Rabies vaccine and neuraxial anaesthesia | Rewari | Southern ...

African Journals Online (AJOL)

This case report of neuraxial anaesthesia for emergency orthopaedic surgery serves to highlight the dilemma faced by anaesthetists when surgical intervention becomes necessary in a patient on anti-rabies vaccine. The two issues of importance are the possible reduction in the efficacy of vaccination by an ...

Association of Hospital-level Neuraxial Anesthesia Use for Hip Fracture Surgery with Outcomes: A Population-based Cohort Study.

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McIsaac, Daniel I; Wijeysundera, Duminda N; Huang, Allen; Bryson, Gregory L; van Walraven, Carl

2018-03-01

There is consistent and significant variation in neuraxial anesthesia use for hip fracture surgery across jurisdictions. We measured the association of hospital-level utilization of neuraxial anesthesia, independent of patient-level use, with 30-day survival (primary outcome) and length of stay and costs (secondary outcomes). We conducted a population-based cohort study using linked administrative data in Ontario, Canada. We identified all hip fracture patients more than 65 yr of age from 2002 to 2014. For each patient, we measured the proportion of hip fracture patients at their hospital who received neuraxial anesthesia in the year before their surgery. Multilevel, multivariable regression was used to measure the association of log-transformed hospital-level neuraxial anesthetic-use proportion with outcomes, controlling for patient-level anesthesia type and confounders. Of 107,317 patients, 57,080 (53.2%) had a neuraxial anesthetic; utilization varied from 0 to 100% between hospitals. In total, 9,122 (8.5%) of patients died within 30 days of surgery. Survival independently improved as hospital-level neuraxial use increased (P = 0.009). Primary and sensitivity analyses demonstrated that most of the survival benefit was realized with increase in hospital-level neuraxial use above 20 to 25%; there did not appear to be a substantial increase in survival above this point. No significant associations between hospital neuraxial anesthesia-use and other outcomes existed. Hip fracture surgery patients at hospitals that use more than 20 to 25% neuraxial anesthesia have improved survival independent of patient-level anesthesia type and other confounders. The underlying causal mechanism for this association requires a prospective study to guide improvements in perioperative care and outcomes of hip fracture patients. An online visual overview is available for this article at http://links.lww.com/ALN/B634.

Brief report: a cost analysis of neuraxial anesthesia to facilitate external cephalic version for breech fetal presentation.

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Carvalho, Brendan; Tan, Jonathan M; Macario, Alex; El-Sayed, Yasser Y; Sultan, Pervez

2013-07-01

In this study, we sought to determine whether neuraxial anesthesia to facilitate external cephalic version (ECV) increased delivery costs for breech fetal presentation. Using a computer cost model, which considers possible outcomes and probability uncertainties at the same time, we estimated total expected delivery costs for breech presentation managed by a trial of ECV with and without neuraxial anesthesia. From published studies, the average probability of successful ECV with neuraxial anesthesia was 60% (with individual studies ranging from 44% to 87%) compared with 38% (with individual studies ranging from 31% to 58%) without neuraxial anesthesia. The mean expected total delivery costs, including the cost of attempting/performing ECV with anesthesia, equaled $8931 (2.5th-97.5th percentile prediction interval $8541-$9252). The cost was $9207 (2.5th-97.5th percentile prediction interval $8896-$9419) if ECV was attempted/performed without anesthesia. The expected mean incremental difference between the total cost of delivery that includes ECV with anesthesia and ECV without anesthesia was $-276 (2.5th-97.5th percentile prediction interval $-720 to $112). The total cost of delivery in women with breech presentation may be decreased (up to $720) or increased (up to $112) if ECV is attempted/performed with neuraxial anesthesia compared with ECV without neuraxial anesthesia. Increased ECV success with neuraxial anesthesia and the subsequent reduction in breech cesarean delivery rate offset the costs of providing anesthesia to facilitate ECV.

Neuraxial anesthesia for orthopedic surgery: systematic review and meta-analysis of randomized clinical trials

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Fabiano Timbó Barbosa

Full Text Available CONTEXT AND OBJECTIVE: Taking the outcome of mortality into consideration, there is controversy about the beneficial effects of neuraxial anesthesia for orthopedic surgery. The aim of this study was to compare the effectiveness and safety of neuraxial anesthesia versus general anesthesia for orthopedic surgery. DESIGN AND SETTING: Systematic review at Universidade Federal de Alagoas. METHODS: We searched the Cochrane Central Register of Controlled Trials (Issue 10, 2012, PubMed (1966 to November 2012, Lilacs (1982 to November 2012, SciELO, EMBASE (1974 to November 2012 and reference lists of the studies included. Only randomized controlled trials were included. RESULTS: Out of 5,032 titles and abstracts, 17 studies were included. There were no statistically significant differences in mortality (risk difference, RD: -0.01; 95% confidence interval, CI: -0.04 to 0.01; n = 1903, stroke (RD: 0.02; 95% CI: -0.04 to 0.08; n = 259, myocardial infarction (RD: -0.01; 95% CI: -0.04 to 0.02; n = 291, length of hospitalization (mean difference, -0.05; 95% CI: -0.69 to 0.58; n = 870, postoperative cognitive dysfunction (RD: 0.00; 95% CI: -0.04 to 0.05; n = 479 or pneumonia (odds ratio, 0.61; 95% CI: 0.25 to 1.49; n = 167. CONCLUSION: So far, the evidence available from the studies included is insufficient to prove that neuraxial anesthesia is more effective and safer than general anesthesia for orthopedic surgery. However, this systematic review does not rule out clinically important differences with regard to mortality, stroke, myocardial infarction, length of hospitalization, postoperative cognitive dysfunction or pneumonia.

