WorldWideScience

Sample records for blockade reduces prolonged

  1. 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

    2015-01-01

    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

  2. Prolongation of rapacuronium neuromuscular blockade by clindamycin and magnesium.

    Science.gov (United States)

    Sloan, Paul A; Rasul, Mazhar

    2002-01-01

    We report a prolonged neuromuscular block with the nondepolarizing muscle relaxant rapacuronium in the presence of clindamycin. Even when using "short-acting" muscle relaxants, the anesthesiologist must routinely monitor the neuromuscular function.

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

    LENUS (Irish Health Repository)

    Weekes, G

    2010-07-01

    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.

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

    LENUS (Irish Health Repository)

    Weekes, G

    2012-02-01

    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.

  5. [Prolonged blockade of nervus ischiadicus in a system of complex treatment of patients, suffering complicated diabetic foot syndrome].

    Science.gov (United States)

    Shapoval, S D; Savon, I L; Sofilkanych, M M

    2015-03-01

    General principles of treatment in patients, suffering diabetic foot syndrome, are adduced. There was proved, that reconvalescence of the patients depends not only on quality of complex treatment, but from optimal choice of anesthesia method, its impact on postoperative period course. Application of prolonged blockade of n. ischiadicus gives possibility to perform operative intervention on the lower extremity in full volume, guarantees sufficient motor and sensory block, permits patients to reject from application of narcotic analgetics, to reduce the dose of strong nonnarcotic analgetics, the terms of transition of the wound process phase I into phase II, promotes early activization of patients postoperatively, constitutes alternative for other methods of anesthesiological support.

  6. Beta adrenergic blockade reduces utilitarian judgement

    Science.gov (United States)

    Sylvia, Terbeck; Guy, Kahane; Sarah, McTavish; Julian, Savulescu; Neil, Levy; Miles, Hewstone; Cowen, Philip J.

    2013-01-01

    Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were ‘up close and personal’. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel. PMID:23085134

  7. Sugammadex rescue following prolonged rocuronium neuromuscular blockade with ‘recurarisation’ in a patient with severe renal failure

    Science.gov (United States)

    Lobaz, Steven; Sammut, Mario; Damodaran, Anand

    2013-01-01

    We describe our experience of a 71-year-old patient with severe renal failure, who exhibited an unusually prolonged rocuronium-induced neuromuscular blockade (>4 h) and apparent recurarisation, following emergency rapid sequence induction (RSI). At the end of operation, 45 min post induction, train-of-four (TOF) testing had been 4/4 prior to wake up. No respiratory effort was seen 150 min postinduction, despite further neostigmine/glycopyrrolate and repeat TOF 4/4. The patient was resedated and transferred to the intensive care unit (ICU). At 180 min postinduction, fade was evident on TOF, suggestive of rocuronium reblockade. At 285 min, the patient was extubated safely following sugammadex administration and discharged uneventfully from the ICU. An important lesson to recognise is the potential for extremely prolonged neuromuscular blockade following rocuronium in patients with severe renal failure, particularly when using the higher doses (1.2 mg/kg) required for RSI, and that TOF in such cases may not be reliable in detecting residual blockade. PMID:23396837

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Human adipose tissue blood flow during prolonged exercise, III. Effect of beta-adrenergic blockade, nicotinic acid and glucose infusion

    DEFF Research Database (Denmark)

    Bülow, J

    1981-01-01

    Subcutaneous adipose tissue blood flow (ATBF) was measured in six male subjects by the 133Xe-washout technique during 3-4 h of exercise at a work load corresponding to an oxygen uptake of about 1.71/min. The measurements were done during control conditions, during blockade of lipolysis by nicotinic...... of work. No increase in lipolysis and no increase in ATBF were found when lipolysis was blocked by nicotinic acid (0.3 g/h). Propranolol treatment (0.15 mg/kg) reduced lipolysis and nearly abolished the increase in ATBF during exercise. Intravenous administration of glucose (about 0.25 g/min) did...

  10. Human adipose tissue blood flow during prolonged exercise, III. Effect of beta-adrenergic blockade, nicotinic acid and glucose infusion

    DEFF Research Database (Denmark)

    Bülow, J

    1981-01-01

    acid, during acute i.v. beta-adrenergic blockade by propranolol, and during continuous i.v. infusion of glucose. The most pronounced lipid mobilization and utilization during work was seen in the control experiments where ATBF rose 3-fold on average from the initial rest period to the third hour...... of work. No increase in lipolysis and no increase in ATBF were found when lipolysis was blocked by nicotinic acid (0.3 g/h). Propranolol treatment (0.15 mg/kg) reduced lipolysis and nearly abolished the increase in ATBF during exercise. Intravenous administration of glucose (about 0.25 g/min) did......Subcutaneous adipose tissue blood flow (ATBF) was measured in six male subjects by the 133Xe-washout technique during 3-4 h of exercise at a work load corresponding to an oxygen uptake of about 1.71/min. The measurements were done during control conditions, during blockade of lipolysis by nicotinic...

  11. Competing for Consciousness: Prolonged Mask Exposure Reduces Object Substitution Masking

    Science.gov (United States)

    Goodhew, Stephanie C.; Visser, Troy A. W.; Lipp, Ottmar V.; Dux, Paul E.

    2011-01-01

    In object substitution masking (OSM) a sparse, temporally trailing 4-dot mask impairs target identification, even though it has different contours from, and does not spatially overlap with the target. Here, we demonstrate a previously unknown characteristic of OSM: Observers show reduced masking at prolonged (e.g., 640 ms) relative to intermediate…

  12. Blockade of Inflammation and Apoptosis Pathways by siRNA Prolongs Cold Preservation Time and Protects Donor Hearts in a Porcine Model

    Directory of Open Access Journals (Sweden)

    Jia Wei

    2017-12-01

    Full Text Available In donor hearts from mini pigs, overtime cold preservation and ischemia-reperfusion injury cause poor graft quality and impaired heart function. Blockage of complement, apoptosis, and inflammation is considered a strategy for attenuating ischemia-reperfusion injury and protecting cardiac function. Minipig donor hearts were perfused and preserved in Celsior solution or transfection reagent containing Celsior solution with scramble siRNA or siRNAs targeting complement 3, caspase-8, caspase-3, and nuclear factor κB-p65 genes at 4°C and subsequently hemo-reperfused ex vivo (38°C or transplanted into recipients. The protective effect of the siRNA solution was evaluated by measuring cell apoptosis, structural alteration, protein markers for tissue damage and oxidative stress, and cardiac function. We found a reduction in cell apoptosis, myocardial damage, and tissue inflammation by reduced biochemistry and markers and protein expression of proinflammatory cytokines and improvement in cardiac function, as shown by the improved hemodynamic indices in 12-hr-preserved siRNA-treated hearts of both ex vivo and orthotopic transplantation models. These findings demonstrate that blockade of inflammation and apoptosis pathways using siRNA can prolong cold preservation time and better protect donor heart function in cardiac transplantation of large animals, which may be beneficial for human heart preservation.

  13. ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments.

    Science.gov (United States)

    Hatakeyama, Shinji; Summermatter, Serge; Jourdain, Marie; Melly, Stefan; Minetti, Giulia C; Lach-Trifilieff, Estelle

    2016-01-01

    Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time

  14. Isoproterenol reduces ischemia-reperfusion lung injury despite beta-blockade.

    Science.gov (United States)

    Takashima, Seiki; Schlidt, Scott A; Koukoulis, Giovanna; Sevala, Mayura; Egan, Thomas M

    2005-06-01

    If lungs could be retrieved from non-heart-beating donors (NHBDs), the shortage of lungs for transplantation could be alleviated. The use of lungs from NHBDs is associated with a mandatory warm ischemic interval, which results in ischemia-reperfusion injury upon reperfusion. In an earlier study, rat lungs retrieved 2-h postmortem from NHBDs had reduced capillary leak measured by filtration coefficient (Kfc) when reperfused with isoproterenol (iso), associated with an increase in lung tissue levels of cyclic AMP (cAMP). The objective was to determine if this decrease in Kfc was because of beta-stimulation, or would persist despite beta-blockade. Donor rats were treated intraperitoneally with beta-blockade (propranolol or pindolol) or carrier, sacrificed, and lungs were retrieved immediately or 2 h postmortem. The lungs were reperfused with or without iso and the beta-blockers in the reperfusate. Outcome measures were Kfc, wet:dry weight ratio (W/D), lung levels of adenine nucleotides and cAMP. Lungs retrieved immediately after death had normal Kfc and W/D. After 2 h of ischemia, Kfc and W/D were markedly elevated in controls (no drug) and lungs reperfused with beta-blockers alone. Isoproterenol-reperfusion decreased Kfc and W/D significantly (P < 0.01) even in the presence of beta-blockade. Lung cAMP levels were increased only with iso in the absence of beta-blockade. The attenuation of ischemia-reperfusion injury because of iso occurs even in the presence of beta-blockade, and may not be a result of beta-stimulated increased cAMP.

  15. Isatis tinctoria L. combined with co-stimulatory molecules blockade prolongs survival of cardiac allografts in alloantigen-primed mice.

    Science.gov (United States)

    Kang, Xiangpeng; Chen, Jibing; Qin, Qing; Wang, Feng; Wang, Yongzhi; Lan, Tianshu; Xu, Shuo; Wang, Feiyu; Xia, Junjie; Ekberg, Henrik; Qi, Zhongquan; Liu, Zhongchen

    2010-05-01

    Memory T cells present a unique challenge in transplantation. Although memory T cells express robust immune responses to invading pathogens, they may be resistant to the effects of immunosuppressive therapies used to prolong graft survival. In previous studies, we found that compound K, the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., reduced acute cardiac allograft rejection in mice (Wang et al., 2009 [1]). Here, we further investigated the effect of compound K on cardiac allograft rejection in alloantigen-primed mice. We found that compound K significantly inhibited CD4(+) and CD8(+) memory T cells proliferation in a mixed lymphocyte reaction (MLR). In vivo, compound K combined with anti-CD154 and anti-LFA-1 monoclonal antibodies (mAbs) significantly extended the survival time of heart grafts in alloantigen-primed mice with no obvious toxic side effects. Furthermore, our data suggests that compound K works by reducing the expression of both IL-2 and IFN-gamma within the graft rather than enhancing expression of regulatory T cells (Tregs). Compound K can also inhibit the alloresponses of memory T cells, while increasing the proportion of CD4(+) memory T cells in the spleen of the recipients and significantly reducing the level of alloantibodies in the serum. Our study highlights the unique immune effects of compound K that may be further explored for clinical use in extending the survival of transplant grafts. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  16. Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest

    Science.gov (United States)

    Tian, Fangyun; Liu, Tiecheng; Xu, Gang; Li, Duan; Ghazi, Talha; Shick, Trevor; Sajjad, Azeem; Wang, Michael M.; Farrehi, Peter; Borjigin, Jimo

    2018-01-01

    Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG) and electroencephalogram (EEG) signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients. PMID:29487541

  17. Adrenergic Blockade Bi-directionally and Asymmetrically Alters Functional Brain-Heart Communication and Prolongs Electrical Activities of the Brain and Heart during Asphyxic Cardiac Arrest

    Directory of Open Access Journals (Sweden)

    Fangyun Tian

    2018-02-01

    Full Text Available Sudden cardiac arrest is a leading cause of death in the United States. The neurophysiological mechanism underlying sudden death is not well understood. Previously we have shown that the brain is highly stimulated in dying animals and that asphyxia-induced death could be delayed by blocking the intact brain-heart neuronal connection. These studies suggest that the autonomic nervous system plays an important role in mediating sudden cardiac arrest. In this study, we tested the effectiveness of phentolamine and atenolol, individually or combined, in prolonging functionality of the vital organs in CO2-mediated asphyxic cardiac arrest model. Rats received either saline, phentolamine, atenolol, or phentolamine plus atenolol, 30 min before the onset of asphyxia. Electrocardiogram (ECG and electroencephalogram (EEG signals were simultaneously collected from each rat during the entire process and investigated for cardiac and brain functions using a battery of analytic tools. We found that adrenergic blockade significantly suppressed the initial decline of cardiac output, prolonged electrical activities of both brain and heart, asymmetrically altered functional connectivity within the brain, and altered, bi-directionally and asymmetrically, functional, and effective connectivity between the brain and heart. The protective effects of adrenergic blockers paralleled the suppression of brain and heart connectivity, especially in the right hemisphere associated with central regulation of sympathetic function. Collectively, our results demonstrate that blockade of brain-heart connection via alpha- and beta-adrenergic blockers significantly prolonged the detectable activities of both the heart and the brain in asphyxic rat. The beneficial effects of combined alpha and beta blockers may help extend the survival of cardiac arrest patients.

  18. Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward.

    Science.gov (United States)

    Sanders, Amy Cecilia; Hussain, Ali J; Hen, René; Zhuang, Xiaoxi

    2007-11-01

    The therapeutic effects of chronic selective serotonin reuptake inhibitors (SSRIs) are well documented, yet the elementary behavioral processes that are affected by such treatment have not been fully investigated. We report here the effects of chronic fluoxetine treatment and genetic deletion of the serotonin transporter (SERT) on food reinforced behavior in three paradigms: the progressive ratio operant task, the concurrent choice operant task, and the Pavlovian-to-Instrumental transfer task. We consistently find that chronic pharmacological blockade or genetic deletion of SERT result in similar behavioral consequences: reduced operant responding for natural reward. This is in line with previous studies reporting declines in operant responding for drugs and intracranial self-stimulation with fluoxetine treatment, suggesting that the effect of SERT blockade can be generalized to different reward types. Detailed analyses of behavioral parameters indicate that this reduction in operant responding affect both goal-directed and non-goal-directed behaviors without affecting the Pavlovian cue-triggered excessive operant responding. In addition, both pharmacological and genetic manipulations reduce locomotor activity in the open field novel environment. Our data contrast with the effect of dopamine in increasing operant responding for natural reward specifically in goal-directed behaviors and in increasing Pavlovian cue-triggered excessive operant responding. Serotonin and dopamine have been proposed to serve opposing functions in motivational processes. Our data suggest that their interactions do not result in simple opponency. The fact that pharmacological blockade and genetic deletion of SERT have similar behavioral consequences reinforces the utility of the SERT null mice for investigation of the mechanisms underlying chronic SSRIs treatment.

  19. Prolonged hypothyroidism severely reduces ovarian follicular reserve in adult rats

    NARCIS (Netherlands)

    Meng, Li; Rijntjes, Eddy; Swarts, Hans J.M.; Keijer, Jaap; Teerds, Katja J.

    2017-01-01

    Background: There is substantial evidence both in humans and in animals that a prolonged reduction in plasma thyroid hormone concentration leads to reproductive problems, including disturbed folliculogenesis, impaired ovulation and fertilization rates, miscarriage and pregnancy complications. The

  20. Need for beta-blockade in hypertension reduced with long-term minoxidil.

    Science.gov (United States)

    Brunner, H R; Jaeger, P; Ferguson, R K; Jequier, E; Turini, G; Gavras, H

    1978-01-01

    Sequential changes in plasma renin activity and urinary aldosterone and noradrenaline were assessed in eight patients with severe hypertension after minoxidil had been added to their treatment. Doses of 2.5--27.5 (mean 12.5) mg/day reduced the mean blood pressure from 166/113 +/-6/2 mm Hg to 124/88+/-4/2 mm Hg in one week. Plasma renin activity and urinary aldosterone and noradrenaline increased twofold to threefold initially but returned to baseline values within two to three weeks and remained unchanged during a mean follow-up of 5.1 months. Beta-blocking drugs were then withdrawn slowly in six patients without adverse effects, though blood pressure and heart rate increased in three patients, who required minimal doses of beta-blockers. Plasma renin activity and urinary aldosterone and noradrenaline did not change significantly after beta-blockade had been stopped. We conclude that the need for beta-blockade is greatly reduced with long-term minoxidil treatment and that it may be unnecessary in some patients. PMID:28811

  1. Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man

    DEFF Research Database (Denmark)

    Simonsen, Lene; Enevoldsen, Lotte H; Stallknecht, Bente

    2008-01-01

    During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined....... Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data...... circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays...

  2. Recovery from prolonged deep rocuronium-induced neuromuscular blockade: A randomized comparison of sugammadex reversal with spontaneous recovery.

    Science.gov (United States)

    Rahe-Meyer, N; Berger, C; Wittmann, M; Solomon, C; Abels, E A M; Rietbergen, H; Reuter, D A

    2015-07-01

    Deep neuromuscular blockade (NMB) may not always be maintained to the end of surgery and the depth of block may be allowed to gradually diminish over time, particularly if reversal of NMB is not routinely performed. The current study aimed to assess recovery from deep rocuronium-induced NMB with sugammadex compared with placebo, provide data regarding the extent of residual blockade after deep rocuronium-induced NMB (placebo group), and to determine whether complete and reliable recovery could be provided by sugammadex (sugammadex group). This was a randomized, placebo-controlled, safety-assessor-blinded study in adult patients of American Society of Anesthesiologists Class I to III. Patients with clinically relevant kidney or liver insufficiency were excluded. Anesthesia was administered as routinely practiced at each study site. Rocuronium 0.6 mg/kg was administered for intubation, with maintenance doses of 0.1-0.2 mg/kg as needed. After the last rocuronium dose, at deep NMB (target depth 1-2 post-tetanic counts), patients received a single dose of sugammadex 4.0 mg/kg or placebo as randomized. The primary endpoint was time from sugammadex or placebo administration to recovery of the train-of-four (TOF) ratio to 0.9. Safety was assessed through monitoring of adverse events, vital signs and physical examination. Patients were also assessed for evidence of residual or recurrence of NMB. With this design, the study will provide data regarding the extent of residual blockade under these conditions (placebo group), and determine whether complete and reliable recovery could be provided by sugammadex (sugammadex group). Recovery to a TOF ratio of ≥ 0.9 with sugammadex was significantly faster (~ 40 times) than spontaneous recovery: geometric mean (95 % confidence interval) times were 2.2 (1.9-2.5) and 89.8 (80.1-100.7) min, respectively (p sugammadex, with median time to recovery > 1.5 h in the placebo group and one patient taking 4.8 h to achieve a

  3. Prolonged hypothyroidism severely reduces ovarian follicular reserve in adult rats.

    Science.gov (United States)

    Meng, Li; Rijntjes, Eddy; Swarts, Hans J M; Keijer, Jaap; Teerds, Katja J

    2017-03-16

    There is substantial evidence both in humans and in animals that a prolonged reduction in plasma thyroid hormone concentration leads to reproductive problems, including disturbed folliculogenesis, impaired ovulation and fertilization rates, miscarriage and pregnancy complications. The objective of the present study is to examine the consequences of chronic hypothyroidism, induced in adulthood, for the size of the ovarian follicle pool. In order to investigate this, adult female rats were provided either a control or an iodide deficient diet in combination with perchlorate supplementation to inhibit iodide uptake by the thyroid. Sixteen weeks later animals were sacrificed. Blood was collected for hormone analyses and ovaries were evaluated histologically. At the time of sacrifice, plasma thyroid-stimulating hormone concentrations were 20- to 40-fold increased, thyroxine concentrations were negligible while tri-iothyronin concentrations were decreased by 40% in the hypothyroid group, confirming that the animals were hypothyroid. Primordial, primary and preantral follicle numbers were significantly lower in the hypothyroid ovaries compared to the euthyroid controls, while a downward trend in antral follicle and corpora lutea numbers was observed. Surprisingly the percentage of atretic follicles was not significantly different between the two groups, suggesting that the reduced preantral and antral follicle numbers were presumably not the consequence of increased degeneration of these follicle types in the hypothyroid group. Plasma anti-Müllerian hormone (AMH) levels showed a significant correlation with the growing follicle population represented by the total ovarian number of primary, preantral and antral follicles, suggesting that also under hypothyroid conditions AMH can serve as a surrogate marker to assess the growing ovarian follicle population. The induction of a chronic hypothyroid condition in adult female rats negatively affects the ovarian follicular

  4. 5HT2A receptor blockade in dorsomedial striatum reduces repetitive behaviors in BTBR mice.

    Science.gov (United States)

    Amodeo, D A; Rivera, E; Cook, E H; Sweeney, J A; Ragozzino, M E

    2017-03-01

    Restricted and repetitive behaviors are a defining feature of autism, which can be expressed as a cognitive flexibility deficit or stereotyped, motor behaviors. There is limited knowledge about the underlying neuropathophysiology contributing to these behaviors. Previous findings suggest that central 5HT 2A receptor activity is altered in autism, while recent work indicates that systemic 5HT 2A receptor antagonist treatment reduces repetitive behaviors in an idiopathic model of autism. 5HT 2A receptors are expressed in the orbitofrontal cortex and striatum. These two regions have been shown to be altered in autism. The present study investigated whether 5HT 2A receptor blockade in the dorsomedial striatum or orbitofrontal cortex in the BTBR mouse strain, an idiopathic model of autism, affects the phenotype related to restricted and repetitive behaviors. Microinfusion of the 5HT 2A receptor antagonist, M100907 into the dorsomedial striatum alleviated a reversal learning impairment and attenuated grooming behavior. M100907 infusion into the orbitofrontal cortex increased perseveration during reversal learning and potentiated grooming. These findings suggest that increased 5HT 2A receptor activity in the dorsomedial striatum may contribute to behavioral inflexibility and stereotyped behaviors in the BTBR mouse. 5HT 2A receptor signaling in the orbitofrontal cortex may be critical for inhibiting a previously learned response during reversal learning and expression of stereotyped behavior. The present results suggest which brain areas exhibit abnormalities underlying repetitive behaviors in an idiopathic mouse model of autism, as well as which brain areas systemic treatment with M100907 may principally act on in BTBR mice to attenuate repetitive behaviors. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  5. Improving Neuromuscular Monitoring and Reducing Residual Neuromuscular Blockade With E-Learning

    DEFF Research Database (Denmark)

    Thomsen, Jakob Louis Demant; Mathiesen, Ole; Hägi-Pedersen, Daniel

    2017-01-01

    BACKGROUND: Muscle relaxants facilitate endotracheal intubation under general anesthesia and improve surgical conditions. Residual neuromuscular blockade occurs when the patient is still partially paralyzed when awakened after surgery. The condition is associated with subjective discomfort and an......-learning module can increase anesthetists' use of neuromuscular monitoring. TRIAL REGISTRATION: Clinicaltrials.gov NCT02925143; https://clinicaltrials.gov/ct2/show/NCT02925143 (Archived by WebCite® at http://www.webcitation.org/6s50iTV2x)....

  6. Leptin receptor blockade reduces intrahepatic vascular resistance and portal pressure in an experimental model of rat liver cirrhosis.

    Science.gov (United States)

    Delgado, María Gabriela; Gracia-Sancho, Jordi; Marrone, Giusi; Rodríguez-Vilarrupla, Aina; Deulofeu, Ramon; Abraldes, Juan G; Bosch, Jaume; García-Pagán, Juan Carlos

    2013-10-01

    Increased hepatic vascular resistance mainly due to elevated vascular tone and to fibrosis is the primary factor in the development of portal hypertension in cirrhosis. Leptin, a hormone associated with reduction in nitric oxide bioavailability, vascular dysfunction, and liver fibrosis, is increased in patients with cirrhosis. We aimed at evaluating whether leptin influences the increased hepatic resistance in portal hypertension. CCl4-cirrhotic rats received the leptin receptor-blocker ObR antibody, or its vehicle, every other day for 1 wk. Hepatic and systemic hemodynamics were measured in both groups. Hepatic nitric oxide production and bioavailability, together with oxidative stress, nitrotyrosinated proteins, and liver fibrosis, were evaluated. In cirrhotic rats, leptin-receptor blockade significantly reduced portal pressure without modifying portal blood flow, suggesting a reduction in the intrahepatic resistance. Portal pressure reduction was associated with increased nitric oxide bioavailability and with decreased O2(-) levels and nitrotyrosinated proteins. No changes in systemic hemodynamics and liver fibrosis were observed. In conclusion, the present study shows that blockade of the leptin signaling pathway in cirrhosis significantly reduces portal pressure. This effect is probably due to a nitric oxide-mediated reduction in the hepatic vascular tone.

  7. Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis.

    Science.gov (United States)

    Cuccurullo, Alessandra; Greco, Elisabetta; Lupia, Enrico; De Giuli, Paolo; Bosco, Ornella; Martin-Conte, Erica; Spatola, Tiziana; Turco, Emilia; Montrucchio, Giuseppe

    2016-01-01

    Thrombopoietin (TPO), a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions. We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP) model. In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01), and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05), respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01), and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05). Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01) and from 1.43±0.37 to 0.40±0.16 (P<0.05), respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01) and from 1.25±0.31 to 0.13±0.13 (P<0.001), respectively, in the

  8. Blockade of Thrombopoietin Reduces Organ Damage in Experimental Endotoxemia and Polymicrobial Sepsis.

    Directory of Open Access Journals (Sweden)

    Alessandra Cuccurullo

    Full Text Available Thrombopoietin (TPO, a growth factor primarily involved in thrombopoiesis may also have a role in the pathophysiology of sepsis. In patients with sepsis, indeed, TPO levels are markedly increased, with disease severity being the major independent determinant of TPO concentrations. Moreover, TPO increases and correlates with ex vivo indices of platelet activation in patients with burn injury upon sepsis development, and may contribute to depress cardiac contractility in septic shock. Still, the role of TPO in sepsis pathophysiology remains controversial, given the protective role of TPO in other experimental disease models, for instance in doxorubicin-induced cardiotoxicity and myocardial ischemia/reperfusion injury. The aim of our study was to define the contribution of TPO in the development of organ damage induced by endotoxemia or sepsis, and to investigate the effects of inhibiting TPO in these conditions.We synthesized a chimeric protein able to inhibit TPO, mTPOR-MBP, and studied its effect in two murine experimental models, acute endotoxemia and cecal ligation and puncture (CLP model.In both models, TPO levels markedly increased, from 289.80±27.87 pg/mL to 465.60±45.92 pg/mL at 3 hours in the LPS model (P<0.01, and from 265.00±26.02 pg/mL to 373.70±26.20 pg/mL in the CLP model (P<0.05, respectively. Paralleling TPO levels, also platelet-monocyte aggregates increased, from 32.86±2.48% to 46.13±1.39% at 3 hours in the LPS model (P<0.01, and from 43.68±1.69% to 56.52±4.66% in the CLP model (P<0.05. Blockade of TPO by mTPOR-MBP administration reduced histological damage in target organs, namely lung, liver, and gut. In particular, neutrophil infiltration and lung septal thickening were reduced from a score of 1.86±0.34 to 0.60±0.27 (P<0.01 and from 1.43±0.37 to 0.40±0.16 (P<0.05, respectively, in the LPS model at 3 hours, and from a score of 1.75±0.37 to 0.38±0.18 (P<0.01 and from 1.25±0.31 to 0.13±0.13 (P<0.001, respectively

  9. Improving Neuromuscular Monitoring and Reducing Residual Neuromuscular Blockade With E-Learning

    DEFF Research Database (Denmark)

    Thomsen, Jakob Louis Demant; Mathiesen, Ole; Hägi-Pedersen, Daniel

    2017-01-01

    neuromuscular blockade in surgical patients at 6 Danish teaching hospitals. METHODS: In this interrupted time series study, we are collecting data repeatedly, in consecutive 3-week periods, before and after the intervention, and we will analyze the effect using segmented regression analysis. Anesthesia...... and an increased risk of respiratory complications. Use of an objective neuromuscular monitoring device may prevent residual block. Despite this, many anesthetists refrain from using the device. Efforts to increase the use of objective monitoring are time consuming and require the presence of expert personnel...... practice, and patient outcomes. The primary outcome is use of neuromuscular monitoring in patients according to the type of muscle relaxant received. Secondary outcomes include last recorded train-of-four value, administration of reversal agents, and time to discharge from the postanesthesia care unit...

  10. VEGF receptor blockade markedly reduces retinal microglia/macrophage infiltration into laser-induced CNV.

    Directory of Open Access Journals (Sweden)

    Hu Huang

    Full Text Available Although blocking VEGF has a positive effect in wet age-related macular degeneration (AMD, the effect of blocking its receptors remains unclear. This was an investigation of the effect of VEGF receptor (VEGFR 1 and/or 2 blockade on retinal microglia/macrophage infiltration in laser-induced choroidal neovascularization (CNV, a model of wet AMD. CNV lesions were isolated by laser capture microdissection at 3, 7, and 14 days after laser and analyzed by RT-PCR and immunofluorescence staining for mRNA and protein expression, respectively. Neutralizing antibodies for VEGFR1 or R2 and the microglia inhibitor minocycline were injected intraperitoneally (IP. Anti-CD11b, CD45 and Iba1 antibodies were used to confirm the cell identity of retinal microglia/macrophage, in the RPE/choroidal flat mounts or retinal cross sections. CD11b(+, CD45(+ or Iba1(+ cells were counted. mRNA of VEGFR1 and its three ligands, PlGF, VEGF-A (VEGF and VEGF-B, were expressed at all stages, but VEGFR2 were detected only in the late stage. PlGF and VEGF proteins were expressed at 3 and 7 days after laser. Anti-VEGFR1 (MF1 delivered IP 3 days after laser inhibited infiltration of leukocyte populations, largely retinal microglia/macrophage to CNV, while anti-VEGFR2 (DC101 had no effect. At 14 days after laser, both MF1 and DC101 antibodies markedly inhibited retinal microglia/macrophage infiltration into CNV. Therefore, VEGFR1 and R2 play differential roles in the pathogenesis of CNV: VEGFR1 plays a dominant role at 3 days after laser; but both receptors play pivotal roles at 14 days after laser. In vivo imaging demonstrated accumulation of GFP-expressing microglia into CNV in both CX3CR1(gfp/gfp and CX3CR1(gfp/+ mice. Minocycline treatment caused a significant increase in lectin(+ cells in the sub-retinal space anterior to CNV and a decrease in dextran-perfused neovessels compared to controls. Targeting the chemoattractant molecules that regulate trafficking of retinal microglia

  11. Both acute and prolonged administration of EPO reduce cerebral and systemic vascular conductance in humans

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Kim, Yu-Sok; Krogh-Madsen, Rikke

    2012-01-01

    Administration of erythropoietin (EPO) has been linked to cerebrovascular events. EPO reduces vascular conductance, possibly because of the increase in hematocrit. Whether EPO in itself affects the vasculature remains unknown; here it was evaluated in healthy males by determining systemic...... and cerebrovascular variables following acute (30,000 IU/d for 3 d; n=8) and chronic (5000 IU/week for 13 wk; n=8) administration of EPO, while the responsiveness of the vasculature was challenged during cycling exercise, with and without hypoxia. Prolonged administration of EPO increased hematocrit from 42.5 ± 3...

  12. The combination of sugammadex and neostigmine can reduce the dosage of sugammadex during recovery from the moderate neuromuscular blockade.

    Science.gov (United States)

    Cheong, Soon Ho; Ki, Seunghee; Lee, Jiyong; Lee, Jeong Han; Kim, Myoung-Hun; Hur, Dongki; Cho, Kwangrae; Lim, Se Hun; Lee, Kun Moo; Kim, Young-Jae; Lee, Wonjin

    2015-12-01

    Sugammadex is a novel neuromuscular reversal agent, but its associated hypersensitivity reaction and high cost have been obstacles to its widespread use. In the interest of reducing the necessary dosage of sugammadex, the reversal time of the combined use of sugammadex and neostigmine from moderate neuromuscular blockade were investigated. The patients enrolled ranged in age from 18 to 65 years old with American Society of Anesthesiologists class 1 or 2. The subjects were randomly assigned into one of the four groups (Group S2, S1, SN, and N; n = 30 per group). The reversal agents of each groups were as follows: S2 - sugammadex 2 mg/kg, S1 - sugammadex 1 mg/kg, SN - sugammadex 1 mg/kg + neostigmine 50 µg/kg + glycopyrrolate 10 µg/kg, N - neostigmine 50 µg/kg + glycopyrrolate 10 µg/kg. The time to recovery of the train-of-four (TOF) ratio was checked in each group. The time to 90% recovery of TOF ratio was 182.6 ± 88.9, 371.1 ± 210.4, 204.3 ± 103.2, 953.2 ± 379.7 sec in group S2, S1, SN and N, respectively. Group SN showed a significantly shorter recovery time than did group S1 and N (P sugammadex and neostigmine may be helpful to decrease the recovery time and can also reduce the required dosage of sugammadex. However, the increased incidence of systemic muscarinic side effects must be considered.

  13. Evidence for reduced arterial plasma input, prolonged lung retention and reduced lung monoamine oxidase in smokers

    International Nuclear Information System (INIS)

    Logan, Jean; Fowler, Joanna S.

    2005-01-01

    We have previously found that smokers have reduced brain monoamine oxidase (MAO) A and B using positron emission tomography (PET) and the irreversible mechanism-based radiotracers [ 11 C]-labeled clorgyline (CLG) and deprenyl (DEP) and their deuterated analogs (D CLG, D DEP). More recently, we have estimated MAO A and B activity in other organs using the deuterium isotope effect to determine binding specificity for MAO and a three-compartment model to estimate k 3 , the model term proportional to MAO A activity. Here, we have investigated the robustness of the model term k 3 for estimating lung MAO A and B in light of our unexpected finding that lung MAO activity (k 3 ) was reduced for smokers relative to nonsmokers, although radiotracer uptake in the lungs was similar at peak and plateau for the two groups. Methods: Time-activity data from lung and arterial plasma were used from seven nonsmokers and seven smokers scanned previously with CLG and D CLG, and five nonsmokers and nine smokers scanned previously with DEP and D DEP. The measured time-activity curves for lung and plasma and the integrals for the arterial plasma time-activity curves were compared at an early time point (2.5 min) and at the end of the study (55 min). A three-compartment irreversible model was used to estimate the differences between smokers and nonsmokers, and the stability of the parameter (k 3 ) while varying model assumptions for the relative fractions of lung tissue, blood and air in the PET voxel. Results: The peak in the arterial plasma input function and the integral of the arterial plasma time-activity curve over the first 2.5 min after radiotracer injection were significantly lower for smokers relative to nonsmokers for all four tracers. However, although the peak and plateau of the lung time-activity curves were similar for smokers and nonsmokers, the decline in radioactivity from peak to plateau was slower for smokers for all tracers. Using a three-compartment irreversible model

  14. Renal function after prolonged hypotensive anesthesia and surgery in dogs with reduced renal mass.

    Science.gov (United States)

    Stone, E A; Rawlings, C A; Finco, D R; Crowell, W A

    1981-10-01

    The effect of prolonged hypotensive anesthesia and surgery on renal function was studied in 8 dogs with decreased renal mass. Renal mass was reduced by unilateral nephrectomy and ligation of 4 of the 6 terminal renal artery branches of the opposite kidney. One week after reduction in renal mass, the dogs were azotemic with a serum urea nitrogen (SUN) value of 65.8 +/- 11.5 mg/dl. Glomerular filtration rate, as estimated by 14C-inulin clearance, was 0.66 +/- 0.19 ml/kg of body weight/hour. A mean arterial pressure of less than 75 mm of Hg was maintained for 4 hours in dogs given 2.3 +/- 0.7% halothane. An exploratory laparotomy lasting 1 hour was performed. The day after the hypotensive episode, 3 dogs began vomiting, became dehydrated, and had SUN values greater than 100 mg/dl. The SUN values returned to base-line values after the dogs were rehydrated. Eight days after the hypotensive episode, 14C-inulin clearance decreased 15.2 +/- 8.2% (P less than 0.005) compared with base-line clearance values. Light microscopic and electron microscopic observations of the kidneys did not demonstrate acute renal failure. Prolonged hypotensive anesthesia can cause a decrease in renal function, and may cause prerenal uremia and/or acute renal failure.

  15. Hypoxic ventilatory sensitivity in men is not reduced by prolonged hyperoxia (Predictive Studies V and VI)

    Science.gov (United States)

    Gelfand, R.; Lambertsen, C. J.; Clark, J. M.; Hopkin, E.

    1998-01-01

    Potential adverse effects on the O2-sensing function of the carotid body when its cells are exposed to toxic O2 pressures were assessed during investigations of human organ tolerance to prolonged continuous and intermittent hyperoxia (Predictive Studies V and VI). Isocapnic hypoxic ventilatory responses (HVR) were determined at 1.0 ATA before and after severe hyperoxic exposures: 1) continuous O2 breathing at 1.5, 2.0, and 2.5 ATA for 17.7, 9.0, and 5.7 h and 2) intermittent O2 breathing at 2.0 ATA (30 min O2-30 min normoxia) for 14.3 O2 h within 30-h total time. Postexposure curvature of HVR hyperbolas was not reduced compared with preexposure controls. The hyperbolas were temporarily elevated to higher ventilations than controls due to increments in respiratory frequency that were proportional to O2 exposure time, not O2 pressure. In humans, prolonged hyperoxia does not attenuate the hypoxia-sensing function of the peripheral chemoreceptors, even after exposures that approach limits of human pulmonary and central nervous system O2 tolerance. Current applications of hyperoxia in hyperbaric O2 therapy and in subsea- and aerospace-related operations are guided by and are well within these exposure limits.

  16. Blockade of central vasopressin receptors reduces the cardiovascular response to acute stress in freely moving rats.

    Science.gov (United States)

    Stojicić, S; Milutinović-Smiljanić, S; Sarenac, O; Milosavljević, S; Paton, J F R; Murphy, D; Japundzić-Zigon, N

    2008-04-01

    To investigate the contribution of central vasopressin receptors to blood pressure (BP) and heart rate (HR) response to stress we injected non-peptide selective V(1a) (SR49059), V(1b) (SSR149415), V(2) (SR121463) receptor antagonists, diazepam or vehicle in the lateral cerebral ventricle of conscious freely moving rats stressed by blowing air on their heads for 2 min. Cardiovascular effects of stress were evaluated by analyzing maximum increase of BP and HR (MAX), latency of maximum response (LAT), integral under BP and HR curve (integral), duration of their recovery and spectral parameters of BP and HR indicative of increased sympathetic outflow (LF(BP) and LF/HF(HR)). Moreover, the increase of serum corticosterone was measured. Exposure to air-jet stress induced simultaneous increase in BP and HR followed by gradual decline during recovery while LF(BP) oscillation remained increased as well as serum corticosterone level. Rats pre-treated with vasopressin receptor antagonists were not sedated while diazepam induced sedation that persisted during exposure to stress. V(1a), V(1b) and V(2) receptor antagonists applied separately did not modify basal values of cardiovascular parameters but prevented the increase in integral(BP). In addition, V(1b) and V(2) receptor antagonists reduced BP(MAX) whereas V(1a), V(1b) antagonist and diazepam reduced HR(MAX) induced by exposure to air-jet stress. All drugs shortened the recovery period, prevented the increase of LF(BP) without affecting the increase in serum corticosterone levels. Results indicate that vasopressin receptors located within the central nervous system mediate, in part, the cardiovascular response to air-jet stress without affecting either the neuroendocrine component or inducing sedation. They support the view that the V(1b) receptor antagonist may be of potential therapeutic value in reducing arterial pressure induced by stress-related disorders.

  17. Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss.

    Science.gov (United States)

    Dawson, Alison J; Kilpatrick, Eric S; Coady, Anne-Marie; Elshewehy, Abeer M M; Dakroury, Youssra; Ahmed, Lina; Atkin, Stephen L; Sathyapalan, Thozhukat

    2017-07-14

    Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Treatment with rimonabant for 12 weeks reduced both ALT and weight (p weight. There was a significant reduction of weight with orlistat (p weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered).

  18. Prolonged hydrocephalus induced by intraventricular hemorrhage in rats is reduced by curcumin therapy.

    Science.gov (United States)

    Qi, Zhihua; Zhang, Huiqin; Fu, Chuhua; Liu, Xiao; Chen, Bo; Dang, Yanwei; Chen, Huayun; Liu, Lijun

    2017-01-10

    Prolonged hydrocephalus is a major cause of severe disability and death of intraventricular hemorrhage (IVH) patients. However, the therapeutic options to minimize the detrimental effects of post-hemorrhagic hydrocephalus are limited. Curcumin has been reported to confer neuroprotective effects in numerous neurological diseases and injuries, but its role in IVH-induced hydrocephalus has not been determined. The aim of present study was to determine whether curcumin treatment ameliorates blood brain barrier (BBB) damage and reduces the incidence of post-hemorrhagic hydrocephalus in IVH rat model. Autologous blood intraventricular injection was used to establish the IVH model. Our results revealed that repeated intraperitoneal injection of curcumin ameliorated IVH-induced learning and memory deficits as determined by Morris water maze and reduced the incidence of post-hemorrhagic hydrocephalus in a dose-dependent manner at 28 d post-IVH induction. Further, the increased BBB permeability and brain edema induced by IVH were significantly reduced by curcumin administration. In summary, these findings highlighted the important role of curcumin in improving neurological function deficits and protecting against BBB disruption via promoting the neurovascular unit restoration, and thus it reduced the severity of post-hemorrhagic hydrocephalus in the long term. It is believed that curcumin might prove to be an effective therapeutic component in prevent the post-IVH hydrocephalus in the near future. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  19. Aldosterone Blockade Reduces Mortality without Changing Cardiac Remodeling in Spontaneously Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Marcelo D.M. Cezar

    2013-11-01

    Full Text Available Background: The role of aldosterone blockers during transition from long-term compensated hypertrophy to dilated failure is not completely understood. In this study we evaluated the effects of early administration of spironolactone on cardiac remodeling, myocardial function, and mortality in spontaneously hypertensive rats (SHR. Methods: Sixteen-month-old SHR received no treatment (SHR-C, n=72 or spironolactone (SHR-SPR, 20 mg/kg/day, n=34 for six months. Echocardiogram was performed before and after treatment. Myocardial function was analyzed in left ventricular (LV papillary muscle preparations. Myocardial collagen and hydroxyproline concentration were evaluated by morphometry and spectrophotometry, respectively. LV gene expression was assessed by real time RT-PCR. Statistics: Student's t test; Log rank test (Kaplan Meyer. Results: SHR-C and SHR-SPR presented mortality rates of 71 and 38%, respectively (p=0.004. Systolic arterial pressure did not differ between groups (SHR-C 199±43; SHR-SPR 200±35 mmHg. Initial and final echocardiograms did not show significant differences in cardiac structures or LV function between groups. Myocardial function was similar between groups at basal and after inotropic stimulation. Collagen fractional area, hydroxyproline concentration, gene expression for α- and β-myosin heavy chain, atrial natriuretic peptide, and Serca2a were not different between groups. Conclusion: Early spironolactone administration reduces mortality without changing cardiac remodeling in spontaneous hypertensive rats.

  20. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity

    Directory of Open Access Journals (Sweden)

    David P. Sparling

    2016-02-01

    Full Text Available Objective: As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs, which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj and the obligate γ-secretase component Nicastrin (A-Nicastrin. Methods: Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes. Results: GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action. Conclusions: Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D. Keywords: Notch, γ-secretase complex, Insulin resistance

  1. A high sodium intake reduces antiproteinuric response to renin-angiotensin-aldosterone system blockade in kidney transplant recipients.

    Science.gov (United States)

    Monfá, Elena; Rodrigo, Emilio; Belmar, Lara; Sango, Cristina; Moussa, Fozi; Ruiz San Millán, Juan Carlos; Piñera, Celestino; Fernández-Fresnedo, Gema; Arias, Manuel

    Post-transplant proteinuria is associated with lower graft and patient survival. Renin-angiotensin-aldosterone system blockers are used to reduce proteinuria and improve renal outcome. Although it is known that a high salt intake blunts the antiproteinuric effect of ACEI and ARB drugs in non-transplant patients, this effect has not been studied in kidney transplant recipients. To analyse the relationship between sodium intake and the antiproteinuric effect of ACEI/ARB drugs in kidney transplant recipients. We selected 103 kidney transplant recipients receiving ACEI/ARB drugs for more than 6 months due to proteinuria>1 g/day. Proteinuria was analysed at baseline and at 6 months after starting ACEI/ARB treatment. Salt intake was estimated by urinary sodium to creatinine ratio (uNa/Cr). Proteinuria fell to less than 1g/day in 46 patients (44.7%). High uNa/Cr was associated with a smaller proteinuria decrease (r=-0.251, P=.011). The percentage proteinuria reduction was significantly lower in patients in the highest uNa/Cr tertile [63.9% (IQR 47.1%), 60.1% (IQR 55.4%), 38.9% (IQR 85.5%), P=.047]. High uNa/Cr independently relates (OR 2.406 per 100 mEq/g, 95% CI: 1.008-5.745, P=.048) to an antiproteinuric response <50% after renin-angiotensin-aldosterone system blockade. A high salt intake results in a smaller proteinuria decrease in kidney transplant recipients with proteinuria treated with ACEI/ARB drugs. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  2. Hydrazinonicotinamide prolongs quantum dot circulation and reduces reticuloendothelial system clearance by suppressing opsonization and phagocyte engulfment

    Science.gov (United States)

    Jung, Kyung-Ho; Park, Jin Won; Paik, Jin-Young; Lee, Eun Jeong; Choe, Yearn Seong; Lee, Kyung-Han

    2012-12-01

    In this study, we investigated the effects of hydrazinonicotinamide (HYNIC)—a bifunctional crosslinker widely used to 99mTc radiolabel protein and nanoparticles for imaging studies—on quantum dot opsonization, macrophage engulfment and in vivo kinetics. In streptavidin-coated quantum dots (SA-QDots), conjugation with HYNIC increased the net negative charge without affecting the zeta potential. Confocal microscopy and fluorescence-activated cell sorting showed HYNIC attachment to suppress SA-QDot engulfment by macrophages. Furthermore, HYNIC conjugation suppressed surface opsonization by serum protein including IgG. When intravenously injected into mice, HYNIC conjugation significantly prolonged the circulation of SA-QDots and reduced their hepatosplenic uptake. Diminished reticuloendothelial system clearance of SA-QDots and aminoPEG-QDots by HYNIC conjugation was also demonstrated by in vivo and ex vivo optical imaging. The effects of HYNIC on the opsonization, phagocytosis and in vivo kinetics of quantum dots were reversed by removal of the hydrazine component from HYNIC. Thus, surface functionalization with HYNIC can improve the in vivo kinetics of quantum dots by reducing phagocytosis via suppression of surface opsonization.

  3. IL-2-Mediated In Vivo Expansion of Regulatory T Cells Combined with CD154–CD40 Co-Stimulation Blockade but Not CTLA-4 Ig Prolongs Allograft Survival in Naive and Sensitized Mice

    Directory of Open Access Journals (Sweden)

    Dela Golshayan

    2017-04-01

    Full Text Available In recent years, regulatory T cells (Treg-based immunotherapy has emerged as a promising strategy to promote operational tolerance after solid organ transplantation (SOT. However, a main hurdle for the therapeutic use of Treg in transplantation is their low frequency, particularly in non-lymphopenic hosts. We aimed to expand Treg directly in vivo and determine their efficacy in promoting donor-specific tolerance, using a stringent experimental model. Administration of the IL-2/JES6-1 immune complex at the time of transplantation resulted in significant expansion of donor-specific Treg, which suppressed alloreactive T cells. IL-2-mediated Treg expansion in combination with short-term CD154–CD40 co-stimulation blockade, but not CTLA-4 Ig or rapamycin, led to tolerance to MHC-mismatched skin grafts in non-lymphopenic mice, mainly by hindering alloreactive CD8+ effector T cells and the production of alloantibodies. Importantly, this treatment also allowed prolonged survival of allografts in the presence of either donor-specific or cross-reactive memory cells. However, late rejection occurred in sensitized hosts, partly mediated by activated B cells. Overall, these data illustrate the potential but also some important limitations of Treg-based therapy in clinical SOT as well as the importance of concomitant immunomodulatory strategies in particular in sensitized hosts.

  4. Saline Flush After Rocuronium Bolus Reduces Onset Time and Prolongs Duration of Effect: A Randomized Clinical Trial.

    Science.gov (United States)

    Ishigaki, Sayaka; Masui, Kenichi; Kazama, Tomiei

    2016-03-01

    Circulatory factors modify the onset time of neuromuscular-blocking drugs. Therefore, we hypothesized that infusion of a saline flush immediately after rocuronium administration would shorten the onset time without influencing the duration of the rocuronium effect. Forty-eight patients were randomly allocated to the control or saline flush group. Anesthesia was induced and maintained with propofol and remifentanil, and all patients received 0.6 mg/kg rocuronium in 10 mL of normal saline. In the saline flush group, 20 mL normal saline was immediately infused after rocuronium administration. Neuromuscular blockade was assessed using acceleromyography at the adductor pollicis muscle with train-of-four (TOF) stimulation. The neuromuscular indices for rocuronium were calculated as follows: the latent onset time, defined as the time from the start of rocuronium infusion until first occurrence of depression of the first twitch of the TOF (T1) ≥5%; onset time, defined as the time from the start of rocuronium infusion until first occurrence of depression of the T1 ≥95%; clinical duration, defined as the time from the start of rocuronium administration until T1 recovered to 25% of the final T1 value; recovery index, defined as the time for recovery of T1 from 25% to 75% of the final T1 value; and the total recovery time, defined as the time from the start of rocuronium administration until reaching a TOF ratio of 0.9. Significance was designated at P rocuronium bolus by 17%, 24%, and 14%, respectively. In addition, the recovery phase was significantly prolonged in the saline flush group. The mean clinical duration (5th-95th percentile range) in the saline flush group and control group was 35 minutes (27-63 minutes) and 31 minutes (19-48 minutes; P = 0.032), respectively; the recovery index was 13 minutes (8-25 minutes) and 10 minutes (7-19 minutes; P = 0.019), respectively; and the total recovery time was 61 minutes (44-108 minutes) and 50 minutes (35-93 minutes; P = 0

  5. Reducing pressure ulcers in patients with prolonged acute mechanical ventilation: a quasi-experimental study.

    Science.gov (United States)

    Loudet, Cecilia Inés; Marchena, María Cecilia; Maradeo, María Roxana; Fernández, Silvia Laura; Romero, María Victoria; Valenzuela, Graciela Esther; Herrera, Isabel Eustaquia; Ramírez, Martha Teresa; Palomino, Silvia Rojas; Teberobsky, Mariana Virginia; Tumino, Leandro Ismael; González, Ana Laura; Reina, Rosa; Estenssoro, Elisa

    2017-01-01

    To determine the effectiveness of a quality management program in reducing the incidence and severity of pressure ulcers in critical care patients. This was a quasi-experimental, before-and-after study that was conducted in a medical-surgical intensive care unit. Consecutive patients who had received mechanical ventilation for ≥ 96 hours were included. A "Process Improvement" team designed a multifaceted interventional process that consisted of an educational session, a pressure ulcer checklist, a smartphone application for lesion monitoring and decision-making, and a "family prevention bundle". Fifty-five patients were included in Pre-I group, and 69 were included in the Post-I group, and the incidence of pressure ulcers in these groups was 41 (75%) and 37 (54%), respectively. The median time for pressure ulcers to develop was 4.5 [4 - 5] days in the Pre-I group and 9 [6 - 20] days in the Post-I group after admission for each period. The incidence of advanced-grade pressure ulcers was 27 (49%) in the Pre-I group and 7 (10%) in the Post-I group, and finally, the presence of pressure ulcers at discharge was 38 (69%) and 18 (26%), respectively (p pressure ulcers. The duration of mechanical ventilation and the presence of organ failure were positively associated with the development of pressure ulcers, while the multifaceted intervention program acted as a protective factor. A quality program based on both a smartphone application and family participation can reduce the incidence and severity of pressure ulcers in patients on prolonged acute mechanical ventilation.

  6. Modified single prolonged stress reduces cocaine self-administration during acquisition regardless of rearing environment.

    Science.gov (United States)

    Hofford, Rebecca S; Prendergast, Mark A; Bardo, Michael T

    2018-02-15

    Until recently, there were few rodent models available to study the interaction of post-traumatic stress disorder (PTSD) and drug taking. Like PTSD, single prolonged stress (SPS) produces hypothalamic-pituitary-adrenal (HPA) axis dysfunction and alters psychostimulant self-administration. Other stressors, such as isolation stress, also alter psychostimulant self-administration. However, it is currently unknown if isolation housing combined with SPS can alter the acquisition or maintenance of cocaine self-administration. The current study applied modified SPS (modSPS; two hours restraint immediately followed by cold swim stress) to rats raised in an isolation condition (Iso), enrichment condition (Enr), or standard condition (Std) to measure changes in cocaine self-administration and HPA markers. Regardless of rearing condition, rats exposed to modSPS had greater corticosterone (CORT) release and reduced cocaine self-administration during initial acquisition compared to non-stressed controls. In addition, during initial acquisition, rats that received both Iso rearing and modSPS showed a more rapid increase in cocaine self-administration across sessions compared to Enr and Std rats exposed to modSPS. Following initial acquisition, a dose response analysis showed that Iso rats were overall most sensitive to changes in cocaine unit dose; however, modSPS had no effect on the cocaine dose response curve. Further, there was no effect of either modSPS or differential rearing on expression of glucocorticoid receptor (GR) in hypothalamus, medial prefrontal cortex, amygdala, or nucleus accumbens. By using modSPS in combination with Iso housing, this study identified unique contributions of each stressor to acquisition of cocaine self-administration. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. [A project to reduce the incidence of facial pressure ulcers caused by prolonged surgery with prone positioning].

    Science.gov (United States)

    Lee, Wen-Yi; Lin, Pao-Chen; Weng, Chia-Hsing; Lin, Yi-Lin; Tsai, Wen-Lin

    2012-06-01

    We observed in our institute a 13.6% incidence of prolonged surgery (>4 hours) induced facial pressure ulcers that required prone positioning. Causes identified included: (1) customized silicon face pillows used were not suited for every patient; (2) our institute lacked a standard operating procedure for prone positioning; (3) our institute lacked a postoperative evaluation and audit procedure for facial pressure ulcers. We designed a strategy to reduce post-prolonged surgery facial pressure ulcer incidence requiring prone positioning by 50% (i.e., from 13.6% to 6.8%). We implemented the following: (1) Created a new water pillow to relieve facial pressure; (2) Implemented continuing education pressure ulcer prevention and evaluation; (3) Established protocols on standard care for prone-position patients and proper facial pressure ulcer identification; (4) Established a face pressure ulcers accident reporting mechanism; and (5) Established an audit mechanism facial pressure ulcer cases. After implementing the resolution measures, 116 patients underwent prolonged surgery in a prone position (mean operating time: 298 mins). None suffered from facial pressure ulcers. The measures effectively reduced the incidence of facial pressure ulcers from 13.6% to 0.0%. The project used a water pillow to relieve facial pressure and educated staff to recognize and evaluate pressure ulcers. These measures were demonstrated effective in reducing the incidence of facial pressure ulcers caused by prolonged prone positioning.

  8. Central Neuraxial Blockade-Assisted External Cephalic Version in Reducing Caesarean Section Rate: Systematic Review and Meta-Analysis

    Science.gov (United States)

    Bolaji, Ibrahim; Alabi-Isama, Lillian

    2009-01-01

    We review the medical literature on the success, safety and economic value of central neuraxial blockade-assisted (CNB) external cephalic version from randomized controlled studies identified from 1951 to 2009. The result showed that more women had successful ECV with regional anaesthesia with corresponding reduction in caesarean section rate. They were 1.5 times more likely than women not receiving anaesthesia to have a successful ECV. The number to treat is six women needed to receive anaesthesia for 1 baby to be turned from breech to cephalic presentation. Feto-maternal morbidity was not increased in the CNB-aided group consisting of only transient bradycardia. Although the appropriate amount of force for safe version has not been quantified, there was no report of uterine rupture despite removal of these patients from “excessive force-pain biofeedback loop” induced through motor nerve blockade. We can attribute 30% of cost savings amounting to £42,150.00 directly to CNB using the most up to date Health Resource Group Code (HRG4). The initial results are encouraging but until the benefits and safety of CNB-aided ECV are substantiated by large randomized, blinded controlled trials, this practice cannot be universally recommended. PMID:20069044

  9. Central Neuraxial Blockade-Assisted External Cephalic Version in Reducing Caesarean Section Rate: Systematic Review and Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Ibrahim Bolaji

    2009-01-01

    Full Text Available We review the medical literature on the success, safety and economic value of central neuraxial blockade-assisted (CNB external cephalic version from randomized controlled studies identified from 1951 to 2009. The result showed that more women had successful ECV with regional anaesthesia with corresponding reduction in caesarean section rate. They were 1.5 times more likely than women not receiving anaesthesia to have a successful ECV. The number to treat is six women needed to receive anaesthesia for 1 baby to be turned from breech to cephalic presentation. Feto-maternal morbidity was not increased in the CNB-aided group consisting of only transient bradycardia. Although the appropriate amount of force for safe version has not been quantified, there was no report of uterine rupture despite removal of these patients from “excessive force-pain biofeedback loop” induced through motor nerve blockade. We can attribute 30% of cost savings amounting to £42,150.00 directly to CNB using the most up to date Health Resource Group Code (HRG4. The initial results are encouraging but until the benefits and safety of CNB-aided ECV are substantiated by large randomized, blinded controlled trials, this practice cannot be universally recommended.

