic neurotransmission in BLA is not the functional equivalent of local activation of GABAergic signaling, and raise interesting questions regarding the functional microcircuitry of the nonhuman primate amygdala in the context of social behavior. (PsycINFO Database Record

  8. Stellate ganglion blockade for analgesia following upper limb surgery.

    LENUS (Irish Health Repository)

    McDonnell, J G


    We report the successful use of a stellate ganglion block as part of a multi-modal postoperative analgesic regimen. Four patients scheduled for orthopaedic surgery following upper limb trauma underwent blockade of the stellate ganglion pre-operatively under ultrasound guidance. Patients reported excellent postoperative analgesia, with postoperative VAS pain scores between 0 and 2, and consumption of morphine in the first 24 h ranging from 0 to 14 mg. While these are preliminary findings, and must be confirmed in a clinical trial, they highlight the potential for stellate ganglion blockade to provide analgesia following major upper limb surgery.

  9. Multibit CkNOT quantum gates via Rydberg blockade

    DEFF Research Database (Denmark)

    Isenhower, L.; Saffman, Mark; Mølmer, Klaus


    Long range Rydberg blockade interactions have the potential for efficient implementation of quantum gates between multiple atoms. Here we present and analyze a protocol for implementation of a k-atom controlled NOT (CkNOT) neutral atom gate. This gate can be implemented using sequential or simult......Long range Rydberg blockade interactions have the potential for efficient implementation of quantum gates between multiple atoms. Here we present and analyze a protocol for implementation of a k-atom controlled NOT (CkNOT) neutral atom gate. This gate can be implemented using sequential...

  10. Spin and polarized current from Coulomb blockaded quantum dots. (United States)

    Potok, R M; Folk, J A; Marcus, C M; Umansky, V; Hanson, M; Gossard, A C


    We report measurements of spin transitions for GaAs quantum dots in the Coulomb blockade regime and compare ground and excited state transport spectroscopy to direct measurements of the spin polarization of emitted current. Transport spectroscopy reveals both spin-increasing and spin-decreasing transitions, as well as higher-spin ground states, and allows g factors to be measured down to a single electron. The spin of emitted current in the Coulomb blockade regime, measured using spin-sensitive electron focusing, is found to be polarized along the direction of the applied magnetic field regardless of the ground state spin transition.

  11. Combination approaches with immune checkpoint blockade in cancer therapy

    Directory of Open Access Journals (Sweden)

    Maarten Swart


    Full Text Available In healthy individuals, immune checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune checkpoint blockade of cytotoxic T lymphocyte antigen-4 (CTLA-4 and programmed death-1 (PD-1 emerged as promising strategies to activate anti-tumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune checkpoint blockade, aimed at increasing response-rates to the single treatments.

  12. Neural Blockade for Persistent Pain After Breast Cancer Surgery

    DEFF Research Database (Denmark)

    Wijayasinghe, Nelun; Andersen, Kenneth Geving; Kehlet, Henrik


    Persistent pain after breast cancer surgery is predominantly a neuropathic pain syndrome affecting 25% to 60% of patients and related to injury of the intercostobrachial nerve, intercostal nerves, and other nerves in the region. Neural blockade can be useful for the identification of nerves...... involved in neuropathic pain syndromes or to be used as a treatment in its own right. The purpose of this review was to examine the evidence for neural blockade as a potential diagnostic tool or treatment for persistent pain after breast cancer surgery. In this systematic review, we found only 7 studies (n...

  13. Pharmacology of the hypothermic response to 5-HT1A receptor activation in humans. (United States)

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


    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.

  14. The 5-HT2A receptor antagonist M100907 produces antiparkinsonian effects and decreases striatal glutamate

    Directory of Open Access Journals (Sweden)

    Twum eAnsah


    Full Text Available 5-HT plays a regulatory role in voluntary movements of the basal ganglia and have a major impact on disorders of the basal ganglia such as Parkinson’s disease (PD. Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of Parkinson’s disease.

  15. Peripheral metabolic effects of endocannabinoids and cannabinoid receptor blockade. (United States)

    Engeli, Stefan


    The endocannabinoid system consists of endogenous arachidonic acid derivates that activate cannabinoid receptors. The two most prominent endocannabinoids are anandamide and 2-arachidonoyl glycerol. In obesity, increased concentrations of circulating and tissue endocannabinoid levels have been described, suggesting increased activity of the endocannabinoid system. Increased availability of endocannabinoids in obesity may over-stimulate cannabinoid receptors. Blockade of cannabinoid type 1 (CB1) receptors was the only successful clinical development of an anti-obesity drug during the last decade. Whereas blockade of CB1 receptors acutely reduces food intake, the long-term effects on metabolic regulation are more likely mediated by peripheral actions in liver, skeletal muscle, adipose tissue, and the pancreas. Lipogenic effects of CB1 receptor signalling in liver and adipose tissue may contribute to regional adipose tissue expansion and insulin resistance in the fatty liver. The association of circulating 2-arachidonoyl glycerol levels with decreased insulin sensitivity strongly suggests further exploration of the role of endocannabinoid signalling for insulin sensitivity in skeletal muscle, liver, and adipose tissue. A few studies have suggested a specific role for the regulation of adiponectin secretion from adipocytes by endocannabinoids, but that has to be confirmed by more experiments. Also, the potential role of CB1 receptor blockade for the stimulation of energy expenditure needs to be studied in the future. Despite the current discussion of safety issues of cannabinoid receptor blockade, these findings open a new and exciting perspective on endocannabinoids as regulators of body weight and metabolism.

  16. Optimising abdominal space with deep neuromuscular blockade in gynaecologic laparoscopy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Gätke, M R; Springborg, H H


    neuromuscular blockade (NMB) would enlarge surgical space, measured as the distance from the sacral promontory to the trocar in patients undergoing gynaecologic laparoscopy. METHODS: Fourteen patients were randomised in an assessor-blinded crossover design. The distance from the sacral promontory to the trocar...

  17. Is deep neuromuscular blockade beneficial in laparoscopic surgery?

    DEFF Research Database (Denmark)

    Madsen, M V; Staehr-Rye, A K; Claudius, C;


    BACKGROUND: Deep neuromuscular blockade during laparoscopic surgery may provide some clinical benefit. We present the 'Pro-' argument in this paired position paper. METHODS: We reviewed recent evidence from a basic database of references which we agreed on with the 'Con-' side, and present this i...

  18. Sodium intake, RAAS-blockade and progressive renal disease

    NARCIS (Netherlands)

    de Borst, Martin H; Navis, Gerjan


    Pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin converting enzyme inhibitors or angiotensin receptor blockers is the current standard treatment to prevent progressive renal function loss in patients with chronic kidney disease. Yet in many patients the rena

  19. Entanglement of two ground state neutral atoms using Rydberg blockade

    DEFF Research Database (Denmark)

    Miroshnychenko, Yevhen; Browaeys, Antoine; Evellin, Charles;


    We report on our recent progress in trapping and manipulation of internal states of single neutral rubidium atoms in optical tweezers. We demonstrate the creation of an entangled state between two ground state atoms trapped in separate tweezers using the effect of Rydberg blockade. The quality...... of the entanglement is measured using global rotations of the internal states of both atoms....

  20. Topological matter with collective encoding and Rydberg blockade

    DEFF Research Database (Denmark)

    Nielsen, Anne E. B.; Mølmer, Klaus


    We propose to use a permutation symmetric sample of multilevel atoms to simulate the properties of topologically ordered states. The Rydberg blockade interaction is used to prepare states of the sample which are equivalent to resonating valence bond states, Laughlin states, and string-net condens......-net condensates and to create and study the properties of their quasi-particle-like fundamental excitations....

  1. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse


    Tumor responses to programmed cell death protein 1 (PD-1) blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated, and single-cell infiltrates were analyzed by multi...

  2. Coulomb blockade and superuniversality of the theta angle

    NARCIS (Netherlands)

    Burmistrov, I.S.; Pruisken, A.M.M.


    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 f

  3. Why not treat human cancer with interleukin-1 blockade?

    NARCIS (Netherlands)

    Dinarello, C.A.


    The clinical successes of targeting angiogenesis provide a basis for trials of interleukin-1 (IL-1) blockade and particularly anti-IL-1beta as an add-on therapy in human metastatic disease. In animal studies for over 20 years, IL-1 has been demonstrated to increase adherence of tumor cells to the en

  4. Non-linear HRV indices under autonomic nervous system blockade. (United States)

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


    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.

  5. Merchant Shipping in a Chinese Blockade of Taiwan (United States)


    8:14:41 AM Color profile: Disabled Composite Default screen privateers, and blockade runners risking death in conflicts to which they had no...particular vessel at any given time, then, can be a challenging endeavor in- volving a maze of corporate relationships and contractual legalese. But more

  6. Benefits and harms of perioperative beta-blockade

    DEFF Research Database (Denmark)

    Wetterslev, Jørn; Juul, Anne Benedicte


    randomized trials. However, confidence intervals of the intervention effects in the meta-analyses are wide, leaving room for both benefits and harms. The largest observational study performed suggests that perioperative beta-blockade is associated with higher mortality in patients with low cardiac risk...

  7. Effect of spinal sympathetic blockade upon postural changes of blood flow in human peripheral tissues

    DEFF Research Database (Denmark)

    Skagen, K; Haxholdt, O; Henriksen, O


    local nervous blockade was induced by Lidocaine in 133Xe labelled subcutaneous tissue on one side. During epidural blockade and tilt blood flow increased by 12% whereas blood flow decreased by 30% on the control side. Thus epidural blockade had no influence on the vasoconstrictor response...

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yuanyuan; Yuan, Fahuan; Cao, Xuejiao [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Zhai, Zhifang [Department of Dermatology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Gang Huang [Department of Medical Genetics, Third Military Medical University, Chongqing 430038 (China); Du, Xiang; Wang, Yiqin; Zhang, Jingbo; Huang, Yunjian; Zhao, Jinghong [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China); Hou, Weiping, E-mail: [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)


    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. Landing gear noise attenuation (United States)

    Moe, Jeffrey W. (Inventor); Whitmire, Julia (Inventor); Kwan, Hwa-Wan (Inventor); Abeysinghe, Amal (Inventor)


    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.

  10. Adenosine A2A receptors and A2A receptor heteromers as key players in striatal function

    Directory of Open Access Journals (Sweden)

    Sergi eFerre


    Full Text Available A very significant density of adenosine adenosine A2A receptors (A2ARs is present in the striatum, where they are preferentially localized postsynaptically in striatopallidal medium spiny neurons (MSNs. In this localization A2ARs establish reciprocal antagonistic interactions with dopamine D2 receptors (D2Rs. In one type of interaction, A2AR and D2R are forming heteromers and, by means of an allosteric interaction, A2AR counteracts D2R-mediated inhibitory modulation of the effects of NMDA receptor stimulation in the striato-pallidal neuron. This interaction is probably mostly responsible for the locomotor depressant and activating effects of A2AR agonist and antagonists, respectively. The second type of interaction involves A2AR and D2R that do not form heteromers and takes place at the level of adenylyl-cyclase (AC. Due to a strong tonic effect of endogenous dopamine on striatal D2R, this interaction keeps A2AR from signaling through AC. However, under conditions of dopamine depletion or with blockade of D2R, A2AR-mediated AC activation is unleashed with an increased gene expression and activity of the striato-pallidal neuron and with a consequent motor depression. This interaction is probably the main mechanism responsible for the locomotor depression induced by D2R antagonists. Finally, striatal A2ARs are also localized presynaptically, in cortico-striatal glutamatergic terminals that contact the striato-nigral MSN. These presynaptic A2ARs heteromerize with A1 receptors (A1Rs and their activation facilitates glutamate release. These three different types of A2ARs can be pharmacologically dissected by their ability to bind ligands with different affinity and can therefore provide selective targets for drug development in different basal ganglia disorders.

  11. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy (United States)

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B.


    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing. PMID:27847783

  12. Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy. (United States)

    Swart, Maarten; Verbrugge, Inge; Beltman, Joost B


    In healthy individuals, immune-checkpoint molecules prevent autoimmune responses and limit immune cell-mediated tissue damage. Tumors frequently exploit these molecules to evade eradication by the immune system. Over the past years, immune-checkpoint blockade of cytotoxic T lymphocyte antigen-4 and programed death-1 emerged as promising strategies to activate antitumor cytotoxic T cell responses. Although complete regression and long-term survival is achieved in some patients, not all patients respond. This review describes promising, novel combination approaches involving immune-checkpoint blockade in the context of the cancer-immunity cycle, aimed at increasing response rates to the single treatments. Specifically, we discuss combinations that promote antigen release and presentation, that further amplify T cell activation, that inhibit trafficking of regulatory T cells or MSDCs, that stimulate intratumoral T cell infiltration, that increase cancer recognition by T cells, and that stimulate tumor killing.

  13. Lifting the Franck-Condon blockade in driven quantum dots (United States)

    Haughian, Patrick; Walter, Stefan; Nunnenkamp, Andreas; Schmidt, Thomas L.


    Electron-vibron coupling in quantum dots can lead to a strong suppression of the average current in the sequential tunneling regime. This effect is known as Franck-Condon blockade and can be traced back to an overlap integral between vibron states with different electron numbers which becomes exponentially small for large electron-vibron coupling strength. Here, we investigate the effect of a time-dependent drive on this phenomenon, in particular the effect of an oscillatory gate voltage acting on the electronic dot level. We employ two different approaches: perturbation theory based on nonequilibrium Keldysh Green's functions and a master equation in Born-Markov approximation. In both cases, we find that the drive can lift the blockade by exciting vibrons. As a consequence, the relative change in average current grows exponentially with the drive strength.

  14. PD-1 blockade expands intratumoral T memory cells (United States)

    Ribas, Antoni; Shin, Daniel Sanghoon; Zaretsky, Jesse; Frederiksen, Juliet; Cornish, Andrew; Avramis, Earl; Seja, Elizabeth; Kivork, Christine; Siebert, Janet; Kaplan-Lefko, Paula; Wang, Xiaoyan; Chmielowski, Bartosz; Glaspy, John A.; Tumeh, Paul C.; Chodon, Thinle; Pe’er, Dana; Comin-Anduix, Begoña


    Tumor responses to PD-1 blockade therapy are mediated by T cells, which we characterized in 102 tumor biopsies obtained from 53 patients treated with pembrolizumab, an antibody to PD-1. Biopsies were dissociated and single cell infiltrates were analyzed by multicolor flow cytometry using two computational approaches to resolve the leukocyte phenotypes at the single cell level. There was a statistically significant increase in the frequency of T cells in patients who responded to therapy. The frequency of intratumoral B cells and monocytic myeloid-derived suppressor cells (moMDSCs) significantly increased in patients’ biopsies taken on treatment. The percentage of cells with a T regulatory phenotype, monocytes, and NK cells did not change while on PD-1 blockade therapy. CD8+ T memory cells were the most prominent phenotype that expanded intratumorally on therapy. However, the frequency of CD4+ T effector memory cells significantly decreased on treatment, whereas CD4+ T effector cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 were detected in two patients with regressing melanoma. In conclusion, PD-1 blockade increases the frequency of T cells, B cells, and MDSCs in tumors, with the CD8+ T effector memory subset being the major T-cell phenotype expanded in patients with a response to therapy. PMID:26787823

  15. Neuromuscular blockade in cardiac surgery: An update for clinicians

    Directory of Open Access Journals (Sweden)

    Hemmerling Thomas


    Full Text Available There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

  16. Intrathecal rimantadine induces motor, proprioceptive, and nociceptive blockades in rats. (United States)

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


    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.

  17. Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders. (United States)

    Zhong, Chunlong; Luo, Qizhong; Jiang, Jiyao


    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.

  18. Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine. (United States)

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


    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.

  19. Planetary Ices Attenuation Properties (United States)

    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.

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

    Scislo, Tadeusz J; O'Leary, Donal S


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

    Kiyatkin, E A


    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.

  2. Lower lid entropion secondary to treatment with alpha-1a receptor antagonist: a case report

    Directory of Open Access Journals (Sweden)

    Simcock Peter


    Full Text Available Abstract Introduction The use of alpha-1a receptor antagonists (tamsulosin is widely accepted in the treatment of benign prostatic hypertrophy (BPH. It has previously been implicated as a causative agent in intra-operative floppy iris syndrome due to its effects on the smooth muscle. We report a case of lower lid entropion that may be related to a patient commencing treatment of tamsulosin. Case presentation A 74-year-old Caucasian man was started on alpha 1-a receptor antagonist (Tamsulosin treatment for benign prostatic hypertrophy. Eight days later, he presented to the ophthalmology unit with a right lower lid entropion which was successfully treated surgically with a Weiss procedure. Conclusion We report a case of lower lid entropion that may be secondary to the recent use of an alpha-1a blocker (tamsulosin. This can be explained by considering the effect of autonomic blockade on alpha-1 receptors in the Muller's muscle on a patient that may already have an anatomical predisposition to entropion formation due to a further reduction in muscle tone.

  3. Frequency Dependent Attenuation Revisited

    CERN Document Server

    Richard, Kowar; Xavier, Bonnefond


    The work is inspired by thermo-and photoacoustic imaging, where recent efforts are devoted to take into account attenuation and varying wave speed parameters. In this paper we study causal equations describing propagation of attenuated pressure waves. We review standard models like frequency power laws and and the thermo-viscous equation. The lack of causality of standard models in the parameter range relevant for photoacoustic imaging requires to derive novel equations. The main ingredients for deriving causal equations are the Kramers-Kronig relation and the mathematical concept of linear system theory. The theoretical results of this work are underpined by numerical experiments.

  4. Effects of adductor-canal-blockade on pain and ambulation after total knee arthroplasty

    DEFF Research Database (Denmark)

    Jenstrup, M T; Jæger, P; Lund, J;


    Total knee arthroplasty (TKA) is associated with intense post-operative pain. Besides providing optimal analgesia, reduction in side effects and enhanced mobilization are important in this elderly population. The adductor-canal-blockade is theoretically an almost pure sensory blockade. We...... hypothesized that the adductor-canal-blockade may reduce morphine consumption (primary endpoint), improve pain relief, enhance early ambulation ability, and reduce side effects (secondary endpoints) after TKA compared with placebo....

  5. Effect of epidural blockade and oxygen therapy on changes in subcutaneous oxygen tension after abdominal surgery

    DEFF Research Database (Denmark)

    Rosenberg, J; Pedersen, U; Erichsen, C J


    oxygen tension, arterial oxygen saturation, heart rate, and skin temperature on the day after operation, and arterial blood for gas analysis was drawn every 15 min during the study. A fluid challenge (10 ml saline/kg body wt) did not alter any of the measured values. The epidural blockade did not change...... any of the measured values. Oxygen therapy before epidural blockade increased median subcutaneous oxygen tension from 60 to 71 mmHg (P tension with oxygen therapy was 30 (15-55) min...... without epidural blockade and 15 (10-20) min with blockade (P tension with or without oxygen therapy after elective uncomplicated major abdominal surgery....

  6. Prolonged nerve blockade in a patient treated with lithium

    Directory of Open Access Journals (Sweden)

    Lehavi A


    Full Text Available Amit Lehavi, Boris Shenderey, Yeshayahu (Shai KatzDepartment of Anesthesiology, Rambam Health Care Campus, Haifa, IsraelAbstract: We report a case of a patient, chronically treated with oral lithium, who presented with an extremely prolonged (42-hour duration of sensory and motor paralysis following an uneventful infraclavicular block for hand surgery that was performed under ultrasound guidance using bupivacaine and lidocaine. Due to its direct effect on nerve conduction of action potential, we propose that lithium may have had a role in the unusually prolonged duration of a peripheral nerve block.Keywords: nerve blockade, lithium, duration, anesthesia

  7. Quantum confinement and Coulomb blockade in isolated nanodiamond crystallites (United States)

    Bolker, Asaf; Saguy, Cecile; Tordjman, Moshe; Kalish, Rafi


    We present direct experimental evidence of quantum confinement effects in single isolated nanodiamonds by scanning tunneling spectroscopy. For grains smaller than 4.5 nm, the band gap was found to increase with decreasing nanodiamond size and a well-defined, evenly spaced, 12-peak structure was observed on the conduction band side of the conductance curves. We attribute these peaks to the Coulomb blockade effect, reflecting the 12-fold degeneracy of the first electron-energy level in the confined nanodiamond. The present results shed light on the size dependence of the electronic properties of single nanodiamonds and are of major importance for future nanodiamond-based applications.

  8. The serotonin 5-Hydroxytryptaphan1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, stimulates sympathetic-dependent increases in venous tone during hypovolemic shock. (United States)

    Tiniakov, Ruslan; Scrogin, Karie E


    Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.

  9. Adenosine A2A receptor and ecto-5'-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE). (United States)

    Barros-Barbosa, Aurora R; Ferreirinha, Fátima; Oliveira, Ângela; Mendes, Marina; Lobo, M Graça; Santos, Agostinho; Rangel, Rui; Pelletier, Julie; Sévigny, Jean; Cordeiro, J Miguel; Correia-de-Sá, Paulo


    Refractoriness to existing medications of up to 80 % of the patients with mesial temporal lobe epilepsy (MTLE) prompts for finding new antiepileptic drug targets. The adenosine A2A receptor emerges as an interesting pharmacological target since its excitatory nature partially counteracts the dominant antiepileptic role of endogenous adenosine acting via inhibitory A1 receptors. Gain of function of the excitatory A2A receptor has been implicated in a significant number of brain pathologies commonly characterized by neuronal excitotoxicity. Here, we investigated changes in the expression and cellular localization of the A2A receptor and of the adenosine-generating enzyme, ecto-5'-nucleotidase/CD73, in the hippocampus of control individuals and MTLE human patients. Western blot analysis indicates that the A2A receptor is more abundant in the hippocampus of MTLE patients compared to control individuals. Immunoreactivity against the A2A receptor predominates in astrocytes staining positively for the glial fibrillary acidic protein (GFAP). No co-localization was observed between the A2A receptor and neuronal cell markers, like synaptotagmin 1/2 (nerve terminals) and neurofilament 200 (axon fibers). Hippocampal astrogliosis observed in MTLE patients was accompanied by a proportionate increase in A2A receptor and ecto-5'-nucleotidase/CD73 immunoreactivities. Given our data, we hypothesize that selective blockade of excessive activation of astrocytic A2A receptors and/or inhibition of surplus adenosine formation by membrane-bound ecto-5'-nucleotidase/CD73 may reduce neuronal excitability, thus providing a novel therapeutic target for drug-refractory seizures in MTLE patients.

  10. CTLA4 blockade broadens the peripheral T cell receptor repertoire (United States)

    Robert, Lidia; Tsoi, Jennifer; Wang, Xiaoyan; Emerson, Ryan; Homet, Blanca; Chodon, Thinle; Mok, Stephen; Huang, Rong Rong; Cochran, Alistair J.; Comin-Anduix, Begonya; Koya, Richard C.; Graeber, Thomas G.; Robins, Harlan; Ribas, Antoni


    Purpose To evaluate the immunomodulatory effects of CTLA-4 blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). Experimental Design We used next generation sequencing to study the complementarity determining region 3 (CDR3) from the rearranged T cell receptor (TCR) variable beta (V-beta) in PBMC of 21 patients, at baseline and 30–60 days after receiving tremelimumab. Results After receiving tremelimumab there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (p=0.01) and for Shannon index diversity (p=0.04). In comparison, serially collected PBMC from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over one year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared to patients without toxicity (p=0.05). No relevant differences were noted between clinical responders and non-responders. Conclusions CTLA4 blockade with tremelimumab diversifies the peripheral T cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system. PMID:24583799

  11. Emerging role of checkpoint blockade therapy in lymphoma (United States)

    Galanina, Natalie; Kline, Justin; Bishop, Michael R.


    Following the successful application of immune checkpoint blockade therapy (CBT) in refractory solid tumors, it has recently gained momentum as a promising modality in the treatment of relapsed lymphoma. This significant therapeutic advance stems from decades of research that elucidated the role of immune regulation pathways and the mechanisms by which tumors can engage these critical pathways to escape immune detection. To date, two main pathways, the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1), have emerged as key targets of CBT demonstrating unprecedented activity particularly in heavily pretreated relapsed/refractory Hodgkin lymphoma and some forms of non-Hodgkin disease. Herein we provide a brief discussion of checkpoint blockade in the context of lymphoma biology with a specific focus on novel checkpoint inhibitors and their therapeutic activity. We discuss current clinical trials and the landscape of CBT to underscore both the remarkable progress and foreseeable limitations of this novel treatment strategy. In particular, we build upon state-of-the-art knowledge and clinical insights gained from the early trials to review potential approaches to how CBT may be integrated with other treatment modalities, including chemoimmunotherapy to improve patient outcomes in the future. Finally, as the role of CBT evolves to potentially become a cornerstone of therapy in refractory/relapsed lymphoma, we briefly emphasize the importance of predictive biomarkers in an effort to select appropriate patients who are most likely to derive benefit from CBT. PMID:28203344

  12. Immunomodulation by gadolinium chloride-induced Kupffer cell phagocytosis blockade

    Energy Technology Data Exchange (ETDEWEB)

    Lazar, G.; Husztik, E.; Kiss, I.; Szakacs, J. [Albert Szent-Gyoergyi Medical Univ., Szeged (Hungary). Inst. of Pathophysiology; Lazar, G. Jr. [Department of Surgery, Albert Szent-Gyoergyi Medical University, PO Box 531, 6701 Szeged (Hungary); Olah, J. [Department of Dermatology, Albert Szent-Gyoergyi Medical University, PO Box 531, 6701 Szeged (Hungary)


    Gadolinium chloride (GdCl{sub 3}), a rare earth metal salt, depresses macrophage activity, and is commonly used to study the physiology of the reticuloendothelial system. In the present work, the effect of GdCl{sub 3}-induced Kupffer cell blockade on the humoral immune response in mice to sheep red blood cells (SRBC) was investigated. Kupffer cell phagocytosis blockade was found to increase both the primary and secondary immune responses to SRBC. The primary immune response was significantly augmented in animals injected intravenously with GdCl{sub 3} 2, 3 or 4 days before injection of the cellular antigen, but GdCl{sub 3} injected 7 days before the antigen did not modify the immune response. Increased secondary humoral immune responses were also observed. When GdCl{sub 3} was injected 2 days before the second dose of antigen, the numbers of both IgM and IgG-producing plaque forming cells were augmented. GdCl{sub 3} injected 2 days before the first dose of SRBC did not modify the humoral immune response. Earlier studies with {sup 51}Cr-labelled foreign red blood cells suggested that the augmentation of the humoral immune response in GdCl{sub 3}-pretreated mice is a consequence of the spillover of the antigen from the liver into the spleen and other extrahepatic reticuloendothelial organs. (orig.) 15 refs.

  13. Our experience on brachial plexus blockade in upper extremity surgery

    Directory of Open Access Journals (Sweden)

    Ömer Uslukaya


    Full Text Available Objective: Peripheral nerve blocks are usually used either alone or along with general anesthesia for postoperative analgesia. We also aimed to present the results and experiences.Materials and methods: This retrospective study was conducted to scan the files of patients who underwent orthopedic upper extremity surgery with peripheral nerve block between September 2009 and October 2010. After ethics committee approval was obtained, 114 patients who were ASA physical status I-III, aged 18-70, performed upper extremity surgery in the Orthopedics and Traumatology Clinic were included to study. Patients’ demographic data, clinical diagnoses, premedication status, peripheral block type, local anesthetic dose, stimuplex needle types, hemodynamic parameters at the during surgery, the first postoperative analgesic requirements, complications and patient satisfaction were recorded.Results: Demographic data were similar to each other. Brachial plexus block was commonly performed for the forearm surgery. Infraclavicular block was performed the most frequently to patients. As the classical methods in the supine position were preferred in 98.2% of patients, Stimuplex A needle (B. Braun, Melsungen AG, Germany have been used for blockage in 80.7% of patients. Also, in 54.4% of patients, 30 ml of local anesthetic solution composed of bupivacaine + prilocaine was used for blockade. Blocks applied to patients had provided adequate anesthesia.Conclusion: Since the brachial plexus blockade guided peripheral nerve stimulator for upper extremity surgery provide adequate depth of anesthesia and analgesia, it may be a good alternative to general anesthesia because of unwanted side effects

  14. Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

    Directory of Open Access Journals (Sweden)

    Esposito Emanuela


    neuroprotective effects of the A2A agonist are due to A2A receptor desensitization. When the A2A antagonist and agonist were centrally injected into injured SC, only SCH58261 appeared neuroprotective, while CGS21680 was ineffective. Conclusions Our results indicate that the A2A antagonist protects against SCI by acting on centrally located A2A receptors. It is likely that blockade of A2A receptors reduces excitotoxicity. In contrast, neuroprotection afforded by the A2A agonist may be primarily due to peripheral effects.

  15. Improving the efficacy of RAAS blockade in patients with chronic kidney disease

    NARCIS (Netherlands)

    Lambers Heerspink, Hiddo J.; de Borst, Martin H.; Bakker, Stephan J. L.; Navis, Gerjan J.


    I Reduction of blood pressure and proteinuria by blockade of the renin-angiotensin-aldosterone system (RAAS) has been the cornerstone of renoprotective intervention for patients with chronic kidney disease (CKD) for many years. Despite the proven efficacy of RAAS blockade, however, the reduction in

  16. Disentangling the effects of spin-orbit and hyperfine interactions on spin blockade

    NARCIS (Netherlands)

    Nadj-Perge, S.; Frolov, S.M.; Van Tilburg, J.W.W.; Danon, J.; Nazarov, Y.V.; Algra, R.; Bakkers, E.P.A.M.; Kouwenhoven, L.P.


    We have achieved the few-electron regime in InAs nanowire double quantum dots. Spin blockade is observed for the first two half-filled orbitals, where the transport cycle is interrupted by forbidden transitions between triplet and singlet states. Partial lifting of spin blockade is explained by spin

  17. Epidural anaesthesia with levobupivacaine and ropivacaine : effects of age on the pharmacokinetics, neural blockade and haemodynamics

    NARCIS (Netherlands)

    Simon, Mischa J.G.


    Epidural neural blockade results from processes after the administration of a local anaesthetic in the epidural space until the uptake in neural tissue. The pharmacokinetics, neural blockade and haemodynamics after epidural anaesthesia may be influenced by several factors, with age as the most impor

  18. Ultrasonic attenuation in pearlitic steel. (United States)

    Du, Hualong; Turner, Joseph A


    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.

  19. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    NARCIS (Netherlands)

    Humalda, J.K.; Lambers Heerspink, H.J.; Kwakernaak, A.J.; Slagman, M.C.; Waanders, F.; Vervloet, M.G.; Wee, P.M. Ter; Navis, G.; Borst, M.H. de; Wee, P.M. ter; Vervloet, M.; Bindels, R.J.; Hoenderop, J.G.J.; Hillebrands, J.L.


    BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  20. Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

    NARCIS (Netherlands)

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerarda; de Borst, Martin H


    Background: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patient

  1. Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution? (United States)

    Athyros, Vasilios G; Mikhailidis, Dimitri P; Kakafika, Anna I; Tziomalos, Konstantinos; Karagiannis, Asterios


    This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin-angiotensin-aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT(1) blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. 'Ang II reactivation' and 'ALDO escape' or 'breakthrough' have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 - 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT(2)-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

  2. The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity.

    Directory of Open Access Journals (Sweden)

    Anissa Kempf


    Full Text Available 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.

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

    CERN Document Server

    Litinskaya, Marina; Pupillo, Guido


    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 ranges 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 examine also 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.

  4. Edge-state blockade of transport in quantum dot arrays (United States)

    Benito, Mónica; Niklas, Michael; Platero, Gloria; Kohler, Sigmund


    We propose a transport blockade mechanism in quantum dot arrays and conducting molecules based on an interplay of Coulomb repulsion and the formation of edge states. As a model we employ a dimer chain that exhibits a topological phase transition. The connection to a strongly biased electron source and drain enables transport. We show that the related emergence of edge states is manifest in the shot noise properties as it is accompanied by a crossover from bunched electron transport to a Poissonian process. For both regions we develop a scenario that can be captured by a rate equation. The resulting analytical expressions for the Fano factor agree well with the numerical solution of a full quantum master equation.

  5. Coulomb blockade and BLOCH oscillations in superconducting Ti nanowires. (United States)

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


    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.

  6. Inelastic Photon Scattering via the Intracavity Rydberg Blockade (United States)

    Grankin, A.; Brion, E.; Boddeda, R.; Ćuk, S.; Usmani, I.; Ourjoumtsev, A.; Grangier, P.


    Electromagnetically induced transparency (EIT) in a ladder system involving a Rydberg level is known to yield giant optical nonlinearities for the probe field, even in the few-photon regime. This enhancement is due to the strong dipole-dipole interactions between Rydberg atoms and the resulting excitation blockade phenomenon. In order to study such highly correlated media, ad hoc models or low-excitation assumptions are generally used to tackle their dynamical response to optical fields. Here, we study the behavior of a cavity Rydberg-EIT setup in the nonequilibrium quantum field formalism, and we obtain analytic expressions for elastic and inelastic components of the cavity transmission spectrum, valid up to higher excitation numbers than previously achieved. This allows us to identify and interpret a polaritonic resonance structure, to our knowledge unreported so far.

  7. Abdominal compartment syndrome successfully treated with neuromuscular blockade

    Directory of Open Access Journals (Sweden)

    Kris T Chiles


    Full Text Available A 48 year old male admitted to the intensive care unit after a cardiac arrest complicated by a stroke intra-operatively during automatic implantable cardioverter defibrillator placement. He post-operatively developed a rigid abdomen, elevated peak and plateau pressures, hypoxia and renal insufficiency. He was diagnosed with abdominal compartment syndrome with an intra-abdominal compartment pressure of 40mmHg. The patient was administered 10 mg of intravenous cisatracuriumbesylate in preparation for bedside surgical abdominal decompression. Cisatracurium eliminated the patients need for surgical intervention by reducing his abdominal compartment pressures to normal and improving his hypoxia and renal function. This case illustrates that neuromuscular blockade should be attempted in patients with abdominal compartment syndrome prior to surgical intervention.

  8. Investigation of uncertainty components in Coulomb blockade thermometry

    Energy Technology Data Exchange (ETDEWEB)

    Hahtela, O. M.; Heinonen, M.; Manninen, A. [MIKES Centre for Metrology and Accreditation, Tekniikantie 1, 02150 Espoo (Finland); Meschke, M.; Savin, A.; Pekola, J. P. [Low Temperature Laboratory, Aalto University, Tietotie 3, 02150 Espoo (Finland); Gunnarsson, D.; Prunnila, M. [VTT Technical Research Centre of Finland, Tietotie 3, 02150 Espoo (Finland); Penttilä, J. S.; Roschier, L. [Aivon Oy, Tietotie 3, 02150 Espoo (Finland)


    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.

  9. Blockade of Ets-1 attenuates epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. (United States)

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


    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.

  10. Central blockade of melanocortin receptors attenuates the metabolic and locomotor responses to peripheral interleukin-1beta administration. (United States)

    Whitaker, Keith W; Reyes, Teresa M


    Loss of appetite and cachexia is an obstacle in the treatment of chronic infection and cancer. Proinflammatory cytokines released from activated immune cells and acting in the central nervous system (CNS) are prime candidates for mediating these metabolic changes, potentially affecting both energy intake as well as energy expenditure. The effect of intravenous administration of two proinflammatory cytokines, interleukin (IL)-1beta (15 microg/kg) and tumor necrosis factor (TNF)-alpha (10 microg/kg), on food and water intake, locomotor activity, oxygen consumption (VO2), and respiratory exchange ratio (RER) was evaluated. The two cytokines elicited a comparable decrease in food intake and activated similar numbers of cells in the paraventricular nucleus of the hypothalamus (PVH), a region that plays a critical role in the regulation of appetite and metabolism (determined via expression of the immediate early gene, c-fos). However, only IL-1beta reduced locomotion and RER, and increased VO2, while TNF-alpha was without effect. To examine the role of the melanocortins in mediating IL-1beta- induced metabolic changes, animals were pretreated centrally with a melanocortin receptor antagonist, HS014. Pretreatment with HS014 blocked the effect of IL-1beta on food intake and RER at later time points (beyond 8 h post injection), as well as the hypoactivity and increased metabolic rate. Further, HS014 blocked the induction of Fos-ir in the PVH. These data highlight the importance of the melanocortin system, particularly within the PVH, in mediating a broad range of metabolic responses to IL-1beta.

  11. Targeted to medication-induced dyskinesia and tardive dyskinesia: A role of 5-HT1A receptor

    Institute of Scientific and Technical Information of China (English)

    ZHEN Xue-chu


    Objective To outline the recent progress in drug discovery for medication-induced dyskinesia (Parkinson disease, PD) and tardive diskinesia (schizophrenia) with emphasizing the role of 5-HT1A receptor. Methods Development of extrapyramidal syndrome (EPS) followed either chronic L-DOPA administration in PD (L-DOPA-induced dyskinesia, LID) or antipsychotic treatment in schizophrenia (Tardive dyskinesia, TD) remains a challenge in the clinical practice and drug discovery. In addition to the abnormal dopamine activity in the nigrostrial area that contributes to the LID or TD, recent information indicates that 5-HT1A receptor also plays an important role which is merging as promising target in treatment of LID or TD. Results l-Stepholidine (l-SPD), isolated from the Chinese herb Stephania, is known as a dual dopamine receptor agent (D1 receptor agonistic and D2 antagonistic activity). In addition, we further demonstrated that l-SPD binds to 5-HT1A receptor and exhibits a partial agonistic activity. In LID rat model, l-SPD not only attenuated the development of L-DOPA-induced dyskinesia (LID), but also relived the established LID. The effect of l-SPD on LID was completely blocked by pretreatment of 5-HT1A receptor antagonist, indicating the role of 5-HT1A receptor. Furthermore, we designed and synthesis a dual dopamine/5-HT1A receptor agonist MCL-135, which also exhibits a significant relief on LID while elicits its antiparkinsonian action. Conclusions 5-HT1A receptor plys an important role in the development of LID, targeted to dual dopamine/5-HT receptor may represent a promising strategy for drug design and discovery in LID and TD treatment.

  12. 5-HT(1A) receptors and memory. (United States)

    Meneses, Alfredo; Perez-Garcia, Georgina


    The study of 5-hydroxytryptamine (5-HT) systems has benefited from the identification, classification and cloning of multiple 5-HT receptors (5-HT(1)-5-HT(7)). Increasing evidence suggests that 5-HT pathways, reuptake site/transporter complex and 5-HT receptors represent a strategic distribution for learning and memory. A key question still remaining is whether 5-HT markers (e.g., receptors) are directly or indirectly contributing to the physiological and pharmacological basis of memory and its pathogenesis or, rather, if they represent protective or adaptable mechanisms (at least in initial stages). In the current paper, the major aim is to revise recent advances regarding mammalian 5-HT(1A) receptors in light of their physiological, pathophysiological and therapeutic implications in memory. An attempt is made to identify and discuss sources of discrepancies by employing an analytic approach to examine the nature and degree of difficulty of behavioral tasks used, as well as implicating other factors (for example, brain areas, training time or duration, and drug administration) which might offer new insights into the understanding and interpretation of these data. In this context, 8-OH-DPAT deserves special attention since for many years it has been the more selective 5-HT drug and, hence, more frequently used. As 5-HT(1A) receptors are key components of serotonergic signaling, investigation of their memory mechanisms and action sites and the conditions under which they might operate, could yield valuable insights. Moreover, selective drugs with agonists, neutral antagonists or inverse agonist properties for 5-HT(1A) (and 5-HT(7)) receptors may constitute a new therapeutic opportunity for learning and memory disorders.

  13. Coulomb blockade effect simulation to the electrical characteristic of silicon based single electron transistor (United States)

    Nugraha, Mohamad Insan; Darma, Yudi


    In this paper, we simulate the effect of interaction between electrons on the electrical characteristic of silicon based single electron transistor (SET). The interaction between electrons is defined in the term of Coulomb blockade effect. These electrical characteristics involve conductance and I-V characteristic in SET structure. The simulation results show that when Coulomb blockade effect is included, the characteristic of I-V and conductance in SET shift to right. In addition, by reducing the quantum dot size, Coulomb blockade effect contributes greater effect. These results are shown in the characteristic of I-V and conductance which shift greater to the right in smaller quantum dot.

  14. Effect of unilateral vagus blockade on antigen-induced airway obstruction. (United States)

    Zimmermann, I; Islam, M S; Ulmer, W T


    Respiratory hypersensitivity and the effect of unilateral vagus blockade on the same, after the use of Ascaris extract aerosol, are studied in three boxer dogs with spontaneous reactivity to this aerosol. The dogs were exposed initially to Ascaris extract aerosol, and this exposure was repeated after unilateral vagus blockade and after its lavage. The principal parameters, deltaPoes (mm Hg)/100 ml TV, are given as a measurement of airway flow resistance and respiratory rates. The spontaneous respiratory distress observed in all the animals after exposure to the mentioned aerosol was avoided with unilateral blockade of the nervus vagus.

  15. Room temperature Coulomb blockade mediated field emission via self-assembled gold nanoparticles (United States)

    Wang, Fei; Fang, Jingyue; Chang, Shengli; Qin, Shiqiao; Zhang, Xueao; Xu, Hui


    Coulomb blockade mediated field-emission current was observed in single-electron tunneling devices based on self-assembled gold nanoparticles at 300 K. According to Raichev's theoretical model, by fixing a proper geometric distribution of source, island and drain, the transfer characteristics can be well explained through a combination of Coulomb blockade and field emission. Coulomb blockade and field emission alternately happen in our self-assembled devices. The Coulomb island size derived from the experimental data is in good agreement with the average size of the gold nanoparticles used in the device. The integrated tunneling can be adjusted via a gate electrode.

  16. Demonstration of strong Rydberg blockade in three-atom systems with anisotropic interactions

    CERN Document Server

    Barredo, Daniel; Labuhn, Henning; Béguin, Lucas; Vernier, Aline; Nogrette, Florence; Lahaye, Thierry; Browaeys, Antoine


    We study the Rydberg blockade in a system of three atoms arranged in different 2D geometries (linear and triangular configurations). In the strong blockade regime, we observe high-contrast, coherent collective oscillations of the single excitation probability, and an almost perfect van der Waals blockade. Our data is consistent with a total population in doubly and triply excited states below 2%. In the partial blockade regime, we directly observe the anisotropy of the van der Waals interactions between $|nD\\rangle$ Rydberg states in the triangular configuration. A simple model, that only uses independently measured two-body van der Waals interactions, fully reproduces the dynamics of the system without any adjustable parameter. These results are extremely promising for scalable quantum information processing and quantum simulation with neutral atoms.