Optimal anaesthesia techniques for penile surgeries

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Yu. A. Myagkov

2016-01-01

Full Text Available Spinal anaesthesia as a method of central neuraxial blockade is the best choice for penile surgeries due to the following reasons: protection against intraoperative stress and early postoperative pain, simplicity of the procedure which does not depend on constitutional and anatomical features of a patient, prevention of postoperative complications.

Caudal anesthesia in a patient with peritonitis: Is it safe??

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H Kako

2016-01-01

Full Text Available Neuraxial anesthesia combined with general anesthesia has become a widely accepted method of providing effective postoperative analgesia and decreasing intraoperative anesthetic needs in the pediatric population. In clinical practice, there still appears to be hesitancy for the use of a neuraxial technique (spinal or epidural in patients at risk for bacteremia or with an on-going systemic infection. However, evidence-based medicine lacks any data to support an increase in the risk of infectious complications following neuraxial anesthesia. We present two pediatric patients with intra-abdominal infectious processes who received caudal epidural blockade for postoperative operative analgesia. The use of neuraxial techniques in patients at risk for bacteremia is reviewed, evidence-based medicine regarding the risks of infection discussed, and the potential favorable effects of neuraxial blockade on the neurohumoral response to sepsis and the systemic inflammatory responses presented.

Neuraxial analgesia effects on labor progression: facts, fallacies, uncertainties, and the future

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Grant, Erica N.; Tao, Weike; Craig, Margaret; McIntire, Donald; Leveno, Kenneth

2014-01-01

Approximately 60% of women who labor receive some form of neuraxial analgesia, but concerns have been raised regarding whether it negatively impacts the labor and delivery process. In this review, we attempt to clarify what has been established as truths, falsities, and uncertainties regarding the effects of this form of pain relief on labor progression, negative and/or positive. Additionally, although the term “epidural” has become synonymous with neuraxial analgesia, we discuss two other techniques, combined spinal-epidural and continuous spinal analgesia, that are gaining popularity, as well as their effects on labor progression. PMID:25088476

Lessons learned from a single institution's retrospective analysis of emergent cesarean delivery following external cephalic version with and without neuraxial anesthesia.

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Ainsworth, A; Sviggum, H P; Tolcher, M C; Weaver, A L; Holman, M A; Arendt, K W

2017-05-01

To evaluate the risk of emergent cesarean delivery with the use of neuraxial anesthesia for external cephalic version in a single practice. Randomized trials have shown increased external cephalic version success when neuraxial anesthesia is used, without additional risk. We hypothesized that in our actual clinical practice, outside the confines of randomized trials, neuraxial anesthesia could be associated with an increased risk of emergent cesarean delivery. This retrospective cohort study included all women who underwent external cephalic version at a single institution with and without neuraxial anesthesia. The primary outcome was the incidence of emergent cesarean delivery (defined as delivery within 4hours of version). Secondary outcomes were version success and ultimate mode of delivery. A total of 135 women underwent external cephalic version procedures; 58 with neuraxial anesthesia (43.0%) and 77 without (57.0%). Location of the procedure, tocolytic therapy, and gestational age were different between groups. An increased rate of emergent cesarean delivery was found in procedures with neuraxial anesthesia compared to procedures without (5/58 (8.6%) compared to 0/77 (0.0%); 95% CI for difference, 1.4 to 15.8%; P=0.013). In this single hospital's practice, patients who may be at higher risk of complications and have a lesser likelihood of success were provided NA for ECV. As a result, the use of neuraxial anesthesia for external cephalic version was associated with a higher rate of emergent cesarean delivery. Obstetric and anesthetic practices should evaluate their patient selection and procedure protocol for external cephalic version under neuraxial anesthesia. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

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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.

Blockade of central nicotine acetylcholine receptor signaling attenuate ghrelin-induced food intake in rodents.