  10. Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

    Science.gov (United States)

    Pollard, C E; Valentin, J-P; Hammond, T G

    2008-08-01

    Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

  11. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    Luis R. Cassinotti

    2018-02-01

    Full Text Available Overactivity of the sympathetic nervous system and central endothelins (ETs are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA-salt hypertensive rats. Following brain ET receptor type A (ETA blockade by BQ610 (selective antagonist, transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ETA blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein in the right OB of hypertensive animals. However, ETA blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ETA are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  12. Chronic Blockade of Brain Endothelin Receptor Type-A (ETA) Reduces Blood Pressure and Prevents Catecholaminergic Overactivity in the Right Olfactory Bulb of DOCA-Salt Hypertensive Rats.

    Science.gov (United States)

    Cassinotti, Luis R; Guil, María J; Schöller, Mercedes I; Navarro, Mónica P; Bianciotti, Liliana G; Vatta, Marcelo S

    2018-02-27

    Overactivity of the sympathetic nervous system and central endothelins (ETs) are involved in the development of hypertension. Besides the well-known brain structures involved in the regulation of blood pressure like the hypothalamus or locus coeruleus, evidence suggests that the olfactory bulb (OB) also modulates cardiovascular function. In the present study, we evaluated the interaction between the endothelinergic and catecholaminergic systems in the OB of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Following brain ET receptor type A (ET A ) blockade by BQ610 (selective antagonist), transcriptional, traductional, and post-traductional changes in tyrosine hydroxylase (TH) were assessed in the OB of normotensive and DOCA-salt hypertensive rats. Time course variations in systolic blood pressure and heart rate were also registered. Results showed that ET A blockade dose dependently reduced blood pressure in hypertensive rats, but it did not change heart rate. It also prevented the increase in TH activity and expression (mRNA and protein) in the right OB of hypertensive animals. However, ET A blockade did not affect hemodynamics or TH in normotensive animals. Present results support that brain ET A are not involved in blood pressure regulation in normal rats, but they significantly contribute to chronic blood pressure elevation in hypertensive animals. Changes in TH activity and expression were observed in the right but not in the left OB, supporting functional asymmetry, in line with previous studies regarding cardiovascular regulation. Present findings provide further evidence on the role of ETs in the regulation of catecholaminergic activity and the contribution of the right OB to DOCA-salt hypertension.

  13. Lupus nephritis: prolonged immunoadsorption (IAS) reduces proteinuria and stabilizes global disease activity.

    Science.gov (United States)

    Stummvoll, Georg H; Schmaldienst, Sabine; Smolen, Josef S; Derfler, Kurt; Biesenbach, Peter

    2012-02-01

    Systemic lupus erythematosus (SLE) is characterized by pathogenic autoantibodies, which can be removed by extracorporeal procedures. While previous studies have shown short-term efficacy of immunoadsorption (IAS) in SLE, no information on long-term benefit and safety is available. IAS was offered to patients with highly active renal disease when conventional therapy had failed. Eleven patients entered the prolonged IAS programme and were followed for up to 10 years (mean 6.4 ± 3.5). Efficacy of IAS was determined by reduction in proteinuria (primary outcome), global disease activity [SLE Disease Activity Index (SLEDAI)] and anti-double-stranded DNA (anti-dsDNA) levels (secondary outcomes). Full/partial remission was defined as ≤ 0.5/≤ 1.0 g/day for proteinuria, ≤ 5/≤ 8 for SLEDAI and ≤ 25/≤ 50 IU/mL for anti-dsDNA levels. We further assessed flares, infections, malignancies and procedure-related adverse events. Short-term IAS (≤ 1 year) resulted in a significant reduction of proteinuria (9.2 ± 3.7 to 2.3 ± 2.4, P = 0.0001), disease activity (SLEDAI 19 ± 8 to 4 ± 2, P = 0.0004) and dsDNA levels (168 ± 205 to 45 ± 34, P = 0.001). In patients without remission after 1 year (n = 5), prolonged IAS decreased proteinuria from 4.3 ± 2.4 to 0.5 ± 0.4 g/day, P = 0.02. At the end of observation, complete remission in proteinuria was achieved in seven patients (64%) and partial remission in two (18%) additional patients. One patient flared and was discontinued; in all other patients, disease activity and anti-dsDNA stabilized at remission levels. Flares (0.28 ± 0.30) and infections (0.66 ± 0.70 per patient/year) were relatively uncommon; no malignancies, anaphylactic or orthostatic adverse events were observed. IAS is effective in short-term use but prolonged IAS can provide additional therapeutic benefit while showing an acceptable safety profile. The vast majority of initially therapy-refractory patients met the remission criteria at the end of

  14. TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

    Science.gov (United States)

    Greco, Stephanie H; Tomkötter, Lena; Vahle, Anne-Kristin; Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

    2015-01-01

    Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

  15. TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia.

    Directory of Open Access Journals (Sweden)

    Stephanie H Greco

    Full Text Available Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival.

  16. NO-flurbiprofen reduces amyloid β, is neuroprotective in cell culture, and enhances cognition in response to cholinergic blockade

    Science.gov (United States)

    Abdul-Hay, Samer O.; Luo, Jia; Ashghodom, Rezene T.; Thatcher, Gregory R.J.

    2009-01-01

    The nonsteroidal anti-inflamatory drug (NSAID) flurbiprofen is a selective amyloid lowering agent (SALA) which has been studied clinically in Alzheimer’s disease. HCT-1026 is an ester prodrug of flurbiprofen incorporating a nitrate carrier moiety that in vivo provides NO bioactivity and an improved safety profile. In vitro, HCT-1026 retained the COX inhibitory and NSAID activity of flurbiprofen, but at concentrations at which levels of Aβ1–42 were lowered by flurbiprofen, Aβ1–42 levels were elevated 200% by HCT-1026. Conversely, at lower concentrations, HCT-1026 behaved as a SALA with greater potency than flurbiprofen. The difference in concentration responses between flurbiprofen and HCT-1026 in vitro suggests different cellular targets; and in no case did a combination of nitrate drug with flurbiprofen provide similar actions. In vivo, HCT-1026 was observed to reverse cognitive deficits induced by scopolamine in two behavioral assays; activity that was also shown by a classical nitrate drug, but not by flurbiprofen. The ability to restore aversive memory and spatial working and reference memory after cholinergic blockade has been demonstrated by other agents that stimulate NO/cGMP signaling. These observations add positively to the preclinical profile of HCT-1026 and NO chimeras in Alzheimer’s disease. PMID:19702655

  17. TGF-β Blockade Reduces Mortality and Metabolic Changes in a Validated Murine Model of Pancreatic Cancer Cachexia

    Science.gov (United States)

    Rokosh, Rae; Avanzi, Antonina; Mahmood, Syed Kashif; Deutsch, Michael; Alothman, Sara; Alqunaibit, Dalia; Ochi, Atsuo; Zambirinis, Constantinos; Mohaimin, Tasnima; Rendon, Mauricio; Levie, Elliot; Pansari, Mridul; Torres-Hernandez, Alejandro; Daley, Donnele; Barilla, Rocky; Pachter, H. Leon; Tippens, Daniel; Malik, Hassan; Boutajangout, Allal; Wisniewski, Thomas; Miller, George

    2015-01-01

    Cancer cachexia is a debilitating condition characterized by a combination of anorexia, muscle wasting, weight loss, and malnutrition. This condition affects an overwhelming majority of patients with pancreatic cancer and is a primary cause of cancer-related death. However, few, if any, effective therapies exist for both treatment and prevention of this syndrome. In order to develop novel therapeutic strategies for pancreatic cancer cachexia, appropriate animal models are necessary. In this study, we developed and validated a syngeneic, metastatic, murine model of pancreatic cancer cachexia. Using our model, we investigated the ability of transforming growth factor beta (TGF-β) blockade to mitigate the metabolic changes associated with cachexia. We found that TGF-β inhibition using the anti-TGF-β antibody 1D11.16.8 significantly improved overall mortality, weight loss, fat mass, lean body mass, bone mineral density, and skeletal muscle proteolysis in mice harboring advanced pancreatic cancer. Other immunotherapeutic strategies we employed were not effective. Collectively, we validated a simplified but useful model of pancreatic cancer cachexia to investigate immunologic treatment strategies. In addition, we showed that TGF-β inhibition can decrease the metabolic changes associated with cancer cachexia and improve overall survival. PMID:26172047

  18. Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis.

    Directory of Open Access Journals (Sweden)

    Motoh Iwasa

    Full Text Available Long-term supplementation with branched-chain amino acids (BCAA is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05. The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver.

  19. Cold intermittent cardioplegia reduces the acidosis during prolonged cardiac surgery with cardiopulmonary bypass.

    Science.gov (United States)

    Nollo, Giandomenico; Ferrari, Paolo; Graffigna, Angelo C

    2011-01-01

    The effect on acid-base balance efficacy of intermittent warm and cold blood cardioplegia (IWBC, ICBC) was assessed in 44 patients who underwent cardiac surgery with prolonged aortic cross clamping. With this purpose a customized multi sensor probe was inserted in the coronary sinus, and pH, PO(2), PCO(2) and temperature were continuously measured at 1 Hz sampling rate. The mean cross-clamping time was of 76 ± 26 min on 19 IWBC cases and of 80 ± 24 min on 14 ICBC cases. With IWBC perfusion, at the end of every ischemic period, the lowest pH and PO(2) progressively decreased and the maximal PCO(2) increased. During ICBC the minimum of pH and PO(2) and maximum of PCO2 at the end of different ischemic period during time were constant, also during long cross-clamping time. With IWBC, myocardial ischemia seemed not completely reversed by standardized reperfusions, as reflected by steady deterioration of PCO(2) and pH after each reperfusion.

  20. Reduced transpiration response to precipitation pulses precedes mortality in a piñon-juniper woodland subject to prolonged drought.

    Science.gov (United States)

    Plaut, Jennifer A; Wadsworth, W Duncan; Pangle, Robert; Yepez, Enrico A; McDowell, Nate G; Pockman, William T

    2013-10-01

    Global climate change is predicted to alter the intensity and duration of droughts, but the effects of changing precipitation patterns on vegetation mortality are difficult to predict. Our objective was to determine whether prolonged drought or above-average precipitation altered the capacity to respond to the individual precipitation pulses that drive productivity and survival. We analyzed 5 yr of data from a rainfall manipulation experiment in piñon-juniper (Pinus edulis-Juniperus monosperma) woodland using mixed effects models of transpiration response to event size, antecedent soil moisture, and post-event vapor pressure deficit. Replicated treatments included irrigation, drought, ambient control and infrastructure control. Mortality was highest under drought, and the reduced post-pulse transpiration in the droughted trees that died was attributable to treatment effects beyond drier antecedent conditions and reduced event size. In particular, trees that died were nearly unresponsive to antecedent shallow soil moisture, suggesting reduced shallow absorbing root area. Irrigated trees showed an enhanced response to precipitation pulses. Prolonged drought initiates a downward spiral whereby trees are increasingly unable to utilize pulsed soil moisture. Thus, the additive effects of future, more frequent droughts may increase drought-related mortality. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

  1. Reduced vergence adaptation is associated with a prolonged output of convergence accommodation in convergence insufficiency.

    Science.gov (United States)

    Sreenivasan, Vidhyapriya; Bobier, William R

    2014-07-01

    Convergence insufficiency (CI) is a developmental visual anomaly defined clinically by a reduced near point of convergence, a reduced capacity to view through base-out prisms (fusional convergence); coupled with asthenopic symptoms typically blur and diplopia. Experimental studies show reduced vergence parameters and tonic adaptation. Based upon current models of accommodation and vergence, we hypothesize that the reduced vergence adaptation in CI leads to excessive amounts of convergence accommodation (CA). Eleven CI participants (mean age=17.4±2.3 years) were recruited with reduced capacity to view through increasing magnitudes of base out (BO) prisms (mean fusional convergence at 40 cm=12±0.9Δ). Testing followed our previous experimental design for (n=11) binocularly normal adults. Binocular fixation of a difference of Gaussian (DoG) target (0.2 cpd) elicited CA responses during vergence adaptation to a 12Δ BO. Vergence and CA responses were obtained at 3 min intervals over a 15 min period and time course were quantified using exponential decay functions. Results were compared to previously published data on eleven binocular normals. Eight participants completed the study. CI's showed significantly reduced magnitude of vergence adaptation (CI: 2.9Δ vs. normals: 6.6Δ; p=0.01) and CA reduction (CI=0.21 D, Normals=0.55 D; p=0.03). However, the decay time constants for adaptation and CA responses were not significantly different. CA changes were not confounded by changes in tonic accommodation (Change in TA=0.01±0.2D; p=0.8). The reduced magnitude of vergence adaptation found in CI patients resulting in higher levels of CA may potentially explain their clinical findings of reduced positive fusional vergence (PFV) and the common symptom of blur. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis.

    Science.gov (United States)

    Robertson, Jamie; Porter, Duncan; Sattar, Naveed; Packard, Chris J; Caslake, Muriel; McInnes, Iain; McCarey, David

    2017-11-01

    Patients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes. In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three intravenous infusions of the IL-6R blocker tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL. Serum total cholesterol (4.8 vs 5.7 mmol/L, p=0.003), LDL-c (2.9 vs 3.4 mmol/L, p=0.014) and high-density lipoprotein cholesterol (1.23 vs 1.52 mmol/L, p=0.006) increased following tocilizumab therapy. The LDL FCR fell from a state of hypercatabolism to a value approximating that of the normal population (0.53 vs 0.27 pools/day, p=0.006). Changes in FCR correlated tightly with changes in serum LDL-c and C-reactive protein but not Clinical Disease Activity Index. Patients with RA have low serum LDL-c due to hypercatabolism of LDL particles. IL-6 blockade normalises this catabolism in a manner associating with the acute phase response (and thus hepatic IL-6 signalling) but not with RA disease activity as measured clinically. We demonstrate that IL-6 is one of the key drivers of inflammation-driven dyslipidaemia. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  3. Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression.

    Science.gov (United States)

    Cheng, Chia-Wei; Adams, Gregor B; Perin, Laura; Wei, Min; Zhou, Xiaoying; Lam, Ben S; Da Sacco, Stefano; Mirisola, Mario; Quinn, David I; Dorff, Tanya B; Kopchick, John J; Longo, Valter D

    2014-06-05

    Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Branched-Chain Amino Acid Supplementation Reduces Oxidative Stress and Prolongs Survival in Rats with Advanced Liver Cirrhosis

    Science.gov (United States)

    Mifuji-Moroka, Rumi; Hara, Nagisa; Miyachi, Hirohide; Sugimoto, Ryosuke; Tanaka, Hideaki; Fujita, Naoki; Gabazza, Esteban C.; Takei, Yoshiyuki

    2013-01-01

    Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (PBCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver. PMID:23936183

  5. An e-health intervention designed to increase workday energy expenditure by reducing prolonged occupational sitting habits.

    Science.gov (United States)

    Pedersen, Scott J; Cooley, Paul D; Mainsbridge, Casey

    2014-01-01

    Desk-based employees face multiple workplace health hazards such as insufficient physical activity and prolonged sitting. The objective of this study was to increase workday energy expenditure by interrupting prolonged occupational sitting time and introducing short-bursts of physical activity to employees' daily work habits. Over a 13-week period participants (n=17) in the intervention group were regularly exposed to a passive prompt delivered through their desktop computer that required them to stand up and engage in a short-burst of physical activity, while the control group (n=17) was not exposed to this intervention. Instead, the control group continued with their normal work routine. All participants completed a pre- and post- intervention survey to estimate workplace daily energy expenditure (calories). There was a significant 2 (Group) × 2 (Test) interaction, F (1, 32)=9.26, p employee work-related energy expenditure. Engaging employees in regular short-bursts of physical activity during the workday resulted in reduced sitting time, which may have long-term effects on the improvement of employee health.

  6. Do Prolonged Prophylactic Antibiotics Reduce the Incidence of Surgical-Site Infections in Immediate Prosthetic Breast Reconstruction?

    Science.gov (United States)

    Wang, Frederick; Chin, Robin; Piper, Merisa; Esserman, Laura; Sbitany, Hani

    2016-12-01

    Approximately 50,000 women in the United States undergo mastectomy and immediate prosthetic breast reconstruction annually, and most receive postoperative prophylactic antibiotics. The effect of these antibiotics on the risk of surgical-site infections remains unclear. The authors searched the Medline, Embase, and Cochrane Library databases for studies that compared less than 24 hours and greater than 24 hours of antibiotics following immediate prosthetic breast reconstruction. Primary outcomes were surgical-site infections and implant loss. Conservative random effects models were used to obtain pooled relative risk estimates. The authors identified 927 studies, but only four cohort studies and one randomized controlled trial met their inclusion criteria. Unadjusted incidences of surgical-site infections were 14 percent with more than 24 hours of antibiotics, 19 percent with less than 24 hours of antibiotics, and 16 percent overall. Unadjusted incidences of implant loss were 8 percent with more than 24 hours of antibiotics, 10 percent with less than 24 hours of antibiotics, and 9 percent overall. The pooled relative risk of implant loss was 1.17 (95 percent CI, 0.39 to 3.6) with less than 24 hours of antibiotics, which was not statistically significant. Prolonged antibiotic use did not have a statistically significant effect on reducing surgical-site infections or implant loss. There was significant heterogeneity between studies, and prolonged antibiotics may have increased the risk of implant loss in the randomized controlled trial. Definitive evidence may only be obtained with data from more prospective randomized controlled trials.

  7. Selective blockade of B7-H3 enhances antitumour immune activity by reducing immature myeloid cells in head and neck squamous cell carcinoma.

    Science.gov (United States)

    Mao, Liang; Fan, Teng-Fei; Wu, Lei; Yu, Guang-Tao; Deng, Wei-Wei; Chen, Lei; Bu, Lin-Lin; Ma, Si-Rui; Liu, Bing; Bian, Yansong; Kulkarni, Ashok B; Zhang, Wen-Feng; Sun, Zhi-Jun

    2017-09-01

    Immature myeloid cells including myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) promote tumour growth and metastasis by facilitating tumour transformation and angiogenesis, as well as by suppressing antitumour effector immune responses. Therefore, strategies designed to reduce MDSCs and TAMs accumulation and their activities are potentially valuable therapeutic goals. In this study, we show that negative immune checkpoint molecule B7-H3 is significantly overexpressed in human head and neck squamous cell carcinoma (HNSCC) specimen as compared with normal oral mucosa. Using immunocompetent transgenic HNSCC models, we observed that targeting inhibition of B7-H3 reduced tumour size. Flow cytometry analysis revealed that targeting inhibition of B7-H3 increases antitumour immune response by decreasing immunosuppressive cells and promoting cytotoxic T cell activation in both tumour microenvironment and macroenvironment. Our study provides direct in vivo evidence for a rationale for B7-H3 blockade as a future therapeutic strategy to treat patients with HNSCC. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Lean Six Sigma to Reduce Intensive Care Unit Length of Stay and Costs in Prolonged Mechanical Ventilation.

    Science.gov (United States)

    Trzeciak, Stephen; Mercincavage, Michael; Angelini, Cory; Cogliano, William; Damuth, Emily; Roberts, Brian W; Zanotti, Sergio; Mazzarelli, Anthony J

    Patients with prolonged mechanical ventilation (PMV) represent important "outliers" of hospital length of stay (LOS) and costs (∼$26 billion annually in the United States). We tested the hypothesis that a Lean Six Sigma (LSS) approach for process improvement could reduce hospital LOS and the associated costs of care for patients with PMV. Before-and-after cohort study. Multidisciplinary intensive care unit (ICU) in an academic medical center. Adult patients admitted to the ICU and treated with PMV, as defined by diagnosis-related group (DRG). We implemented a clinical redesign intervention based on LSS principles. We identified eight distinct processes in preparing patients with PMV for post-acute care. Our clinical redesign included reengineering daily patient care rounds ("Lean ICU rounds") to reduce variation and waste in these processes. We compared hospital LOS and direct cost per case in patients with PMV before (2013) and after (2014) our LSS intervention. Among 259 patients with PMV (131 preintervention; 128 postintervention), median hospital LOS decreased by 24% during the intervention period (29 vs. 22 days, p < .001). Accordingly, median hospital direct cost per case decreased by 27% ($66,335 vs. $48,370, p < .001). We found that a LSS-based clinical redesign reduced hospital LOS and the costs of care for patients with PMV.

  9. Linking physiological and cellular responses to thermal stress: β-adrenergic blockade reduces the heat shock response in fish.

    Science.gov (United States)

    Templeman, Nicole M; LeBlanc, Sacha; Perry, Steve F; Currie, Suzanne

    2014-08-01

    When faced with stress, animals use physiological and cellular strategies to preserve homeostasis. We were interested in how these high-level stress responses are integrated at the level of the whole animal. Here, we investigated the capacity of the physiological stress response, and specifically the β-adrenergic response, to affect the induction of the cellular heat shock proteins, HSPs, following a thermal stress in vivo. We predicted that blocking β-adrenergic stimulation during an acute heat stress in the whole animal would result in reduced levels of HSPs in red blood cells (RBCs) of rainbow trout compared to animals where adrenergic signaling remained intact. We first determined that a 1 h heat shock at 25 °C in trout acclimated to 13 °C resulted in RBC adrenergic stimulation as determined by a significant increase in cell swelling, a hallmark of the β-adrenergic response. A whole animal injection with the β2-adrenergic antagonist, ICI-118,551, successfully reduced this heat-induced RBC swelling. The acute heat shock caused a significant induction of HSP70 in RBCs of 13 °C-acclimated trout as well as a significant increase in plasma catecholamines. When heat-shocked fish were treated with ICI-118,551, we observed a significant attenuation of the HSP70 response. We conclude that circulating catecholamines influence the cellular heat shock response in rainbow trout RBCs, demonstrating physiological/hormonal control of the cellular stress response.

  10. 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 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.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.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.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.

  11. A Pilot Study of Increasing Nonpurposeful Movement Breaks at Work as a Means of Reducing Prolonged Sitting

    Directory of Open Access Journals (Sweden)

    Dean Cooley

    2013-01-01

    Full Text Available There is a plethora of workplace physical activity interventions designed to increase purposeful movement, yet few are designed to alleviate prolonged occupational sitting time. A pilot study was conducted to test the feasibility of a workplace e-health intervention based on a passive approach to increase nonpurposeful movement as a means of reducing sitting time. The study was trialled in a professional workplace with forty-six participants (33 females and 13 males for a period of twenty-six weeks. Participants in the first thirteen weeks received a passive prompt every 45 minutes on their computer screen reminding them to stand and engage in nonpurposeful activity throughout their workday. After thirteen weeks, the prompt was disabled, and participants were then free to voluntary engage the software. Results demonstrated that when employees were exposed to a passive prompt, as opposed to an active prompt, they were five times more likely to fully adhere to completing a movement break every hour of the workday. Based on this pilot study, we suggest that the notion that people are willing to participate in a coercive workplace e-health intervention is promising, and there is a need for further investigation.

  12. Blockade of A2b Adenosine Receptor Reduces Tumor Growth and Immune Suppression Mediated by Myeloid-Derived Suppressor Cells in a Mouse Model of Melanoma

    Directory of Open Access Journals (Sweden)

    Raffaella Iannone

    2013-12-01

    Full Text Available The A2b receptor (A2bR belongs to the adenosine receptor family. Emerging evidence suggest that A2bR is implicated in tumor progression in some murine tumor models, but the therapeutic potential of targeting A2bR in melanoma has not been examined. This study first shows that melanoma-bearing mice treated with Bay 60-6583, a selective A2bR agonist, had increased melanoma growth. This effect was associated with higher levels of immune regulatory mediators interleukin-10 (IL-10 and monocyte chemoattractant protein 1 (MCP-1 and accumulation of tumor-associated CD11b positive Gr1 positive cells (CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs. Depletion of CD11b+Gr1+ cells completely reversed the protumor activity of Bay 60-6583. Conversely, pharmacological blockade of A2bR with PSB1115 reversed immune suppression in the tumor microenvironment, leading to a significant melanoma growth delay. PSB1115 treatment reduced both levels of IL-10 and MCP-1 and CD11b+Gr1+ cell number in melanoma lesions. These effects were associated with higher frequency of tumor-infiltrating CD8 positive (CD8+ T cells and natural killer T (NKT cells and increased levels of T helper 1 (Th1-like cytokines. Adoptive transfer of CD11b+Gr1+ cells abrogated the antitumor activity of PSB1115. These data suggest that the antitumor activity of PSB1115 relies on its ability to lower accumulation of tumor-infiltrating MDSCs and restore an efficient antitumor T cell response. The antitumor effect of PSB1115 was not observed in melanoma-bearing nude mice. Furthermore, PSB1115 enhanced the antitumor efficacy of dacarbazine. These data indicate that A2bR antagonists such as PSB1115 should be investigated as adjuvants in the treatment of melanoma.

  13. Electrocardiographic Screening for Prolonged QT Interval to Reduce Sudden Cardiac Death in Psychiatric Patients: A Cost-Effectiveness Analysis.

    Directory of Open Access Journals (Sweden)

    Antoine Poncet

    Full Text Available Sudden cardiac death is a leading cause of mortality in psychiatric patients. Long QT (LQT is common in this population and predisposes to Torsades-de-Pointes (TdP and subsequent mortality.To estimate the cost-effectiveness of electrocardiographic screening to detect LQT in psychiatric inpatients.We built a decision analytic model based on a decision tree to evaluate the cost-effectiveness and utility of LQT screening from a health care perspective. LQT proportion parameters were derived from an in-hospital cross-sectional study. We performed experts' elicitation to estimate the risk of TdP, given extent of QT prolongation. A TdP reduction of 65% after LQT detection was based on positive drug dechallenge rate and through adequate treatment and electrolyte adjustments. The base-case model uncertainty was assessed with one-way and probabilistic sensitivity analyses. Finally, the TdP related mortality and TdP avoidance parameters were varied in a two-way sensitivity analysis to assess their effect on the Incremental Cost-Effectiveness Ratio (ICER.Costs, Quality Ajusted Life Year (QALY, ICER, and probability of cost effectiveness thresholds ($ 10,000, $25,000, and $50,000 per QALY.In the base-case scenario, the numbers of patients needed to screen were 1128 and 2817 to avoid one TdP and one death, respectively. The ICER of systematic ECG screening was $8644 (95%CI, 3144-82 498 per QALY. The probability of cost-effectiveness was 96% at a willingness-to-pay of $50,000 for one QALY. In sensitivity analyses, results were sensitive to the case-fatality of TdP episodes and to the TdP reduction following the diagnosis of LQT.In psychiatric hospitals, performing systematic ECG screening at admission help reduce the number of sudden cardiac deaths in a cost-effective fashion.

  14. Pathological prolongation of action potential duration as a cause of the reduced alpha-adrenoceptor-mediated negative inotropy in streptozotocin-induced diabetic mice myocardium.

    Science.gov (United States)

    Kanae, Haruna; Hamaguchi, Shogo; Wakasugi, Yumi; Kusakabe, Taichi; Kato, Keisuke; Namekata, Iyuki; Tanaka, Hikaru

    2017-11-01

    Effect of pathological prolongation of action potential duration on the α-adrenoceptor-mediated negative inotropy was studied in streptozotocin-induced diabetic mice myocardium. In streptozotocin-treated mouse ventricular myocardium, which had longer duration of action potential than that in control mice, the negative inotropic response induced by phenylephrine was smaller than that in control mice. 4-Aminopyridine prolonged the action potential duration and decreased the negative inotropy in control mice. Cromakalim shortened the action potential duration and increased the negative inotropy in streptozotocin-treated mice. These results suggest that the reduced α-adrenoceptor-mediated inotropy in the diabetic mouse myocardium is partly due to its prolonged action potential. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  15. Coulomb Blockade Plasmonic Switch.

    Science.gov (United States)

    Xiang, Dao; Wu, Jian; Gordon, Reuven

    2017-04-12

    Tunnel resistance can be modulated with bias via the Coulomb blockade effect, which gives a highly nonlinear response current. Here we investigate the optical response of a metal-insulator-nanoparticle-insulator-metal structure and show switching of a plasmonic gap from insulator to conductor via Coulomb blockade. By introducing a sufficiently large charging energy in the tunnelling gap, the Coulomb blockade allows for a conductor (tunneling) to insulator (capacitor) transition. The tunnelling electrons can be delocalized over the nanocapacitor again when a high energy penalty is added with bias. We demonstrate that this has a huge impact on the plasmonic resonance of a 0.51 nm tunneling gap with ∼70% change in normalized optical loss. Because this structure has a tiny capacitance, there is potential to harness the effect for high-speed switching.

  16. Neurohumoral blockade in CHF management

    Directory of Open Access Journals (Sweden)

    Roland Willenbrock

    2000-03-01

    Full Text Available Is heart failure an endocrine disease? Historically, congestive heart failure (CHF has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors, gynaecomastia (with spironolactone and fatigue (with beta-blockers.New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT1-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT1-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP. Combined with its tight, long-lasting binding to AT1-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.

  17. Neuraxial blockade for external cephalic version: Cost analysis.

    Science.gov (United States)

    Yamasato, Kelly; Kaneshiro, Bliss; Salcedo, Jennifer

    2015-07-01

    Neuraxial blockade (epidural or spinal anesthesia/analgesia) with external cephalic version increases the external cephalic version success rate. Hospitals and insurers may affect access to neuraxial blockade for external cephalic version, but the costs to these institutions remain largely unstudied. The objective of this study was to perform a cost analysis of neuraxial blockade use during external cephalic version from hospital and insurance payer perspectives. Secondarily, we estimated the effect of neuraxial blockade on cesarean delivery rates. A decision-analysis model was developed using costs and probabilities occurring prenatally through the delivery hospital admission. Model inputs were derived from the literature, national databases, and local supply costs. Univariate and bivariate sensitivity analyses and Monte Carlo simulations were performed to assess model robustness. Neuraxial blockade was cost saving to both hospitals ($30 per delivery) and insurers ($539 per delivery) using baseline estimates. From both perspectives, however, the model was sensitive to multiple variables. Monte Carlo simulation indicated neuraxial blockade to be more costly in approximately 50% of scenarios. The model demonstrated that routine use of neuraxial blockade during external cephalic version, compared to no neuraxial blockade, prevented 17 cesarean deliveries for every 100 external cephalic versions attempted. Neuraxial blockade is associated with minimal hospital and insurer cost changes in the setting of external cephalic version, while reducing the cesarean delivery rate. © 2015 The Authors. Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

  18. Tetrodotoxin-Bupivacaine-Epinephrine Combinations for Prolonged Local Anesthesia

    Directory of Open Access Journals (Sweden)

    Christina Bognet

    2011-12-01

    Full Text Available Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL solutions, with or without epinephrine 5 µg/mL (1:200,000 in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001 or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001. Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.

  19. Improving Neuromuscular Monitoring and Reducing Residual Neuromuscular Blockade With E-Learning: Protocol for the Multicenter Interrupted Time Series INVERT Study.

    Science.gov (United States)

    Thomsen, Jakob Louis Demant; Mathiesen, Ole; Hägi-Pedersen, Daniel; Skovgaard, Lene Theil; Østergaard, Doris; Engbaek, Jens; Gätke, Mona Ring

    2017-10-06

    Muscle relaxants facilitate endotracheal intubation under general anesthesia and improve surgical conditions. Residual neuromuscular blockade occurs when the patient is still partially paralyzed when awakened after surgery. The condition is associated with subjective discomfort and an increased risk of respiratory complications. Use of an objective neuromuscular monitoring device may prevent residual block. Despite this, many anesthetists refrain from using the device. Efforts to increase the use of objective monitoring are time consuming and require the presence of expert personnel. A neuromuscular monitoring e-learning module might support consistent use of neuromuscular monitoring devices. The aim of the study is to assess the effect of a neuromuscular monitoring e-learning module on anesthesia staff's use of objective neuromuscular monitoring and the incidence of residual neuromuscular blockade in surgical patients at 6 Danish teaching hospitals. In this interrupted time series study, we are collecting data repeatedly, in consecutive 3-week periods, before and after the intervention, and we will analyze the effect using segmented regression analysis. Anesthesia departments in the Zealand Region of Denmark are included, and data from all patients receiving a muscle relaxant are collected from the anesthesia information management system MetaVision. We will assess the effect of the module on all levels of potential effect: staff's knowledge and skills, patient care practice, and patient outcomes. The primary outcome is use of neuromuscular monitoring in patients according to the type of muscle relaxant received. Secondary outcomes include last recorded train-of-four value, administration of reversal agents, and time to discharge from the postanesthesia care unit as well as a multiple-choice test to assess knowledge. The e-learning module was developed based on a needs assessment process, including focus group interviews, surveys, and expert opinions. The e

  20. Dietary Supplementation with the Microalga Galdieria sulphuraria (Rhodophyta Reduces Prolonged Exercise-Induced Oxidative Stress in Rat Tissues

    Directory of Open Access Journals (Sweden)

    Simona Carfagna

    2015-01-01

    Full Text Available We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion.

  1. Dietary supplementation with the microalga Galdieria sulphuraria (Rhodophyta) reduces prolonged exercise-induced oxidative stress in rat tissues.

    Science.gov (United States)

    Carfagna, Simona; Napolitano, Gaetana; Barone, Daniela; Pinto, Gabriele; Pollio, Antonino; Venditti, Paola

    2015-01-01

    We studied the effects of ten-day 1% Galdieria sulphuraria dietary supplementation on oxidative damage and metabolic changes elicited by acute exercise (6-hour swimming) determining oxygen consumption, lipid hydroperoxides, protein bound carbonyls in rat tissue (liver, heart, and muscle) homogenates and mitochondria, tissue glutathione peroxidase and glutathione reductase activities, glutathione content, and rates of H2O2 mitochondrial release. Exercise increased oxidative damage in tissues and mitochondria and decreased tissue content of reduced glutathione. Moreover, it increased State 4 and decreased State 3 respiration in tissues and mitochondria. G. sulphuraria supplementation reduced the above exercise-induced variations. Conversely, alga supplementation was not able to modify the exercise-induced increase in mitochondrial release rate of hydrogen peroxide and in liver and heart antioxidant enzyme activities. The alga capacity to reduce lipid oxidative damage without reducing mitochondrial H2O2 release can be due to its high content of C-phycocyanin and glutathione, which are able to scavenge peroxyl radicals and contribute to phospholipid hydroperoxide metabolism, respectively. In conclusion, G. sulphuraria ability to reduce exercise-linked oxidative damage and mitochondrial dysfunction makes it potentially useful even in other conditions leading to oxidative stress, including hyperthyroidism, chronic inflammation, and ischemia/reperfusion.

  2. Dynamic Succession of Groundwater Sulfate-Reducing Communities during Prolonged Reduction of Uranium in a Contaminated Aquifer

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Ping [Univ. of Oklahoma, Norman, OK (United States); He, Zhili [Univ. of Oklahoma, Norman, OK (United States); Van Nostrand, Joy D. [Univ. of Oklahoma, Norman, OK (United States); Qin, Yujia [Univ. of Oklahoma, Norman, OK (United States); Deng, Ye [Univ. of Oklahoma, Norman, OK (United States); Chinese Academy of Sciences (CAS), Beijing (China); Wu, Liyou [Univ. of Oklahoma, Norman, OK (United States); Tu, Qichao [Univ. of Oklahoma, Norman, OK (United States); Zhejiang Univ., Hangzhou (China); Wang, Jianjun [Univ. of Oklahoma, Norman, OK (United States); Chinese Academy of Sciences (CAS), Nanjing (China); Schadt, Christopher W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); W. Fields, Matthew [Montana State Univ., Bozeman, MT (United States); Hazen, Terry C. [Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Arkin, Adam P. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Stahl, David A. [Univ. of Washington, Seattle, WA (United States); Zhou, Jizhong [Univ. of Oklahoma, Norman, OK (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Tsinghua Univ., Beijing (China)

    2017-03-16

    To further understand the diversity and dynamics of SRB in response to substrate amendment, we sequenced in this paper genes coding for the dissimilatory sulfite reductase (dsrA) in groundwater samples collected after an emulsified vegetable oil (EVO) amendment, which sustained U(VI)-reducing conditions for one year in a fast-flowing aquifer. EVO amendment significantly altered the composition of groundwater SRB communities. Sequences having no closely related-described species dominated (80%) the indigenous SRB communities in nonamended wells. After EVO amendment, Desulfococcus, Desulfobacterium, and Desulfovibrio, known for long-chain-fatty-acid, short-chain-fatty-acid and H2 oxidation and U(VI) reduction, became dominant accounting for 7 ± 2%, 21 ± 8%, and 55 ± 8% of the SRB communities, respectively. Succession of these SRB at different bioactivity stages based on redox substrates/products (acetate, SO4–2, U(VI), NO3, Fe(II), and Mn(II)) was observed. Desulfovibrio and Desulfococcus dominated SRB communities at 4–31 days, whereas Desulfobacterium became dominant at 80–140 days. By the end of the experiment (day 269), the abundance of these SRB decreased but the overall diversity of groundwater SRB was still higher than non-EVO controls. Up to 62% of the SRB community changes could be explained by groundwater geochemical variables, including those redox substrates/products. A significant (P < 0.001) correlation was observed between groundwater U(VI) concentrations and Desulfovibrio abundance. Finally, our results showed that the members of SRB and their dynamics were correlated significantly with slow EVO biodegradation, electron donor production and maintenance of U(VI)-reducing conditions in the aquifer.

  3. Mao-to Prolongs the Survival of and Reduces TNF-α Expression in Mice with Viral Myocarditis

    Directory of Open Access Journals (Sweden)

    Zhu Shijie

    2010-01-01

    Full Text Available Goal of this study was to evaluate effects of Mao-to on development of myocarditis induced by encephalomyocarditis (EMC virus in mice. Mice were randomly divided into five groups. Group N included uninfected controls (n = 18, while group A, B and C underwent intraperitoneal injection of EMC virus. Group A was administered oral saline from day 0 to day 4. Group B was administered oral Mao-to (500 mg−1 kg−1 day−1 from day 0 to day 4. Group C was administered Mao-to from day 2 to day 6. Group D was administered Mao-to from day 5 to day 10. Treated mice were followed for survival rates during 2 weeks after infection. Body weight (BW and organ weights including heart (HW, lungs, thymus and spleen were examined on days 4, 6 and 14. Survival rate of group C (36.4% was significantly improved compared with group A, B or D (0% of each, P < 0.05. HW and HW/BW ratio in group C was significantly (P < 0.05 lower than those in group A, B or D. Viral titers of hearts were significantly different among groups A, B and C. Cardiac expression in tumor necrosis factor-α (TNF-α was significantly reduced in group C in comparison with group A, B or D on day 6 by immunohistochemical study. Administration of Mao-to starting on day 2 improves mortality resulting from viral myocarditis in mice with reduced expression of cardiac TNF-α. These findings suggest that timing of Mao-to is crucial for preventing cardiac damage in mice with viral myocarditis.

  4. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade

    OpenAIRE

    Mohamed B. Ezzelarab; Lien Lu; William F. Shufesky; Adrian E. Morelli; Adrian E. Morelli; Angus W. Thomson; Angus W. Thomson

    2018-01-01

    Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differ...

  5. Neuromuscular blockade in the elderly patient

    Directory of Open Access Journals (Sweden)

    Lee LA

    2016-06-01

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

  6. A hip abduction exercise prior to prolonged standing increased movement while reducing cocontraction and low back pain perception in those initially reporting low back pain.

    Science.gov (United States)

    Viggiani, Daniel; Callaghan, Jack P

    2016-12-01

    Persons who develop low back pain from prolonged standing exhibit increased muscle cocontraction, decreased movement and increased spine extension. However, it is unclear how these factors relate to pain development. The purpose of this study was to use hip abductor fatigue to manipulate muscle activity patterns and determine its effects on standing behaviours and pain development. Forty participants stood for two hours twice, once following a hip abductor fatigue exercise (fatigue), and once without exercise beforehand (control). Trunk and gluteal muscle activity were measured to determine cocontraction. Lumbo-pelvic angles and force plates were used to assess posture and movement strategies. Visual analog scales differentiated pain (PDs) and non-pain developers (NPDs). PDs reported less low back pain during the fatigue session, with females having earlier reductions of similar scale than males. The fatigue session reduced gluteal and trunk cocontraction and increased centre of pressure movement; male and female PDs had opposing spine posture compensations. Muscle fatigue prior to standing reduced cocontraction, increased movement during standing and reduced the low back pain developed by PDs; the timing of pain reductions depended on spine postures adopted during standing. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Interrupting prolonged sitting with brief bouts of light walking or simple resistance activities reduces resting blood pressure and plasma noradrenaline in type 2 diabetes.

    Science.gov (United States)

    Dempsey, Paddy C; Sacre, Julian W; Larsen, Robyn N; Straznicky, Nora E; Sethi, Parneet; Cohen, Neale D; Cerin, Ester; Lambert, Gavin W; Owen, Neville; Kingwell, Bronwyn A; Dunstan, David W

    2016-12-01

    Prolonged sitting is increasingly recognized as a ubiquitous cardiometabolic risk factor, possibly distinct from lack of physical exercise. We examined whether interrupting prolonged sitting with brief bouts of light-intensity activity reduced blood pressure (BP) and plasma noradrenaline in type 2 diabetes (T2D). In a randomized crossover trial, 24 inactive overweight/obese adults with T2D (14 men; mean ± SD; 62 ± 6 years) consumed standardized meals during 3 × 8 h conditions: uninterrupted sitting (SIT); sitting + half-hourly bouts of walking (3.2 km/h for 3-min) (light-intensity walking); and sitting + half-hourly bouts of simple resistance activities for 3 min (SRAs), each separated by 6-14 days washout. Resting seated BP was measured hourly (mean of three recordings, ≥20-min postactivity). Plasma noradrenaline was measured at 30-min intervals for the first hour after meals and hourly thereafter. Compared with SIT, mean resting SBP and DBP were significantly reduced (P light-intensity walking (mean ± SEM; -14 ± 1/-8 ± 1 mmHg) and SRA (-16 ± 1/-10 ± 1 mmHg), with a more pronounced effect for SRA (P light-intensity walking). Similarly, mean plasma noradrenaline was significantly reduced for both light-intensity walking (-0.3 ± 0.1 nmol/l) and SRA (-0.6 ± 0.1 nmol/l) versus SIT, with SRA lower than light-intensity walking (P light-intensity walking (-3 ± 1 bpm; P light-intensity walking or SRA reduces resting BP and plasma noradrenaline in adults with T2D, with SRA being more effective. Given the ubiquity of sedentary behaviors and poor adherence to structured exercise, this approach may have important implications for BP management in patients with T2D.

  8. Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.

    Science.gov (United States)

    Kwun, Jean; Farris, Alton B; Song, Hyunjin; Mahle, William T; Burlingham, William J; Knechtle, Stuart J

    2015-12-01

    Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.

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

    DEFF Research Database (Denmark)

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

    1976-01-01

    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 signif...... determinants for the exercise-induced glucagon secretion in man. It is suggested that decreased glucose availability enhances the secretion of glucagon and epinephrine during prolonged exercise....

  10. 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.

  11. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b+ Ly6Chi cells to tumor tissue reduces tumor growth

    International Nuclear Information System (INIS)

    Deronic, Adnan; Leanderson, Tomas; Ivars, Fredrik

    2016-01-01

    Previous work has demonstrated immunomodulatory, anti-tumor, anti-metastatic and anti-angiogenic effects of the small molecule quinoline-3-carboxamide tasquinimod in pre-clinical cancer models. To better understand the anti-tumor effects of tasquinimod in transplantable tumor models, we have evaluated the impact of the compound both on recruitment of myeloid cells to tumor tissue and on tumor-induced myeloid cell expansion as these cells are known to promote tumor development. Mice bearing subcutaneous 4 T1 mammary carcinoma tumors were treated with tasquinimod in the drinking water. A BrdU-based flow cytometry assay was utilized to assess the impact of short-term tasquinimod treatment on myeloid cell recruitment to tumors. Additionally, long-term treatment was performed to study the anti-tumor effect of tasquinimod as well as its effects on splenic myeloid cells and their progenitors. Myeloid cell populations were also immune-depleted by in vivo antibody treatment. Short-term tasquinimod treatment did not influence the proliferation of splenic Ly6C hi and Ly6G hi cells, but instead reduced the influx of Ly6C hi cells to the tumor. Treatment with tasquinimod for various periods of time after tumor inoculation revealed that the anti-tumor effect of this compound mainly operated during the first few days of tumor growth. Similar to tasquinimod treatment, antibody-mediated depletion of Ly6C hi cells within that same time frame, caused reduced tumor growth, thereby confirming a significant role for these cells in tumor development. Additionally, long-term tasquinimod treatment reduced the splenomegaly and expansion of splenic myeloid cells during a later phase of tumor development. In this phase, tasquinimod normalized the tumor-induced alterations in myeloerythroid progenitor cells in the spleen but had only limited impact on the same populations in the bone marrow. Our results indicate that tasquinimod treatment reduces tumor growth by operating early after tumor

  12. Autologous fibrin sealant reduces the incidence of prolonged air leak and duration of chest tube drainage after lung volume reduction surgery: a prospective randomized blinded study.

    Science.gov (United States)

    Moser, C; Opitz, I; Zhai, W; Rousson, V; Russi, E W; Weder, W; Lardinois, D

    2008-10-01

    Prolonged air leak is reported in up to 50% of patients after lung volume reduction surgery. The effect of an autologous fibrin sealant on the intensity and duration of air leak and on the time to chest drain removal after lung volume reduction surgery was investigated in a randomized prospective clinical trial. Twenty-five patients underwent bilateral thoracoscopic lung volume reduction surgery. In each patient, an autologous fibrin sealant was applied along the staple lines on one side, whereas no additional measure was taken on the other side. Randomization of treatment was performed at the end of the resection on the first side. Air leak was assessed semiquantitatively by use of a severity score (0 = no leak; 4 = continuous severe leak) by two investigators blinded to the treatment. Mean value of the total severity scores for the first 48 hours postoperative was significantly lower in the treated group (4.7 +/- 7.7) than in the control group (16.0 +/- 10.1) (P drainage were also significantly reduced after application of the sealant (4.5% and 2.8 +/- 1.9 days versus 31.8% and 5.9 +/- 2.9 days) (P = .03 and P drainage.

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

    DEFF Research Database (Denmark)

    Brueckmann, B; Sasaki, N; Grobara, P

    2015-01-01

    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...... 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...... measured at PACU entry. Zero out of 74 sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch® SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], P

  14. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo.

    Science.gov (United States)

    Koo, G C; Blake, J T; Talento, A; Nguyen, M; Lin, S; Sirotina, A; Shah, K; Mulvany, K; Hora, D; Cunningham, P; Wunderler, D L; McManus, O B; Slaughter, R; Bugianesi, R; Felix, J; Garcia, M; Williamson, J; Kaczorowski, G; Sigal, N H; Springer, M S; Feeney, W

    1997-06-01

    The voltage activated K+ channel (Kv1.3) has recently been identified as the molecule that sets the resting membrane potential of peripheral human T lymphoid cells. In vitro studies indicate that blockage of Kv1.3 inhibits T cell activation, suggesting that Kv1.3 may be a target for immunosuppression. However, despite the in vitro evidence, there has been no in vivo demonstration that blockade of Kv1.3 will attenuate an immune response. The difficulty is due to species differences, as the channel does not set the membrane potential in rodent peripheral T cells. In this study, we show that the channel is present on peripheral T cells of miniswine. Using the peptidyl Kv1.3 inhibitor, margatoxin, we demonstrate that Kv1.3 also regulates the resting membrane potential, and that blockade of Kv1.3 inhibits, in vivo, both a delayed-type hypersensitivity reaction and an Ab response to an allogeneic challenge. In addition, prolonged Kv1.3 blockade causes reduced thymic cellularity and inhibits the thymic development of T cell subsets. These results provide in vivo evidence that Kv1.3 is a novel target for immunomodulation.

  15. A New Approach: Regional Nerve Blockade for Angioplasty of the Lower Limb

    International Nuclear Information System (INIS)

    Marcus, A.J.; Lotzof, K.; Kamath, B.S.K.; Shanthakumar, R.E.; Munir, N.; Loh, A.; Bird, R.; Howard, A.

    2006-01-01

    Purpose. An audit study investigated the pilot use of regional nerve block analgesia (as an alternative to sedative/opiate, general or central neuraxial anesthesia) performed by radiologists with the assistance of imaging techniques during complex prolonged angiography. Methods. Radiologists were trained by anesthetic consultants to administer and use lower limb peripheral nerve block for difficult prolonged angioplasty procedures for patients with severe lower limb rest pain who were unable to lie in the supine position. In a pilot study 25 patients with limb-threatening ischemia received sciatic and femoral nerve blockade for angioplasty. The technique was developed and perfected in 12 patients and in a subsequent 13 patients the details of the angiography procedures, peripheral anesthesia, supplementary analgesia, complications, and pain assessment scores were recorded. Pain scores were also recorded in 11 patients prior to epidural/spinal anesthesia for critical ischemic leg angioplasty. Results. All patients with peripheral nerve blockade experienced a reduction in their ischemic rest pain to a level that permitted angioplasty techniques to be performed without spinal, epidural or general analgesia. In patients undergoing complex angioplasty intervention, the mean pain score by visual analogue scale was 3.7, out of a maximum score of 10. Conclusions. The successful use of peripheral nerve blocks was safe and effective as an alternative to sedative/opiate, epidural or general anesthesia in patients undergoing complex angiography and has optimized the use of radiological and anesthetic department resources. This has permitted the frequent radiological treatment of patients with limb-threatening ischemia and reduced delays caused by the difficulty in enlisting the help of anesthetists, often at short notice, from the busy operating lists

  16. Interaction of antibiotics on pipecuronium-induced neuromuscular blockade.

    Science.gov (United States)

    de Gouw, N E; Crul, J F; Vandermeersch, E; Mulier, J P; van Egmond, J; Van Aken, H

    1993-01-01

    To measure the interaction of two antibiotics (clindamycin and colistin) on neuromuscular blockade induced by pipecuronium bromide (a new long-acting, steroidal, nondepolarizing neuromuscular blocking drug). Prospective, randomized, placebo-controlled study. Inpatient gynecologic and gastroenterologic service at a university medical center. Three groups of 20 ASA physical status I and II patients with normal kidney and liver function, taking no medication, and undergoing elective surgery under general anesthesia. Anesthesia was induced with propofol and alfentanil intravenously (IV) and maintained with a propofol infusion and 60% nitrous oxide in oxygen. Pipecuronium bromide 50 micrograms/kg was administered after reaching a stable baseline of single-twitch response. At 25% recovery of pipecuronium-induced neuromuscular blockade, patients received one of two antibiotics, clindamycin 300 mg or colistin 1 million IU, or a placebo. The recovery index (RI, defined as time from 25% to 75% recovery of neuromuscular blockade) was measured using the single-twitch response of the adductor pollicis muscle with supramaximal stimulation of the ulnar nerve at the wrist. RI after administration of an antibiotic (given at 25% recovery) was measured and compared with RI of the control group using Student's unpaired t-test. Statistical analyses of the results showed a significant prolongation of the recovery time (from 25% to 75% recovery) of 40 minutes for colistin. When this type of antibiotic is used during anesthesia with pipercuronium as a muscle relaxant, one must be aware of a significant prolongation of an already long-acting neuromuscular blockade and (although not observed in this study) possible problems in antagonism.

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

    DEFF Research Database (Denmark)

    Jenstrup, M T; Jæger, P; Lund, J

    2012-01-01

    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 hypothe...... 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.......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...

  18. Management of prolonged pregnancy

    International Nuclear Information System (INIS)

    Iqbal, S.

    2004-01-01

    Objective: To compare two strategies for management of prolonged pregnancy (= or >294 days) i.e. induction (intervention) versus expectant management (non-intervention) and evaluate the associated feto-maternal risks. Subjects and Methods: One hundred cases of uncomplicated prolonged gestation were selected. The gestational age was confirmed by ultrasound in first trimester. One group (50 patients) was managed by intervention i.e. induction of labour (group A) and other group (50 patients) by non-intervention i.e. expectant management (group B). In group A intervention was done at 42 weeks. In expectant group, the methods of monitoring were fetal kick charting recorded daily by the patient, and ultrasound for amniotic fluid index. The biophysical profile score and NST (non stress test) were performed once a week till 42 weeks and then twice weekly. Results: The frequency of prolonged pregnancy was found to be 10.9%. There was no significant difference in the number of spontaneous vaginal deliveries between the two groups. The rate of LSCS (lower segment caesarean section) was higher in intervention group ( 30% versus 18% ). The neonatal depression at birth was more in group B ( 10% versus 4%) and at 5 minutes almost same between two groups (4% versus 2%). There were 11 cases of meconium aspiration syndrome, leading to one neonatal death. Among nine perinatal deaths two were neonatal deaths. Seven cases of intrauterine deaths in which antepartum deaths occurred because of non compliance of patients. No cause could be detected for the other three fetuses. Conclusion: There was increased LSCS rate in group A. However in expectant group B perinatal mortality was about twice more as compared to intervention group. Active early intervention at 42 weeks is warranted to reduce perinatal morbidity and mortality. (author)

  19. Intractable diarrhea in hyperthyroidism: management with beta-adrenergic blockade.

    Science.gov (United States)

    Bricker, L A; Such, F; Loehrke, M E; Kavanaugh, K

    2001-01-01

    To describe a patient with intractable diarrhea and thyrotoxic Graves' disease, for whom b-adrenergic blockade ultimately proved to be effective therapy for the diarrhea, and to review the types of hyperthyroidism-associated diarrhea. We present the clinical course of a young man with a prolonged siege of diarrhea that proved elusive to diagnostic inquiries and resistant to all means of management until its endocrine basis was discovered. Control of such cases with b-adrenergic blockade is discussed, as are the pathophysiologic bases of intestinal hypermotility in hyperthyroidism. A 26-year-old man with Down syndrome, and no prior gastrointestinal disorder, had insidious, chronic, constant diarrhea, which was associated with loss of 14 kg during a 5-month period. Numerous laboratory and imaging studies and endoscopic examinations failed to disclose the cause of the diarrhea. Furthermore, a broad range of antibiotics and other empiric remedies failed to control the problem. No other symptoms of hyperthyroidism were reported, but when the endocrinopathy was suspected and identified, the diarrhea was promptly controlled by treatment with propranolol. In patients with hyperthyroidism, two types of diarrheal disorders have been described-secretory diarrhea and steatorrhea; bile acid malabsorption may have a role in either of these settings. In addition to its capacity for blocking the peripheral effects of thyroid hormone on the heart and central nervous system, b-adrenergic blockade is effective in slowing intestinal transit time and ameliorating the uncommon diarrhea associated with hyperthyroidism. Thyroid hormone in excess, among its other possible effects on the gastrointestinal tract, may exert a stimulatory effect by means of intermediary sympathetic activation, as it does with the heart. Thus, sympathetic blockade can mimic the salutary effects on the gastrointestinal tract conventionally brought about by direct antithyroid therapy, and well before the

  20. Coulomb blockade induced by magnetic field

    International Nuclear Information System (INIS)

    Kusmartsev, F.V.

    1992-01-01

    In this paper, the authors found that a Coulomb blockade can be induced by magnetic field. The authors illustrated this effect on the example of a ring consisting of two and many Josephson junctions. For the ring with two junctions we present an exact solution. The transition into Coulomb blockade state on a ring transforms into a linear array of Josephson junctions, although in latter case the effect of magnetic field disappears. In the state of Coulomb blockade the magnetization may be both diamagnetic and paramagnetic. The Coulomb blockade may also be removed by external magnetic field

  1. Renin-angiotensin system blockade therapy after transcatheter aortic valve implantation.

    Science.gov (United States)

    Ochiai, Tomoki; Saito, Shigeru; Yamanaka, Futoshi; Shishido, Koki; Tanaka, Yutaka; Yamabe, Tsuyoshi; Shirai, Shinichi; Tada, Norio; Araki, Motoharu; Naganuma, Toru; Watanabe, Yusuke; Yamamoto, Masanori; Hayashida, Kentaro

    2018-04-01

    The persistence of left ventricular (LV) hypertrophy is associated with poor clinical outcomes after transcatheter aortic valve implantation (TAVI) for aortic stenosis. However, the optimal medical therapy after TAVI remains unknown. We investigated the effect of renin-angiotensin system (RAS) blockade therapy on LV hypertrophy and mortality in patients undergoing TAVI. Between October 2013 and April 2016, 1215 patients undergoing TAVI were prospectively enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry. This cohort was stratified according to the postoperative usage of RAS blockade therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Patients with at least two prescriptions dispensed 180 days apart after TAVI and at least a 6-month follow-up constituted the RAS blockade group (n=371), while those not prescribed any ACE inhibitors or ARBs after TAVI were included in the no RAS blockade group (n=189). At 6 months postoperatively, the RAS blockade group had significantly greater LV mass index regression than the no RAS blockade group (-9±24% vs -2±25%, p=0.024). Kaplan-Meier analysis revealed a significantly lower cumulative 2-year mortality in the RAS blockade than that in the no RAS blockade group (7.5% vs 12.5%; log-rank test, p=0.031). After adjusting for confounding factors, RAS blockade therapy was associated with significantly lower all-cause mortality (HR, 0.45; 95% CI 0.22 to 0.91; p=0.025). Postoperative RAS blockade therapy is associated with greater LV mass index regression and reduced all-cause mortality. These data need to be confirmed by a prospective randomised controlled outcome trial. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  2. Resistance to bleomycin in cancer cell lines is characterized by prolonged doubling time, reduced DNA damage and evasion of G2/M arrest and apoptosis.