  17. Mefloquine gap junction blockade and risk of pregnancy loss. (United States)

    Nevin, Remington Lee


    Obstetric use of the antimalarial drug mefloquine has historically been discouraged during the first trimester and immediately before conception owing to concerns of potential fetal harm. With the rise of resistance to the antimalarial drug sulfadoxine-pyrimethamine (SP), mefloquine is now being considered as a replacement for SP for universal antenatal administration to women from malaria-endemic regions. Recent recommendations have also suggested that mefloquine may be used cautiously among pregnant travelers who cannot otherwise avoid visiting these areas. Mefloquine has been demonstrated to cause blockade of gap junction protein alpha 1 (GJA1) gap junction intercellular communication (GJIC), and recent evidence suggests that GJA1 GJIC is critical to successful embryonic implantation and early placental development. During routine use, mefloquine accumulates in organ and peripheral tissue, crosses the blood-placental barrier, and may plausibly accumulate in developing decidua and trophoblast at concentrations sufficient to interfere with GJA1 GJIC and, thus, cause deleterious effects on fetal outcomes. This conclusion is supported by epidemiological evidence that demonstrates use of the drug during early development is associated with an increased risk of miscarriage and stillbirth. Confirmatory studies are pending, but the available experimental and epidemiological evidence support renewed adherence, where feasible, to existing mefloquine package insert guidance that women avoid the drug during the periconceptional period.


    Directory of Open Access Journals (Sweden)

    A. V. Bogolyubova


    Full Text Available Immune checkpoints represent the system of inhibitory mechanisms regulating the activation of the immune response, preventing the autoimmune processes and modulating the immune response by decreasing the immune cell-mediated damage of tissues and organs. Tumor cells may utilize these checkpoints to prevent the activation of tumor-specific lymphocytes, thereby acquiring resistance against the immune response. The blockade of inhibitory signal that is transduced in immune checkpoints leading to the reactivation of antitumor immune response is a promising method of tumor immunotherapy. Since the majority of immune checkpoints are based on the ligand-receptor interactions, one of contemporary modalities of anti-tumor therapy is based on the development of ligandor receptor-blocking therapeutic monoclonal antibodies, as well as soluble recombinant receptors capable of competing for a ligand and thereby modulating the signal transduction. In the past few years, this field of tumor immunotherapy experienced an impressive success; however, the potential tradeoff for altering of the natural suppressive mechanisms is the development of the autoimmune reactions.

  19. Fc gamma RI blockade and modulation for immunotherapy. (United States)

    Wallace, P K; Keler, T; Guyre, P M; Fanger, M W


    Splenectomy and corticosteroids are the treatment of choice for patients with immune thrombocytopenic purpura (ITP). However, for the 10%-15% of patients who do not respond to conventional therapy, high-dose i.v. IgG can induce life-saving transient responses. The benefits of i.v. IgG have been attributed to Fc receptor blockade; however, the involvement of the individual Fc receptors for IgG (Fc gamma R) in ITP remain to be more completely defined. Recently a mAb, designated mAb H22, which recognizes an epitope on Fc gamma RI (CD64) outside the ligand-binding domain, was humanized. Because mAb H22 is a human IgG1 and Fc gamma RI has a high affinity for human IgG1 antibodies, we predicted that mAb H22 would bind to the Fc gamma RI ligand-binding site through its Fc domain and to its external Fc gamma RI epitope through both Fab domains. These studies demonstrate that mAb H22 blocked Fc gamma RI-mediated phagocytosis of opsonized red blood cells more effectively than an irrelevant IgG. Moreover, cross-linking Fc gamma RI with mAb H22 down-modulated Fc gamma RI expression on monocytes, an effect seen within 2 h.

  20. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)


    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.

  1. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Directory of Open Access Journals (Sweden)

    Brian J. Ahn


    Full Text Available 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.

  2. Long term Survival with CTLA-4 blockade Using Tremelimumab (United States)

    Eroglu, Zeynep; Kim, Dae Won; Wang, Xiaoyan; Camacho, Luis H.; Chmielowski, Bartosz; Seja, Elizabeth; Villanueva, Arturo; Ruchalski, Kathleen; Glaspy, John A.; Kim, Kevin B.; Hwu, Wen-Jen; Ribas, Antoni


    Purpose One of the hallmarks of cancer immunotherapy is the long duration of responses, evident with cytokines like interleukin-2 or a variety of cancer vaccines. However, there is limited information available on very long term outcomes of patients treated with anti-CTLA-4 antibodies. Tremelimumab is an anti-CTLA-4 antibody of Ig G2 istoype initially tested in patients with advanced melanoma over 12 years ago. Methods We reviewed the outcomes of patients with advanced melanoma enrolled in four phase 1 and 2 tremelimumab trials at two sites to determine response rates and long-term survival. Results A total of 143 patients were enrolled at two institutions from 2002 to 2008. Tremelimumab administration varied between a single dose of 0.01 mg/kg and 15 mg/kg every 3 months. Median overall survival was 13 months (95% CI, 10–16.6), ranging from less than a month to 12+ years. An objective response rate of 15.6% was observed, with median duration of response of 6.5 years, range of 3 to 136+ months. The Kaplan-Meier estimated 5 year survival rate was 20% (95% CI, 13–26%), with 10 and 12.5 year survival rates of 16% (95% CI, 9–23%). Conclusions CTLA-4 blockade with tremelimumab can lead to very long duration of objective anti-tumor responses beyond 12 years. PMID:26364516

  3. Effect of 5-HT7 receptor blockade on liver regeneration after 60-70% partial hepatectomy


    Tzirogiannis, Konstantinos N; Kourentzi, Kalliopi T; Zyga, Sofia; Papalimneou, Vassiliki; Tsironi, Maria; Grypioti, Agni D; Protopsaltis, Ioannis; Panidis, Dimitrios; Panoutsopoulos, Georgios I


    Background Serotonin exhibits a vast repertoire of actions including cell proliferation and differentiation. The effect of serotonin, as an incomplete mitogen, on liver regeneration has recently been unveiled and is mediated through 5-HT2 receptor. The aim of the present study was to investigate the effect of 5-HT7 receptor blockade on liver regeneration after partial hepatectomy. Methods Male Wistar rats were subjected to 60-70% partial hepatectomy. 5-HT7 receptor blockade was applied by int...

  4. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Institute of Scientific and Technical Information of China (English)

    Yan-Huan Feng; Ping Fu


    Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS) among patients with type 2 diabetic kidney disease.Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use ofmonotherapy, without applying any language restrictions.Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy,""dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc.Study Selection: The selected articles were carefully reviewed.We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus.Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin Ⅱ receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension.However, existing literature has presented mixed results, in particular, related to patient safety.In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons.Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility.Further trials are warranted to study the combination therapy as an evidence-based practice.

  5. Efficacy of regional renal nerve blockade in patients with chronic refractory heart failure

    Institute of Scientific and Technical Information of China (English)

    DAI Qi-ming; FEN Yi; LU Jing; MA Gen-shan


    Background Increased renal sympathetic nerve activity can result in diuretic resistance in patients with chronic congestive heart failure.We investigated the effect of regional renal nerve blockade on the patients with chronic refractory heart failure and diuretic resistance.Methods Eighteen patients with chronic refractory heart failure were enrolled (mean age (64±11) years).The patients were randomly divided into two groups (renal nerve blockade group and standard therapy group,n=9 each).Renal nerve blockade was performed by percutaneous injection of local anaesthetic under computed tomographic guidance.Heart rate,mean arterial blood pressure,plasma and urine electrolytes,neurohormones,factional excretion of sodium (FENa),24-hour urine volume were monitored at baseline and the first 24 hours after therapy.Dyspnea and oedema were also evaluated.The major adverse cardiovascular events (MACE),plasma brain natriuretic peptide (BNP) level and left ventricular ejection fraction (LVEF) were compared between the two groups during the 3-12 months follow-up period.Results No complication was observed during the acute phase of renal nerve blockade.After renal nerve blockade,the 24-hour urine volume and FENa were significantly increased,while the level of plasma rennin,angiotensin Ⅱ,aldosterone,BNP and atrial natriuretic peptide as well as dyspnea and oedema were significantly reduced in renal nerve blockade group compared with baseline and standard therapy group.During three to 12 months of follow-up,the rate of MACE and plasma BNP level were significantly lower,while LVEF was significantly higher in renal nerve blockade group than those in standard therapy group.Conclusion Regional renal nerve blockade may be a safe and effective treatment for patients with chronic refractory heart failure.

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

    Institute of Scientific and Technical Information of China (English)

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


    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. Dual Blockade of the Renin-angiotensin-aldosterone System in Type 2 Diabetic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng


    Full Text Available Objective: To examine the efficacy and safety of dual blockade of the renin-angiotensin-aldosterone system (RAAS among patients with type 2 diabetic kidney disease. Data Sources: We searched the major literature repositories, including the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE, for randomized clinical trials published between January 1990 and October 2015 that compared the efficacy and safety of the use of dual blockade of the RAAS versus the use of monotherapy, without applying any language restrictions. Keywords for the searches included "diabetic nephropathy," "chronic kidney disease," "chronic renal insufficiency," "diabetes mellitus," "dual therapy," "combined therapy," "dual blockade," "renin-angiotensin system," "angiotensin-converting enzyme inhibitor," "angiotensin-receptor blocker," "aldosterone blockade," "selective aldosterone blockade," "renin inhibitor," "direct renin inhibitor," "mineralocorticoid receptor blocker," etc. Study Selection: The selected articles were carefully reviewed. We excluded randomized clinical trials in which the kidney damage of patients was related to diseases other than diabetes mellitus. Results: Combination treatment with an angiotensin-converting enzyme inhibitor supplemented by an angiotensin II receptor blocking agent is expected to provide a more complete blockade of the RAAS and a better control of hypertension. However, existing literature has presented mixed results, in particular, related to patient safety. In view of this, we conducted a comprehensive literature review in order to explain the rationale for dual blockade of the RAAS, and to discuss the pros and cons. Conclusions: Despite the negative results of some recent large-scale studies, it may be immature to declare that the dual blockade is a failure because of the complex nature of the RAAS surrounding its diversified functions and utility. Further trials are warranted to study the combination therapy as an

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

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


    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.

  9. Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice. (United States)

    Lasaro, Marcio O; Sazanovich, Marina; Giles-Davis, Wynetta; Mrass, Paulus; Bunte, Ralph M; Sewell, Duane A; Hussain, S Farzana; Fu, Yang-Xin; Weninger, Wolfgang; Paterson, Yvonne; Ertl, Hildegund Cj


    Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.

  10. An mRNA expression analysis of stimulation and blockade of 5-HT7 receptors during memory consolidation. (United States)

    Pérez-García, Georgina; Gonzalez-Espinosa, Claudia; Meneses, Alfredo


    Despite the compelling support for 5-hydroxytryptamine (5-HT) receptors participation in learning and memory in mammal species, the molecular basis had been largely absent from any discussion of its mechanistic underpinnings. Here, we report that reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that there was a higher level of expression of the investigated 5-HT receptor mRNAs in autoshaping-trained relative to untrained groups. Actually, pharmacological naïve untrained and autoshaping-trained rats showed significant differences, the latter groups expressing, in decreasing order, 5-HT1A memory consolidation, we combined selective 5-HT7 receptors stimulation or blockade in the same animals, and brain areas individually analyzed. 5-HT7 receptors were strongly expressed in all the three brain areas of vehicle-trained rats relative to untrained group. The potential selective 5-HT7 receptor agonist AS 19 enhanced memory consolidation, attenuated mRNA receptors expression, and the facilitatory memory effect was reversed by SB-269970. Finally, pharmacological stimulation of 5-HT7 receptors reversed scopolamine- or dizocilpine-induced amnesia and receptor down-regulation.

  11. Blockade of cannabinoid CB1 and CB2 receptors does not prevent the antipruritic effect of systemic paracetamol. (United States)

    Saglam, Gulis; Gunduz, Ozgur; Ulugol, Ahmet


    Cannabinoid CB1 receptors have been shown to mediate the antinociceptive, but not the hypothermic, action of the worldwide used analgesic, paracetamol. Since itch and pain sensations share many similarities, the purpose of the present study was to investigate whether blockade of cannabinoid CB1 and CB2 receptors participates in the antipruritic activity of paracetamol in mice. Scratching behavior was induced by intradermal serotonin injection into the rostral part of the back of the mice. After serotonin administration, scratching of the injected site by the hind paws were videotaped and counted for 30 min. Serotonin-induced scratching behavior was attenuated with high-dose paracetamol (300 mg/kg). The CB1 receptor antagonist, AM-251 (1 mg/kg), and the CB2 receptor antagonist, SR-144528 (1 mg/kg), did not alter the anti-scratching behavioral effect of paracetamol. Our results indicate that, in contrast to its antinociceptive action, but similar to its hypothermic effect, cannabinoid receptors are not involved in the antipruritic activity of paracetamol.

  12. Effect of beta-blockade on low-dose dobutamine-induced changes in left ventricular function in healthy volunteers: assessment by gated SPET myocardial perfusion scintigraphy

    Energy Technology Data Exchange (ETDEWEB)

    Everaert, H.; Vanhove, C.; Franken, P.R. [Division of Nuclear Medicine, University Hospital, Free University of Brussels (AZ VUB), Brussels (Belgium)


    Viability studies are often performed in patients receiving beta-blocking agents. However, the intake of beta-blocking agents could influence the identification of viable myocardium when low-dose dobutamine is used to demonstrate inotropic reserve. The aim of this study was to quantify the effect of beta-blockade on global and regional left ventricular function in healthy volunteers using low-dose dobutamine gated single-photon emission tomographic (SPET) myocardial perfusion scintigraphy. Ten subjects were studied once ''on'' and once ''off'' beta-blocker therapy (metoprolol succinate, 100 mg day{sup -1}). On each occasion four consecutive gated SPET acquisitions (of 7 min duration) were recorded after injection of 925 MBq technetium-99m tetrofosmin on a triple-headed camera equipped with focussing (Cardiofocal) collimators. Acquisitions were made at rest (baseline 1 and 2) and 5 min after the beginning of the infusion of 5 and 10 {mu}g kg{sup -1} min{sup -1} dobutamine. Wall thickening (WT) was quantified using a method based on circumferential profile analysis. Left ventricular ejection fraction (LVEF) was obtained using the Cedars-Sinai algorithm. Blood pressure (BP) and heart rate (HR) were recorded at the end of each acquisition. At baseline LVEF, WT and systolic BP values under beta-blockade were not significantly different from those obtained in the non-beta-blocked state. The mean HR and diastolic BP at baseline were lower under beta-blockade. Dobutamine administration (at 5 and 10 {mu}g kg{sup -1} min{sup -1}) induced a significant increase in WT, LVEF and systolic BP in all subjects both on and off beta-blockade. The increases in WT, LVEF and systolic BP in the beta-blocked state were less pronounced but not significantly different. HR increased significantly at 10 {mu}g kg{sup -1} min{sup -1} dobutamine without beta-blocker administration, while no increase in HR was observed in the beta-blocked state. Beta

  13. Serum Amyloid A Receptor Blockade and Incorporation into High-Density Lipoprotein Modulates Its Pro-Inflammatory and Pro-Thrombotic Activities on Vascular Endothelial Cells

    Directory of Open Access Journals (Sweden)

    Belal Chami


    Full Text Available The acute phase protein serum amyloid A (SAA, a marker of inflammation, induces expression of pro-inflammatory and pro-thrombotic mediators including ICAM-1, VCAM-1, IL-6, IL-8, MCP-1 and tissue factor (TF in both monocytes/macrophages and endothelial cells, and induces endothelial dysfunction—a precursor to atherosclerosis. In this study, we determined the effect of pharmacological inhibition of known SAA receptors on pro-inflammatory and pro-thrombotic activities of SAA in human carotid artery endothelial cells (HCtAEC. HCtAEC were pre-treated with inhibitors of formyl peptide receptor-like-1 (FPRL-1, WRW4; receptor for advanced glycation-endproducts (RAGE, (endogenous secretory RAGE; esRAGE and toll-like receptors-2/4 (TLR2/4 (OxPapC, before stimulation by added SAA. Inhibitor activity was also compared to high-density lipoprotein (HDL, a known inhibitor of SAA-induced effects on endothelial cells. SAA significantly increased gene expression of TF, NFκB and TNF and protein levels of TF and VEGF in HCtAEC. These effects were inhibited to variable extents by WRW4, esRAGE and OxPapC either alone or in combination, suggesting involvement of endothelial cell SAA receptors in pro-atherogenic gene expression. In contrast, HDL consistently showed the greatest inhibitory action, and often abrogated SAA-mediated responses. Increasing HDL levels relative to circulating free SAA may prevent SAA-mediated endothelial dysfunction and ameliorate atherogenesis.

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

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    Lin Chen

    Full Text Available 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.

  15. PD-1 blockade induces responses by inhibiting adaptive immune resistance (United States)

    Tumeh, Paul C.; Harview, Christina L.; Yearley, Jennifer H.; Shintaku, I. Peter; Taylor, Emma J. M.; Robert, Lidia; Chmielowski, Bartosz; Spasic, Marko; Henry, Gina; Ciobanu, Voicu; West, Alisha N.; Carmona, Manuel; Kivork, Christine; Seja, Elizabeth; Cherry, Grace; Gutierrez, Antonio; Grogan, Tristan R.; Mateus, Christine; Tomasic, Gorana; Glaspy, John A.; Emerson, Ryan O.; Robins, Harlan; Pierce, Robert H.; Elashoff, David A.; Robert, Caroline; Ribas, Antoni


    Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types.1–5 One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8 T-cells (termed adaptive immune resistance).6,7 Here we show that pre-existing CD8 T-cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, and PD-L1 expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance. PMID:25428505

  16. Blockade of mast cell activation reduces cutaneous scar formation. (United States)

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


    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.

  17. Semiactive control for vibration attenuation

    Energy Technology Data Exchange (ETDEWEB)

    Leitmann, G. [Univ. of California, Berkeley, CA (United States). Coll. of Engineering


    With the advent of materials, such as electrorheological fluids, whose material properties can be altered rapidly by means of external stimuli, employing such materials as actuators for the controlled attenuation of undesirable vibrations is now possible. Such control schemes are dubbed semiactive in that they attenuate vibrations whether applied actively or passively. The author investigates various such control schemes, allowing for both separate and joint control of the stiffness and damping characteristics of the material.

  18. O exercício físico atenua o déficit autonômico cardíaco induzido pelo bloqueio da síntese do óxido nítrico El ejercicio físico atenúa el déficit autonómico cardiaco inducido por el bloqueo de la síntesis de óxido nítrico Physical exercise attenuates the cardiac autonomic deficit induced by nitric oxide synthesis blockade

    Directory of Open Access Journals (Sweden)

    Bruno Rafael Orsini Rossi


    íntesis del NO sobre el control autonómico cardiovascular en ratones sometidos al ejercicio aerobio durante diez semanas. MÉTODOS: Se dividieron ratones wistar en cuatro grupos: control tratados con ración y agua ad libitum durante diez semanas (RC; control tratados con NG-nitro-L-arginina metil éster (L-NAME en la última semana (RCL; entrenados durante diez semanas en cinta motorizada (RT; entrenados por diez semanas y tratados con L-NAME en la última semana (RTL. Se investigó el control autonómico cardiovascular en todos los grupos con la utilización de doble bloqueo con metilatropina y propranolol, y análisis de la variabilidad. RESULTADOS: Los grupos RCL y RTL presentaron hipertensión. El grupo RCL presentó taquicardia y predominio del tono simpático en la determinación de la FC tras el bloqueo autonómico farmacológico. El grupo RT presentó bradicardia y menor frecuencia cardiaca (FC intrínseca en relación a los demás. La evaluación de la variabilidad de la FC mostró menores valores absolutos y normalizados en la banda de baja frecuencia (BF en el grupo RCL. El grupo RTL presentó elevación en la banda de BF en valores absolutos. El análisis de la variabilidad de la PAS mostró que los grupos RCL y RTL presentaron mayores valores en la banda de BF. CONCLUSIÓN: El ejercicio físico previo impidió el déficit en el control autonómico cardiaco inducido por el tratamiento con L-NAME, pero no impidió el aumento en la variabilidad de la PAS.BACKGROUND: The nitric oxide (NO synthesis blockade is characterized by an increase in the cardiac sympathetic activity and the physical training promotes the decrease in the sympathetic activity. OBJECTIVE: We investigated the effect of the NO synthesis blockade on the autonomic cardiovascular control in rats submitted to aerobic exercises during a 10-week period. METHODS: Male Wistar rats were divided in four groups: control rats, treated with chow food and water ad libitum for 10 weeks (CR; control rats

  19. Reduced response to IKr blockade and altered hERG1a/1b stoichiometry in human heart failure. (United States)

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


    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

  20. Acute AT(1)-receptor blockade reverses the hemodynamic and baroreflex impairment in adult sheep exposed to antenatal betamethasone. (United States)

    Shaltout, Hossam A; Rose, James C; Figueroa, Jorge P; Chappell, Mark C; Diz, Debra I; Averill, David B


    To accelerate lung development and protect neonates from other early developmental problems, synthetic steroids are administered maternally in the third trimester, exposing fetuses that are candidates for premature delivery to them. However, steroid exposure at this point of gestation may lead to elevated blood pressure [mean arterial pressure (MAP)] during adolescence. We hypothesize that fetal exposure to steroids activates the renin-angiotensin system, inducing an elevation in blood pressure and attenuation of baroreflex sensitivity (BRS) that is angiotensin II dependent in early adulthood. To test this hypothesis, fetal sheep were exposed to betamethasone (Beta) or vehicle (control) administered to ewes at day 80 of gestation and delivered at full term. At 1.8 yr of age, male offspring were instrumented for conscious recording of MAP, heart rate, and measurement of BRS [as low-frequency-alpha, high-frequency-alpha, sequence (seq) UP, seq DOWN, and seq TOTAL]. Beta-exposed sheep (n = 6) had higher MAP than control sheep (n = 5) (93 + or - 2 vs. 84 + or - 2 mmHg, P < 0.01). Acute blockade of angiotensin type 1 receptors with candesartan (0.3 mg/kg iv) normalized MAP in Beta-exposed sheep (85 + or - 4 mmHg), with no effect in control sheep (82 + or - 3 mmHg). Before angiotensin type 1 blockade, BRS maximum gain was significantly lower in Beta-exposed vs. control sheep (11 + or - 3 vs. 26 + or - 3 ms/mmHg, P < 0.0.01). However, 45 min after candesartan injection, BRS was increased in Beta-exposed (21 + or - 5 ms/mmHg) and control (35 + or - 4 ms/mmHg) sheep. Heart rate variability (HRV) and blood pressure variability (BPV) revealed lower HRV (SD of beat-to-beat interval and root mean square of successive beat-to-beat differences in R-R interval duration) and higher BPV (SD of MAP, systolic arterial pressure in low-frequency range) in Beta-exposed sheep. Candesartan partially restored HRV in Beta-exposed sheep and fully corrected BPV. Thus, in utero exposure to

  1. Spinal blockades of class I antiarrythmic drugs with bupivacaine by isobolographic analysis in rats. (United States)

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


    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.

  2. Evaluation of epidural blockade as therapy for patients with sciatica secondary to lumbar disc herniation

    Directory of Open Access Journals (Sweden)

    Rogerio Carlos Sanfelice Nunes


    Full Text Available ABSTRACT OBJECTIVE: Sciatic pain secondary to lumbar disc herniation is a complex condition that is often highly limiting. The causes of pain in disc herniation are multifactorial. Two physiopathological mechanisms are involved in discogenic pain: mechanical deformation of nerve roots and a biochemical inflammatory component resulting from contact between the intervertebral disc and neural tissue, by way of the nucleus pulposus. The aim of this study was to evaluate the efficacy and safety of epidural blockade as therapy for bulging lumbar disc herniation. METHODS: A clinical study was conducted based on a retrospective and prospective survey. The blockade consisted of interlaminar puncture and bolus drug delivery. The number of procedures varied according to the clinical response, as determined through weekly evaluations and then 30, 90, and 180 days after the final session. A total of 124 patients who received one to five blockades were evaluated. RESULTS: The success rate (defining success as a reduction in sciatic pain of at least 80% was 75.8%. CONCLUSION: The results demonstrated the therapeutic action of epidural blockade over the short term, i.e. in cases of acute pain, thus showing that intense and excruciating sciatic pain can be relieved through this technique. Because of the multifactorial genesis of sciatica and the difficulties encountered by healthcare professionals in treating this condition, epidural blockade can become part of therapeutic arsenal available. This procedure is situated between conservative treatment with an eminently clinical focus and surgical approaches.

  3. Quantum Interference Induced Photon Blockade in a Coupled Single Quantum Dot-Cavity System

    CERN Document Server

    Tang, Jing; Xu, Xiulai


    We propose an experimental scheme to implement a strong photon blockade with a single quantum dot coupled to a nanocavity. The photon blockade effect can be tremendously enhanced by driving the cavity and the quantum dot simultaneously with two classical laser fields. This enhancement of photon blockade is ascribed to the quantum interference effect to avoid two-photon excitation of the cavity field. Comparing with Jaynes-Cummings model, the second-order correlation function at zero time delay $g^{(2)}(0)$ in our scheme can be reduced by two orders of magnitude and the system sustains a large intracavity photon number. A red (blue) cavity-light detuning asymmetry for photon quantum statistics with bunching or antibunching characteristics is also observed. The photon blockade effect has a controllable flexibility by tuning the relative phase between the two pumping laser fields and the Rabi coupling strength between the quantum dot and the pumping field. Moreover, the photon blockade scheme based on quantum in...

  4. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression.

    Directory of Open Access Journals (Sweden)

    Matthew E Hardee

    important angiogenic factor that regulates the induction of tumor cell-induced neovascularization and growth during the initial stages of tumorigenesis. The suppression of tumor angiogenesis and progression by erythropoietin blockade suggests that erythropoietin may constitute a potential target for the therapeutic modulation of angiogenesis in cancer.

  5. A genetic variation in the adenosine A2A receptor gene (ADORA2A) contributes to individual sensitivity to caffeine effects on sleep. (United States)

    Rétey, J V; Adam, M; Khatami, R; Luhmann, U F O; Jung, H H; Berger, W; Landolt, H-P


    Caffeine is the most widely used stimulant in Western countries. Some people voluntarily reduce caffeine consumption because it impairs the quality of their sleep. Studies in mice revealed that the disruption of sleep after caffeine is mediated by blockade of adenosine A2A receptors. Here we show in humans that (1) habitual caffeine consumption is associated with reduced sleep quality in self-rated caffeine-sensitive individuals, but not in caffeine-insensitive individuals; (2) the distribution of distinct c.1083T>C genotypes of the adenosine A2A receptor gene (ADORA2A) differs between caffeine-sensitive and -insensitive adults; and (3) the ADORA2A c.1083T>C genotype determines how closely the caffeine-induced changes in brain electrical activity during sleep resemble the alterations observed in patients with insomnia. These data demonstrate a role of adenosine A2A receptors for sleep in humans, and suggest that a common variation in ADORA2A contributes to subjective and objective responses to caffeine on sleep.

  6. Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors. (United States)

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


    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.

  7. Adenosine A2A receptor deficiency up-regulates cystatin F expression in white matter lesions induced by chronic cerebral hypoperfusion. (United States)

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


    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.

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

    Directory of Open Access Journals (Sweden)

    Wei Duan

    Full Text Available 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.

  9. Photoacoustic Imaging Taking into Account Attenuation

    CERN Document Server

    Kowar, Richard


    First, we review existing attenuation models and discuss their causality properties, which we believe to be essential for algorithms for inversion with attenuated data. Then, we survey causality properties of common attenuation models. We also derive integro-differential equations which the attenuated waves are satisfying. In addition we discuss the ill--conditionness of the inverse problem for calculating the unattenuated wave from the attenuated one.

  10. Attenuation in Superconducting Circular Waveguides

    Directory of Open Access Journals (Sweden)

    K. H. Yeap


    Full Text Available We present an analysis on wave propagation in superconducting circular waveguides. In order to account for the presence of quasiparticles in the intragap states of a superconductor, we employ the characteristic equation derived from the extended Mattis-Bardeen theory to compute the values of the complex conductivity. To calculate the attenuation in a circular waveguide, the tangential fields at the boundary of the wall are first matched with the electrical properties (which includes the complex conductivity of the wall material. The matching of fields with the electrical properties results in a set of transcendental equations which is able to accurately describe the propagation constant of the fields. Our results show that although the attenuation in the superconducting waveguide above cutoff (but below the gap frequency is finite, it is considerably lower than that in a normal waveguide. Above the gap frequency, however, the attenuation in the superconducting waveguide increases sharply. The attenuation eventually surpasses that in a normal waveguide. As frequency increases above the gap frequency, Cooper pairs break into quasiparticles. Hence, we attribute the sharp rise in attenuation to the increase in random collision of the quasiparticles with the lattice structure.

  11. Two-atom Rydberg blockade using direct 6S to nP excitation (United States)

    Hankin, A. M.; Jau, Y.-Y.; Parazzoli, L. P.; Chou, C. W.; Armstrong, D. J.; Landahl, A. J.; Biedermann, G. W.


    We explore a single-photon approach to Rydberg state excitation and Rydberg blockade. Using detailed theoretical models, we show the feasibility of direct excitation, predict the effect of background electric fields, and calculate the required interatomic distance to observe Rydberg blockade. We then measure and control the electric field environment to enable coherent control of Rydberg states. With this coherent control, we demonstrate Rydberg blockade of two atoms separated by 6.6(3) μm. When compared with the more common two-photon excitation method, this single-photon approach is advantageous because it eliminates channels for decoherence through photon scattering and ac Stark shifts from the intermediate state while moderately increasing Doppler sensitivity.

  12. Local identifiability and sensitivity analysis of neuromuscular blockade and depth of hypnosis models. (United States)

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


    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.

  13. Prevalence of saphenous nerve injury after adductor-canal-blockade in patients receiving total knee arthroplasty

    DEFF Research Database (Denmark)

    Henningsen, Maja; Jæger, Pia; Hilsted, K L;


    BACKGROUND: Adductor-canal-blockade is a new technique for pain relief after knee surgery. This block could cause nerve injury and the aim of this follow-up study was to determine the prevalence of saphenous nerve injury in patients receiving adductor-canal-blockade for pain treatment after total...... knee arthroplasty. METHODS: All patients included in two former studies of adductor-canal-blockade following total knee arthroplasty were invited to participate in this follow-up study 3-6 months after surgery. We examined the cutaneous area on the medial aspect of the lower leg (medial crural branch......, 76 patients could not discriminate between blunt and sharp stimulation with a needle, 81 patients could not discriminate between cold and warmth, and 82 patients displayed an altered sensation to light brush. CONCLUSION: We found no indications of saphenous nerve injury caused by the adductor-canal...

  14. A high fidelity Rydberg blockade entangling gate using shaped, analytic pulses

    CERN Document Server

    Theis, L S; Wilhelm, F K; Saffmann, M


    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 $50\\;{\\rm ns}$, 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.

  15. Glucagon and plasma catecholamines during beta-receptor blockade in exercising man

    DEFF Research Database (Denmark)

    Galbo, H; Holst, Janett; Christensen, N J


    Seven men ran at 60% of individual maximal oxygen uptake to exhaustion during beta-adrenergic blockade with propranolol (P), during lipolytic blockade with nicotinic acid (N), or without drugs (C). The total work times (83 +/- 9 (P), 122 +/- 8 (N), 166 +/- 10 (C) min, mean and SE) differed...... decrease glucagon concentrations increased progressively in parallel with declining plasma glucose and were at exhaustion always three times preexercise values. Thus beta-adrenergic blockade did not diminish the glucagon response. Nor was this response increased when alpha-receptor stimulation in P...... experiments was intensified. Carbohydrate combustion was smaller and NEFA and glycerol concentrations in serum larger during C experiments. Alanine concentrations were never raised at exhaustion. Accordingly, neither stimulation of adrenergic receptors nor NEFA and alanine concentrations are major...

  16. Ctla-4 blockade plus adoptive T-cell transfer promotes optimal melanoma immunity in mice. (United States)

    Mahvi, David A; Meyers, Justin V; Tatar, Andrew J; Contreras, Amanda; Suresh, Marulasiddappa; Leverson, Glen E; Sen, Siddhartha; Cho, Clifford S


    Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive therapeutic benefit. C57BL/6 mice were inoculated with syngeneic B16F10 melanoma tumors transfected to express low levels of the lymphocytic choriomeningitis virus peptide GP33 (B16GP33), and treated with no immunotherapy, CTLA-4 blockade, ACT, or combination immunotherapy of CTLA-4 blockade with ACT. Combination immunotherapy resulted in optimal control of B16GP33 melanoma tumors. Combination immunotherapy promoted a stronger local immune response reflected by enhanced tumor-infiltrating lymphocyte populations, and a stronger systemic immune responses reflected by more potent tumor antigen-specific T-cell activity in splenocytes. In addition, whereas both CTLA-4 blockade and combination immunotherapy were able to promote long-term immunity against B16GP33 tumors, only combination immunotherapy was capable of promoting immunity against parental B16F10 tumors as well. Our findings suggest that a combinatorial approach using CTLA-4 blockade with nonlymphodepletional ACT may promote additive endogenous and exogenous T-cell activities that enable greater therapeutic efficacy in the treatment of melanoma.

  17. Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination. (United States)

    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


    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.

  18. Renal and cardiac function during alpha1-beta-blockade in congestive heart failure

    DEFF Research Database (Denmark)

    Heitmann, M; Davidsen, U; Stokholm, K H


    The kidney and the neurohormonal systems are essential in the pathogenesis of congestive heart failure (CHF) and the physiologic response. Routine treatment of moderate to severe CHF consists of diuretics, angiotensin-converting enzyme (ACE) inhibition and beta-blockade. The need for control...... of renal function during initiation of ACE-inhibition in patients with CHF is well known. The aim of this study was to investigate whether supplementation by a combined alpha1-beta-blockade to diuretics and ACE-inhibition might improve cardiac function without reducing renal function....

  19. Ultrasound guided intercostobrachial nerve blockade in patients with persistent pain after breast cancer surgery

    DEFF Research Database (Denmark)

    Wijayasinghe, Nelun; Duriaud, Helle M; Kehlet, Henrik;


    BACKGROUND: Persistent pain after breast cancer surgery (PPBCS) affects 25 - 60% of breast cancer survivors and damage to the intercostobrachial nerve (ICBN) has been implicated as the cause of this predominantly neuropathic pain. Local anesthetic blockade of the ICBN could provide clues...... determined the sonoanatomy of the ICBN and part 2 examined effects of the ultrasound-guided ICBN blockade in patients with PPBCS. SETTING: Section for Surgical Pathophysiology at Rigshospitalet, Copenhagen, Denmark. METHODS: Part 1: Sixteen unoperated, pain free breast cancer patients underwent systematic...

  20. Dynamical Coulomb blockade of the nonlocal conductance in normalmetal/superconductor hybrid structures

    Energy Technology Data Exchange (ETDEWEB)

    Kolenda, Stefan; Wolf, Michael J.; Beckmann, Detlef [Institut fuer Nanotechnologie, KIT, 76021 Karlsruhe (Germany)


    In normalmetal/superconductor hybrid structures nonlocal conductance is determined by crossed Andreev reflection (CAR) and elastic cotunneling (EC). This was investigated recently both experimentally and theoretically. Dynamical Coulomb blockade of EC and CAR was predicted theoretically. Here we report on experimental investigations of these effects. We found signatures of dynamical Coulomb blockade in local and nonlocal conductance in the normal state. In the superconducting state, we find s-shaped nonlocal differential conductance curves as a function of bias applied on both contacts. These curves were observed for bias voltages both below and above the gap. We compare our results to theory.

  1. Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review

    DEFF Research Database (Denmark)

    Sjølie, A K; Dodson, P; Hobbs, F R R


    Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates...... the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril....... The clinical implications of these new data are discussed....

  2. Ultrasound Guided Intercostobrachial Nerve Blockade in Patients with Persistent Pain after Breast Cancer Surgery

    DEFF Research Database (Denmark)

    Wijayasinghe, Nelun; Duriaud, Helle M; Kehlet, Henrik


    BACKGROUND: Persistent pain after breast cancer surgery (PPBCS) affects 25 - 60% of breast cancer survivors and damage to the intercostobrachial nerve (ICBN) has been implicated as the cause of this predominantly neuropathic pain. Local anesthetic blockade of the ICBN could provide clues...... determined the sonoanatomy of the ICBN and part 2 examined effects of the ultrasound-guided ICBN blockade in patients with PPBCS. SETTING: Section for Surgical Pathophysiology at Rigshospitalet, Copenhagen, Denmark. METHODS: Part 1: Sixteen unoperated, pain free breast cancer patients underwent systematic...

  3. Influence of pudendal nerve blockade on stress relaxation in the female urethra

    DEFF Research Database (Denmark)

    Thind, P; Bagi, P; Mieszczak, C;


    dilatation, P alpha and P beta are pressure decay, and tau alpha and tau beta are time constants. The time constants have previously proved independent of the way the dilatation is performed. The urethral stress relaxation obtained in 10 healthy women before and after pudendal nerve blockade was analysed...... by the mathematical model and the pressure parameters and time constants determined. The fast time constant, tau beta, was reduced by the nerve blockade, whereas tau alpha was unaffected, however, both P alpha and P beta were reduced. No single stress relaxation parameter can therefore be related to the muscle...

  4. X-Ray Attenuation Cell

    Energy Technology Data Exchange (ETDEWEB)

    Ryutov, D.; Toor, A.


    To minimize the pulse-to-pulse variation, the LCLS FEL must operate at saturation, i.e. 10 orders of magnitude brighter spectral brilliance than 3rd-generation light sources. At this intensity, ultra-high vacuums and windowless transport are required. Many of the experiments, however, will need to be conducted at a much lower intensity thereby requiring a reliable means to reduce the x-ray intensity by many orders of magnitude without increasing the pulse-to-pulse variation. In this report we consider a possible solution for controlled attenuation of the LCLS x-ray radiation. We suggest using for this purpose a windowless gas-filled cell with the differential pumping. Although this scheme is easily realizable in principle, it has to be demonstrated that the attenuator can be made short enough to be practical and that the gas loads delivered to the vacuum line of sight (LOS) are acceptable. We are not going to present a final, optimized design. Instead, we will provide a preliminary analysis showing that the whole concept is robust and is worth further study. The spatial structure of the LCLS x-ray pulse at the location of the attenuator is shown in Fig. 1. The central high-intensity component, due to the FEL, has a FWHM of {approx}100 {micro}m. A second component, due to the undulator's broad band spontaneous radiation is seen as a much lower intensity ''halo'' with a FWHM of 1 mm. We discuss two versions of the attenuation cell. The first is directed towards a controlled attenuation of the FEL up to the 4 orders of magnitude in the intensity, with the spontaneous radiation halo being eliminated by collimators. In the second version, the spontaneous radiation is not sacrificed but the FEL component (as well as the first harmonic of the spontaneous radiation) gets attenuated by a more modest factor up to 100. We will make all the estimates assuming that the gas used in the attenuator is Xenon and that the energy of the FEL is 8.25 keV. At

  5. Continuous positive airway pressure breathing increases cranial spread of sensory blockade after cervicothoracic epidural injection of lidocaine.

    NARCIS (Netherlands)

    Visser, W.A.; Eerd, M.J. van; Seventer, R. van; Gielen, M.J.M.; Giele, J.L.P.; Scheffer, G.J.


    BACKGROUND: Continuous positive airway pressure (CPAP) increases the caudad spread of sensory blockade after low-thoracic epidural injection of lidocaine. We hypothesized that CPAP would increase cephalad spread of blockade after cervicothoracic epidural injection. METHODS: Twenty patients with an e

  6. Effect of adductor-canal-blockade on established, severe post-operative pain after total knee arthroplasty

    DEFF Research Database (Denmark)

    Jaeger, P; Grevstad, Ulrik; Henningsen, Maja;


    In this proof-of-concept study, we investigated the effect of the predominantly sensory adductor-canal-blockade on established pain in the early post-operative period after total knee arthroplasty (TKA). We hypothesised that the adductor-canal-blockade would reduce pain during flexion of the knee...

  7. Attenuation in silica-based optical fibers

    DEFF Research Database (Denmark)

    Wandel, Marie Emilie


    In this thesis on attenuation in silica based optical fibers results within three main topics are reported. Spectral attenuation measurements on transmission fibers are performed in the wide wavelength range 290 nm – 1700 nm. The measured spectral attenuation is analyzed with special emphasis...... on absorption peaks in order to investigate the cause of an unusual high attenuation in a series of transmission fibers. Strong indications point to Ni2+ in octahedral coordination as being the cause of the high attenuation. The attenuation of fibers having a high core refractive index is analyzed and the cause...... of the high attenuation measured in such fibers is described as being due to scattering of light on fluctuations of the core diameter. A novel semi-empirical model for predicting the attenuation of high index fibers is presented. The model is shown to be able to predict the attenuation of high index fibers...

  8. The suprasacral parallel shift vs lumbar plexus blockade with ultrasound guidance in healthy volunteers - a randomised controlled trial

    DEFF Research Database (Denmark)

    Bendtsen, T F; Pedersen, E M; Haroutounian, S


    in a randomised crossover trial comparing the new suprasacral with a lumbar plexus block. The primary outcome was sensory dermatome anaesthesia of L2-S1. Secondary outcomes were peri-neural analgesic spread estimated with magnetic resonance imaging, sensory blockade of dermatomes L2-S3, motor blockade, volunteer...... discomfort, arterial blood pressure change, block performance time, lidocaine pharmacokinetics and complications. Only one volunteer in the suprasacral group had sensory blockade of all dermatomes L2-S1. Epidural spread was verified by magnetic resonance imaging in seven of the 34 trials (two suprasacral...... and five lumbar plexus blocks). Success rates of the sensory and motor blockade were 88-100% for the major lumbar plexus nerves with the suprasacral technique, and 59-88% with the lumbar plexus block (p > 0.05). Success rate of motor blockade was 50% for the lumbosacral trunk with the suprasacral technique...