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Dickson, S L; Hrabovszky, E; Hansson, C; Jerlhag, E; Alvarez-Crespo, M; Skibicka, K P; Molnar, C S; Liposits, Z; Engel, J A; Egecioglu, E

2010-12-29

Here we sought to determine whether ghrelin's central effects on food intake can be interrupted by nicotine acetylcholine receptor (nAChR) blockade. Ghrelin regulates mesolimbic dopamine neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens, partly via cholinergic VTA afferents originating in the laterodorsal tegmental area (LDTg). Given that these cholinergic projections to the VTA have been implicated in natural as well as drug-induced reinforcement, we sought to investigate the role of cholinergic signaling in ghrelin-induced food intake as well as fasting-induced food intake, for which endogenous ghrelin has been implicated. We found that i.p. treatment with the non-selective centrally active nAChR antagonist, mecamylamine decreased fasting-induced food intake in both mice and rats. Moreover, central administration of mecamylamine decreased fasting-induced food intake in rats. I.c.v. ghrelin-induced food intake was suppressed by mecamylamine i.p. but not by hexamethonium i.p., a peripheral nAChR antagonist. Furthermore, mecamylamine i.p. blocked food intake following ghrelin injection into the VTA. Expression of the ghrelin receptor, the growth hormone secretagogue receptor 1A, was found to co-localize with choline acetyltransferase, a marker of cholinergic neurons, in the LDTg. Finally, mecamylamine treatment i.p. decreased the ability of palatable food to condition a place preference. These data suggest that ghrelin-induced food intake is partly mediated via nAChRs and that nicotinic blockade decreases the rewarding properties of food. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

The use of lumbar X-rays to facilitate neuraxial anaesthesia during ...

African Journals Online (AJOL)

The use of lumbar X-rays to facilitate neuraxial anaesthesia during knee replacement surgery in patients who have had previous spinal surgery. ... The study group comprised 100 patients, scheduled for knee replacement surgery. ... Only four of a total of 23 combined spinal epidural procedures were not successful.

Peripheral nerve blocks as the sole anesthetic technique in a patient with severe Duchenne muscular dystrophy.

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Bang, Seung Uk; Kim, Yee Suk; Kwon, Woo Jin; Lee, Sang Mook; Kim, Soo Hyang

2016-04-01

General anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are associated with high risks of complications, including rhabdomyolysis, malignant hyperthermia, hemodynamic instability, and postoperative mechanical ventilation. Here, we describe peripheral nerve blocks as a safe approach to anesthesia in a patient with severe Duchenne muscular dystrophy who was scheduled to undergo surgery. A 22-year-old male patient was scheduled to undergo reduction and internal fixation of a left distal femur fracture. He had been diagnosed with Duchenne muscular dystrophy at 5 years of age, and had no locomotive capability except for that of the finger flexors and toe extensors. He had developed symptoms associated with dyspnea 5 years before and required intermittent ventilation. We blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus under ultrasound on the left leg. The patient underwent a successful operation using peripheral nerve blocks with no complications. In conclusion general anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are unsafe approaches to anesthesia because of hemodynamic instability and respiratory depression. Peripheral nerve blocks are the best way to reduce the risks of critical complications, and are a safe and feasible approach to anesthesia in patients with severe Duchenne muscular dystrophy.

Evaluation of two different dosages of local anesthetic solution used for ultrasound-guided femoral nerve block for pain relief and positioning for central neuraxial block in patients of fracture neck of the femur

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Abhijit A Karmarkar

2017-01-01

Full Text Available Introduction: Surgical management of the fracture femur is preferred so as to prevent complications associated with prolonged immobilization. Central neuraxial blockade (CNB is an attractive option for these patients, and an optimal positioning of the patient is a definite requirement. Owing to the pain associated with movement of the fractured limb, it becomes difficult for the patients to give suitable positioning. Femoral nerve block (FNB features as a rescue analgesia so as to provide adequate analgesia for facilitation of satisfactory positioning. Aim: This study aims to compare analgesic effect of two different dosages of local anesthetic (LA solution administered for ultrasonography (USG-guided FNB given to facilitate optimal positioning for conduct of CNB. Materials and Methods: After taking permission from the institutional review board, eighty patients were enrolled in the study to find out the efficacy of dosage of LA solution for FNB in providing pain relief caused by movement of fractured limb during conduct of regional anesthesia. Informed consent was taken. All patients were given USG-guided FNB. Patients were randomized using a computer-generated random number table, into two groups of forty patients each. Group A patients received USG-guided 12 ml of LA solution containing 10 ml lignocaine solution without preservative (2% plus 2 ml normal saline (NS, while Group B patients received USG-guided 15 ml of LA solution containing 13 ml lignocaine solution without preservative (2% plus 2 ml NS for positioning before combined spinal epidural. Results: A total of eighty patients, divided randomly into two groups, were enrolled in the study. Demographics (age, sex, weight, and American Society of Anesthesiologists grades were similar in both groups. No statistical significance was found in the numeric rating scale scores at baseline, zero minutes, 5, and 15 min in both the groups. Conclusion: USG-guided FNB with 12 ml of LA solution was

The Use of Neuraxial Catheters for Postoperative Analgesia in Neonates: A Multicenter Safety Analysis from the Pediatric Regional Anesthesia Network.