    Directory of Open Access Journals (Sweden)

    Qi Wang

    Full Text Available To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines.Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352% in BLM-resistant sub-clones (p<0.05 for both. Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05. Significantly reduced DNA damage (COMET and γ-H2AX assays, G2/M arrest, and apoptosis (p<0.05 for each set of comparison following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05.Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis.

  3. Neuraxial blockade for external cephalic version: a systematic review.

    Science.gov (United States)

    Sultan, P; Carvalho, B

    2011-10-01

    The desire to decrease the number of cesarean deliveries has renewed interest in external cephalic version. The rationale for using neuraxial blockade to facilitate external cephalic version is to provide abdominal muscular relaxation and reduce patient discomfort during the procedure, so permitting successful repositioning of the fetus to a cephalic presentation. This review systematically examined the current evidence to determine the safety and efficacy of neuraxial anesthesia or analgesia when used for external cephalic version. A systematic literature review of studies that examined success rates of external cephalic version with neuraxial anesthesia was performed. Published articles written in English between 1945 and 2010 were identified using the Medline, Cochrane, EMBASE and Web of Sciences databases. Six, randomized controlled studies were identified. Neuraxial blockade significantly improved the success rate in four of these six studies. A further six non-randomized studies were identified, of which four studies with control groups found that neuraxial blockade increased the success rate of external cephalic version. Despite over 850 patients being included in the 12 studies reviewed, placental abruption was reported in only one patient with a neuraxial block, compared with two in the control groups. The incidence of non-reassuring fetal heart rate requiring cesarean delivery in the anesthesia groups was 0.44% (95% CI 0.15-1.32). Neuraxial blockade improved the likelihood of success during external cephalic version, although the dosing regimen that provides optimal conditions for successful version is unclear. Anesthetic rather than analgesic doses of local anesthetics may improve success. The findings suggest that neuraxial blockade does not compromise maternal or fetal safety during external cephalic version. Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.

  4. Acute effects of beta blockade and exercise on mood and anxiety.

    Science.gov (United States)

    Head, A; Kendall, M J; Ferner, R; Eagles, C

    1996-09-01

    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. 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. Compared to placebo, resting "tension", "depression", and "total mood disturbance" were significantly higher on propranolol 80 mg, but all were reduced with exercise. "Fatigue" and "confusion" were also higher on propranolol, and were unaffected by exercise. "Fatigue" was also higher than placebo after exercise on metoprolol 100 mg. "Anxiety" was unaffected by drug treatment or exercise. The evidence that beta blockers, and particularly propranolol, have adverse effects on mood was confirmed. It would be preferable to prescribe a beta blocker which does not adversely alter mood states. However, exercise significantly reduced the measures of "tension" and "depression" which were adversely increased by propranolol. Exercise prescription may therefore not only be compatible with beta blockade, but a highly desirable adjuvant therapy.

  5. Detecting phonon blockade with photons

    International Nuclear Information System (INIS)

    Didier, Nicolas; Pugnetti, Stefano; Fazio, Rosario; Blanter, Yaroslav M.

    2011-01-01

    Measuring the quantum dynamics of a mechanical system, when few phonons are involved, remains a challenge. We show that a superconducting microwave resonator linearly coupled to the mechanical mode constitutes a very powerful probe for this scope. This new coupling can be much stronger than the usual radiation pressure interaction by adjusting a gate voltage. We focus on the detection of phonon blockade, showing that it can be observed by measuring the statistics of the light in the cavity. The underlying reason is the formation of an entangled state between the two resonators. Our scheme realizes a phonotonic Josephson junction, giving rise to coherent oscillations between phonons and photons as well as a self-trapping regime for a coupling smaller than a critical value. The transition from the self-trapping to the oscillating regime is also induced dynamically by dissipation.

  6. Contemporary views on the lawfulness of naval blockades

    NARCIS (Netherlands)

    Fink, M.D.

    2011-01-01

    The traditional law of blockade has several technical requirements that if not met renders a blockade unlawful. These traditional requirements balance the interests of the belligerent and neutrals. A more contemporary view on the law of blockade, however, emphasizes that blockades are also subject

  7. Deep Neuromuscular Blockade Improves Laparoscopic Surgical Conditions

    DEFF Research Database (Denmark)

    Rosenberg, Jacob; Herring, W Joseph; Blobner, Manfred

    2017-01-01

    INTRODUCTION: Sustained deep neuromuscular blockade (NMB) during laparoscopic surgery may facilitate optimal surgical conditions. This exploratory study assessed whether deep NMB improves surgical conditions and, in doing so, allows use of lower insufflation pressures during laparoscopic cholecys...

  8. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Adachi, Takaomi; Sugiyama, Noriyuki; Gondai, Tatsuro; Yagita, Hideo; Yokoyama, Takahiko

    2013-01-01

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  9. Effects of sugammadex on incidence of postoperative residual neuromuscular blockade: a randomized, controlled study.

    Science.gov (United States)

    Brueckmann, B; Sasaki, N; Grobara, P; Li, M K; Woo, T; de Bie, J; Maktabi, M; Lee, J; Kwo, J; Pino, R; Sabouri, A S; McGovern, F; Staehr-Rye, A K; Eikermann, M

    2015-11-01

    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. Adult patients undergoing abdominal surgery received rocuronium, followed 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 neuromuscular blockade at PACU admission, defined as a train-of-four (TOF) ratio sugammadex patients and 33 out of 76 (43.4%) usual care patients had TOF-Watch SX-assessed residual neuromuscular blockade at PACU admission (odds ratio 0.0, 95% CI [0-0.06], Psugammadex vs usual care (14.7 vs. 18.6 min respectively; P=0.02). After abdominal surgery, sugammadex reversal eliminated residual neuromuscular blockade in the PACU, and shortened the time from start of study medication administration to the time the patient was ready for discharge from the operating room. Clinicaltrials.gov:NCT01479764. © The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  10. Exhaustion from prolonged gambling

    Directory of Open Access Journals (Sweden)

    Fatimah Lateef

    2013-01-01

    Full Text Available Complaints of fatigue and physical exhaustion are frequently seen in the acute medical setting, especially amongst athletes, army recruits and persons involved in strenuous and exertional physical activities. Stress-induced exhaustion, on the other hand, is less often seen, but can present with very similar symptoms to physical exhaustion. Recently, three patients were seen at the Department of Emergency Medicine, presenting with exhaustion from prolonged involvement in gambling activities. The cases serve to highlight some of the physical consequences of prolonged gambling.

  11. Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation.

    Science.gov (United States)

    Bald, Tobias; Landsberg, Jennifer; Lopez-Ramos, Dorys; Renn, Marcel; Glodde, Nicole; Jansen, Philipp; Gaffal, Evelyn; Steitz, Julia; Tolba, Rene; Kalinke, Ulrich; Limmer, Andreas; Jönsson, Göran; Hölzel, Michael; Tüting, Thomas

    2014-06-01

    Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell-poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4(R24C) mice, which imitate human immune cell-poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies. Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell-poor tumors to cellular immune surveillance. ©2014 American Association for Cancer Research.

  12. [Pathophysiology of prolonged hypokinesia].

    Science.gov (United States)

    Kovalenko, E A

    1976-01-01

    Hypokinesia is an important problem in modern medicine. In the pathogenetic effect of prolonged hypokinesia the main etiological factor is diminished motor activity; of major importance are disorders in the energy and plastic metabolism which affect the muscle system; the contributing factors are cardiovascular deconditioning and orthostatic intolerance. This is attributed to a decreased oxygen supply and eliminated hydrostatic influences during a prolonged recumbency. Blood redistribution in the vascular bed is related to the Gauer-Henry reflex and subsequent changes in the fluid-electrolyte balance. Decreased load on the bone system induces changes in the protein-phosphate-calcium metabolism, diminished bone density and increased calcium content in the blood and urine. Changes in the calcium metabolism are systemic. The activity of the higher nervous system and reflex functions is lowered. Changes in the function of the autonomic nervous system which include a noticeable decline of its adaptive-trophic role as a result of the decrease of afferent and efferent impulsation are of great importance. Changes in the hormonal function involve a peculiar stress-reaction which develops at an early stage of hypokinesia as a response to an unusual situation. Prolonged hypokinesia may result in a disturbed function of the pituitary-adrenal system. It is assumed that prolonged hypokinesia may induce a specific disease of hypokinesia during which man cannot lead a normal mode of life and work.

  13. 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

    2012-01-01

    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...... (primary end point) and at rest, as well as reducing morphine consumption and morphine-related side effects (secondary outcomes) compared with placebo....

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

    Science.gov (United States)

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

    2014-12-01

    Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and nonmalignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in patients with bone cancer. Using a mouse graft model of bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced bone destruction, delayed time to bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck cancer, early blockade of NGF reduced weight loss in mice with bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40% to 70%, depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late-stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to bone may help preserve the integrity and use, delay the time to tumor-induced bone fracture, and maintain body weight. ©2014 American Association for Cancer Research.

  15. Sugammadex: A Review of Neuromuscular Blockade Reversal.

    Science.gov (United States)

    Keating, Gillian M

    2016-07-01

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

  16. Effects of angiotensin II receptor blockade on cerebral, cardiovascular, counter-regulatory, and symptomatic responses during hypoglycaemia in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Færch, Louise H; Thorsteinsson, Birger; Tarnow, Lise

    2015-01-01

    INTRODUCTION: High spontaneous activity of the renin-angiotensin system (RAS) results in more pronounced cognitive impairment and more prolonged QTc interval during hypoglycaemia in type 1 diabetes. We tested whether angiotensin II receptor blockade improves cerebral and cardiovascular function d...

  17. Coulomb Blockade of Tunnel-Coupled Quantum Dots

    National Research Council Canada - National Science Library

    Golden, John

    1997-01-01

    .... Though classical charging models can explain the Coulomb blockade of an isolated dot, they must be modified to explain the Coulomb blockade of dots coupled through the quantum mechanical tunneling of electrons...

  18. Objective neuromuscular monitoring of neuromuscular blockade in Denmark

    DEFF Research Database (Denmark)

    Söderström, C M; Eskildsen, K Z; Gätke, M R

    2017-01-01

    BACKGROUND: Neuromuscular blocking agents are commonly used during general anaesthesia but can lead to postoperative residual neuromuscular blockade and associated morbidity. With appropriate objective neuromuscular monitoring (objNMM) residual blockade can be avoided. In this survey, we investig...

  19. Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaine

    NARCIS (Netherlands)

    Stevens, M. F.; Hoppe, M.; Holthusen, H.; Lipfert, P.

    2004-01-01

    BACKGROUND: In isolated nerves, tetrodotoxin (TTX) blocks nerve conduction longer than bupivacaine. In vivo, however, both substances block nerve conduction to an equal duration, presumably because the hydrophilic TTX binds only weakly to the perineural tissue. High molecular weight hyaluronic acid

  20. Profile of sugammadex for reversal of neuromuscular blockade in the elderly: current perspectives.

    Science.gov (United States)

    Carron, Michele; Bertoncello, Francesco; Ieppariello, Giovanna

    2018-01-01

    The number of elderly patients is increasing worldwide. This will have a significant impact on the practice of anesthesia in future decades. Anesthesiologists must provide care for an increasing number of elderly patients, who have an elevated risk of perioperative morbidity and mortality. Complications related to postoperative residual neuromuscular blockade, such as muscle weakness, airway obstruction, hypoxemia, atelectasis, pneumonia, and acute respiratory failure, are more frequent in older than in younger patients. Therefore, neuromuscular blockade in the elderly should be carefully monitored and completely reversed before awakening patients at the end of anesthesia. Acetylcholinesterase inhibitors are traditionally used for reversal of neuromuscular blockade. Although the risk of residual neuromuscular blockade is reduced by reversal with neostigmine, it continues to complicate the postoperative course. Sugammadex represents an innovative approach to reversal of neuromuscular blockade induced by aminosteroid neuromuscular-blocking agents, particularly rocuronium, with useful applications in clinical practice. However, aging is associated with certain changes in the pharmacokinetics of sugammadex, and to date there has been no thorough evaluation of the use of sugammadex in elderly patients. The aim of this review was to perform an analysis of the use of sugammadex in older adults based on the current literature. Major issues surrounding the physiologic and pharmacologic effects of aging in elderly patients and how these may impact the routine use of sugammadex in elderly patients are discussed.

  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

    2011-01-01

    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...

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

    DEFF Research Database (Denmark)

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

    2002-01-01

    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....

  3. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    OpenAIRE

    Arvind Chaturvedi; H H Dash

    2011-01-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and...

  4. Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

    Science.gov (United States)

    Sade-Feldman, Moshe; Jiao, Yunxin J; Chen, Jonathan H; Rooney, Michael S; Barzily-Rokni, Michal; Eliane, Jean-Pierre; Bjorgaard, Stacey L; Hammond, Marc R; Vitzthum, Hans; Blackmon, Shauna M; Frederick, Dennie T; Hazar-Rethinam, Mehlika; Nadres, Brandon A; Van Seventer, Emily E; Shukla, Sachet A; Yizhak, Keren; Ray, John P; Rosebrock, Daniel; Livitz, Dimitri; Adalsteinsson, Viktor; Getz, Gad; Duncan, Lyn M; Li, Bo; Corcoran, Ryan B; Lawrence, Donald P; Stemmer-Rachamimov, Anat; Boland, Genevieve M; Landau, Dan A; Flaherty, Keith T; Sullivan, Ryan J; Hacohen, Nir

    2017-10-26

    Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

  5. The effect of α1 -adrenergic blockade on post-exercise brachial artery flow-mediated dilatation at sea level and high altitude.

    Science.gov (United States)

    Tymko, Michael M; Tremblay, Joshua C; Hansen, Alex B; Howe, Connor A; Willie, Chris K; Stembridge, Mike; Green, Daniel J; Hoiland, Ryan L; Subedi, Prajan; Anholm, James D; Ainslie, Philip N

    2017-03-01

    Our objective was to quantify endothelial function (via brachial artery flow-mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate-intensity cycling exercise with and without administration of an α 1 -adrenergic blockade. Brachial endothelial function did not differ between sea level and high altitude at rest, nor following maximal exercise. At sea level, endothelial function decreased following 30 min of moderate-intensity exercise, and this decrease was abolished with α 1 -adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate-intensity exercise, and administration of α 1 -adrenergic blockade resulted in an increase in flow-mediated dilatation. Our data indicate that post-exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high-altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function. We examined the hypotheses that (1) at rest, endothelial function would be impaired at high altitude compared to sea level, (2) endothelial function would be reduced to a greater extent at sea level compared to high altitude after maximal exercise, and (3) reductions in endothelial function following moderate-intensity exercise at both sea level and high altitude are mediated via an α 1 -adrenergic pathway. In a double-blinded, counterbalanced, randomized and placebo-controlled design, nine healthy participants performed a maximal-exercise test, and two 30 min sessions of semi-recumbent cycling exercise at 50% peak output following either placebo or α 1 -adrenergic blockade (prazosin; 0.05 mg kg  -1 ). These experiments were completed at both sea-level (344 m) and high altitude (3800 m). Blood pressure (finger photoplethysmography

  6. The effect of α1‐adrenergic blockade on post‐exercise brachial artery flow‐mediated dilatation at sea level and high altitude

    Science.gov (United States)

    Tremblay, Joshua C.; Hansen, Alex B.; Howe, Connor A.; Willie, Chris K.; Stembridge, Mike; Green, Daniel J.; Hoiland, Ryan L.; Subedi, Prajan; Anholm, James D.; Ainslie, Philip N.

    2016-01-01

    Key points Our objective was to quantify endothelial function (via brachial artery flow‐mediated dilatation) at sea level (344 m) and high altitude (3800 m) at rest and following both maximal exercise and 30 min of moderate‐intensity cycling exercise with and without administration of an α1‐adrenergic blockade.Brachial endothelial function did not differ between sea level and high altitude at rest, nor following maximal exercise.At sea level, endothelial function decreased following 30 min of moderate‐intensity exercise, and this decrease was abolished with α1‐adrenergic blockade. At high altitude, endothelial function did not decrease immediately after 30 min of moderate‐intensity exercise, and administration of α1‐adrenergic blockade resulted in an increase in flow‐mediated dilatation.Our data indicate that post‐exercise endothelial function is modified at high altitude (i.e. prolonged hypoxaemia). The current study helps to elucidate the physiological mechanisms associated with high‐altitude acclimatization, and provides insight into the relationship between sympathetic nervous activity and vascular endothelial function. Abstract We examined the hypotheses that (1) at rest, endothelial function would be impaired at high altitude compared to sea level, (2) endothelial function would be reduced to a greater extent at sea level compared to high altitude after maximal exercise, and (3) reductions in endothelial function following moderate‐intensity exercise at both sea level and high altitude are mediated via an α1‐adrenergic pathway. In a double‐blinded, counterbalanced, randomized and placebo‐controlled design, nine healthy participants performed a maximal‐exercise test, and two 30 min sessions of semi‐recumbent cycling exercise at 50% peak output following either placebo or α1‐adrenergic blockade (prazosin; 0.05 mg kg −1). These experiments were completed at both sea‐level (344 m) and high altitude (3800

  7. Efficient Multiparticle Entanglement via Asymmetric Rydberg Blockade

    DEFF Research Database (Denmark)

    Saffman, Mark; Mølmer, Klaus

    2009-01-01

    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 t....... 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.......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...

  8. Profile of sugammadex for reversal of neuromuscular blockade in the elderly: current perspectives

    Directory of Open Access Journals (Sweden)

    Carron M

    2017-12-01

    Full Text Available Michele Carron, Francesco Bertoncello, Giovanna Ieppariello Department of Medicine, Anesthesiology, and Intensive Care, University of Padova, Padua, Italy Abstract: The number of elderly patients is increasing worldwide. This will have a significant impact on the practice of anesthesia in future decades. Anesthesiologists must provide care for an increasing number of elderly patients, who have an elevated risk of perioperative morbidity and mortality. Complications related to postoperative residual neuromuscular blockade, such as muscle weakness, airway obstruction, hypoxemia, atelectasis, pneumonia, and acute respiratory failure, are more frequent in older than in younger patients. Therefore, neuromuscular blockade in the elderly should be carefully monitored and completely reversed before awakening patients at the end of anesthesia. Acetylcholinesterase inhibitors are traditionally used for reversal of neuromuscular blockade. Although the risk of residual neuromuscular blockade is reduced by reversal with neostigmine, it continues to complicate the postoperative course. Sugammadex represents an innovative approach to reversal of neuromuscular blockade induced by aminosteroid neuromuscular-blocking agents, particularly rocuronium, with useful applications in clinical practice. However, aging is associated with certain changes in the pharmacokinetics of sugammadex, and to date there has been no thorough evaluation of the use of sugammadex in elderly patients. The aim of this review was to perform an analysis of the use of sugammadex in older adults based on the current literature. Major issues surrounding the physiologic and pharmacologic effects of aging in elderly patients and how these may impact the routine use of sugammadex in elderly patients are discussed. Keywords: sugammadex, aging, elderly, neuromuscular blockade, rocuronium, anesthesia, safety

  9. Endothelin-A receptor blockade slows the progression of renal injury in experimental renovascular disease.

    Science.gov (United States)

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

    2011-07-01

    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.

  10. Comparison of peripheral nerve blockade characteristics between non-diabetic patients and patients suffering from diabetic neuropathy: a prospective cohort study.

    Science.gov (United States)

    Baeriswyl, M; Taffé, P; Kirkham, K R; Bathory, I; Rancati, V; Crevoisier, X; Cherix, S; Albrecht, E

    2018-06-02

    Animal data have demonstrated increased block duration after local anaesthetic injections in diabetic rat models. Whether the same is true in humans is currently undefined. We, therefore, undertook this prospective cohort study to test the hypothesis that type-2 diabetic patients suffering from diabetic peripheral neuropathy would have increased block duration after ultrasound-guided popliteal sciatic nerve block when compared with patients without neuropathy. Thirty-three type-2 diabetic patients with neuropathy and 23 non-diabetic control patients, scheduled for fore-foot surgery, were included prospectively. All patients received an ultrasound-guided popliteal sciatic nerve block with a 30 ml 1:1 mixture of lidocaine 1% and bupivacaine 0.5%. The primary outcome was time to first opioid request after block procedure. Secondary outcomes included the time to onset of sensory blockade, and pain score at rest on postoperative day 1 (numeric rating scale 0-10). These outcomes were analysed using an accelerated failure time regression model. Patients in the diabetic peripheral neuropathy group had significantly prolonged median (IQR [range]) time to first opioid request (diabetic peripheral neuropathy group 1440 (IQR 1140-1440 [180-1440]) min vs. control group 710 (IQR 420-1200 [150-1440] min, p = 0.0004). Diabetic peripheral neuropathy patients had a time ratio of 1.57 (95%CI 1.10-2.23, p peripheral neuropathy group 0 (IQR 0-1 [0-5]) vs. control group 3 (IQR 0-5 [0-9]), p = 0.001). In conclusion, after an ultrasound-guided popliteal sciatic nerve block, patients with diabetic peripheral neuropathy demonstrated reduced time to onset of sensory blockade, with increased time to first opioid request when compared with patients without neuropathy. © 2018 The Association of Anaesthetists.

  11. Blockade of KCa3.1 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction

    Directory of Open Access Journals (Sweden)

    Chen-Hui Ju

    2015-07-01

    Full Text Available Background/Aims: After myocardial infarction (MI, cardiac fibrosis greatly contributes to left ventricular remodeling and heart failure. The intermediate-conductance calcium-activated potassium Channel (KCa3.1 has been recently proposed as an attractive target of fibrosis. The present study aimed to detect the effects of KCa3.1 blockade on ventricular remodeling following MI and its potential mechanisms. Methods: Myocardial expression of KCa3.1 was initially measured in a mouse MI model by Western blot and real time-polymerase chain reaction. Then after treatment with TRAM-34, a highly selective KCa3.1 blocker, heart function and fibrosis were evaluated by echocardiography, histology and immunohistochemistry. Furthermore, the role of KCa3.1 in neonatal mouse cardiac fibroblasts (CFs stimulated by angiotensin II (Ang II was tested. Results: Myocardium expressed high level of KCa3.1 after MI. Pharmacological blockade of KCa3.1 channel improved heart function and reduced ventricular dilation and fibrosis. Besides, a lower prevalence of myofibroblasts was found in TRAM-34 treatment group. In vitro studies KCa3.1 was up regulated in CFs induced by Ang II and suppressed by its blocker.KCa3.1 pharmacological blockade attenuated CFs proliferation, differentiation and profibrogenic genes expression and may regulating through AKT and ERK1/2 pathways. Conclusion: Blockade of KCa3.1 is able to attenuate ventricular remodeling after MI through inhibiting the pro-fibrotic effects of CFs.

  12. Nonadiabatic holonomic quantum computation using Rydberg blockade

    Science.gov (United States)

    Kang, Yi-Hao; Chen, Ye-Hong; Shi, Zhi-Cheng; Huang, Bi-Hua; Song, Jie; Xia, Yan

    2018-04-01

    In this paper, we propose a scheme for realizing nonadiabatic holonomic computation assisted by two atoms and the shortcuts to adiabaticity (STA). The blockade effect induced by strong Rydberg-mediated interaction between two Rydberg atoms provides us the possibility to simplify the dynamics of the system, and the STA helps us design pulses for implementing the holonomic computation with high fidelity. Numerical simulations show the scheme is noise immune and decoherence resistant. Therefore, the current scheme may provide some useful perspectives for realizing nonadiabatic holonomic computation.

  13. Blockade of serotonin 5-HT2A receptors potentiates dopamine D2 activation-induced disruption of pup retrieval on an elevated plus maze, but has no effect on D2 blockade-induced one.

    Science.gov (United States)

    Nie, Lina; Di, Tianqi; Li, Yu; Cheng, Peng; Li, Ming; Gao, Jun

    2018-06-23

    Appetitive aspect of rat maternal behavior, such as pup retrieval, is motivationally driven and sensitive to dopamine disturbances. Activation or blockade of dopamine D 2 receptors causes a similar disruption of pup retrieval, which may also reflect an increase in maternal anxiety and/or a disruption of executive function. Recent work indicates that serotonin 5-HT 2A receptors also play an important role in rat maternal behavior. Given the well-known modulation of 5-HT 2A on the mesolimbic and mesocortical dopamine functions, the present study examined the extent to which blockade of 5-HT 2A receptors on dopamine D 2 -mediated maternal effects using a pup retrieval on the elevated plus maze (EPM) test. Sprague-Dawley postpartum female rats were acutely injected with quinpirole (a D 2 agonist, 0.10 and 0.25 mg/kg, sc), or haloperidol (a D 2 antagonist, 0.1 or 0.2 mg/kg, sc), in combination of MDL100907 (a 5-HT 2A receptor antagonist, 1.0 mg/kg, sc, 30 min before quinpirole or haloperidol injection) or saline and tested at 30, 90 and 240 min after quinpirole or haloperidol injection on postpartum days 3 and 7. Quinpirole and haloperidol decreased the number of pup retrieved (an index of maternal motivation) and sequential retrieval score (an index of executive function), prolonged the pup retrieval latencies, reduced the percentage of time spent on the open arms (an index of maternal anxiety), and decreased the distance travelled on the maze in a dose-dependent and time-dependent fashion. MDL100907 treatment by itself had no effect on pup retrieval, but it exacerbated the quinpirole-induced disruption of pup retrieval, but had no effect on the haloperidol-induced one. These findings suggest a complex interactive effect between 5-HT 2A and D 2 receptors on one or several maternal processes (maternal motivation, anxiety and executive function), and support the idea that one molecular mechanism by which 5-HT 2A receptors mediate maternal behavior is through

  14. Rocuronium blockade reversal with sugammadex vs. neostigmine

    DEFF Research Database (Denmark)

    Wu, Xinmin; Oerding, Helle; Liu, Jin

    2014-01-01

    BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 μg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety-assessor......BACKGROUND: This study compared efficacy and safety of the selective relaxant binding agent sugammadex (2 mg/kg) with neostigmine (50 μg/kg) for neuromuscular blockade (NMB) reversal in Chinese and Caucasian subjects. METHODS: This was a randomized, active-controlled, multicenter, safety...... twitch reappearance, after last rocuronium dose, subjects received sugammadex 2 mg/kg or neostigmine 50 μg/kg plus atropine 10-20 μg/kg, according to randomization. Primary efficacy variable was time from sugammadex/neostigmine to recovery of the train-of-four (TOF) ratio to 0.9. RESULTS: Overall, 230...... Chinese subjects (sugammadex, n = 119, neostigmine, n = 111); and 59 Caucasian subjects (sugammadex, n = 29, neostigmine, n = 30) had evaluable data. Geometric mean (95% CI) time to recovery to TOF ratio 0.9 was 1.6 (1.5-1.7) min with sugammadex vs 9.1 (8.0-10.3) min with neostigmine in Chinese subjects...

  15. Bronchopulmonary C-fibers' IL1RI contributes to the prolonged apneic response to intra-atrial injection of capsaicin by prenatal nicotinic exposure in rat pups

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Lei; Zhuang, Jianguo; Xu, Fadi, E-mail: fxu@lrri.org

    2016-07-15

    Prenatal nicotinic exposure (PNE) as a SIDS model reportedly sensitizes bronchopulmonary C-fibers (PCFs), contributing to the prolonged PCF-mediated apnea in rat pups, but the relevant mechanisms are not fully understood. Pulmonary IL-1β upregulated by cigarette smoke is known to stimulate or sensitize PCFs acting via IL-1 type I receptor (IL1RI) and inhibit inspiration frequency. Because of its upregulation observed in SIDS victims, we hypothesized that PNE increased pulmonary IL-1β release and IL1RI expression in pulmonary C-neurons via action on α7 nicotinic acetylcholine receptors (α7nAChR) to induce the prolonged PCF-mediated apnea. IL-1β in BALF and IL1RI in the nodose/jugular (N/J) ganglion and vagal pulmonary C-neurons retrogradely-traced were compared between Ctrl (saline) and PNE pups and among the vehicle-treated Ctrl and PNE and methyllycaconitine (a selective α7nAChR antagonist)-treated PNE pups. The effect of IL-1RI blockade (IL-1Ra) on the PCF-mediated apnea was also compared between Ctrl and PNE pups. PNE significantly elevated IL-1β in BALF and upregulated IL1RI gene and protein expression in N/J ganglia and gene in vagal pulmonary C-neurons. All of these responses were eliminated by pretreatment with blockade of α7nAChR. In addition, the prolonged PCF-mediated apnea in PNE pups was significantly shortened by right atrial bolus injection of IL-1Ra. We conclude that PNE enhances pulmonary IL-1β release and PCF IL1RI expression acting via α7nAChR in contributing to sensitization of PCFs and prolongation of the PCF-mediated apneic response. - Highlights: • PNE increased pulmonary IL-1β release and IL1R1 expression in the N/J ganglia. • PNE elevated IL1R1 mRNA in vagal pulmonary C-neurons. • Blockage of peripheral IL1R1 reduced the PNE-induced PCF sensitization. • PNE induced the changes in IL-1β and IL1R1 dependent on action of α7nAChR.

  16. Use of brachial plexus blockade and medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (Acinonyx jubatus).

    Science.gov (United States)

    Kimeli, Peter; Mogoa, Eddy M; Mwangi, Willy E; Kipyegon, Ambrose N; Kirui, Gilbert; Muasya, Daniel W; Mande, John D; Kariuki, Edward; Mijele, Dominic

    2014-10-10

    Regional anaesthetic techniques have been used in combination with systemic analgesics during small animal surgery to provide multimodal analgesia. Brachial plexus nerves block using local anaesthetics provides analgesia of the thoracic limb through desensitization of the nerves that provide sensory and motor innervation. This has been shown to reduce intra-operative anesthetic requirements and provide postoperative pain relief. Decreasing the doses of general anaesthetics allows more stable cardiopulmonary function during anaesthesia and the development of less side effects. The present case reports a successful use of brachial plexus blockade to supplement medetomidine-ketamine-isoflurane anaesthesia for repair of radio-ulna fracture in an adult cheetah (acinonyx jubatus). An adult male Cheetah weighing about 65 kg was presented with a history of leg carrying lameness of the left forelimb sustained following a car accident a week earlier. Clinical examination under general anaesthesia revealed slight dehydration and a swelling with a wound on the caudo-medial aspect of the left radio-ulna region. Crepitation was present on manipulation and radiography confirmed a complete transverse radio-ulna fracture of the left forelimb, which required open reduction and internal fixation. Brachial plexus blockade using lignocaine hydrochloride was used to supplement medetomidine-ketamine-isoflurane anaesthesia for the surgical procedure. Isoflurane anaesthesia was maintained at 0.5 - 2.0% throughout the surgical procedure, which was uneventful. Temperature and cardio-pulmonary parameters remained stable intra-operatively. Limb paralysis extended for 5 hours post-operatively, suggesting prolonged anaesthesia. To the researchers' knowledge, this is the first reported case of the use of brachial plexus blockade to supplement general anaesthesia to facilitate forelimb surgery in an adult cheetah. The use of brachial plexus block with a light plane of general anaesthesia proved to

  17. Prolongation of islet allograft survival

    International Nuclear Information System (INIS)

    Lacy, P.E.; Davie, J.M.; Finke, E.H.; Scharp, D.W.

    1979-01-01

    Pretreatment of donor rats with irradiation and silica followed by in vitro culture of the islets for 1 to 2 days prolonged survival of allografts across a minor histocompatibility barrier if hand-picked, clean islets were used for transplantation. Pretreatment of donor rats with irradiation and silica in conjunction with a single injection of antilymphocyte serum (ALS) into the recipient produced a prolongation of survival of hand-picked islets transplanted across a major histocompatibility barrier

  18. Genetic influence on prolonged gestation

    DEFF Research Database (Denmark)

    Laursen, Maja; Bille, Camilla; Olesen, Annette Wind

    2004-01-01

    OBJECTIVE: The purpose of this study was to test a possible genetic component to prolonged gestation. STUDY DESIGN: The gestational duration of single, first pregnancies by both female and male twins was obtained by linking the Danish Twin Registry, The Danish Civil Registration System, and the D...... factors. CONCLUSION: Maternal genes influence prolonged gestation. However, a substantial paternal genetic influence through the fetus was not found....

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    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...

  20. The impact of acute preoperative beta-blockade on perioperative ...

    African Journals Online (AJOL)

    To determine the impact of acute preoperative β-blockade on the incidence of perioperative cardiovascular morbidity and all- ... Our findings suggest that acute preoperative β-blockade is associated with an increased risk of perioperative cardiac ..... Shammash JB, Trost JC, Gold JM, Berlin JA, Golden MA, Kimmel SE.

  1. A Markov computer simulation model of the economics of neuromuscular blockade in patients with acute respiratory distress syndrome

    Directory of Open Access Journals (Sweden)

    Chow John L

    2006-03-01

    Full Text Available Abstract Background Management of acute respiratory distress syndrome (ARDS in the intensive care unit (ICU is clinically challenging and costly. Neuromuscular blocking agents may facilitate mechanical ventilation and improve oxygenation, but may result in prolonged recovery of neuromuscular function and acute quadriplegic myopathy syndrome (AQMS. The goal of this study was to address a hypothetical question via computer modeling: Would a reduction in intubation time of 6 hours and/or a reduction in the incidence of AQMS from 25% to 21%, provide enough benefit to justify a drug with an additional expenditure of $267 (the difference in acquisition cost between a generic and brand name neuromuscular blocker? Methods The base case was a 55 year-old man in the ICU with ARDS who receives neuromuscular blockade for 3.5 days. A Markov model was designed with hypothetical patients in 1 of 6 mutually exclusive health states: ICU-intubated, ICU-extubated, hospital ward, long-term care, home, or death, over a period of 6 months. The net monetary benefit was computed. Results Our computer simulation modeling predicted the mean cost for ARDS patients receiving standard care for 6 months to be $62,238 (5% – 95% percentiles $42,259 – $83,766, with an overall 6-month mortality of 39%. Assuming a ceiling ratio of $35,000, even if a drug (that cost $267 more hypothetically reduced AQMS from 25% to 21% and decreased intubation time by 6 hours, the net monetary benefit would only equal $137. Conclusion ARDS patients receiving a neuromuscular blocker have a high mortality, and unpredictable outcome, which results in large variability in costs per case. If a patient dies, there is no benefit to any drug that reduces ventilation time or AQMS incidence. A prospective, randomized pharmacoeconomic study of neuromuscular blockers in the ICU to asses AQMS or intubation times is impractical because of the highly variable clinical course of patients with ARDS.

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

    DEFF Research Database (Denmark)

    Thind, P; Bagi, P; Mieszczak, C

    1996-01-01

    The urethral pressure decay following a sudden and sustained dilatation corresponds to stress relaxation. Urethral stress relaxation can be described by the equation Pt = Pequ + P alpha e-t/tau alpha + P beta e-t/tau beta, where Pt is the pressure at time t, Pequ is the equilibrium pressure after...... 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...

  3. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    OpenAIRE

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103-104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min...

  4. Interplay between superconductivity and Coulomb blockade

    Energy Technology Data Exchange (ETDEWEB)

    Lorenz, Thomas; Sprenger, Susanne; Scheer, Elke [Universitaet Konstanz (Germany)

    2016-07-01

    Studying the interplay between superconductivity and Coulomb blockade (CB) can be achieved by investigating an all superconducting single electron transistor (SSET) consisting of an island coupled to the leads by two tunneling contacts. The majority of experiments performed so far were using superconducting tunnel contacts made from oxide layers, in which multiple Andreev reflections (MAR) can be excluded. Using a mechanically controlled break junction (MCBJ) made of aluminum enables tuning the contributions of MAR in one junction continuously and thereby addressing different transport regimes within the same sample. Our results offer the possibility to attribute particular features in the transport characteristics to the transmission probabilities of individual modes in the MCBJ contact. We discuss our findings in terms of dynamical CB, SSET behaviour and MAR when continuously opening the MCBJ from the fully closed state to a tunneling contact.

  5. RECONSTRUCTION OF ATROPHIC MAXILLA BY ANTERIOR ILIAC CREST BONE GRAFTING VIA NEUROAXIAL BLOCKADE TECHNIQUE: A CASE REPORT

    Directory of Open Access Journals (Sweden)

    Erol CANSIZ

    2017-01-01

    Full Text Available Anterior iliac crest bone grafting is a well-established modality in the treatment of alveolar bone deficiencies. However, this procedure may also have considerable postoperative morbidity which is mostly related to general anesthesia. Postoperative pain-related complications can be managed by neuroaxial blockade techniques which provide adequate surgical analgesia and reduce postoperative pain. This clinical report describes the reconstruction of a severely atrophic maxilla with anterior iliac crest bone grafting using combined spinal epidural anesthesia. Neuroaxial blockade techniques may be a useful alternative to eliminate general anesthesia related challenges of anterior iliac crest bone grafting procedures.

  6. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    International Nuclear Information System (INIS)

    Gan, Lu; Xue, Jian-Xin; Li, Xin; Liu, De-Song; Ge, Yan; Ni, Pei-Yan; Deng, Lin; Lu, You; Jiang, Wei

    2011-01-01

    Highlights: → Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. → Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. → VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. → LPA-LPAR1/3 signaling regulated TGFβ1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. → LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGFβ1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the

  7. Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Gan, Lu [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Xue, Jian-Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu (China); Li, Xin [Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Liu, De-Song [Department of Pediatrics, Sichuan Provincial Hospital of Women and Children, Chengdu (China); Ge, Yan; Ni, Pei-Yan; Deng, Lin [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Lu, You, E-mail: radyoulu@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu (China); Jiang, Wei, E-mail: wcumsjw72@hotmail.com [State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu (China); Molecular Medicine Research Center, West China Hospital, Sichuan University, Chengdu (China)

    2011-05-27

    Highlights: {yields} Lysophosphatidic acid (LPA) levels and its receptors LPAR1/3 transcripts were elevated during the development of radiation-induced lung fibrosis. {yields} Lung fibrosis was obviously alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. {yields} VPC12249 administration effectively inhibited radiation-induced fibroblast accumulation in vivo, and suppressed LPA-induced fibroblast proliferation in vitro. {yields} LPA-LPAR1/3 signaling regulated TGF{beta}1 and CTGF expressions in radiation-challenged lungs, but only influenced CTGF expression in cultured fibroblasts. {yields} LPA-LPAR1/3 signaling induced fibroblast proliferation through a CTGF-dependent pathway, rather than through TGF{beta}1 activation. -- Abstract: Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor {beta}1 (TGF{beta}1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTGF. Together, our data suggest that the LPA-LPAR1

  8. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade.

    Science.gov (United States)

    Ezzelarab, Mohamed B; Lu, Lien; Shufesky, William F; Morelli, Adrian E; Thomson, Angus W

    2018-01-01

    Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4 + T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4 + T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4 + CTLA4 hi , but not CD4 + CTLA4 med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4 + CTLA4 hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4 + CTLA4 hi /CD4 + CTLA4 med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4 + CTLA4 hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

  9. Complete androgen blockade safely allows for delay of cytotoxic chemotherapy in castration refractory prostate cancer

    Directory of Open Access Journals (Sweden)

    Rafael A. Kaliks

    2010-06-01

    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.

  10. Pauli Spin Blockade and the Ultrasmall Magnetic Field Effect

    KAUST Repository

    Danon, Jeroen

    2013-08-06

    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.

  11. Pauli Spin Blockade and the Ultrasmall Magnetic Field Effect

    KAUST Repository

    Danon, Jeroen; Wang, Xuhui; Manchon, Aurelien

    2013-01-01

    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.

  12. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults

    DEFF Research Database (Denmark)

    Hristovska, Ana-Marija; Duch, Patricia; Allingstrup, Mikkel

    2017-01-01

    , and undesirable autonomic responses. Sugammadex is a selective relaxant-binding agent specifically developed for rapid reversal of non-depolarizing neuromuscular blockade induced by rocuronium. Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety......, reduced incidence of residual block on recovery, and more efficient use of healthcare resources. OBJECTIVES: The main objective of this review was to compare the efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade caused by non-depolarizing neuromuscular agents......-depolarizing neuromuscular blocking agents for an elective in-patient or day-case surgical procedure. We included all trials comparing sugammadex versus neostigmine that reported recovery times or adverse events. We included any dose of sugammadex and neostigmine and any time point of study drug administration. DATA...

  13. Blockade of the SNARE protein syntaxin 1 inhibits glioblastoma tumor growth.

    Directory of Open Access Journals (Sweden)

    Fausto Ulloa

    Full Text Available Glioblastoma (GBM is the most prevalent adult brain tumor, with virtually no cure, and with a median overall survival of 15 months from diagnosis despite of the treatment. SNARE proteins mediate membrane fusion events in cells and are essential for many cellular processes including exocytosis and neurotransmission, intracellular trafficking and cell migration. Here we show that the blockade of the SNARE protein Syntaxin 1 (Stx1 function impairs GBM cell proliferation. We show that Stx1 loss-of-function in GBM cells, through ShRNA lentiviral transduction, a Stx1 dominant negative and botulinum toxins, dramatically reduces the growth of GBM after grafting U373 cells into the brain of immune compromised mice. Interestingly, Stx1 role on GBM progression may not be restricted just to cell proliferation since the blockade of Stx1 also reduces in vitro GBM cell invasiveness suggesting a role in several processes relevant for tumor progression. Altogether, our findings indicate that the blockade of SNARE proteins may represent a novel therapeutic tool against GBM.

  14. Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice

    Directory of Open Access Journals (Sweden)

    Misa Oyama

    2017-03-01

    Full Text Available To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.

  15. Prolonged unexplained fatigue in paediatrics

    NARCIS (Netherlands)

    Bakker, R.J.

    2010-01-01

    Prolonged Unexplained Fatigue in Paediatrics. Fatigue, as the result of mental or physical exertion, will disappear after rest, drinks and food. Fatigue as a symptom of illness will recover with the recovering of the illness. But when fatigue is ongoing for a long time, and not the result of

  16. Physiology Of Prolonged Bed Rest

    Science.gov (United States)

    Greenleaf, John E.

    1991-01-01

    Report describes physiological effects of prolonged bed rest. Rest for periods of 24 hours or longer deconditions body to some extent; healing proceeds simultaneously with deconditioning. Report provides details on shifts in fluid electrolytes and loss of lean body mass, which comprises everything in body besides fat - that is, water, muscle, and bone. Based on published research.

  17. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia

    Directory of Open Access Journals (Sweden)

    Arvind Chaturvedi

    2011-01-01

    Full Text Available Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  18. Prolonged vertigo and ataxia after mandibular nerve block for treatment of trigeminal neuralgia.

    Science.gov (United States)

    Chaturvedi, Arvind; Dash, Hh

    2011-07-01

    Common complications of neurolytic mandibular nerve block are hypoesthesia, dysesthesia, and chemical neuritis. We report a rare complication, prolonged severe vertigo and ataxia, after neurolytic mandibular blockade in a patient suffering from trigeminal neuralgia. Coronoid approach was used for right sided mandibular block. After successful test injection with local anesthetic, absolute alcohol was given for neurolytic block. Immediately after alcohol injection, patient developed nausea and vomiting along with severe vertigo, ataxia and hypertension. Neurological evaluation was normal except for the presence of vertigo and ataxia. Computerised tomography scan brain was also normal. Patient was admitted for observation and symptomatic treatment was given. Vertigo and ataxia gradually improved over 24 hours.

  19. Computational assignment of redox states to Coulomb blockade diamonds.

    Science.gov (United States)

    Olsen, Stine T; Arcisauskaite, Vaida; Hansen, Thorsten; Kongsted, Jacob; Mikkelsen, Kurt V

    2014-09-07

    With the advent of molecular transistors, electrochemistry can now be studied at the single-molecule level. Experimentally, the redox chemistry of the molecule manifests itself as features in the observed Coulomb blockade diamonds. We present a simple theoretical method for explicit construction of the Coulomb blockade diamonds of a molecule. A combined quantum mechanical/molecular mechanical method is invoked to calculate redox energies and polarizabilities of the molecules, including the screening effect of the metal leads. This direct approach circumvents the need for explicit modelling of the gate electrode. From the calculated parameters the Coulomb blockade diamonds are constructed using simple theory. We offer a theoretical tool for assignment of Coulomb blockade diamonds to specific redox states in particular, and a study of chemical details in the diamonds in general. With the ongoing experimental developments in molecular transistor experiments, our tool could find use in molecular electronics, electrochemistry, and electrocatalysis.

  20. Radiotherapy and immune checkpoint blockades: a snapshot in 2016

    Energy Technology Data Exchange (ETDEWEB)

    Koo, Tae Yool [Dept. of Radiation Oncology, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon (Korea, Republic of); Kim, In Ah [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2016-12-15

    Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of immune checkpoint blockades due to its potent pro-immune effect. This review will cover the current issue and the future perspectives for combined with radiotherapy and immune checkpoint blockades based upon the available preclinical and clinical data.

  1. From Napoleon To Netanyahu: Blockading Through Two Centuries

    Science.gov (United States)

    2016-04-01

    Hemisphere. With a range of only 2,500 miles per load of coal, steam powered ships could not reach Europe without refueling. Blockading actions at Vera ...BIBLIOGRAPHY Calore, Paul. Naval Campaigns of the Civil War. Jefferson, NC: McFarland and Co., 2003. Davis, Lance E . and Stanley L...Lance E . Davis and Stanley L. Engerman, Naval Blockades in Peace and War: An Economic History Since 1750

  2. Heat Coulomb blockade of one ballistic channel

    Science.gov (United States)

    Sivre, E.; Anthore, A.; Parmentier, F. D.; Cavanna, A.; Gennser, U.; Ouerghi, A.; Jin, Y.; Pierre, F.

    2018-02-01

    Quantum mechanics and Coulomb interaction dictate the behaviour of small circuits. The thermal implications cover fundamental topics from quantum control of heat to quantum thermodynamics, with prospects of novel thermal machines and an ineluctably growing influence on nanocircuit engineering. Experimentally, the rare observations thus far include the universal thermal conductance quantum and heat interferometry. However, evidence for many-body thermal effects paving the way to markedly different heat and electrical behaviours in quantum circuits remains wanting. Here we report on the observation of the Coulomb blockade of electronic heat flow from a small metallic circuit node, beyond the widespread Wiedemann-Franz law paradigm. We demonstrate this thermal many-body phenomenon for perfect (ballistic) conduction channels to the node, where it amounts to the universal suppression of precisely one quantum of conductance for the transport of heat, but none for electricity. The inter-channel correlations that give rise to such selective heat current reduction emerge from local charge conservation, in the floating node over the full thermal frequency range (laws for thermal transport in nanocircuits.

  3. Checkpoint blockade in combination with cancer vaccines.

    Science.gov (United States)

    Morse, Michael A; Lyerly, H Kim

    2015-12-16

    Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. 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

    1997-03-01

    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.

  5. RD50 Prolongation Request 2018

    CERN Document Server

    Casse, Gianluigi

    2018-01-01

    With this document, we request the prolongation of the CERN RD50 research program for 5 years. A very brief historical review of the RD50 research program since the RD50 project approval by the Research Board in the year 2002 is presented and the biggest RD50 achievements are highlighted. The present composition of the collaboration, its organizational structure, and the research methodology are described. The role of RD50 in the present various upgrade and research programs of the LHC Experiments community is given and the overall work plan explained. Finally, a detailed 5-years work program with precise milestones and deliverables for the various research activities is presented. We conclude with our prolongation request towards the LHCC.

  6. Influence of beta blockade on gastric acid secretion and changes in gastric mucosal blood flow before and after parietal cell vagotomy in dogs and man

    DEFF Research Database (Denmark)

    Hovendal, C P; Bech, K; Bekker, C

    1983-01-01

    The aim of the present study was, in paired experiments in dogs, to examine the effect of beta-receptor blockade on gastric acid secretion and mucosal blood flow before and after parietal cell vagotomy (PCV). The secretory response to pentagastrin was reduced after vagotomy. beta-Adrenergic block......The aim of the present study was, in paired experiments in dogs, to examine the effect of beta-receptor blockade on gastric acid secretion and mucosal blood flow before and after parietal cell vagotomy (PCV). The secretory response to pentagastrin was reduced after vagotomy. beta...

  7. Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

    Directory of Open Access Journals (Sweden)

    Kia J Langford-Smith

    Full Text Available Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM:blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan. We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

  8. Signal one and two blockade are both critical for non-myeloablative murine HSCT across a major histocompatibility complex barrier.

    Science.gov (United States)

    Langford-Smith, Kia J; Sandiford, Zara; Langford-Smith, Alex; Wilkinson, Fiona L; Jones, Simon A; Wraith, J Ed; Wynn, Robert F; Bigger, Brian W

    2013-01-01

    Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.

  9. A multicentre randomized controlled trial of gentle assisted pushing in the upright posture (GAP) or upright posture alone compared with routine practice to reduce prolonged second stage of labour (the Gentle Assisted Pushing study): study protocol.

    Science.gov (United States)

    Hofmeyr, G Justus; Singata, Mandisa; Lawrie, Theresa; Vogel, Joshua P; Landoulsi, Sihem; Seuc, Armando H; Gülmezoglu, A Metin

    2015-12-16

    Fundal pressure (pushing on the upper part of the uterus in the direction of the birth canal) is often performed in routine practice, however the benefit and indications for its use are unclear and vigorous pressure is potentially harmful. There is some evidence that it may be applied routinely or to expedite delivery in some situations (e.g. fetal distress or maternal exhaustion), particularly in settings where other methods of achieving delivery (forceps, vacuum) are not available. Gentle assisted pushing (GAP) is an innovative method of applying gentle but steady pressure to the uterine fundus with the woman in an upright posture. This trial aims to evaluate the use of GAP in an upright posture, or upright posture alone, on reducing the mean time of delivery and the associated maternal and neonatal complications in women not having delivered following 15-30 min in the second stage of labour. We will conduct a multicentre, randomized, unblinded, controlled trial with three parallel arms (1:1:1). 1,145 women will be randomized at three hospitals in South Africa. Women will be eligible for inclusion if they are ≥18 years old, nulliparous, gestational age ≥ 35 weeks, have a singleton pregnancy in cephalic presentation and vaginal delivery anticipated. Women with chronic medical conditions or obstetric complications are not eligible. If eligible women are undelivered following 15-30 min in the second stage of labour, they will be randomly assigned to: 1) GAP in the upright posture, 2) upright posture only and 3) routine practice (recumbent/supine posture). The primary outcome is the mean time from randomization to complete delivery. Secondary outcomes include operative delivery, adverse neonatal outcomes, maternal adverse events and discomfort. This trial will establish whether upright posture and/or a controlled method of applying fundal pressure (GAP) can improve labour outcomes for women and their babies. If fundal pressure is found to have a measurable

  10. Costimulatory signal blockade in murine relapsing experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

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

    1999-01-01

    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...... B7) after immunization or after the first attack protects from EAE. Treatment with a combination of CTLA4Ig and MR1 provides additive protection, and is associated with complete absence of mononuclear cell infiltrates in the central nervous system, and marked suppression of proliferation of primed T...... cells in the periphery. Selective B7-1 blockade did not protect from EAE. These observations have implications for therapy of autoimmune diseases....

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

    LENUS (Irish Health Repository)

    McDonnell, J G

    2012-01-31

    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.

  12. Neural Blockade for Persistent Pain After Breast Cancer Surgery

    DEFF Research Database (Denmark)

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

    2014-01-01

    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......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...

  13. Combination approaches with immune checkpoint blockade in cancer therapy

    Directory of Open Access Journals (Sweden)

    Maarten Swart

    2016-11-01

    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.

  14. Lack of Association Between the Use of Nerve Blockade and the Risk of Postoperative Chronic Opioid Use Among Patients Undergoing Total Knee Arthroplasty: Evidence From the Marketscan Database.

    Science.gov (United States)

    Sun, Eric C; Bateman, Brian T; Memtsoudis, Stavros G; Neuman, Mark D; Mariano, Edward R; Baker, Laurence C

    2017-09-01

    Total knee arthroplasty (TKA) is associated with high rates of prolonged opioid use after surgery (10%-34%). By decreasing opioid use in the immediate postoperative period, perioperative nerve blockade has been hypothesized to decrease the risk of persistent opioid use. Using health care utilization data, we constructed a sample of 120,080 patients undergoing TKA between 2002 and 2012 and used billing data to identify the utilization of peripheral or neuraxial blockade. We then used a multivariable logistic regression to estimate the association between nerve blockade and the risk of chronic opioid use, defined as having filled ≥10 prescriptions or ≥120 days' supply for an opioid in the first postsurgical year. Our analyses were adjusted for an extensive set of potential confounding variables, including medical comorbidities, previous opioid use, and previous use of other medications. We did not find an association between nerve blockade and the risk of postsurgical chronic opioid use across any of these 3 groups: adjusted relative risk (ARR) 0.984 for patients opioid-naïve in the year before surgery (98.3% confidence interval [CI], 0.870-1.12, P = .794), ARR 1.02 for intermittent opioid users (98.3% CI, 0.948-1.09, P = .617), and ARR 0.986 (98.3% CI, 0.963-1.01, P = .257) for chronic opioid users. Similar results held for alternative measures of postsurgical opioid use. Although the use of perioperative nerve blockade for TKA may improve short-term outcomes, the analyzed types of blocks do not appear to decrease the risk of persistent opioid use in the longer term.

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

    Science.gov (United States)

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

    2016-03-01

    X-linked acrogigantism (X-LAG) syndrome is a newly described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated GH and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GHRH levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(d-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome. © 2016 Society for Endocrinology.

  16. Partial neuromuscular blockade in humans enhances muscle blood flow during exercise independently of muscle oxygen uptake and acetylcholine receptor blockade

    DEFF Research Database (Denmark)

    Hellsten, Ylva; Krustrup, Peter; Iaia, F Marcello

    2009-01-01

    This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one-legged k......This study examined the role of acetylcholine for skeletal muscle blood flow during exercise by use of the competitive neuromuscular blocking agent cisatracurium in combination with the acetylcholine receptor blocker glycopyrrone. Nine healthy male subjects performed a 10-min bout of one...... conductance during exercise, events that are not associated with either acetylcholine or an increased oxygen demand. The results do not support an essential role for acetylcholine, released form the neuromuscular junction, in exercise hyperaemia or for the enhanced blood flow during neuromuscular blockade....... The enhanced exercise hyperemia during partial neuromuscular blockade may be related to a greater recruitment of fast-twitch muscle fibres. Key words: blood flow, neuromuscular blockade, exercise, skeletal muscle....

  17. Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys.

    NARCIS (Netherlands)

    Boer, H.D. de; Egmond, J. van; Pol, F. van de; Bom, A.; Booij, L.H.D.J.

    2006-01-01

    BACKGROUND: Reversal of neuromuscular blockade can be accomplished by chemical encapsulation of rocuronium by sugammadex, a synthetic gamma-cyclodextrin derivative. The current study determined the feasibility of reversal of rocuronium-induced profound neuromuscular blockade with sugammadex in the

  18. Prolonged Intermittent Renal Replacement Therapy.

    Science.gov (United States)

    Edrees, Fahad; Li, Tingting; Vijayan, Anitha

    2016-05-01

    Prolonged intermittent renal replacement therapy (PIRRT) is becoming an increasingly popular alternative to continuous renal replacement therapy in critically ill patients with acute kidney injury. There are significant practice variations in the provision of PIRRT across institutions, with respect to prescription, technology, and delivery of therapy. Clinical trials have generally demonstrated that PIRRT is non-inferior to continuous renal replacement therapy regarding patient outcomes. PIRRT offers cost-effective renal replacement therapy along with other advantages such as early patient mobilization and decreased nursing time. However, due to lack of standardization of the procedure, PIRRT still poses significant challenges, especially pertaining to appropriate drug dosing. Future guidelines and clinical trials should work toward developing consensus definitions for PIRRT and ensure optimal delivery of therapy. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  19. 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.