  9. Josephson tunnel junction microwave attenuator

    DEFF Research Database (Denmark)

    Koshelets, V. P.; Shitov, S. V.; Shchukin, A. V.


    A new element for superconducting electronic circuitry-a variable attenuator-has been proposed, designed, and successfully tested. The principle of operation is based on the change in the microwave impedance of a superconductor-insulator-superconductor (SIS) Josephson tunnel junction when dc bias...

  10. Compact plasmonic variable optical attenuator

    DEFF Research Database (Denmark)

    Leosson, Kristjan; Rosenzveig, Tiberiu; Hermannsson, Pétur Gordon


    We demonstrate plasmonic nanowire-based thermo-optic variable optical attenuators operating in the 1525-1625 nm wavelength range. The devices have a footprint as low as 1 mm, extinction ratio exceeding 40 dB, driving voltage below 3 V, and full modulation bandwidth of 1 kHz. The polarization...

  11. Selective α1-adrenergic blockade disturbs the regional distribution of cerebral blood flow during static handgrip exercise. (United States)

    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


    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 blood flow (+80.9 ± 62.5 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 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.

  12. Blockade of CCR2 reduces macrophage influx and development of chronic renal damage in murine renovascular hypertension. (United States)

    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


    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.

  13. Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice.

    Directory of Open Access Journals (Sweden)

    Selina Christen

    Full Text Available Type 1 diabetes (T1D results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM family proteins JAM-B and JAM-C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP. Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.

  14. Blockade of CXCR1/2 chemokine receptors protects against brain damage in ischemic stroke in mice

    Directory of Open Access Journals (Sweden)

    Larissa Fonseca da Cunha Sousa


    Full Text Available OBJECTIVE: Ischemic stroke may result from transient or permanent reductions of regional cerebral blood flow. Polymorphonuclear neutrophils have been described as the earliest inflammatory cells to arrive in ischemic tissue. CXCR1/2 receptors are involved in the recruitment of these cells. However, the contribution of these chemokine receptors during transient brain ischemia in mice remains poorly understood. In this work, we investigated the effects of reparixin, an allosteric antagonist of CXCR1/2 receptors, in a model of middle cerebral artery occlusion and reperfusion in mice. METHODS: C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-iβ was measured by ELISA. RESULTS: Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-iβ were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment. CONCLUSIONS: Our results suggest that the blockade of the CXCR1/2 receptors by reparixin promotes neuroprotective effects by reducing the levels of polymorphonuclear infiltration in the brain and the tissue damage associated with middle cerebral artery occlusion and reperfusion.

  15. Stormwater Attenuation by Green Roofs (United States)

    Sims, A.; O'Carroll, D. M.; Robinson, C. E.; Smart, C. C.


    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.

  16. CB1 cannabinoid receptor-mediated anandamide signalling reduces the defensive behaviour evoked through GABAA receptor blockade in the dorsomedial division of the ventromedial hypothalamus. (United States)

    Dos Anjos-Garcia, Tayllon; Ullah, Farhad; Falconi-Sobrinho, Luiz Luciano; Coimbra, Norberto Cysne


    The effects of cannabinoids in brain areas expressing cannabinoid receptors, such as hypothalamic nuclei, are not yet well known. Several studies have demonstrated the role of hypothalamic nuclei in the organisation of behavioural responses induced through innate fear and panic attacks. Panic-prone states are experimentally induced in laboratory animals through a reduction in the GABAergic activity. The aim of the present study was to examine panic-like elaborated defensive behaviour evoked by GABAA receptor blockade with bicuculline (BIC) in the dorsomedial division of the ventromedial hypothalamus (VMHdm). We also aimed to characterise the involvement of endocannabinoids and the CB1 cannabinoid receptor in the modulation of elaborated defence behavioural responses organised with the VMHdm. The guide-cannula was stereotaxicaly implanted in VMHdm and the animals were treated with anandamide (AEA) at different doses, and the effective dose was used after the pre-treatment with the CB1 receptor antagonist AM251, followed by GABAA receptor blockade in VMHdm. The results showed that the intra-hypothalamic administration of AEA at an intermediate dose (5 pmol) attenuated defence responses induced through the intra-VMHdm microinjection of bicuculline (40 ng). This effect, however, was inhibited when applied central microinjection of the CB1 receptor antagonist AM251 in the VMHdm. Moreover, AM251 potentiates de non-oriented escape induced by bicuculline, effect blocked by pre-treatment with the TRPV1 channel antagonist 6-I-CPS. These results indicate that AEA modulates the pro-aversive effects of intra-VMHdm-bicuculline treatment, recruiting CB1 cannabinoid receptors and the TRPV1 channel is involved in the AM251-related potentiation of bicuculline effects on non-oriented escape behaviour.

  17. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G


    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  18. Reversal of prolonged rocuronium neuromuscular blockade with sugammadex in an obstetric patient with transverse myelitis.

    LENUS (Irish Health Repository)

    Weekes, G


    A 38-year-old wheelchair-bound primigravida with transverse myelitis presented at 38 weeks of gestation for elective caesarean section. Transverse myelitis, which is characterised by bilateral inflammation of the spinal cord and myelin destruction, is associated with myopathy, autonomic dysreflexia and pulmonary aspiration. Regional anaesthesia was contraindicated in this case as the patient had undergone two previous lumbar spinal fusion procedures. Rocuronium 1.2 mg\\/kg was used to facilitate rapid intubating conditions. The caesarean section proceeded uneventfully, but even after administration of neostigmine the patient exhibited prolonged neuromuscular blockade. After 3 h and 15 min sugammadex was obtained to reverse neuromuscular blockade; the drug was not stocked in our hospital. Sugammadex 4 mg\\/kg resulted in complete reversal of blockade after 2 min. We believe that myopathy associated with transverse myelitis led to the prolonged duration of action of rocuronium. Sugammadex is a relatively new drug with few reported side effects. In this case it was used to reverse neuromuscular blockade and prevented prolonged postoperative ventilatory support.

  19. Pumping of Vibrational Excitations in the Coulomb-Blockade Regime in a Suspended Carbon Nanotube

    NARCIS (Netherlands)

    Hüttel, A.K.; Witkamp, B.; Leijnse, M.; Wegewijs, M.R.; Van der Zant, H.S.J.


    Low-temperature transport spectroscopy measurements on a suspended few-hole carbon nanotube quantum dot are presented, showing a gate-dependent harmonic excitation spectrum which, strikingly, occurs in the Coulomb-blockade regime. The quantized excitation energy corresponds to the scale expected for

  20. Gender differences in the long QT syndrome: Effects of β-adrenoceptor blockade

    NARCIS (Netherlands)

    Conrath, Chantal E; Wilde, Arthur A.M; Jongbloed, Rosalie J.E; Alders, Mariëlle; Van Langen, Irene M; Peter Van Tintelen, J.; Doevendans, Pieter A; Opthof, Tobias


    Background: Gender differences have been reported in patients with the congenital long QT syndrome (LQTS). We analyzed whether electrocardiographic differences existed in females, males, girls and boys in response to β-adrenoceptor blockade. Methods: 12-lead ECGs before and during β-adrenoceptor blo

  1. Sinus node function after autonomic blockade in normals and in sick sinus syndrome. (United States)

    Sethi, K K; Jaishankar, S; Balachander, J; Bahl, V K; Gupta, M P


    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.

  2. Effects of axillary blockade on regional cerebral blood flow during dynamic hand contractions

    DEFF Research Database (Denmark)

    Friedman, D B; Friberg, L; Payne, G;


    Regional cerebral blood flow (rCBF) was measured at orbitomeatal (OM) plane +5.0 and +9.0 cm in 10 subjects at rest and during dynamic hand contractions before and after axillary blockade. Handgrip strength was significantly reduced, and rating of perceived exertion increased after blockade. During...... hand contractions before blockade, contralateral hemispheric cerebral blood flow (CBF) at OM +9.0 increased from a resting value of 58 (49-75) to 63 (52-82) ml.100 g-1.min-1; contralateral motor sensory rCBF at OM +9 from 58 (50-77) to 71 (64-84); motor sensory rCBF at OM +5 from 67 (54-76) to 77 (64......-87) and 70 (62-84) contralaterally and ipsilaterally, respectively; and supplementary motor area (SM) rCBF from 64 (53-69) to 75 (67-88) ml.100 g-1.min-1. During dynamic hand contractions after axillary blockade, CBF did not increase at OM +5 or in the SM. Furthermore, contralateral motor sensory rCBF at OM...

  3. Alpha-receptor blockade improves muscle perfusion and glucose uptake in heart failure.

    NARCIS (Netherlands)

    Gomes, M.E.R.; Mulder, A.; Bellersen, L.; Verheugt, F.W.A.; Smits, P.; Tack, C.J.J.


    AIMS: Alpha-adrenergic receptor-mediated vasoconstriction might underlie the insulin resistance seen in conditions associated with increased sympathetic tone, like chronic heart failure (CHF). Alpha-adrenergic receptor blockade by phentolamine could improve forearm blood flow (FBF) and forearm gluco

  4. Effect of axillary blockade on regional cerebral blood flow during static handgrip

    DEFF Research Database (Denmark)

    Friedman, D B; Friberg, L; Mitchell, J H


    . Median handgrip force during the control study was 41 (range 24-68) N, which represented 10% of the initial maximal voluntary contraction (MVC) and was 24 (18-36) N after axillary blockade (P less than 0.05), which represented 21% of the new MVC. During static handgrip, the rating of perceived exertion...

  5. Coulomb blockade model of permeation and selectivity in biological ion channels (United States)

    Kaufman, I. Kh; McClintock, P. V. E.; Eisenberg, R. S.


    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.

  6. Neuromuscular blockade for optimising surgical conditions during abdominal and gynaecological surgery

    DEFF Research Database (Denmark)

    Madsen, M V; Staehr-Rye, A K; Gätke, M R


    BACKGROUND: The level of neuromuscular blockade (NMB) that provides optimal surgical conditions during abdominal surgery has not been well established. The aim of this systematic review was to evaluate current evidence on the use of neuromuscular blocking agents in order to optimise surgical cond...

  7. Glucose intolerance induced by blockade of central FGF receptors is linked to an acute stress response

    Directory of Open Access Journals (Sweden)

    Jennifer M. Rojas


    Conclusions: The effect of acute inhibition of central FGFR signaling to impair glucose tolerance likely involves a stress response associated with pronounced, but transient, sympathoadrenal activation and an associated reduction of insulin secretion. Whether this effect is a true consequence of FGFR blockade or involves an off-target effect of the FGFR inhibitor requires additional study.

  8. Beta adrenergic blockade in the treatment of sustained ventricular tachycardia or ventricular fibrillation

    NARCIS (Netherlands)

    Wiesfeld, ACP; Crijns, HJGM; Tuininga, YS; Lie, KI


    The value of beta-blockers as antiarrhythmic drugs in patients with sustained VT or VF has received only little attention. This article summarizes the current state of knowledge regarding the identification of patients with sustained VT or VF with the highest benefit of beta-blockade. The antiarrhyt

  9. Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. (United States)

    Deutsch, M; Graffeo, C S; Rokosh, R; Pansari, M; Ochi, A; Levie, E M; Van Heerden, E; Tippens, D M; Greco, S; Barilla, R; Tomkötter, L; Zambirinis, C P; Avanzi, N; Gulati, R; Pachter, H L; Torres-Hernandez, A; Eisenthal, A; Daley, D; Miller, G


    Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.


    NARCIS (Netherlands)



    To establish the effects of alpha-adrenoceptor blockade on dopamine-induced changes in renal hemodynamics and sodium excretion, dopamine dose-response curves were performed without and with pre-treatment with the selective postsynaptic alpha-1-adrenoceptor antagonist prazosin in normal volunteers an

  11. Improvement of Sodium Status to Optimize the Efficacy of Renin-Angiotensin System Blockade

    NARCIS (Netherlands)

    Laverman, Gozewijn D.; Navis, Gerjan


    Blockade of the renin-angiotensin-aldosterone system (RAAS) offers superior renoprotection in the treatment of patients with hypertension, but the efficacy of RAAS inhibition strongly depends on sodium status, presumably in relation to extracellular volume status. Because assessing volume status by

  12. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity

    NARCIS (Netherlands)

    Boon, M.R.; Kooijman, S.; Dam, A.D. van; Pelgrom, L.R.; Berbée, J.F.P.; Visseren, C.A.R.; Aggele, R.C. van; Hoek, A.M. van den; Sips, H.C.M.; Lombès, M.; Havekes, L.M.; Tamsma, J.T.; Guigas, B.; Meijer, O.C.; Jukema, J.W.; Rensen, P.C.N.


    The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The m

  13. The effect of RAAS blockade on markers of renal tubular damage in diabetic nephropathy

    DEFF Research Database (Denmark)

    Nielsen, Stine; Rossing, Kasper; Hess, Georg


    Blockade of the renin-angiotensin-aldosterone system (RAAS) affects both the glomerulus and tubules. We aimed to investigate the effect of irbesartan on the tubular markers: urinary (u) neutrophil gelatinase associated protein (NGAL), Kidney injury molecule 1 (KIM1) and liver-fatty acid-binding p...

  14. Nonlinear modifications of photon correlations via controlled single and double Rydberg blockade (United States)

    Liu, Yi-Mou; Tian, Xue-Dong; Yan, Dong; Zhang, Yan; Cui, Cui-Li; Wu, Jin-Hui


    We study the optical response of cold rubidium atoms driven into the four-level Y configuration exhibiting two high Rydberg levels in the regime of electromagnetically induced transparency (EIT). Atoms excited to either Rydberg level interact with each other just via self-blockade potentials (I) or also via cross blockade potentials (II). Numerical results show a few interesting quantum phenomena on the transmitted properties of a weak probe field owing to controlled single and double Rydberg blockade. In case (I), it is viable to switch between single-photon outputs with vanishing (invariable) two-photon (three-photon) correlation and photon-pair outputs with vanishing (invariable) three-photon (two-photon) correlation. Such output switch can be easily done by modulating frequencies and intensities of two strong coupling fields to create a degenerate EIT window or two separated EIT windows. In case (II), we find that two-photon and three-photon correlations decrease together at a degenerate EIT window center while increasing together between two separated EIT windows. Such consistent changes are observed because both correlations are modified by the identical polarizability degradation though depending on single and double Rydberg blockade, respectively.

  15. The efficacy of adductor canal blockade after minor arthroscopic knee surgery

    DEFF Research Database (Denmark)

    Espelund, M; Fomsgaard, J S; Haraszuk, J;


    BACKGROUND: Adductor canal blockade (ACB) has been demonstrated to be effective in the treatment of post-operative pain after major knee surgery. We hypothesised that the ACB would reduce pain and analgesic requirements after minor arthroscopic knee surgery. METHODS: Seventy-two patients scheduled...

  16. Fascia iliaca compartment blockade for acute pain control in hip fracture patients

    DEFF Research Database (Denmark)

    Foss, Nicolai B; Kristensen, Billy B; Bundgaard, Morten


    Hip fracture patients are in severe pain upon arrival at the emergency department. Pain treatment is traditionally based on systemic opioids. No study has examined the effect of fascia iliaca compartment blockade (FICB) in acute hip fracture pain management within a double-blind, randomized setup....

  17. The antihypertensive effectiveness and safety of dual RAAS blockade with aliskiren and valsartan. (United States)

    Chrysant, Steven G


    The renin-angiotensin-aldosterone system (RAAS) is a major factor for the development and maintenance of hypertension and a major cause for cardiovascular remodeling and cardiovascular complications through its active peptide angiotensin (Ang) II. Blockade of RAAS with ACE inhibitors (ACEIs) results in suppression of Ang II levels, which eventually return to baseline levels after prolonged ACEI administration. This leads to an escape phenomenon through generation of Ang II from enzymes other than ACE and led to the hypothesis that dual blockade of RAAS with an ACEI/Ang receptor blocker (ARB) combination could lead to total blockade of RAAS, since ARBs block the action of Ang II at the AT1 receptor level, irrespective of the mechanism of Ang II generation and will have an additive blood pressure (BP)-lowering effect. However, this hypothesis has not materialized clinically, as the ACEI/ARB combination produces modest BP reductions that are not significantly greater than monotherapy with the component drugs, and is frequently associated with higher incidence of side effects. A new dual RAAS blockade with the direct renin inhibitor aliskiren and the ARB valsartan produces greater BP reductions than monotherapy with the component drugs and is safe and well tolerated. The combination of aliskiren with valsartan, and with other antihypertensive drugs is discussed.

  18. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. (United States)

    Wong, Raymond M; Scotland, Ron R; Lau, Roy L; Wang, Changyu; Korman, Alan J; Kast, W M; Weber, Jeffrey S


    Negative co-stimulatory signaling mediated via cell surface programmed death (PD)-1 expression modulates T and B cell activation and is involved in maintaining peripheral tolerance. In this study, we examined the effects of a fully human PD-1-abrogating antibody on the in vitro expansion and function of human vaccine-induced CD8+ T cells (CTLs) specific for the melanoma-associated antigens glycoprotein 100 (gp100) and melanoma antigen recognized by T cells (MART)-1. PD-1 blockade during peptide stimulation augmented the absolute numbers of CD3+, CD4+, CD8+ and gp100/MART-1 MHC:peptide tetramer+ CTLs. This correlated with increased frequencies of IFN-gamma-secreting antigen-specific cells and augmented lysis of gp100+/MART-1+ melanoma targets. PD-1 blockade also increased the fraction of antigen-specific CTLs that recognized melanoma targets by degranulation, suggesting increased recognition efficiency for cognate peptide. The increased frequencies and absolute numbers of antigen-specific CTLs by PD-1 blockade resulted from augmented proliferation, not decreased apoptosis. Kinetic analysis of cytokine secretion demonstrated that PD-1 blockade increased both type-1 and type-2 cytokine accumulation in culture without any apparent skewing of the cytokine repertoire. These findings have implications for developing new cancer immunotherapy strategies.

  19. The future of cancer therapy: Selecting patients who respond to PD-1/L1 blockade (United States)

    Ribas, Antoni; Tumeh, Paul C.


    Summary It is conceivable that, in the near future, an assay that defines the likelihood of a patient with advanced cancer to respond to immunotherapy based on PD-1/L1 blockade will be the initial decision point to select the treatment of patients with any cancer type. PMID:24970841

  20. Prolonged analgesia following preoperative bupivacaine neural blockade for oral surgery performed under general anesthesia. (United States)

    Chapman, P J; Ganendran, A


    The effectiveness of prolonged neural blockade following removal of impacted third molars under general anesthesia was evaluated in a controlled clinical study. There was a significant reduction in the amount of postoperative pain experienced, and no complications, either local or systemic, occurred. The technique has advantages, especially when general anesthesia is administered to outpatients.

  1. The problem of true macroscopic charge quantization in the Coulomb blockade

    NARCIS (Netherlands)

    Burmistrov, I.S.; Pruisken, A.M.M.; Bonča, J.; Kruchinin, S.


    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 fi

  2. The effect of neuromuscular blockade on canine laparoscopic ovariectomy: A double-blinded, prospective clinical trial

    NARCIS (Netherlands)

    van Goethem, B.; van Nimwegen, S.A.; Akkerdaas, L.C.; Murrell, J.C.; Kirpensteijn, J.


    The Effect of Neuromuscular Blockade on Canine Laparoscopic Ovariectomy: A Double-Blinded, Prospective Clinical Trial Bart Van Goethem, Diplomate ECVS, Sebastiaan Alexander van Nimwegen, PhD, Ies Akkerdaas, DVM, Joanna Claire Murrell, BVSc., PhD, Diplomate ECVAA, and Jolle Kirpensteijn, PhD, Diploma

  3. CT-guided thoracic sympathetic blockade for palmar hyperhidrosis: Immediate results and postoperative quality of life. (United States)

    Guo, Jian-Guo; Fei, Yong; Huang, Bing; Yao, Ming


    The purpose of this study was to evaluate the results, complications, and degree of satisfaction among patients who underwent a CT-guided percutaneous puncture thoracic sympathetic blockade. A total of 186 patients underwent CT-guided thoracic sympathetic blockade based on case histories and a prospective pre- and postoperative questionnaire survey. The study sample was composed of 93 patients with an age range from 18 to 34years and a diagnosis with primary palmar hyperhidrosis (severe in some patients). Percutaneous puncture thoracic sympathetic blockade guided by CT was performed under local anesthesia in all patients. Heart rate (HR), non-invasive blood pressure (NIBP), arterial oxygen saturation (SPO2), perfusion index (PI), and palmar temperature (T) were monitored before and after treatment. Follow-up included a questionnaire on life quality and degree of satisfaction. Ten minutes after treatment, the SPO2, PI, and temperature all raised remarkably ([92.75±2.02]% vs. [98.85±1.09]%, [1.55±0.69]% vs. [8.60±0.94]%, [30.95±1.27]°C vs. [35.75±0.55]°C, respectively, Phyperhidrosis, 87.6% reported improvement in their quality of life. CT-guided percutaneous puncture thoracic sympathetic blockade is a safe, effective, and minimally invasive technique for the treatment of palmar hyperhidrosis. Despite the high rate of compensatory hyperhidrosis, it produces a high rate of patient satisfaction.

  4. Differential effects of B7-1 blockade in the rat experimental autoimmune encephalomyelitis model

    DEFF Research Database (Denmark)

    Gallon, L; Chandraker, A; Issazadeh-Navikas, Shohreh;


    Blocking the CD28-B7 T cell costimulatory activation pathway protects animals from developing experimental autoimmune encephalomyelitis (EAE). In the mouse EAE model, selective blockade of B7-1 by specific mAbs has been shown to protect animals from EAE. In the Lewis rat model, we have shown that...

  5. Photon Routing in Cavity QED: Beyond the Fundamental Limit of Photon Blockade

    CERN Document Server

    Rosenblum, Serge; Dayan, Barak


    The most simple and seemingly straightforward application of the photon blockade effect, in which the transport of one photon prevents the transport of others, would be to separate two incoming indistinguishable photons to different output ports. We show that time-energy uncertainty relations inherently prevent this ideal situation when the blockade is implemented by a two-level system. The fundamental nature of this limit is revealed in the fact that photon blockade in the strong coupling regime of cavity QED, resulting from the nonlinearity of the Jaynes-Cummings energy level structure, exhibits efficiency and temporal behavior identical to those of photon blockade in the bad cavity regime, where the underlying nonlinearity is that of the atom itself. We demonstrate that this limit can be exceeded, yet not avoided, by exploiting time-energy entanglement between the incident photons. Finally, we show how this limit can be circumvented completely by using a three-level atom coupled to a single-sided cavity, e...

  6. Photon routing in cavity QED: Beyond the fundamental limit of photon blockade

    Energy Technology Data Exchange (ETDEWEB)

    Rosenblum, Serge; Dayan, Barak [Department of Chemical Physics, Weizmann Institute of Science, Rehovot 76100 (Israel); Parkins, Scott [Department of Physics, University of Auckland, Private Bag 92019, Auckland (New Zealand)


    The most simple and seemingly straightforward application of the photon blockade effect, in which the transport of one photon prevents the transport of others, would be to separate two incoming indistinguishable photons to different output ports. We show that time-energy uncertainty relations inherently prevent this ideal situation when the blockade is implemented by a two-level system. The fundamental nature of this limit is revealed in the fact that photon blockade in the strong coupling regime of cavity QED, resulting from the nonlinearity of the Jaynes-Cummings energy level structure, exhibits efficiency and temporal behavior identical to those of photon blockade in the bad cavity regime, where the underlying nonlinearity is that of the atom itself. We demonstrate that this limit can be exceeded, yet not avoided, by exploiting time-energy entanglement between the incident photons. Finally, we show how this limit can be circumvented completely by using a three-level atom coupled to a single-sided cavity, enabling an ideal and robust photon routing mechanism.

  7. Oxidative Stress Modulates DNA Methylation during Melanocyte Anchorage Blockade Associated with Malignant Transformation

    Directory of Open Access Journals (Sweden)

    Ana C.E. Campos


    Full Text Available Both oxidative/nitrosative stress and alterations in DNA methylation are observed during carcinogenesis of different tumor types, but no clear correlation between these events has been demonstrated until now. Melanoma cell lines were previously established after submitting the nontumorigenic melanocyte lineage, melan-a, to cycles of anchorage blockade. In this work, increased intracellular oxidative species and nitric oxide levels, as well as alterations in the DNA methylation, were observed after melan-a detachment, which were also associated with a decrease in intracellular homocysteine (Hey, an element in the methionine (universal methyl donor cycle. This alteration was accompanied by increase in glutathione (GSH levels and methylated DNA content. Furthermore, a significant increase in dnmti and 3b expression was identified along melan-a anchorage blockade. LG-Nitro-L-arginine methyl esther (L-NAME, known as a nitric oxide synthase (NOS inhibitor, and N-acetyl-L-cysteine (NAC prevented the increase in global DNA methylation, as well as the increase in dnmti and 3b expression, observed during melan-a detachment. Interestingly, both L-NAME and NAC did not inhibit nitric oxide (NO production in these cells, but abrogated superoxide anion production during anchorage blockade. In conclusion, oxidative stress observed during melanocyte anchorage blockade seems to modulate DNA methylation levels and may directly contribute to the acquisition of an anoikis-resistant phenotype through an epigenetic mechanism.

  8. Surgical Space Conditions During Low-Pressure Laparoscopic Cholecystectomy with Deep Versus Moderate Neuromuscular Blockade

    DEFF Research Database (Denmark)

    Staehr-Rye, Anne K; Rasmussen, Lars S.; Rosenberg, Jacob;


    described, but deep neuromuscular blockade may be beneficial. We investigated if deep muscle relaxation would be associated with a higher proportion of procedures with "optimal" surgical space conditions compared with moderate relaxation during low-pressure (8 mm Hg) laparoscopic cholecystectomy. METHODS...... with surgical space conditions that were marginally better than with moderate muscle relaxation during low-pressure laparoscopic cholecystectomy....

  9. CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial

    NARCIS (Netherlands)

    A.W.R. van Kuijk; C.E. Vergunst; D.M. Gerlag; B. Bresnihan; J.J. Gomez-Reino; R. Regine; P.C. Verschueren; C. van der Leij; M. Maas; M.C. Kraan; P.P. Tak


    Objective C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects o

  10. Optimized surgical space during low-pressure laparoscopy with deep neuromuscular blockade

    DEFF Research Database (Denmark)

    Staehr-Rye, Anne K; Rasmussen, Lars S; Rosenberg, Jacob;


    Laparoscopic cholecystectomy (LC) can be performed using low intra-abdominal pressure (space conditions using either deep, continuous muscle relaxation or moderate blockade during low-pressure (8 mm......Hg) LC. We hypothesized that a deep neuromuscular block would be associated with a higher proportion of optimal surgical space conditions....

  11. Impact of Growth Hormone Receptor Blockade on Substrate Metabolism during Fasting in Healthy Subjects


    Moller, Louise; Norrelund, Helene; Jessen, Niels; Flyvbjerg, Allan; Steen B Pedersen; Bruce D Gaylinn; Liu, Jianhua; Thorner, Michael O.; Moller, Niels; Lunde Jorgensen, Jens Otto


    Context: Experimental studies in GH-deficient patients and in healthy subjects receiving somatostatin-infusion suggest that GH is an important regulator of substrate metabolism during fasting. These models may not adequately reflect the selective effects of GH, and GH receptor (GHR) blockade offers a new model to define the metabolic role of GH.

  12. Serotonin type-1A receptor imaging in depression

    Energy Technology Data Exchange (ETDEWEB)

    Drevets, Wayne C. E-mail:; Frank, Ellen; Price, Julie C.; Kupfer, David J.; Greer, Phil J.; Mathis, Chester


    Regional 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl-{sup 11}C]WAY-100635 {l_brace}[{sup 11}C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide{r_brace}. The mean 5-HT{sub 1A} receptor BP was reduced 42% in the midbrain raphe and 25-33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT{sub 1A} receptor BP are consistent with in vivo evidence that 5-HT{sub 1A} receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT{sub 1A} receptor expression in primary mood disorders.

  13. Cannabidiol induces rapid-acting antidepressant-like effects and enhances cortical 5-HT/glutamate neurotransmission: role of 5-HT1A receptors. (United States)

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


    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.

  14. Ferrite attenuator modulation improves antenna performance (United States)

    Hooks, J. C.; Larson, S. G.; Shorkley, F. H.; Williams, B. T.


    Ferrite attenuator inserted into appropriate waveguide reduces the gain of the antenna element which is causing interference. Modulating the ferrite attenuator to change the antenna gain at the receive frequency permits ground tracking until the antenna is no longer needed.

  15. Analgesic efficacy of the ultrasound-guided blockade of the transversus abdominis plane - a systematic review

    Directory of Open Access Journals (Sweden)

    Javier Ripollés


    Full Text Available BACKGROUND: The transverse abdominal plan blockade is a block of abdominal wall that has diffused rapidly in the clinical practice as part of a multimodal analgesia for abdominal surgery. The performance of the ultrasound-guided technique has allowed the lowering of potential complications, as well as new approaches that were carried out according to the descriptions, and the prospective studies would make it possible to utilize the transverse abdominal plan blockade in different surgical interventions; however, the results obtained in randomized clinical trials are inconsistent.OBJECTIVES: To prepare a systematic review aiming to determine the efficacy of the ultrasound-guided transverse abdominal plan blockade for different surgical interventions, as well as the indications according to the approaches and their influences.METHODS: Two research approaches, one manual, and the other in Pubmed returned 28 randomized clinical trials where intervention with ultrasound-guided transverse abdominal plan blockades was performed to compare the analgesic efficacy in contrast to another technique in adults, published between 2007 and October 2013, in English or Spanish, with Jadad score > 1, according to the inclusion criteria for this review. The authors analyzed independently all the randomized clinical trials.CONCLUSIONS: The transverse abdominal plan blockades have been shown to be an effective technique in colorectal surgery, cesarean section, cholecystectomy, hysterectomy, appendectomy, donor nephrectomy, retropubic prostatectomy, and bariatric surgery. However, the data found in randomized clinical trial are not conclusive, and as a result, it is necessary to develop new and well designed randomized clinical trial, with enough statistical power to compare different approaches, drugs, doses, and volumes for the same intervention, aiming to answer the current questions and their effects in the habitual clinical practice.

  16. Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

    Directory of Open Access Journals (Sweden)

    Yuki Hamano


    Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.


    Energy Technology Data Exchange (ETDEWEB)

    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


    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).

  18. [5-HT1A/5-HT7 receptor interplay: Chronic activation of 5-HT7 receptors decreases the functional activity of 5-HT1A receptor and its сontent in the mouse brain]. (United States)

    Kondaurova, E M; Bazovkina, D V; Naumenko, V S


    Serotonin receptors 5-HT1A and 5-HT7 are involved in the development of various psychopathologies. Some data indicate that there is an interplay between 5-HT1A 5-HT7 receptors that could be implicated in the regulation of their function. This work analyzed the effects of chronic 5-HT7 activation on the functional activity of 5-HT7 and 5-HT1A receptors, on the corresponding protein levels, and on the expression of genes encoding 5-HT7 and 5-HT1A receptors in the mouse brain. Chronic administration of the 5-HT7 selective agonist LP44 (20.5 nmol, i.c.v., 14 days) produced considerable desensitization of both 5-HT7 and 5-HT1A receptors. In LP44-treated mice, the hypothermic responses mediated by both 5-HT7 and 5-HT1A receptors were attenuated. Moreover, the levels of 5-HT1A receptor protein in the midbrain and the frontal cortex of LP44-treated mice were significantly decreased. However, the brain levels of 5-HT7 receptor protein did not differ between LP44-treated and control mice. Chronic LP44 treatment did not alter the expression of the 5-HT7 and 5-HT1A receptor genes in all investigated brain structure. These data suggest that 5-HT7 receptors participate in the posttranscriptional regulation of the 5-HT1A receptors functioning.

  19. Chlorine signal attenuation in concrete. (United States)

    Naqvi, A A; Maslehuddin, M; ur-Rehman, Khateeb; Al-Amoudi, O S B


    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. Mechanisms of geometrical seismic attenuation

    Directory of Open Access Journals (Sweden)

    Igor B. Morozov


    Full Text Available In several recent reports, we have explained the frequency dependence of the apparent seismic quality-factor (Q observed in many studies according to the effects of geometrical attenuation, which was defined as the zero-frequency limit of the temporal attenuation coefficient. In particular, geometrical attenuation was found to be positive for most waves traveling within the lithosphere. Here, we present three theoretical models that illustrate the origin of this geometrical attenuation, and we investigate the causes of its preferential positive values. In addition, we discuss the physical basis and limitations of both the conventional and new attenuation models. For waves in media with slowly varying properties, geometrical attenuation is caused by variations in the wavefront curvature, which can be both positive (for defocusing and negative (for focusing. In media with velocity/density contrasts, incoherent reflectivity leads to geometrical-attenuation coefficients which are proportional to the mean squared reflectivity and are always positive. For «coherent» reflectivity, the geometrical attenuation is approximately zero, and the attenuation process can be described according to the concept of «scattering Q». However, the true meaning of this parameter is in describing the mean reflectivity within the medium, and not that of the traditional resonator quality factor known in mechanics. The general conclusion from these models is that non-zero and often positive levels of geometrical attenuation are common in realistic, heterogeneous media, both observationally and theoretically. When transformed into the conventional Q-factor form, this positive geometrical attenuation leads to Q values that quickly increase with frequency. These predictions show that the positive frequency-dependent Q observed in many datasets might represent artifacts of the transformations of the attenuation coefficients into Q.

  1. Novel MEMS variable optical attenuator

    Institute of Scientific and Technical Information of China (English)

    Maosong Wu(吴茂松); Chunsheng Yang(杨春生); Xinhui Mao(茅昕辉); Xiaolin Zhao(赵小林); Bingchu Cai(蔡炳初)


    A novel MEMS variable optical attenuator (VOA), which has completely different attenuation mechanismfrom those in literatures, is proposed and demonstrated in this paper. The basic operation principle is thatthe optical power coupled between two initially aligned single-mode fibers will be continuously attenuatedwhile the end of one of the fibers is deflected from the initial position. A micromachined solenoid typeinductor with a U-shaped permalloy magnetic core is used to attract the deflectable fiber that has apermalloy coat on its end. To fabricate the multi-layer three-dimensional inductive component, a newUV-LIGA process for thick photoresists is developed, combining advantages of both SU-8 and AZ-4000series photoresists. The inductive component is approximately 1.7 mm× 1.3 mm×50μm in size and has alow resistance value (~ 2.1Ω). The whole size of the VOA before packaging is 30 mm×2 mm×0.6 mm.The first prototype shows less then 3-dB insertion loss at 0-dB attenuation and nearly 40-dB attenuationrange with less than 20 mW electrical input power at wavelength 1550 nm.

  2. Alterations in the oxygen deficit-oxygen debt relationships with beta-adrenergic receptor blockade in man. (United States)

    Hughson, R L


    The effects of beta-adrenergic receptor blockade (100 mg oral metoprolol) or matched placebo on gas exchange kinetics were studied in six males. Ventilation and gas exchange were monitored in four transitions for each treatment from loadless pedalling (0 W) to a selected work rate (100 W) and back to 0 W. Breath-by-breath data were averaged for analysis. Oxygen uptake (VO2) kinetics were significantly slowed at the onset of exercise and recovery by beta-blockade. This resulted in larger oxygen deficit and oxygen debt (671 +/- 115, 586 +/- 87 ml O2, respectively) for beta-blockade than for placebo (497 +/- 87, 474 +/- 104 ml O2). In addition, oxygen deficit was significantly larger than oxygen debt during beta-blockade tests. These results can be explained by greater utilization of oxygen and creatine phosphate stores as well as anaerobic glycolysis at the onset of 100 W exercise with beta-blockade. Carbon dioxide output (VCO2) kinetics were significantly slowed by beta-blockade only at the onset of exercise. Expired ventilation (VE) kinetics were not affected by beta-blockade. At 0 W, VE was significantly reduced by beta-blockade. Heart rate was lower at all times with beta-blockade. Kinetics of heart rate were not affected. These data for VO2 kinetics at the start and end of exercise indicate that even in moderate-intensity exercise, lactic acid production can contribute significantly to energy supply. The use of the term ' alactic ' to describe the deficit and debt associated with this exercise is not appropriate.

  3. Serotonin-1A receptor polymorphism (rs6295 associated with thermal pain perception.

    Directory of Open Access Journals (Sweden)

    Fredrik Lindstedt

    Full Text Available BACKGROUND: Serotonin (5-HT is highly involved in pain regulation and serotonin-1A (5-HT1A receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities. METHODS: Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C-49°C. Nociceptive-flexion reflex (NFR thresholds were also assessed. RESULTS: Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged. CONCLUSION/SIGNIFICANCE: To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a 'hypo- to hyperalgesic' response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain

  4. Serotonin 2A Receptors, Citalopram and Tryptophan-Depletion

    DEFF Research Database (Denmark)

    Macoveanu, Julian; Hornboll, Bettina; Elliott, Rebecca;


    in serotonergic regulation of response inhibition. In 24 healthy adults, we used (18)F-altanserin positron emission tomography to assess cerebral 5-HT(2A) receptors, which have been related to impulsivity. We then investigated the impact of two acute manipulations of brain serotonin levels on behavioral...

  5. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn;


    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclin......Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...... antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor...

  6. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

    Directory of Open Access Journals (Sweden)

    Lyte Mark


    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  7. Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis

    Directory of Open Access Journals (Sweden)

    Pollizzi Kristen


    Full Text Available Abstract Background Tuberous sclerosis (TSC is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235. Results Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week and NVP-BEZ235 (45 mg/kg PO QD had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation. Conclusion Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.

  8. Evidence that the positive inotropic effects of the alkylxanthines are not due to adenosine receptor blockade. (United States)

    Collis, M. G.; Keddie, J. R.; Torr, S. R.


    We investigated the possibility that the positive inotropic effects of the alkylxanthines are due to adenosine receptor blockade. The potency of 8-phenyltheophylline, theophylline and enprofylline as adenosine antagonists was assessed in vitro, using the guinea-pig isolated atrium, and in vivo, using the anaesthetized dog. The order of potency of the alkylxanthines as antagonists of the negative inotropic response to 2-chloroadenosine in vitro, and of the hypotensive response to adenosine in vivo was 8-phenyltheophylline greater than theophylline greater than enprofylline. The order of potency of the alkylxanthines as positive inotropic and chronotropic agents in the anaesthetized dog was enprofylline greater than theophylline greater than 8-phenyltheophylline. The results of this study indicate that the inotropic effects of the alkylxanthines in the anaesthetized dog are not due to adenosine receptor blockade. PMID:6322898

  9. Split-dose atropine versus glycopyrrolate with neostigmine for reversal of gallamine-induced neuromuscular blockade

    DEFF Research Database (Denmark)

    Wetterslev, J; Jarnvig, I; Jørgensen, L N


    The effects of a split-dose of atropine sulphate versus a single dose of glycopyrrolate given with neostigmine for the reversal of gallamine-induced neuromuscular blockade were studied in 55 patients undergoing gynaecological surgery. The patients were randomized to receive either a single dose...... of glycopyrrolate (7 or two doses of atropine (8 each), given with an interval of 1 min. There were no differences between the two methods with respect to percentage heart rate changes, salivation or arousal time. Four patients demonstrated cardiac arhythmias in the atropine group......, whereas none occurred in the glycopyrrolate group (P less than 0.05). It is concluded that a split-dose of atropine has similar chronotropic effects to a single dose of glycopyrrolate for the reversal of gallamine-induced neuromuscular blockade. However, the finding of a higher incidence of cardiac...

  10. Rydberg-Blockade Effects in Autler-Townes Spectra of Ultracold Strontium

    CERN Document Server

    DeSalvo, B J; Gaul, C; Pohl, T; Yoshida, S; Burgdörfer, J; Hazzard, K R A; Dunning, F B; Killian, T C


    We present a combined experimental and theoretical study of the effects of Rydberg interactions on Autler-Townes spectra of ultracold gases of atomic strontium. Realizing two-photon Rydberg excitation via a long-lived triplet state allows us to probe the thus far unexplored regime where Rydberg state decay presents the dominant decoherence mechanism. The effects of Rydberg interactions are observed in shifts, asymmetries, and broadening of the measured atom-loss spectra. The experiment is analyzed within a one-body density matrix approach, accounting for interaction-induced level shifts and dephasing through nonlinear terms that approximately incorporate correlations due to the Rydberg blockade. This description yields good agreement with our experimental observations for short excitation times. For longer excitation times, the loss spectrum is altered qualitatively, suggesting additional dephasing mechanisms beyond the standard blockade mechanism based on pure van der Waals interactions.

  11. Quantum transport through a Coulomb blockaded quantum emitter coupled to a plasmonic dimer. (United States)

    Goker, A; Aksu, H


    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.

  12. Phonon blockade in a nanomechanical resonator resonantly coupled to a qubit

    CERN Document Server

    Xu, Xun-Wei; Liu, Yu-xi


    We study phonon statistics in a nanomechanical resonator (NAMR) which is resonantly coupled to a qubit. We find that there are two different mechanisms for phonon blockade in such a resonantly coupled NAMR-qubit system. One is due to the strong anharmonicity of the NAMR-qubit system with large coupling strength; the other one is due to the destructive interference between different paths for two-phonon excitation in the NAMR-qubit system with a moderate coupling strength. In order to enlarge the mean phonon number for strong phonon antibunching with a moderate NAMR-qubit coupling strength, we assume that two external driving fields are applied to the NAMR and qubit, respectively. In this case, we find that the phonon blockades under two mechanisms can appear at the same frequency regime by optimizing the strength ratio and phase difference of the two external driving fields.

  13. Photon-blockade as protection in photosynthesis Antenna with cyclic structures

    CERN Document Server

    Dong, Hui; Yi, Zhenhuan; Agarwal, Girish S; Scully, Marlan O


    Excess energy absorbed by the light-harvesting antennas could be potentially harmful to the photosynthesis complexes. The biological system has developed various mechanisms, e.g. non-photon chemical quenching, to prevent these damages by dissipating energy into the surrounding environment. In additional to this well-known mechanism, we hypothesise a new protection mechanism of suppressing the probability of double excitation in photosynthesis system, where pigment-protein complexes form cyclic structures with dipole-dipole interaction between adjacent chlorophylls. We also demonstrate robustness of the photon blockade against the disorder in the ring structures. The photon blockade can explain the recent observation on the suppression of simultaneous emission of two photons in natural photosynthetic antennas.