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Long, Justin B; Joselyn, Anita S; Bhalla, Tarun; Tobias, Joseph D; De Oliveira, Gildasio S; Suresh, Santhanam

2016-06-01

Currently, there is limited evidence to support the safety of neuraxial catheters in neonates. Safety concerns have been cited as a major barrier to performing large randomized trials in this population. The main objective of this study is to examine the safety of neuraxial catheters in neonates across multiple institutions. Specifically, we sought to determine the incidence of overall and individual complications encountered when neuraxial catheters were used for postoperative analgesia in neonates. This was an observational study that used the Pediatric Regional Anesthesia Network database. Complications and adverse events were defined by the presence of at least 1 of the following intraoperative and/or postoperative factors: catheter malfunction (dislodgment/occlusion), infection, block abandoned (unable to place), block failure (no evidence of block), vascular (blood aspiration/hematoma), local anesthetic systemic toxicity, excessive motor block, paresthesia, persistent neurologic deficit, and other (e.g., intra-abdominal misplacement, tremors). Additional analyses were performed to identify the use of potentially toxic doses of local anesthetics. The study cohort included 307 neonates with a neuraxial catheter. There were 41 adverse events and complications recorded, resulting in an overall incidence of complications of 13.3% (95% confidence interval, 9.8%-17.4%). Among the complications, catheter malfunction, catheter contamination, and vascular puncture were common. None of the complications resulted in long-term complications and/or sequelae, resulting in an estimated incidence of any serious complications of 0.3% (95% confidence interval, 0.08%-1.8%). There were 120 of 307 patients who received intraoperative and/or postoperative infusions consistent with a potentially toxic local anesthetic dose in neonates. The incidence of potentially toxic local anesthetic infusion rates increased over time (P = 0.008). Neuraxial catheter techniques for intraoperative

Major complications of central neuraxial block: report on the Third National Audit Project of the Royal College of Anaesthetists.

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Cook, T M; Counsell, D; Wildsmith, J A W

2009-02-01

Serious complications of central neuraxial block (CNB) are rare. Limited information on their incidence and impact impedes clinical decision-making and patient consent. The Royal College of Anaesthetists Third National Audit Project was designed to inform this situation. A 2 week national census estimated the number of CNB procedures performed annually in the UK National Health Service. All major complications of CNBs performed over 1 yr (vertebral canal abscess or haematoma, meningitis, nerve injury, spinal cord ischaemia, fatal cardiovascular collapse, and wrong route errors) were reported. Each case was reviewed by an expert panel to assess causation, severity, and outcome. 'Permanent' injury was defined as symptoms persisting for more than 6 months. Efforts were made to validate denominator (procedures performed) and numerator (complications) data through national databases. The census phase produced a denominator of 707,455 CNB. Eighty-four major complications were reported, of which 52 met the inclusion criteria at the time they were reported. Data were interpreted 'pessimistically' and 'optimistically'. 'Pessimistically' there were 30 permanent injuries and 'optimistically' 14. The incidence of permanent injury due to CNB (expressed per 100,000 cases) was 'pessimistically' 4.2 (95% confidence interval 2.9-6.1) and 'optimistically' 2.0 (1.1-3.3). 'Pessimistically' there were 13 deaths or paraplegias, 'optimistically' five. The incidence of paraplegia or death was 'pessimistically' 1.8 per 100,000 (1.0-3.1) and 'optimistically' 0.7 (0-1.6). Two-thirds of initially disabling injuries resolved fully. The data are reassuring and suggest that CNB has a low incidence of major complications, many of which resolve within 6 months.

A randomised controlled trial comparing the effect of adjuvant ...

African Journals Online (AJOL)

Background: Intrathecal adjuvants are added to local anaesthetics to improve the quality of neuraxial blockade and prolong the duration of analgesia during spinal anaesthesia. Used intrathecally, fentanyl improves the quality of spinal blockade as compared to plain bupivacaine and confers a short duration of post ...

Neuraxial Analgesia In Neonates And Infants: Review of Clinical and Preclinical Strategies for the Development of Safety and Efficacy Data

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Walker, Suellen M.; Yaksh, Tony L.

2015-01-01

Neuraxial agents provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improve analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by addition of clonidine, ketamine, neostigmine or tramadol to single shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side-effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, the second half of this review presents preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial agents with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation prior to adoption of new analgesics or preparations into routine clinical practice. PMID:22798528

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.

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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.

Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data.

Science.gov (United States)

Walker, Suellen M; Yaksh, Tony L

2012-09-01

Neuraxial drugs provide robust pain control, have the potential to improve outcomes, and are an important component of the perioperative care of children. Opioids or clonidine improves analgesia when added to perioperative epidural infusions; analgesia is significantly prolonged by the addition of clonidine, ketamine, neostigmine, or tramadol to single-shot caudal injections of local anesthetic; and neonatal intrathecal anesthesia/analgesia is increasing in some centers. However, it is difficult to determine the relative risk-benefit of different techniques and drugs without detailed and sensitive data related to analgesia requirements, side effects, and follow-up. Current data related to benefits and complications in neonates and infants are summarized, but variability in current neuraxial drug use reflects the relative lack of high-quality evidence. Recent preclinical reports of adverse effects of general anesthetics on the developing brain have increased awareness of the potential benefit of neuraxial anesthesia/analgesia to avoid or reduce general anesthetic dose requirements. However, the developing spinal cord is also vulnerable to drug-related toxicity, and although there are well-established preclinical models and criteria for assessing spinal cord toxicity in adult animals, until recently there had been no systematic evaluation during early life. Therefore, in the second half of this review, we present preclinical data evaluating age-dependent changes in the pharmacodynamic response to different spinal analgesics, and recent studies evaluating spinal toxicity in specific developmental models. Finally, we advocate use of neuraxial drugs with the widest demonstrable safety margin and suggest minimum standards for preclinical evaluation before adoption of new analgesics or preparations into routine clinical practice.