  20. Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

    Science.gov (United States)

    Davidson, Joanne O.; Drury, Paul P.; Green, Colin R.; Nicholson, Louise F.; Bennet, Laura; Gunn, Alistair J.

    2014-01-01

    Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia. PMID:24865217

  1. A New Biomarker of Hedonic Eating? A Preliminary Investigation of Cortisol and Nausea Responses to Acute Opioid Blockade

    OpenAIRE

    Daubenmier, Jennifer; Lustig, Robert H.; Hecht, Frederick M.; Kristeller, Jean; Woolley, Josh; Adam, Tanja; Dallman, Mary; Epel, Elissa

    2013-01-01

    Overweight and obese individuals differ in their degree of hedonic eating. This may reflect adaptations in reward-related neural circuits, regulated in part by opioidergic activity. We examined an indirect, functional measure of central opioidergic activity by assessing cortisol and nausea responses to acute opioid blockade using the opioid antagonist naltrexone in overweight/obese women (mean BMI = 31.1 ± 4.8) prior to the start of a mindful eating intervention to reduce stress eating. In ad...

  2. 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

    1982-01-01

    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...

  3. 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

    1994-01-01

    The effect of oxygen therapy (37% by face mask) and epidural local anesthetic blockade (9 ml 0.5% bupivacaine at Th9-11 level) on wound oxygenation was evaluated in eight otherwise healthy patients undergoing elective colorectal resection. The patients were monitored continuously for subcutaneous...... without epidural blockade and 15 (10-20) min with blockade (P surgery....

  4. Use of ropivacain and lidocaine for axillary plexus blockade ...

    African Journals Online (AJOL)

    Use of ropivacain and lidocaine for axillary plexus blockade. ... of the juvenile anatomy, psychological barriers, time constraints on block ... children in the age group of 2 to 10 years and undergoing short upper limb surgery. ... Browse By Category · Browse Alphabetically · Browse By Country · List All Titles · Free To Read ...

  5. 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

  6. Effective dermatomal blockade after subcostal transversus abdominis plane block

    DEFF Research Database (Denmark)

    Mitchell, Anja Ulrike; Torup, Henrik; Hansen, Egon G

    2012-01-01

    . Sensory assessment of a TAP block may guide the decision on the extent of the block. The purpose of this study was to investigate if the dermatomal extent of sensory blockade after injection of 20 ml 0.5% ropivacaine bilaterally into the TAP can be assessed using cold and pinprick sensation....

  7. Neuromuscular blockade for improvement of surgical conditions during laparotomy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Scheppan, Susanne; Kissmeyer, Peter

    2015-01-01

    neuromuscular blockade (NMB), defined as a post-tetanic-count (PTC) of 0-1, paralyses the abdominal wall muscles and the diaphragm. We hypothesised that deep NMB (PTC 0-1) would improve surgical conditions during upper laparotomy as compared to standard NMB with bolus administration. METHODS...

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

    NARCIS (Netherlands)

    Dinarello, C.A.

    2010-01-01

    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

  9. Topological matter with collective encoding and Rydberg blockade

    DEFF Research Database (Denmark)

    Nielsen, Anne E. B.; Mølmer, Klaus

    2010-01-01

    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....

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

    DEFF Research Database (Denmark)

    Miroshnychenko, Yevhen; Browaeys, Antoine; Evellin, Charles

    2011-01-01

    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....

  11. Effect of Dual Blockade of Renin-Angiotensin Aldosterone System ...

    African Journals Online (AJOL)

    Purpose: To investigate the dual effect of angiotensin blockade by irbesartan and enalapril on proteinuria in diabetic patients with azotemia. Methods: Patients with diabetes of > 5 years duration, proteinuria at a nephrotic level and serum creatinine > 1.5 mg/dL were enrolled in the study. Forty-five enrolled patients were ...

  12. CARDIOVASCULAR ENDOCRINOLOGY Dual RAAS blockade has dual effects on outcome

    NARCIS (Netherlands)

    Heerspink, Hiddo J. Lambers; de Zeeuw, Dick

    Makani and colleagues report that dual blockade of the renin-angiotensin-aldosterone system is associated with harm despite previous studies showing that this approach decreases blood pressure and albuminuria. Do these results imply that we should abandon surrogate markers? Or should we become more

  13. Benefits and harms of perioperative beta-blockade

    DEFF Research Database (Denmark)

    Wetterslev, Jørn; Juul, Anne Benedicte

    2006-01-01

    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...

  14. Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma

    International Nuclear Information System (INIS)

    Chi, Kwan-Hwa; Liao, Chao-Sheng; Chang, Chih-Chia; Ko, Hui-Ling; Tsang, Yuk-Wah; Yang, Kuo-Ching; Mehta, Minesh P.

    2010-01-01

    Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial α-fetoprotein (AFP) kinetics, and survival. Results: Of 23 evaluable patients, 60% had ≥2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had ≥50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had ≥Grade 2 elevation of liver enzymes, and 15 had ≥Grade 2 thrombocytopenia. Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

  15. Prolonged pregnancy: Methods, Causal Determinants and Outcome

    DEFF Research Database (Denmark)

    Olesen, Annette Wind

    Summary Prolonged pregnancy, defined as a pregnancy with a gestational length of 294 days or more, is a frequent condition. It is associated with an increased risk of fetal and maternal complications. Little is known about the aetiology of prolonged pregnancy. The aims of the thesis were 1......) to study the incidence of prolonged pregnancy as a function of methods for determining gestational age; 2) to determine the risk of obstetrical and fetal complications in prolonged pregnancy; 3) to validate the self-reported gestational age in the National Birth Cohort; 4) to determine whether...... the risk of recurrence of prolonged pregnancy as a function of change in male partner and social conditions (IV). The National Birth Cohort provided data for the study on prenatal risk indicators of prolonged pregnancy in a follow-up design (V). The self-reported gestational ages from this database...

  16. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition

    Science.gov (United States)

    Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Feng, Yang; Dimitrov, Dimiter S.; Jones, David R.; Sadelain, Michel; Adusumilli, Prasad S.

    2016-01-01

    Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1–mediated (PD-1–mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB–based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. PMID:27454297

  17. Role of the pH in state-dependent blockade of hERG currents

    Science.gov (United States)

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-10-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action.

  18. Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.

    Science.gov (United States)

    Pedersen, Morten Høgild; Svart, Mads Vandsted; Lebeck, Janne; Bidlingmaier, Martin; Stødkilde-Jørgensen, Hans; Pedersen, Steen Bønløkke; Møller, Niels; Jessen, Niels; Jørgensen, Jens O L

    2017-04-01

    Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance. To study the metabolic effects of GH blockade during fasting in obese subjects. Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies. GH levels increased with fasting (P fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA. Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects. Copyright © 2017 by the Endocrine Society

  19. Mechanism of blood pressure and R-R variability: insights from ganglion blockade in humans

    Science.gov (United States)

    Zhang, Rong; Iwasaki, Kenichi; Zuckerman, Julie H.; Behbehani, Khosrow; Crandall, Craig G.; Levine, Benjamin D.; Blomqvist, C. G. (Principal Investigator)

    2002-01-01

    Spontaneous blood pressure (BP) and R-R variability are used frequently as 'windows' into cardiovascular control mechanisms. However, the origin of these rhythmic fluctuations is not completely understood. In this study, with ganglion blockade, we evaluated the role of autonomic neural activity versus other 'non-neural' factors in the origin of BP and R-R variability in humans. Beat-to-beat BP, R-R interval and respiratory excursions were recorded in ten healthy subjects (aged 30 +/- 6 years) before and after ganglion blockade with trimethaphan. The spectral power of these variables was calculated in the very low (0.0078-0.05 Hz), low (0.05-0.15 Hz) and high (0.15-0.35 Hz) frequency ranges. The relationship between systolic BP and R-R variability was examined by cross-spectral analysis. After blockade, R-R variability was virtually abolished at all frequencies; however, respiration and high frequency BP variability remained unchanged. Very low and low frequency BP variability was reduced substantially by 84 and 69 %, respectively, but still persisted. Transfer function gain between systolic BP and R-R interval variability decreased by 92 and 88 % at low and high frequencies, respectively, while the phase changed from negative to positive values at the high frequencies. These data suggest that under supine resting conditions with spontaneous breathing: (1) R-R variability at all measured frequencies is predominantly controlled by autonomic neural activity; (2) BP variability at high frequencies (> 0.15 Hz) is mediated largely, if not exclusively, by mechanical effects of respiration on intrathoracic pressure and/or cardiac filling; (3) BP variability at very low and low frequencies (rhythmicity; and (4) the dynamic relationship between BP and R-R variability as quantified by transfer function analysis is determined predominantly by autonomic neural activity rather than other, non-neural factors.

  20. Macroscopic quantum tunneling in Josephson tunnel junctions and Coulomb blockade in single small tunnel junctions

    International Nuclear Information System (INIS)

    Cleland, A.N.

    1991-04-01

    Experiments investigating the process of macroscopic quantum tunneling in a moderately-damped, resistively shunted, Josephson junction are described, followed by a discussion of experiments performed on very small capacitance normal-metal tunnel junctions. The experiments on the resistively-shunted Josephson junction were designed to investigate a quantum process, that of the tunneling of the Josephson phase variable under a potential barrier, in a system in which dissipation plays a major role in the dynamics of motion. All the parameters of the junction were measured using the classical phenomena of thermal activation and resonant activation. Theoretical predictions are compared with the experimental results, showing good agreement with no adjustable parameters; the tunneling rate in the moderately damped (Q ∼ 1) junction is seen to be reduced by a factor of 300 from that predicted for an undamped junction. The phase is seen to be a good quantum-mechanical variable. The experiments on small capacitance tunnel junctions extend the measurements on the larger-area Josephson junctions from the region in which the phase variable has a fairly well-defined value, i.e. its wavefunction has a narrow width, to the region where its value is almost completely unknown. The charge on the junction becomes well-defined and is predicted to quantize the current through the junction, giving rise to the Coulomb blockade at low bias. I present the first clear observation of the Coulomb blockade in single junctions. The electrical environment of the tunnel junction, however, strongly affects the behavior of the junction: higher resistance leads are observed to greatly sharpen the Coulomb blockade over that seen with lower resistance leads. I present theoretical descriptions of how the environment influences the junctions; comparisons with the experimental results are in reasonable agreement

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

    Directory of Open Access Journals (Sweden)

    Alper Otunctemur

    2013-06-01

    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.

  2. Genetic disassociation of autoimmunity and resistance to costimulation blockade-induced transplantation tolerance in nonobese diabetic mice.

    Science.gov (United States)

    Pearson, Todd; Markees, Thomas G; Serreze, David V; Pierce, Melissa A; Marron, Michele P; Wicker, Linda S; Peterson, Laurence B; Shultz, Leonard D; Mordes, John P; Rossini, Aldo A; Greiner, Dale L

    2003-07-01

    Curing type 1 diabetes by islet transplantation requires overcoming both allorejection and recurrent autoimmunity. This has been achieved with systemic immunosuppression, but tolerance induction would be preferable. Most islet allotransplant tolerance induction protocols have been tested in nonobese diabetic (NOD) mice, and most have failed. Failure has been attributed to the underlying autoimmunity, assuming that autoimmunity and resistance to transplantation tolerance have a common basis. Out of concern that NOD biology could be misleading in this regard, we tested the hypothesis that autoimmunity and resistance to transplantation tolerance in NOD mice are distinct phenotypes. Unexpectedly, we observed that (NOD x C57BL/6)F(1) mice, which have no diabetes, nonetheless resist prolongation of skin allografts by costimulation blockade. Further analyses revealed that the F(1) mice shared the dendritic cell maturation defects and abnormal CD4(+) T cell responses of the NOD but had lost its defects in macrophage maturation and NK cell activity. We conclude that resistance to allograft tolerance induction in the NOD mouse is not a direct consequence of overt autoimmunity and that autoimmunity and resistance to costimulation blockade-induced transplantation tolerance phenotypes in NOD mice can be dissociated genetically. The outcomes of tolerance induction protocols tested in NOD mice may not accurately predict outcomes in human subjects.

  3. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade: A Randomized Clinical Trial

    NARCIS (Netherlands)

    de Vries, Laura V.; Dobrowolski, Linn C.; van den Bosch, Jacqueline J. O. N.; Riphagen, Ineke J.; Krediet, C. T. Paul; Bemelman, Frederike J.; Bakker, Stephan J. L.; Navis, Gerjan

    2016-01-01

    In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown. We therefore

  4. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade : A Randomized Clinical Trial

    NARCIS (Netherlands)

    de Vries, Laura V; Dobrowolski, Linn C; van den Bosch, Jacqueline J O N; Riphagen, Ineke J; Krediet, C T Paul; Bemelman, Frederike J; Bakker, Stephan J L; Navis, Gerjan

    BACKGROUND: In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown.

  5. Effect of selective blockade of oxygen consumption, glucose transport, and Ca2+ influx on thyroxine action in human mononuclear cells

    DEFF Research Database (Denmark)

    Kvetny, J; Matzen, L E

    1990-01-01

    The effect of selective blockade of cellular glucose transporters, Ca2+ influx, and mitochondrial oxygen consumption on thyroxine (T4)-stimulated oxygen consumption and glucose uptake was examined in human mononuclear blood cells. Blockade of glucose transporters by cytochalasin B (1 x 10(-5) mol....../L) and of Ca2+ influx by alprenolol (1 x 10(-5) mol/L) and verapamil (4 x 10(-4) mol/L) inhibited T4-activated glucose uptaken and reduced T4-stimulated oxygen consumption by 20%. Uncoupling of mitochondrial oxygen consumption by azide (1 x 10(-3) mol/L) inhibited T4-stimulated oxygen consumption, but had...... no effect on glucose uptake. We conclude that T4-stimulated glucose uptake in human mononuclear blood cells is dependent on intact glucose transporters and Ca2+ influx, but not on mitochondrial oxygen consumption. However, oxygen consumption is, in part, dependent on intact glucose uptake....

  6. Safety information on QT-interval prolongation

    DEFF Research Database (Denmark)

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

    2014-01-01

    Prolongation of the QT interval can predispose to fatal ventricular arrhythmias. Differences in QT-labeling language can result in miscommunication and suboptimal risk mitigation. We systematically compared the phraseology used to communicate on QT-prolonging properties of 144 drugs newly approve...

  7. Risk factors for QTc interval prolongation

    NARCIS (Netherlands)

    Heemskerk, Charlotte P.M.; Pereboom, Marieke; van Stralen, Karlijn; Berger, Florine A.; van den Bemt, Patricia M.L.A.; Kuijper, Aaf F.M.; van der Hoeven, Ruud T M; Mantel-Teeuwisse, Aukje K.; Becker, Matthijs L

    2018-01-01

    Purpose: Prolongation of the QTc interval may result in Torsade de Pointes, a ventricular arrhythmia. Numerous risk factors for QTc interval prolongation have been described, including the use of certain drugs. In clinical practice, there is much debate about the management of the risks involved. In

  8. Prenatal risk indicators of a prolonged pregnancy

    DEFF Research Database (Denmark)

    Olesen, Annette Wind; Westergaard, Jes Grabow; Olsen, Jørn

    2006-01-01

    BACKGROUND: Few prenatal risk factors of prolonged pregnancy, a pregnancy of 42 weeks or more, are known. The objective was to examine whether sociodemographic, reproductive, toxicologic, or medical health conditions were associated with the risk of prolonged pregnancy. METHODS: Data from...

  9. Kinin B1 receptor blockade and ACE inhibition attenuate cardiac postinfarction remodeling and heart failure in rats

    International Nuclear Information System (INIS)

    Lin, Xinchun; Bernloehr, Christian; Hildebrandt, Tobias; Stadler, Florian J.; Doods, Henri; Wu, Dongmei

    2016-01-01

    Introduction: The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results: Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, and improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion: The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor. - Highlights: • We examined the role of kinin B1 receptors in the development of heart failure. • Kinin B1 receptor blockade attenuates post-infarction cardiac remodeling. • Kinin B1 receptor blockade improves dysfunction, and prevented heart failure. • B1 receptor blockade does not affect the cardio-protection of an ACE inhibitor.

  10. Kinin B1 receptor blockade and ACE inhibition attenuate cardiac postinfarction remodeling and heart failure in rats

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Xinchun [Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140 (United States); Bernloehr, Christian; Hildebrandt, Tobias [Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach (Germany); Stadler, Florian J., E-mail: fjstadler@szu.edu.cn [Shenzhen Engineering Laboratory for Advanced Technology of Ceramics, Shenzhen 518060 (China); Doods, Henri [Boehringer Ingelheim Pharma GmbH & Co.KG, Biberach (Germany); Wu, Dongmei, E-mail: dongmeiwu@bellsouth.net [Department of Research, Mount Sinai Medical Center, Miami Beach, FL 33140 (United States); Department of BIN Convergence Technology, Chonbuk National University (Korea, Republic of)

    2016-08-15

    Introduction: The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results: Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, and improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion: The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor. - Highlights: • We examined the role of kinin B1 receptors in the development of heart failure. • Kinin B1 receptor blockade attenuates post-infarction cardiac remodeling. • Kinin B1 receptor blockade improves dysfunction, and prevented heart failure. • B1 receptor blockade does not affect the cardio-protection of an ACE inhibitor.

  11. [Brain function recovery after prolonged posttraumatic coma].

    Science.gov (United States)

    Klimash, A V; Zhanaidarov, Z S

    2016-01-01

    To explore the characteristics of brain function recovery in patients after prolonged posttraumatic coma and with long-unconscious states. Eighty-seven patients after prolonged posttraumatic coma were followed-up for two years. An analysis of a clinical/neurological picture after a prolonged episode of coma was based on the dynamics of vital functions, neurological status and patient's reactions to external stimuli. Based on the dynamics of the clinical/neurological picture that shows the recovery of functions of the certain brain areas, three stages of brain function recovery after a prolonged episode of coma were singled out: brain stem areas, diencephalic areas and telencephalic areas. These functional/anatomic areas of brain function recovery after prolonged coma were compared to the present classifications.

  12. 9. Nuclear power plant service life prolongation

    International Nuclear Information System (INIS)

    Evropin, S.V.

    1998-01-01

    The problem of prolongation of nuclear power plant service life duration is discussed. A schematic diagram of the program developed in the course of activities dealing with NPP service time prolongation is shown and analyzed in details. It is shown that the basic moment when determining the strategy for NPP service time prolongation is the positive confirmation of the agreement between the NPP safety provisions and modern safety requirements. The other very important aspect of the problem is engineering substantiation of the measures assuring the reactor operation prolongation. The conclusion is made that available methods of recovering reactor materials properties, main components repair and replacement, the modern techniques for nondestructive testing of metals and NPP pipelines, as well as the developed approaches to reactor facility safety improvements make the prolongation of the Russian NPP service lifetimes possible from engineering viewpoint and economically desirable

  13. Intercostal nerve blockade with a mixture of bupivacaine and phenol enhance the efficacy of intravenous patient-controlled analgesia in the control of post-cholecystectomy pain.

    Science.gov (United States)

    Maidatsi, P; Gorgias, N; Zaralidou, A; Ourailoglou, V; Giala, M

    1998-09-01

    Prolonged nerve conduction blockade has been proposed to result from the summed effects of charged and neutral local anaesthetics. Thirty-seven patients were randomly allocated to receive intravenous patient-controlled analgesia alone or combined with intercostal blockade (T7-T11) with a mixture of 0.45% bupivacaine and 0.6% phenol for post-cholecystectomy analgesia. Adequacy of pain relief was measured by patient scores on a 10-cm visual analogue scale and by dose-demand ratio, amounts of loading dose and total consumption of morphine and also the duration of patient-controlled analgesia in each group. No differences were found between groups in post-operative scores, dose-demand ratios and loading doses of morphine. However, in the combined treatment group, a significantly lower total consumption of morphine (P < 0.05), associated with a shorter duration of patient-controlled analgesia (P < 0.02) and a decreased mean number of unsuccessful demands (P < 0.001) were recorded. Intercostal blockade with bupivacaine-phenol supplements intravenous patient-controlled analgesia for post-cholecystectomy pain relief.

  14. Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

    Science.gov (United States)

    Holmgaard, Rikke B.; Brachfeld, Alexandra; Gasmi, Billel; Jones, David R.; Mattar, Marissa; Doman, Thompson; Murphy, Mary; Schaer, David; Wolchok, Jedd D.; Merghoub, Taha

    2016-01-01

    ABSTRACT Colony stimulating factor-1 (CSF-1) is produced by a variety of cancers and recruits myeloid cells that suppress antitumor immunity, including myeloid-derived suppressor cells (MDSCs.) Here, we show that both CSF-1 and its receptor (CSF-1R) are frequently expressed in tumors from cancer patients, and that this expression correlates with tumor-infiltration of MDSCs. Furthermore, we demonstrate that these tumor-infiltrating MDSCs are highly immunosuppressive but can be reprogrammed toward an antitumor phenotype in vitro upon CSF-1/CSF-1R signaling blockade. Supporting these findings, we show that inhibition of CSF-1/CSF-1R signaling using an anti-CSF-1R antibody can regulate both the number and the function of MDSCs in murine tumors in vivo. We further find that treatment with anti-CSF-1R antibody induces antitumor T-cell responses and tumor regression in multiple tumor models when combined with CTLA-4 blockade therapy. However, this occurs only when administered after or concurrent with CTLA-4 blockade, indicating that timing of each therapeutic intervention is critical for optimal antitumor responses. Importantly, MDSCs present within murine tumors after CTLA-4 blockade showed increased expression of CSF-1R and were capable of suppressing T cell proliferation, and CSF-1/CSF-1R expression in the human tumors was not reduced after treatment with CTLA-4 blockade immunotherapy. Taken together, our findings suggest that CSF-1R-expressing MDSCs can be targeted to modulate the tumor microenvironment and that timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to checkpoint based immunotherapy. Significance: Infiltration by immunosuppressive myeloid cells contributes to tumor immune escape and can render patients resistant or less responsive to therapeutic intervention with checkpoint blocking antibodies. Our data demonstrate that blocking CSF-1/CSF-1R signaling using a monoclonal antibody directed to CSF-1R can regulate both the number

  15. Prolonged local anesthetic action through slow release from poly (lactic acid co castor oil).

    Science.gov (United States)

    Sokolsky-Papkov, Marina; Golovanevski, Ludmila; Domb, Abraham J; Weiniger, Carolyn F

    2009-01-01

    To evaluate a new formulation of bupivacaine loaded in an injectable fatty acid based biodegradable polymer poly(lactic acid co castor oil) in prolonging motor and sensory block when injected locally. The polyesters were synthesized from DL: -lactic acid and castor oil with feed ratio of 4:6 and 3:7 w/w. Bupivacaine was dispersed in poly(fatty ester) liquid and tested for drug release in vitro. The polymer p(DLLA:CO) 3:7 loaded with 10% bupivacaine was injected through a 22G needle close to the sciatic nerve of ICR mice and the duration of sensory and motor nerve blockade was measured. The DL: -lactic acid co castor oil p(DLLA:CO) 3:7 released 65% of the incorporated bupivacaine during 1 week in vitro. Single injection of 10% bupivacaine loaded into this polymer caused motor block that lasted 24 h and sensory block that lasted 48 h. Previously we developed a ricinoleic acid based polymer with incorporated bupivacaine which prolonged anesthesia to 30 h. The new polymer poly(lactic acid co castor oil) 3:7 provides slow release of effective doses of the incorporated local anesthetic agent and prolongs anesthesia to 48 h.

  16. The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation

    Directory of Open Access Journals (Sweden)

    Kannan P. Samy

    2017-01-01

    Full Text Available Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb and islet xenotransplantation (>600 days with anti-CD154mAb with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.

  17. Features of History, Anthropometric Data and Individual Functions of the Liver in Children with Prolonged Jaundice

    Directory of Open Access Journals (Sweden)

    O.V. Tyajka

    2016-11-01

    Full Text Available Background. Neonatal jaundice is one of the urgent problems in neonatology. There is a tendency to increase the incidence of prolonged jaundice. The aim of our study was to explore the features of history, anthropometric data and some liver functions in children with prolonged jaundice. Materials and methods. The study involved 111 children with prolonged jaundice aged from 3 weeks to 3 months. In all children with prolonged jaundice, we have examined complete blood count, urinalysis, blood chemistry (determination of total bilirubin and fractions, total protein, albumin, glucose and used instrumental methods of examination — ultrasound of the abdominal cavity and cranial ultrasonography, electrocardiography. Most children with prolonged jaundice were breastfed and were term infants. Results. Indicators of physical development at birth (body weight, body length, head circumference, chest circumference in children with prolonged jaundice and in healthy children had not statistically significant differences. Neonatal jaundice was prolonged in children, who were born from the first pregnancy, — 60 children (54.1 %. A high level of total and indirect bilirubin was accompanied by a low level of albumin in the blood serum of children with prolonged jaundice. Protein-synthesis function of the liver was reduced in children with prolonged jaundice.

  18. Coherent-feedback-induced controllable optical bistability and photon blockade

    International Nuclear Information System (INIS)

    Liu, Yu-Long; Liu, Zhong-Peng; Zhang, Jing

    2015-01-01

    It is well known that some nonlinear phenomena such as strong photon blockade are difficult to observe in optomechanical systems with current experimental technology. Here we present a coherent feedback control strategy in which a linear cavity is coherently controlled by an optomechanical controller in a feedback manner. The coherent feedback loop transfers quantum nonlinearity from the controller to the controlled cavity causing destructive quantum interference to occur, and making it possible to observe strong nonlinear effects. With the help of the coherent feedback loop, large and tunable bistability and strong photon blockade of the cavity modes can be achieved even in the optomechanical weak coupling regime. Additionally, the coherent feedback loop leads to two-photon and multiphoton tunnelings for the controlled linear cavity, which are also typical quantum nonlinear phenomena. We hope that our work can give new perspectives on engineering nonlinear interactions in quantum systems. (paper)

  19. Berry-phase blockade in single-molecule magnets

    OpenAIRE

    Gonzalez, Gabriel; Leuenberger, Michael N.

    2006-01-01

    We formulate the problem of electron transport through a single-molecule magnet (SMM) in the Coulomb blockade regime taking into account topological interference effects for the tunneling of the large spin of a SMM. The interference originates from spin Berry phases associated with different tunneling paths. We show that in the case of incoherent spin states it is essential to place the SMM between oppositely spin-polarized source and drain leads in order to detect the spin tunneling in the s...

  20. Chemical pleurodesis for prolonged postoperative air leak in primary spontaneous pneumothorax

    Directory of Open Access Journals (Sweden)

    Cheng-Hung How

    2014-05-01

    Conclusion: Chemical pleurodesis using OK-432 or minocycline is safe and convenient for prolonged air leak after thoracoscopic treatment for PSP. Our experience suggested that OK-432 may be more effective than minocycline in reducing air leak.

  1. Silent ischemia and beta-blockade

    DEFF Research Database (Denmark)

    Egstrup, K

    1991-01-01

    and should also be directed at the other coronary artery risk factors of the patients. The effects of beta-blockers, which reduce the duration and frequency of silent ischemic episodes, is well described. The effect is most pronounced in the morning, when the frequency of ischemia is highest......, and the mechanism of action seems mainly mediated through a reduction in myocardial oxygen demand. beta-Blockers have shown effectiveness in both effort-induced angina and mixed angina, and increased anti-ischemic potency may be achieved by combination therapy with a calcium antagonist. Abrupt withdrawal of beta-blockers...

  2. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4+CTLA4hi T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade

    Directory of Open Access Journals (Sweden)

    Mohamed B. Ezzelarab

    2018-02-01

    Full Text Available Donor-derived regulatory dendritic cell (DCreg infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag 4 (CTLA4 and programmed cell death protein 1 (PD1 by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig is associated with reduced differentiation and development of regulatory T cells (Treg. We hypothesized that upregulation of CTLA4 by donor-reactive CD4+ T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4+ T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4+CTLA4hi, but not CD4+CTLA4med/lo T cells following allo-stimulation, associated with a significant reduction in the CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4+CTLA4hi T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4+CTLA4hi/CD4+CTLA4med/lo T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4+CTLA4hi T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade.

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

    Directory of Open Access Journals (Sweden)

    Hemmerling Thomas

    2008-01-01

    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.

  4. Risk Factors of Prolonged Hospitalization in Patients with Hyperemesis Gravidarum

    Directory of Open Access Journals (Sweden)

    Hasan Onur Topcu

    2015-03-01

    Conclusion: Number of vomiting per day and maternal serum TSH levels could help physicians to estimate the risk of prolonged hospitalization; however further investigations are needed in large population studies. Identifying the high risk patients is important both for prevention of HEG and beginning appropriate antiemetic treatment to avoid complications to reduce the economic costs. [Cukurova Med J 2015; 40(1.000: 113-118

  5. Prolonged CT urography in duplex kidney.

    Science.gov (United States)

    Gong, Honghan; Gao, Lei; Dai, Xi-Jian; Zhou, Fuqing; Zhang, Ning; Zeng, Xianjun; Jiang, Jian; He, Laichang

    2016-05-13

    Duplex kidney is a common anomaly that is frequently associated with multiple complications. Typical computed tomography urography (CTU) includes four phases (unenhanced, arterial, parenchymal and excretory) and has been suggested to considerably aid in the duplex kidney diagnosi. Unfortunately, regarding duplex kidney with prolonged dilatation, the affected parenchyma and tortuous ureters demonstrate a lack of or delayed excretory opacification. We used prolonged-delay CTU, which consists of another prolonged-delay phase (1- to 72-h delay; mean delay: 24 h) to opacify the duplicated ureters and affected parenchyma. Seventeen patients (9 males and 8 females; age range: 2.5-56 y; mean age: 40.4 y) with duplex kidney were included in this study. Unenhanced scans did not find typical characteristics of duplex kidney, except for irregular perirenal morphology. Duplex kidney could not be confirmed on typical four-phase CTU, whereas it could be easily diagnosed in axial and CT-3D reconstruction using prolonged CTU (prolonged-delay phase). Between January 2005 and October 2010, in this review board-approved study (with waived informed consent), 17 patients (9 males and 8 females; age range: 2.5 ~ 56 y; mean age: 40.4 y) with suspicious duplex kidney underwent prolonged CTU to opacify the duplicated ureters and confirm the diagnosis. Our results suggest the validity of prolonged CTU to aid in the evaluation of the function of the affected parenchyma and in the demonstration of urinary tract malformations.

  6. Licence prolongations of US nuclear power plants

    International Nuclear Information System (INIS)

    2004-04-01

    Licences of US nuclear reactors were initially attributed for a 40 years duration. However, the vast majority of the reactors can benefit of a licence prolongation for a period of 20 years maximum. This article recalls first the procedure to follow for the licence prolongation demands (safety analysis, components aging, environmental impact statement), and then it makes a status of the accepted prolongations, of the demands under examination, and of the demands that should be presented in the next 5 years. (J.S.)

  7. Adrenergic blockade in diabetic and uninephrectomized rats

    DEFF Research Database (Denmark)

    Thulesen, J; Poulsen, Steen Seier; Jørgensen, P E

    1999-01-01

    The present study reports on the effects of adrenergic blocking agents on the renal growth and on the renal content and urinary excretion of epidermal growth factor (EGF) in streptozotocin-induced diabetic or uninephrectomized rats. Diabetic and uninephrectomized rats were allocated to groups...... treated with either saline or adrenergic antagonists and compared to controls and sham-operated controls, respectively. 24-hour urine samples were obtained on days 7, 14, and 21 and renal tissue samples on day 21. The 24-hour urinary excretion of EGF from controls and saline-treated diabetic rats...... was comparable. In adrenergic antagonist treated diabetic rats, it was reduced by at least 40% throughout the study period. Uninephrectomy caused a 50% reduction in the urinary excretion of EGF. This was not influenced by treatment with an adrenergic antagonist. After 3 weeks, saline-treated diabetic rats had...

  8. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    Science.gov (United States)

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  9. Nicotinic receptor blockade decreases fos immunoreactivity within orexin/hypocretin-expressing neurons of nicotine-exposed rats.

    Science.gov (United States)

    Simmons, Steven J; Gentile, Taylor A; Mo, Lili; Tran, Fionya H; Ma, Sisi; Muschamp, John W

    2016-11-01

    Tobacco smoking is the leading cause of preventable death in the United States. Nicotine is the principal psychoactive ingredient in tobacco that causes addiction. The structures governing nicotine addiction, including those underlying withdrawal, are still being explored. Nicotine withdrawal is characterized by negative affective and cognitive symptoms that enhance relapse susceptibility, and suppressed dopaminergic transmission from ventral tegmental area (VTA) to target structures underlies behavioral symptoms of nicotine withdrawal. Agonist and partial agonist therapies help 1 in 4 treatment-seeking smokers at one-year post-cessation, and new targets are needed to more effectively aid smokers attempting to quit. Hypothalamic orexin/hypocretin neurons send excitatory projections to dopamine (DA)-producing neurons of VTA and modulate mesoaccumbal DA release. The effects of nicotinic receptor blockade, which is commonly used to precipitate withdrawal, on orexin neurons remain poorly investigated and present an attractive target for intervention. The present study sought to investigate the effects of nicotinic receptor blockade on hypothalamic orexin neurons using mecamylamine to precipitate withdrawal in rats. Separate groups of rats were treated with either chronic nicotine or saline for 7-days at which point effects of mecamylamine or saline on somatic signs and anxiety-like behavior were assessed. Finally, tissue from rats was harvested for immunofluorescent analysis of Fos within orexin neurons. Results demonstrate that nicotinic receptor blockade leads to reduced orexin cell activity, as indicated by lowered Fos-immunoreactivity, and suggest that this underlying cellular activity may be associated with symptoms of nicotine withdrawal as effects were most prominently observed in rats given chronic nicotine. We conclude from this study that orexin transmission becomes suppressed in rats upon nicotinic receptor blockade, and that behavioral symptoms associated

  10. Eomesodermin(lo) CTLA4(hi) Alloreactive CD8+ Memory T Cells Are Associated With Prolonged Renal Transplant Survival Induced by Regulatory Dendritic Cell Infusion in CTLA4 Immunoglobulin-Treated Nonhuman Primates.

    Science.gov (United States)

    Ezzelarab, Mohamed B; Lu, Lien; Guo, Hao; Zahorchak, Alan F; Shufesky, William F; Cooper, David K C; Morelli, Adrian E; Thomson, Angus W

    2016-01-01

    Memory T cells (Tmem), particularly those resistant to costimulation blockade (CB), are a major barrier to transplant tolerance. The transcription factor Eomesodermin (Eomes) is critical for Tmem development and maintenance, but its expression by alloactivated T cells has not been examined in nonhuman primates. We evaluated Eomes and coinhibitory cytotoxic T lymphocyte antigen-4 (CTLA4) expression by alloactivated rhesus monkey T cells in the presence of CTLA4 immunoglobulin, both in vitro and in renal allograft recipients treated with CTLA4Ig, with or without regulatory dendritic cell (DCreg) infusion. In normal monkeys, CD8+ T cells expressed significantly more Eomes than CD4+ T cells. By contrast, CD8+ T cells displayed minimal CTLA4. Among T cell subsets, central Tmem (Tcm) expressed the highest levels of Eomes. Notably, Eomes(lo)CTLA4(hi) cells displayed higher levels of CD25 and Foxp3 than Eomes(hi)CTLA4(lo) CD8+ T cells. After allostimulation, distinct proliferating Eomes(lo)CTLA4(hi) and Eomes(hi)CTLA4(lo) CD8+ T cell populations were identified, with a high proportion of Tcm being Eomes(lo)CTLA4(hi). CB with CTLA4Ig during allostimulation of CD8+ T cells reduced CTLA4 but not Eomes expression, significantly reducing Eomes(lo)CTLA4(hi) cells. After transplantation with CB and rapamycin, donor-reactive Eomes(lo)CTLA4(hi) CD8+ T cells were reduced. However, in monkeys also given DCreg, absolute numbers of these cells were elevated significantly. Low Eomes and high CTLA4 expression by donor-reactive CD8+ Tmem is associated with prolonged renal allograft survival induced by DCreg infusion in CTLA4Ig-treated monkeys. Prolonged allograft survival associated with DCreg infusion may be related to maintenance of donor-reactive Eomes(lo)CTLA4(hi) Tcm.

  11. Eomesoderminlo CTLA4hi Alloreactive CD8+ Memory T Cells Are Associated With Prolonged Renal Transplant Survival Induced by Regulatory Dendritic Cell Infusion in CTLA4Ig-Treated Non-Human Primates

    Science.gov (United States)

    Ezzelarab, Mohamed B.; Lu, Lien; Guo, Hao; Zahorchak, Alan F.; Shufesky, William F.; Cooper, David K.C.; Morelli, Adrian E.; Thomson, Angus W.

    2015-01-01

    Background Memory T cells (Tmem), particularly those resistant to costimulation blockade (CB), are a major barrier to transplant tolerance. The transcription factor Eomesodermin (Eomes) is critical for Tmem development and maintenance, but its expression by alloactivated T cells has not been examined in non-human primates. Methods We evaluated Eomes and co-inhibitory cytotoxic T lymphocyte antigen-4 (CTLA4) expression by alloactivated rhesus monkey T cells in the presence of CTLA4 immunoglobulin (Ig), both in vitro and in renal allograft recipients treated with CTLA4Ig, with or without regulatory dendritic cell (DCreg) infusion. Results In normal monkeys, CD8+ T cells expressed significantly more Eomes than CD4+T cells. By contrast, CD8+T cells displayed minimal CTLA4. Among T cell subsets, central Tmem (Tcm) expressed the highest levels of Eomes. Notably, EomesloCTLA4hi cells displayed higher levels of CD25 and Foxp3 than EomeshiCTLA4lo CD8+ T cells. Following allostimulation, distinct proliferating EomesloCTLA4hi and EomeshiCTLA4lo CD8+ T cell populations were identified, with a high proportion of Tcm being EomesloCTLA4hi. CB with CTLA4Ig during allostimulation of CD8+T cells reduced CTLA4 but not Eomes expression, significantly reducing EomesloCTLA4hi cells. After transplantation with CB and rapamycin, donor-reactive EomesloCTLA4hi CD8+T cells were reduced. However, in monkeys also given DCreg, absolute numbers of these cells were elevated significantly. Conclusions Low Eomes and high CTLA4 expression by donor-reactive CD8+ Tmem is associated with prolonged renal allograft survival induced by DCreg infusion in CTLA4Ig-treated monkeys. Prolonged allograft survival associated with DCreg infusion may be related to maintenance of donor-reactive EomesloCTLA4hi Tcm. PMID:26680373

  12. Prolonged delirium misdiagnosed as a mood disorder.

    Science.gov (United States)

    Cao, Fei; Salem, Haitham; Nagpal, Caesa; Teixeira, Antonio L

    2017-01-01

    Delirium can be conceptualized as an acute decline in cognitive function that typically lasts from hours to a few days. Prolonged delirium can also affect patients with multiple predisposing and/or precipitating factors. In clinical practice, prolonged delirium is often unrecognized, and can be misdiagnosed as other psychiatric disorders. We describe a case of a 59-year-old male presenting with behavioral and cognitive symptoms that was first misdiagnosed as a mood disorder in a general hospital setting. After prolonged delirium due to multiple factors was confirmed, the patient was treated accordingly with symptomatic management. He evolved with progressive improvement of his clinical status. Early diagnosis and management of prolonged delirium are important to improve patient prognosis and avoid iatrogenic measures.

  13. QT Prolongation due to Graves’ Disease

    Directory of Open Access Journals (Sweden)

    Zain Kulairi

    2017-01-01

    Full Text Available Hyperthyroidism is a highly prevalent disease affecting over 4 million people in the US. The disease is associated with many cardiac complications including atrial fibrillation and also less commonly with ventricular tachycardia and fibrillation. Many cardiac pathologies have been extensively studied; however, the relationship between hyperthyroidism and rate of ventricular repolarization manifesting as a prolonged QTc interval is not well known. Prolonged QTc interval regardless of thyroid status is a risk factor for cardiovascular mortality and life-threatening ventricular arrhythmia. The mechanism regarding the prolongation of the QT interval in a hyperthyroid patient has not been extensively investigated although its clinical implications are relevant. Herein, we describe a case of prolonged QTc in a patient who presented with signs of hyperthyroidism that was corrected with return to euthyroid status.

  14. Prolonged parenteral nutrition after neonatal gastrointestinal surgery

    DEFF Research Database (Denmark)

    Estmann, Anne; Qvist, Niels; Husby, Steffen

    2002-01-01

    to diagnosis and clinical course. METHODOLOGY: This study reviews the clinical course of infants with gastrointestinal disease (gastroschisis, intestinal atresia, omphalocele, volvulus, Hirschsprung's disease and necrotizing enterocolitis) with a prolonged need for parenteral nutrition in the Western part...

  15. Prolonged Pregnancy: Methods, Causal Determinants and Outcome

    DEFF Research Database (Denmark)

    Olesen, Annette Wind

    ) to study the incidence of prolonged pregnancy as a function of methods for determining gestational age; 2) to determine the risk of obstetrical and fetal complications in prolonged pregnancy; 3) to validate the self-reported gestational age in the National Birth Cohort; 4) to determine whether...... an ultrasound scan in the first or second trimester, or menstrual history was best at predicting the day of delivery; 5) to study the risk of recurrence of prolonged pregnancy as a function of change in male partner, social status and municipality; and 6) to detect prenatal risk indicators of prolonged...... of perinatal and obstetrical complications was high in post-term delivery compared to term delivery (OR between 1.2 and 3.1). The risk of perinatal death (OR=1.36 (1.08-1.72)) was also higher in the post-term group (I). The self-reported gestational ages in the National Birth Cohort correlated well with data...

  16. Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study

    Directory of Open Access Journals (Sweden)

    Velayudha Sidda Reddy

    2013-01-01

    Full Text Available Background: Alpha 2 -adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory, motor blockade and postoperative analgesia obtained with spinal anesthesia. Aim: The objectives of this study are to compare and evaluate the efficacy of intravenous dexmedetomidine premedication with clonidine and placebo on spinal blockade duration, postoperative analgesia and sedation in patients undergoing surgery under bupivacaine intrathecal block. Materials and Methods: In this prospective, randomized, double-blind placebo-controlled study, 75 patients of the American Society of Anesthesiologists status I or II, scheduled for orthopedic lower limb surgery under spinal anesthesia, were randomly allocated into three groups of 25 each. Group DE received dexmedetomidine 0.5 μgkg−1 , group CL received clonidine 1.0 μgkg−1 and placebo group PL received 10 ml of normal saline intravenously before subarachnoid anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset time and regression times of sensory and motor blockade, the maximum upper level of sensory blockade were recorded. Duration of postoperative analgesia and sedation scores along with side effects were also recorded. Data was analyzed using analysis of variance or Chi-square test, and the value of P < 0.05 was considered statistically significant. Results: The sensory block level was higher with dexmedetomidine (T4 ± 1 than clonidine (T6 ± 1 or placebo (T6 ± 2. Dexmedetomidine also increased the time (243.35 ± 56.82 min to first postoperative analgesic request compared with clonidine (190.93 ± 42.38 min, P < 0.0001 and placebo (140.75 ± 28.52 min, P < 0.0001. The maximum Ramsay sedation score was greater in the dexmedetomidine group than other two groups (P < 0.0001. Conclusion: Premedication with intravenous dexmedetomidine is better than intravenous clonidine to provide intraoperative sedation and postoperative analgesia during bupivacaine

  17. Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study

    Science.gov (United States)

    Reddy, Velayudha Sidda; Shaik, Nawaz Ahmed; Donthu, Balaji; Reddy Sannala, Venkata Krishna; Jangam, Venkatsiva

    2013-01-01

    Background: Alpha2-adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory, motor blockade and postoperative analgesia obtained with spinal anesthesia. Aim: The objectives of this study are to compare and evaluate the efficacy of intravenous dexmedetomidine premedication with clonidine and placebo on spinal blockade duration, postoperative analgesia and sedation in patients undergoing surgery under bupivacaine intrathecal block. Materials and Methods: In this prospective, randomized, double-blind placebo-controlled study, 75 patients of the American Society of Anesthesiologists status I or II, scheduled for orthopedic lower limb surgery under spinal anesthesia, were randomly allocated into three groups of 25 each. Group DE received dexmedetomidine 0.5 μgkg−1, group CL received clonidine 1.0 μgkg−1 and placebo group PL received 10 ml of normal saline intravenously before subarachnoid anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset time and regression times of sensory and motor blockade, the maximum upper level of sensory blockade were recorded. Duration of postoperative analgesia and sedation scores along with side effects were also recorded. Data was analyzed using analysis of variance or Chi-square test, and the value of P < 0.05 was considered statistically significant. Results: The sensory block level was higher with dexmedetomidine (T4 ± 1) than clonidine (T6 ± 1) or placebo (T6 ± 2). Dexmedetomidine also increased the time (243.35 ± 56.82 min) to first postoperative analgesic request compared with clonidine (190.93 ± 42.38 min, P < 0.0001) and placebo (140.75 ± 28.52 min, P < 0.0001). The maximum Ramsay sedation score was greater in the dexmedetomidine group than other two groups (P < 0.0001). Conclusion: Premedication with intravenous dexmedetomidine is better than intravenous clonidine to provide intraoperative sedation and postoperative analgesia during bupivacaine spinal anesthesia

  18. QT interval prolongation associated with sibutramine treatment

    Science.gov (United States)

    Harrison-Woolrych, Mira; Clark, David W J; Hill, Geraldine R; Rees, Mark I; Skinner, Jonathan R

    2006-01-01

    Aims To investigate a possible association of sibutramine with QT interval prolongation. Methods Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. Results The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QTc at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. Conclusions This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval. PMID:16542208

  19. 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

    2014-01-01

    : In this assessor-blinded study, 48 patients undergoing elective laparoscopic cholecystectomy were administered rocuronium for neuromuscular blockade and randomized to either deep neuromuscular blockade (rocuronium bolus plus infusion maintaining a posttetanic count 0-1) or moderate neuromuscular blockade...... (rocuronium repeat bolus only for inadequate surgical conditions with spontaneous recovery of neuromuscular function). Patients received anesthesia with propofol, remifentanil, and rocuronium. The primary outcome was the proportion of procedures with optimal surgical space conditions (assessed by the surgeon...

  20. Prolonged Exposure Therapy For Post Traumatic Stress Disorder

    Directory of Open Access Journals (Sweden)

    Levent SÜTÇÝGÝL

    2012-08-01

    Full Text Available Post-traumatic Stress Disorder (PTSD is a psychiatric illness that usually develops after an event that threatens one’s life and body integrity and it affects quality of life and impairs social functioning significantly. Many studies have shown therapeutic effect of cognitive behavioral therapies on posttraumatic stress disorder, so that these therapies take part in the first step of treatment guides. Exposure is a practice that is generally used to reduce pathological fear and related emotions common in posttraumatic stress disorder (PTSD and other anxiety disorders. During exposure, patients intentionally confront with feared objects, situations, thoughts and similar stimuli in order to reduce anxiety level. Exposure can be divided into two main techniques as in vivo exposure and imaginal exposure. Prolonged exposure therapy is a specialized treatment program configured for the treatment of posttraumatic stress disorder and it is based on emotional processing theory. Program is comprised of four main components: (a Psycho-education about trauma and posttraumatic disorders, (b Training for breathing exercises, (c repeated facing with objects, persons, situations and thoughts which causes re-experience about trauma, (d Patient are instructed for telling repeatedly and loudly about traumatic experiences . Prolonged exposure usually involves 9 to 12 sessions, each lasting about 60-90 minutes, administered once or twice a week. Prolonged exposure therapy was started to be implemented since the 1980s, during this period the effectiveness of the therapy has been shown in various empirical studies. [JCBPR 2012; 1(2.000: 98-104

  1. Prolonged Exposure Therapy For Post Traumatic Stress Disorder

    Directory of Open Access Journals (Sweden)

    Levent SÜTÇİGİL

    2012-07-01

    Full Text Available Post-traumatic Stress Disorder (PTSD is a psychiatric illness that usually develops after an event that threatens one’s life and body integrity and it affects quality of life and impairs social functioning significantly. Many studies have shown therapeutic effect of cognitive behavioral therapies on posttraumatic stress disorder, so that these therapies take part in the first step of treatment guides. Exposure is a practice that is generally used to reduce pathological fear and related emotions common in posttraumatic stress disorder (PTSD and other anxiety disorders. During exposure, patients intentionally confront with feared objects, situations, thoughts and similar stimuli in order to reduce anxiety level. Exposure can be divided into two main techniques as in vivo exposure and imaginal exposure. Prolonged exposure therapy is a specialized treatment program configured for the treatment of posttraumatic stress disorder and it is based on emotional processing theory. Program is comprised of four main components: (a Psycho-education about trauma and posttraumatic disorders, (b Training for breathing exercises, (c repeated facing with objects, persons, situations and thoughts which causes re-experience about trauma, (d Patient are instructed for telling repeatedly and loudly about traumatic experiences . Prolonged exposure usually involves 9 to 12 sessions, each lasting about 60-90 minutes, administered once or twice a week. Prolonged exposure therapy was started to be implemented since the 1980s, during this period the effectiveness of the therapy has been shown in various empirical studies.

  2. Quality of drug label information on QT interval prolongation

    DEFF Research Database (Denmark)

    Warnier, Miriam J; Holtkamp, Frank A; Rutten, Frans H

    2014-01-01

    BACKGROUND: Information regarding QT-prolongation in the drug label may vary between products. This could lead to suboptimal risk minimization strategies. OBJECTIVE: To systematically assess the variation in the extent and content of information on QT prolongation in the summary of product......-prolongation'/'QT-prolongation') and the advice on cautionary measures pertaining to QT-prolongation in the label were examined, as well as their association. RESULTS: Of the 175 screened products, 44 contained information on QT in the SPC ('no QT-prolongation': 23%, 'unclear drug-QT association': 43%, 'possibly QT-prolongation': 16%, 'QT......-prolongation': 18%). 62% contained advices to act with caution in patients with additional risk factors for QT-prolongation. Products that more likely to have QT-prolonging properties according to the SPC provided more information on QT-prolongation in the SPC ('no prolongation': 10% and for the category 'QT...

  3. 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

    2008-01-01

    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......Saline administration may change renin system (RAAS) activity and sodium excretion at constant mean arterial pressure (MAP). We hypothesized that such responses are elicited mainly by renal sympathetic nerve activity by beta1-receptors (beta1-RSNA), and tested the hypothesis by studying RAAS......-loading decreased plasma renin (PRC) by 1/3, AngII by 1/2, and aldosterone (pAldo) by 2/3, (all psodium excretion increased indistinguishably with and without metoprolol (16+/-2 to 71...

  4. Management of Residual Neuromuscular Blockade Recovery: Age-Old Problem with a New Solution

    Directory of Open Access Journals (Sweden)

    Michael S. Green

    2017-01-01

    Full Text Available Neostigmine has been traditionally used as the agent of choice to reverse Neuromuscular Blockade (NMB after muscle paralysis during general anesthesia. However, the use of neostigmine has not been without untoward events. Sugammadex is a novel drug that selectively binds to aminosteroid nondepolarizing muscle relaxants and reverses even a deep level of NMB. Controversy exists regarding the optimal dose of sugammadex that is effective in reversing the NMB after the incomplete reversal with neostigmine and glycopyrrolate. We discuss a case where sugammadex reduced the time of the recovery from NMB in a patient who had incomplete antagonisms following adequate treatment with neostigmine, aiding timely extubation without persistent residual NMB, and hence prevented the requirement of postoperative ventilation and the improvement in patient care. More randomized control studies are needed in order to conclude the appropriate dose of sugammadex in cases of incomplete reversal.

  5. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy

    DEFF Research Database (Denmark)

    Andersen, S; Tarnow, L; Rossing, P

    2000-01-01

    BACKGROUND: Angiotensin I-converting enzyme (ACE) inhibitors reduce angiotensin II formation and induce bradykinin accumulation. Animal studies suggest that bradykinin may play a role for the effects of ACE inhibition on blood pressure and kidney function. Therefore, we compared the renal and hem...... inhibition is primarily caused by interference in the renin-angiotensin system. Our study suggest that losartan represents a valuable new drug in the treatment of hypertension and proteinuria in type 1 diabetic patients with diabetic nephropathy....... and hemodynamic effects of specific intervention in the renin-angiotensin system by blockade of the angiotensin II subtype-1 receptor to the effect of ACE inhibition. METHODS: A randomized, double-blind, cross-over trial was performed in 16 type 1 diabetic patients (10 men), age 42 +/- 2 years (mean +/- SEM...

  6. Autonomic Blockade Reverses Endothelial Dysfunction in Obesity-Associated Hypertension.

    Science.gov (United States)

    Gamboa, Alfredo; Figueroa, Rocío; Paranjape, Sachin Y; Farley, Ginnie; Diedrich, Andre; Biaggioni, Italo

    2016-10-01

    Impaired nitric oxide (NO) vasodilation (endothelial dysfunction) is associated with obesity and thought to be a factor in the development of hypertension. We previously found that NO synthesis inhibition had similar pressor effects in obese hypertensives compared with healthy control during autonomic blockade, suggesting that impaired NO vasodilation is secondary to sympathetic activation. We tested this hypothesis by determining the effect of autonomic blockade (trimethaphan 4 mg/min IV) on NO-mediated vasodilation (increase in forearm blood flow to intrabrachial acetylcholine) compared with endothelial-independent vasodilation (intrabrachial sodium nitroprusside) in obese hypertensive subjects (30blood flow (from 3.9±0.7 to 5.2±1.2 mL/100 mL per minute, P=0.078). As expected, NO-mediated vasodilation was blunted on the intact day compared with NO-independent vasodilation; forearm blood flow increased from 3.6±0.6 to 10.1±1.1 with the highest dose of nitroprusside, but only from 3.7±0.4 to 7.2±0.8 mL/100 mL per minute with the highest dose of acetylcholine, Pblood flow responses to acetylcholine were restored by autonomic blockade and were no longer different to nitroprusside (from 6.2±1.1 to 11.4±1.6 mL/100 mL per minute and from 5.2±0.9 to 12.5±0.9, respectively, P=0.58). Our results support the concept that sympathetic activation contributes to the impairment in NO-mediated vasodilation seen in obesity-associated hypertension and provides further rationale to explore it as a therapeutic target. © 2016 American Heart Association, Inc.

  7. Effects of Dietary Sodium Restriction in Kidney Transplant Recipients Treated With Renin-Angiotensin-Aldosterone System Blockade: A Randomized Clinical Trial.

    Science.gov (United States)

    de Vries, Laura V; Dobrowolski, Linn C; van den Bosch, Jacqueline J O N; Riphagen, Ineke J; Krediet, C T Paul; Bemelman, Frederike J; Bakker, Stephan J L; Navis, Gerjan

    2016-06-01

    In patients with chronic kidney disease receiving renin-angiotensin-aldosterone system (RAAS) blockade, dietary sodium restriction is an often-used treatment strategy to reduce blood pressure (BP) and albuminuria. Whether these effects extend to kidney transplant recipients is unknown. We therefore studied the effects of dietary sodium restriction on BP and urinary albumin excretion (UAE) in kidney transplant recipients receiving RAAS blockade. Two-center randomized crossover trial. Stable outpatient kidney transplant recipients with creatinine clearance > 30mL/min, BP ≥120/80mmHg, receiving stable RAAS blockade therapy. 6-week regular-sodium diet (target, 150mmol/24 h) and a 6-week low-sodium diet (target, 50mmol/24 h). Main outcome parameters were systolic and diastolic BP, UAE, and estimated glomerular filtration rate (eGFR) at the end of each diet period. Dietary adherence was assessed by 24-hour urinary sodium excretion. We randomly assigned 23 kidney transplant recipients, of whom 22 (mean age, 58±8 [SD] years; 50% men; mean eGFR, 51±21mL/min/1.73m(2)) completed the study. One patient withdrew from the study because of concerns regarding orthostatic hypotension on the low-sodium diet. Sodium excretion decreased from 164±50mmol/24 h during the regular-sodium diet to 87±55mmol/24 h during the low-sodium diet (mean difference, -77 [95% CI, -110 to -44] mmol/24 h; Padherence to sodium diet was achieved in 86% of patients. In stable kidney transplant recipients receiving RAAS blockade, dietary sodium restriction effectively reduces BP without affecting eGFR. Dietary sodium restriction is relevant to BP management in kidney transplant recipients receiving RAAS blockade. Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  8. Predictors of responses to immune checkpoint blockade in advanced melanoma

    DEFF Research Database (Denmark)

    Jacquelot, N; Roberti, M P; Enot, D P

    2017-01-01

    Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs....... Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we...

  9. Berry-Phase Blockade in Single-Molecule Magnets

    Science.gov (United States)

    González, Gabriel; Leuenberger, Michael N.