  14. Antigen-induced airway obstruction and the influence of vagus blockade. (United States)

    Zimmermann, I; Islam, M S; Lanser, K; Ulmer, W T


    Respiratory hypersensitivity to Ascaris antigens is carried out on 9 dogs. The participation of vagus reflex on this respiratory distress is studied in 4 of these dogs. The dogs were exposed initially to Ascaris aerosol, then to egg albumin and NaCl aerosol for control, and once more to Ascaris aerosol after bilateral vagi blockade and lavage, respectively. The principal parameters studied were deltaPoes (mm Hg)/100 ml TV as a measurement of flow resistance in the airways, and respiratory rates (Poes=changes of oesphagus pressure; TV=tidal volume). All the animals presented a significant respiratory distress with Ascaris aerosol, which could be clearly avoided with the central bilateral blockade of nervus vagus.

  15. Intestinal microbiome analyses identify melanoma patients at risk for checkpoint-blockade-induced colitis. (United States)

    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


    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.

  16. A Rydberg blockade CNOT gate and entanglement in a 2D array of neutral atom qubits

    CERN Document Server

    Maller, K M; Xia, T; Sun, Y; Piotrowicz, M J; Carr, A W; Isenhower, L; Saffman, M


    We present experimental results on two-qubit Rydberg blockade quantum gates and entanglement in a two-dimensional qubit array. Without post selection against atom loss we achieve a Bell state fidelity of $0.73\\pm 0.05$, the highest value reported to date. The experiments are performed in an array of single Cs atom qubits with a site to site spacing of $3.8 ~ \\mu\\rm m$. Using the standard protocol for a Rydberg blockade C$_Z$ gate together with single qubit operations we create Bell states and measure their fidelity using parity oscillations. We analyze the role of AC Stark shifts that occur when using two-photon Rydberg excitation and show how to tune experimental conditions for optimal gate fidelity.

  17. Robust and High Fidelity Quantum Logic with the Rydberg-Dressed Blockade (United States)

    Keating, Tyler; Cook, Robert; Deutsch, Ivan; Hankin, Aaron; Jau, Yuan-Yu; Biedermann, Grant


    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 logic.

  18. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study - Efficacy, safety, and pharmacokinetics

    NARCIS (Netherlands)

    Sparr, Harald J.; Vermeyen, Karel M.; Beaufort, Anton M.; Rietbergen, Henk; Proost, Johannes H.; Saldien, Vera; Velik-Salchner, Corinna; Wierda, J. Mark K. H.


    Background: Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. Methods: Ninety-eight male adult patients were rando

  19. Continuous adductor-canal-blockade for adjuvant post-operative analgesia after major knee surgery: preliminary results

    DEFF Research Database (Denmark)

    Lund, J; Jenstrup, M T; Jæger, P;


    Because both the saphenous nerve and in part the obturator nerve are traversing the adductor canal of the thigh, we hypothesised that repeated administration of a local anaesthetic (LA) into this aponeurotic space could be a useful option for post-operative analgesia after knee replacement surgery....... A systematic search of the literature pertinent to the blockade of the saphenous and/or obturator nerves for pain relief after knee surgery was conducted. Further, pain and opioid requirements were evaluated in eight patients receiving a continuous blockade of the saphenous and obturator nerve (adductor-canal......-blockade) after total knee arthroplasty (TKA). Finally, we performed cross-sectional MR scans of the adductor canal after injection of ropivacaine 30ml in one patient. The systematic literature search revealed only one controlled study, where selective blockade of the saphenous nerve was investigated...

  20. Continuous positive airway pressure breathing increases the spread of sensory blockade after low-thoracic epidural injection of lidocaine.

    NARCIS (Netherlands)

    Visser, W.A.; Gielen, M.J.M.; Giele, J.L.P.


    Factors affecting the distribution of sensory blockade after epidural injection of local anesthetics remain incompletely clarified. To evaluate if increasing intrathoracic pressure affects the spread of thoracic epidural anesthesia, we randomized 20 patients who received an epidural catheter at the

  1. Vaccination with Dendritic Cell Myeloma Fusions in Conjunction With Stem Cell Transplantation and PD1 Blockade (United States)


    blockade, immunotherapy , multiple myeloma 16. SECURITY CLASSIFICATION OF: STRACT AGES RESPONSIBLE PERSON 17. LIMITATION OF AB 18. NUMBER OF P 19a...10/1/11 2 POSSIBLE N/A NONE RESOLVED PM09 Thyroid Function, 10/31/11 1 POSSIBLE N/A Low NONE RESOLVED PM09 Eosinophils, Elevated 12/12/11 1...AE Start Date CTC Grade Relationship to CT- 011 Relationship toVaccine Action Taken Regarding TX Outcome PM10 Thyroid Function, Low

  2. The genomic landscape of response to EGFR blockade in colorectal cancer. (United States)

    Bertotti, Andrea; Papp, Eniko; Jones, Siân; Adleff, Vilmos; Anagnostou, Valsamo; Lupo, Barbara; Sausen, Mark; Phallen, Jillian; Hruban, Carolyn A; Tokheim, Collin; Niknafs, Noushin; Nesselbush, Monica; Lytle, Karli; Sassi, Francesco; Cottino, Francesca; Migliardi, Giorgia; Zanella, Eugenia R; Ribero, Dario; Russolillo, Nadia; Mellano, Alfredo; Muratore, Andrea; Paraluppi, Gianluca; Salizzoni, Mauro; Marsoni, Silvia; Kragh, Michael; Lantto, Johan; Cassingena, Andrea; Li, Qing Kay; Karchin, Rachel; Scharpf, Robert; Sartore-Bianchi, Andrea; Siena, Salvatore; Diaz, Luis A; Trusolino, Livio; Velculescu, Victor E


    Colorectal cancer is the third most common cancer worldwide, with 1.2 million patients diagnosed annually. In late-stage colorectal cancer, the most commonly used targeted therapies are the monoclonal antibodies cetuximab and panitumumab, which prevent epidermal growth factor receptor (EGFR) activation. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in colorectal cancer and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in colorectal cancer on response to anti-EGFR antibody therapy, here we perform complete exome sequence and copy number analyses of 129 patient-derived tumour grafts and targeted genomic analyses of 55 patient tumours, all of which were KRAS wild-type. We analysed the response of tumours to anti-EGFR antibody blockade in tumour graft models and in clinical settings and functionally linked therapeutic responses to mutational data. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumours with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumour graft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluating response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and delineate new avenues for intervention in managing colorectal cancer.

  3. Effect of {beta}{sub 1} adrenergic receptor blockade on myocardial blood flow and vasodilatory capacity

    Energy Technology Data Exchange (ETDEWEB)

    Boettcher, M.; Czernin, J.; Sun, K. [Univ. of California, Los Angeles, CA (United States)] [and others


    The {beta}{sub 1} receptor blockade reduces cardiac work and may thereby lower myocardial blood flow (MBF) at rest. The effect of {beta}{sub 1} receptor blockade on hyperemic MBF is unknown. To evaluate the effect of selective {beta}{sub 1} receptor blockade on MBF at rest and during dipyridamole induced hyperemia, 10 healthy volunteers (8 men, 2 women, mean age 24 {+-} 5 yr) were studied using {sup 13}N-ammonia PET (two-compartment model) under control conditions and again during metoprolol (50 mg orally 12 hr and 1 hr before the study). The resting rate pressure product (6628 {+-} 504 versus 5225 {+-} 807) and heart rate (63 {+-} 6-54 {plus_minus} 5 bpm) declined during metoprolol (p < 0.05). Similarly, heart rate and rate pressure product declined from the baseline dipyridamole study to dipyridamole plus metoprolol (p < 0.05). Resting MBF declined in proportion to cardiac work by approximately 20% from 0.61 {+-} 0.09-0.51 {+-} 0.10 ml/g/min (p < 0.05). In contrast, hyperemic MBF increased when metoprolol was added to dipyridamole (1.86 {plus_minus} 0.27 {+-} 0.45 ml/g/min; p<0.05). The decrease in resting MBF together with the increase in hyperemic MBF resulted in a significant increase in the myocardial flow reserve during metoprolol (3.14 {+-} 0.80-4.61 {+-} 0.68; p<0.01). The {beta}{sub 1} receptor blockade increases coronary vasodilatory capacity and myocardial flow reserve. However, the mechanisms accounting for this finding remain uncertain. 32 refs., 2 figs., 2 tabs.

  4. Prolonged blockade of the brachial plexus for the early rehabilitation of children with posttraumatic elbow contractures

    Directory of Open Access Journals (Sweden)

    D. V. Zabolotsky


    Full Text Available Objective. Improvement of surgical treatment outcomes in children with post-traumatic elbow contractures. Materials and methods. The study is based on the diagnostic findings of 48 children with post-traumatic elbow contractures who were treated at the Turner Scientific and Research Institute for Children’s Orthopedics. All children underwent complex rehabilitation after reconstructive intra-articular surgery to work out passive motions in the elbow using ARTROMOT-E2 device. The patients of the study group started rehabilitation in the first days after reconstructive intra-articular surgery in the background of prolonged blockade of the brachial plexus. In the control group, the rehabilitation was carried out traditionally on the 6th day after surgery without regional anesthesia. The patients of the study group were supplied with Contiplex SU perinural catheters for prolonged blockade of the brachial plexus using ultrasound (Edge SonoSite and neurostimulation (Stimuplex® HNS12 before surgery. For perioperative blockade of the brachial plexus we used intermittent injection of 0.5% ropivacaine (2 mg / kg. The severity of pain at the stages of rehabilitation was assessed using 10-point grading scale (FPS-R. The range of active and passive motions in the joints was evaluated by measuring the range of motions with a fleximeter. Results. Intermittent injection of ropivacaine before rehabilitation allowed to correct post-traumatic elbow contractures in children in the first days after surgery associated with the minimum subjective pain level and stable hemodynamic parameteres, accompanied with a significant increase of the elbow motion range in comparison with the group of the patients who were not performed regional anesthesia . Conclusion. Prolonged blockade of the brachial plexus in rehabilitation treatment of children with post-traumatic contractures provides appropriate analgesic and myoneural block components from the 1st day after intra

  5. Quantized current blockade and hydrodynamic correlations in biopolymer translocation through nanopores: evidence from multiscale simulations

    CERN Document Server

    Bernaschi, Massimo; Succi, Sauro; Fyta, Maria; Kaxiras, Efthimios


    We present a detailed description of biopolymer translocation through a nanopore in the presence of a solvent, using an innovative multi-scale methodology which treats the biopolymer at the microscopic scale as combined with a self-consistent mesoscopic description for the solvent fluid dynamics. We report evidence for quantized current blockade depending on the folding configuration and offer detailed information on the role of hydrodynamic correlations in speeding-up the translocation process.

  6. You are what you eat: dietary salt intake and renin-angiotensin blockade in diabetic nephropathy. (United States)

    Charytan, David M; Forman, John P


    Interactions between sodium intake, the renin-angiotensin system, and renal and cardiovascular outcomes are incompletely understood. The analysis by Lambers Heerspink et al. shows that angiotensin receptor blockade improves diabetic nephropathy and cardiovascular disease more when dietary sodium intake is low, and suggests possible harm when sodium intake is high. These findings highlight dietary salt as a modifiable cardiovascular and renal risk factor and emphasize the need for detailed mechanistic studies.

  7. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma (United States)

    Zaretsky, Jesse M.; Desrichard, Alexis; Walsh, Logan A.; Postow, Michael A.; Wong, Phillip; Ho, Teresa S.; Hollmann, Travis J.; Bruggeman, Cameron; Kannan, Kasthuri; Li, Yanyun; Elipenahli, Ceyhan; Liu, Cailian; Harbison, Christopher T.; Wang, Lisu; Ribas, Antoni


    BACKGROUND Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti–CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells. METHODS We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients. RESULTS Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P = 0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neo-antigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti–CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab. CONCLUSIONS These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti–CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.) PMID:25409260

  8. Deterministic generation of non-classical states of light using photon blockade

    CERN Document Server

    Faraon, Andrei; Vuckovic, Jelena


    The generation of non-classical 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 timescales is presented.

  9. Systemic blockade of D2-like dopamine receptors facilitates extinction of conditioned fear in mice


    Ponnusamy, Ravikumar; Nissim, Helen A.; Barad, Mark


    Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear con...

  10. Israel’s Blockade of Gaza, the Mavi Marmara Incident, and Its Aftermath (United States)


    constructively to “legitimate” international criticism and to lift the blockade.23 German Chancellor Angela Merkel expressed her “deep concern” to both...British PM Tells Netanyahu Israeli Raid on Ship was ‘Unacceptable’,” Agence France Presse, June 1, 2010. 24 “ Merkel tells Israeli, Turkish Leaders of... Interview by Francesco Battistini, “The Only Mistake Lay in Underestimating the Pacifists,” Milan Corriere della Sera, June 9, 2010, Open Source Center

  11. Imaging Rayleigh wave attenuation with USArray (United States)

    Bao, Xueyang; Dalton, Colleen A.; Jin, Ge; Gaherty, James B.; Shen, Yang


    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.

  12. Effects of alpha-adrenoceptor and of combined sympathetic and parasympathetic blockade on cardiac performance and vascular resistance

    DEFF Research Database (Denmark)

    Kelbaek, H; Frandsen, Henrik Lund; Hilsted, J


    1. Cardiac performance and vascular resistance was studied in seven healthy men by radionuclide cardiography and venous plethysmography before and after alpha-adrenoceptor blockade with phentolamine and after combined alpha-adrenoceptor, beta-adrenoceptor (propranolol) and parasympathetic (atropine...... propranolol and atropine were added. 3. These results indicate that peripheral vasoconstriction especially that exerted by alpha-adrenoceptor nervous tone in skeletal muscle restricts left ventricular emptying of the intact heart. During pharmacologic blockade of the sympathetic and parasympathetic nervous...

  13. MFN Status, Trade Embargoes, Sanctions and Blockades: An Examination of Some Overlooked Property, Contract and Other Human Rights Issues


    Robert W. McGee


    Most Favored Nation (MFN) status, trade embargoes and blockades have traditionally been used to entice nations to alter their behavior or to punish them for certain behavior. The intentions behind these policies are generally noble, at least on the surface. However, instituting these policies has side-effects. For example, FDR's blockade of raw materials against the Japanese in Manchuria in the 1930s arguably led to the bombing of Pearl Harbor, which got the United States involved in World Wa...

  14. Combined androgen blockade in the treatment of advanced prostate cancer--an overview. The Scandinavian Prostatic Cancer Group

    DEFF Research Database (Denmark)

    Iversen, P


    The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed.......The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed....

  15. Hepatic structural enhancement and insulin resistance amelioration due to AT1 receptor blockade. (United States)

    Souza-Mello, Vanessa


    Over the last decade, the role of renin-angiotensin system (RAS) on the development of obesity and its comorbidities has been extensively addressed. Both circulating and local RAS components are up-regulated in obesity and involved in non-alcoholic fatty liver disease onset. Pharmacological manipulations of RAS are viable strategies to tackle metabolic impairments caused by the excessive body fat mass. Renin inhibitors rescue insulin resistance, but do not have marked effects on hepatic steatosis. However, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARB) yield beneficial hepatic remodeling. ARBs elicit body mass loss and normalize insulin levels, tackling insulin resistance. Also, this drug class increases adiponectin levels, besides countering interleukin-6, tumoral necrosis factor-alpha, and transforming growth factor-beta 1. The latter is essential to prevent from liver fibrosis. When conjugated with peroxisome proliferator-activated receptor (PPAR)-alpha activation, ARB fully rescues fatty liver. These effects might be orchestrated by an indirect up-regulation of MAS receptor due to angiotensin II receptor type 1 (AT1R) blockade. These associations of ARB with PPAR activation and ACE2-angiotensin (ANG) (1-7)-MAS receptor axis deserve a better understanding. This editorial provides a brief overview of the current knowledge regarding AT1R blockade effects on sensitivity to insulin and hepatic structural alterations as well as the intersections of AT1R blockade with peroxisome proliferator-activated receptor activation and ACE2-ANG (1-7) - MAS receptor axis.

  16. [Sympathetically maintained pain (SMP): phentolamine test vs sympathetic nerve blockade. Comparison of two diagnostic methods]. (United States)

    Wehnert, Y; Müller, B; Larsen, B; Kohn, D


    The objective of our study was to clarify whether the phentolamine test is as suitable as sympathetic blockade in diagnosing cases of sympathetically maintained pain. The specificity and the sensitivity of both procedures were examined within a prospective and randomized study. Both a local sympathetic blockade and an intravenous phentolamine infusion were carried out in 29 patients with persistent pain in the area of the upper or lower extremities. A significant improvement was defined as reduction of pain of at least 50%. There were no complications in either test procedure. The phentolamine test registers sympathetically maintained pain well when it has a positive result (specificity of 83%). However, the phentolamine test shows only a low sensitivity of 69%. The phentolamine test, on the other hand, can be realized very easily and safely. Therefore, based on the results obtained, it is recommended that the phentolamine test be applied for primary diagnosis. In case of a negative result, further diagnosis should follow subsequently, for example with local sympathetic blockade.

  17. The Impact of CXCR4 Blockade on the Survival of Rat Brain Cortical Neurons (United States)

    Merino, José Joaquín; Garcimartín, Alba; López-Oliva, María Elvira; Benedí, Juana; González, María Pilar


    Background: Chemokine receptor type 4 (CXCR4) plays a role in neuronal survival/cell repair and also contributes to the progression of cancer and neurodegenerative diseases. Chemokine ligand 12 (CXCL12) binds to CXCR4. In this study, we have investigated whether CXCR4 blockade by AMD3100 (a CXCR4 antagonist, member of bicyclam family) may affect neuronal survival in the absence of insult. Thus, we have measured the mitochondrial membrane potential (MMP), Bax and Bcl-2 protein translocation, and cytochrome c release in AMD3100-treated brain cortical neurons at 7 DIV (days in vitro). Methods: For this aim, AMD3100 (200 nM) was added to cortical neurons for 24 h, and several biomarkers like cell viability, reactive oxygen species (ROS) generation, lactate dehydrogenase (LDH) release, caspase-3/9 activity, proteins Bax and Bcl-2 translocation, and cytochrome c release were analyzed by immunoblot. Results: CXCR4 blockade by AMD3100 (200 nM, 24 h) induces mitochondrial hyperpolarization and increases caspase-3/9 hyperpolarization without affecting LDH release as compared to untreated controls. AMD3100 also increases cytochrome c release and promotes Bax translocation to the mitochondria, whereas it raises cytosolic Bcl-2 levels in brain cortical neurons. Conclusion: CXCR4 blockade induces cellular death via intrinsic apoptosis in rat brain cortical neurons in absence of insult. PMID:27916896

  18. A pharmacological analysis of serotonergic receptors: effects of their activation of blockade in learning. (United States)

    Meneses, A; Hong, E


    1. The authors have tested several 5-HT selective agonists and antagonists (5-HT1A/1B, 5-HT2A/2B/2C, 5-HT3 or 5-HT4), an uptake inhibitor and 5-HT depletors in the autoshaping learning task. 2. The present work deals with the receptors whose stimulation increases or decreases learning. 3. Impaired consolidation of learning was observed after the presynaptic activation of 5-HT1B, 5-HT3 or 5-HT4 or the blockade of postsynaptic 5-HT2C/2B receptors. 4. In contrast, an improvement occurred after the presynaptic activation of 5-HT1A, 5-HT2C, and the blockade of presynaptic 5-HT2A, 5-HT2C and 5-HT3 receptors. 5. The blockade of postsynaptic 5-HT1A, 5-HT1B, 5-HT3 or 5-HT4 receptors and 5-HT inhibition of synthesis and its depletion did no alter learning by themselves. 6. The present data suggest that multiple pre- and postsynaptic serotonergic receptors are involved in the consolidation of learning. 7. Stimulation of most 5-HT receptors increases learning, however, some of 5-HT subtypes seem to limit the data storage. 8. Furthermore, the role of 5-HT receptors in learning seem to require an interaction with glutamatergic, GABAergic and cholinergic neurotransmission systems.

  19. Van der Waals Interactions and Dipole Blockade in a Cold Rydberg Gas Probed by Microwave Spectroscopy (United States)

    Nguyen, Thanh Long; Celistrino Teixeira, Raul; Hermann Avigliano, Carla; Cantat Moltrecht, Tigrane; Raimond, Jean Michel; Haroche, Serge; Gleyzes, Sebastiens; Brune, Michel


    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.

  20. Investigation of Prolactin Receptor Activation and Blockade Using Time-Resolved Fluorescence Resonance Energy Transfer

    Directory of Open Access Journals (Sweden)

    Estelle eTallet


    Full Text Available The prolactin receptor (PRLR is emerging as a therapeutic target in oncology. Knowledge-based drug design led to the development of a pure PRLR antagonist (Del1-9-G129R-hPRL that was recently shown to prevent PRL-induced mouse prostate tumorogenesis. In humans, the first gain-of-function mutation of the PRLR (PRLRI146L was recently identified in breast tumor patients. At the molecular level, the actual mechanism of action of these two novel players in the PRL system remains elusive. In this study, we addressed whether constitutive PRLR activation (PRLRI146L or PRLR blockade (antagonist involved alteration of receptor oligomerization and/or of inter-chain distances compared to unstimulated and PRL-stimulated PRLR. Using a combination of various biochemical and spectroscopic approaches (co-IP, blue-native electrophoresis, BRET1, we demonstrated that preformed PRLR homodimers are altered neither by PRL- or I146L-induced receptor triggering, nor by antagonist-mediated blockade. These findings were confirmed using a novel time-resolved fluorescence resonance energy transfer (TR-FRET technology that allows monitoring distance changes between cell-surface tagged receptors. This technology revealed that PRLR blockade or activation did not involve detectable distance changes between extracellular domains of receptor chains within the dimer. This study merges with our previous structural investigations suggesting that the mechanism of PRLR activation solely involves intermolecular contact adaptations leading to subtle intramolecular rearrangements.

  1. Blockade of Vascular Endothelial Growth Factor Receptor 1 Prevents Inflammation and Vascular Leakage in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Jianbo He


    Full Text Available Diabetic retinopathy (DR is a leading cause of blindness in working age adults. The objective of this study is to investigate the effects of vascular endothelial growth factor receptor 1 (VEGFR1 blockade on the complications of DR. Experimental models of diabetes were induced with streptozotocin (STZ treatment or Insulin2 gene mutation (Akita in mice. Protein expression and localization were examined by western blots (WB and immunofluorescence (IF. mRNA expression was quantified by PCR array and real-time PCR. The activity of VEGFR1 signaling was blocked by a neutralizing antibody called MF1. Vascular leakage was evaluated by measuring the leakage of [3H]-mannitol tracer into the retina and the IF staining of albumin. VEGFR1 blockade significantly inhibited diabetes-related vascular leakage, leukocytes-endothelial cell (EC adhesion (or retinal leukostasis, expression of intercellular adhesion molecule- (ICAM- 1 protein, abnormal localization and degeneration of the tight junction protein zonula occludens- (ZO- 1, and the cell adhesion protein vascular endothelial (VE cadherin. In addition, VEGFR1 blockade interfered with the gene expression of 10 new cytokines and chemokines: cxcl10, il10, ccl8, il1f6, cxcl15, ccl4, il13, ccl6, casp1, and ccr5. These results suggest that VEGFR1 mediates complications of DR and targeting this signaling pathway represents a potential therapeutic strategy for the prevention and treatment of DR.

  2. Hypotensive effect of angiotensin II after AT1-receptor blockade with losartan. (United States)

    Matys, T; Pawlak, R; Kucharewicz, I; Chabielska, E; Buczko, W


    Recent data suggest that hypotensive effect of losartan may not be attributed solely to AT1-receptor blockade, but also to excessive AT2 or other receptors stimulation by elevated angiotensin II and its derivative peptides. Therefore in the present study we examined the effect of angiotensin II on mean blood pressure after AT -receptor blockade with losartan. Male Wistar rats were anaesthetised and received injection of either losartan (30 mg/kg, 1 ml/kg, i.v.) or saline (the same volume and route) followed by bolus injection of angiotensin II (100, 300 or 1,000 ng/kg; 1 ml/kg, i.v.) or 1-hour infusion of angiotensin II (200 ng/kg/min; 2.5 ml/kg/h, i.v.). Control animals received saline instead. Angiotensin II, given either as the injection or the infusion, caused an evident increase in mean blood pressure (p ranged from 0.05 to 0.001 depending on the experimental group). Losartan caused a rapid drop in mean blood pressure and blunted the hypertensive effect of angiotensin II (p < 0.01). Moreover, in the losartan-pretreated animals the hypotensive phase was enhanced by the infusion, but not single injection of angiotensin II, which was most evident from the 30 th minute of observation (p < 0.05 vs control). In conclusion, hypotensive effect of losartan may be amplified by simultaneous increase in angiotensin II level, the situation observed during chronic AT1-receptor blockade.

  3. System identification of closed-loop cardiovascular control: effects of posture and autonomic blockade (United States)

    Mullen, T. J.; Appel, M. L.; Mukkamala, R.; Mathias, J. M.; Cohen, R. J.


    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.

  4. The effect of beta blockade on stress-induced cognitive dysfunction in adolescents. (United States)

    Faigel, H C


    Test anxiety is severely disabling to students whose fear of examinations causes cognitive dysfunction that paralyzes their thinking the way stage fright impairs actors ability to act. In studies using subjective evaluations among actors and musicians, beta-blockade relieved stage fright and has been used informally to treat test anxiety in students without objective measures of effectiveness. The Scholastic Aptitude Test (SAT) was chosen as an objective test instrument to confirm the effect of beta-blockade on test anxiety and performance. Thirty-two high school students who had already taken the SAT before enrolling in this study and who had stress-induced cognitive dysfunction on exams were given 40 mg of propranolol one hour before they retook those tests. Mean SAT scores with beta-blockade were 130 points higher than on the initial SAT done before entering the study without medication (p = less than .01). A single dose of propranolol immediately before the SAT permitted improved performance in students prone to cognitive dysfunction due to test anxiety.

  5. Prevention of atherosclerosis by specific AT1-receptor blockade with candesartan cilexetil

    Directory of Open Access Journals (Sweden)

    Vasilios Papademetriou


    Full Text Available Several studies indicate that blockade of the renin-angiotensin-aldosterone system (RAAS can prevent atherosclerosis and vascular events, but the precise mechanisms involved are still unclear. In this study, we investigated the effect of the AT 1-receptor blocker, candesartan, in the prevention of atherosclerosis in Watanabe heritable hyperlipidaemic (WHHL rabbits and also the effect of AT1-receptor blockade in the uptake of oxidised LDL by macrophage cell cultures. In the first set of experiments, 12 WHHL rabbits were randomly assigned to three groups: placebo, atenolol 5 mg/kg daily or candesartan 2 mg/kg daily for six months. Compared with controls and atenolol-treated rabbits, candesartan treatment resulted in a significant 50—60% reduction of atherosclerotic plaque formation and a 66% reduction in cholesterol accumulation in the thoracic aorta.Studies in macrophage cultures indicated that candesartan prevented uptake of oxidised LDL-(oxLDL-cholesterol by cultured macrophages. Candesartan inhibited the uptake of oxLDL in a dose-dependent manner, reaching a maximum inhibition of 70% at concentrations of 5.6 µg/ml. Further studies in other animal models and well-designed trials in humans are warranted to further explore the role of AT1-receptor blockade in the prevention of atherosclerosis.

  6. Dan Nang Xue blockade with Innovar and Atropine to prevent internal organpull response

    Institute of Scientific and Technical Information of China (English)

    Yu Chuan Liu; Qi Sheng Liang; Yun Chun Zhang; Xue Wu Ling


    AIM To observe the effects of Innovar and Atropine on Visceral pull response.METHODS Patients were randomly divided into two groups. The experimental group was treated by DanNang Xue blockade with Innovar 4 mL and Atropine 0.5 mg (n = 40) and the control group was treated byabdominal vagus blockade with 10 mL of 10 g/L Lidocaine (n = 40). Dan Nang Xue was chosen for insertionof No 5 needle (5 cm in length) after local sterilization. The acupoint of Dan Nang Xue is located at theoutside of knee-jont and it is one-finger wider below Yanglingquan can be found. A sensitive point. Theneedle was inserted between tibia and fibulae, lifted, thrusted and twirled until the patient felt ache. Innovarand Atropine were injected on Dan Nang Xue and the acupoint was gently messaged.RESULTS Patients in the experimental group remained quiet during operation. Neither nausea or vomitingnor uncomfortable reaction was complained, 85% of the patients belonged to grade m. Acupunctureenhanced the peristalsis of gallbladder and biliary secretions. Atropine relieved muscular spasm andprevented vomiting. A low heart rate was noted in the control during abdominal survey and gallbladder pull(P<0.05).CONCLUSION Dan Nang Xue blockade with innovar and atropine can prevent visceral pull response.


    Directory of Open Access Journals (Sweden)

    Shwetha S


    Full Text Available BACKGROUND: Occurrence of undetected residual neuromuscular blockade is a common event in the post anaesthesia care unit. AIM: To compare the incidence and degree of residual neuromuscular blockade with the use of intermediate acting neuromuscular blocking agents Atracurium and Vecuronium. METHODS: 360 patients satisfying the inclusion and exclusion criteria were enrolled in the study and randomly allocated into one of the two study groups of 180 each to receive either Atracurium or Vecuronium intraoperatively. The anaesthesiologist blinded from the study extubated the patient based on the standard clinical criteria and the corresponding Train of Four(TOF ratios were noted by a blinded research assistant using a TOF watch (TOF- Watch® SX Organon, Ireland Ltd., Dublin, Ireland. Residual neuromuscular blockade was defined as a TOF ratio of 0.9 thirty minutes after tracheal extubation. CONCLUSION: We conclude from our study that significant post-operative residual curarization (TOF < 0.9 exists in majority of patients at the time of tracheal extubation (54.4% incidence despite the use of intermediate acting neuromuscular blocking drugs. The incidence and degree of post-operative residual curarization is significantly greater with Vecuronium compared to Atracurium. Thus we suggest that quantitative neuromuscular monitoring is required to assure complete neuromuscular recovery.

  8. Tolerance in the anxiolytic profile following repeated administration of diazepam but not buspirone is associated with a decrease in the responsiveness of postsynaptic 5-HT-1A receptors. (United States)

    Khan, Asma; Haleem, D J


    To understand the role of serotonin (5-hydroxytryptamine; 5-HT)-1A receptors in the treatment of anxiety and the development of tolerance to benzodiazepines the present study was designed to monitor the responsiveness of postsynaptic 5-HT-1A receptors following repeated administration of diazepam and buspirone. Results show that tolerance in the anxiolytic profile is produced following repeated administration (2 weeks) of diazepam (2 mg/kg) but not buspirone (0.5 mg/kg). The behavioral effects of 8-OH-DPAT at a dose of 0.25 mg/kg were monitored 3 days after repeated administration of saline or buspirone or diazepam. The results show that 8-OH-DPAT elicited forepaw treading was smaller in repeated diazepam but not repeated buspirone injected rats, while hyperlocomotive effects of 8-OH-DPAT were smaller in both repeated buspirone and repeated diazepam injected rats. The results suggest that postsynaptic 5-HT-1A receptor-dependent responses were attenuated following long-term administration of diazepam but not buspirone. Role of 5-HT-1A receptors in the development of tolerance to the anxiolytic effects of diazepam but not buspirone is discussed.

  9. Effects of intra-prelimbic prefrontal cortex injection of cannabidiol on anxiety-like behavior: involvement of 5HT1A receptors and previous stressful experience. (United States)

    Fogaça, M V; Reis, F M C V; Campos, A C; Guimarães, F S


    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.

  10. Effect of unilateral vagus blockade on allergen-induced airway obstruction: results of short- and long-term experiments. (United States)

    Zimmermann, I; Ulmer, W T


    Unilateral application of ascaris extract on segment bronchus as the influence of contralateral vagus blockade on reflex bronchoconstriction was studied on four boxer dogs in a first group (A) of experiments: ascaris extract was applied in liquid form directly through a catheter into the right segment bronchus. This application was repeated after contralateral vagus blockade and once more after its lavage. All the animals showed an increase of airway resistance under local application of ascaris extract which could not be avoided by contralateral central vagus blockade. In the second group (B) isolation of unilateral vagus for reproducible performance of blockade as a long-term model was investigated in three boxer dogs for 7 weeks and the influence of this method of unilateral vagus blockade on exposure to allergen aerosol was studied. The unilateral blockade of the nerve vagus was again always successful in decreasing the reflex bronchoconstriction following allergen inhalation. The effect of unilateral section of nervus vagus 3 weeks after this vagotomy was tested on two boxer dogs. Reflex bronchoconstriction following ascaris extract inhalation can be avoided by unilateral section of the nervus vagus the first time after section. Three weeks after this unilateral vagotomy, the reflex bronchoconstriction becomes managed by the remaining vagus trunk to the same degree as observed by bilateral intact vagi.

  11. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent.

    Directory of Open Access Journals (Sweden)

    Hua Ying

    Full Text Available 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

  12. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent. (United States)

    Ying, Hua; Qin, An; Cheng, Tak S; Pavlos, Nathan J; Rea, Sarah; Dai, Kerong; Zheng, Ming H


    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


    Energy Technology Data Exchange (ETDEWEB)

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


    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.

  14. Magnetoelectric Composite Based Microwave Attenuator (United States)

    Tatarenko, A. S.; Srinivasan, G.


    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).

  15. Attenuation map reconstruction from TOF PET data

    CERN Document Server

    Yang, Qingsong; Wang, Ge


    To reconstruct a radioactive tracer distribution with positron emission tomography (PET), the background attenuation correction is needed to eliminate image artifacts. Recent research shows that time-of-flight (TOF) PET data determine the attenuation sinogram up to a constant, and its gradient can be computed using an analytic algorithm. In this paper, we study a direct estimation of the sinogram only from TOF PET data. First, the gradient of the attenuation sinogram is estimated using the aforementioned algorithm. Then, a relationship is established to link the differential attenuation sinogram and the underlying attenuation background. Finally, an iterative algorithm is designed to determine the attenuation sinogram accurately and stably. A 2D numerical simulation study is conducted to verify the correctness of our proposed approach.

  16. The effects of stiripentol on GABA(A) receptors. (United States)

    Fisher, Janet L


    The anticonvulsant stiripentol (Diacomittm) has been shown to have a positive impact on control of seizures for many patients with Dravet syndrome. As with most antiepileptic drugs, stiripentol has multiple mechanisms of action. Its direct anticonvulsant activity is likely due to enhancement of inhibitory, γ-aminobutyric acid (GABA)ergic neurotransmission. Stiripentol was shown to increase the activity of both neuronal and recombinant GABA(A) receptors at clinically relevant concentrations. At recombinant receptors, stiripentol was found to act through a unique site in a subunit-dependent manner. Positive modulation by stiripentol was most effective at GABA(A) receptors containing an α3 subunit. The expression of the α3 subunit is developmentally regulated, with highest levels in the immature brain. This subunit selectivity may explain the greater clinical efficacy of stiripentol in childhood-onset epilepsies, including Dravet syndrome.

  17. The effects of a 5-HT5A receptor antagonist in a ketamine-based rat model of cognitive dysfunction and the negative symptoms of schizophrenia. (United States)

    Nikiforuk, Agnieszka; Hołuj, Małgorzata; Kos, Tomasz; Popik, Piotr


    Serotonin (5-HT) receptors still represent promising targets for the development of novel multireceptor or stand-alone antipsychotic drugs with a potential to ameliorate cognitive impairments and negative symptoms in schizophrenia. The 5-HT5A receptor, one of the least known members of the serotonin receptor family, has also drawn attention in this regard. Although the antipsychotic efficacy of 5-HT5A antagonists is still equivocal, recent experimental data suggest the cognitive-enhancing activity of this strategy. The aim of the present study was to evaluate pro-cognitive and pro-social efficacies of the 5-HT5A receptor antagonist in a rat pharmacological model of schizophrenia employing the administration of the NMDA receptor antagonist, ketamine. The ability of SB-699551 to reverse ketamine-induced cognitive deficits in the attentional set-shifting task (ASST) and novel object recognition task (NORT) was examined. The compound's efficacy against ketamine-induced social withdrawal was assessed in the social interaction test (SIT) and in the social choice test (SCT). The results demonstrated the efficacy of SB-699551 in ameliorating ketamine-induced impairments on the ASST and NORT. Moreover, the tested compound also enhanced set-shifting performance in cognitively unimpaired control rats and improved object recognition memory in conditions of delay-induced natural forgetting. The pro-social activity of SB-699551 was demonstrated on both employed paradigms, the SIT and SCT. The present study suggests the preclinical efficacy of a strategy based on the blockade of 5-HT5A receptors against schizophrenia-like cognitive deficits and negative symptoms. The utility of this receptor as a target for improvement of cognitive and social dysfunctions warrants further studies.

  18. Emodin ameliorated lipopolysaccharide-induced fulminant hepatic failure by blockade of TLR4/MD2 complex expression in D-galactosamine-sensitized mice. (United States)

    Yin, Xinru; Gong, Xia; Jiang, Rong; Kuang, Ge; Wang, Bin; Zhang, Li; Xu, Ge; Wan, Jingyuan


    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.

  19. Circadian rhythm of heart rate in the rabbit: prolongation of action potential duration by sustained beta adrenoceptor blockade is not due to associated bradycardia. (United States)

    Vaughan Williams, E M; Dennis, P D; Garnham, C


    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.

  20. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. (United States)

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


    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.

  1. Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. (United States)

    Espejo-Porras, Francisco; Fernández-Ruiz, Javier; Pertwee, Roger G; Mechoulam, Raphael; García, Concepción


    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

  2. Positron emission tomography study of pindolol occupancy of 5-HT{sub 1A} receptors in humans: preliminary analyses

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, Diana; Mawlawi, Osama; Hwang, Dah-Ren; Kent, Justine; Simpson, Norman; Parsey, Ramin V.; Hashimoto, Tomoki; Slifstein, Mark; Huang Yiyun; Heertum, Ronald van; Abi-Dargham, Anissa; Caltabiano, Stephen; Malizia, Andrea; Cowley, Hugh; Mann, J. John; Laruelle, Marc


    Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT{sub 1A} autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT{sub 1A} receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT{sub 1A} receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT{sub 1A} antagonist [carbonyl-{sup 11}C]WAY-100635 or [carbonyl-{sup 11}C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide abbreviated as [{sup 11}C]WAY-100635. Pindolol dose-dependently decreased [{sup 11}C]WAY-100635 BP. Combining all the regions, occupancy was 20 {+-} 8% at scan 2, 14 {+-} 8% at scan 3, and 44 {+-} 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT{sub 1A} receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5

  3. Stimulation of postsynapse adrenergic α2A receptor improves attention/cognition performance in an animal model of attention deficit hyperactivity disorder. (United States)

    Kawaura, Kazuaki; Karasawa, Jun-ichi; Chaki, Shigeyuki; Hikichi, Hirohiko


    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. Optimal ultrasonic array focusing in attenuative media. (United States)

    Ganguli, A; Gao, R X; Liang, K; Jundt, J


    This paper presents a parametric study on the efficiency of ultrasound focusing in an attenuative medium, using phased arrays. Specifically, an analytical model of ultrasound wave focusing in a homogeneous, isotropic and attenuative fluid with point sources is presented. Calculations based on the model have shown that in an attenuative medium, an optimum frequency exists for the best focusing performance for a particular size of aperture and focal distance. The effect of different f numbers on the focusing performance in the attenuative medium is further investigated. The information obtained from the analytical model provides insights into the design and installation of a phased transducer array for energy efficient wave focusing.

  5. Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Towards the therapeutics of cognitive impairment of schizophrenia

    Directory of Open Access Journals (Sweden)

    Takashi eUehara


    Full Text Available Rationale Augmentation therapy with serotonin-1A (5-HT1A receptor partial agonists has been suggested to improve cognitive deficits in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production.Objectives and methods The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days of tandospirone (0.05 and 5 mg/kg on brain energy metabolism, as represented by extracellular lactate concentration (eLAC in the medial prefrontal cortex (mPFC of young adult rats..Results Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot shock stress (FS. Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment.Conclusions These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism based on brain energy metabolism by which 5-HT1A agonism improve cognitive impairment in schizophrenia and related disorders.

  6. Wideband, 50 dB Attenuation Range Liquid Crystal Based Variable Optical Attenuator

    Institute of Scientific and Technical Information of China (English)

    J.J.; Pan; Henry; He; Eric; Zhang


    A compact variable optical attenuator, covering C and L bands with over 50 dB attenuation range, is realized using a single liquid crystal cell with a tilted fused silica coating compensating the cell's small residual birefringence.

  7. Ultrasonic attenuation in cuprate superconductors

    Indian Academy of Sciences (India)

    T Gupta; D M Gaitonde


    We calculate the longitudinal ultrasonic attenuation rate (UAR) in clean d-wave superconductors in the Meissner and the mixed phases. In the Meissner phase we calculate the contribution of previously ignored processes involving the excitation of a pair of quasi-holes or quasi-particles. There is a contribution ∝ in the regime B ≪ F ≪ 0 and a contribution ∝ 1/ in the regime F ≪ B ≪ 0. We find that these contributions to the UAR are large and cannot be ignored. In the mixed phase, using a semi-classical description, we calculate the electronic quasi-particle contribution to the UAR which at very low , has a independent term proportional to $\\sqrt{H}$.