Review article: clinical implications of enteric and central D2 receptor blockade by antidopaminergic gastrointestinal prokinetics.

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Tonini, M; Cipollina, L; Poluzzi, E; Crema, F; Corazza, G R; De Ponti, F

2004-02-15

Antidopaminergic gastrointestinal prokinetics (bromopride, clebopride, domperidone, levosulpiride and metoclopramide) have been exploited clinically for the management of motor disorders of the upper gastrointestinal tract, including functional dyspepsia, gastric stasis of various origins and emesis. The prokinetic effect of these drugs is mediated through the blockade of enteric (neuronal and muscular) inhibitory D2 receptors. The pharmacological profiles of the marketed compounds differ in terms of their molecular structure, affinity at D2 receptors, ability to interact with other receptor systems [5-hydroxytryptamine-3 (5-HT3) and 5-HT4 receptors for metoclopramide; 5-HT4 receptors for levosulpiride) and ability to permeate the blood-brain barrier (compared with the other compounds, domperidone does not easily cross the barrier). It has been suggested that the serotonergic (5-HT4) component of some antidopaminergic prokinetics may enhance their therapeutic efficacy in gastrointestinal disorders, such as functional dyspepsia and diabetic gastroparesis. The antagonism of central D2 receptors may lead to both therapeutic (e.g. anti-emetic effect due to D2 receptor blockade in the area postrema) and adverse (including hyperprolactinaemia and extrapyramidal dystonic reactions) effects. As the pituitary (as well as the area postrema) is outside the blood-brain barrier, hyperprolactinaemia is a side-effect occurring with all antidopaminergic prokinetics, although to different extents. Extrapyramidal reactions are most commonly observed with compounds crossing the blood-brain barrier, although with some differences amongst the various agents. Prokinetics with a high dissociation constant compared with that of dopamine at the D2 receptor (i.e. compounds that bind loosely to D2 receptors in the nigrostriatal pathway) elicit fewer extrapyramidal signs and symptoms. A knowledge of central and peripheral D2 receptor pharmacology can help the clinician to choose between the

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....

Risk of Epidural Hematoma after Neuraxial Techniques in Thrombocytopenic Parturients : A Report from the Multicenter Perioperative Outcomes Group

NARCIS (Netherlands)

Lee, Linden O.; Bateman, Brian T.; Kheterpal, Sachin; Klumpner, Thomas T.; Housey, Michelle; Aziz, Michael F.; Hand, Karen W.; MacEachern, Mark; Goodier, Christopher G.; Bernstein, Jeffrey; Bauer, Melissa E.; Lirk, Philip; Wilczak, Janet; Soto, Roy; Tom, Simon; Cuff, Germaine; Biggs, Daniel A.; Coffman, Traci; Saager, Leif; Levy, Warren J.; Godbold, Michael; Pace, Nathan L.; Wethington, Kevin L.; Paganelli, William C.; Durieux, Marcel E.; Domino, Karen B.; Nair, Bala; Ehrenfeld, Jesse M.; Wanderer, Jonathan P.; Schonberger, Robert B.; Berris, Joshua; Lins, Steven; Coles, Peter; Cummings, Kenneth C.; Maheshwari, Kamal; Berman, Mitchell F.; Wedeven, Christopher; LaGorio, John; Fleishut, Peter M.; Ellis, Terri A.; Molina, Susan; Carl, Curtis; Kadry, Bassam; van Klei, Wilton A A; Pasma, Wietze; Jameson, Leslie C.; Helsten, Daniel L.; Avidan, Michael S.

BACKGROUND:: Thrombocytopenia has been considered a relative or even absolute contraindication to neuraxial techniques due to the risk of epidural hematoma. There is limited literature to estimate the risk of epidural hematoma in thrombocytopenic parturients. The authors reviewed a large

Neuraxial analgesia to increase the success rate of external cephalic version: a systematic review and meta-analysis of randomized controlled trials.

Science.gov (United States)

Magro-Malosso, Elena Rita; Saccone, Gabriele; Di Tommaso, Mariarosaria; Mele, Michele; Berghella, Vincenzo