    2007-06-01

    We formulate the problem of electron transport through a single-molecule magnet (SMM) in the Coulomb blockade regime taking into account topological interference effects for the tunneling of the large spin of a SMM. The interference originates from spin Berry phases associated with different tunneling paths. We show that, in the case of incoherent spin states, it is essential to place the SMM between oppositely spin-polarized source and drain leads in order to detect the spin tunneling in the stationary current, which exhibits topological zeros as a function of the transverse magnetic field.

  10. VEGF blockade inhibits angiogenesis and reepithelialization of endometrium.

    Science.gov (United States)

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

    2008-10-01

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

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

    International Nuclear Information System (INIS)

    Lazar, G.; Husztik, E.; Kiss, I.; Szakacs, J.; Olah, J.

    1998-01-01

    Gadolinium chloride (GdCl 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 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 3 2, 3 or 4 days before injection of the cellular antigen, but GdCl 3 injected 7 days before the antigen did not modify the immune response. Increased secondary humoral immune responses were also observed. When GdCl 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 3 injected 2 days before the first dose of SRBC did not modify the humoral immune response. Earlier studies with 51 Cr-labelled foreign red blood cells suggested that the augmentation of the humoral immune response in GdCl 3 -pretreated mice is a consequence of the spillover of the antigen from the liver into the spleen and other extrahepatic reticuloendothelial organs. (orig.)

  12. Localized CD47 blockade enhances immunotherapy for murine melanoma.

    Science.gov (United States)

    Ingram, Jessica R; Blomberg, Olga S; Sockolosky, Jonathan T; Ali, Lestat; Schmidt, Florian I; Pishesha, Novalia; Espinosa, Camilo; Dougan, Stephanie K; Garcia, K Christopher; Ploegh, Hidde L; Dougan, Michael

    2017-09-19

    CD47 is an antiphagocytic ligand broadly expressed on normal and malignant tissues that delivers an inhibitory signal through the receptor signal regulatory protein alpha (SIRPα). Inhibitors of the CD47-SIRPα interaction improve antitumor antibody responses by enhancing antibody-dependent cellular phagocytosis (ADCP) in xenograft models. Endogenous expression of CD47 on a variety of cell types, including erythrocytes, creates a formidable antigen sink that may limit the efficacy of CD47-targeting therapies. We generated a nanobody, A4, that blocks the CD47-SIRPα interaction. A4 synergizes with anti-PD-L1, but not anti-CTLA4, therapy in the syngeneic B16F10 melanoma model. Neither increased dosing nor half-life extension by fusion of A4 to IgG2a Fc (A4Fc) overcame the issue of an antigen sink or, in the case of A4Fc, systemic toxicity. Generation of a B16F10 cell line that secretes the A4 nanobody showed that an enhanced response to several immune therapies requires near-complete blockade of CD47 in the tumor microenvironment. Thus, strategies to localize CD47 blockade to tumors may be particularly valuable for immune therapy.

  13. The effect of adhesion molecule blockade on pulmonary reperfusion injury.

    Science.gov (United States)

    Levine, Adrian J; Parkes, Karen; Rooney, Stephen J; Bonser, Robert S

    2002-04-01

    Selectins are the molecules involved in the initial adhesion of the activated neutrophil on pulmonary endothelium. We investigated the efficacy of selectin blockade in a selective (monoclonal antibody RMP-1) and nonselective (Fucoidin) manner in pulmonary reperfusion injury. Groups of six rat lungs were flushed with University of Wisconsin solution then stored at 4 degrees C for 4 hours. They then underwent sanguinous reperfusion for 30 minutes during which functional measures (gas exchange, pulmonary artery pressure, and airway pressure) of lung performance were made. After reperfusion we estimated their capillary filtration coefficient (Kfc units g/cm water/minute/g wet lung tissue) using a gravimetric technique. Four groups were studied: group I had no reperfusion, group II had 30 minutes of reperfusion, group III had infusion of 20 mg/kg Fucoidin before reperfusion, and group IV had infusion of 20 microg/mL RMP-1 before reperfusion. Reperfusion injury was found between groups I and II by an increase in capillary filtration coefficient (1.048 +/- 0.316 to 3.063 +/- 0.466, p Kfc than group II (0.967 +/- 0.134 and 1.205 +/- 0.164, respectively, p < 0.01). There was no significant functional difference between groups II, III, and IV. Reperfusion-induced hyperpermeability was ameliorated by selective (RMP-1) and nonselective (Fucoidin) selectin blockade.

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

    Science.gov (United States)

    Watts, Iain P

    2015-12-01

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

  15. Sodium channel blockade with QRS widening after an escitalopram overdose.

    Science.gov (United States)

    Schreffler, Susan M; Marraffa, Jeanna M; Stork, Christine M; Mackey, Jennifer

    2013-09-01

    Escitalopram is rarely associated with prolongation of the QTc interval; however, there are no reported cases of QRS complex widening associated with escitalopram overdose. We report a case of a patient who presented with both QRS complex widening and QTc interval prolongation after an escitalopram overdose. A 16-year-old girl presented to the emergency department after ingestion of escitalopram, tramadol/acetaminophen, and hydrocodone/acetaminophen. Laboratory results were significant for 4-hour acetaminophen 21.1 μg/mL. Serum electrolytes including potassium, magnesium, and calcium were all normal. Initial electrocardiogram (ECG) revealed a widened QRS with an incomplete right bundle branch pattern. After administration of 100-mEq sodium bicarbonate, a repeat ECG revealed narrowing of the QRS complex and a prolonged QTc interval. Magnesium sulfate 2 g intravenous and sodium bicarbonate drip were initiated. A repeat ECG, 1 hour after the second, revealed normalization of the QRS complex and QTc interval. Prolongation of the QTc interval is an expected effect of escitalopram. Both escitalopram and citalopram are metabolized to the cardiotoxic metabolite S-didesmethylcitalopram and didesmethylcitalopram, respectively, which have been implicated in numerous cardiac abnormalities including widening of the QRS complex. Although never previously described with escitalopram, this mechanism provides a reasonable explanation for the QRS complex widening and incomplete right bundle branch block that occurred in our patient. Both QRS complex widening and QTc interval prolongation should be monitored in cases of escitalopram and citalopram overdoses.

  16. Diclofenac prolongs repolarization in ventricular muscle with impaired repolarization reserve.

    Directory of Open Access Journals (Sweden)

    Attila Kristóf

    Full Text Available BACKGROUND: The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. METHODS: Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. RESULTS: Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM. The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl(2 application. Diclofenac (3 mg/kg did not prolong while dofetilide (25 µg/kg significantly lengthened the QT(c interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QT(c. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%. In single ventricular cells diclofenac (30 µM decreased the amplitude of rapid (I(Kr and slow (I(Ks delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (I(Ca was slightly diminished, but the transient outward (I(to and inward rectifier (I(K1 potassium currents were not influenced. CONCLUSIONS: Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve.

  17. Diclofenac Prolongs Repolarization in Ventricular Muscle with Impaired Repolarization Reserve

    Science.gov (United States)

    Kristóf, Attila; Husti, Zoltán; Koncz, István; Kohajda, Zsófia; Szél, Tamás; Juhász, Viktor; Biliczki, Péter; Jost, Norbert; Baczkó, István; Papp, Julius Gy; Varró, András; Virág, László

    2012-01-01

    Background The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle. Methods Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model. Results Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QTc interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QTc. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (IKr) and slow (IKs) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (ICa) was slightly diminished, but the transient outward (Ito) and inward rectifier (IK1) potassium currents were not influenced. Conclusions Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve. PMID:23300901

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

    NARCIS (Netherlands)

    Simon, Mischa J.G.

    2006-01-01

    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

  19. Effects of TGF-β signaling blockade on human A549 lung adenocarcinoma cell lines.

    Science.gov (United States)

    Xu, Cheng-Cheng; Wu, Lei-Ming; Sun, Wei; Zhang, Ni; Chen, Wen-Shu; Fu, Xiang-Ning

    2011-01-01

    Transforming growth factor β (TGF-β) is overexpressed in a wide variety of cancer types including lung adenocarcinoma (LAC), and the TGF-β signaling pathway plays an important role in tumor development. To determine whether blockade of the TGF-β signaling pathway can inhibit the malignant biological behavior of LAC, RNA interference (RNAi) technology was used to silence the expression of TGF-β receptor, type II (TGFβRII) in the LAC cell line, A549, and its effects on cell proliferation, invasion and metastasis were examined. Three specific small interfering RNAs (siRNAs) designed for targeting human TGFβRII were transfected into A549 cells. The expression of TGFβRII was detected by Western blot analysis. Cell proliferation was measured by MTT and clonogenic assays. Cell apoptosis was assessed by flow cytometry. The invasion and metastasis of A549 cells were investigated using the wound healing and Matrigel invasion assays. The expression of PI3K, phosphorylated Smad2, Smad4, Akt, Erk1/2, P38 and MMPs was detected by Western blot analysis. The TGFβRII siRNA significantly reduced the expression of TGFβRII in A549 cells. The knockdown of TGFβRII in A549 cells resulted in the suppression of cell proliferation, invasion and metastasis and induced cell apoptosis. In addition to the Smad-dependent pathway, independent pathways including the Erk MAPK, PI3K/Akt and p38 MAPK pathways, as well as the expression of MMPs and VEGF, were inhibited. In conclusion, TGF-β signaling is required for LAC progression. Therefore, the blockade of this signaling pathway by the down-regulation of TGFβRII using SiRNA may provide a potential gene therapy for LAC.

  20. Mineralocorticoid receptor blockade prevents stress-induced modulation of multiple memory systems in the human brain.

    Science.gov (United States)

    Schwabe, Lars; Tegenthoff, Martin; Höffken, Oliver; Wolf, Oliver T

    2013-12-01

    Accumulating evidence suggests that stress may orchestrate the engagement of multiple memory systems in the brain. In particular, stress is thought to favor dorsal striatum-dependent procedural over hippocampus-dependent declarative memory. However, the neuroendocrine mechanisms underlying these modulatory effects of stress remain elusive, especially in humans. Here, we targeted the role of the mineralocorticoid receptor (MR) in the stress-induced modulation of dorsal striatal and hippocampal memory systems in the human brain using a combination of event-related functional magnetic resonance imaging and pharmacologic blockade of the MR. Eighty healthy participants received the MR antagonist spironolactone (300 mg) or a placebo and underwent a stressor or control manipulation before they performed, in the scanner, a classification task that can be supported by the hippocampus and the dorsal striatum. Stress after placebo did not affect learning performance but reduced explicit task knowledge and led to a relative increase in the use of more procedural learning strategies. At the neural level, stress promoted striatum-based learning at the expense of hippocampus-based learning. Functional connectivity analyses showed that this shift was associated with altered coupling of the amygdala with the hippocampus and dorsal striatum. Mineralocorticoid receptor blockade before stress prevented the stress-induced shift toward dorsal striatal procedural learning, same as the stress-induced alterations of amygdala connectivity with hippocampus and dorsal striatum, but resulted in significantly impaired performance. Our findings indicate that the stress-induced shift from hippocampal to dorsal striatal memory systems is mediated by the amygdala, required to preserve performance after stress, and dependent on the MR. © 2013 Society of Biological Psychiatry.

  1. 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.

    2007-01-01

    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

  2. Donor Diabetes and Prolonged Cold Ischemia Time Synergistically Increase the Risk of Graft Failure After Liver Transplantation

    NARCIS (Netherlands)

    Brüggenwirth, Isabel M A; Dolgin, Natasha H; Porte, Robert J; Bozorgzadeh, Adel; Martins, Paulo N A

    BACKGROUND: Both prolonged cold ischemia time (CIT) and donor history of diabetes mellitus (DM) are associated with reduced graft survival after liver transplantation. However, it is unknown whether the adverse effect of prolonged CIT on posttransplant graft survival is more pronounced after

  3. Does a 'tight' hamstring predict low back pain reporting during prolonged standing?

    Science.gov (United States)

    Raftry, Sean M; Marshall, Paul W M

    2012-06-01

    The purpose of this study was to investigate the relationship between hamstring passive stiffness and extensibility in asymptomatic individuals with the reporting of low back pain during 2-h prolonged standing. Twenty healthy participants with no history of low back pain (mean±SD, age 22.6±2.7 years, height 1.74±0.09 m, weight 76.2±14.8 kg). Low back pain (VAS score; mm) was continuously monitored during 2-h prolonged standing. Hamstring extensibility, passive stiffness, and stretch tolerance were measured before and after prolonged standing using an instrumented straight leg raise (iSLR). Ten participants reported a clinically relevant increase (Δ VAS>10mm) in low back pain during prolonged standing. Hamstring extensiblity (leg°(max)), passive stiffness (Nm.°(-1)), and stretch tolerance (VAS; mm) were no different between pain developers and non-pain developers. No changes in hamstring measures were observed following 2-h prolonged standing. No relationship was observed in this study between measures of hamstring extensibility and the reporting of low back pain during prolonged standing. There is no evidence to recommend hamstring extensibility interventions (i.e. passive stretching) as a means of reducing pain reporting in occupations requiring prolonged standing. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. SALIVARY ANTIMICROBIAL PROTEIN RESPONSE TO PROLONGED RUNNING

    Directory of Open Access Journals (Sweden)

    Suzanne Schneider

    2013-01-01

    Full Text Available Prolonged exercise may compromise immunity through a reduction of salivary antimicrobial proteins (AMPs. Salivary IgA (IgA has been extensively studied, but little is known about the effect of acute, prolonged exercise on AMPs including lysozyme (Lys and lactoferrin (Lac. Objective: To determine the effect of a 50-km trail race on salivary cortisol (Cort, IgA, Lys, and Lac. Methods: 14 subjects: (6 females, 8 males completed a 50km ultramarathon. Saliva was collected pre, immediately after (post and 1.5 hrs post race ( 1.5. Results: Lac concentration was higher at 1.5 hrs post race compared to post exercise (p0.05. IgA concentration, secretion rate, and IgA/Osm were lower 1.5 hrs post compared to pre race (p<0.05. Cort concentration was higher at post compared to 1.5 (p<0.05, but was unaltered from pre race levels. Subjects finished in 7.81 ± 1.2 hrs. Saliva flow rate did not differ between time points. Saliva Osm increased at post (p<0.05 compared to pre race. Conclusions: The intensity could have been too low to alter Lys and Lac secretion rates and thus, may not be as sensitive as IgA to changes in response to prolonged running. Results expand our understanding of the mucosal immune system and may have implications for predicting illness after prolonged running.

  5. Prolonged displacement may compromise resilience in Eritrean ...

    African Journals Online (AJOL)

    Objective: to assess the impact of prolonged displacement on the resilience of Eritrean mothers. Methods: an adapted SOC scale (short form) was administered. Complementary qualitative data were gathered from study participants' spontaneous reactions to and commentaries on the SOC scale. Results: Displaced ...

  6. Prolonged Cholestatic Jaundice Associated With Flurbiprofen.

    Science.gov (United States)

    Dogan, Serkan; Celikbilek, Mehmet; Demirkan, Kutay; Yilmaz, Semih; Deniz, Kemal; Gursoy, Sebnem; Yucesoy, Mehmet

    2014-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed drugs throughout the world for pain relief. Although the adverse effects of NSAIDs to the liver are well known, flurbiprofen-induced liver cholestasis is extremely rare. Herein, we present a patient with prolonged icterus that is associated with the use of flurbiprofen without causing ductopenia. © The Author(s) 2013.

  7. Hippocampal Abnormalities after Prolonged Febrile Convulsions

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2003-11-01

    Full Text Available Hippocampal volume and T2 relaxation times were determined in an MRI study of 14 children with prolonged febrile convulsions (PFC who were investigated, 1 within 5 days of a PFC, and 2 at follow-up 4-8 months after the acute study, at the Institute of Child Health, University College, and Great Ormond Street Hospital, London, UK.

  8. Acute Right Ventricular Dysfunction Complicating Prolonged ...

    African Journals Online (AJOL)

    We report a case of transient right ventricular dysfunction associated with prolonged cardiac tamponade, an unusual complication of uncertain etiology. We believe that in this case dynamic coronary flow restriction resulted in ischemic injury and stunning of the right ventricle. Other possible causes are briefly reviewed. Right ...

  9. Prolonged QRS Widening After Aripiprazole Overdose.

    Science.gov (United States)

    Mazer-Amirshahi, Maryann; Porter, Robert; Dewey, Kayla

    2018-05-05

    Aripiprazole is an atypical antipsychotic with a long half-life. Overdose can result in protracted somnolence and cardiac disturbances, particularly QT interval prolongation. This is a single case report of a 14-year-old boy who took an overdose of aripiprazole and developed QRS widening. A 14-year-old boy intentionally ingested 20 tablets of aripiprazole (5 mg). He was brought to the emergency department when his ingestion was discovered. The patient's vital signs were as follows: temperature, 37.7°C; heart rate, 108 beats/min; blood pressure, 138/98 mm Hg; and respirations, 16 breaths/min. Activated charcoal was administered within 90 minutes of ingestion. Initial electrocardiogram (EKG) showed sinus tachycardia, with a QRS of 138 ms and QT interval of 444 ms. QRS duration was 90 ms on an EKG performed 3 months earlier. A bolus of sodium bicarbonate was administered, and the patient was transferred to the pediatric intensive care unit. Repeat EKG demonstrated a QRS of 156 ms, and a sodium bicarbonate infusion was initiated. The patient continued to have QRS prolongation for the next 8 days, reaching a peak of 172 ms 3 days postingestion. Despite aggressive treatment with sodium bicarbonate, there was persistent QRS prolongation; however, the patient did not have any dysrhythmias and remained hemodynamically stable. The patient was discharged 9 days postingestion when the QRS duration normalized to 82 ms. Genetic testing revealed that the patient was a CYP2D6 poor metabolizer. This case suggests that aripiprazole toxicity may possibly be associated with QRS prolongation without associated dysrhythmias or cardiovascular compromise. In addition, toxicity may be prolonged in patients who are CYP2D6 poor metabolizers.

  10. 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: hwp0518@aliyun.com [Department of Nephrology, Xinqiao Hospital, PLA, Third Military Medical University, Chongqing 400037 (China)

    2014-11-15

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

  11. Intrathecal tramadol as and adjuvant in subrachnoid block to prolong the duration of analgesia

    International Nuclear Information System (INIS)

    Zahid, F.; Tarar, H. M.; Tariq, M.; Nazir, H.; Zafar, I.; Munir, S.

    2017-01-01

    Objective: To assess the effect of intrathecal tramadol added to bupivacaine to prolong the duration of analgesia in subarachnoid block for lower limb orthopedic surgeries. Study Design: Randomized controlled trial. Place and Duration of Study: Anesthesia department of Combined Military Hospital Sialkot, from Nov 2015 to Apr 2016. Material and Methods: Patients were selected by non-probability consecutive sampling. One hundred and fifty patients from American Society of Anesthesiologists (ASA) I, II and III category fulfilling inclusion criteria undergoing various lower limb orthopedic surgeries were divided into two groups by lottery system. Group tramadol bupivacaine (TB) received 25mg (1 ml) of tramadol plus 2ml (10mg) of 0.5 percent bupivacaine while group bupivacaine alone (SB) received 1 ml normal saline plus 2ml (10mg) of 0.5 percent bupivacaine. Time to first analgesia request was noted as a measure of duration of analgesia. Time of onset of sensory block level and peak sensory block level and time to reach the peak sensory block level were also noted. Quality of anesthesia was compared among two groups. Data were analyzed by using SPSS version 22. Results: Four patients were excluded from the study. The duration of anesthesia was effectively prolonged in group TB 181.56 ± 12.42 mins as compared to group SB 120.93 ± 15.54 mins. VAS score was significantly lower in group TB. Higher peak sensory block levels (T6) were achieved in group TB as compared to group SB. However time to reach the peak sensory block levels were significantly longer in group TB. (4.5 ± 0.47mins vs 3.09 ± 0.54 mins). Conclusion: This study showed that intrathecal tramadol (25mg) can safely be used along with bupivacaine in subarachnoid blockade to prolong the duration of analgesia and improve the quality of anesthesia as well. (author)

  12. Licence prolongations of US nuclear power plants; Les prolongations de licence des centrales nucleaires americaines

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2004-04-01

    Licences of US nuclear reactors were initially attributed for a 40 years duration. However, the vast majority of the reactors can benefit of a licence prolongation for a period of 20 years maximum. This article recalls first the procedure to follow for the licence prolongation demands (safety analysis, components aging, environmental impact statement), and then it makes a status of the accepted prolongations, of the demands under examination, and of the demands that should be presented in the next 5 years. (J.S.)

  13. Coulomb Blockade in a Two-Dimensional Conductive Polymer Monolayer.

    Science.gov (United States)

    Akai-Kasaya, M; Okuaki, Y; Nagano, S; Mitani, T; Kuwahara, Y

    2015-11-06

    Electronic transport was investigated in poly(3-hexylthiophene-2,5-diyl) monolayers. At low temperatures, nonlinear behavior was observed in the current-voltage characteristics, and a nonzero threshold voltage appeared that increased with decreasing temperature. The current-voltage characteristics could be best fitted using a power law. These results suggest that the nonlinear conductivity can be explained using a Coulomb blockade (CB) mechanism. A model is proposed in which an isotropic extended charge state exists, as predicted by quantum calculations, and percolative charge transport occurs within an array of small conductive islands. Using quantitatively evaluated capacitance values for the islands, this model was found to be capable of explaining the observed experimental data. It is, therefore, suggested that percolative charge transport based on the CB effect is a significant factor giving rise to nonlinear conductivity in organic materials.

  14. Investigation of uncertainty components in Coulomb blockade thermometry

    International Nuclear Information System (INIS)

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

    2013-01-01

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

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  16. 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)

    2013-09-11

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

  17. Neuromuscular blockade for improvement of surgical conditions during laparotomy

    DEFF Research Database (Denmark)

    Madsen, Matias Vested; Scheppan, Susanne; Kissmeyer, Peter

    2015-01-01

    INTRODUCTION: During laparotomy, surgeons frequently experience difficult surgical conditions if the patient's abdominal wall or diaphragm is tense. This issue is particularly pertinent while closing the fascia and placing the intestines into the abdominal cavity. Establishment of a deep neuromus......INTRODUCTION: During laparotomy, surgeons frequently experience difficult surgical conditions if the patient's abdominal wall or diaphragm is tense. This issue is particularly pertinent while closing the fascia and placing the intestines into the abdominal cavity. Establishment of a deep...... neuromuscular blockade (NMB), defined as a post-tetanic-count (PTC) of 0-1, paralyses the abdominal wall muscles and the diaphragm. We hypothesised that deep NMB (PTC 0-1) would improve surgical conditions during upper laparotomy as compared to standard NMB with bolus administration. METHODS...

  18. Ultra-high-ohmic microstripline resistors for Coulomb blockade devices

    International Nuclear Information System (INIS)

    Lotkhov, Sergey V

    2013-01-01

    In this paper, we report on the fabrication and low-temperature characterization of ultra-high-ohmic microstripline resistors made of a thin film of weakly oxidized titanium. Nearly linear voltage–current characteristics were measured at temperatures down to T ∼ 20 mK for films with sheet resistivities as high as ∼7 kΩ, i.e. about an order of magnitude higher than our previous findings for weakly oxidized Cr. Our analysis indicates that such an improvement can help to create an advantageous high-impedance environment for different Coulomb blockade devices. Further properties of the Ti film addressed in this work show the promise of low-noise behavior of the resistors when applied in different realizations of the quantum standard of current. (paper)

  19. Femoral Nerve Injury Following a Lumbar Plexus Blockade

    Directory of Open Access Journals (Sweden)

    İrfan Güngör

    2014-06-01

    Full Text Available Background: Lumbar plexus blockade (LPB combined with sciatic nerve block (SNB is frequently used for lower extremity surgery. Perioperative nerve injury is a rarely encountered complication of peripheral nerve blocks (PNB. Case Report: Here we report a 44-year-old male patient who developed a partial femoral nerve injury (FNI following a LPB which was performed before the surgery of a patellar fracture. The clinical and electroneuromyographic findings of the patient were recovered almost completely within the following six months. Conclusion: The presented case demonstrated a FNI despite the absence of any pain or paresthesia sensation, with the disappearance of motor response under 0.3 mA of neurostimulation in the experienced hands.

  20. PD-1 Blockade Expands Intratumoral Memory T Cells

    DEFF Research Database (Denmark)

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

    2016-01-01

    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 significantly increased in patients' biopsies taken on treatment. The percentage of cells with a regulatory T-cell phenotype, monocytes, and natural killer cells did not change while on PD-1 blockade therapy. CD8+ memory T cells were the most prominent phenotype that expanded intratumorally...... on therapy. However, the frequency of CD4+ effector memory T cells significantly decreased on treatment, whereas CD4+ effector T cells significantly increased in nonresponding tumors on therapy. In peripheral blood, an unusual population of blood cells expressing CD56 was detected in two patients...

  1. Treatment of resting tremor by beta-adrenergic blockade.

    Science.gov (United States)

    Foster, N L; Newman, R P; LeWitt, P A; Gillespie, M M; Chase, T N

    1984-10-01

    The effect of nadolol, a peripherally acting beta-adrenergic blocker, on resting tremor was examined in eight patients with idiopathic Parkinson's disease. With the use of a double-blind, placebo-controlled study of crossover design, patients received 80 to 320 mg of nadolol for 6 weeks while continuing their previous treatment regimen. Accelerometer readings showed a progressive reduction in tremor amplitude, but no change in tremor frequency, with increasing nadolol dosage. Maximum benefit was achieved at 240 mg, when resting tremor improved 50% (p less than 0.01). Physician ratings confirmed these findings. The results suggest that response to beta-adrenergic blockade may not be limited to postural or intention tremor and that such agents may not reliably differentiate between the tremor of Parkinson's disease and essential tremor.

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

    Science.gov (United States)

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

    2015-05-01

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

  3. Effects of magnesium chloride on rocuronium-induced neuromuscular blockade and sugammadex reversal in an isolated rat phrenic nerve-hemidiaphragm preparation: An in-vitro study.

    Science.gov (United States)

    Sung, Tae-Yun; You, Hwang-Ju; Cho, Choon-Kyu; Choi, Hey Ran; Kim, Yong Beom; Shin, Yong Sup; Yang, Hong Seuk

    2018-03-01

    Magnesium potentiates the effects of nondepolarising muscle relaxants. However, few studies have used magnesium chloride (MgCl2). Sugammadex reverses neuromuscular block by steroidal nondepolarising muscle relaxants. To assess the effects of MgCl2 on rocuronium-induced neuromuscular blockade and its reversal by sugammadex. In-vitro experimental study. Animal laboratory, Asan Medical Center, Seoul, South Korea, from 20 March 2016 to 3 April 2016. Forty male Sprague Dawley rats. Left phrenic nerve-hemidiaphragms from 40 Sprague Dawley rats were allocated randomly to four groups (1, 2, 3 and 4 mmol l MgCl2 group, n = 10 each). Rocuronium was administered cumulatively until the first twitch of train-of-four (TOF) disappeared completely. Then, equimolar sugammadex was administered. The effective concentration (EC) of rocuronium was obtained in each group. After administering sugammadex, recovery of the first twitch height and the TOF ratio were measured for 30 min. EC50, EC90 and EC95 significantly decreased as the concentration of MgCl2 increased (all P ≤ 0.001), except the comparison between the 3 and 4 mmol l MgCl2 groups. After administration of sugammadex, the maximal TOF ratio (%) was lower in the 4 mmol l MgCl2 group than the 1 mmol l MgCl2 group [median 91.7 interquartile range (83.4 to 95.8) vs. 98.3 interquartile range (92.2 to 103.4), P = 0.049]. The mean time (s) from sugammadex injection to achieving maximal first twitch was significantly prolonged in the 4 mmol l MgCl2 group vs. the 1 mmol l MgCl2 and 2 mmol l MgCl2 groups [1483.9 (± 237.0) vs. 1039.0 (± 351.8) and 926.0 (± 278.1), P = 0.022 and 0.002, respectively]. Increases in MgCl2 concentration reduce the ECs of rocuronium. In addition, administering sugammadex equimolar to the administered rocuronium shows limited efficacy as MgCl2 concentration is increased. The in-vitro study was not registered in a database.

  4. Photon blockade in optomechanical systems with a position-modulated Kerr-type nonlinear coupling

    Science.gov (United States)

    Zhang, X. Y.; Zhou, Y. H.; Guo, Y. Q.; Yi, X. X.

    2018-03-01

    We explore the photon blockade in optomechanical systems with a position-modulated Kerr-type nonlinear coupling, i.e. H_int˜\\hat{a}\\dagger2\\hat{a}^2(\\hat{b}_1^\\dagger+\\hat{b}_1) . We find that the Kerr-type nonlinear coupling can enhance the photon blockade greatly. We evaluate the equal-time second-order correlation function of the cavity photons and find that the optimal photon blockade does not happen at the single photon resonance. By working within the few-photon subspace, we get an approximate analytical expression for the correlation function and the condition for the optimal photon blockade. We also find that the photon blockade effect is not always enhanced as the Kerr-type nonlinear coupling strength g 2 increases. At some values of g 2, the photon blockade is even weakened. For the system we considered here, the second-order correlation function can be smaller than 1 even in the unresolved sideband regime. By numerically simulating the master equation of the system, we also find that the thermal noise of the mechanical environment can enhance the photon blockade. We give out an explanation for this counter-intuitive phenomenon qualitatively.

  5. Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in experimental colitis

    Directory of Open Access Journals (Sweden)

    Willis Cynthia R

    2012-10-01

    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

  6. Severe bradycardia and prolonged hypotension in ciguatera.

    Science.gov (United States)

    Chan, Thomas Yan Keung

    2013-06-01

    Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed.

  7. Prolonged preconditioning with natural honey against myocardial infarction injuries.

    Science.gov (United States)

    Eteraf-Oskouei, Tahereh; Shaseb, Elnaz; Ghaffary, Saba; Najafi, Moslem

    2013-07-01

    Potential protective effects of prolonged preconditioning with natural honey against myocardial infarction were investigated. Male Wistar rats were pre-treated with honey (1%, 2% and 4%) for 45 days then their hearts were isolated and mounted on a Langendorff apparatus and perfused with a modified Krebs-Henseleit solution during 30 min regional ischemia fallowed by 120 min reperfusion. Two important indexes of ischemia-induced damage (infarction size and arrhythmias) were determined by computerized planimetry and ECG analysis, respectively. Honey (1% and 2%) reduced infarct size from 23±3.1% (control) to 9.7±2.4 and 9.5±2.3%, respectively (Phoney (1%) significantly reduced (PHoney (1% and 2%) also significantly decreased number of ventricular ectopic beats (VEBs). In addition, incidence and duration of reversible ventricular fibrillation (Rev VF) were lowered by honey 2% (Phoney produced significant reduction in the incidences of VT, total and Rev VF, duration and number of VT. The results showed cardioprotective effects of prolonged pre-treatment of rats with honey following myocardial infarction. Maybe, the existence of antioxidants and energy sources (glucose and fructose) in honey composition and improvement of hemodynamic functions may involve in those protective effects.

  8. Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients

    NARCIS (Netherlands)

    Slagman, Maartje C. J.; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D.

    Background. Renin angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both

  9. Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients

    NARCIS (Netherlands)

    Slagman, Maartje C. J.; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D.

    2012-01-01

    Background. Renin angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both

  10. Variation in Definition of Prolonged Mechanical Ventilation.

    Science.gov (United States)

    Rose, Louise; McGinlay, Michael; Amin, Reshma; Burns, Karen Ea; Connolly, Bronwen; Hart, Nicholas; Jouvet, Philippe; Katz, Sherri; Leasa, David; Mawdsley, Cathy; McAuley, Danny F; Schultz, Marcus J; Blackwood, Bronagh

    2017-10-01

    Consistency of definitional criteria for terminology applied to describe subject cohorts receiving mechanical ventilation within ICU and post-acute care settings is important for understanding prevalence, risk stratification, effectiveness of interventions, and projections for resource allocation. Our objective was to quantify the application and definition of terms for prolonged mechanical ventilation. We conducted a scoping review of studies (all designs except single-case study) reporting a study population (adult and pediatric) using the term prolonged mechanical ventilation or a synonym. We screened 5,331 references, reviewed 539 full-text references, and excluded 120. Of the 419 studies (representing 38 countries) meeting inclusion criteria, 297 (71%) reported data on a heterogeneous subject cohort, and 66 (16%) included surgical subjects only (46 of those 66, 70% cardiac surgery). Other studies described COPD (16, 4%), trauma (22, 5%), neuromuscular (17, 4%), and sepsis (1, 0.2%) cohorts. A total of 741 terms were used to refer to the 419 study cohorts. The most common terms were: prolonged mechanical ventilation (253, 60%), admission to specialized unit (107, 26%), and long-term mechanical ventilation (79, 19%). Some authors (282, 67%) defined their cohorts based on duration of mechanical ventilation, with 154 studies (55%) using this as the sole criterion. We identified 37 different durations of ventilation ranging from 5 h to 1 y, with > 21 d being the most common (28 of 282, 7%). For studies describing a surgical cohort, minimum ventilation duration required for inclusion was ≥ 24 h for 20 of 66 studies (30%). More than half of all studies (237, 57%) did not provide a reason/rationale for definitional criteria used, with only 28 studies (7%) referring to a consensus definition. We conclude that substantial variation exists in the terminology and definitional criteria for cohorts of subjects receiving prolonged mechanical ventilation. Standardization of

  11. Prolonged Exposure: a Rapid Treatment for Phobias

    Science.gov (United States)

    Watson, J. P.; Gaind, R.; Marks, I. M.

    1971-01-01

    Ten adult patients with long-standing specific phobias were treated by prolonged continuous exposure to their phobic objects in fantasy and reality without avoidance. All patients were greatly helped by four to five hours' treatment in two or three sessions, and all improved more after practice than after imaginal sessions. The treatment method is more economical and efficient than other methods described so far. PMID:5539135

  12. Ultrasound guided pectoral nerve blockade versus thoracic spinal blockade for conservative breast surgery in cancer breast: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Hala M.S. ELdeen

    2016-01-01

    Conclusion: In conclusion, both Pecs and TSB provide effective intraoperative anesthesia and prolonged postoperative pain relief after breast surgery, but the Pecs block is technically simple and easy to learn with few contraindications, provides hemodynamic stability, and has a low complication rate and it is therefore a safe and effective technique in performing intraoperative anesthesia and controlling postoperative pain after unilateral conservative breast surgery.

  13. Blockade of TGF-β 1 Signalling Inhibits Cardiac NADPH Oxidase Overactivity in Hypertensive Rats

    Directory of Open Access Journals (Sweden)

    José Luis Miguel-Carrasco

    2012-01-01

    Full Text Available NADPH oxidases constitute a major source of superoxide anion (⋅O2 - in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-β 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-β 1 receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-β 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-β 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-β 1.

  14. Effect of cannabinoids CB1 receptors blockade on hemodynamic parameters and endothelial function at the immobilization stress in the experiment

    Directory of Open Access Journals (Sweden)

    S. V. Gavreliuk

    2017-12-01

    Full Text Available The aim of the study was to evaluate the response of hemodynamic parameters and changes in endothelial function in modeling of CB1 cannabinoid receptors blockade in chronic stress. Materials and мethods. The study was performed on four groups of hundred-day-old rats, which were examined by ultrasonic scanning during the ten-day period of the experiment. The first group consisted of intact animals; the second group – animals, which were exposed to immobilization stress; the third – animals which were given a solution of rimonabant hydrochloride at the rate of 10 mg×kg-1 of animal weight per day daily per os; the fourth group consisted of animals which daily received a solution of rimonabant hydrochloride at the rate of 10 mg×kg-1 of animal weight per day and were exposed to immobilization stress. The intraluminal vessel diameter, the intima-media complex thickness, endothelium-dependent and endothelium-independent dilation were quantified in the ultrasound examination. Quantitative characteristics of the blood flow were studied: peak systolic velocity, end diastolic velocity, resistive index and peak-systolic/end-diastolic ratio, and estimated mean blood flow velocity. Results. It has been found that the effect of chronic immobilization stress in 100-day-old male rats causes intima-media complex structure and thickness change, endothelial dysfunction and increase in the abdominal aorta intraluminal diameter. Hemodynamics changes are characterized by a decrease in the average blood flow velocity and an increase in the values of indices characterizing the vascular wall peripheral resistance. Prolonged blockade of cannabinoids CB1 receptors leads to endothelial dysfunction development, a decrease in the intraluminal diameter of the abdominal aorta and a decrease in the average blood flow velocity while vascular wall elastic properties maintaining. This affects the sensitivity of cardiovascular system to nitrogen oxide, which is manifested by

  15. The changes of spontaneous motility in chick embryos after blockade of NO-synthase.

    Science.gov (United States)

    Sedlácek, J

    1996-01-01

    The consequences of the blockade of NO-synthase (NOS) for the development, frequency and reactivity of spontaneous motility were investigated in chick embryos aged 4-19 day of incubation. 1. Acute NOS blockade evoked by N-nitro-L-arginine- methylester (L-NAME) (20 mg/kg egg weight-e.w.) caused on day 17 of incubation the short-lasting depression of spontaneous motility to 50% of resting motor activity. L-NAME was in spinal embryos without any effect. Chronic application of L-NAME (1.70 mg/kg e.w./24 h) from day 4 of incubation led after the first 4 days of continual supply to the development of reduced spontaneous motility on one hand, on the other hand it changed the efficacy of central activatory (NMDA, pentylenetetrazole) and inhibitory drugs (ketamine, glycine). L-NAME and L-arginine in different mutual combinations manifested in 17-day-old embryos their typical effect, though the depressory effect of L-NAME took a swifter course than the activatory effect of L-arginine. 2. Aminoguanidine (AmG) (9.8 and 20 mg/kg e.w.) evoked from day 17 of incubation the significant biphasic change of spontaneous motility only: initial depression was replaced by later activation. AmG was in spinal embryos without effect again. Chronic application of AmG (5.29 +/- 0.51 mg/kg e.w./24 h) showed in 17-day-old embryos a reduction of resting motility dependent on the duration of AmG influence during incubation. Another expression was the changed reactivity of spontaneous motility to some centrally effective drugs (ketamine, NMDA, D-cycloserine, glycine, pentylenetetrazole). 3. 7-nitroindazole (7-NIZ) (15 and 30 mg/kg e.w.) caused the significant decrease of spontaneous motility in chick embryos already from day 15 of incubation; the depression after the lower dosis had an interrupted course, whereas after the higher dosis it was a continuous one. 7-NIZ blocked in 17-day-old embryos the activatory effect of L-arginine, reduced the paroxysmal activation of motility evoked by NMDA and

  16. Blockade of Nociceptin Signaling Reduces Biochemical, Structural and Cognitive Deficits after Traumatic Brain Injury

    Science.gov (United States)

    2010-07-01

    also will determine if ORL1 antagonists block downstream gene transcription subsequent to enzyme activation. BODY: Task 1a was to optimize blast...value between 60 and 80 psi at which defects in vestibulomotor function can be detected. These findings could potentially become a clinical...nociceptin-mediated desensitization of opioid receptor-like 1 receptor and mu opioid receptors involves protein kinase C: a molecular mechanism for

  17. Prolonged labour as indication for emergency caesarean section

    DEFF Research Database (Denmark)

    Maaløe, Nanna; Sorensen, B L; Onesmo, R

    2012-01-01

    To audit the quality of obstetric management preceding emergency caesarean sections for prolonged labour.......To audit the quality of obstetric management preceding emergency caesarean sections for prolonged labour....

  18. Effects of a novel bradykinin B1 receptor antagonist and angiotensin II receptor blockade on experimental myocardial infarction in rats.

    Directory of Open Access Journals (Sweden)

    Dongmei Wu

    Full Text Available The aim of the present study was to evaluate the cardiovascular effects of the novel bradykinin B1 receptor antagonist BI-113823 following myocardial infarction (MI and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin II type 1 (AT1 receptor antagonist after MI in rats.Sprague Dawley rats were subjected to permanent occlusion of the left descending coronary artery. Cardiovascular function was determined at 7 days post MI. Treatment with either B1 receptor antagonist (BI-113823 or AT1 receptor antagonist (irbesartan alone or in combination improved post-MI cardiac function as evidenced by attenuation of elevated left ventricular end diastolic pressure (LVEDP; greater first derivative of left ventricular pressure (± dp/dt max, left ventricle ejection fraction, fractional shorting, and better wall motion; as we as reductions in post-MI up-regulation of matrix metalloproteinases 2 (MMP-2 and collagen III. In addition, the cardiac up-regulation of B1 receptor and AT1 receptor mRNA were markedly reduced in animals treated with BI 113823, although bradykinin B2 receptor and angiotensin 1 converting enzyme (ACE1 mRNA expression were not significantly affected by B1 receptor blockade.The present study demonstrates that treatment with the novel B1 receptor antagonist, BI-113823 improves post-MI cardiac function and does not influence the cardiovascular effects of AT1 receptor antagonist following MI.

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

    Science.gov (United States)

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

  20. Combined blockade of vascular endothelial growth factor and programmed death 1 pathways in advanced kidney cancer.

    Science.gov (United States)

    Einstein, David J; McDermott, David F

    2017-06-01

    Targeted and immune-based therapies have improved outcomes in advanced kidney cancer, yet novel strategies are needed to extend the duration of these benefits and expand them to more patients. Combined inhibition of vascular endothelial growth factor (VEGF) and the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathways with therapeutic agents already in clinical use may offer such a strategy. Here, we describe the development and clinical evaluation of VEGF inhibitors and, separately, PD-1/PD-L1 inhibitors. We present preclinical evidence of interaction between these pathways and the rationale for combined blockade. Beyond well-known effects on pathologic angiogenesis, VEGF blockade also may decrease immune tolerance and enhance PD-1/PD-L1 blockade. We conclude with the results of several early trials of combined VEGF and PD-1/PD-L1 blockade, which demonstrate encouraging antitumor activity, and we pose questions for future study.

  1. Effects of dual renin-angiotensin system blockade on proteinuria in a ...

    African Journals Online (AJOL)

    Kidney diseases manifesting as proteinuria or elevated creatinine are increasingly prevalent complications of HIV infection. We report the effects of dual renin-angiotensin system blockade on proteinuria in a hypertensive black African HIV-infected patient.

  2. Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion.

    Science.gov (United States)

    Lindesmith, Lisa C; Mallory, Michael L; Debbink, Kari; Donaldson, Eric F; Brewer-Jensen, Paul D; Swann, Excel W; Sheahan, Timothy P; Graham, Rachel L; Beltramello, Martina; Corti, Davide; Lanzavecchia, Antonio; Baric, Ralph S

    2018-01-01

    Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach for identifying conserved GII.4 norovirus epitopes. Utilizing a unique set of virus-like particles (VLPs) representing the in vivo -evolved sequence diversity within an immunocompromised person, we identify key residues within epitope F, a conserved GII.4 blockade antibody epitope. The residues critical for antibody binding are proximal to evolving blockade epitope E. Like epitope F, antibody blockade of epitope E was temperature sensitive, indicating that particle conformation regulates antibody access not only to the conserved GII.4 blockade epitope F but also to the evolving epitope E. These data highlight novel GII.4 mechanisms to protect blockade antibody epitopes, map essential residues of a GII.4 conserved epitope, and expand our understanding of how viral particle dynamics may drive antigenicity and antibody-mediated protection by effectively shielding blockade epitopes. Our data support the notion that GII.4 particle breathing may well represent a major mechanism of humoral immune evasion supporting cyclic pandemic virus persistence and spread in human populations. IMPORTANCE In this study, we use norovirus virus-like particles to identify key residues of a conserved GII.4 blockade antibody epitope. Further, we identify an additional GII.4 blockade antibody epitope to be occluded, with antibody access governed by temperature and particle dynamics. These findings provide additional support for particle conformation-based presentation of binding residues mediated by a particle

  3. Negative differential resistance in nanoscale transport in the Coulomb blockade regime

    International Nuclear Information System (INIS)

    Parida, Prakash; Lakshmi, S; Pati, Swapan K

    2009-01-01

    Motivated by recent experiments, we have studied the transport behavior of coupled quantum dot systems in the Coulomb blockade regime using the master (rate) equation approach. We explore how electron-electron interactions in a donor-acceptor system, resembling weakly coupled quantum dots with varying charging energy, can modify the system's response to an external bias, taking it from normal Coulomb blockade behavior to negative differential resistance (NDR) in the current-voltage characteristics.

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

    Directory of Open Access Journals (Sweden)

    Yan-Huan Feng

    2016-01-01

    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

  5. Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis

    OpenAIRE

    Lebre, M.C.; Vergunst, C.E.; Choi, I.Y.K.; Aarrass, S.; Oliveira, A.S.F.; Wyant, T.; Horuk, R.; Reedquist, K.A.; Tak, P.P.

    2011-01-01

    BACKGROUND: The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. METHODOLOGY/PRINCIPAL FINDINGS: Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either ...

  6. Laryngotracheal Injury following Prolonged Endotracheal Intubation

    Directory of Open Access Journals (Sweden)

    J. Mehdizadeh

    2006-07-01

    Full Text Available Background: Prolonged endotracheal intubation is a growing method for supporting ventilation in patients who require intensive care. Despite considerable advancement in endotracheal intubation, this method still has some complications; the most important is laryngo-tracheal injuries. Methods: Over a 2-year period, this retrospective study was conducted on 57 patients with history of prolonged intubation who were referred to the ENT Department of Amir Alam Hospital. For each patient, a complete evaluation including history, physical examination, and direct laryngoscopy and bronchoscopy was done under general anesthesia. Results: Fifty-seven patients (44 male; mean age, 23.014.7 years were studied. Mean intubation period was 15.88 days. The most common presenting symptom was dyspnea (62%. Head trauma was responsible for most cases of intubation (72.4%. The most common types of tracheal and laryngeal lesions were tracheal (56.9% and subglottic (55.2% stenosis, respectively. Mean length of tracheal stenosis was 0.810.83 cm. There was a statistically significant relationship between length of tracheal stenosis and intubation period (P=0.0001 but no relation was observed between tracheal stenosis and age, sex, and etiology of intubation (All P=NS. Among the glottic lesions, inter- arytenoids adhesion was the most common lesion (25.9%. No statistically significant relation was found between glottic and subglottic lesions and age, sex and intubation period (all P=NS. Length of stenosis and intubation period was significantly greater in tracheal/ subglottic lesions than those in glottic/ supraglottic lesions (all P=NS. Conclusion: After prolonged endotracheal intubation, laryngo-tracheal lesions had no relation with patient’s age, sex, and cause of intubation.There was direct relation between length of tracheal stenosis and intubation period. Glottic lesions were more commonly observed in head trauma patients. Lesion length and intubation

  7. Survival without sequelae after prolonged cardiopulmonary resuscitation after electric shock.

    Science.gov (United States)

    Motawea, Mohamad; Al-Kenany, Al-Sayed; Hosny, Mostafa; Aglan, Omar; Samy, Mohamad; Al-Abd, Mohamed

    2016-03-01

    "Electrical shock is the physiological reaction or injury caused by electric current passing through the human body. It occurs upon contact of a human body part with any source of electricity that causes a sufficient current through the skin, muscles, or hair causing undesirable effects ranging from simple burns to death." Ventricular fibrillation is believed to be the most common cause of death after electrical shock. "The ideal duration of cardiac resuscitation is unknown. Typically prolonged cardiopulmonary resuscitation is associated with poor neurologic outcomes and reduced long term survival. No consensus statement has been made and traditionally efforts are usually terminated after 15-30 minutes." The case under discussion seems worthy of the somewhat detailed description given. It is for a young man who survived after 65 minutes after electrical shock (ES) after prolonged high-quality cardiopulmonary resuscitation (CPR), multiple defibrillations, and artificial ventilation without any sequelae. Early start of adequate chest compressions and close adherence to advanced cardiac life support protocols played a vital role in successful CPR.

  8. CTLA-4 blockade and the renaissance of cancer immunotherapy.

    Science.gov (United States)

    Mocellin, Simone; Nitti, Donato

    2013-12-01

    Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) plays a key role in restraining the adaptive immune response of T-cells towards a variety of antigens including tumor associated antigens (TAAs). The blockade of this immune checkpoint elicits an effective anticancer immune response in a range of preclinical models, suggesting that naturally occurring (or therapeutically induced) TAA specific lymphocytes need to be "unleashed" in order to properly fight against malignant cells. Therefore, investigators have tested this therapeutic hypothesis also in humans: the favorable results obtained with this strategy in patients with advanced cutaneous melanoma are revolutionizing the management of this highly aggressive disease and are fueling new enthusiasm on cancer immunotherapy in general. Here we summarize the biology of CTLA-4, overview the experimental data supporting the rational for targeting CTLA-4 to treat cancer and review the main clinical findings on this novel anticancer approach. Moreover, we critically discuss the current challenges and potential developments of this promising field of cancer immunotherapy. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Observation of the Photon-Blockade Breakdown Phase Transition

    Directory of Open Access Journals (Sweden)

    J. M. Fink

    2017-01-01

    Full Text Available Nonequilibrium phase transitions exist in damped-driven open quantum systems when the continuous tuning of an external parameter leads to a transition between two robust steady states. In second-order transitions this change is abrupt at a critical point, whereas in first-order transitions the two phases can coexist in a critical hysteresis domain. Here, we report the observation of a first-order dissipative quantum phase transition in a driven circuit quantum electrodynamics system. It takes place when the photon blockade of the driven cavity-atom system is broken by increasing the drive power. The observed experimental signature is a bimodal phase space distribution with varying weights controlled by the drive strength. Our measurements show an improved stabilization of the classical attractors up to the millisecond range when the size of the quantum system is increased from one to three artificial atoms. The formation of such robust pointer states could be used for new quantum measurement schemes or to investigate multiphoton phases of finite-size, nonlinear, open quantum systems.

  10. 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: okadah@upmc.edu [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)

    2013-11-01

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

  11. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  12. Coulomb blockade and transfer of electrons one by one

    International Nuclear Information System (INIS)

    Pothier, Hugues

    1991-01-01

    Zero point fluctuations of the charge on the capacitance of a tunnel junction connected to a bias circuit are in almost all experimental situations larger than the electron charge. As a consequence, the effects of charge granularity are hidden, but in circuits with 'islands', which are electrodes connected to the rest of the circuit only through tunnel junctions and capacitors. The island charge being quantized, its fluctuations are blocked. If the island capacitance is sufficiently small, no electron can enter the island because of the increase of electrostatic energy that would occur. We have observed this effect, called 'Coulomb blockade', in the 'single electron box', where an island is formed between a tunnel junction and a capacitor. A bias voltage source coupled to the island through the capacitor allows to control the number of electrons. We have designed and operated two devices with nano-scale tunnel junctions based on this principle, the 'turnstile' and the 'pump', through which the current is controlled electron by electron. In our experiments, the precision of the transfer is of the order of one percent. It should be a million time better in versions of these devices with more junctions. One could then use them for a new measurement of the fine structure constant alpha. (author) [fr

  13. Topical Drug Formulations for Prolonged Corneal Anesthesia

    Science.gov (United States)

    Wang, Liqiang; Shankarappa, Sahadev A.; Tong, Rong; Ciolino, Joseph B.; Tsui, Jonathan H.; Chiang, Homer H.; Kohane, Daniel S.

    2013-01-01

    Purpose Ocular local anesthetics (OLA’s) currently used in routine clinical practice for corneal anesthesia are short acting and their ability to delay corneal healing makes them unsuitable for long-term use. In this study, we examined the effect on the duration of corneal anesthesia of the site-1 sodium channel blocker tetrodotoxin (TTX), applied with either proparacaine or the chemical permeation enhancer OTAB. The effect of test solutions on corneal healing was also studied. Methods Solutions of TTX, proparacaine, and OTAB, singly or in combination were applied topically to the rat cornea. The blink response, an indirect measure of corneal sensitivity, was recorded using a Cochet-Bonnet esthesiometer, and the duration of corneal anesthesia calculated. The effect of test compounds on the rate of corneal epithelialization was studied in vivo following corneal debridement. Results Combination of TTX and proparacaine resulted in corneal anesthesia that was 8–10 times longer in duration than that from either drug administered alone, while OTAB did not prolong anesthesia. The rate of corneal healing was moderately delayed following co-administration of TTX and proparacaine. Conclusion Co-administration of TTX and proparacaine significantly prolonged corneal anesthesia but in view of delayed corneal re-epithelialization, caution is suggested in use of the combination. PMID:23615270

  14. BLOCKADE OF PGE2, PGD2 RECEPTORS CONFERS PROTECTION AGAINST PREPATENT SCHISTOSOMIASIS MANSONI IN MICE.

    Science.gov (United States)

    Abdel-Ghany, Rasha; Rabia, Ibrahim; El-Ahwany, Eman; Saber, Sameh; Gamal, Rasha; Nagy, Faten; Mahmoud, Olaa; Hamad, Rabab Salem; Barakat, Walled

    2015-12-01

    Schistosomiasis is a chronic disease with considerable social impact. Despite the availability of affordable chemotherapy, drug treatment has not significantly reduced the overall number of disease cases. Among other mechanisms, the parasite produces PGE2 and PGD2 to evade host immune defenses. To investigate the role of PGE2 and PGD2 in schistosomiasis, we evaluated the effects of L-161,982, Ah6809 (PGE2 receptor antagonists alone of combined with each other) and MK-0524 (PGD2 receptor antagonist) during prepatent Schistosoma mansoni infection. Drugs were administered intraperitoneally an hour before and 24 hours after infection of C57BL/6 mice with 100 Schistosoma mansoni cercariae. L-161,982, Ah6809, their combination and MK-0524 caused partial protection against pre-patent S. mansoni infection which was mediated by biasing the immune response towards Th1 phenotype. These results showed that blockade of PGE2 and PGD2 receptors confers partial protection against pre-patent S. mansoni infection in mice and that they may be useful as adjunctive therapy to current anti-schistosomal drugs or vaccines.

  15. N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection.

    Science.gov (United States)

    Costa, Vivian V; Del Sarto, Juliana L; Rocha, Rebeca F; Silva, Flavia R; Doria, Juliana G; Olmo, Isabella G; Marques, Rafael E; Queiroz-Junior, Celso M; Foureaux, Giselle; Araújo, Julia Maria S; Cramer, Allysson; Real, Ana Luíza C V; Ribeiro, Lucas S; Sardi, Silvia I; Ferreira, Anderson J; Machado, Fabiana S; de Oliveira, Antônio C; Teixeira, Antônio L; Nakaya, Helder I; Souza, Danielle G; Ribeiro, Fabiola M; Teixeira, Mauro M

    2017-04-25

    Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N -methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration. IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment. Copyright © 2017 Costa et al.

  16. PCA3 Silencing Sensitizes Prostate Cancer Cells to Enzalutamide-mediated Androgen Receptor Blockade.

    Science.gov (United States)

    Özgür, Emre; Celik, Ayca Iribas; Darendeliler, Emin; Gezer, Ugur

    2017-07-01

    Prostate cancer (PCa) is an androgen-dependent disease. Novel anti-androgens (i.e. enzalutamide) have recently been developed for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). Evidence is accumulating that prostate cancer antigen 3 (PCA3) is involved in androgen receptor (AR) signaling. Here, in combination with enzalutamide-mediated AR blockade, we investigated the effect of PCA3 targeting on the viability of PCa cells. In hormone-sensitive LNCaP cells, AR-overexpressing LNCaP-AR + cells and VCaP cells (representing CRPC), PCA3 was silenced using siRNA oligonucleotides. Gene expression and cell viability was assessed in PCA3-silenced and/or AR-blocked cells. PCA3 targeting reduced the expression of AR-related genes (i.e. prostate-specific antigen (PSA) and prostate-specific transcript 1 (non-protein coding) (PCGEM1)) and potentiated the effect of enzalutamide. Proliferation of PCa cells was suppressed upon PCA3 silencing with a greater effect in LNCaP-AR + cells. Furthermore, PCA3 silencing sensitized PCa cells to enzalutamide-induced loss of cell growth. PCA3, as a therapeutic target in PCa, might be used to potentiate AR antagonists. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  17. N-Methyl-d-Aspartate (NMDA Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection

    Directory of Open Access Journals (Sweden)

    Vivian V. Costa

    2017-04-01

    Full Text Available Zika virus (ZIKV infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801, agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.

  18. Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade

    Directory of Open Access Journals (Sweden)

    Gregg W. Crabtree

    2016-10-01

    Full Text Available Proline dehydrogenase (PRODH, which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease.

  19. Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade.