    Directory of Open Access Journals (Sweden)

    Eduardo Fonseca-Pedrero


    Full Text Available Psychotic syndrome includes several devastating mental disorders characterized by a rupture of higher mental functions. The signs and symptoms of psychosis begin in adolescence or early adulthood and usually begin gradually and progress over time. Attenuated psychosis syndrome is a new DSM-5 diagnostic proposal which deals with identifying people at high-risk mental state (ARMS/UHR which may be a predictor of conversion to psychosis. The potential benefit would be that if psychotic disorder is treated more effectively in its early stages, it could produce a lasting beneficial effect that probably could not be achieved with later intervention. This syndrome has generated intense discussion in specialized scientific and professional forums, crisscrossing arguments in favor and against its inclusion. HRMS is preferentially evaluated in the adolescent or young adult population. HRMS evolution is associated with a higher rate of transition toward nonaffective psychosis, although it can evolve toward other mental disorders, remain stable or remit over time. Empirical evidence shows that early intervention seems to have a certain beneficial effect, although for now the results are still insufficient and contradictory. The lack of specificity of symptoms in predicting psychosis, presence of certain limitations (e.g., stigmatization, results found in early interventions and lack of empirical evidence, have led to include the attenuated psychosis syndrome in the DSM-5 Appendix III. The main benefits and limitations of including this supposed category, possible lessons learned from this type of study and future lines of action are discussed in the light of these findings.

  9. Using psilocybin to investigate the relationship between attention, working memory, and the serotonin 1A and 2A receptors. (United States)

    Carter, Olivia L; Burr, David C; Pettigrew, John D; Wallis, Guy M; Hasler, Felix; Vollenweider, Franz X


    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.

  10. Robust GLP-1 secretion by basic L-amino acids does not require the GPRC6A receptor. (United States)

    Clemmensen, Christoffer; Jørgensen, Christinna V; Smajilovic, Sanela; Bräuner-Osborne, Hans


    The G protein-coupled receptor GPRC6A (GPCR, Class C, group 6, subtype A) has been proposed to be a sensor for basic L-amino acids that are hypothesized to translate ingestive behaviour to endocrine information. However, the contribution of the GPRC6A receptor to L-amino acid-induced glucagon-like peptide 1 (GLP-1) secretion is unclear. Therefore, to discover whether the GPRC6A receptor is indispensible for amino acid-induced secretion of GLP-1, we treated, with oral gavage, GPRC6A knock-out (KO) and wild-type (WT) littermate mice with GPRC6A ligands (L-arginine and L-ornithine) and assessed GLP-1 levels in circulation. We found that oral administration of both L-arginine and L-ornithine significantly increased total plasma GLP-1 levels to a similar level in GPRC6A KO and WT mice 15 minutes after gavage (both amino acids) and accumulated up to 60 minutes after gavage (L-arginine). Conversely, GLP-1 secretion at the 30- and 60-minute time points in the KO mice was attenuated and did not reach statistical significance. In summary, these data confirm that L-arginine is a potent GLP-1 secretagogue and show that the main effect occurs independently of GPRC6A. In addition, this is the first study to show that also L-ornithine powerfully elicits GLP-1 release in vivo.

  11. 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. (United States)

    Pamenter, Matthew E; Nguyen, Jetson; Carr, John A; Powell, Frank L


    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 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.

  12. Attenuation characteristics of a light attenuator combined by polarizers with different extinction ratios

    Institute of Scientific and Technical Information of China (English)

    Huang Chong; Deng Peng; Zhao Shuang; Chen Hai-Qing


    This paper deals with a systematical analysis and an algorithm of attenuation characteristics of a light attenuator combined by n pieces of polarizers(n-LACP)whose extinction ratios are different from each other.The attenuation ratio expression of a two-LACP is deduced. We find that the monotonic attenuation interval depends on the first polarizer and that the attenuation range depends on the second one.For the three-LACP,a method for obtaining a monotonic attenuation interval is proposed.Moreover,the attenuation ratio expression is demonstrated.Analysis and experiment show that when the initial status of the three-LACP is at the maximum output,if the second or third polarizer rotates alone,the minimum attenuation ratios can reach K2-1and K3-1,respectively,and if the first polarizer rotates,a minimum attenuation ratio of K2-1K3-1can be obtained(K1,K2 and K3 represent the extinction ratios of the three polarizers in turn).Furthermore,the attenuation ratio expression of n-LACP and the relevant attenuation characteristics are proposed.The minimum attenuation ratio of an n-LACP is(K2K3...Kn)-1.

  13. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade. (United States)

    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


    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.


    Institute of Scientific and Technical Information of China (English)

    BI Weiping; MU Xiaowu; SUN Yuqiang


    In present paper, the disturbance attenuation problem of uncertain nonlinear cascaded systems is studied. Based on the adding one power integrator technique and recursive design, a feedback controller that solves the disturbance attenuation problem is constructed for uncertain nonlinear cascaded systems with internal stability.

  15. Light attenuation on Chlorella vulgaris cells (United States)

    Krol, Tadeusz; Lotocka, Maria


    The laboratory measurements of spectrum of light attenuation on phytoplankton particles i.e. monoculture of unicellural green algae Chlorella vulgaris are presented. The measurements were carried out for alive culture and the cultures subjected to chemical (NaOH) or physical (ultrasounds) modification. The distinct changes in the light attenuation spectrum were a result of modification of the internal cell structures.

  16. Attenuation coefficients for water quality trading. (United States)

    Keller, Arturo A; Chen, Xiaoli; Fox, Jessica; Fulda, Matt; Dorsey, Rebecca; Seapy, Briana; Glenday, Julia; Bray, Erin


    Water quality trading has been proposed as a cost-effective approach for reducing nutrient loads through credit generation from agricultural or point source reductions sold to buyers facing costly options. We present a systematic approach to determine attenuation coefficients and their uncertainty. Using a process-based model, we determine attenuation with safety margins at many watersheds for total nitrogen (TN) and total phosphorus (TP) loads as they transport from point of load reduction to the credit buyer. TN and TP in-stream attenuation generally increases with decreasing mean river flow; smaller rivers in the modeled region of the Ohio River Basin had TN attenuation factors per km, including safety margins, of 0.19-1.6%, medium rivers of 0.14-1.2%, large rivers of 0.13-1.1%, and very large rivers of 0.04-0.42%. Attenuation in ditches transporting nutrients from farms to receiving rivers is 0.4%/km for TN, while for TP attenuation in ditches can be up to 2%/km. A 95 percentile safety margin of 30-40% for TN and 6-10% for TP, applied to the attenuation per km factors, was determined from the in-stream sensitivity of load reductions to watershed model parameters. For perspective, over 50 km a 1% per km factor would result in 50% attenuation = 2:1 trading ratio.

  17. Ultrasound fields in an attenuating medium

    DEFF Research Database (Denmark)

    Jensen, Jørgen Arendt; Gandhi,, D; O'Brien,, W.D., Jr.


    Ultrasound fields propagating in tissue will undergo changes in shape not only due to diffraction, but also due to the frequency dependent attenuation. Linear fields can be fairly well predicted for a non-attenuating medium like water by using the Tupholme-Stepanishen method for calculating...... the spatial impulse response, whereas the field cannot readily be found for an attenuating medium. In this paper we present a simulation program capable of calculating the field in a homogeneous attenuating medium. The program splits the aperture into rectangles and uses a far-field approximation for each...... of the rectangles and sums all contributions to arrive at the spatial impulse response for the aperture and field point. This approach makes it possible to model all transducer apertures, and the program can readily calculate the emitted, pulse-echo and continuous wave field. Attenuation is included by splitting...

  18. Serotonin 1A receptors alter expression of movement representations. (United States)

    Scullion, Kathleen; Boychuk, Jeffery A; Yamakawa, Glenn R; Rodych, Justin T G; Nakanishi, Stan T; Seto, Angela; Smith, Victoria M; McCarthy, Ryan W; Whelan, Patrick J; Antle, Michael C; Pittman, Quentin J; Teskey, G Campbell


    Serotonin has a myriad of central functions involving mood, appetite, sleep, and memory and while its release within the spinal cord is particularly important for generating movement, the corresponding role on cortical movement representations (motor maps) is unknown. Using adult rats we determined that pharmacological depletion of serotonin (5-HT) via intracerebroventricular administration of 5,7 dihydroxytryptamine resulted in altered movements of the forelimb in a skilled reaching task as well as higher movement thresholds and smaller maps derived using high-resolution intracortical microstimulation (ICMS). We ruled out the possibility that reduced spinal cord excitability could account for the serotonin depletion-induced changes as we observed an enhanced Hoffman reflex (H-reflex), indicating a hyperexcitable spinal cord. Motor maps derived in 5-HT1A receptor knock-out mice also showed higher movement thresholds and smaller maps compared with wild-type controls. Direct cortical application of the 5-HT1A/7 agonist 8-OH-DPAT lowered movement thresholds in vivo and increased map size in 5-HT-depleted rats. In rats, electrical stimulation of the dorsal raphe lowered movement thresholds and this effect could be blocked by direct cortical application of the 5-HT1A antagonist WAY-100135, indicating that serotonin is primarily acting through the 5-HT1A receptor. Next we developed a novel in vitro ICMS preparation that allowed us to track layer V pyramidal cell excitability. Bath application of WAY-100135 raised the ICMS current intensity to induce action potential firing whereas the agonist 8-OH-DPAT had the opposite effect. Together our results demonstrate that serotonin, acting through 5-HT1A receptors, plays an excitatory role in forelimb motor map expression.

  19. Electromyographic monitoring of facial nerve under different levels of neuromuscular blockade during middle ear microsurgery

    Institute of Scientific and Technical Information of China (English)

    CAI Yi-rong; XU Jing; CHEN Lian-hua; CHI Fang-lu


    Background The evoked electromyography (EMG) is frequently used to identify facial nerve in order to prevent its damage during surgeries. Partial neuromuscular blockade (NMB) has been suggested to favor EMG activity and insure patients' safety. The aim of this study was to determine an adequate level of NMB correspondent to sensible facial nerve identification by evaluating the relationship between facial EMG responses and peripheral NMB levels during the middle ear surgeries.Methods Facial nerve evoked EMG and NMB monitoring were performed simultaneously in 40 patients who underwent tympanoplasty. Facial electromyographic responses were recorded by insertion of needle electrodes into the orbicularis oris and orbicularis oculi muscles after electrical stimulation on facial nerve. The NMB was observed objectively with the hypothenar muscle's twitching after electrical stimulation of ulnar nerve, and the intensity of blockade was adjusted at levels of 0, 25%, 50%, 75%, 90%, and 100% respectively with increased intravenous infusion of Rocuronium (muscle relaxant).Results All of the patients had detectable EMG responses at the levels of NMB ≤50%. Four out of forty patients had no EMG response at the levels of NMB ≥75%. A significant linear positive correlation was present between stimulation thresholds and NMB levels while a linear negative correlation was present between EMG amplitudes and NMB levels.Conclusions The facial nerve monitoring via facial electromyographic responses can be obtained when an intraoperative partial neuromuscular blockade is induced to provide an adequate immobilization of the patient. The 50% NMB should be considered as the choice of anesthetic management for facial nerve monitoring in otologic microsurgery based on the relationship of correlation.

  20. Blockade of sonic hedgehog signal pathway enhances antiproliferative effect of EGFR inhibitor in pancreatic cancer cells

    Institute of Scientific and Technical Information of China (English)

    Wei-guo HU; Tao LIU; Jiong-xin XIONG; Chun-you WANG


    Aim: To investigate the expression of sonic hedgehog (SHH) and epidermal growth factor receptor (EGFR) signal molecules in pancreatic cancer cells, and to assess the inhibitory effects through the blockade of the SHH and EGFR signaling path- ways by cyclopamine and Iressa, respectively. Methods: The expression of SHH and EGFR in pancreatic cancer cell lines (PANC-1, SUIT-2, and ASPC-1) was de-tected by RT-PCR and Western blot analysis. After treatment with different con-centrations of cyclopamine, alone or in combination with Iressa, the antiproliferative effect on pancreatic cancer cells was analyzed by methyl thiazolyl tetrazolium assays. A flow cytometry analysis was used to detect the cellular cycle distribu-tion and apoptosis of pancreatic cancer cells. Results: All of the 3 pancreatic cancer cell lines expressed SHH, Smoothened (SMO), and EGFR. Cyclopamine could downregulate the expression of EGFR in all cell lines. Cyclopamine or Iressa could induce a growth inhibitory effect in a dose-dependent manner. Moreover,the combined use of 2.5 μmol/L cyclopamine and 1 μmol/L Iressa induced an enhanced inhibitory effect and a greater apoptosis rate than any agent alone. The percentage of the cell population of the G0/G1 and sub-G1 phases was significantly increased along with the increasing dose of cyclopamine and/or Iressa. Conclusion: The blockade of the sonic hedgehog signal pathway enhances the antiproliferative effect of the EGFR inhibitor through the downregulation of its expression in pancreatic cancer cells. The simultaneous blockade of SHH and EGFR signaling represents possible targets of new treatment strategies for pan-creatic carcinoma.

  1. Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Advani P


    Full Text Available Pooja Advani,1 Lauren Cornell,2 Saranya Chumsri,1 Alvaro Moreno-Aspitia1 1Division of Hematology and Oncology, 2Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA Abstract: Human epidermal growth factor receptor 2 (HER2 is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. Keywords: HER2, dual blockade, neoadjuvant, adjuvant, breast cancer, trastuzumab

  2. Human milk effects on neutrophil calcium metabolism: blockade of calcium influx after agonist stimulation. (United States)

    Chacon-Cruz, E; Oelberg, D G; Buescher, E S


    Neutrophils are the predominant cellular mediators of acute inflammation, and human milk suppresses multiple neutrophil functions. We sought to determine whether these effects were mediated through disruption of normal intracellular Ca2+ homeostasis. Exposure of human neutrophils to human milk, followed by washing, resulted in altered Ca2+ transient responses to formyl-peptide stimulation in which the peak cytosolic free Ca2+ concentration ([free Ca]) was the same as in unexposed cells, but the postpeak decline in [free Ca] was more rapid. This effect was observed after human milk exposures as brief as 10 s, persisted for up to 4 h after human milk removal, and was concentration dependent. On the basis of experiments examining Ca2+-free conditions followed by Ca2+ supplementation, and experiments examining spontaneous and stimulated manganese and barium influx into neutrophils, the human milk effect was due to blockade of Ca2+ influx. Decreased Ca2+ transient responses to other physiologic stimuli (IL-8, opsonized Staphylococcus aureus, and immune complexes) were observed after human milk exposures. Rat intestinal epithelial cells and HL-60 cells failed to show these effects, suggesting a selective effect on mature inflammatory cells. Characterization of the Ca2+-blocking activity showed it was heat and acid stable in human milk with a molecular mass between 30-100 kD. Commercial human milk lactoferrin exhibited Ca2+ influx blockade activity, but recombinant human lactoferrin showed none. Separation of the activity by heparin affinity chromatography showed that it was distinct from lactoferrin. Human milk-induced blockade of Ca2+ influx provides a potential mechanism for broad suppression of neutrophil functions that may contribute to the antiinflammatory properties of human milk.

  3. Endothelin receptor a blockade is an ineffective treatment for adriamycin nephropathy. (United States)

    Tan, Roderick J; Zhou, Lili; Zhou, Dong; Lin, Lin; Liu, Youhua


    Endothelin is a vasoconstricting peptide that plays a key role in vascular homeostasis, exerting its biologic effects via two receptors, the endothelin receptor A (ETA) and endothelin receptor B (ETB). Activation of ETA and ETB has opposing actions, in which hyperactive ETA is generally vasoconstrictive and pathologic. Selective ETA blockade has been shown to be beneficial in renal injuries such as diabetic nephropathy and can improve proteinuria. Atrasentan is a selective pharmacologic ETA blocker that preferentially inhibits ETA activation. In this study, we evaluated the efficacy of ETA blockade by atrasentan in ameliorating proteinuria and kidney injury in murine adriamycin nephropathy, a model of human focal segmental glomerulosclerosis. We found that ETA expression was unaltered during the course of adriamycin nephropathy. Whether initiated prior to injury in a prevention protocol (5 mg/kg/day, i.p.) or after injury onset in a therapeutic protocol (7 mg/kg or 20 mg/kg three times a week, i.p.), atrasentan did not significantly affect the initiation and progression of adriamycin-induced albuminuria (as measured by urinary albumin-to-creatinine ratios). Indices of glomerular damage were also not improved in atrasentan-treated groups, in either the prevention or therapeutic protocols. Atrasentan also failed to improve kidney function as determined by serum creatinine, histologic damage, and mRNA expression of numerous fibrosis-related genes such as collagen-I and TGF-β1. Therefore, we conclude that selective blockade of ETA by atrasentan has no effect on preventing or ameliorating proteinuria and kidney injury in adriamycin nephropathy.

  4. The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy

    Directory of Open Access Journals (Sweden)

    Alper Otunctemur


    Full Text Available Aim: Transrectal ultrasound (TRUS guided prostete biopsy is accepted as a standard procedure in the diagnosis of prostate cancer. Many different protocoles are applied to reduce the pain during the process. In this study we aimed to the comparison of two procedure with intrarectal lidocaine gel and periprostatice nerve blockade respective- ly in addition to perianal intrarectal lidocaine gel on the pain control in prostate biop- sy by TRUS. Methods: 473 patients who underwent prostate biopsy guided TRUS between 2008-2012 were included in the study. 10-point linear visual analog pain scale(VAS was used to evaluate the pain during biopsy. The patients were divided into two groups according to anesthesia procedure. In Group 1, there were 159 patients who had perianal-intrarectal lidocaine gel, in Group 2 there were 314 patients who had periprostatic nerve blockade in addition to intrarectal lidocain gel. The pain about probe manipulation was aseesed by VAS-1 and during the biopsy needle entries was evalu- ated by VAS-2. Results were compared with Mann-Whitney U and Pearson chi-square test. Results: Mean VAS-2 scores in Group 1 and Group 2 were 4.54 ± 1.02 and 2.06 ± 0.79 respectively. The pain score was determined significantly lower in the Group 2 (p = 0.001. In both groups there was no significant difference in VAS-1 scores, patient’s age, prostate volume, complication rate and PSA level. Conclusion: The combination of periprostatic nerve blockade and intrarectal lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel.

  5. Endothelin receptor a blockade is an ineffective treatment for adriamycin nephropathy.

    Directory of Open Access Journals (Sweden)

    Roderick J Tan

    Full Text Available Endothelin is a vasoconstricting peptide that plays a key role in vascular homeostasis, exerting its biologic effects via two receptors, the endothelin receptor A (ETA and endothelin receptor B (ETB. Activation of ETA and ETB has opposing actions, in which hyperactive ETA is generally vasoconstrictive and pathologic. Selective ETA blockade has been shown to be beneficial in renal injuries such as diabetic nephropathy and can improve proteinuria. Atrasentan is a selective pharmacologic ETA blocker that preferentially inhibits ETA activation. In this study, we evaluated the efficacy of ETA blockade by atrasentan in ameliorating proteinuria and kidney injury in murine adriamycin nephropathy, a model of human focal segmental glomerulosclerosis. We found that ETA expression was unaltered during the course of adriamycin nephropathy. Whether initiated prior to injury in a prevention protocol (5 mg/kg/day, i.p. or after injury onset in a therapeutic protocol (7 mg/kg or 20 mg/kg three times a week, i.p., atrasentan did not significantly affect the initiation and progression of adriamycin-induced albuminuria (as measured by urinary albumin-to-creatinine ratios. Indices of glomerular damage were also not improved in atrasentan-treated groups, in either the prevention or therapeutic protocols. Atrasentan also failed to improve kidney function as determined by serum creatinine, histologic damage, and mRNA expression of numerous fibrosis-related genes such as collagen-I and TGF-β1. Therefore, we conclude that selective blockade of ETA by atrasentan has no effect on preventing or ameliorating proteinuria and kidney injury in adriamycin nephropathy.

  6. Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases?

    DEFF Research Database (Denmark)

    Febbraio, M A; Rose-John, S; Pedersen, B K


    Interleukin-6 (IL-6) has been linked to a myriad of diseases associated with inflammation, including rheumatoid arthritis (RA), Crohn's disease, and several types of cancer. In 2009 the US Food and Drug Administration accepted a complete-response submission for the use of Actemra (tocilizumab), t......), the first humanized IL-6 receptor-inhibiting monoclonal antibody, for the treatment of RA. Although this treatment will certainly help in managing inflammatory disorders such as RA, we suggest that side effects of such blockade may be excess weight gain and hyperlipidemia....

  7. Transport in superlattices of magnetic nanoparticles: coulomb blockade, hysteresis, and switching induced by a magnetic field. (United States)

    Tan, Reasmey P; Carrey, Julian; Desvaux, Céline; Grisolia, Jérémie; Renaud, Philippe; Chaudret, Bruno; Respaud, Marc


    We report on magnetotransport measurements on millimetric superlattices of Co-Fe nanoparticles surrounded by an organic layer. At low temperature, the transition between the Coulomb blockade and the conductive regime becomes abrupt and hysteretic. The transition between both regimes can be induced by a magnetic field, leading to a novel mechanism of magnetoresistance. Between 1.8 and 10 K, a high-field magnetoresistance attributed to magnetic disorder at the surface of the particles is also observed. Below 1.8 K, this magnetoresistance abruptly collapses and a low-field magnetoresistance is observed.

  8. Density functional theory of the Seebeck coefficient in the Coulomb blockade regime (United States)

    Yang, Kaike; Perfetto, Enrico; Kurth, Stefan; Stefanucci, Gianluca; D'Agosta, Roberto


    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.

  9. Coulomb blockade in a Si channel gated by an Al single-electron transistor


    Sun, L.; K. R. Brown; Kane, B. E.


    We incorporate an Al-AlO_x-Al single-electron transistor as the gate of a narrow (~100 nm) metal-oxide-semiconductor field-effect transistor (MOSFET). Near the MOSFET channel conductance threshold, we observe oscillations in the conductance associated with Coulomb blockade in the channel, revealing the formation of a Si single-electron transistor. Abrupt steps present in sweeps of the Al transistor conductance versus gate voltage are correlated with single-electron charging events in the Si t...

  10. Normotensive sodium loading in normal man: Regulation of renin secretion during beta-receptor blockade

    DEFF Research Database (Denmark)

    Mølstrøm, Simon; Larsen, Nils Heden; Simonsen, Jane Angel;


    and renal excretion during slow saline loading at constant plasma sodium con-centration (Na-loading: 12 micromol Na(+) kg(-1) min(-1) for 4 h). Normal subjects were studied on low-sodium intake with and without beta1-adrenergic blockade by metoprolol. Metoprolol per se reduced RAAS activity as expected. Na......-loading decreased plasma renin (PRC) by 1/3, AngII by 1/2, and aldosterone (pAldo) by 2/3, (all pmetoprolol administration. Concomitantly, sodium excretion increased indistinguishably with and without metoprolol (16+/-2 to 71...

  11. Microwave probes Dipole Blockade and van der Waals Forces in a Cold Rydberg Gas

    CERN Document Server

    Teixeira, R Celistrino; Nguyen, Thanh Long; Cantat-Moltrecht, T; Raimond, Jean-Michel; Haroche, S; Gleyzes, S; Brune, M


    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.

  12. Antidiuretic effect of ritodrine with and without beta-adrenergic blockade. (United States)

    Gerritse, R; Pinas, I M; Reuwer, P J; Haspels, A A; Charbon, G A; Beijer, H J


    Dose-related effects of ritodrine and ritodrine combined with metoprolol on urinary excretion rate were studied in anesthetized dogs. Urine production was abruptly reduced after a total dose of 4 of ritodrine. This effect could not be antagonized by metoprolol, although the ritodrine-induced decrease of mean arterial pressure and renal arterial blood flow was significantly inhibited. The possible role of fluid retention during tocolytic treatment, even with beta-adrenergic blockade, in the etiology of pulmonary edema is discussed with a review on recent literature.

  13. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity (United States)

    Chamoto, Kenji; Chowdhury, Partha S.; Kumar, Alok; Sonomura, Kazuhiro; Matsuda, Fumihiko; Fagarasan, Sidonia; Honjo, Tasuku


    Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade. PMID:28096382

  14. Block of GABA(A) receptor ion channel by penicillin: electrophysiological and modeling insights toward the mechanism. (United States)

    Rossokhin, Alexey V; Sharonova, Irina N; Bukanova, Julia V; Kolbaev, Sergey N; Skrebitsky, Vladimir G


    GABA(A) receptors (GABA(A)R) mainly mediate fast inhibitory neurotransmission in the central nervous system. Different classes of modulators target GABA(A)R properties. Penicillin G (PNG) belongs to the class of noncompetitive antagonists blocking the open GABA(A)R and is a prototype of β-lactam antibiotics. In this study, we combined electrophysiological and modeling approaches to investigate the peculiarities of PNG blockade of GABA-activated currents recorded from isolated rat Purkinje cells and to predict the PNG binding site. Whole-cell patch-сlamp recording and fast application system was used in the electrophysiological experiments. PNG block developed after channel activation and increased with membrane depolarization suggesting that the ligand binds within the open channel pore. PNG blocked stationary component of GABA-activated currents in a concentration-dependent manner with IC50 value of 1.12mM at -70mV. The termination of GABA and PNG co-application was followed by a transient tail current. Protection of the tail current from bicuculline block and dependence of its kinetic parameters on agonist affinity suggest that PNG acts as a sequential open channel blocker that prevents agonist dissociation while the channel remains blocked. We built the GABA(A)R models based on nAChR and GLIC structures and performed an unbiased systematic search of the PNG binding site. Monte-Carlo energy minimization was used to find the lowest energy binding modes. We have shown that PNG binds close to the intracellular vestibule. In both models the maximum contribution to the energy of ligand-receptor interactions revealed residues located on the level of 2', 6' and 9' rings formed by a bundle of M2 transmembrane segments, indicating that these residues most likely participate in PNG binding. The predicted structural models support the described mechanism of PNG block.

  15. Acute pancreatitis-induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism. (United States)

    Fink, G; Yang, J; Carter, G; Norman, J


    Interleukin-1 beta (IL-1) is a proinflammatory cytokine which is produced within the pancreas during acute pancreatitis reaching levels which are toxic to many cell types. Since antagonism of this cytokine provides dramatic survival benefits during lethal pancreatitis, we hypothesized that IL-1 had direct secretagogue and cytolytic effects within the pancreas. The effect of IL-1 on pancreatic exocrine function and tissue viability was assessed in vivo by blockade of IL-1 with varying doses of IL-1 receptor antagonist (IL-1ra) prior to the induction of either moderate (caerulein-induced) or severe (choline deficient diet-induced) necrotizing pancreatitis. Subsequent in vitro studies were conducted to determine the direct effect of IL-1 on dispersed rat acini prepared through collagenase digestion. Amylase release was measured after a 30-min incubation with varying doses of recombinant IL-1 beta. Viability was determined in the presence of IL-1 via trypan blue exclusion at multiple time points. Blockade of the IL-1 receptor decreased pancreatic amylase release and tissue necrosis in both models of pancreatitis in a dose-dependent fashion (1.0 mg/kg, P = NS; 10 mg/kg, P amylase release and tissue necrosis are significantly attenuated during experimental pancreatitis by IL-1 antagonism. These changes do not appear to be due to the direct action of IL-1 on pancreatic acini and are likely due to more complex interactions between acini and cytokine-producing leukocytes.

  16. Attenuation of diacylglycerol second messengers

    Energy Technology Data Exchange (ETDEWEB)

    Bishop, W.R.; Ganong, B.R.; Bell, R.M.


    Diacylglycerol(DAG) derived from phosphatidylinositol activates protein kinase C in agonist-stimulated cells. At least two pathways may contribute to the attenuation of the DAG signal: (1) phosphorylation to phosphatidic acid(PA) by DAG kinase(DGK), and (2) deacylation by DAG and monoacylglycerol lipases. A number of DAG analogs were tested as substrates and inhibitors of partially purified pig brain DGK. Two analogs were potent inhibitors in vitro, 1-monooleoylglycerol(MOG,K/sub I/ = 91 and diotanoylethyleneglycol (diC/sub 8/EG, K/sub I/ = 58 These compounds were tested in human platelets. DiC/sub 8/EG inhibited (70 - 100%) (/sup 32/P/sub i/) incorporation into PA in thrombin-stimulated platelets. Under these conditions the DAG signal was somewhat long-lived but was still metabolized, presumably by the lipase pathway. MOG treatment elevated DAG levels up to 4-fold in unstimulated platelets. The DAG formed was in a pool where it did not activate protein kinase C. Thrombin-stimulation of MOG-treated platelets resulted in DAG levels 10-fold higher than control platelets. This appears to be due to the inability of these platelets to metabolize agonist-linked DAG via the lipase pathway. The development of specific inhibitors of DAG kinase and DAG lipase, in conjunction with mass quantification of DAG levels as used here, will provide further insights into the regulation of DAG second messengers.

  17. Live attenuated intranasal influenza vaccine. (United States)

    Esposito, Susanna; Montinaro, Valentina; Groppali, Elena; Tenconi, Rossana; Semino, Margherita; Principi, Nicola


    Annual vaccination is the most effective means of preventing and controlling influenza epidemics, and the traditional trivalent inactivated vaccine (TIV) is by far the most widely used. Unfortunately, it has a number of limitations, the most important of which is its poor immunogenicity in younger children and the elderly, the populations at greatest risk of severe influenza. Live attenuated influenza vaccine (LAIV) has characteristics that can overcome some of these limitations. It does not have to be injected because it is administered intranasally. It is very effective in children and adolescents, among whom it prevents significantly more cases of influenza than the traditional TIV. However, its efficacy in adults has not been adequately documented, which is why it has not been licensed for use by adults by the European health authorities. LAIV is safe and well tolerated by children aged > 2 y and adults, but some concerns arisen regarding its safety in younger children and subjects with previous asthma or with recurrent wheezing. Further studies are needed to solve these problems and to evaluate the possible role of LAIV in the annual vaccination of the general population.

  18. Effect of local anesthetics on serotonin1A receptor function. (United States)

    Rao, Bhagyashree D; Shrivastava, Sandeep; Chattopadhyay, Amitabha


    The fundamental mechanism behind the action of local anesthetics is still not clearly understood. Phenylethanol (PEtOH) is a constituent of essential oils with a pleasant odor and can act as a local anesthetic. In this work, we have explored the effect of PEtOH on the function of the hippocampal serotonin1A receptor, a representative neurotransmitter receptor belonging to the G protein-coupled receptor (GPCR) family. Our results show that PEtOH induces reduction in ligand binding to the serotonin1A receptor due to lowering of binding affinity, along with a concomitant decrease in the degree of G-protein coupling. Analysis of membrane order using the environment-sensitive fluorescent probe DPH revealed decrease in membrane order with increasing PEtOH concentration, as evident from reduction in rotational correlation time of the probe. Analysis of results obtained shows that the action of local anesthetics could be attributed to the combined effects of specific interaction of the receptor with anesthetics and alteration of membrane properties (such as membrane order). These results assume relevance in the perspective of anesthetic action and could be helpful to achieve a better understanding of the possible role of anesthetics in the function of membrane receptors.

  19. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference

    DEFF Research Database (Denmark)

    Sørensen, Gunnar; Wörtwein, Gitta; Fink-Jensen, Anders


    . In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence...... the induction, extinction or reinstatement of a conditioned cocaine response. We found that the Y5 antagonist L-152,804 causes faster extinction and reduced reinstatement of cocaine-induced CPP but did not reduce the ability of cocaine to induce CPP. Similarly, Y5-KO mice displayed faster extinction......, and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data show that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance...

  20. Spin blockade and coherent dynamics of high-spin states in a three-electron double quantum dot (United States)

    Chen, Bao-Bao; Wang, Bao-Chuan; Cao, Gang; Li, Hai-Ou; Xiao, Ming; Guo, Guang-Can; Jiang, Hong-Wen; Hu, Xuedong; Guo, Guo-Ping


    Asymmetry in a three-electron double quantum dot (DQD) allows spin blockade, when spin-3/2 (quadruplet) states and spin-1/2 (doublet) states have different charge configurations. We have observed this DQD spin blockade near the (1,2)-(2,1) charge transition using a pulsed-gate technique and a charge sensor. We, then, use this spin blockade to detect Landau-Zener-Stückelberg interference and coherent oscillations between the spin quadruplet and doublet states. Such studies add to our understandings of coherence and control properties of three-spin states in a double dot, which, in turn, would benefit explorations into various qubit encoding schemes in semiconductor nanostructures.

  1. Graphene-based Electronically Tuneable Microstrip Attenuator

    Directory of Open Access Journals (Sweden)

    L. Pierantoni


    Full Text Available This paper presents the design of a graphene- based electronically tuneable microstrip attenuator operating at a frequency of 5 GHz. The use of graphene as a variable resistor is discussed and the modelling of its electromagnetic properties at microwave frequencies is fully addressed. The design of the graphene-based attenuator is described. The structure integrates a patch of graphene, whose characteristics can range from being a fairly good conductor to a highly lossy material, depending on the applied voltage. By applying the proper voltage through two high-impedance bias lines, the surface resistivity of graphene can be modified, thereby changing the insertion loss of the microstrip attenuator.

  2. Structure-activity relationship between carboxylic acids and T cell cycle blockade. (United States)

    Gilbert, Kathleen M; DeLoose, Annick; Valentine, Jimmie L; Fifer, E Kim


    This study was designed to examine the potential structure-activity relationship between carboxylic acids, histone acetylation and T cell cycle blockade. Toward this goal a series of structural homologues of the short-chain carboxylic acid n-butyrate were studied for their ability to block the IL-2-stimulated proliferation of cloned CD4+ T cells. The carboxylic acids were also tested for their ability to inhibit histone deacetylation. In addition, Western blotting was used to examine the relative capacity of the carboxlic acids to upregulate the cyclin kinase-dependent inhibitor p21cip1 in T cells. As shown earlier n-butyrate effectively inhibited histone deacetylation. The increased acetylation induced by n-butyrate was associated with the upregulation of the cyclin-dependent kinase inhibitor p21cip1 and the cell cycle blockade of CD4+ T cells. Of the other carboxylic acids studied, the short chain acids, C3-C5, without branching were the best inhibitors of histone deacetylase. This inhibition correlated with increased expression of the cell cycle blocker p21cip1, and the associated suppression of CD4+ T cell proliferation. The branched-chain carboxylic acids tested were ineffective in all the assays. These results underline the relationship between the ability of a carboxylic acid to inhibit histone deacetylation, and their ability to block T cell proliferation, and suggests that branching inhibits these effects.

  3. A mean field approach to Coulomb blockade for a disordered assembly of quantum dots

    Indian Academy of Sciences (India)

    Akashdeep Kamra; Praveen Pathak; Vijay A Singh


    The Coulomb blockade (CB) in quantum dots (QDs) is by now well documented. It has been used to guide the fabrication of single electron transistors. Even the most sophisticated techniques for synthesizing QDs (e.g. MOCVD/MBE) result in an assembly in which a certain amount of disorder is inevitable. On the other hand, theoretical approaches to CB limit themselves to an analysis of a single QD. In the present work we consider two types of disorders: (i) size disorder; e.g. QDs have a distribution of sizes which could be unimodal or bimodal in nature. (ii) Potential disorder with the confining potential assuming a variety of shapes depending on growth condition and external fields. We assume a Gaussian distribution in disorder in both size and potential and employ a simplified mean field theory. To do this we rely on the scaling laws for the CB (also termed as Hubbard ) obtained for an isolated QD [1]. We analyze the distribution in the Hubbard as a consequence of disorder and observe that Coulomb blockade is partially suppressed by the disorder. Further, the distribution in is a skewed Gaussian with enhanced broadening.

  4. Blockade of leukocyte haptokinesis and haptotaxis by ketoprofen, diclofenac and SC-560

    Directory of Open Access Journals (Sweden)

    Paskauskas Saulius


    Full Text Available Abstract Background Nonsteroidal anti-inflammatory drugs (NSAID represent a one of the most widely used anti-inflammatory substances. Their anti-inflammatory effects are mainly based on inhibition of cyclooxygenase. The potential direct effect of NSAID on leukocyte migration was poorly investigated. Using time-lapse microscopy and 96-well fluorescence-based assay, we studied the effect of three different NSAID, ketoprofen, diclofenac and SC-560, on leukocyte haptokinesis and haptotaxis in vivo and in vitro. Results NSAID induced an immediate inhibiting effect on leukocyte migration both in vitro and in vivo. This effect was dose-dependent and was not restricted to a specific type of leukocytes. The inhibition of leukocyte migration by NSAID was partially re-stored after removal of inhibiting agent. Only complete blockade of leukocyte migration was accompanied by a strong reduction of [Ca2+]i. Conclusions NSAID strongly supress leukocyte migration. The results of the present study may have important clinical implications since blockade of leukocyte migration can be achieved after topical application of NSAID.

  5. Age dependence of the rapid antidepressant and synaptic effects of acute NMDA receptor blockade

    Directory of Open Access Journals (Sweden)

    Elena eNosyreva


    Full Text Available Ketamine is a NMDA receptor antagonist that produces rapid antidepressant responses in individuals with major depressive disorder. The antidepressant action of ketamine has been linked to blocking NMDA receptor activation at rest, which inhibits eukaryotic elongation factor2 kinase leading to desuppression of protein synthesis and synaptic potentiation in the CA1 region of the hippocampus. Here, we investigated ketamine mediated antidepressant response and the resulting synaptic potentiation in juvenile animals. We found that ketamine did not produce an antidepressant response in juvenile animals in the novelty suppressed feeding or the forced swim test. In addition ketamine application failed to trigger synaptic potentiation in hippocampal slices obtained from juvenile animals, unlike its action in slices from older animals (6-9 weeks old. The inability of ketamine to trigger an antidepressant response or subsequent synaptic plasticity processes suggests a developmental component to ketamine mediated antidepressant efficacy. We also show that the NMDAR antagonist AP5 triggers synaptic potentiation in mature hippocampus similar to the action of ketamine, demonstrating that global competitive blockade of NMDA receptors is sufficient to trigger this effect. These findings suggest that global blockade of NMDA receptors in developmentally mature hippocampal synapses are required for the antidepressant efficacy of ketamine.

  6. Complete androgen blockade safely allows for delay of cytotoxic chemotherapy in castration refractory prostate cancer

    Directory of Open Access Journals (Sweden)

    Rafael A. Kaliks


    Full Text Available PURPOSE: Complete androgen blockade (CAB does not prolong overall survival (OS in patients with castration refractory prostate cancer (CRPC. Although there is variable clinical benefit with second-line hormone manipulation, we do not know which patients might benefit the most. OBJECTIVES: To identify clinical predictors of benefit of complete androgen blockade. MATERIALS AND METHODS: We reviewed the records for 54 patients who received treatment with CAB in the setting of disease progression despite castration. We evaluated progression-free survival (PFS and OS according to PSA at diagnosis, Gleason scores, age, testosterone level, and duration of prior disease control during castration in first line treatment. RESULTS: Among 54 patients who received CAB, the median PFS was 9 months (CI 4.3-13.7 and OS was 36 months (CI 24-48. We did not find an effect of PSA at diagnosis (p = 0.32, Gleason score (p = 0.91, age (p = 0.69 or disease control during castration (p = 0.87 on PFS or OS. Thirty-four patients subsequently received chemotherapy, with a mean OS of 21 months (CI 16.4-25.5, median not reached. CONCLUSION: Age, Gleason score, PSA at diagnosis and length of disease control with castration did not affect PFS or OS. In the absence of predictors of benefit, CAB should still be considered in CRPC.

  7. Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

    Directory of Open Access Journals (Sweden)

    Joanne O Davidson

    Full Text Available 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.

  8. Effects of Adrenergic Blockade on Postpartum Adaptive Responses Induced by Labor Contractions (United States)

    Ronca, April E.; Mills, N. A.; Lam, K. P.; Hayes, L. E.; Bowley, Susan M. (Technical Monitor)


    Prenatal exposure to labor contractions augments the expression of postnatal adaptive responses in newborn rats. Near-term rat fetuses exposed prenatally to simulated labor contractions and delivered by cesarean section breath and attach to nipples at greater frequencies than non-stimulated fetuses. Plasma NE (norepinephrine) and EPI (epinephrine) was significantly elevated in newborn rats exposed to vaginal birth or simulated labor contractions (compressions) with cesarean delivery as compared to non-compressed fetuses. In the present study, we investigated adrenergic mechanisms underlying labor-induced postnatal adaptive responses. Following spinal transection of late pregnant rat dams, fetuses were administered neurogenic or non-neurogenic adrenergic blockade: 1) bretylium (10 mg/kg sc) to prevent sympathetic neuronal release, 2) hexamethonium (30 mg/kg) to produce ganglionic blockade, 3) phenoxybenzanune (10mg/kg sc), an a- adrenergic receptor antagonist, 4) ICI-118551, 10 mg/kg sc), a b receptor antagonist, or 5) vehicle alone. Fetuses were either compressed (C) or non-compressed (NC) prior to cesarean delivery. a- and b- adrenergic antagonists reduced respiration and nipple attachment rates while sympathetic and vehicle alone did not. These results provide additional support for the hypothesis that adaptive neonatal effects of labor contractions are mediated by adrenal and extra-adrenal catecholamines.

  9. Isobolographic analysis of interaction between nisoxetine- and mepivacaine-induced spinal blockades in rats. (United States)

    Leung, Yuk-Man; Chu, Chin-Chen; Kuo, Chang-Shin; Chen, Yu-Wen; Hung, Ching-Hsia; Wang, Jhi-Joung


    Although nisoxetine has been shown to elicit cutaneous (peripheral) anesthesia, spinal (central) anesthesia with nisoxetine was not exposed. The aim of this study was to examine spinal anesthesia of nisoxetine and its influence on the antinociceptive action of mepivacaine. We compared nisoxetine with an established local anesthetic mepivacaine for spinal anesthesia after rats were intrathecally injected with drugs. The drugs were spinally administered alone as well as in combination, and their potencies were compared via dose-response curves and isobolographic analysis. We showed that nisoxetine, as well as mepivacaine elicited spinal anesthesia in dose-dependent manners. On a 50% effective dose (ED₅₀) basis, the spinal block effect of nisoxetine in motor function, proprioception, and nociception [0.99 (0.91-1.10), 0.85 (0.76-0.95), 0.82 (0.74-0.89)] was more potent (P < 0.05) than that of mepivacaine [1.28 (1.21-1.34), 1.14 (1.07-1.22), 0.99 (0.93-1.05)], respectively. Furthermore, the nociceptive/sensory blockade (ED₅₀) was greater than the motor blockade in both nisoxetine and mepivacaine groups (P < 0.05). Saline group (vehicle) produced no spinal anesthesia. Coadministration of nisoxetine with mepivacaine displayed an additive effect. Our data reported nisoxetine produced significant anesthesia at spinal level, and additive interaction with the local anesthetic, mepivacaine. Intrathecal nisoxetine elicited more potent spinal anesthesia than mepivacaine.