2016-09-01

External cephalic version is a medical procedure in which the fetus is externally manipulated to assume the cephalic presentation. The use of neuraxial analgesia for facilitating the version has been evaluated in several randomized clinical trials, but its potential effects are still controversial. The objective of the study was to evaluate the effectiveness of neuraxial analgesia as an intervention to increase the success rate of external cephalic version. Searches were performed in electronic databases with the use of a combination of text words related to external cephalic version and neuraxial analgesia from the inception of each database to January 2016. We included all randomized clinical trials of women, with a gestational age ≥36 weeks and breech or transverse fetal presentation, undergoing external cephalic version who were randomized to neuraxial analgesia, including spinal, epidural, or combined spinal-epidural techniques (ie, intervention group) or to a control group (either intravenous analgesia or no treatment). The primary outcome was the successful external cephalic version. The summary measures were reported as relative risk or as mean differences with a 95% confidence interval. Nine randomized clinical trials (934 women) were included in this review. Women who received neuraxial analgesia had a significantly higher incidence of successful external cephalic version (58.4% vs 43.1%; relative risk, 1.44, 95% confidence interval, 1.27-1.64), cephalic presentation in labor (55.1% vs 40.2%; relative risk, 1.37, 95% confidence interval, 1.08-1.73), and vaginal delivery (54.0% vs 44.6%; relative risk, 1.21, 95% confidence interval, 1.04-1.41) compared with those who did not. Women who were randomized to the intervention group also had a significantly lower incidence of cesarean delivery (46.0% vs 55.3%; relative risk, 0.83, 95% confidence interval, 0.71-0.97), maternal discomfort (1.2% vs 9.3%; relative risk, 0.12, 95% confidence interval, 0

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.

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.

Kinetic considerations in the choice of treatment schedules for neuraxis radiotherapy

International Nuclear Information System (INIS)

Wheldon, T.E.

1993-01-01

Neuraxis radiotherapy of radiosensitive tumours such as medulloblastoma is usually carried out using conventionally sized fractions and a shrinking field technique. Plowman and Doughty (Br.J.Radiol., 64 (1991) 603-607) have proposed a partial transmission block (PTB) technique which entails the use of small daily doses over a conventional time period. Radiobiological analysis suggests that, although the PTB technique may be adequate for slowly growing tumours, therapeutic efficacy is likely to be compromised where the tumour doubling time is short. Accelerated hyperfractionation (twice daily fractions) provides a possible alternative to both conventional scheduling and the PTB technique. Direct measurement of the kinetics of tumour cells in CSF, where possible, may provide useful guidance in the choice of regimes. (author)

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

Successful Ultrasound-Guided Femoral Nerve Blockade and Catheterization in a Patient with Von Willebrand Disease

Directory of Open Access Journals (Sweden)

Youmna E. DiStefano

2015-01-01

Full Text Available Peripheral nerve blockade (PNB is superior to neuraxial anesthesia and/or opioid therapy for perioperative analgesia in total knee replacement (TKR. Evidence on the safety of PNB in patients with coagulopathy is lacking. We describe the first documented account of continuous femoral PNB for perioperative analgesia in a patient with Von Willebrand Disease (vWD. Given her history of opioid tolerance and after an informative discussion, a continuous femoral PNB was planned for in this 34-year-old female undergoing TKR. A Humate-P intravenous infusion was started and the patient was positioned supinely. Using sterile technique with ultrasound guidance, a Contiplex 18 Gauge Tuohy needle was advanced in plane through the fascia iliaca towards the femoral nerve. A nerve catheter was threaded through the needle and secured without complications. Postoperatively, a levobupivacaine femoral catheter infusion was maintained, and twice daily Humate-P intravenous infusions were administered for 48 hours; enoxaparin thromboprophylaxis was initiated thereafter. The patient was discharged uneventfully on postoperative day 4. Given documentation of delayed, unheralded bleeding from PNB in coagulopathic patients, we recommend individualized PNB in vWD patients. Multidisciplinary team involvement is required to guide factor supplementation and thromboprophylaxis, as is close follow-up to elicit signs of bleeding throughout the delayed postoperative period.

RANDOMISED CONTROLLED STUDY COMPARING A 0.75% ROPIVACAINE TO A CONVENTIONAL DOSE OF HYPERBARIC BUPIVACAINE FOR CESARIAN SECTION BY EPIDURAL ANALGESIA

Directory of Open Access Journals (Sweden)

Porika

2015-09-01

Full Text Available Central neuraxial blocked is one of the safest and efficacious methods of anaesthesia and analgesia. It has the added advantage of prolonged pain relief into the postoperative period. Epidural analgesia has increased steadily in popularity when compared to spinal anaesthes ia due to its neurological consequences and improved post - operative analgesia with epidural Opioids and as a consequence decreased side effects and prolonged the duration of analgesia. Present study is undertaken to compare hemodynamic and analgesic charac teristics using a 0.75% ropivacaine to a conventional dose of 0.5% bupivacaine for cesarean section under epidural anaesthesia. This study was conducted in ASA Grade I 50 singleton parturient to compare hemodynamics, APGAR scores and analgesic characterist ics of ropivacaine and bupivacaine. We have observed that the onset of sensory blockade was slower with ropivacaine and the duration of sensory blockade was also less. Whereas there was no significant change in haemodynamics and APGAR scores with both the drugs.

Accidental deposition of local anaesthetic in the subdural space ...

African Journals Online (AJOL)

The incidence of accidental injection of local anaesthetic into the subdural space during neuraxial blockade is rare. The presentation of unexplainable clinical signs that do not match the clinical picture of subarachnoid or intravascular injection of the local anaesthetic agent should invoke high suspicion of unintentional ...