    Science.gov (United States)

    Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A; Gogos, Joseph A

    2016-10-04

    Proline dehydrogenase (PRODH), which degrades L-proline, resides within the schizophrenia-linked 22q11.2 deletion suggesting a role in disease. Supporting this, elevated L-proline levels have been shown to increase risk for psychotic disorders. Despite the strength of data linking PRODH and L-proline to neuropsychiatric diseases, targets of disease-relevant concentrations of L-proline have not been convincingly described. Here, we show that Prodh-deficient mice with elevated CNS L-proline display specific deficits in high-frequency GABA-ergic transmission and gamma-band oscillations. We find that L-proline is a GABA-mimetic and can act at multiple GABA-ergic targets. However, at disease-relevant concentrations, GABA-mimesis is limited to competitive blockade of glutamate decarboxylase leading to reduced GABA production. Significantly, deficits in GABA-ergic transmission are reversed by enhancing net GABA production with the clinically relevant compound vigabatrin. These findings indicate that accumulation of a neuroactive metabolite can lead to molecular and synaptic dysfunction and help to understand mechanisms underlying neuropsychiatric disease. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Normotensive sodium loading in conscious dogs: Regulation of renin secretion during beta receptor blockade

    DEFF Research Database (Denmark)

    Bie, Peter; Mølstrøm, Simon; Wamberg, Søren

    2009-01-01

    Cl (20 micromol/kg/min for 180 min, NaLoad) during regular or low-sodium diet (0.03 mmol/kg/d, LowNa) with and without metoprolol (2 mg/kg plus 0.9 mg/kg/h). Vasopressin V2 receptors were blocked by Otsuka compound OPC31260 to facilitate clearance measurements. Body fluid volume was maintained by servo-controlled...... that in this setting, renin secretion and renin-dependent sodium excretion are controlled by via the renal nerves and therefore eliminated or reduced by blocking the action of norepinephrine on the juxtaglomerular cells with the beta1-receptor antagonist metoprolol. This was tested in conscious dogs by infusion of Na...... irrespective of diet. In conclusion, PRC depended on dietary sodium and beta1-adrenergic control as expected; however, the acute sodium-driven decrease in PRC at constant MAP and GFR was unaffected by beta1-receptor blockade demonstrating that renin may be regulated without changes in MAP, GFR, or beta1...

  1. IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse

    Directory of Open Access Journals (Sweden)

    Kostek Matthew C

    2012-06-01

    Full Text Available Abstract Background IL-6 is a pleiotropic cytokine that modulates inflammatory responses and plays critical roles in muscle maintenance and remodeling. In the mouse model (mdx of Duchenne Muscular Dystrophy, IL-6 and muscle inflammation are elevated, which is believed to contribute to the chronic inflammation and failure of muscle regeneration in DMD. The purpose of the current study was to examine the effect of blocking IL-6 signaling on the muscle phenotype including muscle weakness and pathology in the mdx mouse. Methods A monoclonal antibody against the IL-6 receptor (IL-6r mAb that blocks local and systemic IL-6 signaling was administered to mdx and BL-10 mice for 5 weeks and muscle function, histology, and inflammation were examined. Results IL-6r mAb treatment increased mdx muscle inflammation including total inflammation score and ICAM-1 positive lumens in muscles. There was no significant improvement in muscle strength nor muscle pathology due to IL-6r mAb treatment in mdx mice. Conclusions These results showed that instead of reducing inflammation, IL-6 signaling blockade for 5 weeks caused an increase in muscle inflammation, with no significant change in indices related to muscle regeneration and muscle function. The results suggest a potential anti-inflammatory instead of the original hypothesized pro-inflammatory role of IL-6 signaling in the mdx mice.

  2. Intercellular adhesion molecule-1 blockade attenuates inflammatory response and improves microvascular perfusion in rat pancreas grafts.

    Science.gov (United States)

    Preissler, Gerhard; Eichhorn, Martin; Waldner, Helmut; Winter, Hauke; Kleespies, Axel; Massberg, Steffen

    2012-10-01

    After pancreas transplantation (PTx), early capillary malperfusion and leukocyte recruitment indicate the manifestation of severe ischemia/reperfusion injury (IRI). Oscillatory blood-flow redistribution (intermittent capillary perfusion, IP), leading to an overall decrease in erythrocyte flux, precedes complete microvascular perfusion failure with persistent blood flow cessation. We addressed the role of intercellular adhesion molecule-1 (ICAM-1) for leukocyte-endothelial interactions (LEIs) after PTx and evaluated the contribution of IP and malperfusion. Pancreas transplantation was performed in rats after 18-hour preservation, receiving either isotype-matched IgG or monoclonal anti-ICAM-1 antibodies (10 mg/kg intravenously) once before reperfusion. Leukocyte-endothelial interaction, IP, erythrocyte flux, and functional capillary density, respectively, were examined in vivo during 2-hour reperfusion. Nontransplanted animals served as controls. Tissue samples were analyzed by histomorphometry. In grafts of IgG-treated animals, IP was encountered already at an early stage after reperfusion and steadily increased over 2 hours, whereas erythrocyte flux declined continuously. In contrast, inhibition of ICAM-1 significantly improved erythrocyte flux and delayed IP appearance by 2 hours. Further, anti-ICAM-1 significantly reduced LEI and leukocyte tissue infiltration when compared to IgG; edema development was less pronounced in response to anti-ICAM-1 monoclonal antibody. Intercellular adhesion molecule-1 blockade significantly attenuates IRI via immediate reduction of LEI and concomitant improvement of capillary perfusion patterns, emphasizing its central role during IRI in PTx.

  3. Impact of prolonged leucine supplementation on protein synthesis and lean growth in neonatal pigs

    Science.gov (United States)

    Most low-birth weight infants experience extrauterine growth failure due to reduced nutrient intake as a result of feeding intolerance. The objective of this study was to determine whether prolonged enteral leucine supplementation improves lean growth in neonatal pigs fed a restricted protein diet. ...

  4. Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2

    DEFF Research Database (Denmark)

    Grubb, Søren Jahn; Aistrup, Gary L; Koivumäki, Jussi T

    2015-01-01

    to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVβ2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca(2+) entry into the cell, thereby...

  5. CNS fatigue provoked by prolonged exercise in the heat

    DEFF Research Database (Denmark)

    Nybo, Lars

    2010-01-01

    to the brain. However, exercise with superimposed hyperthermia is not only a challenge to the brain it also provides an excellent model for studying factors of importance for central fatigue. Excessive heat storage within the brain appears to be the primary cause for the central fatigue during exercise......Exercise-induced hyperthermia is associated with central fatigue as indicated by an impaired ability to sustain maximal motor activation during prolonged voluntary efforts. Therefore, exercise in hot environments challenges not only to the cardiorespiratory and locomotive systems but also...... to aggravate central fatigue and degrade exercise performance. Hyperthermia mediated central fatigue may include other cerebral perturbations such as reduced perfusion of the brain, accumulation of ammonia or depletion of neuronal energy stores, but further research is needed to elucidate their possible...

  6. Effect of prolonged continuous irradiation of humoral immunity of mice

    International Nuclear Information System (INIS)

    Kirillova, E.N.; Muksinova, K.N.; Skukovskaya, T.L.

    1988-01-01

    Changes in the content and function of cell populations and subpopulations involved in the humoral response of mice to the thymus-dependent antigen were investigated. The effect was followed during a prolonged continuous exposure to 137 C gamma-emitter (total dose - 5 Gy and daily dose - 12 cGy for 22 hours) and after its termination. The data obtained give evidence for a decrease of the pool of polypotent lymphocyte precursors (CFUs), stable moderate hypoplasia of central and peripheral organs of the immune system, distinct inhibition of antibody production at the expense of reduced activity of precursors of lymphocytes, B-lymphocytes and T-helpers. In the remote post-irradiation period residual radiation damage was seen in polypotent and committed precursors of lymphocytes and T-helpers, which was responsible for the trend towards the decline of antibody production, hypoplasia in the spleen and lymph nodes being persistent

  7. Beta-adrenergic blockade for the treatment of hyperthyroidism.

    Science.gov (United States)

    Geffner, D L; Hershman, J M

    1992-07-01

    To review the clinical and biochemical effects of beta-adrenergic blocking drugs on hyperthyroidism. Studies published since 1972 were identified through a computerized search of MEDLINE and extensive searching of the bibliographies of the articles identified. Based on an understanding of the differences in beta-blocker metabolism in euthyroid and hyperthyroid patients, we reviewed the differences in pharmacokinetics and metabolic and clinical outcomes during their use in hyperthyroidism, as reported in the articles reviewed. beta Blockers have been used to modify the severity of the hyperadrenergic symptoms of hyperthyroidism for the past 20 years. The clinical efficacy of these agents is affected by hyperthyroid-induced alterations in their gastrointestinal absorption, hepatic metabolism, and renal excretion. The mechanisms whereby these clinical changes are effected is unknown. The agents differ in their beta 1 cardioselectivity, membrane-stabilizing activity, intrinsic sympathomimetic activity, and lipid solubility. They do not appear to alter synthesis or secretion of thyroid hormone by the thyroid gland. Their effects on thyroxine metabolism are contradictory. Decreased thyroxine to triiodothyronine conversion is caused by some, but not all, beta blockers, and this appears to correlate with membrane-stabilizing activity. There does not appear to be any alteration in catecholamine sensitivity during beta-adrenergic blockade. The principal mechanism of action of beta blockers in hyperthyroidism is to antagonize beta-receptor-mediated effects of catecholamines. beta Blockers are effective in treating hypermetabolic symptoms in a variety of hyperthyroid states. Used alone, they offer significant symptomatic relief. They are also useful adjuvants to antithyroid medications, surgery, and radioactive iodide treatment in patients with Graves' disease and toxic nodular goiters.

  8. Survey of external cephalic version for breech presentation and neuraxial blockade use.

    Science.gov (United States)

    Weiniger, Carolyn F; Sultan, Pervez; Dunn, Ashley; Carvalho, Brendan

    2016-11-01

    Neuraxial blockade may increase external cephalic version (ECV) success rates. This survey aimed to assess the frequency and characteristics of neuraxial blockade used to facilitate ECV. We surveyed Society for Obstetric Anesthesia and Perinatology members regarding ECV practice using a 15-item survey developed by 3 obstetric anesthesiologists and tested for face validity. The survey was e-mailed in January 2015 and again in February 2015 to the 1056 Society of Obstetric Anesthesiology and Perinatology members. We present descriptive statistics of responses. Our survey response rate was 322 of 1056 (30.5%). Neuraxial blockade was used for ECV always by 18 (5.6%), often by 52 (16.1%), sometimes by 98 (30.4%), rarely by 78 (24.2%), and never by 46 (14.3%) of respondents. An anesthetic sensory block target was selected by 141 (43.8%) respondents, and analgesic by 102 (31.7%) respondents. Epidural drug doses ranged widely, including sufentanil 5-25 μg; lidocaine 1% or 2% 10-20 mL, bupivacaine 0.0625% to 0.5% 6-15 mL, and ropivacaine 0.2% 20 mL. Intrathecal bupivacaine was used by 182 (56.5%) respondents; the most frequent doses were 2.5 mg used by 24 (7.5%), 7.5 mg used by 35 (10.9%), and 12 mg used by 30 (9.3%). Neuraxial blockade is not universally offered to facilitate ECV, and there is wide variability in neuraxial blockade techniques, in drugs and doses administered, and in the sensory blockade (anesthetic or analgesic) targeted. Future studies need to evaluate and remove barriers to allow for more widespread use of neuraxial blockade for pain relief and to optimize ECV success rates. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. The effect of reticuloendothelial blockade on the blood clearance and tissue distribution of liposomes

    International Nuclear Information System (INIS)

    Souhami, R.L.; Patel, H.M.; Ryman, B.E.

    1981-01-01

    The blood clearance and tissue distribution of liposomes have been studied in mice subjected to reticuloendothelial blockade with dextran sulphate or carbon. The liposomes have been labelled in the lipid membranes with [ 3 H]-cholesterol, [ 14 C]phosphatidylcholine and/or 99 sup(m)Tc and the content with [ 14 C]inulin. Reticuloendothelial blockade has been shown to slow the rate of clearance of neutral, positively and negatively charged liposomes and of both small unilamellar vesicles and large multilamellar vesicles. In normal animals, the liver uptake accounted for only 20-55% of the total injected radioactivity, the amount varying with the charge and size of the liposomes. Following blockade, the liver uptake of charged and neutral multilamellar liposomes was depressed. This was also true for negatively charged small unilamellar vesicles. The degree of depression of hepatic uptake was between 25-50%, which contrasts with the 80-90% reduction in uptake of a wholly phagocytosed particle (sheep red cells). This difference suggets that mechanisms other than Kupffer cell phagocytosis are also responsible for the normal uptake of liposomes into the liver. In the case of neutral and positively charged small unilamellar vesicles, delayed clearance due to blockade was not associated with depressed hepatic uptake. The site of action of blockading agents for these preparations is not clear. With all preparations of liposomes, blockade produced a slight and variable increase in uptake in the lung and spleen. The alteration of distribution of liposomes by reticuloendothelial blockade is therefore not great and the value of the technique in modifying the tissue distribution of substances within liposomes may be limited. (orig.)

  10. Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training.

    Directory of Open Access Journals (Sweden)

    Sheng-Chun Mao

    Full Text Available Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5, but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95 and synapse-associated protein-97 (SAP97. Accordingly, delivery of Tat-GluR2(3Y, a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.

  11. Inhibition of spontaneous recovery of fear by mGluR5 after prolonged extinction training.

    Science.gov (United States)

    Mao, Sheng-Chun; Chang, Chih-Hua; Wu, Chia-Chen; Orejarena, M Juliana; Orejanera, Maria Juliana; Manzoni, Olivier J; Gean, Po-Wu

    2013-01-01

    Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2(3Y), a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.

  12. Multifactorial QT Interval Prolongation and Takotsubo Cardiomyopathy

    Directory of Open Access Journals (Sweden)

    Michael Gysel

    2014-01-01

    Full Text Available A 71-year-old woman collapsed while working as a grocery store cashier. CPR was performed and an AED revealed torsades de pointes (TdP. She was subsequently defibrillated resulting in restoration of sinus rhythm with a QTc interval of 544 msec. Further evaluation revealed a diagnosis of Takotsubo Cardiomyopathy (TCM contributing to the development of a multifactorial acquired long QT syndrome (LQTS. The case highlights the role of TCM as a cause of LQTS in the setting of multiple risk factors including old age, female gender, hypokalemia, and treatment with QT prolonging medications. It also highlights the multifactorial nature of acquired LQTS and lends support to growing evidence of an association with TCM.

  13. Prolonged toxicity from Kambo cleansing ritual.

    Science.gov (United States)

    Li, Kai; Horng, Howard; Lynch, Kara; Smollin, Craig G

    2018-04-02

    Kambo cleanse is a purification, cleansing ritual traditionally performed by South American shaman to confer luck and health to hunters. We report a patient who presented to the emergency department with prolonged symptoms of vomiting, flushing, facial swelling, altered mental status, and agitation requiring chemical restraints, 22 h after a Kambo cleanse. The patient was found with four small, circular, superficial burns to the ankle at the site where the resin was introduced. The cleanse consists of rubbing resin obtained from the secretions of the giant leaf frog (Phyllomedusa bicolor) into superficial wounds to produce intense gastrointestinal symptoms followed by a sensation of increased stamina and strength. The cleanse is now being increasingly performed in Europe and USA.

  14. Bywalled plasma formation in vacuum prolonged channels

    International Nuclear Information System (INIS)

    Korenev, S.A.; Rubin, N.B.

    1982-01-01

    To produce homogeneous along the channel length plasma the application of incomplete rate-in surface dielectric discharge for generating the bywalled plasma in prolonged cylindrical channels at a pressure of the residual gas of P approximately 10 -5 Torr is proposed. Experimental set-up consisted of a pulse voltage generator and a plasma channel. The plasma channel was a coaxial system of three tubes inserted into each other. The first outer tube is made of a stainless steel, the second - of a dielectric material, the third - of smallsized stainless steel greed. It is demonstrated that the plasma being formed in the process is sufficiently homogeneous by concentration of the components, by the channel length and azimuth. The length of the experimental channel under investigation was 1.6 m, its diameter amounted 0.05 m. The maximum concentration of electron component was 10 17 m -3

  15. Neurohumoral responses during prolonged exercise in humans

    DEFF Research Database (Denmark)

    Nybo, Lars; Nielsen, Bodil; Blomstrand, Eva

    2003-01-01

    This study examined neurohumoral alterations during prolonged exercise with and without hyperthermia. The cerebral oxygen-to-carbohydrate uptake ratio (O2/CHO = arteriovenous oxygen difference divided by arteriovenous glucose difference plus one-half lactate), the cerebral balances of dopamine......, and the metabolic precursor of serotonin, tryptophan, were evaluated in eight endurance-trained subjects during exercise randomized to be with or without hyperthermia. The core temperature stabilized at 37.9 +/- 0.1 degrees C (mean +/- SE) in the control trial, whereas it increased to 39.7 +/- 0.2 degrees C...... in the hyperthermic trial, with a concomitant increase in perceived exertion (P exercise trials. Both the arterial and jugular venous dopamine levels...

  16. Prolonged grieving after abortion: a descriptive study.

    Science.gov (United States)

    Brown, D; Elkins, T E; Larson, D B

    1993-01-01

    Although flawed by methodological problems, the research literature tends to provide support for the assumption that induced abortion in the 1st trimester is not accompanied by enduring negative psychological sequelae. In cases where such sequelae are reported, the morbidity is attributed to a pre-existing psychiatric condition or circumstances precipitating the choice of abortion. However, detailed descriptive letters from 45 women prepared in response to a request by a pastor of an upper-middle-class Protestant congregation in Florida indicate that prolonged grieving after abortion may be more widespread phenomenon than previously believed. Letter writers ranged in age from 25-60 years; 75% were unmarried at the time of the procedure and 29% aborted before the legalization of abortion in the US. The most frequently cited long-term sequela, especially among those who felt coerced to abort, was a continued feeling of guilt. Fantasies about the aborted fetus was the next most frequently mentioned experience. Half of the letter writers referred to their abortions, as "murder" and 44% voiced regret about their decision to abort. Other long-term effects included depression (44%), feelings of loss (31%), shame (27%), and phobic responses to infants (13%). For 42% of these women, the adverse psychological effects of abortion endured over 10 years. Since letter-writers came from a self-selected population group with a known bias against abortion and only negative experiences were solicited, these experiences must be regarded as subjectives and anecdotal. However, they draw attention to the need for methodologically sound studies of a possible prolonged grief syndrome among a small percentage of women who have abortions, especially when coercion is involved.

  17. Therapeutic PD-L1 and LAG-3 blockade rapidly clears established blood-stage Plasmodium infection

    Science.gov (United States)

    Butler, Noah S.; Moebius, Jacqueline; Pewe, Lecia L.; Traore, Boubacar; Doumbo, Ogobara K.; Tygrett, Lorraine T.; Waldschmidt, Thomas J.; Crompton, Peter D.; Harty, John T.

    2011-01-01

    Plasmodium infection of erythrocytes induces clinical malaria. Parasite-specific CD4+ T cells correlate with reduced parasite burdens and severity of human malaria, and are required to control blood-stage infection in mice. However, the characteristics of CD4+ T cells that determine protection or parasite persistence remain unknown. Here we show that P. falciparum infection of humans increased expression of an inhibitory receptor (PD-1) associated with T cell dysfunction. In vivo blockade of PD-L1 and LAG-3 restored CD4+ T cell function, amplified T follicular helper cell and germinal center B cell and plasmablast numbers, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, which can be rescued to enhance parasite control using inhibitory therapies. PMID:22157630

  18. Blockade of cannabinoid CB receptor function protects against in vivo disseminating brain damage following NMDA-induced excitotoxicity

    DEFF Research Database (Denmark)

    Hansen, H.H.; Ramos, J.A.; Fernández-Ruiz, J.

    2002-01-01

    -induced excitotoxic damage in the ipsilateral forebrain was not influenced by agonist-stimulated CB receptor function. In contrast, blockade of CB, but not CB, receptor activity evoked a robust neuroprotective response by reducing the infarct area and the number of cortical degenerating neurons. These results suggest...... receptor function on NMDA-induced excitotoxicity. Neonatal (6-day-old) rat pups received a systemic injection of a mixed CB/CB receptor agonist (WIN55,212-2) or their respective antagonists (SR141716A for CB and SR144528 for CB) prior to an unilateral intrastriatal microinjection of NMDA. The NMDA...... a critical involvement of CB receptor tonus on neuronal survival following NMDA receptor-induced excitotoxicity in vivo....

  19. Prolonged pain and disability are common after rib fractures.

    Science.gov (United States)

    Fabricant, Loic; Ham, Bruce; Mullins, Richard; Mayberry, John

    2013-05-01

    The contribution of rib fractures to prolonged pain and disability may be underappreciated and undertreated. Clinicians are traditionally taught that the pain and disability of rib fractures resolves in 6 to 8 weeks. This study was a prospective observation of 203 patients with rib fractures at a level 1 trauma center. Chest wall pain was evaluated by the McGill Pain Questionnaire (MPQ) pain rating index (PRI) and present pain intensity (PPI). Prolonged pain was defined as a PRI of 8 or more at 2 months after injury. Prolonged disability was defined as a decrease in 1 or more levels of work or functional status at 2 months after injury. Predictors of prolonged pain and disability were determined by multivariate analysis. One hundred forty-five male patients and 58 female patients with a mean injury severity score (ISS) of 20 (range, 1 to 59) had a mean of 5.4 rib fractures (range, 1 to 29). Forty-four (22%) patients had bilateral fractures, 15 (7%) had flail chest, and 92 (45%) had associated injury. One hundred eighty-seven patients were followed 2 months or more. One hundred ten (59%) patients had prolonged chest wall pain and 142 (76%) had prolonged disability. Among 111 patients with isolated rib fractures, 67 (64%) had prolonged chest wall pain and 69 (66%) had prolonged disability. MPQ PPI was predictive of prolonged pain (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.4 to 2.5), and prolonged disability (OR, 2.2; 95% CI, 1.5 to 3.4). The presence of significant associated injuries was predictive of prolonged disability (OR, 5.9; 95% CI, 1.4 to 29). Prolonged chest wall pain is common, and the contribution of rib fractures to disability is greater than traditionally expected. Further investigation into more effective therapies that prevent prolonged pain and disability after rib fractures is needed. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Prolonged jaundice in newborns is associated with low antioxidant capacity in breast milk.

    Science.gov (United States)

    Uras, Nurdan; Tonbul, Alpaslan; Karadag, Ahmet; Dogan, Derya G; Erel, Ozcan; Tatli, Mustafa M

    2010-10-01

    In breastfeeding newborns who are otherwise healthy, the mechanism of prolonged jaundice remains unclear. The aim of this study was to investigate relations between prolonged jaundice and oxidative parameters in breast milk. Full-term, otherwise healthy newborns with jaundice lasting more than 2 weeks were enrolled prospectively in the study. As a control group, newborns in the same age group but without prolonged jaundice were selected. All newborns in the study were exclusively breastfed. In the newborns with prolonged jaundice, investigations of the etiology of the jaundice included complete blood count, peripheral blood smear, blood typing, direct Coombs test, measurement of serum levels of total and direct bilirubin, tests for liver and thyroid function (TSH, free T4, total T4), urine culture and measurement of urine reducing substances, and determination of glucose 6 phosphate dehydrogenase enzyme levels. Breast milk was collected from the mothers of the newborns in both groups. The antioxidant status of the breast milk was assessed via determination of total antioxidant capacity (TAC). Oxidative stress was also assessed in breast milk by measurement of total oxidation status (TOS) and calculation of the oxidative stress index (OSI). The prolonged jaundice group differed significantly from the control group in terms of mean TAC and OSI (p antioxidant capacity was found to be decreased.

  1. Effectiveness of Cognitive Processing Therapy and Prolonged Exposure in the Department of Veterans Affairs.

    Science.gov (United States)

    Rutt, Benjamin T; Oehlert, Mary E; Krieshok, Thomas S; Lichtenberg, James W

    2018-04-01

    Objective This study evaluated the effectiveness of cognitive processing therapy and prolonged exposure in conditions reflective of current clinical practice within the Veterans Health Administration. Method This study involved a retrospective review of 2030 charts. A total of 750 veterans from 10 U.S. states who received cognitive processing therapy or prolonged exposure in individual psychotherapy were included in the study (participants in cognitive processing therapy, N = 376; participants in prolonged exposure, N = 374). The main dependent variable was self-reported posttraumatic stress disorder symptoms as measured by total scores on the Posttraumatic Stress Disorder Checklist. The study used multilevel modeling to evaluate the absolute and relative effectiveness of both treatments and determine the relationship between patient-level variables and total Posttraumatic Stress Disorder Checklist scores during treatment. Results Cognitive processing therapy and prolonged exposure were equally effective at reducing total Posttraumatic Stress Disorder Checklist scores. Veterans who completed therapy reported significantly larger reductions in the Posttraumatic Stress Disorder Checklist than patients who did not complete therapy. There were no significant differences in the improvement of posttraumatic stress disorder symptoms with respect to age and three racial/ethnic groups (Caucasian, African American, and Hispanic). Conclusions Cognitive processing therapy and prolonged exposure were shown to be effective in conditions highly reflective of clinical practice and with a highly diverse sample of veterans. Challenges related to dropout from trauma focused therapy should continue to be researched.

  2. β-Adrenoceptor Blockade in the Basolateral Amygdala, But Not the Medial Prefrontal Cortex, Rescues the Immediate Extinction Deficit.

    Science.gov (United States)

    Giustino, Thomas F; Seemann, Jocelyn R; Acca, Gillian M; Goode, Travis D; Fitzgerald, Paul J; Maren, Stephen

    2017-12-01

    Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulation of neural circuits involved in extinction learning. We have shown that systemic β-adrenoceptor blockade with propranolol rescues the IED, but impairs delayed extinction. Here we sought to determine the neural locus of these effects. Rats underwent auditory fear conditioning and then received either immediate (30 min) or delayed (24 h) extinction training. We used bilateral intracranial infusions of propranolol into either the infralimbic division of the medial prefrontal cortex (mPFC) or the basolateral amygdala (BLA) to examine the effects of β-adrenoceptor blockade on immediate and delayed extinction learning. Interestingly, intra-BLA, but not intra-mPFC, propranolol rescued the IED; animals receiving intra-BLA propranolol prior to immediate extinction showed less spontaneous recovery of fear during extinction retrieval. Importantly, this was not due to impaired consolidation of the conditioning memory. In contrast, neither intra-BLA nor intra-mPFC propranolol affected delayed extinction learning. Overall, these data contribute to a growing literature suggesting dissociable roles for key nodes in the fear extinction circuit depending on the timing of extinction relative to conditioning. These data also suggest that heightened noradrenergic activity in the BLA underlies stress-induced extinction deficits. Propranolol may be a useful adjunct to behavioral therapeutic interventions in recently traumatized individuals who are at risk for developing trauma-related disorders.

  3. Adenosine A2A receptor blockade Prevents Rotenone-Induced Motor Impairment in a Rat Model of Parkinsonism

    Directory of Open Access Journals (Sweden)

    Ahmed M Fathalla

    2016-02-01

    Full Text Available Pharmacological studies implicate the blockade of adenosine receptorsas an effective strategy for reducing Parkinson's disease (PD symptoms. The objective of this study is to elucidate the possible protective effects of ZM241385 and 8-cyclopentyl-1,3-dipropylxanthine, two selective A2Aand A1 receptor antagonists, on a rotenone rat model of PD. Rats were split into four groups: vehicle control (1 ml/kg/48 h, rotenone(1.5 mg/kg/48 h, s.c., ZM241385 (3.3 mg/kg/day, i.p and 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg/day, i.p. After that, animals were subjected to behavioral (stride length and grid walking and biochemical (measuring concentration of dopamine levels using high performance liquid chromatography. In the rotenone group, rats displayed a reduced motor activity and disturbed movement coordination in the behavioral tests and a decreased dopamine concentration as foundby high performance liquid chromatography. The effect of rotenone was partially preventedin the ZM241385 group, but not with 8-cyclopentyl-1,3-dipropylxanthine administration. The administration of ZM241385 has led toan improvement improved of motor function and movement coordination (a partial increase of stride length and partial decrease in the number of foot slips and an increase in dopamine concentration in the rotenone-injected rats. However, the 8-cyclopentyl-1,3-dipropylxanthine and rotenone groups were not significantly different. These results indicate that selective A2Areceptor blockade by ZM241385, but not A1receptor blockadeby 8-cyclopentyl-1,3-dipropylxanthine, may treat PD motor symptoms. This reinforces the potential use of A2A receptor antagonists as a treatment strategy for PD patients.. This may provide a more selective treatment strategy for PD patients.

  4. The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

    Science.gov (United States)

    Wheeldon, N M; McDevitt, D G; Lipworth, B J

    1994-08-01

    1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. Angiotensin II blockade causes acute renal failure in eNOS-deficient mice

    Directory of Open Access Journals (Sweden)

    Jürgen Schnermann

    2001-03-01

    Full Text Available Compared with wild-type mice, adult endothelial nitric oxide synthase (eNOS knockout mice (eight months of age have increased blood pressure (BP (126±9 mmHg vs. 100±4 mmHg, and an increased renal vascular resistance (155±16 vs. 65±4 mmHg.min/ml. Renal vascular resistance responses to i.v. administration of noradrenaline were markedly enhanced in eNOS knockout mice. Glomerular filtration rate (GFR of anaesthetised eNOS -/- mice was 324±57 µl/min gKW, significantly lower than the GFR of 761±126 µl/min.gKW in wild-type mice. AT1-receptor blockade with i.v. candesartan (1—1.5 mg/kg reduced arterial blood pressure and renal vascular resistance, and increased renal blood flow (RBF to about the same extent in wild-type and eNOS -/- mice. Candesartan did not alter GFR in wild-type mice (761±126 vs. 720±95 µl/min.gKW, but caused a marked decrease in GFR in eNOS -/- mice (324.5±75.2 vs. 77±18 µl/min.gKW. A similar reduction in GFR of eNOS deficient mice was also caused by angiotensin-converting enzyme (ACE inhibition. Afferent arteriolar granularity, a measure of renal renin expression, was found to be reduced in eNOS -/- compared with wild-type mice. In chronically eNOS-deficient mice, angiotensin II (Ang II is critical for maintaining glomerular filtration pressure and GFR, presumably through its effect on efferent arteriolar tone.

  6. Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation.

    Science.gov (United States)

    Kumari, Archana; Ermilov, Alexandre N; Allen, Benjamin L; Bradley, Robert M; Dlugosz, Andrzej A; Mistretta, Charlotte M

    2015-02-01

    Taste sensation on the anterior tongue requires chorda tympani nerve function and connections with continuously renewing taste receptor cells. However, it is unclear which signaling pathways regulate the receptor cells to maintain chorda tympani sensation. Hedgehog (HH) signaling controls cell proliferation and differentiation in numerous tissues and is active in taste papillae and taste buds. In contrast, uncontrolled HH signaling drives tumorigenesis, including the common skin cancer, basal cell carcinoma. Systemic HH pathway inhibitors (HPIs) lead to basal cell carcinoma regression, but these drugs cause severe taste disturbances. We tested the hypothesis that taste disruption by HPIs reflects a direct requirement for HH signaling in maintaining taste organs and gustatory sensation. In mice treated with the HPI LDE225 up to 28 days, HH-responding cells were lost in fungiform papilla epithelium, and papillae acquired a conical apex. Taste buds were either absent or severely reduced in size in more than 90% of aberrant papillae. Taste bud remnants expressed the taste cell marker keratin 8, and papillae retained expression of nerve markers, neurofilament and P2X3. Chorda tympani nerve responses to taste stimuli were markedly reduced or absent in LDE225-treated mice. Responses to touch were retained, however, whereas cold responses were retained after 16 days of treatment but lost after 28 days. These data identify a critical, modality-specific requirement for HH signaling in maintaining taste papillae, taste buds and neurophysiological taste function, supporting the proposition that taste disturbances in HPI-treated patients are an on-target response to HH pathway blockade in taste organs. Copyright © 2015 the American Physiological Society.

  7. Blockade of MMP14 Activity in Murine Breast Carcinomas: Implications for Macrophages, Vessels, and Radiotherapy

    Science.gov (United States)

    Ager, Eleanor I.; Kozin, Sergey V.; Kirkpatrick, Nathaniel D.; Seano, Giorgio; Kodack, David P.; Askoxylakis, Vasileios; Huang, Yuhui; Goel, Shom; Snuderl, Matija; Muzikansky, Alona; Finkelstein, Dianne M.; Dransfield, Daniel T.; Devy, Laetitia; Boucher, Yves

    2015-01-01

    Background: Matrix metalloproteinase (MMP) 14 may mediate tumor progression through vascular and immune-modulatory effects. Methods: Orthotopic murine breast tumors (4T1 and E0771 with high and low MMP14 expression, respectively; n = 5–10 per group) were treated with an anti-MMP14 inhibitory antibody (DX-2400), IgG control, fractionated radiation therapy, or their combination. We assessed primary tumor growth, transforming growth factor β (TGFβ) and inducible nitric oxide synthase (iNOS) expression, macrophage phenotype, and vascular parameters. A linear mixed model with repeated observations, with Mann-Whitney or analysis of variance with Bonferroni post hoc adjustment, was used to determine statistical significance. All statistical tests were two-sided. Results: DX-2400 inhibited tumor growth compared with IgG control treatment, increased macrophage numbers, and shifted the macrophage phenotype towards antitumor M1-like. These effects were associated with a reduction in active TGFβ and SMAD2/3 signaling. DX-2400 also transiently increased iNOS expression and tumor perfusion, reduced tissue hypoxia (median % area: control, 20.2%, interquartile range (IQR) = 6.4%-38.9%; DX-2400: 1.2%, IQR = 0.2%-3.2%, P = .044), and synergistically enhanced radiation therapy (days to grow to 800mm3: control, 12 days, IQR = 9–13 days; DX-2400 plus radiation, 29 days, IQR = 26–30 days, P < .001) in the 4T1 model. The selective iNOS inhibitor, 1400W, abolished the effects of DX-2400 on vessel perfusion and radiotherapy. On the other hand, DX-2400 was not capable of inducing iNOS expression or synergizing with radiation in E0771 tumors. Conclusion: MMP14 blockade decreased immunosuppressive TGFβ, polarized macrophages to an antitumor phenotype, increased iNOS, and improved tumor perfusion, resulting in reduced primary tumor growth and enhanced response to radiation therapy, especially in high MMP14-expressing tumors. PMID:25710962

  8. 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

    2016-08-01

    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.

  9. Does UTI cause prolonged jaundice in otherwise well infants?

    Science.gov (United States)

    Chowdhury, Tanzila; Kisat, Hamudi; Tullus, Kjell

    2015-07-01

    The symptoms of urinary tract infections in infants are very non-specific and have historically included prolonged hyperbilirubinaemia. We studied the results of routine urine samples in 319 infants with prolonged jaundice. Convincing findings of UTI was not found in any of these children even if one of them was treated with antibiotics after four consecutive urine cultures with different bacteria. A urine culture might thus not be an appropriate investigation in a child with prolonged jaundice without any other symptoms of UTI. • The symptoms of UTI in infancy are very non-specific. • Old studies suggest that prolonged hyperbilirubinaemia is one such symptom; more modern studies give more conflicting results. What is New: • Our study could not confirm that children with prolonged jaundice have an increased risk of UTI. • Routine urine testing is thus not needed in otherwise healthy infants with prolonged jaundice.

  10. Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaine [Corrected from: Acta Anaesthesiol Scand 48 (1), 2004, 128-134

    NARCIS (Netherlands)

    Stevens, M. F.; Hoppe, M.; Holthusen, H.; Lipfert, P.

    2004-01-01

    BACKGROUND: In isolated nerves, tetrodotoxin (TTX) blocks nerve conduction longer than bupivacaine. In vivo, however, both substances block nerve conduction to an equal duration, presumably because the hydrophilic TTX binds only weakly to the perineural tissue. High molecular weight hyaluronic acid

  11. PD-1/CTLA-4 Blockade Inhibits Epstein-Barr Virus-Induced Lymphoma Growth in a Cord Blood Humanized-Mouse Model.

    Directory of Open Access Journals (Sweden)

    Shi-Dong Ma

    2016-05-01

    Full Text Available Epstein-Barr virus (EBV infection causes B cell lymphomas in humanized mouse models and contributes to a variety of different types of human lymphomas. T cells directed against viral antigens play a critical role in controlling EBV infection, and EBV-positive lymphomas are particularly common in immunocompromised hosts. We previously showed that EBV induces B cell lymphomas with high frequency in a cord blood-humanized mouse model in which EBV-infected human cord blood is injected intraperitoneally into NOD/LtSz-scid/IL2Rγnull (NSG mice. Since our former studies showed that it is possible for T cells to control the tumors in another NSG mouse model engrafted with both human fetal CD34+ cells and human thymus and liver, here we investigated whether monoclonal antibodies that block the T cell inhibitory receptors, PD-1 and CTLA-4, enhance the ability of cord blood T cells to control the outgrowth of EBV-induced lymphomas in the cord-blood humanized mouse model. We demonstrate that EBV-infected lymphoma cells in this model express both the PD-L1 and PD-L2 inhibitory ligands for the PD-1 receptor, and that T cells express the PD-1 and CTLA-4 receptors. Furthermore, we show that the combination of CTLA-4 and PD-1 blockade strikingly reduces the size of lymphomas induced by a lytic EBV strain (M81 in this model, and that this anti-tumor effect requires T cells. PD-1/CTLA-4 blockade markedly increases EBV-specific T cell responses, and is associated with enhanced tumor infiltration by CD4+ and CD8+ T cells. In addition, PD-1/CTLA-4 blockade decreases the number of both latently, and lytically, EBV-infected B cells. These results indicate that PD-1/CTLA-4 blockade enhances the ability of cord blood T cells to control outgrowth of EBV-induced lymphomas, and suggest that PD-1/CTLA-4 blockade might be useful for treating certain EBV-induced diseases in humans.

  12. Efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade in adults.

    Science.gov (United States)

    Hristovska, Ana-Marija; Duch, Patricia; Allingstrup, Mikkel; Afshari, Arash

    2017-08-14

    Acetylcholinesterase inhibitors, such as neostigmine, have traditionally been used for reversal of non-depolarizing neuromuscular blocking agents. However, these drugs have significant limitations, such as indirect mechanisms of reversal, limited and unpredictable efficacy, and undesirable autonomic responses. Sugammadex is a selective relaxant-binding agent specifically developed for rapid reversal of non-depolarizing neuromuscular blockade induced by rocuronium. Its potential clinical benefits include fast and predictable reversal of any degree of block, increased patient safety, reduced incidence of residual block on recovery, and more efficient use of healthcare resources. The main objective of this review was to compare the efficacy and safety of sugammadex versus neostigmine in reversing neuromuscular blockade caused by non-depolarizing neuromuscular agents in adults. We searched the following databases on 2 May 2016: Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (WebSPIRS Ovid SP), Embase (WebSPIRS Ovid SP), and the clinical trials registries www.controlled-trials.com, clinicaltrials.gov, and www.centerwatch.com. We re-ran the search on 10 May 2017. We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published, or language. We included adults, classified as American Society of Anesthesiologists (ASA) I to IV, who received non-depolarizing neuromuscular blocking agents for an elective in-patient or day-case surgical procedure. We included all trials comparing sugammadex versus neostigmine that reported recovery times or adverse events. We included any dose of sugammadex and neostigmine and any time point of study drug administration. Two review authors independently screened titles and abstracts to identify trials for eligibility, examined articles for eligibility, abstracted data, assessed the articles, and excluded obviously irrelevant reports. We resolved

  13. Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

    Science.gov (United States)

    Peyre, Matthieu; Cartalat-Carel, Stéphanie; Meyronet, David; Ricard, Damien; Jouvet, Anne; Pallud, Johan; Mokhtari, Karima; Guyotat, Jacques; Jouanneau, Emmanuel; Sunyach, Marie-Pierre; Frappaz, Didier; Honnorat, Jérôme; Ducray, François

    2010-01-01

    Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8–7.7) after PCV onset and 2.7 years (range, 0–7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonald's criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated. PMID:20488959

  14. Fermionic covariant prolongation structure theory for supernonlinear evolution equation

    International Nuclear Information System (INIS)

    Cheng Jipeng; Wang Shikun; Wu Ke; Zhao Weizhong

    2010-01-01

    We investigate the superprincipal bundle and its associated superbundle. The super(nonlinear)connection on the superfiber bundle is constructed. Then by means of the connection theory, we establish the fermionic covariant prolongation structure theory of the supernonlinear evolution equation. In this geometry theory, the fermionic covariant fundamental equations determining the prolongation structure are presented. As an example, the supernonlinear Schroedinger equation is analyzed in the framework of this fermionic covariant prolongation structure theory. We obtain its Lax pairs and Baecklund transformation.

  15. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes

    DEFF Research Database (Denmark)

    Mandrup-Poulsen, Thomas

    2012-01-01

    Proinflammatory cytokines stimulate adaptive immunity and attenuate T cell regulation and tolerance induction. They also profoundly impair β-cell function, proliferation, and viability, activities of similar importance in the context of type 1 diabetes (T1D). Detailed knowledge of the molecular...... mechanisms of β-cell toxicity has been gathered within the last 2-3 decades. However, the efficacy of individual proinflammatory cytokine blockade in animal models of T1D has been inconsistent and generally modest, except in the context of islet transplantation. This suggests that the timing of the cytokine...... blockade relative to anti-β-cell immune activation is critical, and that combination therapy may be required. In randomized, placebo-controlled, clinical trials of limited power, TNF-α (but not IL-1) blockade has yielded moderate but significant improvements in glycemia, insulin requirement, and β...

  16. 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

    2016-01-01

    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...... to pathophysiological mechanisms as well as aiding diagnosis and treatment of PPBCS but has never been attempted. OBJECTIVES: To assess the feasibility of ICBN blockade and assess its effects on pain and sensory function in patients with PPBCS. STUDY DESIGN: This prospective pilot study was performed in 2 parts: Part 1...

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

    Science.gov (United States)

    Széchenyi, Gábor; Pályi, András

    2013-12-01

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

  18. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group.

    Science.gov (United States)

    Büchner, Thomas; Hiddemann, Wolfgang; Berdel, Wolfgang E; Wörmann, Bernhard; Schoch, Claudia; Fonatsch, Christa; Löffler, Helmut; Haferlach, Torsten; Ludwig, Wolf-Dieter; Maschmeyer, Georg; Staib, Peter; Aul, Carlo; Gruneisen, Andreas; Lengfelder, Eva; Frickhofen, Norbert; Kern, Wolfgang; Serve, Hubert L; Mesters, Rolf M; Sauerland, Maria Cristina; Heinecke, Achim

    2003-12-15

    To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age or = 60 years] x 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age or = 60 years) x 8 instead of maintenance. A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P =.0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age > or = 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P =.0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P =.085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P =.026). We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

  19. Carbohydrate Dependence During Prolonged, Intense Endurance Exercise.

    Science.gov (United States)

    Hawley, John A; Leckey, Jill J

    2015-11-01

    A major goal of training to improve the performance of prolonged, continuous, endurance events lasting up to 3 h is to promote a range of physiological and metabolic adaptations that permit an athlete to work at both higher absolute and relative power outputs/speeds and delay the onset of fatigue (i.e., a decline in exercise intensity). To meet these goals, competitive endurance athletes undertake a prodigious volume of training, with a large proportion performed at intensities that are close to or faster than race pace and highly dependent on carbohydrate (CHO)-based fuels to sustain rates of muscle energy production [i.e., match rates of adenosine triphosphate (ATP) hydrolysis with rates of resynthesis]. Consequently, to sustain muscle energy reserves and meet the daily demands of training sessions, competitive athletes freely select CHO-rich diets. Despite renewed interest in high-fat, low-CHO diets for endurance sport, fat-rich diets do not improve training capacity or performance, but directly impair rates of muscle glycogenolysis and energy flux, limiting high-intensity ATP production. When highly trained athletes compete in endurance events lasting up to 3 h, CHO-, not fat-based fuels are the predominant fuel for the working muscles and CHO, not fat, availability becomes rate limiting for performance.

  20. Prolonged disengagement from distractors near the hands

    Directory of Open Access Journals (Sweden)

    Daniel B Vatterott

    2013-08-01

    Full Text Available Because items near our hands are often more important than items far from our hands, the brain processes visual items near our hands differently than items far from our hands. Multiple experiments have attributed this processing difference to spatial attention, but the exact mechanism behind how spatial attention near our hands changes is still under investigation. The current experiments sought to differentiate between two of the proposed mechanisms: a prioritization of the space near the hands and a prolonged disengagement of spatial attention near the hands. To differentiate between these two accounts, we used the additional singleton paradigm in which observers searched for a shape singleton among homogenously shaped distractors. On half the trials, one of the distractors was a different color. Both the prioritization and disengagement accounts predict differently colored distractors near the hands will slow target responses more than differently colored distractors far from the hands, but the prioritization account also predicts faster responses to targets near the hands than far from the hands. The disengagement account does not make this prediction, because attention does not need to be disengaged when the target appears near the hand. We found support for the disengagement account: Salient distractors near the hands slowed responses more than those far from the hands, yet observers did not respond faster to targets near the hands.

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

    DEFF Research Database (Denmark)

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

    1991-01-01

    Regional cerebral blood flow (rCBF) was determined at rest and during static handgrip before and after regional blockade with lidocaine. A fast rotating single photon emission computer tomograph system with 133Xe inhalation was used at orbitomeatal plane (OM) +2.5 and +6.5 cm in eight subjects. M...... static handgrip, there was no increase in rCBF after partial sensory and motor blockade. Thus bilateral activation occurs in the premotor and motor sensory cortex during static handgrip, and this activation requires neural feedback from the contracting muscles....

  2. Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade.

    Science.gov (United States)

    Dejaegher, Joost; Verschuere, Tina; Vercalsteren, Ellen; Boon, Louis; Cremer, Jonathan; Sciot, Raf; Van Gool, Stefaan W; De Vleeschouwer, Steven

    2017-11-01

    Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas. © 2017 UICC.

  3. 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

    2011-01-01

    -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...

  4. [Improvement of approach to performance of lumbar sympathetic blockade in patients with tissue ischemia of the lower extremities].

    Science.gov (United States)

    Panov, V M; Fesenko, U A; Kutsyn, V M

    2014-06-01

    New access for performance of sympathic blockade in region of aortal bifurcation, was elaborated, basing on calculations, conducted on 30 spiral computeric tomograms of lumbar and sacral parts of vertebral column. Application of the method permits to escape such complications, as a renal and the main vessels damage, the sympathetic nerves blockade, do not demand roentgenological control.

  5. Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

    Directory of Open Access Journals (Sweden)

    Kiersten Marie Miles

    Full Text Available The Notch ligand Delta-like 4 (Dll4 is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis. Blockade of the Dll4-Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth. Given the cross-talk between the vascular endothelial growth factor (VEGF and Delta-Notch pathways in tumor angiogenesis, we examined the activity of a function-blocking Dll4 antibody, REGN1035, alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC.Severe combined immunodeficiency (SCID mice bearing patient-derived clear cell RCC xenografts were treated with REGN1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv-aflibercept. Immunohistochemical and immunofluorescent analyses were carried out, as well as magnetic resonance imaging (MRI examinations pre and 24 hours and 2 weeks post treatment. Single agent treatment with REGN1035 resulted in significant tumor growth inhibition (36-62% that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38-54% and ziv-aflibercept (46%. Importantly, combination treatments with REGN1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72-80% growth inhibition, including some tumor regression. Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups. Interestingly, anti-tumor efficacy of the combination of REGN1035 and ziv-aflibercept was also observed in a sunitinib resistant ccRCC model.Overall, these findings demonstrate the potent anti-tumor activity of Dll4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll4 and VEGF signaling pathways, highlighting the therapeutic potential of this treatment modality in RCC.

  6. trans-Caryophyllene, a Natural Sesquiterpene, Causes Tracheal Smooth Muscle Relaxation through Blockade of Voltage-Dependent Ca2+ Channels

    Directory of Open Access Journals (Sweden)

    Jader Santos Cruz

    2012-10-01

    Full Text Available trans-Caryophyllene is a major component in the essential oils of various species of medicinal plants used in popular medicine in Brazil. It belongs to the chemical class of the sesquiterpenes and has been the subject of a number of studies. Here, we evaluated the effects of this compound in airway smooth muscle. The biological activities of trans-caryophyllene were examined in isolated bath organs to investigate the effect in basal tonus. Electromechanical and pharmacomechanical couplings were evaluated through the responses to K+ depolarization and exposure to acetylcholine (ACh, respectively. Isolated cells of rat tracheal smooth muscle were used to investigate trans-caryophyllene effects on voltage-dependent Ca2+ channels by using the whole-cell voltage-clamp configuration of the patch-clamp technique. trans-Caryophyllene showed more efficiency in the blockade of electromechanical excitation-contraction coupling while it has only minor inhibitory effect on pharmacomechanical coupling. Epithelium removal does not modify tracheal smooth muscle response elicited by trans-caryophyllene in the pharmacomechanical coupling. Under Ca2+-free conditions, pre-exposure to trans-caryophyllene did not reduce the contraction induced by ACh in isolated rat tracheal smooth muscle, regardless of the presence of intact epithelium. In the whole-cell configuration, trans-caryophyllene (3 mM, inhibited the inward Ba2+ current (IBa to approximately 50% of control levels. Altogether, our results demonstrate that trans-caryophyllene has anti-spasmodic activity on rat tracheal smooth muscle which could be explained, at least in part, by the voltage-dependent Ca2+ channels blockade.

  7. Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells

    Directory of Open Access Journals (Sweden)

    Grepper Susan

    2009-09-01

    Full Text Available Abstract Background Hepatocellular carcinoma (HCC is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/β-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC. Results We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type β-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased β-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous β-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions. Conclusion Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.

  8. Elevated N-terminal pro-brain natriuretic peptide levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of dietary sodium restriction and diuretics, but not angiotensin receptor blockade, in proteinuric renal patients.

    Science.gov (United States)

    Slagman, Maartje C J; Waanders, Femke; Vogt, Liffert; Damman, Kevin; Hemmelder, Marc; Navis, Gerjan; Laverman, Gozewijn D

    2012-03-01

    Renin-angiotensin aldosterone system (RAAS) blockade only partly reduces blood pressure, proteinuria and renal and cardiovascular risk in chronic kidney disease (CKD) but often requires sodium targeting [i.e. low sodium diet (LS) and/or diuretics] for optimal efficacy. However, both under- and overtitration of sodium targeting can easily occur. We evaluated whether N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker of volume expansion, predicts the benefits of sodium targeting in CKD patients. In a cross-over randomized controlled trial, 33 non-diabetic CKD patients (proteinuria 3.8 ± 0.4 g/24 h, blood pressure 143/86 ± 3/2 mmHg, creatinine clearance 89 ± 5 mL/min) were treated during 6-week periods with placebo, angiotensin receptor blockade (ARB; losartan 100 mg/day) and ARB plus diuretics (losartan 100 mg/day plus hydrochlorothiazide 25 mg/day), combined with LS (93 ± 52 mmol Na(+)/24 h) and regular sodium diet (RS; 193 ± 62 mmol Na(+)/24 h, P diuretics and was normalized by ARB + diuretic + LS [39 (26-59) pg/mL, P = 0.65 versus controls]. NT-proBNP levels above the upper limit of normal (>125 pg/mL) predicted a larger reduction of blood pressure and proteinuria by LS and diuretics but not by ARB, during all steps of the titration regimen. Elevated NT-proBNP levels predict an enhanced anti-hypertensive and anti-proteinuric benefit of sodium targeting, but not RAAS blockade, in proteinuric CKD patients. Importantly, this applies to the untreated condition, as well as to the subsequent treatment steps, consisting of RAAS blockade and even RAAS blockade combined with diuretics. NT-proBNP can be a useful tool to identify CKD patients in whom sodium targeting can improve blood pressure and proteinuria.

  9. Significant prolongation of hamster liver transplant survival in Lewis rats by total-lymphoid irradiation, cyclosporine, and splenectomy

    International Nuclear Information System (INIS)

    Yamaguchi, Y.; Halperin, E.C.; Harland, R.C.; Wyble, C.; Bollinger, R.R.

    1990-01-01

    The effects of total lymphoid irradiation, cyclosporine and splenectomy alone and in combination have been studied in liver transplants from the LVG hamster to the LEW rat. Neither CsA alone, splenectomy alone, nor TLI alone prolonged graft survival. CsA/splenectomy and TLI/CsA produced significant prolongation of graft survival. TLI/CsA/splenectomy prolonged graft survival by over sixfold compared with controls. While CsA alone was ineffective in reducing lymphocytotoxic antidonor antibody, splenectomy alone or CsA/splenectomy did significantly suppress production of antibody. Only very low levels of antibody could be detected in animals treated with TLI/CsA/splenectomy. TLI/CsA/splenectomy has an immunosuppressive effect sufficient to significantly prolong liver graft survival in the LVG hamster to LEW rat combination and may represent a promising treatment protocol in experimental cross-species transplantation

  10. TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis.

    Science.gov (United States)

    Conrad, Curdin; Di Domizio, Jeremy; Mylonas, Alessio; Belkhodja, Cyrine; Demaria, Olivier; Navarini, Alexander A; Lapointe, Anne-Karine; French, Lars E; Vernez, Maxime; Gilliet, Michel

    2018-01-02

    Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2-5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.

  11. Protective effects of C5a blockade in sepsis

    DEFF Research Database (Denmark)

    Czermak, B J; Sarma, V; Pierson, C L

    1999-01-01

    in vitro had greatly reduced production of H2O2, which is known to be essential for the bactericidal function of neutrophils. In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival rates were significantly improved, levels of bacteremia were considerably reduced...

  12. The pharmacokinetics of ropivacaine after four different techniques of brachial plexus blockade.

    NARCIS (Netherlands)

    Rettig, H.C.; Lerou, J.G.C.; Gielen, M.J.M.; Boersma, E.; Burm, A.G.L.

    2007-01-01

    Arterial plasma concentrations of ropivacaine were measured after brachial plexus blockade using four different approaches: lateral interscalene (Winnie), posterior interscalene (Pippa), axillary and vertical infraclavicular. Four groups of 10 patients were given a single 3.75 mg.kg(-1) injection of

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

    DEFF Research Database (Denmark)

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

    2007-01-01

    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....

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

    DEFF Research Database (Denmark)

    Nielsen, Stine; Rossing, Kasper; Hess, Georg

    2012-01-01

    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 protein (LFABP)....

  15. Chronic blockade of angiotensin II action prevents glomerulosclerosis, but induces graft vasculopathy in experimental kidney transplantation

    NARCIS (Netherlands)

    Smit-van Oosten, A; Navis, G; Stegeman, CA; Joles, JA; Klok, PA; Kuipers, F; Tiebosch, ATMG; van Goor, H

    Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases, This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic

  16. A new approach to anesthesia management in myasthenia gravis: reversal of neuromuscular blockade by sugammadex.

    NARCIS (Netherlands)

    Boer, H.D. de; Egmond, J. van; Driessen, J.J.; Booij, L.H.D.J.

    2010-01-01

    A neuromuscular blocking drug (NMBD) induced neuromuscular blockade (NMB) in patients with myasthenia gravis usually dissipates either spontaneously or by administration of neostigmine. We administered sugammadex to a patient with myasthenia gravis to reverse a rocuronium-induced profound NMB. NMBDs

  17. 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.

    2012-01-01

    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,

  18. Israel’s Blockade of Gaza, the Mavi Marmara Incident, and Its Aftermath

    Science.gov (United States)

    2010-06-23

    Rosen , a professor of international law and former diplomat, and Maj. Gen. Amos Horen (Ret.), a former president of Technion (Israel Institute of...However, Israeli Defense Minister Ehud Barak said, after meeting the Secretary General and providing details concerning new steps to ease the blockade

  19. Single-photon blockade in a hybrid cavity-optomechanical system via third-order nonlinearity

    Science.gov (United States)

    Sarma, Bijita; Sarma, Amarendra K.

    2018-04-01

    Photon statistics in a weakly driven optomechanical cavity, with Kerr-type nonlinearity, are analyzed both analytically and numerically. The single-photon blockade effect is demonstrated via calculations of the zero-time-delay second-order correlation function g (2)(0). The analytical results obtained by solving the Schrödinger equation are in complete conformity with the results obtained through numerical solution of the quantum master equation. A systematic study on the parameter regime for observing photon blockade in the weak coupling regime is reported. The parameter regime where the photon blockade is not realizable due to the combined effect of nonlinearities owing to the optomechanical coupling and the Kerr-effect is demonstrated. The experimental feasibility with state-of-the-art device parameters is discussed and it is observed that photon blockade could be generated at the telecommunication wavelength. An elaborate analysis of the thermal effects on photon antibunching is presented. The system is found to be robust against pure dephasing-induced decoherences and thermal phonon number fluctuations.

  20. 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

    2015-08-01

    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.