  10. Bothrops jararacussu venom-induced neuromuscular blockade inhibited by Casearia gossypiosperma Briquet hydroalcoholic extract

    Directory of Open Access Journals (Sweden)

    TM Camargo


    Full Text Available The hydroalcoholic extract of Casearia gossypiosperma Briquet (Flacourtiaceae was standardized for the first time through quality control procedures including pharmacognostic methods, fingerprint chromatograms, defined amounts of marker substances and physicochemical characteristics. The pharmacological activity of C. gossypiosperma (Cg hydroalcoholic extract was assayed by a traditional in vitro test, which involved irreversible neuromuscular blockade induced by Bothrops jararacussu (Bjssu venom (60 µg/mL in mouse phrenic nerve-diaphragm preparations. Bjssu venom blocked muscle activity for 26 (± 2.0 minutes (n = 6. Cg extract (0.1 mg/mL induced changes on the baseline muscle activity without impairing the muscle function and inhibited 87.6% (± 1.8 (n = 6 of the Bjssu venom-induced blockade. Both flavonoids (0.624 g% and polyphenols (4.63 g% from the extract were spectrophotometrically quantified. Therefore, the present study confirms the antibothropic activity of Cg extract, supporting the ethnomedical use of Casearia sp. in the treatment of snakebite victims.

  11. The Benefit of Neuromuscular Blockade in Patients with Postanoxic Myoclonus Otherwise Obscuring Continuous Electroencephalography (CEEG) (United States)

    Hornik, Alejandro; Guerch, Meziane; Veripuram, Anantha; Yerram, Sushma; Ardelt, Agnieszka


    Introduction. Myoclonus status epilepticus is independently associated with poor outcome in coma patients after cardiac arrest. Determining if myoclonus is of cortical origin on continuous electroencephalography (CEEG) can be difficult secondary to the muscle artifact obscuring the underlying CEEG. The use of a neuromuscular blocker can be useful in these cases. Methods. Retrospective review of CEEG in patients with postanoxic myoclonus who received cisatracurium while being monitored. Results. Twelve patients (mean age: 53.3 years; 58.3% male) met inclusion criteria of clinical postanoxic myoclonus. The initial CEEG patterns immediately prior to neuromuscular blockade showed myoclonic artifact with continuous slowing (50%), burst suppression with myoclonic artifact (41.7%), and continuous myogenic artifact obscuring CEEG (8.3%). After intravenous administration of cisatracurium (0.1 mg–2 mg), reduction in artifact improved quality of CEEG recordings in 9/12 (75%), revealing previously unrecognized patterns: continuous EEG seizures (33.3%), lateralizing slowing (16.7%), burst suppression (16.7%), generalized periodic discharges (8.3%), and, in the patient who had an initially uninterpretable CEEG from myogenic artifact, continuous slowing. Conclusion. Short-acting neuromuscular blockade is useful in determining background cerebral activity on CEEG otherwise partially or completely obscured by muscle artifact in patients with postanoxic myoclonus. Fully understanding background cerebral activity is important in prognostication and treatment, particularly when there are underlying EEG seizures. PMID:28265468

  12. The Benefit of Neuromuscular Blockade in Patients with Postanoxic Myoclonus Otherwise Obscuring Continuous Electroencephalography (CEEG

    Directory of Open Access Journals (Sweden)

    Christopher R. Newey


    Full Text Available Introduction. Myoclonus status epilepticus is independently associated with poor outcome in coma patients after cardiac arrest. Determining if myoclonus is of cortical origin on continuous electroencephalography (CEEG can be difficult secondary to the muscle artifact obscuring the underlying CEEG. The use of a neuromuscular blocker can be useful in these cases. Methods. Retrospective review of CEEG in patients with postanoxic myoclonus who received cisatracurium while being monitored. Results. Twelve patients (mean age: 53.3 years; 58.3% male met inclusion criteria of clinical postanoxic myoclonus. The initial CEEG patterns immediately prior to neuromuscular blockade showed myoclonic artifact with continuous slowing (50%, burst suppression with myoclonic artifact (41.7%, and continuous myogenic artifact obscuring CEEG (8.3%. After intravenous administration of cisatracurium (0.1 mg–2 mg, reduction in artifact improved quality of CEEG recordings in 9/12 (75%, revealing previously unrecognized patterns: continuous EEG seizures (33.3%, lateralizing slowing (16.7%, burst suppression (16.7%, generalized periodic discharges (8.3%, and, in the patient who had an initially uninterpretable CEEG from myogenic artifact, continuous slowing. Conclusion. Short-acting neuromuscular blockade is useful in determining background cerebral activity on CEEG otherwise partially or completely obscured by muscle artifact in patients with postanoxic myoclonus. Fully understanding background cerebral activity is important in prognostication and treatment, particularly when there are underlying EEG seizures.

  13. Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats. (United States)

    Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung


    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.

  14. Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

    Energy Technology Data Exchange (ETDEWEB)

    Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.


    In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of /sup 201/Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and /sup 201/Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of /sup 201/Tl uptake in non-occluded endocardium. Uptake of /sup 201/Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

  15. Tumor-Specific Multiple Stimuli-Activated Dendrimeric Nanoassemblies with Metabolic Blockade Surmount Chemotherapy Resistance. (United States)

    Li, Yachao; Xu, Xianghui; Zhang, Xiao; Li, Yunkun; Zhang, Zhijun; Gu, Zhongwei


    Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.

  16. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints (United States)

    Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Richards, William G.; Gandhi, Leena; Redig, Amanda J.; Rodig, Scott J.; Asahina, Hajime; Jones, Robert E.; Kulkarni, Meghana M.; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E.; Johnson, Bruce E.; Janne, Pasi A.; Engelman, Jeffrey A.; Gangadharan, Sidharta P.; Costa, Daniel B.; Freeman, Gordon J.; Bueno, Raphael; Hodi, F. Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S.


    Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade. PMID:26883990

  17. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy (United States)

    Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang


    A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.

  18. Blockade of glutamatergic transmission in perirhinal cortex impairs object recognition memory in macaques. (United States)

    Malkova, Ludise; Forcelli, Patrick A; Wellman, Laurie L; Dybdal, David; Dubach, Mark F; Gale, Karen


    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.

  19. Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma.

    Directory of Open Access Journals (Sweden)

    Begoña Comin-Anduix

    Full Text Available BACKGROUND: The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4 using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC samples from patients with metastatic melanoma. METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p signaling molecules downstream of the T cell receptor (TCR and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. CLINICAL TRIAL REGISTRATION:; Registration numbers NCT00090896 and NCT00471887.

  20. Blockade of PLD2 Ameliorates Intestinal Mucosal Inflammation of Inflammatory Bowel Disease (United States)

    Zhou, Guangxi; Yu, Lin; Yang, Wenjing; Wu, Wei; Fang, Leilei


    Background. Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronically remittent and progressive inflammatory disorders. Phospholipase D2 (PLD2) is reported to be involved in the pathogenesis of several inflammatory diseases. However, the exact role of PLD2 in IBD is obscure. Methods. PLD2 expression was determined in peripheral blood cells and inflamed mucosa from patients with IBD by qRT-PCR. Colonic biopsies were also obtained from CD patients before and after infliximab (IFX) treatment to examine PLD2 expression. PLD2 selective inhibitor (CAY10594) was administrated daily by oral gavage in DSS-induced colitis mice. Bone marrow neutrophils from colitis mice were harvested to examine the migration using Transwell plate. Results. PLD2 was found to be significantly increased in peripheral blood cells and inflamed mucosa in patients with active IBD. Treatment with IFX could significantly decrease PLD2 expression in intestinal mucosa in patients with CD. Moreover, blockade of PLD2 with CAY10594 could markedly ameliorate DSS-induced colitis in mice and promote neutrophil migration. Conclusions. PLD2 plays a critical role in the pathogenesis of IBD. Blockade of PLD2 may serve as a new therapeutic approach for treatment of IBD. PMID:27721573

  1. Has RAAS Blockade Reached Its Limits in the Treatment of Diabetic Nephropathy? (United States)

    Majewski, Collen; Bakris, George L


    Medications that block the renin-angiotensin-aldosterone system (RAAS) are a cornerstone of diabetic nephropathy treatment. These agents play an important role in slowing the nephropathy progression in patients with diabetes. Clinical outcome trials that investigated use of these drug classes in patients with diabetic nephropathy have demonstrated clinical significant benefit in slowing nephropathy progression only in people with >300 mg/day of proteinuria. Thus, guidelines mandate their use in such patients. Conversely, combinations of RAAS blocking agents in these patients can worsen renal outcomes. Moreover, use of RAAS blockers in patients with a glomerular filtration rate below 45 mL/min/1.73 m(2) is limited by hyperkalemia. New agents that predictably bind excess potassium in the colon offer the possibility of extending RAAS inhibitor use in advanced chronic kidney disease (CKD) to allow evaluation of RAAS blockade for nephropathy and cardiovascular outcomes. These new potassium-binding agents may provide an opportunity to continue full-dose RAAS inhibition and assess if the benefits of RAAS blockade seen in stage 3 CKD can be extrapolated to persons with stages 4 and 5 CKD, not previously tested due to hyperkalemia.

  2. Neural blockade during exercise augments central command's contribution to carotid baroreflex resetting (United States)

    Querry, R. G.; Smith, S. A.; Stromstad, M.; Ide, K.; Raven, P. B.; Secher, N. H.


    This investigation was designed to determine central command's role on carotid baroreflex (CBR) resetting during exercise. Nine volunteer subjects performed static and rhythmic handgrip exercise at 30 and 40% maximal voluntary contraction (MVC), respectively, before and after partial axillary neural blockade. Stimulus-response curves were developed using the neck pressure-neck suction technique and a rapid pulse train protocol (+40 to -80 Torr). Regional anesthesia resulted in a significant reduction in MVC. Heart rate (HR) and ratings of perceived exertion (RPE) were used as indexes of central command and were elevated during exercise at control force intensity after induced muscle weakness. The CBR function curves were reset vertically with a minimal lateral shift during control exercise and exhibited a further parallel resetting during exercise with neural blockade. The operating point was progressively reset to coincide with the centering point of the CBR curve. These data suggest that central command was a primary mechanism in the resetting of the CBR during exercise. However, it appeared that central command modulated the carotid-cardiac reflex proportionately more than the carotid-vasomotor reflex.

  3. Entangling atomic spins with a Rydberg-dressed spin-flip blockade (United States)

    Jau, Y.-Y.; Hankin, A. M.; Keating, T.; Deutsch, I. H.; Biedermann, G. W.


    Controlling the quantum entanglement between parts of a many-body system is key to unlocking the power of quantum technologies such as quantum computation, high-precision sensing, and the simulation of many-body physics. The spin degrees of freedom of ultracold neutral atoms in their ground electronic state provide a natural platform for such applications thanks to their long coherence times and the ability to control them with magneto-optical fields. However, the creation of strong coherent coupling between spins has been challenging. Here we demonstrate a strong and tunable Rydberg-dressed interaction between spins of individually trapped caesium atoms with energy shifts of order 1 MHz in units of Planck’s constant. This interaction leads to a ground-state spin-flip blockade, whereby simultaneous hyperfine spin flips of two atoms are inhibited owing to their mutual interaction. We employ this spin-flip blockade to rapidly produce single-step Bell-state entanglement between two atoms with a fidelity >=81(2)%.


    Institute of Scientific and Technical Information of China (English)

    YANG Liu-ping; DENG Jun-hong; ZHONG Hong; HU Jian-bo; WEI Hong-ai; WANG Liang-sheng


    Objective: To assess the effect of transrectal ultrasound guided prostatic nerve blockade on the discomfort associated with systematic biopsy of the prostate. Methods: 73 patients receiving systematic 13 cores biopsy of the prostate were randomized into two groups. Group A(37 cases) received an injection of 5 ml 1% lidocaine into the prostatic neurovascular bundles on each side at the base of the prostate under ultrasound guidance and group B(36 cases) received 5 ml saline injection (0.9% sodium chloride) at the same site. Pain during biopsy was assessed by using a 10-point linear visual analog score (VAS) immediately after the biopsy. Results: The mean pain scores during transrectal prostate biopsy were significantly lower in group A than group B(1.1±0.6 versus 5.9±3.1, t=4.81, P<0.01). During this study no patient in either group had any adverse effect from the injection. Conclusion: Transcrectal ultrasound guided prostatic nerve blockade is a safe and efficacious method for providing satisfactory anesthesia in transrectal prostate biopsy. We recommend its routine administration in all patients during this procedure.

  5. Neurolytic blockade of the obturator nerve in the treatment of idiopatic obturator neuralgia

    Directory of Open Access Journals (Sweden)

    Ćulafić Slobodan


    Full Text Available Introduction. Idiopathic obturator neuralgia is a rare chronic pain condition. It consists of pain radiating from the obturator nerve territory to the inner thigh. However, the symptomatic obturator neuralgia is commonly caused by the obturator canal bowel hernia that causes painful compressive neuropathy in more than 85% of the cases. Case report. A 61-year-old female who underwent right femoral amputation due to the occlusion of the aortofemoral vascular graft, complained of the pain characterized by its localization in the inguinal region and anterointernal side of the right inner thigh. Computer tomography and MRI findings excluded obturator canal herniation or lumbar plexopathy. A diagnosis of the obturator neuralgia was confirmed by an analgesic block of the obturator nerve. Thereafter, the neurolitic blockade of the right obturator nerve was done. The complete pain relief was achieved. Pain relief was complete in three-month follow-up period. Conclusion. Neurolitic blockade is an efficacious method in treating chronic pain caused by the idiopathic obturator neuralgia.

  6. Unexpected High Sensory Blockade during Continuous Spinal Anesthesiology (CSA in an Elderly Patient

    Directory of Open Access Journals (Sweden)

    R. Ketelaars


    Full Text Available A 98-year-old woman presented for a hemiarthroplasty of the left hip. Because of her age and cardiac and pulmonary co-existing diseases we decided to provide adequate regional anesthesia by continuous spinal anesthesia. Fragmented doses of isobaric bupivacaine 0.5% were administered through a system consisting of a spinal catheter connected to an antimicrobial filter. After an uneventful surgical procedure, prior to removal of the catheter, this system was flushed with 10 mL of normal saline in order to try to prevent post-dural-puncture headache. After arrival at the postanesthesia care unit and fifteen minutes after removal of the catheter the patient suffered an unexpected high thoracic sensory blockade and hypotension requiring treatment. The continuous spinal anesthesia technique can be used in selected cases to be able to administer local anesthetic agents in a slow and controlled manner to reach the desired effect. The risk of post-dural-puncture headache using this technique in elderly patients is very low and therefore precludes the need to try to prevent it. We have described a potentially dangerous complication of flushing a bupivacaine-filled system into the spinal canal of an elderly patient resulting in an undesirable high sensory blockade.

  7. Magnetic-anisotropy-induced spin blockade in a single-molecule transistor (United States)

    Luo, Guangpu; Park, Kyungwha


    We present a mechanism for a spin blockade effect associated with a change in the type of magnetic anisotropy over oxidation state in a single molecule transistor, by taking an example of an individual Eu2(C8H8)3 molecule weakly coupled to nonmagnetic electrodes without linker groups. The molecule switches its magnetization direction from in-plane to out-of-plane when it is charged. In other words, the magnetic anisotropy of the molecule changes from easy plane to easy axis when the molecule is charged. By solving the master equation based on a model Hamiltonian, we find that current through the molecule is highly suppressed at low bias independently of gate voltage due to the interplay between spin selection rules and the change in the type of magnetic anisotropy. Transitions between the lowest magnetic levels in successive charge states are forbidden because the magnetic levels differ by |Δ M |>1 /2 due to the change in the type of magnetic anisotropy, although the total spins differ by |Δ S |=1 /2 . This current suppression can be lifted by significant B field, and the threshold B field varies as a function of the field direction and the strength of magnetic anisotropy. The spin blockade effect sheds light on switching the magnetization direction by non-spin-polarized current and on exploring effects of this property coupled to other molecular degrees of freedom.

  8. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy (United States)

    Chen, Qian; Xu, Ligeng; Liang, Chao; Wang, Chao; Peng, Rui; Liu, Zhuang


    A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours. PMID:27767031

  9. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models (United States)

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping


    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  10. Blockade of S100A3 activity inhibits murine hair growth. (United States)

    Guan, W; Deng, Q; Yu, X L; Yuan, Y S; Gao, J; Li, J J; Zhou, L; Xia, P; Han, G Y Q; Han, W; Yu, Y


    Using mouse gene expression microarray analysis, we obtained dynamic expression profiles of the whole genome in a depilation-induced hair growth mouse model. S100A3 expression increased during the anagen phase and returned to normal during the telogen phase. The effects of S100A3 blockade on the hair growth cycle were examined in mice after subcutaneous injection of an anti-mouse S100A3 antibody. Protein localization of S100A3 was confined to the hair shafts during the anagen phase and the sebaceous glands during the telogen phase. S100A3 blockade delayed hair follicle entry into the anagen phase, decreased hair elongation, and reduced the number of hair follicles in the subcutis, which correlated with the downregulated expression of hair growth induction-related genes in vivo. The present study demonstrates that anti-S100A3 antibody inhibits mouse hair growth, suggesting that S100A3 can be used as a target for hair loss treatment.

  11. Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin. (United States)

    Maubec, Eve; Laouénan, Cédric; Deschamps, Lydia; Nguyen, Van Tuan; Scheer-Senyarich, Isabelle; Wackenheim-Jacobs, Anne-Catherine; Steff, Maud; Duhamel, Stéphanie; Tubiana, Sarah; Brahimi, Nesrine; Leclerc-Mercier, Stéphanie; Crickx, Béatrice; Perret, Claudine; Aractingi, Selim; Escoubet, Brigitte; Duval, Xavier; Arnaud, Philippe; Jaisser, Frederic; Mentré, France; Farman, Nicolette


    A major deleterious side effect of glucocorticoids is skin atrophy. Glucocorticoids activate the glucocorticoid and the mineralocorticoid (MR) receptor, both present in the epidermis. We hypothesized that glucocorticoid-induced epidermal atrophy may be related to inappropriate occupancy of MR by glucocorticoids. We evaluated whether epidermal atrophy induced by the topical glucocorticoid clobetasol could be limited by coadministration of MR antagonist. In cultured human skin explants, the epidermal atrophy induced by clobetasol was significantly limited by MR antagonism (canrenoate and eplerenone). Blockade of the epithelial sodium channel ENaC by phenamil was also efficient, identifying a role of MR-ENaC cascade in keratinocytes, acting through restoration of clobetasol-induced impairment of keratinocyte proliferation. In the SPIREPI randomized double-blind controlled trial, gels containing clobetasol, the MR antagonist spironolactone, both agents, or placebo were applied on four zones of the forearms of 23 healthy volunteers for 28 days. Primary outcome was histological thickness of the epidermis with clobetasol alone or clobetasol+spironolactone. Spironolactone alone did not affect the epidermal thickness but coapplication of clobetasol and spironolactone significantly limited clobetasol-induced atrophy and was well tolerated. Altogether, these findings identify MR as a factor regulating epidermal homeostasis and suggest that topical MR blockade could limit glucocorticoid-induced epidermal atrophy.

  12. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. (United States)

    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


    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.

  13. Does perioperative tactile evaluation of the train-of-four response influence the frequency of postoperative residual neuromuscular blockade?

    DEFF Research Database (Denmark)

    Pedersen, T; Viby-Mogensen, J; Bang, U


    The authors conducted a randomized controlled clinical trial to evaluate the usefulness of perioperative manual evaluation of the response to train-of-four (TOF) nerve stimulation. A total of 80 patients were divided into four groups of 20 each. For two groups (one given vecuronium and one...... pancuronium), the anesthetists assessed the degree of neuromuscular blockade during operation and during recovery from neuromuscular blockade by manual evaluation of the response to TOF nerve stimulation. In the other two groups, one of which received vecuronium and the other pancuronium, the anesthetists...

  14. The blockade of renin-angiotensin-aldosterone system in hemodialysis patients to control hypertension and prevent cardiovascular disease: optimal pharmacotherapy. (United States)

    Morishita, Yoshiyuki; Kusano, Eiji


    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in hemodialysis (HD) patients. Hypertension (HT) is a major risk factor for CVD. The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of HT in HD patients. Previous studies suggested that the blockade of RAAS may be effective to control blood pressure (BP) and to prevent CVD in HD patients. A certain level of preventive effects against CVD by RAAS blockade in HD patients has been reported independently from a BP lowering effect. This review focuses on the effect of blocking RAAS in HD patients for the control of HT and the prevention of CVD.

  15. Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

    DEFF Research Database (Denmark)

    Higginson, James; Wackerhage, Henning; Woods, Niall


    A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased......Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin...

  16. Endothelin receptor A antagonism attenuates renal medullary blood flow impairment in endotoxemic pigs.

    Directory of Open Access Journals (Sweden)

    Johan Fenhammar

    Full Text Available BACKGROUND: Endothelin-1 is a potent endogenous vasoconstrictor that contributes to renal microcirculatory impairment during endotoxemia and sepsis. Here we investigated if the renal circulatory and metabolic effects of endothelin during endotoxemia are mediated through activation of endothelin-A receptors. METHODS AND FINDINGS: A randomized experimental study was performed with anesthetized and mechanically ventilated pigs subjected to Escherichia coli endotoxin infusion for five hours. After two hours the animals were treated with the selective endothelin receptor type A antagonist TBC 3711 (2 mg⋅kg(-1, n = 8 or served as endotoxin-treated controls (n = 8. Renal artery blood flow, diuresis and creatinine clearance decreased in response to endotoxemia. Perfusion in the cortex, as measured by laser doppler flowmetry, was reduced in both groups, but TBC 3711 attenuated the decrease in the medulla (p = 0.002. Compared to control, TBC 3711 reduced renal oxygen extraction as well as cortical and medullary lactate/pyruvate ratios (p<0.05 measured by microdialysis. Furthermore, TBC 3711 attenuated the decline in renal cortical interstitial glucose levels (p = 0.02 and increased medullary pyruvate levels (p = 0.03. Decreased creatinine clearance and oliguria were present in both groups without any significant difference. CONCLUSIONS: These results suggest that endothelin released during endotoxemia acts via endothelin A receptors to impair renal medullary blood flow causing ischemia. Reduced renal oxygen extraction and cortical levels of lactate by TBC 3711, without effects on cortical blood flow, further suggest additional metabolic effects of endothelin type A receptor activation in this model of endotoxin induced acute kidney injury.

  17. Precision Model for Microwave Rotary Vane Attenuator

    DEFF Research Database (Denmark)

    Guldbrandsen, Tom


    A model for a rotary vane attenuator is developed to describe the attenuator reflection and transmission coefficients in detail. All the parameters of the model can be measured in situ, i.e., without diassembling any part. The tranmission errors caused by internal reflections are calculated from ...... measurements of the much larger reflection parameters, hence commonly used nonprecision instruments can be used to determine the transmission errors with sufficient accuracy for the highest precision obtainable in standard laboratories....

  18. Wave attenuation charcteristics of tethered float system

    Digital Repository Service at National Institute of Oceanography (India)

    Vethamony, P.

    and transmitted wave powers, transmission coefficients are computed. The results show that transmission coefficient does not vary with changes in wave height or water depth. When depth of submergence of float increases, wave attenuation decreases, showing... that the system performs well when it is just submerged. As float velocity decreases with increase in float size, transmission coefficient increases with increase in float size. The influence of wave period on wave attenuation is remarkable compared to other...


    DEFF Research Database (Denmark)

    Brunskog, Jonas; Lhomond, Alice; Ohlrich, Mogens


    In this paper the attenuation and flanking transmissions of impact noise in lightweight building structures is studied using a modal approach. The structural field is mainly analysed, putting the main attention to the parts being important in the modelling. The amount of attenuation produced...... by the periodically reinforcing beams used in lightweight building structures is analysed. The consequence of these factors in modelling flanking transmission is also discussed....

  20. Light attenuation in estuarine mangrove lakes (United States)

    Frankovich, Thomas A.; Rudnick, David T.; Fourqurean, James W.


    Submerged aquatic vegetation (SAV) cover has declined in brackish lakes in the southern Everglades characterized by low water transparencies, emphasizing the need to evaluate the suitability of the aquatic medium for SAV growth and to identify the light attenuating components that contribute most to light attenuation. Underwater attenuation of downwards irradiance of photosynthetically active radiation (PAR) was determined over a three year period at 42 sites in shallow (lakes in two sub-estuaries in the coastal Everglades, Florida USA. Turbidity, chromophoric dissolved organic matter (CDOM), and phytoplankton chlorophyll a (chl a) were measured concurrently and their respective contributions to the light attenuation rate were estimated. Light transmission to the benthos relative to literature estimates of minimum requirements for SAV growth indicated that the underwater light environment was often unsuitable for SAV. Light attenuation rates (n = 417) corrected for solar elevation angles ranged from 0.16 m-1 to 9.83 m-1 with a mean of 1.73 m-1. High concentrations of CDOM with high specific light absorption contributed the most to light attenuation followed by turbidity and chl a. CDOM alone sufficiently reduces light transmission beyond the estimated limits for SAV growth, making it difficult for ecosystem managers to increase SAV abundance by management activities. Light limitation of SAV in these areas may be a persistent feature because of their proximity to CDOM source materials from the surrounding mangrove swamp. Increasing freshwater flow into these areas may dilute CDOM concentrations and improve the salinity and light climate for SAV communities.

  1. GABAB receptor blockade enhances theta and gamma rhythms in the hippocampus of behaving rats. (United States)

    Leung, L Stan; Shen, Bixia


    The participation of GABA(B) receptors in hippocampal EEG generation was studied by intracerebroventricular (icv) and intracerebral infusions of GABA(B) receptor antagonist p-(3-aminopropyl)-p-diethoxymethyl-phosphinic acid (CGP35348) in freely behaving rats. During awake-immobility, icv CGP35348 induced a theta rhythm and increased gamma waves (30-100 Hz) in the hippocampus. The immobility theta peaked at 6-7 Hz and had a theta phase in CA1 stratum radiatum of approximately 160 degrees with reference to the theta at the alveus, when compared with approximately 130 degrees during walking. Immobility theta power peaks at 6-7 Hz was also found in normal rats, and it was detected in 27% of the EEG segments during immobility. Incidence of immobility theta increased to 87.5% after 480 nmol of CGP35348 icv. Muscarinic antagonist scopolamine (5 mg/kg, ip) suppressed the induction of immobility theta and the gamma power increase after icv CGP35348. CGP35348 icv did not significantly change the hippocampal theta power at 7-8 Hz during walking (theta fundamental), but it increased power at 12-15 Hz, at the second harmonic of theta. CGP35348 icv also increased 30-50 Hz gamma power during walking. Medial septal infusion of CGP35348 (12 nmol in 0.4 microl) increased the power and the frequency of the hippocampal theta second harmonic during walking, but did not increase gamma activity. Infusion of CGP35348 (8 nmol in 0.4 microl) in the hippocampus increased the local gamma activity at 30-100 Hz, but did not induce immobility theta or affect the walking theta rhythm. In conclusion, icv GABA(B) receptor blockade increased an atropine-sensitive input that generated an immobility theta rhythm, while GABA(B) receptor blockade of the medial septum increased atropine-resistant theta harmonics possibly generated by apical dendritic spikes. GABA(B) receptor blockade may enhance cognitive task performance by activating hippocampal theta and gamma rhythms in behaving rats.

  2. The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects

    Directory of Open Access Journals (Sweden)

    Sathananthan M


    Full Text Available Matheni Sathananthan,1 Sayeed Ikramuddin,2 James M Swain,3,6 Meera Shah,1 Francesca Piccinini,4 Chiara Dalla Man,4 Claudio Cobelli,4 Robert A Rizza,1 Michael Camilleri,5 Adrian Vella1 1Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Division of General Surgery, University of Minnesota, Minneapolis, MN, USA; 3Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Information Engineering, University of Padua, Padua, Italy; 5Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA Purpose: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods: We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB. Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA to measure gastrointestinal transit. Insulin action and ß-cell responsivity indices were estimated using the minimal model. Results: Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose

  3. CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

    Energy Technology Data Exchange (ETDEWEB)

    Datir, A., E-mail: [Jackson Memorial Hospital, Miami, FL (United States); Connell, D. [Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex (United Kingdom)


    Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

  4. Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism

    Directory of Open Access Journals (Sweden)

    Christine eDugovic


    Full Text Available In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R and orexin-2 (OX2R receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM and REM sleep following oral dosing (10 and 30 mg/kg at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion. When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.

  5. Inhibition of formyl peptide-stimulated superoxide anion generation by Fal-002-2 occurs mainly through the blockade of the p21-activated kinase and protein kinase C signaling pathways in ratneutrophils. (United States)

    Tsai, Ya-Ru; Huang, Li-Jiau; Lin, Hui-Yi; Hung, Yun-Jie; Lee, Miau-Rong; Kuo, Sheng-Chu; Hsu, Mei-Feng; Wang, Jih-Pyang


    In formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils, a synthetic compound, 6-chloro-2-(2-chlorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Fal-002-2), inhibited superoxide anion (O2(•-)) generation with an IC50 value of about 11μM, which was not mediated by scavenging the generated O2(•-) or by a cytotoxic effect on neutrophils. Fal-002-2 effectively attenuated the phosphorylation of Ser residues in p47(phox) and the association between p47(phox) and p22(phox) in fMLP-stimulated neutrophils. The interaction of p47(phox) with protein kinase C (PKC) isoforms (α, βI, βII, δ and ζ) was attenuated by Fal-002-2 with a similar IC50 value to that required for inhibition of O2(•-) generation, whereas Fal-002-2 had no prominent effect on PKC isoform membrane translocation and did not affect the kinase activity. Moreover, Fal-002-2 had no effect on the phosphorylation of Akt and downstream glycogen synthase kinase-3β, only slightly affected the intracellular free Ca(2+) concentration, phosphorylation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase (MAPK), but effectively attenuated the downstream MAPK-activated protein kinase-2 phosphorylation. The interaction of p21-activated kinase (PAK) 1with p47(phox), phosphorylation of PAK1 (Thr423/Ser144) and the membrane recruitment of PAK1 were effectively inhibited by Fal-002-2. Fal-002-2 also blocked the activation of Rac1 and Cdc42 in a concentration range that effectively inhibited PAK activation. Taken together, these results suggest that Fal-002-2 inhibits fMLP-stimulated O2(•-) generation in neutrophils mainly through the blockade of PKC and PAK signaling pathways and partly through p38 MAPK signaling.

  6. Reversible blockade of complex I or inhibition of PKCβ reduces activation and mitochondria translocation of p66Shc to preserve cardiac function after ischemia.

    Directory of Open Access Journals (Sweden)

    Meiying Yang

    Full Text Available AIM: Excess mitochondrial reactive oxygen species (mROS play a vital role in cardiac ischemia reperfusion (IR injury. P66Shc, a splice variant of the ShcA adaptor protein family, enhances mROS production by oxidizing reduced cytochrome c to yield H2O2. Ablation of p66Shc protects against IR injury, but it is unknown if and when p66Shc is activated during cardiac ischemia and/or reperfusion and if attenuating complex I electron transfer or deactivating PKCβ alters p66Shc activation during IR is associated with cardioprotection. METHODS: Isolated guinea pig hearts were perfused and subjected to increasing periods of ischemia and reperfusion with or without amobarbital, a complex I blocker, or hispidin, a PKCβ inhibitor. Phosphorylation of p66Shc at serine 36 and levels of p66Shc in mitochondria and cytosol were measured. Cardiac functional variables and redox states were monitored online before, during and after ischemia. Infarct size was assessed in some hearts after 120 min reperfusion. RESULTS: Phosphorylation of p66Shc and its translocation into mitochondria increased during reperfusion after 20 and 30 min ischemia, but not during ischemia only, or during 5 or 10 min ischemia followed by 20 min reperfusion. Correspondingly, cytosolic p66Shc levels decreased during these ischemia and reperfusion periods. Amobarbital or hispidin reduced phosphorylation of p66Shc and its mitochondrial translocation induced by 30 min ischemia and 20 min reperfusion. Decreased phosphorylation of p66Shc by amobarbital or hispidin led to better functional recovery and less infarction during reperfusion. CONCLUSION: Our results show that IR activates p66Shc and that reversible blockade of electron transfer from complex I, or inhibition of PKCβ activation, decreases p66Shc activation and translocation and reduces IR damage. These observations support a novel potential therapeutic intervention against cardiac IR injury.

  7. Blockade of Ca2+-activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

    DEFF Research Database (Denmark)

    Madsen, Lars Siim; Christophersen, Palle; Olesen, Søren-Peter


    Voltage- and Ca(2+)-dependent K(+) channels in the membrane of both T and B lymphocytes are important for the cellular immune response. In the current issue of the European Journal of Immunology, Reich et al. demonstrate that selective blockade of the intermediate-conductance Ca(2+)-activated K(+...... of new immune-suppressant drugs for the treatment of autoimmune diseases....

  8. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

    DEFF Research Database (Denmark)

    Köhler, Ralf; Wulff, Heike; Eichler, Ines;


    hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. CONCLUSIONS: The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent...

  9. Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy : a randomised clinical trial

    NARCIS (Netherlands)

    Kwakernaak, Arjan J.; Krikken, Jan A.; Binnenmars, S. Heleen; Visser, Folkert W.; Hemmelder, Marc H.; Woittiez, Arend-Jan; Groen, Henk; Laverman, Gozewijn D.; Navis, Gerjan


    Background Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added

  10. Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer (United States)

    Sobani, Zain A; Sawant, Ashwin; Jafri, Mikram; Correa, Amit Keith; Sahin, Ibrahim Halil


    Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade. PMID:27777877

  11. Selective Blockade of CD28-Mediated T Cell Costimulation Protects Rhesus Monkeys against Acute Fatal Experimental Autoimmune Encephalomyelitis

    NARCIS (Netherlands)

    Haanstra, Krista G.; Dijkman, Karin; Bashir, Noun; Bauer, Jan; Mary, Caroline; Poirier, Nicolas; Baker, Paul; Scobie, Linda; 't Hart, Bert A.; Vanhove, Bernard


    Costimulatory and coinhibitory receptor-ligand pairs on T cells and APC control the immune response. We have investigated whether selective blockade of CD28-CD80/86 costimulatory interactions, which preserves the coinhibitory CTLA4-CD80/86 interactions and the function of regulatory T (Treg) cells,

  12. Effect of serotonin receptor blockade on endocrine and cardiovascular responses to head-up tilt in humans

    DEFF Research Database (Denmark)

    Matzen, S; Secher, N H; Knigge, U


    Effects of blockade of serotonin (5-HT) receptors on the integrated cardiovascular and endocrine adaptations during head-up tilt were investigated in normal men. In control experiments 50 degrees head-up tilt increased heart rate (HR), total peripheral resistance (TPR), plasma renin activity (PRA...

  13. Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: A feasible strategy?

    NARCIS (Netherlands)

    Vogt, Liffert; Navis, Ger Jan; de Zeeuw, Dick


    Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strat

  14. CCR5 Blockade Suppresses Melanoma Development Through Inhibition of IL-6-Stat3 Pathway via Upregulation of SOCS3. (United States)

    Tang, Qiu; Jiang, Jun; Liu, Jian


    In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, we found that chemokine receptor 5 (CCR5) neutralization resulted in reduced melanoma tumor size, decreased percentage of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs), and increased proportion of cluster of differentiation (CD)3+ T cells in tumor tissues. Suppressive activity of MDSCs on CD4+ T cells and CD8+ T cell proliferation is significantly inhibited by anti-CCR5 antibody. CCR5 blockade also suppresses interleukin (IL)-6 induction, which in turn deactivates signal transducer and activator of transcription 3 (Stat3) in tumors. Furthermore, the suppressed B16 tumor growth induced by CCR5 blockade is abolished with additional administration of recombinant IL-6. CCR5 blockade also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and anti-CCR5 antibody fails to suppress expression of phospho-Stat3 (p-Stat3), matrix metallopeptidase 9 (MMP9), and IL-6 in cells transfected with SOCS3 short-interfering RNA (SiRNA). All these data suggest that CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3.

  15. Maximum likelihood estimation of the attenuated ultrasound pulse

    DEFF Research Database (Denmark)

    Rasmussen, Klaus Bolding


    The attenuated ultrasound pulse is divided into two parts: a stationary basic pulse and a nonstationary attenuation pulse. A standard ARMA model is used for the basic pulse, and a nonstandard ARMA model is derived for the attenuation pulse. The maximum likelihood estimator of the attenuated...

  16. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers (United States)

    Moisan, Francois; Francisco, Edgar B.; Brozovic, Anamaria; Duran, George E.; Wang, Yan C.; Chaturvedi, Shalini; Seetharam, Shobha; Snyder, Linda A.; Doshi, Parul; Sikic, Branimir I.


    Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non-MDR paclitaxel resistant ovarian cancer lines ES-2/TP, MES-OV/TP and OVCAR-3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti-human CCL2 antibody CNTO 888 and the anti-mouse MCP-1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer. PMID:24816187

  17. Steroid-Induced Psychosis after EUS-Guided Celiac Plexus Blockade (United States)

    Lewis, Jason J.


    A 46-year-old female with no previous personal or family psychiatric history underwent endoscopic ultrasound (EUS)-guided celiac plexus blockade (CPB) to treat pain related to cystic fibrosis transmembrane conductance regulator-associated chronic pancreatitis. She had excellent response to her first three CPBs using bupivacaine and triamcinolone. The patient’s subsequent CPBs were complicated by symptoms of racing thoughts, delusional thinking, and insomnia. She was diagnosed with acute psychosis secondary to triamcinolone. This is the first reported case of steroid-induced psychosis caused by EUS-guided CPB. Optimal treatment for steroid-induced psychiatric symptoms include dose reduction or discontinuation of steroids and administration of lithium, valproic acid, or atypical antipsychotics. PMID:28144616

  18. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy (United States)

    Topalian, Suzanne L.; Taube, Janis M.; Anders, Robert A.; Pardoll, Drew M.


    With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade. PMID:27079802

  19. Efficient collisional blockade loading of single atom into a tight microtrap

    CERN Document Server

    Fung, Y H


    We show that controlled inelastic collisions can improve the single atom loading efficiency in the collisional blockade regime of optical microtraps. A collisional loss process where only one of the colliding atoms are lost, implemented during loading, enables us to kick out one of the atoms as soon as a second atom enters the optical microtrap. When this happens faster than the pair loss, which has limited the loading efficiency of previous experiments to about 50%, we experimentally observe an enhancement to 80%. A simple analytical theory predicts the loading dynamics. Our results opens up an efficient and fast route for loading individual atoms into optical tweezers and arrays of microtraps that are too tight for easy implementation of the method reported in [1,2]. The loading of tight traps with single atoms is a requirement for their applications in future experiments in quantum information processing and few-body physics.

  20. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade (United States)

    McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles


    As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

  1. Coulomb blockade effects in silicon nanoparticles embedded in thin silicon-rich oxide films

    Energy Technology Data Exchange (ETDEWEB)

    Morales-Sanchez, A; Barreto, J; Dominguez, C [IMB-CNM (CSIC), Campus UAB, Bellaterra 08193, Barcelona (Spain); Aceves, M; Yu, Z [INAOE, Electronics Department, Apartado 51, Puebla, 72000 (Mexico); Luna-Lopez, J A [CCMC, UNAM, Optics Department, Ensenada, BC, 22800 (Mexico)], E-mail:


    Silicon nanoparticles (Si-nps) embedded in silicon oxide matrix were created using silicon-rich oxide (SRO) films deposited by low pressure chemical vapour deposition (LPCVD) followed by a thermal annealing at 1100 deg. C. The electrical properties were studied using metal-oxide-semiconductor (MOS) structures with the SRO films as the active layers. Capacitance versus voltage (C-V) exhibited downward and upward peaks in the accumulation region related to charge trapping and de-trapping effects of Si-nps, respectively. Current versus voltage (I-V) measurements showed fluctuations in the form of spike-like peaks and a clear staircase at room temperature. These effects have been related to the Coulomb blockade (CB) effect in the silicon nanoparticles embedded in SRO films. The observed quantum effects are due to 1 nm nanoparticles.

  2. The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point. (United States)

    Sica, Domenic A


    The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.


    Directory of Open Access Journals (Sweden)

    Lucian Hritcu


    Full Text Available The involvement of catecholamine receptors (D2 dopamine was investigated in restraint stress, influence immune system, with concomitant changes in immune response. Adults rats pretreated once with LPS (a bacterial product (25μg/250μl, i.p., produce an immune response, were subjected to i.p. injection with sulpiride (4 mg/kg b.w., i.p., a selective antagonist for D2 dopamine receptors, after 3 days postimmunization. After 18 days later, we assessed the total protein number, antibody titer, lymphocyte number and albumin/globulin ratio. In summary, we provide that D2 dopamine receptor blockade impaired immune responsiveness in restraint stress.

  4. Neuroticism and serotonin 5-HT1A receptors in healthy subjects

    DEFF Research Database (Denmark)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell


    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy...... and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals...... with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may...