Sectio og Brugadas syndrom

DEFF Research Database (Denmark)

Ammundsen, Henriette Berg; Ekelund, Kim; Afshari, Arash

2016-01-01

to induce fatal arrhythmias in patients with BS and in particular sodium channel blockers i.e. local anaesthetics such as bupivacaine. We report the anaesthetic management of two women with BS during caesarean section and provide a general discussion on the use of bupivacain for neuraxial blockade...

Anesthetic management for Cesarean delivery in parturients with a diagnosis of dwarfism.

Science.gov (United States)

Lange, Elizabeth M S; Toledo, Paloma; Stariha, Jillian; Nixon, Heather C

2016-08-01

The literature on the anesthetic management of parturients with dwarfism is sparse and limited to isolated case reports. Pregnancy complications associated with dwarfism include an increased risk of respiratory compromise, an increased risk of Cesarean delivery, and an unpredictable degree of anesthesia with neuraxial techniques. Therefore, we conducted this retrospective review to evaluate the anesthetic management of parturients with a diagnosis of dwarfism. We used a query of billing data to identify short statured women who underwent a Cesarean delivery during May 1, 2008 to May 1, 2013. We then hand searched the electronic medical record for qualifying patients with heights diagnosis of dwarfism. The extracted data included patient demographics and obstetric and anesthetic information. We identified 13 women with dwarfism who had 15 Cesarean deliveries in total. Twelve of the women had disproportionate dwarfism, and ten of the 15 Cesarean deliveries were due to cephalopelvic disproportion. Neuraxial anesthesia was attempted in 93% of deliveries. The dose chosen for initiation of neuraxial anesthesia was lower than the typical doses used in parturients of normal stature. Neuraxial anesthetic complications included difficult neuraxial placement (64%), high spinal (7%), inadequate surgical level (13%), and unrecognized intrathecal catheter (7%). The data collected suggest that females with a diagnosis of dwarfism may have difficult neuraxial placement and potentially require lower dosages of local anesthetic for both spinal and epidural anesthesia to achieve adequate surgical blockade.

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.

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

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

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

Durability of central aortic valve closure in patients with continuous flow left ventricular assist devices.

Science.gov (United States)

McKellar, Stephen H; Deo, Salil; Daly, Richard C; Durham, Lucian A; Joyce, Lyle D; Stulak, John M; Park, Soon J

2014-01-01

A competent aortic valve is essential to providing effective left ventricular assist device support. We have adopted a practice of central aortic valve closure by placing a simple coaptation stitch at left ventricular assist device implantation in patients with significant aortic insufficiency. We conducted a follow-up study to evaluate the efficacy and durability of this procedure. The study included patients who had undergone continuous flow left ventricular assist device implantation. The patients were divided into 2 groups, those who did not require any aortic procedure because the valve was competent and those who underwent central aortic valve closure for mild or greater aortic regurgitation. The clinical endpoints were mortality, progression or recurrence of aortic insufficiency, and reoperation for aortic valve pathologic features. Aortic insufficiency was measured qualitatively from mild to severe on a scale of 0 to 5. A total of 123 patients received continuous flow left ventricular assist devices from February 2007 to August 2011. Of those, 18 (15%) underwent central aortic valve closure at left ventricular assist device implantation because of significant aortic insufficiency (1.8 ± 1.4) and 105 who did not (competent aortic valve, 0.15 ± 0.43; P assist device-supported patients, with follow-up extending into 2 years. Although aortic insufficiency progressed over time in those with minimal native valve regurgitation initially, no such progression was noted in those with central aortic valve closure. Additional investigation is needed to evaluate whether prophylactic central aortic valve closure should be performed at left ventricular assist device implantation to avoid problematic aortic regurgitation developing over time, in particular in patients undergoing left ventricular assist device implantation for life-long (destination therapy) support. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights

Paraplegia following epidural analgesia: A potentially avoidable cause?

Directory of Open Access Journals (Sweden)

Jeson R Doctor

2014-01-01

Full Text Available Neurological deficit is an uncommon but catastrophic complication of epidural anesthesia. Epidural hematomas and abscesses are the most common causes of such neurological deficit. We report the case of a patient with renal cell carcinoma with lumbar vertebral metastasis who developed paraplegia after receiving thoracic epidural anesthesia for a nephrectomy. Subsequently, on histo-pathological examination of the laminectomy specimen, the patient was found to have previously undiagnosed thoracic vertebral metastases which led to a thoracic epidural hematoma. In addition, delayed reporting of symptoms of neurological deficit by the patient may have impacted his outcome. Careful pre-operative investigation, consideration to using alternative modalities of analgesia, detailed patient counseling and stringent monitoring of patients receiving central neuraxial blockade is essential to prevent such complications.

Neuraxial anesthesia improves long-term survival after total joint replacement: a retrospective nationwide population-based study in Taiwan.