  1. Immunogenic Chemotherapy Sensitizes Renal Cancer to Immune Checkpoint Blockade Therapy in Preclinical Models.

    Science.gov (United States)

    Cui, Shujin

    2017-07-11

    BACKGROUND Renal cell carcinoma (RCC) is among the most common malignant cancers of males worldwide. For advanced RCC patients, there still is no effective therapy. Immune checkpoint blockade therapies have shown benefits for many cancers, but previous clinical trials of immune checkpoint blockade therapies in RCC patients achieved only modest results. MATERIAL AND METHODS We explored the effects of combining chemotherapy with immune checkpoint blockade therapy in RCC xenograft mouse models. We also studied the potential mechanisms by which chemotherapy might enhance the efficacy of immune checkpoint blockade therapy, both in vitro and in vivo. RESULTS Our results showed that many commonly used chemotherapy agents can induce immunogenic marker release in RCC cell lines. Importantly, the RCC xenograft mouse model mice who received the combination treatment of 5-fluorouracil (5-FU) and anti-programmed cell death-ligand 1 (PD-L1) antibodies (Abs) had longer survival times compared to those who received 5-FU or anti-PD-L1 Abs alone. Also, increased key cytokines that promote tumor immunity, such as IL-2, IFN-γ, and TNF-α, as well as tumor-infiltrating cytotoxic T cells, were also increased after the combination treatment. CONCLUSIONS We conclude that 5-FU can sensitize RCC to anti-PD-L1 treatment by releasing the immune suppression in the tumor microenvironment.

  2. Carbohydrate metabolism during prolonged exercise and recovery: interactions between pyruvate dehydrogenase, fatty acids, and amino acids

    DEFF Research Database (Denmark)

    Mourtzakis, Marina; Saltin, B.; Graham, T.

    2006-01-01

    During prolonged exercise, carbohydrate oxidation may result from decreased pyruvate production and increased fatty acid supply and ultimately lead to reduced pyruvate dehydrogenase (PDH) activity. Pyruvate also interacts with the amino acids alanine, glutamine, and glutamate, whereby the decline...... amino acid taken up during exercise and recovery. Alanine and glutamine were also associated...... with pyruvate metabolism, and they comprised 68% of total amino-acid release during exercise and recovery. Thus reduced pyruvate production was primarily associated with reduced carbohydrate oxidation, whereas the greatest production of pyruvate was related to glutamate, glutamine, and alanine metabolism...

  3. Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice.

    Science.gov (United States)

    Ghosh, Sudeshna; Kinsey, Steven G; Liu, Qing-Song; Hruba, Lenka; McMahon, Lance R; Grim, Travis W; Merritt, Christina R; Wise, Laura E; Abdullah, Rehab A; Selley, Dana E; Sim-Selley, Laura J; Cravatt, Benjamin F; Lichtman, Aron H

    2015-08-01

    Inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), the primary hydrolytic enzymes for the respective endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonylglycerol (2-AG), produces antinociception but with minimal cannabimimetic side effects. Although selective inhibitors of either enzyme often show partial efficacy in various nociceptive models, their combined blockade elicits augmented antinociceptive effects, but side effects emerge. Moreover, complete and prolonged MAGL blockade leads to cannabinoid receptor type 1 (CB1) receptor functional tolerance, which represents another challenge in this potential therapeutic strategy. Therefore, the present study tested whether full FAAH inhibition combined with partial MAGL inhibition would produce sustained antinociceptive effects with minimal cannabimimetic side effects. Accordingly, we tested a high dose of the FAAH inhibitor PF-3845 (N-​3-​pyridinyl-​4-​[[3-​[[5-​(trifluoromethyl)-​2-​pyridinyl]oxy]phenyl]methyl]-​1-​piperidinecarboxamide; 10 mg/kg) given in combination with a low dose of the MAGL inhibitor JZL184 [4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate] (4 mg/kg) in mouse models of inflammatory and neuropathic pain. This combination of inhibitors elicited profound increases in brain AEA levels (>10-fold) but only 2- to 3-fold increases in brain 2-AG levels. This combination produced significantly greater antinociceptive effects than single enzyme inhibition and did not elicit common cannabimimetic effects (e.g., catalepsy, hypomotility, hypothermia, and substitution for Δ(9)-tetrahydrocannabinol in the drug-discrimination assay), although these side effects emerged with high-dose JZL184 (i.e., 100 mg/kg). Finally, repeated administration of this combination did not lead to tolerance to its antiallodynic actions in the carrageenan assay or CB1 receptor functional tolerance. Thus, full FAAH inhibition

  4. Use of a sealant to prevent prolonged air leaks after lung resection: a prospective randomized study

    OpenAIRE

    Lequaglie Cosimo; Giudice Gabriella; Marasco Rita; Morte Aniello; Gallo Massimiliano

    2012-01-01

    Abstract Background Pulmonary air leaks are common complications of lung resection and result in prolonged hospital stays and increased costs. The purpose of this study was to investigate whether, compared with standard care, the use of a synthetic polyethylene glycol matrix (CoSeal®) could reduce air leaks detected by means of a digital chest drain system (DigiVent™), in patients undergoing lung resection (sutures and/or staples alone). Methods Patients who intraoperatively showed moderate o...

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

    Directory of Open Access Journals (Sweden)

    Javier Ripollés

    2015-08-01

    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.

  6. Mean arterial pressure following prolonged exercise in the heat

    DEFF Research Database (Denmark)

    Gagnon, D; Lynn, A G; Binder, K

    2012-01-01

    benefit to its regulation. We examined MAP (Finometer) in eight trained (T) and eight untrained (UT) individuals prior to, and following, 120 min of cycling at 42 °C with (HYD) and without (DEHY) fluid replacement. Exercise during DEHY induced significant hyperthermia (T: 39.20 ± 0.52 °C vs UT: 38.70 ± 0......Prolonged exercise in the heat without fluid replacement represents a significant challenge to the regulation of mean arterial pressure (MAP). It is unknown, however, if MAP is equally challenged during the post-exercise period, and whether regular endurance exercise training can provide any.......36 °C, P = 0.941) and body weight losses (T: 3.4 ± 1.2% vs UT: 2.7 ± 0.9%, P = 0.332), which did not differ between groups. Although MAP was equally reduced 5 min into the post-exercise period of DEHY (T: -20 ± 11 mmHg vs UT: -22 ± 13 mmHg, P = 0.800), its subsequent recovery was significantly different...

  7. Response of Escherichia coli to Prolonged Berberine Exposure.

    Science.gov (United States)

    Budeyri Gokgoz, Nilay; Avci, Fatma Gizem; Yoneten, Kubra Karaosmanoglu; Alaybeyoglu, Begum; Ozkirimli, Elif; Sayar, Nihat Alpagu; Kazan, Dilek; Sariyar Akbulut, Berna

    2017-07-01

    Berberine is a plant-derived alkaloid possessing antimicrobial activity; unfortunately, its efflux through multidrug resistance pumps reduces its efficacy. Cellular life span of Escherichia coli is generally shorter with prolonged berberine exposure; nevertheless, about 30% of the cells still remain robust following this treatment. To elucidate its mechanism of action and to identify proteins that could be involved in development of antimicrobial resistance, protein profiles of E. coli cells treated with berberine for 4.5 and 8 hours were compared with control cells. A total of 42 proteins were differentially expressed in cells treated with berberine for 8 hours when compared to control cells. In both 4.5 and 8 hours of berberine-treated cells, carbohydrate and peptide uptake regimens remained unchanged, although amino acid maintenance regimen switched from transport to synthesis. Defect in cell division persisted and this condition was confirmed by images obtained from scanning electron microscopy. Universal stress proteins were not involved in stress response. The significant increase in the abundance of elongation factors could suggest the involvement of these proteins in protection by exhibiting chaperone activities. Furthermore, the involvement of the outer membrane protein OmpW could receive special attention as a protein involved in response to antimicrobial agents, since the expression of only this porin protein was upregulated after 8 hours of exposure.

  8. Glucocorticoid augmentation of prolonged exposure therapy: rationale and case report

    Directory of Open Access Journals (Sweden)

    Laura Pratchett

    2010-12-01

    Full Text Available Rationale: Prolonged exposure (PE therapy has been found to reduce symptoms of posttraumatic stress disorder (PTSD; however, it is difficult for many patients to engage fully in the obligatory retelling of their traumatic experiences. This problem is compounded by the fact that habituation and cognitive restructuring – the main mechanisms through which PE is hypothesized to work – are not instantaneous processes, and often require several weeks before the distress associated with imaginal exposure abates. Case reports: Two cases are described that respectively illustrate the use of hydrocortisone and placebo, in combination with PE, for the treatment of combat-related PTSD. Based on known effects of glucocorticoids on learning and memory performance, we hypothesized that augmentation with hydrocortisone would improve the therapeutic effects of PE by hastening “new” learning and facilitating decreases in the emotional impact of fear memories during the course of treatment. The veteran receiving hydrocortisone augmentation of PE displayed an accelerated and ultimately greater decline in PTSD symptoms than the veteran receiving placebo. Conclusions: While no general conclusion can be derived from comparison of two patients, the findings are consistent with the rationale for augmentation. These case reports support the potential for an appropriately designed and powered clinical trial to examine the efficacy of glucocorticoids in augmenting the effects of psychotherapy for PTSD.

  9. Thermoregulatory responses to skin wetting during prolonged treadmill running.

    Science.gov (United States)

    Bassett, D R; Nagle, F J; Mookerjee, S; Darr, K C; Ng, A V; Voss, S G; Napp, J P

    1987-02-01

    We examined the physiological responses to skin wetting during a 120-min level treadmill run to assess whether skin wetting would reduce the dehydration and the increase in core temperature associated with prolonged exercise. Testing was conducted in an environmental chamber (T = 29.5 degrees C, wind velocity = 3 m X sec-1) under two different humidity conditions (33 or 66% relative humidity). Ten male subjects performed two runs in each humidity condition; one served as a control run. The other included spraying the body with 50 ml of water (T = 29.5 degrees C) every 10 min. Spraying had no effect on rectal temperature (Tre), heart rate, oxygen consumption, perceived exertion, sweat loss, or percent change in plasma volume in both the humid and the dry conditions. Spraying produced a significant reduction in mean skin temperature (Tsk), which increased the (Tre - Tsk) gradient. At the same time, overall skin conductance (K) was decreased, presumably as a result of cutaneous vasoconstriction due to the low Tsk. Since heat transfer from the body's core to the skin is expressed by the equation: heat transfer = K X (Tre - Tsk) the spraying had no effect on heat transfer away from the core, and Tre remained unchanged.

  10. External K+ dependence of strong inward rectifier K+ channel conductance is caused not by K+ but by competitive pore blockade by external Na.

    Science.gov (United States)

    Ishihara, Keiko

    2018-06-15

    Strong inward rectifier K + (sKir) channels determine the membrane potentials of many types of excitable and nonexcitable cells, most notably the resting potentials of cardiac myocytes. They show little outward current during membrane depolarization (i.e., strong inward rectification) because of the channel blockade by cytoplasmic polyamines, which depends on the deviation of the membrane potential from the K + equilibrium potential ( V - E K ) when the extracellular K + concentration ([K + ] out ) is changed. Because their open - channel conductance is apparently proportional to the "square root" of [K + ] out , increases/decreases in [K + ] out enhance/diminish outward currents through sKir channels at membrane potentials near their reversal potential, which also affects, for example, the repolarization and action-potential duration of cardiac myocytes. Despite its importance, however, the mechanism underlying the [K + ] out dependence of the open sKir channel conductance has remained elusive. By studying Kir2.1, the canonical member of the sKir channel family, we first show that the outward currents of Kir2.1 are observed under the external K + -free condition when its inward rectification is reduced and that the complete inhibition of the currents at 0 [K + ] out results solely from pore blockade caused by the polyamines. Moreover, the noted square-root proportionality of the open sKir channel conductance to [K + ] out is mediated by the pore blockade by the external Na + , which is competitive with the external K + Our results show that external K + itself does not activate or facilitate K + permeation through the open sKir channel to mediate the apparent external K + dependence of its open channel conductance. The paradoxical increase/decrease in outward sKir channel currents during alternations in [K + ] out , which is physiologically relevant, is caused by competition from impermeant extracellular Na . © 2018 Ishihara.

  11. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro

    DEFF Research Database (Denmark)

    Fanoe, Søren; Jensen, Gorm Boje; Sjøgren, Per

    2008-01-01

    with the use of these drugs. WHAT THIS PAPER ADDS: This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length. AIMS: During recent years some...... and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro. METHODS: One hundred chronic nonmalignant pain...... patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing h...

  12. Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation

    Science.gov (United States)

    Sobieski, Courtney; Shu, Hong-Jin

    2018-01-01

    Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID:29617444

  13. Thioredoxin priming prolongs lung allograft survival by promoting immune tolerance.

    Directory of Open Access Journals (Sweden)

    Hanbo Hu

    Full Text Available Tolerance to allograft antigen is the major challenge and final goal of transplant medicine. Our previous study demonstrated that thioredoxin-1 (Trx priming of donor lung significantly protected allogeneic lung graft. To determine whether Trx priming of donor lung inhibits allograft rejection, extends allograft survival and induces immune tolerance, orthotopic left lung transplantation was performed from Lewis to Sprague-Dawley rats without immunosuppression. Donor lungs were primed with Trx at 4°C for 4 hr prior to transplantation. After up to 37 days post-transplantation, allograft lung morphology, recipient T cell and humoral alloantigen-specific immune responses were examined. We found that Trx-primed lungs exhibited much reduced acute rejection and associated lung injuries resulting in loss of graft functional area at 5-37 days post-transplant in contrast to the control groups. CD4+ T cells from the recipients with Trx-primed grafts responded to the stimulation of dendritic cells (DCs of donor origin, in contrast to DCs from the third party, with significantly reduced proliferation. Consistent with above findings, we observed that CD4+Foxp3+ regulatory T cells in spleen cells from the recipients with Trx-primed grafts were significantly increased compared to controls, and CD4+ T cells from the recipients with Trx-primed grafts produced much higher levels of immunosuppressive cytokine, IL-10 when stimulated with allogeneic donor DCs. In addition, humoral immune tolerance was also induced as there was no significant increase levels of serum antibodies against donor antigens in Trx-lung recipients when re-challenged with allogeneic donor antigens. Our results demonstrate that one-time Trx-priming of donor lung grafts prior to transplantation significantly prolongs the survival of the grafts through inducing or promoting cellular and humoral alloantigen-specific immune tolerance, which might be associated with the induction of

  14. Predictive factors associated with prolonged chest drain production after esophagectomy

    NARCIS (Netherlands)

    Lagarde, S. M.; Omloo, J. M. T.; Ubbink, D. T.; Busch, O. R. C.; Obertop, H.; van Lanschot, J. J. B.

    2007-01-01

    After esophagectomy, pleural drainage is performed to ensure complete drainage of the pleural cavities. The aim of this study was to detect predisposing factors for prolonged drainage. Patients who underwent transhiatal or extended transthoracic esophagectomy for adenocarcinoma of the distal

  15. Does calcium channel blockade and beta-adrenergic blockade affect platelet function and fibrinolysis to a varying degree?

    DEFF Research Database (Denmark)

    Fornitz, Gitte Gleerup; Mehlsen, J; Winther, K

    1995-01-01

    as the fast-acting inhibitor against tissue plasminogen activator usually termed PAI-1. During atenolol and isradipine therapy, blood pressure (BP) was equally reduced (p ... tended to improve fibrinolysis, as shown by a decrease in PAI, 1 h after exercise. Reducing BP with isradipine or atenolol results in a similar decrease in platelet activity and PAI-level, tested at rest and 1 h after rest, respectively. During exercise, platelet activity increased during atenolol...

  16. Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo.

    Science.gov (United States)

    Zundler, Sebastian; Schillinger, Daniela; Fischer, Anika; Atreya, Raja; López-Posadas, Rocío; Watson, Alastair; Neufert, Clemens; Atreya, Imke; Neurath, Markus F

    2017-11-01

    Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. High expression of αEβ7 was noted on CD8 + and CD4 + Th9 cells, while α4β7 was expressed on CD8 + , Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8 + and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8 + T cells from patients with IBD under vedolizumab therapy. AEβ7 is of key relevance for gut trafficking of IBD CD8 + T cells and CD4 + Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8 + and Th9 cells such as IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Ways to Optimize Therapy of Prolonged Conjugation Jaundice in Infants

    Directory of Open Access Journals (Sweden)

    O.G. Shadrin

    2015-09-01

    Full Text Available The article is devoted to the optimization of the treatment of prolonged conjugation jaundice. Inclusion of ursodeoxycholic acid in the treatment of neonatal prolonged conjugation jaundice in a dose of 15–20 mg/kg of body mass per day increases the terms of regression of clinical and paraclinical signs of jaundice as much as 2 times and leads to cytolysis normalization. The preparation has a sufficient level of safety, there were not revealed side effects whilst its application.

  18. Reversal of neuromuscular blockade by sugammadex in laparoscopic bariatric surgery: In support of dose reduction.

    Science.gov (United States)

    Badaoui, Rachid; Cabaret, Aurélie; Alami, Youssef; Zogheib, Elie; Popov, Ivan; Lorne, Emmanuel; Dupont, Hervé

    2016-02-01

    Sugammadex is the first molecule able to antagonize steroidal muscle relaxants with few adverse effects. Doses are adjusted to body weight and the level of neuromuscular blockade. Sleeve gastrectomy is becoming a very popular form of bariatric surgery. It requires deep muscle relaxation followed by complete and rapid reversal to decrease postoperative and especially post-anaesthetic morbidity. Sugammadex is therefore particularly indicated in this setting. The objective of this study was to evaluate the deep neuromuscular blockade reversal time after administration of various doses of sugammadex (based on real weight or at lower doses). Secondary endpoints were the interval between the sugammadex injection and extubation and transfer from the operating room to the recovery room. We then investigated any complications observed in the recovery room. This pilot, prospective, observational, clinical practice evaluation study was conducted in the Amiens University Hospital. Neuromuscular blockade was induced by rocuronium. At the end of the operation, deep neuromuscular blockade was reversed by sugammadex at the dose of 4mg/kg. Sixty-four patients were included: 31 patients received sugammadex at a dosage based on their real weight (RW) and 33 patients received a lower dose (based on ideal weight [IW]). For identical rocuronium doses calculated based on IBW, sugammadex doses were significantly lower in the IW group: 349 (± 65) mg versus 508 (± 75) mg (Psugammadex and extubation (P=0.07) and transfer from the operating room to the recovery room (P=0.68) were also non-significantly longer in the IW group. The mean dose of sugammadex used by anaesthetists in the IW group was 4mg/kg of ideal weight increased by 35% to 50% (n=20; 351±34mg). No sugammadex adverse effects and no residual neuromuscular blockades were observed. Postoperative nausea and vomiting (PONV) was observed in 19.4% of patients in the real weight group versus 27.3% in the ideal weight group (P

  19. Endocannabinoid receptor blockade increases vascular endothelial growth factor and inflammatory markers in obese women with polycystic ovary syndrome.

    Science.gov (United States)

    Sathyapalan, Thozhukat; Javed, Zeeshan; Kilpatrick, Eric S; Coady, Anne-Marie; Atkin, Stephen L

    2017-03-01

    Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women. Randomized, open-labelled parallel study. Endocrinology outpatient clinic in a referral centre. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m 2 were recruited. Patients were randomized to 1·5 g daily of metformin or 20 mg daily of rimonabant. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P weight loss. © 2016 John Wiley & Sons Ltd.

  20. Routine maintenance prolongs ESP time between failures

    International Nuclear Information System (INIS)

    Hurst, T.; Lannom, R.W.; Divine, D.L.

    1992-01-01

    This paper reports that routine maintenance of electric submersible motors (ESPs) significantly lengthened the mean time between motor failures (MTBF), decreased operating costs, and extended motor run life in the Sacroc Unit of the Kelly-Snyder field in West Texas. After the oil price boom of the early 1980s. rapidly eroding profit margins from producing properties caused a much stronger focus on reducing operating costs. In Sacroc, ESP operating life and repair costs became a major target of cost reduction efforts. The routine ESP maintenance program has been in place for over 3 years

  1. Combined blockade of angiotensin II and prorenin receptors ameliorates podocytic apoptosis induced by IgA-activated mesangial cells.

    Science.gov (United States)

    Leung, Joseph C K; Chan, Loretta Y Y; Saleem, M A; Mathieson, P W; Tang, Sydney C W; Lai, Kar Neng

    2015-07-01

    Glomerulo-podocytic communication plays an important role in the podocytic injury in IgA nephropathy (IgAN). In this study, we examine the role of podocytic angiotensin II receptor subtype 1 (AT1R) and prorenin receptor (PRR) in podocytic apoptosis in IgAN. Polymeric IgA (pIgA) was isolated from patients with IgAN and healthy controls. Conditioned media were prepared from growth arrested human mesangial cells (HMC) incubated with pIgA from patients with IgAN (IgA-HMC media) or healthy controls (Ctl-HMC media). A human podocyte cell line was used as a model to examine the regulation of the expression of AT1R, PRR, TNF-α and CTGF by IgA-HMC media. Podocytic nephrin expression, annexin V binding and caspase 3 activity were used as the functional readout of podocytic apoptosis. IgA-HMC media had no effect on AngII release by podocytes. IgA-HMC media significantly up-regulated the expression of AT1R and PRR, down-regulated nephrin expression and induced apoptosis in podocytes. Mono-blockade of AT1R, PRR, TNF-α or CTGF partially reduced podocytic apoptosis. IgA-HMC media activated NFκB, notch1 and HEY1 expression by podocytes and dual blockade of AT1R with PRR, or anti-TNF-α with anti-CTGF, effectively rescued the podocytic apoptosis induced by IgA-HMC media. Our data suggests that pIgA-activated HMC up-regulates the expression of AT1R and PRR expression by podocytes and the associated activation of NFκB and notch signalling pathways play an essential role in the podocytic apoptosis induced by glomerulo-podocytic communication in IgAN. Simultaneously targeting the AT1R and PRR could be a potential therapeutic option to reduce the podocytic injury in IgAN.

  2. Lentiviral-mediated targeted NF-kappaB blockade in dorsal spinal cord glia attenuates sciatic nerve injury-induced neuropathic pain in the rat.

    Science.gov (United States)

    Meunier, Alice; Latrémolière, Alban; Dominguez, Elisa; Mauborgne, Annie; Philippe, Stéphanie; Hamon, Michel; Mallet, Jacques; Benoliel, Jean-Jacques; Pohl, Michel

    2007-04-01

    Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor kappaB (NF-kappaB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-kappaB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-kappaB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-kappaB super- repressor IkappaBalpha resulted in an inhibition of the NF-kappaB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IkappaBalpha overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-kappaB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-kappaB pathway in the development of neuropathic pain after peripheral nerve injury.

  3. Lentiviral-mediated Targeted NF-κB Blockade in Dorsal Spinal Cord Glia Attenuates Sciatic Nerve Injury-induced Neuropathic Pain in the Rat.

    Science.gov (United States)

    Meunier, Alice; Latrémolière, Alban; Dominguez, Elisa; Mauborgne, Annie; Philippe, Stéphanie; Hamon, Michel; Mallet, Jacques; Benoliel, Jean-Jacques; Pohl, Michel

    2007-04-01

    Neuropathic pain developing after peripheral nerve injury is associated with altered neuronal and glial cell functions in the spinal cord. Activated glia produces algogenic mediators, exacerbating pain. Among the different intracellular pathways possibly involved in the modified glial function, the nuclear factor κB (NF-κB) system is of particular interest, as numerous genes encoding inflammation- and pain-related molecules are controlled by this transcription factor. NF-κB is a pleiotropic factor also involved in central nervous system homeostasy. To study its role in chronic pain, it is thus essential to inhibit the NF-κB pathway selectively in activated spinal glial cells. Here, we show that when restricted to spinal cord and targeted to glial cells, lentiviral vector-mediated delivery of NF-κB super- repressor IκBα resulted in an inhibition of the NF-κB pathway activated in the rat spinal cord after sciatic nerve injury (chronic constriction injury, CCI). Concomitantly, IκBα overproduction prevented the enhanced expression of interleukin-6 and of inducible nitric oxide synthase associated with chronic constriction injury and resulted in prolonged antihyperalgesic and antiallodynic effects. These data show that targeted blockade of NF-κB activity in spinal glia efficiently alleviates pain behavior in CCI rats, demonstrating the active participation of the glial NF-κB pathway in the development of neuropathic pain after peripheral nerve injury. Copyright © 2007 The American Society of Gene Therapy. Published by Elsevier Inc. All rights reserved.

  4. Anti-tumor immunotherapy by blockade of the PD-1/PD-L1 pathway with recombinant human PD-1-IgV.

    Science.gov (United States)

    Zhang, C; Wu, S; Xue, X; Li, M; Qin, X; Li, W; Han, W; Zhang, Y

    2008-01-01

    Blockade of the programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway can delay tumor growth and prolong the survival of tumor-bearing mice. The extracellular immunoglobulin (Ig) V domain of PD-1 is important for the interaction between PD-1 and PD-L1, suggesting that PD-1-IgV may be a potential target for anti-tumor immunotherapy. The extracellular sequence of human PD-1-IgV (hPD-1-IgV) was expressed in Escherichia coli and purified. The anti-tumor effect of hPD-1-IgV on tumor-bearing mice was tested. hPD-1-IgV recombinant protein could bind PD-L1 at molecular and cellular levels and enhance Cytotoxic T Lymphocyte (CTL) activity and anti-tumor effect on tumor-bearing mice in vivo. The percentage of CD4(+)CD25(+) T cells in tumor-bearing mice was decreased compared with control mice after administration of the recombinant protein. Our results suggest that inhibition of the interaction between PD-1 and PD-L1 by hPD-1-IgV may be a promising strategy for specific tumor immunotherapy.

  5. Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA-4-dependent recruitment of nitric oxide-producing macrophages

    Directory of Open Access Journals (Sweden)

    Getts Daniel R

    2012-10-01

    Full Text Available Abstract Infiltration of Ly6Chi monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV, an emerging neurotropic flavivirus, inhibition of Ly6Chi monocyte trafficking into the brain by anti-very late antigen (VLA-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6Chi macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4+ T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO. Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.

  6. Effects of drought and prolonged winter on Townsend's ground squirrel demography in shrubsteppe habitats

    Science.gov (United States)

    Van Horne, Beatrice; Olson, Gail S.; Schooley, Robert L.; Corn, Janelle G.; Burnham, Kenneth P.

    1997-01-01

    During a mark–recapture study of Townsend's ground squirrels (Spermophilus townsendii) on 20 sites in the Snake River Birds of Prey National Conservation Area, Idaho, in 1991 through 1994, 4407 animals were marked in 17639 capture events. This study of differences in population dynamics of Townsend's ground squirrels among habitats spanned a drought near the extreme of the 130-yr record, followed by prolonged winter conditions.Townsend's ground squirrels have a short active season (≈4 mo) in which to reproduce and store fat for overwintering. Their food consists largely of succulent grasses and forbs in this dry shrubsteppe and grassland habitat. The drought in the latter half of the 1992 active season produced early drying of Sandberg's bluegrass (Poa secunda) and was associated with low adult and juvenile body masses prior to immergence into estivation/hibernation. The following prolonged winter was associated with late emergence of females in 1993. Early-season body masses of adults were low in 1993 relative to 1992, whereas percentage of body fat in males was relatively high. These weather patterns in spring 1992 and winter 1993 also resulted in reduced adult persistence through the ≈7-mo inactive period, especially for adult females, and near-zero persistence of >1200 juveniles. Consequently, densities of Townsend's ground squirrels across the 20 livetrap sites declined.The demographic effects of drought and prolonged winter lasted at least through the subsequent breeding season. Adult females that survived these weather extremes produced fewer emergent young per female than did adult females prior to the event. Prior to the drought/prolonged winter, yearling female body masses were higher than, or indistinguishable from, those of adults. Females produced in 1993 had lower body masses as yearlings than did adult females.Demographic response to the drought and prolonged winter varied with habitat; ground squirrels in sagebrush habitat showed less decline

  7. Filter testing and development for prolonged transuranic service and waste reduction

    International Nuclear Information System (INIS)

    Geer, J.A.; Buttedahl, O.I.; Skaats, C.D.; Terada, K.; Woodard, R.W.

    1977-02-01

    The life of High Efficiency Particulate Air (HEPA) filters used in transuranic service is influenced greatly by the gaseous and particulate matter to which the filters are exposed. The most severe conditions encountered at Rocky Flats are at the ventilation systems serving the plutonium recovery operations in Bldg. 771. A project of filter testing and development for prolonged transuranic service and waste reduction was formally initiated at Rocky Flats on July 1, 1975. The project is directed toward improving filtration methods which will prolong the life of HEPA filter systems without sacrificing effectiveness. Another important aspect of the project is to reduce the volume of HEPA filter waste shipped from the plant for long-term storage. Progress to September 30, 1976, is reported

  8. Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility.

    Science.gov (United States)

    Vaithilingam, Vijayaganapathy; Kollarikova, Gabriella; Qi, Meirigeng; Lacik, Igor; Oberholzer, Jose; Guillemin, Gilles J; Tuch, Bernard E

    2011-01-01

    Pericapsular fibrotic overgrowth (PFO) may be attributed to an immune response against microcapsules themselves or to antigen shedding through microcapsule pores from encapsulated islet tissue. Modification of microcapsules aimed at reducing pore size should prevent PFO and improve graft survival. This study investigated the effect of increased gelling time (20 vs. 2 min) in barium chloride on intrinsic properties of alginate microcapsules and tested their biocompatibility in vivo. Prolonged gelling time affected neither permeability nor size of the microcapsules. However, prolonged gelling time for 20 min produced brittle microcapsules compared to 2 min during compression test. Encapsulation of human islets in both types of microcapsules affected neither islet viability nor function. The presence of PFO when transplanted into a large animal model such as baboon and its absence in small animal models such as rodents suggest that the host immune response towards alginate microcapsules is species rather than alginate specific.

  9. Prolonged-release melatonin versus placebo for benzodiazepine discontinuation in patients with schizophrenia or bipolar disorder

    DEFF Research Database (Denmark)

    Baandrup, Lone; Lindschou, Jane; Winkel, Per

    2016-01-01

    OBJECTIVES: We assessed if prolonged-release melatonin can facilitate withdrawal of long-term benzodiazepine usage in patients with schizophrenia or bipolar disorder. METHODS: Randomised, placebo-controlled, blinded, parallel superiority trial of 24 weeks duration. Participants were randomised...... to prolonged-release melatonin 2 mg daily versus matching placebo and were continuously guided to gradually reduce their usual benzodiazepine dosage. The primary outcome was mean benzodiazepine daily dosage at 24 weeks. Secondary outcomes included pattern of benzodiazepine dosage over time, benzodiazepine...... cessation proportion, and benzodiazepine withdrawal symptoms. RESULTS: In total, 86 patients (21-74 years) were enrolled: 42 were randomised to melatonin versus 44 to placebo. We found no significant effect of melatonin on mean benzodiazepine dosage at 24 weeks (melatonin group 8.01 mg versus placebo group...

  10. Nephroprotective action of renin-angiotensin-aldosterone system blockade in chronic kidney disease patients: the landscape after ALTITUDE and VA NEPHRON-D trails.

    Science.gov (United States)

    Rutkowski, Boleslaw; Tylicki, Leszek

    2015-03-01

    The intervention in the renin-angiotensin-aldosterone system (RAAS) is currently the most effective strategy that combines blood pressure lowering and renoprotection. Several large, randomized, controlled trials evidenced the renoprotective potential of the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in nephropathies of almost any etiology. Mineralocorticoid receptor antagonists and direct renin inhibitor, aliskiren, as add-on treatments to standard therapy including the optimal dose of ACEIs or ARBs reduce albuminuria or proteinuria and slow development of renal dysfunction more than placebo. No clinical evidence is available however about whether these strategies may influence on long-term kidney outcome. Three recent trials suggested that aggressive RAAS blockade, that is, combination of 2 RAAS-blocking agents, does not decrease cardiovascular and renal morbidity and may carry an increased risk of serious complications. This article reviews an evidence-based approach on the use of RAAS-inhibiting agents in chronic kidney disease and considers the implementation of dual RAAS blockade with reference to the results of ALTITUDE and VA NEPHRON-D trails aiming to aid clinicians in their treatment decisions for patients with chronic kidney disease. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

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

    DEFF Research Database (Denmark)

    Iversen, P

    1997-01-01

    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....

  12. 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

    1990-01-01

    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...... evaluated the degree of neuromuscular blockade solely by clinical criteria. The use of a nerve stimulator was found to have no effect on the dose of relaxant given during anesthesia, on the need for supplementary doses of anticholinesterase in the recovery room, on the time from end of surgery to end...... of anesthesia, or on the incidence of postoperative residual neuromuscular blockade evaluated clinically. The median (and range of) TOF ratios recorded in the recovery room were 0.75 (0.33-0.96) and 0.79 (0.10-0.97) in the vecuronium groups monitored with and without a nerve stimulator, respectively...

  13. 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

  14. The effect of neuromuscular blockade on oxygen consumption in sedated and mechanically ventilated pediatric patients after cardiac surgery.

    NARCIS (Netherlands)

    Lemson, J.; Driessen, J.J.; Hoeven, J.G. van der

    2008-01-01

    OBJECTIVE: To measure the effect of intense neuromuscular blockade (NMB) on oxygen consumption (VO(2)) in deeply sedated and mechanically ventilated children on the first day after complex congenital cardiac surgery. DESIGN: Prospective clinical interventional study. SETTING: Pediatric intensive

  15. 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.

    2006-01-01

    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

  16. Multibit CkNOT quantum gates via Rydberg blockade

    DEFF Research Database (Denmark)

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

    2011-01-01

    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...... or simultaneous addressing of the control atoms which requires only 2k + 3 or 5 Rydberg π pulses respectively. A detailed error analysis relevant for implementations based on alkali atom Rydberg states is provided which shows that gate errors less than 10% are possible for k = 35....

  17. Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation

    Directory of Open Access Journals (Sweden)

    Karen Miller

    2017-01-01

    Full Text Available Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented.

  18. Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation.

    Science.gov (United States)

    Miller, Karen; Hall, Brian; Tobias, Joseph D

    2017-01-01

    Sugammadex is a novel agent for the reversal of neuromuscular blockade. The speed and efficacy of reversal with sugammadex are significantly faster than acetylcholinesterase inhibitors, such as neostigmine. Sugammadex also has a limited adverse profile when compared with acetylcholinesterase inhibitors, specifically in regard to the incidence of bradycardia. This adverse effect may be particularly relevant in the setting of a heart transplant recipient with a denervated heart. The authors present a case of an 8-year-old child, status postcardiac transplantation, who required anesthetic care for laparoscopy and lysis of intra-abdominal adhesions. Sugammadex was used to reverse neuromuscular blockade and avoid the potential adverse effects of neostigmine. The unique mechanism of action of sugammadex is discussed, previous reports of its use in this unique patient population are reviewed, and its potential benefits compared to traditional acetylcholinesterase inhibitors are presented.

  19. Ultrasonography of the adult thoracic and lumbar spine for central neuraxial blockade.

    Science.gov (United States)

    Chin, Ki Jinn; Karmakar, Manoj Kumar; Peng, Philip

    2011-06-01

    The role of ultrasound in central neuraxial blockade has been underappreciated, partly because of the relative efficacy of the landmark-guided technique and partly because of the perceived difficulty in imaging through the narrow acoustic windows produced by the bony framework of the spine. However, this also is the basis for the utility of ultrasound: an interlaminar window that permits passage of sound waves into the vertebral canal also will permit passage of a needle. In addition, ultrasound aids in identification of intervertebral levels, estimation of the depth to epidural and intrathecal spaces, and location of important landmarks, including the midline and interlaminar spaces. This can facilitate neuraxial blockade, particularly in patients with difficult surface anatomic landmarks. In this review article, the authors summarize the current literature, describe the key ultrasonographic views, and propose a systematic approach to ultrasound imaging for the performance of spinal and epidural anesthesia in the adult patient.

  20. Is lumbosacral plexus blockade effective and safe for surgical anesthesia in total hip replacement?

    DEFF Research Database (Denmark)

    Nielsen, Niels Dalsgaard; Larsen, Jens Rolighed; Børglum, Jens

    Background and Aims Patients scheduled for total hip replacement often presents cardiovascular comorbidity, which increases perioperative risk of complications. This pilot study aimed to compare lumbosacral plexus blockade with continuous and single-dose spinal anesthesia for surgical anesthesia...... had lumbosacral plexus blockade (lumbar plexus block, sacral plexus block and fascia transversalis plane block) with ropivacaine. Group 2 had continuous spinal anesthesia with repeated bupivacaine-doses. Group 3 had single-dose spinal anesthesia with bupivacaine. Hemodynamic data were recorded during...... vascular resistance, and arterial and central venous pressures. (table 1) No patients in group 1 achieved complete surgical anesthesia due to lack of anesthesia of the cranial part of the surgical incision. Conclusions Neither lumbosacral plexus block nor continuous spinal anesthesia affected any...

  1. α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

    Science.gov (United States)

    Lamkin, Donald M.; Sung, Ha Yeon; Yang, Gyu Sik; David, John M.; Ma, Jeffrey C.Y.; Cole, Steve W.; Sloan, Erica K.

    2014-01-01

    Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of β-adrenergic receptors. Catecholamines also signal α-adrenergic receptors, and greater α-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of α-adrenergic receptors can result in elevated catecholamine levels, which may increase β-adrenergic signaling, because pre-synaptic α2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of α-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective α-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective β-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective α2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective α1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that α2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of β-adrenergic signaling on tumor progression-relevant biology. PMID:25462899

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

    OpenAIRE

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

    2005-01-01

    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...

  3. Differential immune microenvironments and response to immune checkpoint blockade amongst molecular subtypes of murine medulloblastoma

    Science.gov (United States)

    Pham, Christina D.; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M.; Yearley, Jennifer H.; Sayour, Elias J.; Pei, Yanxin; Moore, Colin; McLendon, Roger E.; Huang, Jianping; Sampson, John H.; Wechsler-Reya, Robert; Mitchell, Duane A.

    2016-01-01

    PURPOSE Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma (MB), the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and Group 3 MB for preclinical evaluation in immunocompetent C57BL/6 mice. METHODS AND RESULTS Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid derived suppressor cells and tumor-associated macrophages in murine SHH model tumors compared with Group 3 tumors. However, murine Group 3 tumors had higher percentages of CD8+ PD-1+ T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial Group 3 tumors compared to SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1+ peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3+ T cells within the tumor microenvironment. CONCLUSIONS This is the first immunologic characterization of preclinical models of molecular subtypes of MB and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. PMID:26405194

  4. Population pharmacokinetic–pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade

    Science.gov (United States)

    Kleijn, Huub J; Zollinger, Daniel P; van den Heuvel, Michiel W; Kerbusch, Thomas

    2011-01-01

    AIMS An integrated population pharmacokinetic–pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic–pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODS Data (n = 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTS Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg−1 3 min after rocuronium, sugammadex 4 mg kg−1 during deep neuromuscular blockade and sugammadex 2 mg kg−1 during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONS Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min. PMID:21535448

  5. Negative Pressure Pulmonary Edema after Reversing Rocuronium-Induced Neuromuscular Blockade by Sugammadex

    Directory of Open Access Journals (Sweden)

    Manzo Suzuki

    2014-01-01

    Full Text Available Negative pressure pulmonary edema (NPPE is a rare complication that accompanies general anesthesia, especially after extubation. We experienced a case of negative pressure pulmonary edema after tracheal extubation following reversal of rocuronium-induced neuromuscular blockade by sugammadex. In this case, the contribution of residual muscular block on the upper airway muscle as well as large inspiratory forces created by the respiratory muscle which has a low response to muscle relaxants, is suspected as the cause.

  6. 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: ymylh@163.com [Department of Hepatology and Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province 250012 (China)

    2015-08-15

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

  7. Conformational occlusion of blockade antibody epitopes, a novel mechanism of GII.4 human norovirus immune evasion

    OpenAIRE

    Lindesmith, Lisa C.; Mallory, Michael L.; Debbink, Kari; Donaldson, Eric F.; Brewer-Jensen, Paul D.; Swann, Excel W.; Sheahan, Timothy P.; Graham, Rachel L.; Beltramello, Martina; Corti, Davide; Lanzavecchia, Antonio; Baric, Ralph S.

    2018-01-01

    ABSTRACT Extensive antigenic diversity within the GII.4 genotype of human norovirus is a major driver of pandemic emergence and a significant obstacle to development of cross-protective immunity after natural infection and vaccination. However, human and mouse monoclonal antibody studies indicate that, although rare, antibodies to conserved GII.4 blockade epitopes are generated. The mechanisms by which these epitopes evade immune surveillance are uncertain. Here, we developed a new approach f...

  8. Coulomb Blockade Anisotropic Magnetoresistance Effect in a (Ga,Mn)As Single-Electron Transistor

    Czech Academy of Sciences Publication Activity Database

    Wunderlich, J.; Jungwirth, Tomáš; Kaestner, B.; Irvine, A.C.; Shick, Alexander; Stone, N.; Wang, K. Y.; Rana, U.; Giddings, A.D.; Foxon, C. T.; Campion, R. P.; Williams, D.A.; Gallagher, B. L.

    2006-01-01

    Roč. 97, č. 7 (2006), 077201/1-077201/4 ISSN 0031-9007 R&D Projects: GA ČR GA202/05/0575; GA MŠk LC510 Grant - others:EPSRC(GB) GR/S81407/01 Institutional research plan: CEZ:AV0Z10100521 Keywords : anisotropic magnetoresistance * Coulomb blockade * single electron transistor Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 7.072, year: 2006

  9. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  10. Pharmacometabolomic approach to predict QT prolongation in guinea pigs.

    Directory of Open Access Journals (Sweden)

    Jeonghyeon Park

    Full Text Available Drug-induced torsades de pointes (TdP, a life-threatening arrhythmia associated with prolongation of the QT interval, has been a significant reason for withdrawal of several medicines from the market. Prolongation of the QT interval is considered as the best biomarker for predicting the torsadogenic risk of a new chemical entity. Because of the difficulty assessing the risk for TdP during drug development, we evaluated the metabolic phenotype for predicting QT prolongation induced by sparfloxacin, and elucidated the metabolic pathway related to the QT prolongation. We performed electrocardiography analysis and liquid chromatography-mass spectroscopy-based metabolic profiling of plasma samples obtained from 15 guinea pigs after administration of sparfloxacin at doses of 33.3, 100, and 300 mg/kg. Principal component analysis and partial least squares modelling were conducted to select the metabolites that substantially contributed to the prediction of QT prolongation. QTc increased significantly with increasing dose (r = 0.93. From the PLS analysis, the key metabolites that showed the highest variable importance in the projection values (>1.5 were selected, identified, and used to determine the metabolic network. In particular, cytidine-5'-diphosphate (CDP, deoxycorticosterone, L-aspartic acid and stearic acid were found to be final metabolomic phenotypes for the prediction of QT prolongation. Metabolomic phenotypes for predicting drug-induced QT prolongation of sparfloxacin were developed and can be applied to cardiac toxicity screening of other drugs. In addition, this integrative pharmacometabolomic approach would serve as a good tool for predicting pharmacodynamic or toxicological effects caused by changes in dose.

  11. Prolonged peritoneal gene expression using a helper-dependent adenovirus.

    Science.gov (United States)

    Liu, Limin; Shi, Chang-Xin; Ghayur, Ayesha; Zhang, Claire; Su, Je Yen; Hoff, Catherine M; Margetts, Peter J

    2009-01-01

    Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis. The causes of EPS are not well defined and are likely multifactorial. A suitable animal model would facilitate research into the pathophysiology and treatment of EPS. We developed a helper-dependent adenovirus that expresses both green fluorescent protein (GFP) and active transforming growth factor-beta (TGF-beta1; HDAdTGF-beta1). Mice were administered HDAdTGF-beta1 via intraperitoneal injection and the response was compared with mice administered either first-generation adenovirus expressing TGF-beta1 (AdTGF-beta1) or control adenovirus (AdGFP). HDAdTGF-beta1-treated mice continued to express the GFP reporter transgene to day 74, the end of the observation period. Transgene expression lasted less than 28 days in the animals treated with first-generation adenoviruses. Animals treated with first-generation AdTGF-beta1 demonstrated submesothelial thickening and angiogenesis at day 7, with almost complete resolution by day 28. The HDAdTGF-beta1-treated mice demonstrated progressive peritoneal fibrosis with adhesion formation and encapsulation of bowels. Weight gain was significantly reduced in animals treated with HDAdTGF-beta1 compared to both the control-treated animals and the AdTGF-beta1-treated animals. Inflammation was not a major component of the fibroproliferative response. Peritoneal administration of a first-generation AdTGF-beta1 leads to transient gene expression, resulting in a resolving fibrotic response and histology similar to that seen in simple peritoneal sclerosis. Prolonged TGF-beta1 expression induced by the helper-dependent HDAdTGF-beta1 led to changes in peritoneal morphology resembling EPS. This suggests that TGF-beta1 may be a contributing factor in both simple peritoneal sclerosis and EPS. This model will be useful for elucidation of the mechanism of EPS and evaluation of potential treatment.

  12. A Conceptual Framework for Understanding Unintended Prolonged Opioid Use.

    Science.gov (United States)

    Hooten, W Michael; Brummett, Chad M; Sullivan, Mark D; Goesling, Jenna; Tilburt, Jon C; Merlin, Jessica S; St Sauver, Jennifer L; Wasan, Ajay D; Clauw, Daniel J; Warner, David O

    2017-12-01

    An urgent need exists to better understand the transition from short-term opioid use to unintended prolonged opioid use (UPOU). The purpose of this work is to propose a conceptual framework for understanding UPOU that posits the influence of 3 principal domains that include the characteristics of (1) individual patients, (2) the practice environment, and (3) opioid prescribers. Although no standardized method exists for developing a conceptual framework, the process often involves identifying corroborative evidence, leveraging expert opinion to identify factors for inclusion in the framework, and developing a graphic depiction of the relationships between the various factors and the clinical problem of interest. Key patient characteristics potentially associated with UPOU include (1) medical and mental health conditions; (2) pain etiology; (3) individual affective, behavioral, and neurophysiologic reactions to pain and opioids; and (4) sociodemographic factors. Also, UPOU could be influenced by structural and health care policy factors: (1) the practice environment, including the roles of prescribing clinicians, adoption of relevant practice guidelines, and clinician incentives or disincentives, and (2) the regulatory environment. Finally, characteristics inherent to clinicians that could influence prescribing practices include (1) training in pain management and opioid use; (2) personal attitudes, knowledge, and beliefs regarding the risks and benefits of opioids; and (3) professionalism. As the gatekeeper to opioid access, the behavior of prescribing clinicians directly mediates UPOU, with the 3 domains interacting to determine this behavior. This proposed conceptual framework could guide future research on the topic and allow plausible hypothesis-based interventions to reduce UPOU. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  13. Beta 1 versus nonselective blockade in therapy of essential tremor.

    Science.gov (United States)

    Larsen, T A; Teräväinen, H

    1983-01-01

    The beta 1-selective blocker metoprolol was compared to propranolol and a placebo in a double-blind crossover trial in 24 patients with essential tremor. Both beta blockers suppressed the essential tremor, but metoprolol, which caused a mean reduction of 32.0% in tremor intensity from the base-line value, was less effective than propranolol, which reduced mean tremor intensity by 41.3%. Subjective benefit for their tremor was found by 15 of the patients taking propranolol and by one taking metoprolol. The tremor frequency was not affected. No serious side effects were observed. Metoprolol may offer an alternative for those essential tremor patients who cannot tolerate propranolol.

  14. Surface effects on ionic Coulomb blockade in nanometer-size pores

    Science.gov (United States)

    Tanaka, Hiroya; Iizuka, Hideo; Pershin, Yuriy V.; Di Ventra, Massimiliano

    2018-01-01

    Ionic Coulomb blockade in nanopores is a phenomenon that shares some similarities but also differences with its electronic counterpart. Here, we investigate this phenomenon extensively using all-atom molecular dynamics of ionic transport through nanopores of about one nanometer in diameter and up to several nanometers in length. Our goal is to better understand the role of atomic roughness and structure of the pore walls in the ionic Coulomb blockade. Our numerical results reveal the following general trends. First, the nanopore selectivity changes with its diameter, and the nanopore position in the membrane influences the current strength. Second, the ionic transport through the nanopore takes place in a hopping-like fashion over a set of discretized states caused by local electric fields due to membrane atoms. In some cases, this creates a slow-varying ‘crystal-like’ structure of ions inside the nanopore. Third, while at a given voltage, the resistance of the nanopore depends on its length, the slope of this dependence appears to be independent of the molarity of ions. An effective kinetic model that captures the ionic Coulomb blockade behavior observed in MD simulations is formulated.

  15. Room temperature Coulomb blockade mediated field emission via self-assembled gold nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Fei [College of Physics and Electronics, Central South University, Changsha, Hunan 410073 (China); College of Science, National University of Defense Technology, Changsha, Hunan 410073 (China); Fang, Jingyue, E-mail: fjynudt@aliyun.com [College of Science, National University of Defense Technology, Changsha, Hunan 410073 (China); Chang, Shengli; Qin, Shiqiao; Zhang, Xueao [College of Science, National University of Defense Technology, Changsha, Hunan 410073 (China); Xu, Hui, E-mail: cmpxhg@csu.edu.cn [College of Physics and Electronics, Central South University, Changsha, Hunan 410073 (China)

    2017-02-05

    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. - Highlights: • The phenomenon of single-electron field emission in a transistor setting using self-assembled gold nanoparticles was investigated. • The transfer characteristics can be well explained by the model that is a combination of Coulomb blockage and field emission. • This transport mechanism is novel and may be used in many applications in field emission devices.

  16. Surface effects on ionic Coulomb blockade in nanometer-size pores.

    Science.gov (United States)

    Tanaka, Hiroya; Iizuka, Hideo; Pershin, Yuriy V; Ventra, Massimiliano Di

    2018-01-12

    Ionic Coulomb blockade in nanopores is a phenomenon that shares some similarities but also differences with its electronic counterpart. Here, we investigate this phenomenon extensively using all-atom molecular dynamics of ionic transport through nanopores of about one nanometer in diameter and up to several nanometers in length. Our goal is to better understand the role of atomic roughness and structure of the pore walls in the ionic Coulomb blockade. Our numerical results reveal the following general trends. First, the nanopore selectivity changes with its diameter, and the nanopore position in the membrane influences the current strength. Second, the ionic transport through the nanopore takes place in a hopping-like fashion over a set of discretized states caused by local electric fields due to membrane atoms. In some cases, this creates a slow-varying 'crystal-like' structure of ions inside the nanopore. Third, while at a given voltage, the resistance of the nanopore depends on its length, the slope of this dependence appears to be independent of the molarity of ions. An effective kinetic model that captures the ionic Coulomb blockade behavior observed in MD simulations is formulated.

  17. Fear memory in a neurodevelopmental model of schizophrenia based on the postnatal blockade of NMDA receptors.

    Science.gov (United States)

    Latusz, Joachim; Radaszkiewicz, Aleksandra; Bator, Ewelina; Wędzony, Krzysztof; Maćkowiak, Marzena

    2017-02-01

    Epidemiological data have indicated that memory impairment is observed during adolescence in groups at high risk for schizophrenia and might precede the appearance of schizophrenia symptoms in adulthood. In the present study, we used a neurodevelopmental model of schizophrenia based on the postnatal blockade of N-methyl-d-aspartate (NMDA) receptors in rats to investigate fear memory in adolescence and adulthood. The rats were treated with increasing doses of CGP 37849 (CGP), a competitive antagonist of the NMDA receptor (1.25mg/kg on days 1, 3, 6, 9; 2.5mg/kg on days 12, 15, 18 and 5mg/kg on day 21). Fear memory was analysed in delay and trace fear conditioning. Sensorimotor gating deficit, which is another cognitive symptom of schizophrenia, was also determined in adolescent and adult CGP-treated rats. Postnatal CGP administration disrupted cue- and context-dependent fear memory in adolescent rats in both delay and trace conditioning. In contrast, CGP administration evoked impairment only in cue-dependent fear memory in rats exposed to trace but not delay fear conditioning. The postnatal blockade of NMDA receptors induced sensorimotor gating deficits in adult rats but not in adolescent rats. The postnatal blockade of NMDA receptors induced fear memory impairment in adolescent rats before the onset of neurobehavioral deficits associated with schizophrenia. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

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

    DEFF Research Database (Denmark)

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

    1997-01-01

    that CD28-B7 blockade by systemic administration of CTLA4Ig prevents actively induced EAE. Since CTLA4Ig binds to both B7-1 and B7-2, we used a mutant form of CTLA4Ig (CTLA4IgY100F) that binds only B7-1, to study the role of B7-1 blockade in this model. Such a reagent avoids the potential of signaling...... treated with systemic CTLA4gY100F did not. More importantly, systemic administration of CTLA4IgY100F abrogated the protective effect of ex vivo treated APCs. These data suggest an important regulatory role for B7-1, perhaps through binding to CTLA4, in this model of EAE. Understanding the role......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...

  19. Myostatin deficiency but not anti-myostatin blockade induces marked proteomic changes in mouse skeletal muscle.

    Science.gov (United States)

    Salzler, Robert R; Shah, Darshit; Doré, Anthony; Bauerlein, Roy; Miloscio, Lawrence; Latres, Esther; Papadopoulos, Nicholas J; Olson, William C; MacDonald, Douglas; Duan, Xunbao

    2016-07-01

    Pharmacologic blockade of the myostatin (Mstn)/activin receptor pathway is being pursued as a potential therapy for several muscle wasting disorders. The functional benefits of blocking this pathway are under investigation, in particular given the findings that greater muscle hypertrophy results from Mstn deficiency arising from genetic ablation compared to post-developmental Mstn blockade. Using high-resolution MS coupled with SILAC mouse technology, we quantitated the relative proteomic changes in gastrocnemius muscle from Mstn knockout (Mstn(-/-) ) and mice treated for 2-weeks with REGN1033, an anti-Mstn antibody. Relative to wild-type animals, Mstn(-/-) mice had a two-fold greater muscle mass and a >1.5-fold change in expression of 12.0% of 1137 quantified muscle proteins. In contrast, mice treated with REGN1033 had minimal changes in muscle proteome (0.7% of 1510 proteins >1.5-fold change, similar to biological difference 0.5% of 1310) even though the treatment induced significant 20% muscle mass increase. Functional annotation of the altered proteins in Mstn(-/-) mice corroborates the mutiple physiological changes including slow-to-fast fiber type switch. Thus, the proteome-wide protein expression differs between Mstn(-/-) mice and mice subjected to specific Mstn blockade post-developmentally, providing molecular-level insights to inform mechanistic hypotheses to explain the observed functional differences. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

    Directory of Open Access Journals (Sweden)

    Vasilios Papademetriou

    2001-03-01

    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.

  1. The effect of renin-angiotensin system blockade on renal protection in chronic kidney disease patients with hyperkalemia.

    Science.gov (United States)

    Lee, Ju-Hyun; Kwon, Young Eun; Park, Jung Tak; Lee, Mi Jung; Oh, Hyung Jung; Han, Seung Hyeok; Kang, Shin-Wook; Choi, Kyu Hun; Yoo, Tae-Hyun

    2014-12-01

    The aim of this study was to determine the effects of renin-angiotensin system (RAS) blockade maintenance on renal protection in chronic kidney disease (CKD) patients with hyperkalemia occurring during treatment with RAS blockade. CKD III or IV patients, who were prescribed with RAS blockers and also had hyperkalemia, were included. The study population was divided into two groups based on maintenance or withdrawal of RAS blocker. Renal outcomes (doubling of creatinine or end-stage renal disease) and incidence of hyperkalemia were compared between the two groups. Out of 258 subjects who developed hyperkalemia during treatment with RAS blockers, 150 (58.1%) patients continued on RAS blockades, while RAS blockades were discontinued for more than 3 months in the remaining 108 patients. Renal event-free survival was significantly higher in the maintenance group compared with the withdrawal group. Cox proportional hazard ratio for renal outcomes was 1.35 (95% CI: 1.08-1.92, p=0.04) in the withdrawal group compared with the maintenance group. However, the incidence of hyperkalemia and hyperkalemia-related hospitalization or mortality did not differ between the two groups. This study demonstrated that the maintenance of RAS blockade is beneficial for the preservation of renal function and relatively tolerable in patients with CKD and hyperkalemia occurring during treatment with RAS blockade. © The Author(s) 2014.

  2. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery.