  5. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue;


    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

  6. Galectin-3 Blockade Reduces Renal Fibrosis in Two Normotensive Experimental Models of Renal Damage (United States)

    Martinez-Martinez, Ernesto; Ibarrola, Jaime; Calvier, Laurent; Fernandez-Celis, Amaya; Leroy, Celine; Cachofeiro, Victoria; Rossignol, Patrick; Lopez-Andres, Natalia


    Background Galectin-3 (Gal-3), a β-galactoside-binding lectin, is increased in kidney injury and its pharmacological blockade reduces renal damage in acute kidney injury, hyperaldosteronism or hypertensive nephropathy. We herein investigated the effects of pharmacological Gal-3 inhibition by modified citrus pectin (MCP) in early renal damage associated with obesity and aortic stenosis (AS). Results Gal-3 was upregulated in kidneys from high fat diet (HFD) rats and in animals with partial occlusion of ascending aorta (AS). Urinary and plasma neutrophil gelatinase-associated lipocalin (NGAL) and urinary albumin were enhanced in HFD and AS rats. In kidney from obese rats, fibrotic markers (collagen, TFG-β), epithelial-mesenchymal transition molecules (α-smooth muscle actin, E-cadherin), inflammatory mediator (osteopontin) and kidney injury marker (kidney injury molecule-1) were modified. In kidney from AS rats, fibrotic markers (collagen, CTGF), epithelial-mesenchymal transition molecules (fibronectin, α-smooth muscle actin, β-catenin, E-cadherin) and kidney injury markers (NGAL, kidney injury molecule-1) were altered. Histologic observations of obese and AS rat kidneys revealed tubulointerstitial fibrosis. The pharmacological inhibition of Gal-3 with MCP normalized renal Gal-3 levels as well as functional, histological and molecular alterations in obese and AS rats. Conclusions In experimental models of mild kidney damage, the increase in renal Gal-3 expression paralleled with renal fibrosis, inflammation and damage, while these alterations were prevented by Gal-3 blockade. These data suggest that Gal-3 could be a new player in renal molecular, histological and functional alterations at early stages of kidney damage. PMID:27829066

  7. Selective endothelin B receptor blockade does not influence BNP-induced natriuresis in man. (United States)

    van der Zander, K; Houben, A J H M; Webb, D J; Udo, E; Kietselaer, B; Hofstra, L; De Mey, J G R; de Leeuw, P W


    Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) both exhibit natriuretic activity within the human kidney. Furthermore, they both act partly through activation of the endothelial nitric oxide pathway. Since ET-1 may cause vasodilation and natriuresis via stimulation of the ET-B receptor, the aim of the present study was to investigate whether renal ET-B receptors participate in the renal actions of BNP. In this placebo-controlled, crossover study, we infused BNP (4 pmol/kg/min) or placebo (i.v.) for 1 h, with or without co-infusion of the ET-B receptor antagonist BQ-788 (50 nmol/min) for 15 min on 4 separate days, in 10 healthy subjects (mean age 54+/-6 years.). During infusion, we measured effective renal plasma flow (ERPF), and glomerular filtration rate (GFR) using PAH/inulin clearance. Cardiac output was measured before and after infusion, using echocardiography. Blood pressure and heart rate (HR) were monitored as well. Urine and plasma samples were taken every hour to measure diuresis, natriuresis, cyclic 3',5' guanosine monophosphate, and ET-1 levels. BNP with or without ET-B receptor blockade increased natriuresis and diuresis. In addition, BNP alone increased GFR and filtered load, without changing ERPF. BQ-788 infusion did not affect renal hemodynamics or natriuresis. Neither BNP nor BQ-788 altered cardiac output, blood pressure, and heart rate. In conclusion, the present study shows that selective ET-B receptor blockade has no effect on the BNP-induced natriuresis and glomerular filtration rate.

  8. Blockade of Rennin-Angiotensin system blunts the fibrotic response in experimental acute pyelonephritis

    Directory of Open Access Journals (Sweden)

    Singal A


    Full Text Available Aim: To study the impact of Renin-Angiotensin system blockade in experimental acute pyelonephritis, induced by a novel surgical approach via dorsal lumbotomy incision. Materials and Methods : 45 Adult female WISTAR rats aged 8-12 weeks, underwent direct inoculation of 0.1 ml of E.coli suspension into the parenchyma of the surgically exposed kidney. 3 groups of rats were studied: Group A - treated with antibiotics only; Group B- Captopril and antibiotics and Group C- Losartan and antibiotics. Changes of acute inflammation, parenchymal destruction and scarring were compared between the groups on histopathological sections. Kruskal-Wallis test was used for statistical analysis. Results : Changes consistent with acute pyelonephritis were seen in all the kidneys. Mean% scar area in Group A, Group B and Group C was 37.08±1.79, 24.40±1.88 and 24.68±1.32% respectively at end of six weeks. Mean tubular density in Group A, B and C was 17.26±1.92, 47.18±3.00 and 47.00±5.08-tubules/lac mm2 respectively. The differences between the control and the treated animals were significant, though the results did not differ between the losartan and captopril treated rats. Conclusions : Dorsal lumbotomy approach to the kidney provides a good exposure of the kidney. Induction of acute pyelonephritis by direct inoculation of bacteria into renal cortex produced a consistent scar at 6 weeks. Blockade of renin angiotensin system by either captopril or losartan decreased the renal scar area by almost 1/3 at 6 weeks.

  9. β(2)-Adrenoreceptor blockade improves early posttrauma hyperglycemia and pulmonary injury in obese rats. (United States)

    Xiang, Lusha; Lu, Silu; Mittwede, Peter N; Clemmer, John S; Husband, Graham W; Hester, Robert L


    Early hyperglycemia after trauma increases morbidity and mortality. Insulin is widely used to control posttrauma glucose, but this treatment increases the risk of hypoglycemia. We tested a novel method for early posttrauma hyperglycemia control by suppressing hepatic glycogenolysis via β2-adrenoreceptor blockade [ICI-118551 (ICI)]. We have shown that, after severe trauma, obese Zucker (OZ) rats, similar to obese patients, exhibit increased acute lung injury compared with lean Zucker (LZ) rats. We hypothesized that OZ rats exhibit a greater increase in early posttrauma glucose compared with LZ rats, with the increased posttrauma hyperglycemia suppressed by ICI treatment. Orthopedic trauma was applied to both hindlimbs in LZ and OZ rats. Fasting plasma glucose was then monitored for 6 h with or without ICI (0.2 mg·kg(-1)·h(-1) iv.) treatment. One day after trauma, plasma IL-6 levels, lung neutrophil numbers, myeloperoxidase (MPO) activity, and wet-to-dry weight ratios were measured. Trauma induced rapid hepatic glycogenolysis, as evidenced by decreased liver glycogen levels, and this was inhibited by ICI treatment. Compared with LZ rats, OZ rats exhibited higher posttrauma glucose, IL-6, lung neutrophil infiltration, and MPO activity. Lung wet-to-dry weight ratios were increased in OZ rats but not in LZ rats. ICI treatment reduced the early hyperglycemia, lung neutrophil retention, MPO activity, and wet-to-dry weight ratio in OZ rats to levels comparable with those seen in LZ rats, with no effect on blood pressure or heart rate. These results demonstrate that β2-adrenoreceptor blockade effectively reduces the early posttrauma hyperglycemia, which is associated with decreased lung injury in OZ rats.

  10. Response to BRAF inhibition in melanoma is enhanced when combined with immune checkpoint blockade. (United States)

    Cooper, Zachary A; Juneja, Vikram R; Sage, Peter T; Frederick, Dennie T; Piris, Adriano; Mitra, Devarati; Lo, Jennifer A; Hodi, F Stephen; Freeman, Gordon J; Bosenberg, Marcus W; McMahon, Martin; Flaherty, Keith T; Fisher, David E; Sharpe, Arlene H; Wargo, Jennifer A


    BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.

  11. Glioblastoma Eradication Following Immune Checkpoint Blockade in an Orthotopic, Immunocompetent Model. (United States)

    Reardon, David A; Gokhale, Prafulla C; Klein, Sarah R; Ligon, Keith L; Rodig, Scott J; Ramkissoon, Shakti H; Jones, Kristen L; Conway, Amy Saur; Liao, Xiaoyun; Zhou, Jun; Wen, Patrick Y; Van Den Abbeele, Annick D; Hodi, F Stephen; Qin, Lei; Kohl, Nancy E; Sharpe, Arlene H; Dranoff, Glenn; Freeman, Gordon J


    Inhibition of immune checkpoints, including cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and its ligand PD-L1, has demonstrated exciting and durable remissions across a spectrum of malignancies. Combinatorial regimens blocking complementary immune checkpoints further enhance the therapeutic benefit. The activity of these agents for patients with glioblastoma, a generally lethal primary brain tumor associated with significant systemic and microenvironmental immunosuppression, is not known. We therefore systematically evaluated the antitumor efficacy of murine antibodies targeting a broad panel of immune checkpoint molecules, including CTLA-4, PD-1, PD-L1, and PD-L2 when administered as single-agent therapy and in combinatorial regimens against an orthotopic, immunocompetent murine glioblastoma model. In these experiments, we observed long-term tumor-free survival following single-agent anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy in 50%, 20%, and 15% of treated animals, respectively. Combination therapy of anti-CTLA-4 plus anti-PD-1 cured 75% of the animals, even against advanced, later-stage tumors. In long-term survivors, tumor growth was not seen upon intracranial tumor rechallenge, suggesting that tumor-specific immune memory responses were generated. Inhibitory immune checkpoint blockade quantitatively increased activated CD8(+) and natural killer cells and decreased suppressive immune cells in the tumor microenvironment and draining cervical lymph nodes. Our results support prioritizing the clinical evaluation of PD-1, PD-L1, and CTLA-4 single-agent targeted therapy as well as combination therapy of CTLA-4 plus PD-1 blockade for patients with glioblastoma.

  12. Recovery of network-driven glutamatergic activity in rat hippocampal neurons during chronic glutamate receptor blockade. (United States)

    Leininger, Eric; Belousov, Andrei B


    Previous studies indicated that a long-term decrease in the activity of ionotropic glutamate receptors induces cholinergic activity in rat and mouse hypothalamic neuronal cultures. Here we studied whether a prolonged inactivation of ionotropic glutamate receptors also induces cholinergic activity in hippocampal neurons. Receptor activity was chronically suppressed in rat hippocampal primary neuronal cultures with two proportionally increasing sets of concentrations of NMDA plus non-NMDA receptor antagonists: 100 microM/10 microM AP5/CNQX (1X cultures) and 200 microM/20 microM AP5/CNQX (2X cultures). Using calcium imaging we demonstrate that cholinergic activity does not develop in these cultures. Instead, network-driven glutamate-dependent activity, that normally is detected in hyper-excitable conditions, reappears in each culture group in the presence of these antagonists and can be reversibly suppressed by higher concentrations of AP5/CNQX. This activity is mediated by non-NMDA receptors and is modulated by NMDA receptors. Further, non-NMDA receptors, the general level of glutamate receptor activity and CaMK-dependent signaling are critical for development of this network-driven glutamatergic activity in the presence of receptor antagonists. Using electrophysiology, western blotting and calcium imaging we show that some neuronal parameters are either reduced or not affected by chronic glutamate receptor blockade. However, other parameters (including neuronal excitability, mEPSC frequency, and expression of GluR1, NR1 and betaCaMKII) become up-regulated and, in some cases, proportionally between the non-treated, 1X and 2X cultures. Our data suggest recovery of the network-driven glutamatergic activity after chronic glutamate receptor blockade. This recovery may represent a form of neuronal plasticity that compensates for the prolonged suppression of the activity of glutamate receptors.

  13. Viral vector-mediated selective and reversible blockade of the pathway for visual orienting in mice

    Directory of Open Access Journals (Sweden)

    Tadashi eIsa


    Full Text Available Recently, by using a combination of two viral vectors, we developed a technique for pathway-selective and reversible synaptic transmission blockade, and successfully induced a behavioral deficit of dexterous hand movements in macaque monkeys by affecting a population of spinal interneurons. To explore the capacity of this technique to work in other pathways and species, and to obtain fundamental methodological information, we tried to block the crossed tecto-reticular pathway, which is known to control orienting responses to visual targets, in mice. A neuron-specific retrograde gene transfer vector with the gene encoding enhanced tetanus neurotoxin (eTeNT tagged with enhanced green fluorescent protein (EGFP under the control of a tetracycline responsive element was injected into the left medial pontine reticular formation. 7–17 days later, an adeno-associated viral vector with a highly efficient Tet-ON sequence, rtTAV16, was injected into the right superior colliculus. 5–9 weeks later, the daily administration of doxycycline (Dox was initiated. Visual orienting responses toward the left side were impaired 1 - 4 days after Dox administration. Anti-GFP immunohistochemistry revealed that a number of neurons in the intermediate and deep layers of the right superior colliculus were positively stained, indicating eTeNT expression. After the termination of Dox administration, the anti-GFP staining returned to the baseline level within 28 days. A second round of Dox administration, starting from 28 days after the termination of the first Dox administration, resulted in the reappearance of the behavioral impairment. These findings showed that pathway-selective and reversible blockade of synaptic transmission causes behavioral effects also in rodents, and that the crossed tecto-reticular pathway surely controls visual orienting behaviors.

  14. Paradoxical proepileptic response to NMDA receptor blockade linked to cortical interneuron defect in stargazer mice

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    Atul eMaheshwari


    Full Text Available Paradoxical seizure exacerbation by antiepileptic medication is a well-known clinical phenomenon in epilepsy, but the cellular mechanisms remain unclear. One possibility is enhanced network disinhibition by unintended suppression of inhibitory interneurons. We investigated this hypothesis in the stargazer mouse model of absence epilepsy, which bears a mutation in stargazin, an AMPA receptor trafficking protein. If AMPA signaling onto inhibitory GABAergic neurons is impaired, their activation by glutamate depends critically upon NMDA receptors. Indeed, we find that stargazer seizures are exacerbated by NMDA receptor blockade with CPP and MK-801, whereas other genetic absence epilepsy models are sensitive to these antagonists. To determine how an AMPA receptor trafficking defect could lead to paradoxical network activation, we analyzed stargazin and AMPA receptor localization and found that stargazin is detected exclusively in parvalbumin-positive (PV+ fast-spiking interneurons in somatosensory cortex, where it is co-expressed with the AMPA receptor subunit GluA4. PV+ cortical interneurons in stargazer show a near two-fold decrease in the dendrite:soma GluA4 expression ratio compared to wild type littermates. We explored the functional consequence of this trafficking defect on network excitability in neocortical slices. Both NMDA receptor antagonists suppressed 0 Mg2+ induced network discharges in wild type but augmented bursting in stargazer cortex. Interneurons mediate this paradoxical response, since the difference between genotypes was masked by GABA receptor blockade. Our findings provide a cellular locus for AMPA receptor-dependent signaling defects in stargazer cortex and define an interneuron-dependent mechanism for paradoxical seizure exacerbation in absence epilepsy.

  15. Lichenoid Dermatologic Toxicity From Immune Checkpoint Blockade Therapy: A Detailed Examination of the Clinicopathologic Features. (United States)

    Tetzlaff, Michael T; Nagarajan, Priyadharsini; Chon, Susan; Huen, Auris; Diab, Adi; Omar, Pacha; Aung, Phyu P; Torres-Cabala, Carlos A; Mays, Steven R; Prieto, Victor G; Curry, Jonathan L


    Immunotherapy targeting the programmed cell death 1 (PD-1) receptor has demonstrated tremendous promise in the treatment of advanced solid tumors. Dermatologic toxicities, however, are an emerging consequence of this therapy and have been clearly associated with immune checkpoint blockade antibodies. Distinctive clinical and histologic subtypes of dermatologic toxicity secondary to immunotherapy are emerging and include rare autoimmune bullous reactions (eg, bullous pemphigoid) and lichenoid eruptions. We report three patients who developed lichenoid dermatitis while receiving anti-PD-1 antibody therapy. The mean time to onset of lichenoid dermatologic toxicity was 42 days (range: 1-75 days) from initiation of anti-PD-1 antibody therapy. Lesions most frequently presented on the extremities and trunk as pustules, papules, and plaques. The face was not commonly involved. Of the five skin biopsies examined, all demonstrated dense band-like lymphocytic infiltrate, hyperkeratosis, hypergranulosis, saw-tooth rete ridge pattern, and dyskeratosis. Acanthosis was a feature in all of the skin biopsies, and in one, epidermal hyperplasia was prominent. In several skin biopsies, histologic features supporting a lichenoid drug eruption were present, including parakeratosis, spongiosis, periadnexal/perivascular inflammation, and eosinophils. Furthermore, the histologic features varied in skin biopsy specimens taken from the same patient at different sites, supporting a drug reaction. All patients' skin lesions improved with use of steroids: two were treated with topical steroids and one with systemic steroids. Recognition of the histopathologic patterns of dermatologic toxicities resulting from immune checkpoint blockade therapy will become increasingly important for ensuring appropriate management of dermatologic toxicities and optimal patient care.

  16. The interpretation of pain relief and sensory changes following sympathetic blockade. (United States)

    Dellemijn, P L; Fields, H L; Allen, R R; McKay, W R; Rowbotham, M C


    A comparative study of the effects of sympathetic blockade by stellate ganglion block (SGB) and intravenous phentolamine infusion (PhI) was carried out in 24 patients with presumed sympathetically maintained pain of an upper extremity. A total of 15 SGBs and 16 PhIs were performed, with seven patients undergoing both procedures. All patients developed a Horner's syndrome with SGB and nasal stuffiness and cardiovascular changes with PhI. Similar pain relief was obtained with SGB and PhI in six of the seven who underwent both procedures. Pre-procedure patient characteristics including age, sex, duration of pain, historical and physical examination features suggestive of the reflex sympathetic dystrophy syndrome, and sensory disturbances such as allodynia and hyperpathia did not predict pain relief from either procedure. Changes in skin temperature following the sympatholytic procedure did not correlate with pain relief. For PhI, pain relief correlated with the magnitude of decrease in systolic blood pressure. After SGB, changes in quantitative thermal sensory testing (QST) suggestive of a partial deficit in thermal sensation correlated with pain relief. In 20 normal controls, water bath immersion to cool the hand passively by 7 degrees C and warm the hand passively by 4 degrees C had small and selective effects on thermal QST thresholds, but did not produce a general impairment in thermal sensation. In conclusion, the diagnosis of sympathetically maintained pain based on the history and physical examination alone cannot be made with confidence and therefore a sympatholytic procedure is necessary. When SGB produces pain relief but PhI does not, systemic absorption of local anaesthetic and/or sensory blockade by spread to somatic nerves may be the reason. Thus, PhI appears to be a less sensitive but more specific test than SGB. These two procedures provide complementary information and both may be needed to establish the diagnosis of sympathetically maintained pain.

  17. Quorum-sensing blockade as a strategy for enhancing host defences against bacterial pathogens

    DEFF Research Database (Denmark)

    Bjarnsholt, Thomas; Givskov, Michael Christian


    -mediated killing or growth inhibition would be to attenuate the bacteria with respect to pathogenicity. The realization that Pseudomonas aeruginosa, and a number of other pathogens, controls much of their virulence arsenal by means of extracellular signal molecules in a process denoted quorum sensing (QS) gave...... is likely to increase the susceptibility of the infecting organism to host defences and its clearance from the host. The use of QS signal blockers to attenuate bacterial pathogenicity, rather than bacterial growth, is therefore highly attractive, particularly with respect to the emergence of multi...

  18. Cerebral oxygenation decreases during exercise in humans with beta-adrenergic blockade

    DEFF Research Database (Denmark)

    Seifert, T.; Rasmussen, P.; Secher, Niels H.


    AIM: Beta-blockers reduce exercise capacity by attenuated increase in cardiac output, but it remains unknown whether performance also relates to attenuated cerebral oxygenation. METHODS: Acting as their own controls, eight healthy subjects performed a continuous incremental cycle test to exhaustion...... with or without administration of the non-selective beta-blocker propranolol. Changes in cerebral blood flow velocity were measured with transcranial Doppler ultrasound and those in cerebral oxygenation were evaluated using near-infrared spectroscopy and the calculated cerebral mitochondrial oxygen tension...

  19. Nucleus incertus contributes to an anxiogenic effect of buspirone in rats: Involvement of 5-HT1A receptors. (United States)

    Kumar, Jigna Rajesh; Rajkumar, Ramamoorthy; Lee, Liying Corinne; Dawe, Gavin S


    The nucleus incertus (NI), a brainstem structure with diverse anatomical connections, is implicated in anxiety, arousal, hippocampal theta modulation, and stress responses. It expresses a variety of neurotransmitters, neuropeptides and receptors such as 5-HT1A, D2 and CRF1 receptors. We hypothesized that the NI may play a role in the neuropharmacology of buspirone, a clinical anxiolytic which is a 5-HT1A receptor partial agonist and a D2 receptor antagonist. Several preclinical studies have reported a biphasic anxiety-modulating effect of buspirone but the precise mechanism and structures underlying this effect are not well-understood. The present study implicates the NI in the anxiogenic effects of a high dose of buspirone. Systemic buspirone (3 mg/kg) induced anxiogenic effects in elevated plus maze, light-dark box and open field exploration paradigms in rats and strongly activated the NI, as reflected by c-Fos expression. This anxiogenic effect was reproduced by direct infusion of buspirone (5 μg) into the NI, but was abolished in NI-CRF-saporin-lesioned rats, indicating that the NI is present in neural circuits driving anxiogenic behaviour. Pharmacological studies with NAD 299, a selective 5-HT1A antagonist, or quinpirole, a D2/D3 agonist, were conducted to examine the receptor system in the NI involved in this anxiogenic effect. Opposing the 5-HT1A agonism but not the D2 antagonism of buspirone in the NI attenuated the anxiogenic effects of systemic buspirone. In conclusion, 5-HT1A receptors in the NI contribute to the anxiogenic effect of an acute high dose of buspirone in rats and may be functionally relevant to physiological anxiety.

  20. Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans. (United States)

    Valle, Marta; Maqueda, Ana Elda; Rabella, Mireia; Rodríguez-Pujadas, Aina; Antonijoan, Rosa Maria; Romero, Sergio; Alonso, Joan Francesc; Mañanas, Miquel Àngel; Barker, Steven; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi


    Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus β-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.

  1. Comparison of non-attenuation corrected and attenuation corrected myocardial perfusion SPE

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    Hasan Raza


    Conclusion: This study demonstrates that CT based attenuation corrected Tc-99mm sestamibi SPECT myocardial perfusion imaging significantly improved the specificity of the RCA territory compared with non-attenuation corrected Tc-99mm sestamibi SPECT myocardial perfusion imaging in both genders irrespective of BMI.

  2. PD-L1 Blockade Differentially Impacts Regulatory T Cells from HIV-Infected Individuals Depending on Plasma Viremia.

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    Cristina Peligero


    Full Text Available Blocking the PD-1/PD-L1 pathway has emerged as a potential therapy to restore impaired immune responses in human immunodeficiency virus (HIV-infected individuals. Most reports have studied the impact of the PD-L1 blockade on effector cells and neglected possible effects on regulatory T cells (Treg cells, which play an essential role in balancing immunopathology and antiviral effector responses. The aim of this study was to define the consequences of ex vivo PD-L1 blockade on Treg cells from HIV-infected individuals. We observed that HIV infection led to an increase in PD-1+ and PD-L1+ Treg cells. This upregulation correlated with disease progression and decreased under antiretroviral treatment. Treg cells from viremic individuals had a particularly high PD-1 expression and impaired proliferative capacity in comparison with Treg cells from individuals under antiretroviral treatment. PD-L1 blockade restored the proliferative capacity of Treg cells from viremic individuals but had no effect on its suppressive capacity. Moreover, it increased the viral production in cell cultures from viremic individuals. This increase in viral production correlated with an increase in Treg cell percentage and a reduction in the CD4/Treg and CD8/Treg cell ratios. In contrast to the effect of the PD-L1 blockade on Treg cells from viremic individuals, we did not observe a significant effect on the proliferative capacity of Treg cells from individuals in whom viremia was controlled (either spontaneously or by antiretroviral treatment. However, PD-L1 blockade resulted in an increased proliferative capacity of HIV-specific-CD8 T cells in all subjects. Taken together, our findings suggest that manipulating PD-L1 in vivo can be expected to influence the net gain of effector function depending on the subject's plasma viremia.

  3. Vaccine-induced but not tumor-derived Interleukin-10 dictates the efficacy of Interleukin-10 blockade in therapeutic vaccination. (United States)

    Llopiz, Diana; Aranda, Fernando; Díaz-Valdés, Nancy; Ruiz, Marta; Infante, Stefany; Belsúe, Virginia; Lasarte, Juan José; Sarobe, Pablo


    Blocking antibodies against immunosuppressive molecules have shown promising results in cancer patients. However, there are not enough data to define those conditions dictating treatment efficacy. In this scenario, IL-10 is a cytokine with controversial effects on tumor growth. Thus, our aim was to characterize in which setting IL-10 blockade may potentiate the beneficial effects of a therapeutic vaccine In the IL-10-expressing B16-OVA and TC-1 P3 (A15) tumor models, therapeutic vaccination with tumor antigens plus the TLR7 ligand Imiquimod increased IL-10 production. Although blockade of IL-10 signal with anti-IL-10R antibodies did not inhibit tumor growth, when combined with vaccination it enhanced tumor rejection, associated with stronger innate and adaptive immune responses. Interestingly, a similar enhancement on immune responses was observed after simultaneous vaccination and IL-10 blockade in naive mice. However, when using vaccines containing as adjuvants the TLR3 ligand poly(I:C) or anti-CD40 agonistic antibodies, despite tumor IL-10 expression, anti-IL-10R antibodies did not provide any beneficial effect on tumor growth and antitumor immune responses. Of note, as opposed to Imiquimod, vaccination with this type of adjuvants did not induce IL-10 and correlated with a lack of in vitro IL-10 production by dendritic cells (DC). Finally, in B16-OVA-bearing mice, blockade of IL-10 during therapeutic vaccination with a multiple adjuvant combination (MAC) with potent immunostimulatory properties but still inducing IL-10 led to superior antitumor immunity and complete tumor rejection. These results suggest that for therapeutic antitumor vaccination, blockade of vaccine-induced IL-10 is more relevant than tumor-associated IL-10.

  4. Regression of cardiac hypertrophy in the SHR by combined renin-angiotensin system blockade and dietary sodium restriction

    Directory of Open Access Journals (Sweden)

    Emad Abro


    Full Text Available Altered operation of the renin-angiotensin-aldosterone system (RAAS and dietary sodium intake have been identified as independent risk factors for cardiac hypertrophy. The way in which sodium intake and the operation of the renin-angiotensin-aldosterone system interact in the pathogenesis of cardiac hypertrophy is poorly understood. The aims of this study were to investigate the cardiac effects of the renin-angiotensin system (RAS blockade in the spontaneously hypertensive rat (SHR, using co-treatment with an angiotensin II receptor blocker (ARB and an angiotensin-converting enzyme (ACE inhibitor with different sodium intakes. Our experiments with SHR show that, at high levels of sodium intake (4.0%, aggressive RAS blockade treatment with candesartan (3 mg/kg and perindopril (6 mg/kg does not result in regression of cardiac hypertrophy. In contrast, RAS blockade coupled with reduced sodium diet (0.2% significantly regresses cardiac hypertrophy, impairs animal growth and is associated with elevated plasma renin and dramatically suppressed plasma angiotensinogen levels. Histological analyses indicate that the differential effect of reduced sodium on heart growth during RAS blockade is not associated with any change in myocardial interstitial collagen, but reflects modification of cellular geometry. Dimensional measurements of enzymatically-isolated ventricular myocytes show that, in the RAS blocked, reduced sodium group, myocyte length and width were decreased by about 16—19% compared with myocytes from the high sodium treatment group. Our findings highlight the importance of `titrating' sodium intake with combined RAS blockade in the clinical setting to optimise therapeutic benefit.

  5. Attenuation tomography in West Bohemia/Vogtland (United States)

    Mousavi, Sima; Haberland, Christian; Bauer, Klaus; Hejrani, Babak; Korn, Michael


    We present a three-dimensional (3-D) P-wave attenuation (Qp) model for the geodynamically active swarm earthquake area of West Bohemia/Vogtland in the Czech/German border region. Path-averaged attenuation t* is calculated from amplitude spectra of time windows around the P-wave arrivals of local earthquakes. Average t/t* value or Qp for stations close to Nový Kostel are very low (focal zone (increases up to 500 within 80 km distance). The SIMUL2000 tomography scheme is used to invert the t* for P-wave attenuation perturbation. Analysis of resolution shows that our model is well-resolved in the vicinity of earthquake swarm hypocenters. The prominent features of the model are located around Nový Kostel focal zone and its northern vicinity. Beneath Nový Kostel a vertically stretched (down to depth of 11 km) and a highly attenuating body is observed. We believe that this is due to fracturing and high density of cracks inside the weak earthquake swarm zone in conjunction with presence of free gas/fluid. Further north of Nový Kostel two highly attenuating bodies are imaged which could represent fluid channels toward the surface. The eastern anomaly shows a good correlation with the fluid accumulation area which was suggested in 9HR seismic profile.

  6. Editing modifies the GABA(A) receptor subunit alpha3

    DEFF Research Database (Denmark)

    Ohlson, Johan; Pedersen, Jakob Skou; Haussler, David


    Adenosine to inosine (A-to-I) pre-mRNA editing by the ADAR enzyme family has the potential to increase the variety of the proteome. This editing by adenosine deamination is essential in mammals for a functional brain. To detect novel substrates for A-to-I editing we have used an experimental method...... to find selectively edited sites and combined it with bioinformatic techniques that find stem-loop structures suitable for editing. We present here the first verified editing candidate detected by this screening procedure. We show that Gabra-3, which codes for the alpha3 subunit of the GABA(A) receptor......, is a substrate for editing by both ADAR1 and ADAR2. Editing of the Gabra-3 mRNA recodes an isoleucine to a methionine. The extent of editing is low at birth but increases with age, reaching close to 100% in the adult brain. We therefore propose that editing of the Gabra-3 mRNA is important for normal brain...

  7. Live attenuated vaccines for invasive Salmonella infections. (United States)

    Tennant, Sharon M; Levine, Myron M


    Salmonella enterica serovar Typhi produces significant morbidity and mortality worldwide despite the fact that there are licensed Salmonella Typhi vaccines available. This is primarily due to the fact that these vaccines are not used in the countries that most need them. There is growing recognition that an effective invasive Salmonella vaccine formulation must also prevent infection due to other Salmonella serovars. We anticipate that a multivalent vaccine that targets the following serovars will be needed to control invasive Salmonella infections worldwide: Salmonella Typhi, Salmonella Paratyphi A, Salmonella Paratyphi B (currently uncommon but may become dominant again), Salmonella Typhimurium, Salmonella Enteritidis and Salmonella Choleraesuis (as well as other Group C Salmonella). Live attenuated vaccines are an attractive vaccine formulation for use in developing as well as developed countries. Here, we describe the methods of attenuation that have been used to date to create live attenuated Salmonella vaccines and provide an update on the progress that has been made on these vaccines.

  8. Research on Nanosecond Pulse Corona Discharge Attenuation

    Institute of Scientific and Technical Information of China (English)

    HE Zheng-hao; XU Huai-li; BAI Jing; YU Fu-sheng; HU Feng; LI Jin


    A line-to-plate reactor was set-up in the experimental study on the application of nanosecond pulsed corona discharge plasma technology in environmental pollution control.Investigation on the attenuation and distortion of the amplitude of the pulse wave front and the discharge image as well as the waveform along the corona wire was conducted.The results show that the wave front decreases sharply during the corona discharge along the corona wire.The higher the amplitude of the applied pulse is,the more the amplitude of the wave front decreased.The wave attenuation responds in a lower corona discharge inversely.To get a higher efficiency of the line-to-plate reactor a sharp attenuation of the corona has to be considered in practical design.

  9. Is there seismic attenuation in the mantle? (United States)

    Ricard, Y.; Durand, S.; Montagner, J.-P.; Chambat, F.


    The small scale heterogeneity of the mantle is mostly due to the mixing of petrological heterogeneities by a smooth but chaotic convection and should consist in a laminated structure (marble cake) with a power spectrum S(k) varying as 1/k, where k is the wavenumber of the anomalies. This distribution of heterogeneities during convective stirring with negligible diffusion, called Batchelor regime is documented by fluid dynamic experiments and corresponds to what can be inferred from geochemistry and seismic tomography. This laminated structure imposes density, seismic velocity and potentially, anisotropic heterogeneities with similar 1/k spectra. A seismic wave of wavenumber k0 crossing such a medium is partly reflected by the heterogeneities and we show that the scattered energy is proportional to k0S(2k0). The reduction of energy for the propagating wave appears therefore equivalent to a quality factor 1/Q∝k0S(2k0). With the specific 1/k spectrum of the mantle, the resulting apparent attenuation should therefore be frequency independent. We show that the total contribution of 6-9% RMS density, velocity and anisotropy would explain the observed S and P attenuation of the mantle. Although these values are large, they are not unreasonable and we discuss how they depend on the range of frequencies over which the attenuation is explained. If such a level of heterogeneity were present, most of the attenuation of the Earth would be due to small scale scattering by laminations, not by intrinsic dissipation. Intrinsic dissipation must certainly exist but might correspond to a larger, yet unobserved Q. This provocative result would explain the very weak frequency dependence of the attenuation, and the fact that bulk attenuation seems negligible, two observations that have been difficult to explain for 50 years.

  10. MK801 attenuates secondary injury in a mouse experimental compression model of spinal cord trauma

    Directory of Open Access Journals (Sweden)

    Meli Rosaria


    Full Text Available Abstract Background Glutamergic excitotoxicity has been shown to play a deleterious role in the pathophysiology of spinal cord injury (SCI. The aim of this study was to investigate the neuroprotective effect of dizocilpine maleate, MK801 (2 mg/Kg, 30 min and 6 hours after injury in a mice model of SCI. The spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Results Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration and apoptosis. In this study we clearly demonstrated that administration of MK801 attenuated all inflammatory parameters. In fact 24 hours after injury, the degree of spinal cord inflammation and tissue injury (evaluated as histological score, infiltration of neutrophils, NF-κB activation, iNOS, cytokines levels (TNF-α and IL-1β, neurotrophin expression were markedly reduced by MK801 treatment. Moreover, in a separate set of experiments, we have demonstrated that MK801 treatment significantly improved the recovery of locomotory function. Conclusions Blockade of NMDA by MK801 lends support to the potential importance of NMDA antagonists as therapeutic agents in the treatment of acute spinal cord injury.

  11. Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain

    Directory of Open Access Journals (Sweden)

    Bloom Aaron P


    Full Text Available Abstract Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF or its cognate receptor tropomyosin receptor kinase A (TrkA has become an attractive target for attenuating chronic pain. In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection, but not late/acute (initiated day 18 post cancer cell injection administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling. These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients.

  12. Serotonin 2a Receptor and Serotonin 1a Receptor Interact Within the Medial Prefrontal Cortex During Recognition Memory in Mice (United States)

    Morici, Juan F.; Ciccia, Lucia; Malleret, Gaël; Gingrich, Jay A.; Bekinschtein, Pedro; Weisstaub, Noelia V.


    Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR) one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a−/−) with wild type (htr2a+/+) littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex. PMID:26779016

  13. Serotonin 2a Receptor and serotonin 1a receptor interact within the medial prefrontal cortex during recognition memory in mice

    Directory of Open Access Journals (Sweden)

    Juan Facundo Morici


    Full Text Available Episodic memory, can be defined as the memory for unique events. The serotonergic system one of the main neuromodulatory systems in the brain appears to play a role in it. The serotonin 2a receptor (5-HT2aR one of the principal post-synaptic receptors for 5-HT in the brain, is involved in neuropsychiatric and neurological disorders associated with memory deficits. Recognition memory can be defined as the ability to recognize if a particular event or item was previously encountered and is thus considered, under certain conditions, a form of episodic memory. As human data suggest that a constitutively decrease of 5-HT2A signaling might affect episodic memory performance we decided to compare the performance of mice with disrupted 5-HT2aR signaling (htr2a -/- with wild type (htr2a+/+ littermates in different recognition memory and working memory tasks that differed in the level of proactive interference. We found that ablation of 5-HT2aR signaling throughout development produces a deficit in tasks that cannot be solved by single item strategy suggesting that 5-HT2aR signaling is involved in interference resolution. We also found that in the absence of 5-HT2aR signaling serotonin has a deleterious effect on recognition memory retrieval through the activation of 5-HT1aR in the medial prefrontal cortex.

  14. Ultrasound transmission attenuation tomography using energy-scaled amplitude ratios (United States)

    Chen, Ting; Shin, Junseob; Huang, Lianjie


    Ultrasound attenuation of breast tumors is related to their types and pathological states, and can be used to detect and characterize breast cancer. Particularly, ultrasound scattering attenuation can infer the margin properties of breast tumors. Ultrasound attenuation tomography quantitatively reconstructs the attenuation properties of the breast. Our synthetic-aperture breast ultrasound tomography system with two parallel transducer arrays records both ultrasound reflection and transmission signals. We develop an ultrasound attenuation tomography method using ultrasound energy-scaled amplitude decays of ultrasound transmission signals and conduct ultrasound attenuation tomography using a known sound-speed model. We apply our ultrasound transmission attenuation tomography method to a breast phantom dataset, and compare the ultrasound attenuation tomography results with conventional beamforming ultrasound images obtained using reflection signals. We show that ultrasound transmission attenuation tomography complements beamforming images in identifying breast lesions.

  15. A receptor for infectious and cellular prion protein

    Directory of Open Access Journals (Sweden)

    V.R. Martins


    Full Text Available Prions are an unconventional form of infectious agents composed only of protein and involved in transmissible spongiform encephalopathies in humans and animals. The infectious particle is composed by PrPsc which is an isoform of a normal cellular glycosyl-phosphatidylinositol (GPI anchored protein, PrPc, of unknown function. The two proteins differ only in conformation, PrPc is composed of 40% a helix while PrPsc has 60% ß-sheet and 20% a helix structure. The infection mechanism is trigged by interaction of PrPsc with cellular prion protein causing conversion of the latter's conformation. Therefore, the infection spreads because new PrPsc molecules are generated exponentially from the normal PrPc. The accumulation of insoluble PrPsc is probably one of the events that lead to neuronal death. Conflicting data in the literature showed that PrPc internalization is mediated either by clathrin-coated pits or by caveolae-like membranous domains. However, both pathways seem to require a third protein (a receptor or a prion-binding protein either to make the connection between the GPI-anchored molecule to clathrin or to convert PrPc into PrPsc. We have recently characterized a 66-kDa membrane receptor which binds PrPc in vitro and in vivo and mediates the neurotoxicity of a human prion peptide. Therefore, the receptor should have a role in the pathogenesis of prion-related diseases and in the normal cellular process. Further work is necessary to clarify the events triggered by the association of PrPc/PrPsc with the receptor.

  16. Neuroticism and serotonin 5-HT1A receptors in healthy subjects. (United States)

    Hirvonen, Jussi; Tuominen, Lauri; Någren, Kjell; Hietala, Jarmo


    Neuroticism is a personality trait associated with vulnerability for mood and anxiety disorders. Serotonergic mechanisms likely contribute to neuroticism. Serotonin 5-HT1A receptors are altered in mood and anxiety disorders, but whether 5-HT1A receptors are associated with neuroticism in healthy subjects is unclear. We measured brain serotonin 5-HT1A receptor in 34 healthy subjects in vivo using positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635. Binding potential (BPP) was determined using the golden standard of kinetic compartmental modeling using arterial blood samples and radiometabolite determination. Personality traits were assessed using the Karolinska Scales of Personality. We found a strong negative association between serotonin 5-HT1A receptor BPP and neuroticism. That is, individuals with high neuroticism tended to have lower 5-HT1A receptor binding than individuals with low neuroticism. This finding was confirmed with an independent voxel-based whole-brain analysis. Other personality traits did not correlate with 5-HT1A receptor BPP. Previous observations have reported lower serotonin 5-HT1A receptor density in major depression. This neurobiological finding may be a trait-like phenomenon and partly explained by higher neuroticism in patients with affective disorders. The link between personality traits and 5-HT1A receptors should be studied in patients with major depression.

  17. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia

    DEFF Research Database (Denmark)

    Santini, Martin A; Ratner, Cecilia Friis; Aznar, Susana


    Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia...

  18. The role of GABA(A) receptors in the development of alcoholism. (United States)

    Enoch, Mary-Anne


    Alcoholism is a common, heritable, chronic relapsing disorder. GABA(A) receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA(A) receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA(A) receptors: tolerance is associated with generally decreased GABA(A) receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA(A) receptors may be implicated in the switch from heavy drinking to dependence. GABA(A) receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA(A) receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA(A) receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

  19. Loss of serotonin 2A receptors exceeds loss of serotonergic projections in early Alzheimer's disease

    DEFF Research Database (Denmark)

    Marner, Lisbeth; Frøkjær, Vibe; Kalbitzer, Jan;


    In patients with Alzheimer's disease (AD), postmortem and imaging studies have revealed early and prominent reductions in cerebral serotonin 2A (5-HT(2A)) receptors. To establish if this was due to a selective disease process of the serotonin system, we investigated the cerebral 5-HT(2A) receptor...

  20. Touch Attenuates Infants' Physiological Reactivity to Stress (United States)

    Feldman, Ruth; Singer, Magi; Zagoory, Orna


    Animal studies demonstrate that maternal touch and contact regulate infant stress, and handling during periods of maternal deprivation attenuates the stress response. To measure the effects of touch on infant stress reactivity during simulated maternal deprivation, 53 dyads were tested in two paradigms: still-face (SF) and still-face with maternal…

  1. Microwave attenuation with composite of copper microwires

    Energy Technology Data Exchange (ETDEWEB)

    Gorriti, A.G.; Marin, P. [Instituto de Magnetismo Aplicado, (UCM-ADIF-CSIC) and Departamento de Fisica de Materiales (UCM). P.O. Box 155, Las Rozas, Madrid 28230 (Spain); Cortina, D. [Micromag S.L., Las Rozas, Madrid 28230 (Spain); Hernando, A., E-mail: antonio.hernando@adif.e [Instituto de Magnetismo Aplicado, (UCM-ADIF-CSIC) and Departamento de Fisica de Materiales (UCM). P.O. Box 155, Las Rozas, Madrid 28230 (Spain); Micromag S.L., Las Rozas, Madrid 28230 (Spain)


    It is shown that copper microwires composite media attenuates microwave reflection of metallic surfaces. We show how the distance to the metallic surface, as well as the length and volume fraction of microwires, determine the frequency of maximum absorption and the return loss level. Furthermore, we were able to fit the experimental results with a theoretical model based on Maxwell-Garnett mixing formula.

  2. GPR measurements of attenuation in concrete

    Energy Technology Data Exchange (ETDEWEB)

    Eisenmann, David, E-mail:; Margetan, Frank J., E-mail:; Pavel, Brittney, E-mail: [Center for Nondestructive Evaluation, Iowa State University, 1915 Scholl Road, Ames, IA 50011-3042 (United States)


    Ground-penetrating radar (GPR) signals from concrete structures are affected by several phenomenon, including: (1) transmission and reflection coefficients at interfaces; (2) the radiation patterns of the antenna(s) being used; and (3) the material properties of concrete and any embedded objects. In this paper we investigate different schemes for determining the electromagnetic (EM) attenuation of concrete from measured signals obtained using commercially-available GPR equipment. We adapt procedures commonly used in ultrasonic inspections where one compares the relative strengths of two or more signals having different travel paths through the material of interest. After correcting for beam spread (i.e., diffraction), interface phenomena, and equipment amplification settings, any remaining signal differences are assumed to be due to attenuation thus allowing the attenuation coefficient (say, in dB of loss per inch of travel) to be estimated. We begin with a brief overview of our approach, and then discuss how diffraction corrections were determined for our two 1.6 GHz GPR antennas. We then present results of attenuation measurements for two types of concrete using both pulse/echo and pitch/catch measurement setups.

  3. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

    Directory of Open Access Journals (Sweden)

    Willis Cynthia R


    Full Text Available Abstract Background Interleukin-7 (IL-7 acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. Methods We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb-induced colitis in immune-sufficient Mdr1a−/− mice and in T- and B-cell-deficient Rag2−/− mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. Results Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a−/− mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a−/− mice treated with an anti-IL-7R antibody. In Rag2−/− mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. Conclusions Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development

  4. Chloride-cotransport blockade desynchronizes neuronal discharge in the "epileptic" hippocampal slice. (United States)

    Hochman, D W; Schwartzkroin, P A


    Antagonism of the chloride-cotransport system in hippocampal slices has been shown to block spontaneous epileptiform (i.e., hypersynchronized) discharges without diminishing excitatory synaptic transmission. Here we test the hypotheses that chloride-cotransport blockade, with furosemide or low-chloride (low-[Cl(-)](o)) medium, desynchronizes the firing activity of neuronal populations and that this desynchronization is mediated through nonsynaptic mechanisms. Spontaneous epileptiform discharges were recorded from the CA1 and CA3 cell body layers of hippocampal slices. Treatment with low-[Cl(-)](o) medium led to cessation of spontaneous synchronized bursting in CA1 >/=5-10 min before its disappearance from CA3. During the time that CA3 continued to burst spontaneously but CA1 was silent, electrical stimulation of the Schaffer collaterals showed that hyperexcited CA1 synaptic responses were maintained. Paired intracellular recordings from CA1 pyramidal cells showed that during low-[Cl(-)](o) treatment, the timing of action potential discharges became desynchronized; desynchronization was identified with phase lags in firing times of action potentials between pairs of neurons as well as a with a broadening and diminution of the CA1 field amplitude. Continued exposure to low-[Cl(-)](o) medium increased the degree of the firing-time phase shifts between pairs of CA1 pyramidal cells until the epileptiform CA1 field potential was abolished completely. Intracellular recordings during 4-aminopyridine (4-AP) treatment showed that prolonged low-[Cl(-)](o) exposure did not diminish the frequency or amplitude of spontaneous postsynaptic potentials. CA3 antidromic responses to Schaffer collateral stimulation were not significantly affected by prolonged low-[Cl(-)](o) exposure. In contrast to CA1, paired intracellular recordings from CA3 pyramidal cells showed that chloride-cotransport blockade did not cause a significant desynchronization of action potential firing times in the

  5. Effects of beta blockade on sudden cardiac death during acute myocardial infarction and the postinfarction period. (United States)

    Hjalmarson, A


    About half of all deaths after myocardial infarction (MI) are sudden cardiac deaths. Most of these are thought to be due to ventricular fibrillation (VF). A number of interventions and many different antiarrhythmic agents have been investigated, but so far only beta-blocker therapy has been found to produce significant reductions in the risk of sudden cardiac death after MI. Reductions in total mortality and sudden cardiac death were first reported in 1981 in 3 placebo-controlled studies, the Norwegian Timolol Study, the American Beta-Blocker Heart Attack Trial (BHAT), and the Göteborg Metoprolol Trial. A few years later, two very large trials, the Metoprolol in Acute Myocardial Infarction (MIAMI) study and the First International Study of Infarct Survival (ISIS-1), which included 6,000 and 16,000 patients, respectively, showed that beta-blocker therapy could reduce mortality within the first 2 weeks after onset of MI. Data from 24 postinfarction studies with long-term follow-up show an average 20% mortality reduction over 2 years. Pooled results of 28 short-term, randomized, placebo-controlled trials in which beta blockers were given intravenously shortly after onset of MI indicate an average 13% mortality reduction within 2 weeks. In the 16 studies in which the sudden cardiac death rate was reported, the beneficial effect of beta blockade was even more marked: a 34% average reduction of risk. Not all studies with beta blockers, however, have demonstrated a significant reduction in the incidence of sudden cardiac death. Such an effect has been clearly demonstrated only for the more lipophilic beta blockers (timolol, metoprolol, and propranolol). Two of these lipophilic beta blockers, metoprolol and propranolol, have also been shown to prevent VF after MI in clinical studies. Based on observations from animal experiments, it has been proposed that beta blockers with a high degree of lipophilicity penetrate the brain and thereby maintain high vagal tone during

  6. The role of hyaluronidase on lidocaine and bupivacaine pharmacokinetics after peribulbar blockade. (United States)

    Nathan, N; Benrhaiem, M; Lotfi, H; Debord, J; Rigaud, G; Lachatre, G; Adenis, J P; Feiss, P


    Orbital regional anesthesia is the only circumstance where hyaluronidase is routinely added to local anesthetics to accelerate the onset of the block. The aim of this study was to compare the pharmacokinetics of lidocaine and bupivacaine with or without hyaluronidase for peribulbar blockade. Twenty-one patients scheduled for cataract surgery with lens implantation were included in this prospective randomized study. Peribulbar blocks were achieved with plain bupivacaine 0.5% (5.5 mL), lidocaine 2% (5.5 mL), and hyaluronidase (100 IU = 2 mL) (n = 10) ir sterile water (2 mL) (n = 11). Plasma bupivacaine and lidocaine concentrations were measured by high-performance liquid chromatography at regular intervals from the end of the local anesthetic injection until the 360th minute. Maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) were obtained for all the patients except one who needed a supplementary injection and was excluded from the study. The time to onset and duration of the analgesia and akinesia were monitored at the times of sampling. Motor blockade was incomplete in two patients in each group without affecting surgery. The Tmax and absorption half-life (t1/2a) of lidocaine and bupivacaine were not different within each group (P > 0.05). The Tmax of lidocaine was shorter in the presence of hyaluronidase (17.1 +/- 2.6 min vs 32.7 +/- 6.0 min) as well as the Tmax of bupivacaine (16.8 +/- 3.0 min vs 26.5 +/- 4.4 min). The Cmax of lidocaine and bupivacaine were not modified by the addition of hyaluronidase. The clearance, terminal half-life, and volume of distribution were not different between groups. The absorption of lidocaine and bupivacaine from the peribulbar space are hastened by the addition of hyaluronidase. The Tmax of lidocaine is not different from that of bupivacaine within each group suggesting that the absorption of local anesthetics is minimally influenced by the liposolubility of the drugs. Moreover, hyaluronidase influences the

  7. C5a receptor (CD88) inhibition improves hypothermia-induced neuroprotection in an in vitro ischemic model. (United States)

    Thundyil, John; Pavlovski, Dale; Hsieh, Yu-Hsuan; Gelderblom, Mathias; Magnus, Tim; Fairlie, David P; Arumugam, Thiruma V


    The concept of 'salvageble penumbra' has prompted both scientists and physicians to explore various neuroprotective approaches that could be beneficial during stroke therapy. Unfortunately, most of them have proved ineffective in targeting multiple cellular death cascades incited within the ischemic penumbra. Hypothermia has been shown to be capable of addressing this problem to some extent. Although many studies have shown that hypothermia targets several cellular processes, its effects on innate immune receptor-mediated apoptotic death still remain unclear. Moreover, whether inhibiting the signaling of innate immune receptors like complement anaphylatoxin C5a receptor (CD88) plays a role in this hypothermic neuroprotection still need to be deciphered. Using various types of ischemic insults in different neuronal cells, we confirm that hypothermia does indeed attenuate apoptotic neuronal cell death in vitro and this effect can be further enhanced by pharmacologically blocking or knocking out CD88. Thus, our study raises a promising therapeutic possibility of adding CD88 antagonists along with hypothermia to improve stroke outcomes.

  8. Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1. (United States)

    Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R


    The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.

  9. Sizes of mantle heteogeneities and seismic attenuation (United States)

    Ricard, Y. R.; durand, S.; Chambat, F.; Montagner, J.


    The small scale heterogeneity of the mantle, being mostly due to the mixing of petrological heterogeneities by a smooth but chaotic convection should consist in a laminated structure (marble cake) with a power spectrum S(k) varying as 1/k, where k is the wavenumber of the anomalies. This distribution of heterogeneities during convective stirring with negligible diffusion, called Batchelor regime is documented by fluid dynamic experiments and corresponds to what can be inferred from geochemistry and seismic tomography. This laminated structure imposes density, seismic velocity and potentially, anisotropic heterogeneities with similar 1/k spectrums. We show that a seismic wave of wavenumber k_0 crossing such medium is partly reflected by the heterogeneities and the scattered energy has an energy found proportional to k_0 S(2k_0). The reduction of energy for the propagating wave appears therefore equivalent to a quality factor 1/Q proportional to k_0 S(2k_0). With the specific 1/k spectrum of the mantle, the resulting apparent attenuation should therefore be frequency independent. We show that the total contribution of 6-9% RMS density, velocity and anisotropy would explain the observed S and P attenuation of the mantle. Although these values are large there are not unreasonable and we discuss how they are likely overestimated. In this case, most of the attenuation of the Earth would be due to small scale scattering by laminations not by intrinsic dissipation. Intrinsic dissipation must certainly exists but might correspond to a larger, yet unobserved Q. This provocative result would explain the observed very weak frequency dependence of the attenuation, and the fact that bulk attenuation seems negligeable, two observations that have been difficult to explain for 50 years.

  10. Hyperfine-induced valley mixing and the spin-valley blockade in carbon-based quantum dots

    Energy Technology Data Exchange (ETDEWEB)

    Palyi, Andras; Burkard, Guido [Department of Physics, University Konstanz (Germany)


    Hyperfine interaction (HFI) in carbon nanotube and graphene quantum dots is due to the presence of {sup 13}C atoms. We theoretically show that in these structures the short-range nature of the HFI gives rise to a coupling between the valley degree of freedom of the electron and the nuclear spin, in addition to the usual electron spin-nuclear spin coupling. We predict that this property of the HFI affects the Pauli blockade transport in carbon-based double quantum dots. In particular, we show that transport is blocked only if both the spin and the valley degeneracies of the quantum dot levels are lifted, e.g., by an appropriately oriented magnetic field. The blockade is caused by four ''supertriplet'' states in the (1,1) charge configuration.

  11. Postoperative negative pressure pulmonary edema following repetitive laryngospasm even after reversal of neuromuscular blockade by sugammadex: a case report. (United States)

    Lee, Ji Hyeon; Lee, Jae Ho; Lee, Min Hyun; Cho, Hyun Oh; Park, Soon Eun


    Laryngospasm, an occlusion of the glottis, can occur at any time during anesthesia, and is associated with serious perioperative complications such as hypoxia, hypercabia, aspiration, bronchospasm, arrhythmia, prolonged recovery, cardiac collapse, and eventually catastrophic death. Importantly, postoperative negative pressure pulmonary edema (NPPE) is a rare, but well described life-threatening complication related to acute and chronic upper airway obstruction. Sugammadex well known for affirmatively reducing the postoperative pulmonary complications associated with residual neuromuscular blockade may have an indirect role in triggering the negative intrathoracic pressure by raising a rapid and efficacious respiratory muscle strength in acute upper airway obstruction. Herein, we report a case of postoperative NPPE following repetitive laryngospasm even after reversal of rocuronium-induced neuromuscular blockade using sugammadex.

  12. Role of ATP-sensitive potassium channels in the piracetam induced blockade of opioid effects. (United States)

    Rehni, Ashish K; Singh, Nirmal; Jindal, Seema


    The present study has been designed to investigate the effect of piracetam on morphine/ buprenorphine-induced antinociception in rats and effect of piracetam on morphine or minoxidil induced relaxation in KCl-precontracted isolated rat aortic ring preparation. Nociceptive threshold was measured by the tail flick test in rats. The cumulative dose responses of morphine or minoxidil were recorded in KCl-precontracted isolated rat aortic ring preparation. Piracetam attenuated buprenorphine-induced antinociception in rats. Piracetam significantly reduced the morphine and minoxidil induced relaxation in KCl precontracted isolated rat aortic ring preparation suggesting that piracetam interferes with opioid receptor and ATP-sensitive potassium channel (KATP) opener mediated responses in vitro. Thus, it may be suggested that piracetam attenuates opioid effects by an opioid receptor-KATP channel linked mechanism.

  13. NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma



    Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenogr...

  14. Acute effects of beta blockade and exercise on mood and anxiety.


    Head, A; Kendall, M J; Ferner, R; Eagles, C


    OBJECTIVE: To measure the previously reported beta blocker induced adverse changes in mood state and anxiety measures, and to determine if prolonged aerobic exercise attenuates such mood modifications. METHODS: After 4 days of drug treatment with comparable doses of propranolol (40 and 80 mg), metoprolol (50 and 100 mg), or placebo, mood (POMS) and anxiety states (STAI) were assessed in healthy volunteers, before and after 1 h of treadmill walking exercise at 50% maximum oxygen uptake. RESULT...

  15. Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy

    Directory of Open Access Journals (Sweden)

    Weijie Ma


    Full Text Available Abstract Modulating immune inhibitory pathways has been a major recent breakthrough in cancer treatment. Checkpoint blockade antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4 and programed cell-death protein 1 (PD-1 have demonstrated acceptable toxicity, promising clinical responses, durable disease control, and improved survival in some patients with advanced melanoma, non-small cell lung cancer (NSCLC, and other tumor types. About 20 % of advanced NSCLC patients and 30 % of advanced melanoma patients experience tumor responses from checkpoint blockade monotherapy, with better clinical responses seen with the combination of anti-PD-1 and anti-CTLA-4 antibodies. Given the power of these new therapies, it is important to understand the complex and dynamic nature of host immune responses and the regulation of additional molecules in the tumor microenvironment and normal organs in response to the checkpoint blockade therapies. In this era of precision oncology, there remains a largely unmet need to identify the patients who are most likely to benefit from immunotherapy, to optimize the monitoring assays for tumor-specific immune responses, to develop strategies to improve clinical efficacy, and to identify biomarkers so that immune-related adverse events can be avoided. At this time, PD-L1 immunohistochemistry (IHC staining using 22C3 antibody is the only FDA-approved companion diagnostic for patients with NSCLC-treated pembrolizumab, but more are expected to come to market. We here summarize the current knowledge, clinical efficacy, potential immune biomarkers, and associated assays for immune checkpoint blockade therapies in advanced solid tumors.

  16. Blockade of PD-1/PD-L1 promotes adoptive T-cell immunotherapy in a tolerogenic environment.

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    Stephen J P Blake

    Full Text Available Adoptive cellular immunotherapy using in vitro expanded CD8+ T cells shows promise for tumour immunotherapy but is limited by eventual loss of function of the transferred T cells through factors that likely include inactivation by tolerogenic dendritic cells (DC. The co-inhibitory receptor programmed death-1 (PD-1, in addition to controlling T-cell responsiveness at effector sites in malignancies and chronic viral diseases is an important modulator of dendritic cell-induced tolerance in naive T cell populations. The most potent therapeutic capacity amongst CD8+ T cells appears to lie within Tcm or Tcm-like cells but memory T cells express elevated levels of PD-1. Based on established trafficking patterns for Tcm it is likely Tcm-like cells interact with lymphoid-tissue DC that present tumour-derived antigens and may be inherently tolerogenic to develop therapeutic effector function. As little is understood of the effect of PD-1/PD-L1 blockade on Tcm-like CD8+ T cells, particularly in relation to inactivation by DC, we explored the effects of PD-1/PD-L1 blockade in a mouse model where resting DC tolerise effector and memory CD8+ T cells. Blockade of PD-1/PD-L1 promoted effector differentiation of adoptively-transferred Tcm-phenotype cells interacting with tolerising DC. In tumour-bearing mice with tolerising DC, effector activity was increased in both lymphoid tissues and the tumour-site and anti-tumour activity was promoted. Our findings suggest PD-1/PD-L1 blockade may be a useful adjunct for adoptive immunotherapy by promoting effector differentiation in the host of transferred Tcm-like cells.

  17. About the Need of Institutionalisation of Organisational Behaviour for Overcoming the Innovation Blockade in Poland and Ukraine

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    Teresa Bal-Woźniak


    Full Text Available On the example of Poland, paradoxes supporting the innovation blockade and limits of pro-innovation organisational behaviours are indicated in the article. Removing them requires reinstitutionalisation in the direction of subjective approach to innovativeness. The presented diagnosis concerning Poland may be used for defining conclusions in the sphere of actions intended for elimination of restrictions regarding proinnovation barriers of organisational behaviour also present in Ukraine.

  18. Cannabidiol inhibits the reward-facilitating effect of morphine: involvement of 5-HT1A receptors in the dorsal raphe nucleus. (United States)

    Katsidoni, Vicky; Anagnostou, Ilektra; Panagis, George


    Cannabidiol is a non-psychotomimetic constituent of Cannabis sativa, which induces central effects in rodents. It has been shown that cannabidiol attenuates cue-induced reinstatement of heroin seeking. However, to the best of our knowledge, its effects on brain stimulation reward and the reward-facilitating effects of drugs of abuse have not yet been examined. Therefore, we investigated the effects of cannabidiol on brain reward function and on the reward-facilitating effect of morphine and cocaine using the intracranial self-stimulation (ICSS) paradigm. Rats were prepared with a stimulating electrode into the medial forebrain bundle (MFB), and a guide cannula into the dorsal raphe (microinjection experiments), and were trained to respond for electrical brain stimulation. A low dose of cannabidiol did not affect the reinforcing efficacy of brain stimulation, whereas higher doses significantly elevated the threshold frequency required for MFB ICSS. Both cocaine and morphine lowered ICSS thresholds. Cannabidiol inhibited the reward-facilitating effect of morphine, but not cocaine. This effect was reversed by pre-treatment with an intra-dorsal raphe injection of the selective 5-HT1A receptor antagonist WAY-100635. The present findings indicate that cannabidiol does not exhibit reinforcing properties in the ICSS paradigm at any of the doses tested, while it decreases the reward-facilitating effects of morphine. These effects were mediated by activation of 5-HT1A receptors in the dorsal raphe. Our results suggest that cannabidiol interferes with brain reward mechanisms responsible for the expression of the acute reinforcing properties of opioids, thus indicating that cannabidiol may be clinically useful in attenuating the rewarding effects of opioids.

  19. Blockade of glucocorticoid receptors improves cutaneous wound healing in stressed mice. (United States)

    de Almeida, Taís Fontoura; de Castro Pires, Taiza; Monte-Alto-Costa, Andréa


    Stress is an important condition of modern life. The successful wound healing requires the execution of three major overlapping phases: inflammation, proliferation, and remodeling, and stress can disturb this process. Chronic stress impairs wound healing through the activation of the hypothalamic-pituitary-adrenal axis, and the glucocorticoids (GCs) hormones have been shown to delay wound closure. Therefore, the aim of this study was to investigate the effects of a GC receptor antagonist (RU486) treatment on cutaneous healing in chronically stressed mice. Male mice were submitted to rotational stress, whereas control animals were not subjected to stress. Stressed and control animals were treated with RU486. A full-thickness excisional lesion was generated, and seven days later, lesions were recovered. The RU486 treatment improves wound healing since contraction takes place earlier in RU486-treated in comparison to non-treated mice, and the RU486 treatment also improves the angiogenesis in Stress+RU486 mice when compared to stressed animals. The Stress+RU486 group showed a decrease in inflammatory cell infiltration and in hypoxia-inducible factor-1α and inducible nitric oxide synthase expression; meanwhile, there was an increase in myofibroblasts quantity. In conclusion, blockade of GC receptors with RU486 partially ameliorates stress-impaired wound healing, suggesting that stress inhibits healing through more than one functional pathway.

  20. Hyperlipidemia Alters Regulatory T Cell Function and Promotes Resistance to Tolerance Induction Through Costimulatory Molecule Blockade. (United States)

    Bagley, J; Yuan, J; Chandrakar, A; Iacomini, J


    Recent work from our laboratory has shown that hyperlipidemia promotes accelerated rejection of vascularized cardiac allografts in mice by inducing anti-donor Th17 reactivity and production of IL-17. Here, we show that hyperlipidemia also affects FoxP3(+) regulatory T cells (Tregs). Hyperlipidemia promotes the development of Tregs that express low levels of CD25. Hyperlipidemia also promotes a decrease in central Tregs and an increase in effector Tregs that appears to account for the increase in the frequency of CD25(low) Tregs. Alterations in Treg subsets also appear to lead to alterations in Treg function. The ability of FoxP3(+) , CD25(high) , CD4(+) Tregs from hyperlipidemic mice to inhibit proliferation of effector T cells stimulated with anti-CD3 and CD28 was reduced when compared with Tregs from control mice. Regulatory T cells isolated from hyperlipidemic recipients exhibit increased activation of Akt, and a reduction in Bim levels that permits the expansion of FoxP3(+) CD25(low) CD4(+) T cells. Hyperlipidemic mice were also resistant to tolerance induction using costimulatory molecule blockade consisting of anti-CD154 and CTLA4Ig, a strategy that requires Tregs. Together, our data suggest that hyperlipidemia profoundly affects Treg subsets and function as well as the ability to induce tolerance.

  1. Blockade of LFA-1 augments in vitro differentiation of antigen-induced Foxp3+ Treg cells (United States)

    Verhagen, Johan; Wraith, David C.


    Adoptive transfer of antigen-specific, in vitro-induced Foxp3+ Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti-CD28 antibody yields Foxp3+ iTreg cells at a purity of 90–95%, antigen-induced iTreg cells typically do not exceed a purity of 65–75%, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF-β but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90% purity of Foxp3+ iTreg cells. This increased efficacy not only boosts the yield of Foxp3+ iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy. PMID:25108241

  2. Comparison of electromyography and kinemyography during recovery from non-depolarising neuromuscular blockade. (United States)

    Stewart, P A; Freelander, N; Liang, S; Heller, G; Phillips, S


    In this study, two commercially available quantitative neuromuscular function monitoring techniques, electromyography (EMG) and kinemyography (KMG), were compared with respect to repeatability and accuracy during late recovery from neuromuscular blockade. Train-of-four (TOF) ratios were recorded in 30 patients using KMG and EMG at the adductor pollicis muscle. Measurements were taken on the same hand using the Datex-Ohmeda NeuroMuscular Transmission monitor (GE Healthcare, Helsinki, Finland). Instrumental precision was evaluated using the coefficient of repeatability, while accuracy was assessed using the bias and limits of agreement. The coefficients of repeatability were similar for both techniques (0.035 for KMG and 0.043 for EMG), indicating a similar level of precision. KMG overestimated the TOF ratios measured with EMG with a bias of 0.11 (95% limits of agreement: -0.13 to 0.35). At a TOF ratio of 0.90 the bias was 0.08 (95% limits of agreement: -0.08 to 0.25). This means that at a TOF ratio of 0.90 measured with KMG will be approximately equivalent to a TOF ratio of 0.80 measured with EMG at the adductor pollicis muscle, but it may indeed be as low as 0.65 or as high as 1.00. Therefore, TOF ratios measured by KMG and EMG cannot be used interchangeably.

  3. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis. (United States)

    Sühs, Kurt-Wolfram; Fairless, Richard; Williams, Sarah K; Heine, Katrin; Cavalié, Adolfo; Diem, Ricarda


    Optic neuritis is a common clinical manifestation of the chronic inflammatory CNS disease multiple sclerosis that can result in persistent visual impairment caused by degeneration of optic nerve axons and apoptosis of retinal ganglion cells (RGCs). Using a model of experimental autoimmune encephalomyelitis with optic neuritis (Brown Norway rats), we show that administration of the N-methyl-D-aspartate (NMDA) receptor antagonists memantine or MK801 results in RGC protection, axon protection, and reduced demyelination of optic nerves. Calcium imaging revealed that RGC responses to glutamate stimulation predominantly occurred via NMDA receptors and were inhibited by memantine in a dose-dependent manner. In contrast, oligodendrocytes were mainly responsive through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor. This suggests that NMDA receptor blockade protected RGCs directly and that the protection was independent of effects on oligodendrocytes. Moreover, increased RGC survival was observed before the onset of optic nerve demyelination--when RGC degeneration had already started. These results indicate an important pathophysiologic role for NMDA receptor-mediated glutamate toxicity during the induction phase of this disease model and highlight a potential target for therapeutic neuroprotection in human optic neuritis.

  4. The effect of opioid receptor blockade on the neural processing of thermal stimuli.

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    Eszter D Schoell

    Full Text Available The endogenous opioid system represents one of the principal systems in the modulation of pain. This has been demonstrated in studies of placebo analgesia and stress-induced analgesia, where anti-nociceptive activity triggered by pain itself or by cognitive states is blocked by opioid antagonists. The aim of this study was to characterize the effect of opioid receptor blockade on the physiological processing of painful thermal stimulation in the absence of cognitive manipulation. We therefore measured BOLD (blood oxygen level dependent signal responses and intensity ratings to non-painful and painful thermal stimuli in a double-blind, cross-over design using the opioid receptor antagonist naloxone. On the behavioral level, we observed an increase in intensity ratings under naloxone due mainly to a difference in the non-painful stimuli. On the neural level, painful thermal stimulation was associated with a negative BOLD signal within the pregenual anterior cingulate cortex, and this deactivation was abolished by naloxone.

  5. Immune checkpoint blockade therapy: The 2014 Tang prize in biopharmaceutical science

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    Ya-Shan Chen


    Full Text Available The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1 that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

  6. Opioid receptor blockade and warmth-liking: effects on interpersonal trust and frontal asymmetry. (United States)

    Schweiger, Desirée; Stemmler, Gerhard; Burgdorf, Christin; Wacker, Jan


    The emotion 'warmth-liking' (WL) associated with feelings of affection and acceptance is regularly activated in social contexts. WL has been suggested to be more closely related to the consummatory phase of post-goal attainment positive affect than to pre-goal attainment positive affect/approach motivation and to be partly mediated by brain opioids. To validate these assumptions we employed film/imagery to induce either a neutral emotional state or WL in female participants after intake of either placebo or the opioid antagonist naltrexone. Dependent variables were emotion self-report, interpersonal trust (TRUST, i.e. a behavioral indicator of WL) and frontal asymmetry (i.e. an electroencephalogram (EEG) indicator of approach motivation/behavioral activation). We found that participants reported more WL in the placebo/WL group than in the placebo/neutral group and both naltrexone groups. In addition, TRUST increased in the WL group after placebo, but not after naltrexone, and this pattern was reversed in the neutral control groups. Consequently, opioid blockade suppressed or even reversed the effects of the WL induction on the levels of self-report and behavior, respectively. In addition, we observed reduced relative left-frontal asymmetry in the WL (vs neutral) group, consistent with reduced approach motivation. Overall, these results suggest opioidergic influences on WL and TRUST and reduced approach motivation/behavioral activation for the positive emotion WL.

  7. Peroxynitrite induces F-actin depolymerization and blockade of myosin ATPase stimulation. (United States)

    Tiago, Teresa; Ramos, Susana; Aureliano, Manuel; Gutiérrez-Merino, Carlos


    Treatment of F-actin with the peroxynitrite-releasing agent 3-morpholinosydnonimine (SIN-1) produced a dose-dependent F-actin depolymerization. This is due to released peroxynitrite because it is not produced by 'decomposed SIN-1', and it is prevented by superoxide dismutase concentrations efficiently preventing peroxynitrite formation. F-actin depolymerization has been found to be very sensitive to peroxynitrite, as exposure to fluxes as low as 50-100nM peroxynitrite leads to nearly 50% depolymerization in about 1h. G-actin polymerization is also impaired by peroxynitrite although with nearly 2-fold lower sensitivity. Exposure of F-actin to submicromolar fluxes of peroxynitrite produced cysteine oxidation and also a blockade of the ability of actin to stimulate myosin ATPase activity. Our results suggest that an imbalance of the F-actin/G-actin equilibrium can account for the observed structural and functional impairment of myofibrils under the peroxynitrite-mediated oxidative stress reported for some pathophysiological conditions.

  8. Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioural, and neurotoxic effects of methamphetamine (United States)

    Weinshenker, David; Ferrucci, Michela; Busceti, Carla L.; Biagioni, Francesca; Lazzeri, Gloria; Liles, L. Cameron; Lenzi, Paola; Murri, Luigi; Paparelli, Antonio; Fornai, Francesco


    N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus (LC), the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH −/− mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioural stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioural, and neurotoxic effects of METH. PMID:18042179

  9. CTLA-4 blockade in the treatment of rheumatoid arthritis: an update. (United States)

    Cutolo, Maurizio; Sulli, Alberto; Paolino, Sabrina; Pizzorni, Carmen


    Rheumatoid arthritis (RA) is characterized by chronic joint inflammation as well as by extra-articular involvement. The immunopathology of RA is polygenic and involves different cell populations. Patients with an inadequate response to non-biologic disease- modifying antirheumatic drugs (DMARDs) should integrate their therapy with biologic DMARDs. Biologic DMARDs can target several inflammatory cytokines, or CD20+ B cells, or can modulate T-cell co-stimulation and activation. The cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4-Ig: abatacept) that selectively modulates the CD28:CD80/86 co-stimulation signal appears a biologic DMARD interacting with T cells but also with other cell populations involved in RA pathophysiology. Activated B lymphocytes, macrophages, osteoclasts and endothelial cells express the costimulatory molecules (CD80/86) and are downregulated by CTLA-4 blockade. The relatively low frequency and severity of safety issues related to CTLA-4-Ig treatment seems further to confirm the targeted downregulatory action exerted by the fusion protein, which is mainly focussed on activated immune/inflammatory cells.

  10. Vasotocin receptor blockade disrupts maternal care of offspring in a viviparous snake, Sistrurus miliarius

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    Craig M. Lind


    Full Text Available Parental care is a complex social behavior that is widespread among vertebrates. The neuroendocrine regulation of parent-offspring social behavior has been well-described in mammals, and to a lesser extent, in birds and fish. However, little is known regarding the underlying mechanisms that mediate the expression of care behaviors in squamate reptiles. In mammalian model species and humans, posterior pituitary hormones of the oxytocin and vasopressin families mediate parental care behaviors. To test the hypothesis that the regulatory role of posterior pituitary neuropeptides is conserved in a viviparous squamate reptile, we pharmacologically blocked the vasotocin receptor in post-parturient pigmy rattlesnakes, Sistrurus miliarius, and monitored the spatial relationship between mothers and offspring relative to controls. Mothers in the control group demonstrated spatial aggregation with offspring, with mothers having greater post-parturient energy stores aggregating more closely with their offspring. Blockade of vasotocin receptors eliminated evidence of spatial aggregation between mothers and offspring and eliminated the relationship between maternal energetic status and spatial aggregation. Our results are the first to implicate posterior pituitary neuropeptides in the regulation of maternal behavior in a squamate reptile and are consistent with the hypothesis that the neuroendocrine mechanisms underlying social behaviors are broadly conserved among vertebrates.

  11. Cesium blockade of delayed outward currents and electrically induced pacemaker activity in mammalian ventricular myocardium. (United States)

    Meier, C F; Katzung, B G


    The effects of Cs+, 5-25 mM, were studied in cat and guinea pig papillary muscles using voltage clamp and current clamp techniques. In solutions containing normal K+, the major effects of Cs+ were depolarization of the resting potential and reduction of the delayed outward current (ixl) between -80 and -20 mV. Both inward and outward portions of the isochronal current voltage relation (l-s clamps) were reduced by extracellular Cs+. This resulted in a substantial reduction of inward rectification and, by subtraction from the normal I-V relationship, the definition of a Cs+-sensitive component of current. Under current clamp conditions, 5-10 mM Cs+ produced a dose-dependent slowing of repetitive firing induced by depolarization. At higher concentrations (25 mM) the resting potential was depolarized and repetitive activity could not be induced by further depolarization. However, release of hyperpolarizing pulses was followed by prolonged bursts of repetitive action potentials, suggesting partial reversal of blockade or participation of another pacemaker process. The experimental results and a numerical simulation show that under readily attainable conditions, reduction in an outward pacemaker current may slow pacemaker activity.

  12. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation (United States)

    Seshasayee, Dhaya; Lee, Wyne P.; Zhou, Meijuan; Shu, Jean; Suto, Eric; Zhang, Juan; Diehl, Laurie; Austin, Cary D.; Meng, Y. Gloria; Tan, Martha; Bullens, Sherron L.; Seeber, Stefan; Fuentes, Maria E.; Labrijn, Aran F.; Graus, Yvo M.F.; Miller, Lisa A.; Schelegle, Edward S.; Hyde, Dallas M.; Wu, Lawren C.; Hymowitz, Sarah G.; Martin, Flavius


    Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses. PMID:18060034

  13. Blockade of PKC-beta protects HUVEC from advanced glycation end products induced inflammation. (United States)

    Xu, Youhua; Wang, Shanshan; Feng, Liang; Zhu, Quan; Xiang, Ping; He, Bao


    Advanced glycation end products (AGEs) have been recognized as a pivotal inducer in diabetes and kinds of aging-related vasculopathy. Endothelial dysfunction and inflammatory cells adhesion to endothelium have been regarded as important and early factors in the pathogenesis of vascular complications in diabetic patients. Owing to the key role of PKC-beta in AGEs-induced vascular dysfunction, we investigated effects of blocking PKC-beta by LY333531 on macrophage adhesion to HUVEC and the related mechanism. Transwell HUVEC-macrophage co-culture system was established to evaluate macrophage migration and adhesion ability. Immunocytochemistry was applied to examine TGF-beta1, ICAM-1 and RAGE protein expressions by SABC or SABC-AP method; mRNA expression of TGF-beta1, ICAM-1 and RAGE was determined by real-time RT-PCR. SOD and MDA levels in culture supernatant were detected. We found that LY333531 significantly reduced AGEs-induced macrophage adhesion to HUVEC. Blockade of PKC-beta strikingly decreased HUVEC TGF-beta1 and ICAM-1 expression in both protein and mRNA levels, RAGE protein level was also down-regulated. Furthermore, the anti-oxidative stress index, SOD/MDA was dramatically elevated on LY333531 application. Therefore we conclude that LY333531 can reduce AGEs-induced macrophage adhesion to endothelial cells and relieve the local inflammation, this was realized by its effect on decreasing inflammatory cytokines' expression and increasing cell anti-oxidative ability.

  14. Epidural blockades using glucocorticoids: As to how the principles of evidence-based medicine?

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    A. E. Karateev


    Full Text Available Epidural injections (EI of glucocorticoids (GC, the so-called blockades, are frequently recommended a very effective and most modern treatment for nonspecific back pain and lumbar ischialgia. However, EI of drugs (local anesthetics (LA for back pain relief has been practiced ever since 1901 when it was first used by the French physicians J.F. Sicard and F. Cathelin, i.e. it belongs to the oldest therapeutic procedures. Moreover, experts' opinions as to the therapeutic value of EI of GC are rather contradictory. The data of a large number of clinical trials fail to confirm the unambiguous advantage of epidural GC used in combination with LA as compared to the effect of the latter only. According to a number of experts, the effect of EI of GC is only slightly better than that of placebo (physiologic saline and little affects long-term treatment results. Epidural GC may result in rare but very serious, life-threatening complications. Obviously, this method should be used, only after carefully weighing its potential benefits and risks. In any case, EI of GC should not be considered as an alternative to other pharmacological and nonpharmacological therapies.

  15. [Effects of blockade of ionotropic glutamate receptors on the development of pentylenetetrazole kindling in mice]. (United States)

    Lukomskaia, N Ia; Lavrent'eva, V V; Starshinova, L A; Zhabko, E P; Gorbunova, L V; Tikhonova, T B; Gmiro, V E; Magazanik, L G


    Effects of mono- and dicationic derivatives of adamantane and phenylcyclohexyl on the petyleneterazole-induced (35 mg/kg i. p.) kindling were studied in the experiments on mice. Monocationic derivative of phenylcyclohexyl IEM-1921, effectively retarded the development of kindling beginning the dose 0.0001 microM/kg. Memantine: derivative of adamantane (derivative of adamatane) produced the same effect with 100-fold increased dose. Dicationic derivative ofphenylcyclohexyl: IEM-1925, is able to block equally the open channels of both NMDA and subtype of Ca-permeable AMPA receptors. Its effect on kindling differed markedly from selective NMDA antagonists (IEM-1921 and memantine) in more complicated dose-dependence. The retardation of kindling IEM-1925 was induced at 0.001 microM/kg. On the contrary, a 10-time lower dose: 0.0001 microM/kg, facilitated the development of kindling. The observed difference in the activity of selective NMDA antagonists and the drugs combining anti-NMDA and anti-AMPA potency indicates that both types of ionotropic glutamate receptors are involved in the mechanism of petyleneterazole-induced kindling. The integral effect of channel blockade evoked by drugs seems to be dependent not only upon the ratio of the receptor types but on the kinetics of drug action, too.

  16. Use of beta adrenoceptor blockade during and after acute myocardial infarction. (United States)

    Sleight, P


    In the last year, two large randomized controlled trials of metoprolol (MIAMI, almost 6,000 patients) and atenolol (ISIS 1, over 16,000 patients) given intravenously within 12 hours of the onset of acute myocardial infarction reduced mortality by about 15% in low-risk subjects. The reduction was significant for atenolol (2P = 0.04) but not for metoprolol, probably because of the smaller size of that trial. The reduction in mortality in both trials was nearly all in the first 36 hours, a finding that reduced the fears that the treatment might produce irreversible failure, shock, or heart block. Tolerance in these relatively low-risk subjects (control mortality about 5%) was good. Inotropes were used in 1-2% more subjects in the beta-blocked group but were effective in reversing the side effects without increasing mortality. No clear subgroups (age, sex, site, time from onset, initial blood pressure or heart rate) were found in which treatment was more beneficial. In the ISIS study, patients with higher heart rates were more likely to need inotropes after beta blockade and patients with long PR intervals at entry were more likely to develop block. Neither of these complications resulted in excess mortality in the blocked group, which suggests that these adverse effects were largely reversible.

  17. Studies on neuromuscular blockade by boldine in the mouse phrenic nerve-diaphragm. (United States)

    Kang, J J; Cheng, Y W; Fu, W M


    The effects of boldine [(S)-2,9-dihydroxyl-1,10-dimethoxy-aporphine], a major alkaloid in the leaves and bark of Boldo (Peumus boldus Mol.), on neuromuscular transmission were studied using a muscle phrenic-nerve diaphragm preparation. Boldine at concentrations lower than 200 microM preferentially inhibited, after an initial period of twitch augmentation, the nerve-evoked twitches of the mouse diaphragm and left the muscle-evoked twitches unaffected. The twitch inhibition could be restored by neostigmine or washout with Krebs solution. The twitches evoked indirectly and directly were both augmented initially, suggesting that the twitch augmentation induced by boldine was myogenic. Boldine inhibited the acetylcholine-induced contraction of denervated diaphragm dose-dependently with an IC50 value of 13.5 microM. At 50 microM, boldine specifically inhibited the amplitude of the miniature end plate potential. In addition, boldine was similar to d-tubocurarine in its action to reverse the neuromuscular blocking action of alpha-bungarotoxin. These results showed that the neuromuscular blockade by boldine on isolated mouse phrenic-nerve diaphragm might be due to its direct interaction with the postsynaptic nicotinic acetylcholine receptor.

  18. Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody

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    Sophie E. Broughton


    Full Text Available Interleukin-3 (IL-3 is an activated T cell product that bridges innate and adaptive immunity and contributes to several immunopathologies. Here, we report the crystal structure of the IL-3 receptor α chain (IL3Rα in complex with the anti-leukemia antibody CSL362 that reveals the N-terminal domain (NTD, a domain also present in the granulocyte-macrophage colony-stimulating factor (GM-CSF, IL-5, and IL-13 receptors, adopting unique “open” and classical “closed” conformations. Although extensive mutational analyses of the NTD epitope of CSL362 show minor overlap with the IL-3 binding site, CSL362 only inhibits IL-3 binding to the closed conformation, indicating alternative mechanisms for blocking IL-3 signaling. Significantly, whereas “open-like” IL3Rα mutants can simultaneously bind IL-3 and CSL362, CSL362 still prevents the assembly of a higher-order IL-3 receptor-signaling complex. The discovery of open forms of cytokine receptors provides the framework for development of potent antibodies that can achieve a “double hit” cytokine receptor blockade.

  19. In vivo blockade of neural activity alters dendritic development of neonatal CA1 pyramidal cells. (United States)

    Groc, Laurent; Petanjek, Zdravko; Gustafsson, Bengt; Ben-Ari, Yehezkel; Hanse, Eric; Khazipov, Roustem


    During development, neural activity has been proposed to promote neuronal growth. During the first postnatal week, the hippocampus is characterized by an oscillating neural network activity and a rapid neuronal growth. In the present study we tested in vivo, by injecting tetanus toxin into the hippocampus of P1 rats, whether this neural activity indeed promotes growth of pyramidal cells. We have previously shown that tetanus toxin injection leads to a strong reduction in the frequency of spontaneous GABA and glutamatergic synaptic currents, and to a complete blockade of the early neural network activity during the first postnatal week. Morphology of neurobiotin-filled CA1 pyramidal cells was analyzed at the end of the first postnatal week (P6-10). In activity-reduced neurons, the total length of basal dendritic tree was three times less than control. The number, but not the length, of basal dendritic branches was affected. The growth impairment was restricted to the basal dendrites. The apical dendrite, the axons, or the soma grew normally during activity deprivation. Thus, the in vivo neural activity in the neonate hippocampus seems to promote neuronal growth by initiating novel branches.

  20. TNF-α blockade induces IL-10 expression in human CD4+ T cells (United States)

    Evans, Hayley G.; Roostalu, Urmas; Walter, Gina J.; Gullick, Nicola J.; Frederiksen, Klaus S.; Roberts, Ceri A.; Sumner, Jonathan; Baeten, Dominique L.; Gerwien, Jens G.; Cope, Andrew P.; Geissmann, Frederic; Kirkham, Bruce W.; Taams, Leonie S.


    IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3-independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.