    Science.gov (United States)

    Fujita, Ai; Ishibe, Natsuki; Yoshihara, Tatsuya; Ohashi, Jun; Makino, Hideichi; Ikeda, Mizuko; Setoguchi, Hidekazu

    2014-06-01

    Sugammadex rapidly reverses neuromuscular blockade (NMB) induced by rocuronium. NMB induced by rocuronium is prolonged in patients with liver dysfunction, because the drug is mainly excreted into the bile. However, the efficacy and safety of sugammadex in terms of reversing rocuronium-induced NMB in patients with liver dysfunction undergoing hepatic surgery have not been evaluated. This observational study investigated the efficacy and safety of sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Remifentanil/propofol anesthesia was administered to 31 patients: 15 patients in the control group, and 16 patients from a group with liver dysfunction. Rocuronium (0.6 mg/kg) was administered, followed by continuous infusion. The enrolled patients were then subdivided into two groups according to the dose of sugammadex. In the first group a single dose of sugammadex (2.0 mg/kg) was given at the reappearance of the second twitch (T2). In the second group a single dose of sugammadex (4.0 mg/kg) was given at the first twitch response if T2 did not reappear in 15 minutes after stopping rocuronium. The primary outcome was time from administration of sugammadex to recovery of a train-of-four ratio to 0.9. The dose of rocuronium required in the liver dysfunction group was lower than that in the control group (6.2 vs. 8.2 μg/kg/min, p = 0.002). The mean time from the administration of sugammadex to recovery of the train-of-four ratio to 0.9 was not significantly different between the liver dysfunction group and the control group (2.2 minutes vs. 2.0 minutes in the 2 mg/kg administration group, p = 0.44 and 1.9 minutes vs. 1.7 minutes in the 4 mg/kg administration group, p = 0.70, respectively). No evidence of recurarization was observed in any of the patients. Most of the adverse events were found to be mild and such events were not related to the use of sugammadex. None of the patients was eliminated from the study

  3. Correcting magnesium deficiencies may prolong life

    Directory of Open Access Journals (Sweden)

    Rowe WJ

    2012-02-01

    Full Text Available William J RoweFormer Assistant Clinical Professor of Medicine, Medical University of Ohio at Toledo, Ohio, USAAbstract: The International Space Station provides an extraordinary facility to study the accelerated aging process in microgravity, which could be triggered by significant reductions in magnesium (Mg ion levels with, in turn, elevations of catecholamines and vicious cycles between the two. With space flight there are significant reductions of serum Mg (P < 0.0001 that have been shown in large studies of astronauts and cosmonauts. The loss of the functional capacity of the cardiovascular system with space flight is over ten times faster than the course of aging on Earth. Mg is an antioxidant and calcium blocker and in space there is oxidative stress, insulin resistance, and inflammatory conditions with evidence in experimental animals of significant endothelial injuries and damage to mitochondria. The aging process is associated with progressive shortening of telomeres, repetitive DNA sequences, and proteins that cap and protect the ends of chromosomes. Telomerase can elongate pre-existing telomeres to maintain length and chromosome stability. Low telomerase triggers increased catecholamines while the sensitivity of telomere synthesis to Mg ions is primarily seen for the longer elongation products. Mg stabilizes DNA and promotes DNA replication and transcription, whereas low Mg might accelerate cellular senescence by reducing DNA stability, protein synthesis, and function of mitochondria. Telomerase, in binding to short DNAs, is Mg dependent. On Earth, in humans, a year might be required to detect changes in telomeres, but in space there is a predictably much shorter duration required for detection, which is therefore more reasonable in time and cost. Before and after a space mission, telomere lengths and telomerase enzyme activity can be determined and compared with age-matched control rats on Earth. The effect of Mg supplementation

  4. Women's experiences of becoming a mother after prolonged labour.

    Science.gov (United States)

    Nystedt, Astrid; Högberg, Ulf; Lundman, Berit

    2008-08-01

    This paper is a report of a study to explore women's experiences of becoming a mother after prolonged labour. The negativity associated with a complicated labour such as prolonged labour can lead to a struggle to become a healthy mother and could restrict the process of becoming a mother. Interviews were conducted in 2004 with 10 mothers who had been through a prolonged labour with assisted vaginal or caesarean delivery 1-3 months previously. Thematic content analysis was used. Three themes were formulated, describing women's experiences as fumbling in the dark, struggling for motherhood and achieving confidence in being a mother. The difficulties and suffering involved in becoming a mother after a prolonged labour were interpreted to be like 'fumbling in the dark'. Women experienced bodily fatigue, accompanied by feelings of illness and detachment from the child. Having the child when in this condition entailed a struggle to become a mother. In spite of these experiences and the desire to achieve confidence in being a mother, the reassurance of these women regarding their capacity for motherhood was crucial: it was central to their happiness as mothers, encouraged interaction and relationship with the child, and contributed to their adaptation to motherhood. Women experiencing prolonged labour may be comparable with the experience of and recovery from illness, which could contribute to difficulties transitioning to motherhood and limit a woman's ability to be emotionally available for the child.

  5. Prolonged sedentary time and physical activity in workplace and non-work contexts: a cross-sectional study of office, customer service and call centre employees.

    Science.gov (United States)

    Thorp, Alicia A; Healy, Genevieve N; Winkler, Elisabeth; Clark, Bronwyn K; Gardiner, Paul A; Owen, Neville; Dunstan, David W

    2012-10-26

    To examine sedentary time, prolonged sedentary bouts and physical activity in Australian employees from different workplace settings, within work and non-work contexts. A convenience sample of 193 employees working in offices (131), call centres (36) and customer service (26) was recruited. Actigraph GT1M accelerometers were used to derive percentages of time spent sedentary (customer service workers were typically the least sedentary and the most active at work. The workplace is a key setting for prolonged sedentary time, especially for some occupational groups, and the potential health risk burden attached requires investigation. Future workplace regulations and health promotion initiatives for sedentary occupations to reduce prolonged sitting time should be considered.

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

    Science.gov (United States)

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

    2016-09-01

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

  7. Controlling the reproducibility of Coulomb blockade phenomena for gold nanoparticles on an organic monolayer/silicon system.

    Science.gov (United States)

    Caillard, L; Sattayaporn, S; Lamic-Humblot, A-F; Casale, S; Campbell, P; Chabal, Y J; Pluchery, O

    2015-02-13

    Two types of highly ordered organic layers were prepared on silicon modified with an amine termination for binding gold nanoparticles (AuNPs). These two grafted organic monolayers (GOMs), consisting of alkyl chains with seven or 11 carbon atoms, were grafted on oxide-free Si(111) surfaces as tunnel barriers between the silicon electrode and the AuNPs. Three kinds of colloidal AuNPs were prepared by reducing HAuCl4 with three different reactants: citrate (Turkevich synthesis, diameter ∼16 nm), ascorbic acid (diameter ∼9 nm), or NaBH4 (Natan synthesis, diameter ∼7 nm). Scanning tunnel spectroscopy (STS) was performed in a UHV STM at 40 K, and Coulomb blockade behaviour was observed. The reproducibility of the Coulomb behavior was analysed as a function of several chemical and physical parameters: size, crystallinity of the AuNPs, influence of surrounding surfactant molecules, and quality of the GOM/Si interface (degree of oxidation after the full processing). Samples were characterized with scanning tunneling microscope, STS, atomic force microscope, Fourier transform infrared spectroscopy, x-ray photoelectron spectroscopy (XPS), and high resolution transmission electronic microscope. We show that the reproducibility in observing Coulomb behavior can be as high as ∼80% with the Natan synthesis of AuNPs and GOMs with short alkyl chains.

  8. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade

    DEFF Research Database (Denmark)

    Ablamunits, Vitaly; Henegariu, Octavian; Hansen, Jakob Bondo

    2012-01-01

    (ab')(2) fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-1ß mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than......Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1ß. We postulated that blockade of IL-1ß would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F...... arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-¿, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies...

  9. Repeated Blockade of NMDA Receptors during Adolescence Impairs Reversal Learning and Disrupts GABAergic Interneurons in Rat Medial Prefrontal Cortex

    Directory of Open Access Journals (Sweden)

    Jitao eLi

    2016-03-01

    Full Text Available Adolescence is of particular significance to schizophrenia, since psychosis onset typically occurs in this critical period. Based on the N-methyl-D-aspartate (NMDA receptor hypofunction hypothesis of schizophrenia, in this study, we investigated whether and how repeated NMDA receptor blockade during adolescence would affect GABAergic interneurons in rat medial prefrontal cortex (mPFC and mPFC-mediated cognitive functions. Specifically, adolescent rats were subjected to intraperitoneal administration of MK-801 (0.1, 0.2, 0.4 mg/kg, a non-competitive NMDA receptor antagonist, for 14 days and then tested for reference memory and reversal learning in the water maze. The density of parvabumin (PV-, calbindin (CB- and calretinin (CR-positive neurons in mPFC were analyzed at either 24 hours or 7 days after drug cessation. We found that MK-801 treatment delayed reversal learning in the water maze without affecting initial acquisition. Strikingly, MK-801 treatment also significantly reduced the density of PV+ and CB+ neurons, and this effect persisted for 7 days after drug cessation at the dose of 0.2 mg/kg. We further demonstrated that the reduction in PV+ and CB+ neuron densities was ascribed to a downregulation of the expression levels of PV and CB, but not to neuronal death. These results parallel the behavioral and neuropathological changes of schizophrenia and provide evidence that adolescent NMDA receptors antagonism offers a useful tool for unraveling the etiology of the disease.

  10. Proliferation and differentiation of adipose tissue in prolonged lean and obese critically ill patients.

    Science.gov (United States)

    Goossens, Chloë; Vander Perre, Sarah; Van den Berghe, Greet; Langouche, Lies

    2017-12-01

    In prolonged non-obese critically ill patients, preservation of adipose tissue is prioritized over that of the skeletal muscle and coincides with increased adipogenesis. However, we recently demonstrated that in obese critically ill mice, this priority was switched. In the obese, the use of abundantly available adipose tissue-derived energy substrates was preferred and counteracted muscle wasting. These observations suggest that different processes are ongoing in adipose tissue of lean vs. overweight/obese critically ill patients. We hypothesize that to preserve adipose tissue mass during critical illness, adipogenesis is increased in prolonged lean critically ill patients, but not in overweight/obese critically ill patients, who enter the ICU with excess adipose tissue. To test this, we studied markers of adipogenesis in subcutaneous and visceral biopsies of matched lean (n = 24) and overweight/obese (n = 24) prolonged critically ill patients. Secondly, to further unravel the underlying mechanism of critical illness-induced adipogenesis, local production of eicosanoid PPARγ agonists was explored, as well as the adipogenic potential of serum from matched lean (n = 20) and overweight/obese (n = 20) critically ill patients. The number of small adipocytes, PPARγ protein, and CEBPB expression were equally upregulated (p ≤ 0.05) in subcutaneous and visceral adipose tissue biopsies of lean and overweight/obese prolonged critically ill patients. Gene expression of key enzymes involved in eicosanoid production was reduced (COX1, HPGDS, LPGDS, ALOX15, all p ≤ 0.05) or unaltered (COX2, ALOX5) during critical illness, irrespective of obesity. Gene expression of PLA2G2A and ALOX15B was upregulated in lean and overweight/obese patients (p ≤ 0.05), whereas their end products, the PPARγ-activating metabolites 15s-HETE and 9-HODE, were not increased in the adipose tissue. In vitro, serum of lean and overweight/obese prolonged critically ill

  11. Hand rest and wrist support are effective in preventing fatigue during prolonged typing.

    Science.gov (United States)

    Callegari, Bianca; de Resende, Marília Maniglia; da Silva Filho, Manoel

    Case series (longitudinal). Only few reports concerning the efficacy of commonly used strategies for preventing upper limb occupational disorders associated with prolonged typing exist. We aimed to investigate whether the duration of typing and the use of 2 strategies (hand rest and wrist support) changes muscle physiological response and therefore the electromyography records. We enrolled 25 volunteers, who were unfamiliar with the task and did not have musculoskeletal disorders. The subjects underwent 3 prolonged typing protocols to investigate the efficacy of the 2 adopted strategies in reducing the trapezius, biceps brachii, and extensor digitorum communis fatigue. Typing for 1 hour induced muscular fatigue (60%-67% of the subjects). The extensor digitorum communis muscle exhibited the highest percentage of fatigue (72%-84%) after 1 and 4 hours of typing (1 hour, P = .04; 4 hours, P = .02). Fatigue levels in this muscle were significantly reduced (24%) with the use of pause typing (4 hours, P = .045), whereas biceps brachii muscle fatigue was reduced (32%) only with the use of wrist supports (P = .02, after 4 hours). Trapezius muscle fatigue was unaffected by the tested occupational strategies (1 hour, P = .62; 4 hours, P = .85). Despite presenting an overall tendency for fatigue detected during the application of the protocols, the assessed muscles exhibited different behavior patterns, depending on both the preventive strategy applied and the muscle mechanical role during the task. Hand rest and wrist support can successfully reduce muscle fatigue in specific upper limb muscles during prolonged typing, leading to a muscle-selective reduction in the occurrence of fatigue and thus provide direct evidence that they may prevent work-related musculoskeletal disorders. N/A. Copyright © 2016 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

  12. Prolonged social withdrawal disorder: a hikikomori case in Spain.

    Science.gov (United States)

    Ovejero, Santiago; Caro-Cañizares, Irene; de León-Martínez, Victoria; Baca-Garcia, Enrique

    2014-09-01

    The Japanese term hikikomori means literally 'to be confined'. Social withdrawal can be present in severe psychiatric disorders; however, in Japan, hikikomori is a defined nosologic entity. There have been only a few reported cases in occidental culture. We present a case report of a Spanish man with prolonged social withdrawal lasting for 4 years. This is a case of prolonged social withdrawal not bound to culture, as well as the second case of hikikomori reported in Spain. We propose prolonged social withdrawal disorder as a disorder not linked to culture, in contrast to hikikomori. Further documentation of this disorder is still needed to encompass all cases reported in Japan and around the world. © The Author(s) 2013.

  13. Left Ventricular Function After Prolonged Exercise in Equine Endurance Athletes

    DEFF Research Database (Denmark)

    Flethøj, M.; Schwarzwald, C. C.; Haugaard, M. M.

    2016-01-01

    Doppler imaging, and two-dimensional speckle tracking. Correlation between echocardiographic variables and cardiac troponin I was evaluated. Results: Early diastolic myocardial velocities decreased significantly in longitudinal (baseline: −17.4 ± 2.4cm/s; end of ride: −15.8 ± 3.2cm/s (P = .013); morning......Background: Prolonged exercise in human athletes is associated with transient impairment of left ventricular (LV) function, known as cardiac fatigue. Cardiac effects of prolonged exercise in horses remain unknown. Objectives :To investigate the effects of prolonged exercise on LV systolic...... and diastolic function in horses. Animals: Twenty-six horses competing in 120–160 km endurance rides. Methods: Cross-sectional field study. Echocardiography was performed before and after rides, and the following morning, and included two-dimensional echocardiography, anatomical M-mode, pulsed-wave tissue...

  14. Obesity Preserves Myocardial Function During Blockade of the Glycolytic Pathway

    International Nuclear Information System (INIS)

    Campos, Dijon Henrique Salomé de; Leopoldo, André Soares; Lima-Leopoldo, Ana Paula; Nascimento, André Ferreira do; Oliveira-Junior, Silvio Assis de; Silva, Danielle Cristina Tomaz da; Sugizaki, Mario Mateus; Padovani, Carlos Roberto; Cicogna, Antonio Carlos

    2014-01-01

    Obesity is defined by excessive accumulation of body fat relative to lean tissue. Studies during the last few years indicate that cardiac function in obese animals may be preserved, increased or diminished. Study the energy balance of the myocardium with the hypothesis that the increase in fatty acid oxidation and reduced glucose leads to cardiac dysfunction in obesity. 30-day-old male Wistar rats were fed standard and hypercaloric diet for 30 weeks. Cardiac function and morphology were assessed. In this paper was viewed the general characteristics and comorbities associated to obesity. The structure cardiac was determined by weights of the heart and left ventricle (LV). Myocardial function was evaluated by studying isolated papillary muscles from the LV, under the baseline condition and after inotropic and lusitropic maneuvers: myocardial stiffness; postrest contraction; increase in extracellular Ca2+ concentration; change in heart rate and inhibitor of glycolytic pathway. Compared with control group, the obese rats had increased body fat and co-morbities associated with obesity. Functional assessment after blocking iodoacetate shows no difference in the linear regression of DT, however, the RT showed a statistically significant difference in behavior between the control and the obese group, most notable being the slope in group C. The energy imbalance on obesity did not cause cardiac dysfunction. On the contrary, the prioritization of fatty acids utilization provides protection to cardiac muscle during the inhibition of glycolysis, suggesting that this pathway is fewer used by obese cardiac muscle

  15. Obesity Preserves Myocardial Function During Blockade of the Glycolytic Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Campos, Dijon Henrique Salomé de, E-mail: dijoncampos@gmail.com [Departamento de Clínica Médica - Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil); Leopoldo, André Soares; Lima-Leopoldo, Ana Paula [Departamento de Esportes - Centro de Educação Física e Desportos da Universidade Federal do Espírito Santo (UFES), Vitória, ES (Brazil); Nascimento, André Ferreira do [Instituto de Ciências da Saúde da Universidade Federal do Mato Grosso (UFMT), Sinop, MT (Brazil); Oliveira-Junior, Silvio Assis de [Escola de Fisioterapia da Universidade Federal do Mato Grosso do Sul (UFMS), Campo Grande, MS (Brazil); Silva, Danielle Cristina Tomaz da [Departamento de Clínica Médica - Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil); Sugizaki, Mario Mateus [Instituto de Ciências da Saúde da Universidade Federal do Mato Grosso (UFMT), Sinop, MT (Brazil); Padovani, Carlos Roberto [Departamento de Bioestatística, Instituto de Ciências Biológicas da Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil); Cicogna, Antonio Carlos, E-mail: dijoncampos@gmail.com [Departamento de Clínica Médica - Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP), Botucatu, SP (Brazil)

    2014-10-15

    Obesity is defined by excessive accumulation of body fat relative to lean tissue. Studies during the last few years indicate that cardiac function in obese animals may be preserved, increased or diminished. Study the energy balance of the myocardium with the hypothesis that the increase in fatty acid oxidation and reduced glucose leads to cardiac dysfunction in obesity. 30-day-old male Wistar rats were fed standard and hypercaloric diet for 30 weeks. Cardiac function and morphology were assessed. In this paper was viewed the general characteristics and comorbities associated to obesity. The structure cardiac was determined by weights of the heart and left ventricle (LV). Myocardial function was evaluated by studying isolated papillary muscles from the LV, under the baseline condition and after inotropic and lusitropic maneuvers: myocardial stiffness; postrest contraction; increase in extracellular Ca2+ concentration; change in heart rate and inhibitor of glycolytic pathway. Compared with control group, the obese rats had increased body fat and co-morbities associated with obesity. Functional assessment after blocking iodoacetate shows no difference in the linear regression of DT, however, the RT showed a statistically significant difference in behavior between the control and the obese group, most notable being the slope in group C. The energy imbalance on obesity did not cause cardiac dysfunction. On the contrary, the prioritization of fatty acids utilization provides protection to cardiac muscle during the inhibition of glycolysis, suggesting that this pathway is fewer used by obese cardiac muscle.

  16. Obesity Preserves Myocardial Function During Blockade of the Glycolytic Pathway

    Directory of Open Access Journals (Sweden)

    Dijon Henrique Salomé de Campos

    2014-10-01

    Full Text Available Background: Obesity is defined by excessive accumulation of body fat relative to lean tissue. Studies during the last few years indicate that cardiac function in obese animals may be preserved, increased or diminished. Objective: Study the energy balance of the myocardium with the hypothesis that the increase in fatty acid oxidation and reduced glucose leads to cardiac dysfunction in obesity. Methods: 30-day-old male Wistar rats were fed standard and hypercaloric diet for 30 weeks. Cardiac function and morphology were assessed. In this paper was viewed the general characteristics and comorbities associated to obesity. The structure cardiac was determined by weights of the heart and left ventricle (LV. Myocardial function was evaluated by studying isolated papillary muscles from the LV, under the baseline condition and after inotropic and lusitropic maneuvers: myocardial stiffness; postrest contraction; increase in extracellular Ca2+ concentration; change in heart rate and inhibitor of glycolytic pathway. Results: Compared with control group, the obese rats had increased body fat and co-morbities associated with obesity. Functional assessment after blocking iodoacetate shows no difference in the linear regression of DT, however, the RT showed a statistically significant difference in behavior between the control and the obese group, most notable being the slope in group C. Conclusion: The energy imbalance on obesity did not cause cardiac dysfunction. On the contrary, the prioritization of fatty acids utilization provides protection to cardiac muscle during the inhibition of glycolysis, suggesting that this pathway is fewer used by obese cardiac muscle.

  17. Prolonged maintenance of capsaicin-induced hyperalgesia by brief daily vibration stimuli.

    Science.gov (United States)

    Kim, Hee Kee; Schattschneider, Jörn; Lee, Inhyung; Chung, Kyungsoon; Baron, Ralf; Chung, Jin Mo

    2007-05-01

    This study tests the hypothesis that central sensitization initiated by nociceptive input can be maintained by repeated brief innocuous peripheral inputs. Capsaicin was injected intradermally into the hind paw of adult rats. Three different types of daily cutaneous mechanical stimulations (vibration, soft brush, or pressure) were applied to the capsaicin-injected paw for a period of 2 weeks. Daily stimulation consisted of a 10-s stimulation repeated every 30s for 30 min. Foot withdrawal thresholds to von Frey stimuli applied to the paw were measured once a day for 4 weeks. The capsaicin-only group (control rats without daily stimulation) showed hyperalgesia lasting for 3 days. In contrast, hyperalgesia persisted for 2 weeks in the group that received vibration stimulation. Neither the soft brush nor the pressure group showed a significant difference in mechanical threshold from the control group (capsaicin only). The vibration-induced prolonged hyperalgesia was significantly reduced by systemic injection of ifenprodil, an NMDA-receptor antagonist, but it was not influenced by either an AMPA-receptor blocker or a reactive oxygen species (ROS) scavenger. Furthermore, a dorsal column lesion did not interfere with the prolongation of hyperalgesia. Data suggest that vibration-induced prolongation of hyperalgesia is mediated by spinal NMDA-receptors, and a similar mechanism may underlie some forms of chronic pain with no obvious causes, such as complex regional pain syndrome type 1 (CRPS-1).

  18. Studies on Prolonging Storage life and Maintaining Fruit Quality Parameters of Zaghloul Dates

    International Nuclear Information System (INIS)

    ElSalhy, F.T.

    2011-01-01

    This study was carried out to investigate the effect of gamma irradiation ( 1, 2 and 3 kGy) and some natural plant extracts i.e. aloe, ambrosia, cinnamon, chamomile, clove or nigella on prolonging the storage life and some parameters of Zaghloul dates quality under cold storage (5 ±2 C, 90-95 % RH). The weight loss %, decay %, T.S.S. %, total sugars and non-reducing sugars % of Zaghloul dates were increased in most cases with prolonging the storage time. Meanwhile, titratable acidity %, reducing sugars % and tannins content were decreased during storage period (56 days). However, the lowest values of weight loss % and decay % were recorded by aloe extract treatment while the highest values of T.S.S., total sugars, non-reducing sugars, titratable acidity %, reducing sugars % and tannins content were scored by gamma irradiation at 3 kGy. It could be concluded that using irradiation at 3 kGy, aloe, cinnamon or clove can keep the dates (Zaghloul variety) fresh even after 56 days at cold storage with good quality and safety levels of microbes

  19. The effect of badger culling on breakdown prolongation and recurrence of bovine tuberculosis in cattle herds in Great Britain.

    Directory of Open Access Journals (Sweden)

    Katerina Karolemeas

    Full Text Available Bovine tuberculosis is endemic in cattle herds in Great Britain, with a substantial economic impact. A reservoir of Mycobacterium bovis within the Eurasian badger (Meles meles population is thought to have hindered disease control. Cattle herd incidents, termed breakdowns, that are either 'prolonged' (lasting ≥ 240 days or 'recurrent' (with another breakdown within a specified time period may be important foci for onward spread of infection. They drain veterinary resources and can be demoralising for farmers. Randomised Badger Culling Trial (RBCT data were re-analysed to examine the effects of two culling strategies on breakdown prolongation and recurrence, during and after culling, using a Bayesian hierarchical model. Separate effect estimates were obtained for the 'core' trial areas (where culling occurred and the 'buffer' zones (up to 2 km outside of the core areas. For breakdowns that started during the culling period, 'reactive' (localised culling was associated with marginally increased odds of prolongation, with an odds ratio (OR of 1.7 (95% credible interval [CI] 1.1-2.4 within the core areas. This effect was not present after the culling ceased. There was no notable effect of 'proactive' culling on prolongation. In contrast, reactive culling had no effect on breakdown recurrence, though there was evidence of a reduced risk of recurrence in proactive core areas during the culling period (ORs and 95% CIs: 0.82 (0.64-1.0 and 0.69 (0.54-0.86 for 24- and 36-month recurrence respectively. Again these effects were not present after the culling ceased. There seemed to be no effect of culling on breakdown prolongation or recurrence in the buffer zones. These results suggest that the RBCT badger culling strategies are unlikely to reduce either the prolongation or recurrence of breakdowns in the long term, and that reactive strategies (such as employed during the RBCT are, if anything, likely to impact detrimentally on breakdown persistence.

  20. Cerebral ammonia uptake and accumulation during prolonged exercise in humans

    DEFF Research Database (Denmark)

    Nybo, Lars; Dalsgaard, Mads K.; Steensberg, Adam

    2005-01-01

    We evaluated whether peripheral ammonia production during prolonged exercise enhances the uptake and subsequent accumulation of ammonia within the brain. Two studies determined the cerebral uptake of ammonia (arterial and jugular venous blood sampling combined with Kety-Schmidt-determined cerebral...... blood flow; n = 5) and the ammonia concentration in the cerebrospinal fluid (CSF; n = 8) at rest and immediately following prolonged exercise either with or without glucose supplementation. There was a net balance of ammonia across the brain at rest and at 30 min of exercise, whereas 3 h of exercise...... exercise with glucose, and further to 16.1 ± 3.3 µM after the placebo trial (P

  1. Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice

    DEFF Research Database (Denmark)

    Lopez-Contreras, Andres J; Specks, Julia; Barlow, Jacqueline H

    2015-01-01

    In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the...

  2. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

    DEFF Research Database (Denmark)

    van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A

    2015-01-01

    Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons...

  3. Lack of endogenous modulation and reduced decay of prolonged heat pain in older adults.

    Science.gov (United States)

    Riley, Joseph L; King, Christopher D; Wong, Fong; Fillingim, Roger B; Mauderli, Andre P

    2010-07-01

    This study supports the hypothesis that healthy older adults exhibit decreased endogenous pain inhibition compared to younger healthy controls. Twenty-two older adults (56-77years of age) and 27 controls aged 20-49 participated in five experimental sessions following a training session. Each experimental session consisted of five 60-s trials in which the experimental heat stimulus was presented to the thenar eminence of the left palm with or without a conditioning stimulus (cold-water immersion of the foot). The temperature for the palm (44-49 degrees C) and foot (8-16 degrees C) was customized for each subject. The intensity of experimental pain produced by the contact thermode was continuously measured during the 60-s trial with an electronic visual analogue scale. No significant associations were found between subjects rating of concentration and the overall inhibitory effect. Older subjects failed to demonstrate conditioned pain modulation (CPM) and showed facilitation in the trials using painful concurrent immersion of the foot. A novel aspect of the study was that we recorded "pain offset" (i.e., after-sensations) and found that ratings for the older sample decreased at a slower rate than observed for the group of younger adults suggesting increased central sensitization among the older sample. Decrements in CPM could contribute to the greater prevalence of pain in older age. Since a number of neurotransmitter systems are involved in pain modulation, it is possible age-related differences in CPM are due to functional changes in these systems in a number of areas within the neuroaxis. Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Beta-adrenoreceptor blockade abolishes atomoxetine-induced risk taking.

    Science.gov (United States)

    Yang, Fan Nils; Pan, Jing Samantha; Li, Xinwang

    2016-01-01

    Clinical studies have shown that patients with exaggerated risk-taking tendencies have high baseline levels of norepinephrine. In this work, we systemically manipulated norepinephrine levels in rats and studied their behavioral changes in a probabilistic discounting task, which is a paradigm for gauging risk taking. This study aims to explore the effects of the selective norepinephrine reuptake inhibitor (atomoxetine at doses of 0.6, 1.0 and 1.8 mg/kg), and receptor selective antagonists (propranolol at a single dose of 1.0/kg, and prazosin at a single dose of 0.1 mg/kg), on risk taking using a probabilistic discounting task. In this task, there were two levers available to rats: pressing the 'small/certain' lever guaranteed a single food pellet, and pressing the 'large/risky' lever yielded either four pellets or none. The probability of receiving four food pellets decreased across the four experimental blocks from 100% to 12.5%. Atomoxetine increased the tendency to choose the large/risky lever. It significantly reduced the lose-shift effect (i.e. pressing a different lever after losing a trial), but did not affect the win-stay effect (i.e. pressing the same lever after winning a trial). Furthermore, co-administration of beta-adrenoreceptor antagonist, propranolol, eliminated the effects of atomoxetine on risk taking and the lose-shift effect; but co-administration of alpha1-adrenoreceptor antagonist, prazosin, did not. Atomoxetine boosted NE levels and increased risk taking. This was because atomoxetine decreased rats' sensitivity to losses. These effects were likely mediated by beta-adrenoreceptor. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells.

    Science.gov (United States)

    Browning, Cynthia L; Qin, Qin; Kelly, Deborah F; Prakash, Rohit; Vanoli, Fabio; Jasin, Maria; Wise, John Pierce

    2016-09-01

    Genomic instability is one of the primary models of carcinogenesis and a feature of almost all cancers. Homologous recombination (HR) repair protects against genomic instability by maintaining high genomic fidelity during the repair of DNA double strand breaks. The defining step of HR repair is the formation of the Rad51 nucleofilament, which facilitates the search for a homologous sequence and invasion of the template DNA strand. Particulate hexavalent chromium (Cr(VI)), a human lung carcinogen, induces DNA double strand breaks and chromosome instability. Since the loss of HR repair increases Cr(VI)-induced chromosome instability, we investigated the effect of extended Cr(VI) exposure on HR repair. We show acute (24 h) Cr(VI) exposure induces a normal HR repair response. In contrast, prolonged (120 h) exposure to particulate Cr(VI) inhibited HR repair and Rad51 nucleofilament formation. Prolonged Cr(VI) exposure had a profound effect on Rad51, evidenced by reduced protein levels and Rad51 mislocalization to the cytoplasm. The response of proteins involved in Rad51 nuclear import and nucleofilament formation displayed varying responses to prolonged Cr(VI) exposure. BRCA2 formed nuclear foci after prolonged Cr(VI) exposure, while Rad51C foci formation was suppressed. These results suggest that particulate Cr(VI), a major chemical carcinogen, inhibits HR repair by targeting Rad51, causing DNA double strand breaks to be repaired by a low fidelity, Rad51-independent repair pathway. These results further enhance our understanding of the underlying mechanism of Cr(VI)-induced chromosome instability and thus, carcinogenesis. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Use of a sealant to prevent prolonged air leaks after lung resection: a prospective randomized study.

    Science.gov (United States)

    Lequaglie, Cosimo; Giudice, Gabriella; Marasco, Rita; Morte, Aniello Della; Gallo, Massimiliano

    2012-10-08

    Pulmonary air leaks are common complications of lung resection and result in prolonged hospital stays and increased costs. The purpose of this study was to investigate whether, compared with standard care, the use of a synthetic polyethylene glycol matrix (CoSeal®) could reduce air leaks detected by means of a digital chest drain system (DigiVent™), in patients undergoing lung resection (sutures and/or staples alone). Patients who intraoperatively showed moderate or severe air leaks (evaluated by water submersion tests) were intraoperatively randomized to receive just sutures/staples (control group) or sutures/staples plus CoSeal® (sealant group). Differences among the groups in terms of air leaks, prolonged air leaks, time to chest tube removal, length of hospital stay and related costs were assessed. In total, 216 lung resection patients completed the study. Nineteen patients (18.1%) in the control group and 12 (10.8%) patients in the sealant group experienced postoperative air leaks, while a prolonged air leak was recorded in 11.4% (n=12) of patients in the control group and 2.7% (n=3) of patients in the sealant group. The difference in the incidence of air leaks and prolonged air leaks between the two groups was statistically significant (p=0.0002 and p=0.0013). The mean length of hospital stay was significantly shorter in the sealant group (4 days) than the control group (8 days) (p=0.0001). We also observed lower costs in the sealant group than the control group. The use of CoSeal® may decrease the occurrence and severity of postoperative air leaks after lung resection and is associated with shorter hospital stay. Not registered. The trial was approved by the Institutional Review Board of the IRCCS-CROB Basilicata Regional Cancer Institute, Rionero in Vulture, Italy.

  7. Effect of prolonging radiation delivery time on retention of gammaH2AX

    International Nuclear Information System (INIS)

    Moiseenko, Vitali; Banáth, Judit P; Duzenli, Cheryl; Olive, Peggy L

    2008-01-01

    Compared to conventional external beam radiotherapy, IMRT requires significantly more time to deliver the dose. Prolonging dose delivery potentially increases DNA repair which would reduce the biological effect. We questioned whether retention of γH2AX, a measure of lack of repair of DNA damage, would decrease when dose delivery was protracted. Exponentially growing SiHa cervical carinoma cells were irradiated with 6 MV photons in a water tank using a VarianEX linear accelerator. Cells held at 37°C received 2 Gy in 0.5 min and 4 Gy in 1 min. To evaluate effect of dose delivery prolongation, 2 and 4 Gy were delivered in 30 and 60 min. After 24 h recovery, cells were analyzed for clonogenic survival and for residual γH2AX as measured using flow cytometry. Increasing the dose delivery time from 0.5 or 1 min to 30 or 60 min produced a signficant increase in cell survival from 0.45 to 0.48 after 2 Gy, and from 0.17 to 0.20 after 4 Gy. Expression of residual γH2AX decreased from 1.27 to 1.22 relative to background after 2 Gy and 1.46 to 1.39 relative to background after 4 Gy, but differences were not statistically significant. The relative differences in the slopes of residual γH2AX versus dose for acute versus prolonged irradiation bordered on significant (p = 0.055), and the magnitude of the change was consistent with the observed increase in surviving fraction. These results support the concept that DNA repair underlies the increase in survival observed when dose delivery is prolonged. They also help to establish the limits of sensitivity of residual γH2AX, as measured using flow cytometry, for detecting differences in response to irradiation

  8. A double-blind, placebo-controlled study of repetitive transnasal sphenopalatine ganglion blockade with tx360(®) as acute treatment for chronic migraine.

    Science.gov (United States)

    Cady, Roger; Saper, Joel; Dexter, Kent; Manley, Heather R

    2015-01-01

    To determine if repetitive sphenopalatine ganglion (SPG) blocks with 0.5% bupivacaine delivered through the Tx360(®) are superior in reducing pain associated with chronic migraine (CM) compared with saline. The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa (PPF) in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. From an anatomical and physiological perspective, SPG blockade may be an effective acute and preventative treatment for CM. This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition. They were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5% bupivacaine or saline, respectively. The primary end-point was to compare numeric rating scale scores at pretreatment baseline vs 15 minutes, 30 minutes, and 24 hours postprocedure for all 12 treatments. SPG blockade was accomplished with the Tx360(®) , which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space. A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG. The procedure is performed similarly in each nostril. The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5% bupivacaine or saline provided 2 times per week for 6 weeks. Subjects were re-evaluated at 1 and 6 months postfinal procedure. The final dataset included 38 subjects, 26 in the

  9. A Double-Blind, Placebo-Controlled Study of Repetitive Transnasal Sphenopalatine Ganglion Blockade With Tx360® as Acute Treatment for Chronic Migraine

    Science.gov (United States)

    Cady, Roger; Saper, Joel; Dexter, Kent; Manley, Heather R

    2015-01-01

    Objective To determine if repetitive sphenopalatine ganglion (SPG) blocks with 0.5% bupivacaine delivered through the Tx360® are superior in reducing pain associated with chronic migraine (CM) compared with saline. Background The SPG is a small concentrated structure of neuronal tissue that resides within the pterygopalatine fossa (PPF) in close proximity to the sphenopalatine foramen and is innervated by the maxillary division of the trigeminal nerve. From an anatomical and physiological perspective, SPG blockade may be an effective acute and preventative treatment for CM. Method This was a double-blind, parallel-arm, placebo-controlled, randomized pilot study using a novel intervention for acute treatment in CM. Up to 41 subjects could be enrolled at 2 headache specialty clinics in the US. Eligible subjects were between 18 and 80 years of age and had a history of CM defined by the second edition of the International Classification of Headache Disorders appendix definition. They were allowed a stable dose of migraine preventive medications that was maintained throughout the study. Following a 28-day baseline period, subjects were randomized by computer-generated lists of 2:1 to receive 0.5% bupivacaine or saline, respectively. The primary end-point was to compare numeric rating scale scores at pretreatment baseline vs 15 minutes, 30 minutes, and 24 hours postprocedure for all 12 treatments. SPG blockade was accomplished with the Tx360®, which allows a small flexible soft plastic tube that is advanced below the middle turbinate just past the pterygopalatine fossa into the intranasal space. A 0.3 cc of anesthetic or saline was injected into the mucosa covering the SPG. The procedure is performed similarly in each nostril. The active phase of the study consisted of a series of 12 SPG blocks with 0.3 cc of 0.5% bupivacaine or saline provided 2 times per week for 6 weeks. Subjects were re-evaluated at 1 and 6 months postfinal procedure. Results The final dataset

  10. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB₁ receptor blockade.

    Science.gov (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

    2013-03-19

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.

  11. Activation of the sympathetic nervous system mediates hypophagic and anxiety-like effects of CB1 receptor blockade

    Science.gov (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

    2013-01-01

    Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of β-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral β-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors. PMID:23487769

  12. 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

    2014-09-01

    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.

  13. Plasma cell-free mitochondrial DNA declines in response to prolonged moderate aerobic exercise.

    Science.gov (United States)

    Shockett, Penny E; Khanal, Januka; Sitaula, Alina; Oglesby, Christopher; Meachum, William A; Castracane, V Daniel; Kraemer, Robert R

    2016-01-01

    Increased plasma cell-free mitochondrial DNA (cf-mDNA), a damage-associated molecular pattern (DAMP) produced by cellular injury, contributes to neutrophil activation/inflammation in trauma patients and arises in cancer and autoimmunity. To further understand relationships between cf-mDNA released by tissue injury, inflammation, and health benefits of exercise, we examined cf-mDNA response to prolonged moderate aerobic exercise. Seven healthy moderately trained young men (age = 22.4 ± 1.2) completed a treadmill exercise trial for 90 min at 60% VO2 max and a resting control trial. Blood was sampled immediately prior to exercise (0 min = baseline), during (+18, +54 min), immediately after (+90 min), and after recovery (R40). Plasma was analyzed for cf-mDNA, IL-6, and lactate. A significant difference in cf-mDNA response was observed between exercise and control trials, with cf-mDNA levels reduced during exercise at +54 and +90 (with or without plasma volume shift correction). Declines in cf-mDNA were accompanied by increased lactate and followed by an increase in IL-6, suggesting a temporal association with muscle stress and inflammatory processes. Our novel finding of cf-mDNA decline with prolonged moderate treadmill exercise provides evidence for increased clearance from or reduced release of cf-mDNA into the blood with prolonged exercise. These studies contrast with previous investigations involving exhaustive short-term treadmill exercise, in which no change in cf-mDNA levels were reported, and contribute to our understanding of differences between exercise- and trauma-induced inflammation. We propose that transient declines in cf-mDNA may induce health benefits, by reducing systemic inflammation. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  14. Public stigma of prolonged grief disorder : An experimental study

    NARCIS (Netherlands)

    Eisma, Maarten C.

    Prolonged grief disorder (PGD), characterized by severe, persistent and disabling grief, is being considered for inclusion in the International Classification of Diseases’ 11 (ICD-11) and a related disorder, Persistent Complex Bereavement Disorder (PCBD), is included for further investigation in the

  15. Prolonged use of indwelling urinary catheter following acute urinary ...

    African Journals Online (AJOL)

    J.O. Bello

    prolonged use of urinary catheters following acute urinary retention secondary to benign prostate enlarge- ment (BPE) and urethral ... indwelling urinary catheter for >3 months following acute urinary retention due to BPE or USD. The study .... the major health-care financing strategy in Nigeria and accounts for more than ...

  16. Assessing QT interval prolongation and its associated risks with antipsychotics

    DEFF Research Database (Denmark)

    Nielsen, Jimmi; Graff, Claus; Kanters, Jørgen K.

    2011-01-01

    markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled...

  17. MRI findings of prolonged post-traumatic sternal pain

    International Nuclear Information System (INIS)

    Grosse, Alexandra; Grosse, Claudia; Anderson, Suzanne; Steinbach, Lynne

    2007-01-01

    The objective of this study was to characterize the different causes of prolonged sternal pain following thoracic trauma with involvement of the sternum and to define criteria for sternal nonunion diagnosis using MRI. Five patients with abnormalities of the sternum were evaluated for prolonged sternal pain following thoracic trauma using MRI. MR images were evaluated by two radiologists in consensus. The patients were selected from the radiology database, which included 8 patients with post-traumatic prolonged sternal pain. Two patients (n = 2) revealed a sternal nonunion after sternal fracture. One patient had a sternal fracture with delayed union and minor displacement of the sternal halves. Abnormal signal intensity alterations adjacent to and within the manubrio-sternal joint were evident in 2 patients and considered due to trauma-related changes in the manubrio-sternal joint. The 3 patients who were not included in the study had no abnormalities of the sternum: 1 of them proved to have a well-healed sternal fracture and nonunion of a rib fracture, 1 had subtle Tietze's syndrome, and 1 patient revealed no pathological findings on imaging. Various factors may be responsible for prolonged sternal pain following thoracic trauma, and these can be viewed with MRI. In cases of sternal nonunion there was common fluid-like signal in the fracture interspace between the bony edges, and the bone marrow adjacent to the nonunion showed altered signal intensity. MRI identified sternal nonunion and other trauma-related abnormalities of the sternum following chest trauma. (orig.)

  18. Diet-consumer nitrogen isotope fractionation for prolonged fasting arthropods.

    Science.gov (United States)

    Mizota, Chitoshi; Yamanaka, Toshiro

    2011-12-01

    Nitrogen acquisition for cellular metabolism during diapause is a primary concern for herbivorous arthropods. Analyses of naturally occurring stable isotopes of nitrogen help elucidate the mechanism. Relevant articles have cited (58 times up to mid-June 2011) anomalously elevated δ(15)N (per mil deviation of (15)N/(14)N, relative to atmospheric nitrogen=0 ‰) values (diet-consumer nitrogen isotope fractionation; up to 12 ‰) for a prolonged fasting raspberry beetle (Byturus tomentosus Degeer (Coleoptera: Byturidae)), which feeds on red raspberries (Rubus idaeus: δ(15)N= ~ +2 ‰). Biologists have hypothesised that extensive recycling of amino acid nitrogen is responsible for the prolonged fasting. Since this hypothesis was proposed in 1995, scientists have integrated biochemical and molecular knowledge to support the mechanism of prolonged diapausing of animals. To test the validity of the recycling hypothesis, we analysed tissue nitrogen isotope ratios for four Japanese arthropods: the shield bug Parastrachia japonensis Scott (Hemiptera: Cydnidae), the burrower bug Canthophorus niveimarginatus Scott (Hemiptera: Cydnidae), leaf beetle Gastrophysa atrocyanea Motschulsky (Coleoptera: Chrysomelidae) and the Japanese oak silkworm Antheraea yamamai (Lepidoptera: Saturniidae), all of which fast for more than 6 months as part of their life-history strategy. Resulting diet-consumer nitrogen isotope discrimination during fasting ranged from 0 to 7‰, as in many commonly known terrestrial arthropods. We conclude that prolonged fasting of arthropods does not always result in anomalous diet-consumer nitrogen isotope fractionation, since the recycling process is closed or nearly closed with respect to nitrogen isotopes.

  19. Prolonged Intrauterine Retention of Foetal Bones after Midtrimester ...

    African Journals Online (AJOL)

    Prolonged retention of foetal bones in the uterus is a rare complication of induced abortion. We present the case of a 37 year old nullipara with retained foetal bones following a second trimester induced abortion. Accurate diagnosis and removal of the bony fragments led to restoration of fertility and subsequent delivery of a ...

  20. QTc-prolonging drugs and hospitalizations for cardiac arrhythmias

    NARCIS (Netherlands)

    De Bruin, ML; Hoes, AW; Leufkens, HGM

    2003-01-01

    Cardiac arrhythmia as an adverse effect of noncardiac drugs has been an issue of growing importance during the past few years. In this population-based study, we evaluated the risk for serious cardiac arrhythmias during the use of several noncardiac QTc-prolonging drugs in day-to-day practice, and

  1. The Prolonged Neonatal Admission: Implications for our National Children's Hospital

    LENUS (Irish Health Repository)

    McGlacken-Byrne, SM

    2016-06-01

    A significant number of neonates are admitted to tertiary paediatric units for prolonged stays annually, despite limited availability of neonatal beds. As the three Dublin paediatric hospitals merge, this pressure will be transferred to our new National Children’s Hospital.\\r\

  2. The Importance of Prolonged Provocation in Drug Allergy

    DEFF Research Database (Denmark)

    Fransson, Sara; Mosbech, Holger; Kappel, Mogens

    2017-01-01

    BACKGROUND: Drug provocation is the "Gold Standard" in drug allergy investigation. Recent studies suggest that a negative drug provocation on first dose should be followed by a prolonged provocation over several days. OBJECTIVE: To evaluate drug allergy investigations on the basis of drug...

  3. Influence of prolonged cold ischemia in renal transplantation.

    NARCIS (Netherlands)

    Vliet, J.A. van der; Warle, M.C.; Cheung, C.L.; Teerenstra, S.; Hoitsma, A.J.

    2011-01-01

    van der Vliet JA, Warle MC, Cheung CLS, Teerenstra S, Hoitsma AJ. Influence of prolonged cold ischemia in renal transplantation. Clin Transplant 2011: 25: E612-E616. (c) 2011 John Wiley & Sons A/S. Abstract: Aim: To determine to what extent current cold ischemia times (CITs) affect the results of

  4. The impact of obesity on physiological responses during prolonged exercise

    NARCIS (Netherlands)

    Eijsvogels, T.M.H.; Veltmeijer, M.T.; Schreuder, T.H.A.; Poelkens, F.; Thijssen, D.H.J.; Hopman, M.T.E.

    2011-01-01

    Background:Prolonged, moderate-intensity exercise training is routinely prescribed to subjects with obesity. In the general population, this type of exercise can lead to fluid and sodium imbalance. However, little is known whether obesity alters the risk of fluid and sodium imbalances.Objective:This

  5. Physiological response of rabbit bucks to prolonged feeding of ...

    African Journals Online (AJOL)

    Sixty-four (64) weanling rabbit bucks, 5 to 6 weeks old, were involved in a 2 x 4 factorial experiment to evaluate the effects of prolonged feeding of cottonseed cake (CSC) – based diets with or without vitamin E supplementation on the physiological response of the bucks. There were eight treatment combinations comprising ...

  6. Single Prolonged Stress Disrupts Retention of Extinguished Fear in Rats

    Science.gov (United States)

    Knox, Dayan; George, Sophie A.; Fitzpatrick, Christopher J.; Rabinak, Christine A.; Maren, Stephen; Liberzon, Israel

    2012-01-01

    Clinical research has linked post-traumatic stress disorder (PTSD) with deficits in fear extinction. However, it is not clear whether these deficits result from stress-related changes in the acquisition or retention of extinction or in the regulation of extinction memories by context, for example. In this study, we used the single prolonged stress…

  7. Internalized stigma in adults with early phase versus prolonged psychosis.

    Science.gov (United States)

    Firmin, Ruth L; Lysaker, Paul H; Luther, Lauren; Yanos, Philip T; Leonhardt, Bethany; Breier, Alan; Vohs, Jenifer L

    2018-03-30

    Although internalized stigma is associated with negative outcomes among those with prolonged psychosis, surprisingly little work has focused on when in the course of one's illness stigma is internalized and the impact of internalization on symptoms or social functioning over the course of the illness. Therefore, this study investigated whether (1) internalized stigma is greater among those later in the course of psychosis and (2) whether internalized stigma has a stronger negative relationship with social functioning or symptoms among those with prolonged compared to early phase psychosis. Individuals with early phase (n = 40) and prolonged psychosis (n = 71) who were receiving outpatient services at an early-intervention clinic and a VA medical center, respectively, completed self-report measures of internalized stigma and interview-rated measures of symptoms and social functioning. Controlling for education, race and sex differences, internalized stigma was significantly greater among those with prolonged psychosis compared to early phase. Internalized stigma was negatively related to social functioning and positively related to symptoms in both groups. Furthermore, the magnitude of the relationship between cognitive symptoms and internalized stigma was significantly greater among those with early phase. Stereotype endorsement, discrimination experiences and social withdrawal also differentially related to symptoms and social functioning across the 2 samples. Findings suggest that internalized stigma is an important variable to incorporate into models of early psychosis. Furthermore, internalized stigma may be a possible treatment target among those with early phase psychosis. © 2018 John Wiley & Sons Australia, Ltd.

  8. Brain activity and fatigue during prolonged exercise in the heat

    DEFF Research Database (Denmark)

    Nielsen, Bodil; Hyldig, Tino; Bidstrup, F.

    2001-01-01

    We hypothesized that fatigue due to hyperthermia during prolonged exercise in the heat is in part related to alterations in frontal cortical brain activity. The electroencephalographic activity (EEG) of the frontal cortex of the brain was measured in seven cyclists [maximal O2 uptake (VO2max) 4...... min of exercise; P

  9. Streptococcus suis meningitis can require a prolonged treatment course

    Directory of Open Access Journals (Sweden)

    Jean Dejace

    2017-12-01

    Full Text Available We report a case of recrudescent Streptococcus suis meningitis requiring a prolonged treatment course. A few similar cases can be found in the burgeoning literature on what remains a relatively uncommon disease in humans, and these patients should be monitored carefully upon completion of therapy. Keywords: Meningitis, Relapse, Duration, Streptococcus suis

  10. Recognition Memory Is Impaired in Children after Prolonged Febrile Seizures

    Science.gov (United States)

    Martinos, Marina M.; Yoong, Michael; Patil, Shekhar; Chin, Richard F. M.; Neville, Brian G.; Scott, Rod C.; de Haan, Michelle

    2012-01-01

    Children with a history of a prolonged febrile seizure show signs of acute hippocampal injury on magnetic resonance imaging. In addition, animal studies have shown that adult rats who suffered febrile seizures during development reveal memory impairments. Together, these lines of evidence suggest that memory impairments related to hippocampal…

  11. Intrinsic motivation and amotivation in first episode and prolonged psychosis.

    Science.gov (United States)

    Luther, Lauren; Lysaker, Paul H; Firmin, Ruth L; Breier, Alan; Vohs, Jenifer L

    2015-12-01

    The deleterious functional implications of motivation deficits in psychosis have generated interest in examining dimensions of the construct. However, there remains a paucity of data regarding whether dimensions of motivation differ over the course of psychosis. Therefore, this study examined two motivation dimensions, trait-like intrinsic motivation, and the negative symptom of amotivation, and tested the impact of illness phase on the 1) levels of these dimensions and 2) relationship between these dimensions. Participants with first episode psychosis (FEP; n=40) and prolonged psychosis (n=66) completed clinician-rated measures of intrinsic motivation and amotivation. Analyses revealed that when controlling for group differences in gender and education, the FEP group had significantly more intrinsic motivation and lower amotivation than the prolonged psychosis group. Moreover, intrinsic motivation was negatively correlated with amotivation in both FEP and prolonged psychosis, but the magnitude of the relationship did not statistically differ between groups. These findings suggest that motivation deficits are more severe later in the course of psychosis and that low intrinsic motivation may be partially independent of amotivation in both first episode and prolonged psychosis. Clinically, these results highlight the importance of targeting motivation in early intervention services. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Prognostic Significance Of QT Interval Prolongation In Adult ...

    African Journals Online (AJOL)

    Prognostic survival studies for heart-rate corrected QT interval in patients with chronic heart failure are few; although these patients are known to have a high risk of sudden cardiac death. This study was aimed at determining the mortality risk associated with prolonged QTc in Nigerians with heart failure. Ninety-six ...

  13. Prolonged multifocal electroretinographic implicit times in the ocular ischemic syndrome

    DEFF Research Database (Denmark)

    Kofoed, Peter Kristian; Munch, Inger Christine; Sander, Birgit

    2010-01-01

    .4 +/- 1.7 mm Hg, respectively. Summed mfERG implicit times (N1, P1, N2) were prolonged in eyes with OIS, by 7.6%, 6.2%, and 7.5%, respectively, compared with fellow eyes (P macula, whereas the assessment of responses from...

  14. Prolongation Structure of Semi-discrete Nonlinear Evolution Equations

    International Nuclear Information System (INIS)

    Bai Yongqiang; Wu Ke; Zhao Weizhong; Guo Hanying

    2007-01-01

    Based on noncommutative differential calculus, we present a theory of prolongation structure for semi-discrete nonlinear evolution equations. As an illustrative example, a semi-discrete model of the nonlinear Schroedinger equation is discussed in terms of this theory and the corresponding Lax pairs are also given.

  15. Inclusion rate and physiological effects of prolonged feeding of ...

    African Journals Online (AJOL)

    The effect of incluusion of cocoa bean cake (CBC) on productive performance and physiological response of Isa Brown pullets to prolonged feeding of CBC were investigated. Dietary Inclusions or CBC (0, 50, 100 and 200g/ kg-1 diet) were monitored in typical poultry diets from day old to 51 weeks of age. Sexual maturity ...

  16. Preferences for Prolonging Life: A Prospect Theory Approach

    Science.gov (United States)

    Winter, Laraine; Lawton, M. Powell; Ruckdeschel, Katy

    2003-01-01

    Kahneman and Tversky's (1979) Prospect theory was tested as a model of preferences for prolonging life under various hypothetical health statuses. A sample of 384 elderly people living in congregate housing (263 healthy, 131 frail) indicated how long (if at all) they would want to live under each of nine hypothetical health conditions (e.g.,…

  17. Identifying Molecular Targets For PTSD Treatment Using Single Prolonged Stress

    Science.gov (United States)

    2014-10-01

    Post - traumatic stress disorder ( PTSD ) is a chronic, debilitating psychiatric disorder that can...SPS animals. Post - traumatic stress disorder ( PTSD ) is associated with neurocognitive impairments that have been attributed to functional deficits...and resilience. 2. KEYWORDS Post - traumatic stress disorder , Single Prolonged Stress , Neurobiological Mechanisms 5 3. ACCOMPLISHMENTS

  18. Effect Of Prolonged Monocular Occlusion On Latent Nystagms

    NARCIS (Netherlands)

    H.J. Simonsz (Huib); G. Kommerell (Guntram)

    1992-01-01

    textabstractThe authors recorded nystagmus during seeing with one eye in eight patients with latent nystagmus (LN) before and after two or three days of prolonged occlusion of the better eye (POBE). Before POBE, the slow-phase speed of the nystagmus (SPS) was usually higher when the better eye was

  19. Effects of strict prolonged bed rest on cardiorespiratory fitness

    DEFF Research Database (Denmark)

    Ried-Larsen, Mathias; Aarts, Hugo M; Joyner, Michael J

    2017-01-01

    The aim of this systematic review and meta-analysis [International Prospective Register of Systematic Reviews (PROSPERO) CRD42017055619] was to assess the effects of strict prolonged bed rest (without countermeasures) on maximal oxygen uptake (V̇o2max) and to explore sources of variation therein....

  20. Innovative Approaches to Neuraxial Blockade in Children: The Introduction of Epidural Nerve Root Stimulation and Ultrasound Guidance for Epidural Catheter Placement

    Directory of Open Access Journals (Sweden)

    Ban CH Tsui

    2006-01-01

    Full Text Available Continuous epidural blockade remains the cornerstone of pediatric regional anesthesia. However, the risk of catastrophic trauma to the spinal cord when inserting direct thoracic and high lumbar epidural needles in anesthetized or heavily sedated pediatric patients is a concern. To reduce this risk, research has focused on low lumbar or caudal blocks (ie, avoiding the spinal cord and threading catheters from distal puncture sites in a cephalad direction. However, with conventional epidural techniques, including loss-of-resistance for localization of the needle, optimal catheter tip placement is difficult to assess because considerable distances are required during threading. Novel approaches include electrical epidural stimulation for physiological confirmation and segmental localization of epidural catheters, and ultrasound guidance for assessing related neuroanatomy and real-time observation of the needle puncture and, potentially, catheter advancement. The present article provides a brief and focused review of these two advances, and outlines recent clinical experiences relevant to pediatric epidural anesthesia.