Science.gov (United States)

Chen, Wei-Hung; Hung, Kuo-Chuan; Tan, Ping-Heng; Shi, Hon-Yi

2015-04-01

This study explored the effects of general (GA) and neuraxial (NA) anesthesia on the outcomes of primary total joint replacement (TJR) in terms of postoperative mortality, length of stay (LOS), and hospital treatment costs. From 1997 to 2010, this nationwide population-based study retrospectively evaluated 7,977 patients in Taiwan who underwent primary total hip or knee replacement. We generated two propensity-score-matched subgroups, each containing an equal number of patients who underwent TJR with either GA or NA. Of the 7,977 patients, 2,990 (37.5%) underwent GA and 4,987 (62.5%) underwent NA. Propensity-score matching was used to create comparable GA and NA groups adjusted for age, sex, comorbidities, surgery type, hospital volume, and surgeon volume. Survival over the first three years following surgery was similar. The proportion of patients alive up to 14 years postoperatively for those undergoing NA was 58.2% (95% confidence interval [CI] 50.4 to 66.0), and for those undergoing GA it was 57.3% (95% CI 51.4 to 63.2). Neuraxial anesthesia was associated with lower median [interquartile range; IQR] hospital treatment cost ($4,079 [3,805-4,444] vs $4,113 [3,812-4,568]; P anesthesia costs are removed. The mechanism underlying the association between NA and long-term survival is unknown.

Comparative study of peripherally inserted central venous catheter and traditional central catheter assisted with X-ray

International Nuclear Information System (INIS)

Yu Jianchun; Wang Xiurong; Jiang Zhuming

1999-01-01

Objective: To study the feasibility, complications, mid- and long-term advantages of peripherally inserted central catheters (PICC) compared with central venous access assisted with X-ray. Methods: From Jan 1997 to Dec 1998, the authors conducted a study in 60 patients with placed PICC lines and 60 patients with central lines. Study variables included tip placement and complication rates. Results: Tere were on significant differences between PICC and CVC in the successful placement 95.0% and 88.3%, t = 1.745, P 0.19; the mean duration 13(6-98) days and 14 (7-104) days, F = 0.049, P = 0.83; the total occlusion rate 6.7% (4/60) and 5.0%(3/60), t = 0.152, P = 0.70. In PICC patients, the occlusion rate was slightly higher in 3 Fr (20-gauge) catheter (3/20, 15.0%) than in 4 Fr(18-gauge) catheters (1/20, 5.0%), t = 1.111, P=0.29. Phlebitis occurred in 5.0% of patients (3/60) and one catheter fracture was happened on the catheter hub junction (1.7%). In 3 catheter tips dislocation cases, the catheter tips were moved to the optional position assisted with X-ray image. In CVC group, pneumothorax happened in 1 case (1.7%). In 4 catheter dislocation cases, the catheters were with drawn. No catheter-related sepsis and hemo-pneumothorax happened in both group patients. Conclusions: Both PICC and CVC can be acceptable in clinical use. PICC assisted with X-ray possesses the advantages of less trauma, accurate localization preventing some possible severe complications of central venous access such as pneumothorax. The new method provides a reliable, effective venous access for mid-and long-term usage in patients receiving a variety of solutions, primarily parenteral alimentation, chemotherapy or antibiotic infusion

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.

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.

Neuromuscular blockade in cardiac surgery: An update for clinicians

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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.

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.

Revision of loop colostomy under regional anaesthesia and sedation.

Science.gov (United States)

Ng, Oriana; Thong, Sze Ying; Chia, Claramae Shulyn; Teo, Melissa Ching Ching

2015-05-01

Patients presenting for emergency abdominal procedures often have medical issues that cause both general anaesthesia and central neuraxial blockade to pose significant risks. Regional anaesthetic techniques are often used adjunctively for abdominal procedures under general anaesthesia, but there is limited published data on procedures done under peripheral nerve or plexus blocks. We herein report the case of a patient with recent pulmonary embolism and supraventricular tachycardia who required colostomy refashioning. Ultrasonography-guided regional anaesthesia was administered using a combination of ilioinguinal-iliohypogastric, rectus sheath and transversus abdominis plane blocks. This was supplemented with propofol and dexmedetomidine sedation as well as intermittent fentanyl and ketamine boluses to cover for visceral stimulation. We discuss the anatomical rationale for the choice of blocks and compare the anaesthetic conduct with similar cases that were previously reported.

Neuraxial blocks and spinal haematoma: Review of 166 case reports published 1994-2015. Part 1: Demographics and risk-factors.

Science.gov (United States)

Lagerkranser, Michael

2017-04-01

Bleeding into the vertebral canal causing a spinal haematoma (SH) is a rare but serious complication to central neuraxial blocks (CNB). Of all serious complications to CNBs such as meningitis, abscess, cardiovascular collapse, and nerve injury, neurological injury associated with SH has the worst prognosis for permanent harm. Around the turn of the millennium, the first guidelines were published that aimed to reduce the risk of this complication. These guidelines are based on known risk factors for SH, rather than evidence from randomised, controlled trials (RCTs). RCTs, and therefore meta-analysis of RCTs, are not appropriate for identifying rare events. Analysing published case reports of rare complications may at least reveal risk factors and can thereby improve management of CNBs. The aims of the present review were to analyse case reports of SH after CNBs published between 1994 and 2015, and compare these with previous reviews of case reports. MEDLINE and EMBASE were used for identifying case reports published in English, German, or Scandinavian languages, using appropriate search terms. Reference lists were also scrutinised for case reports. Twenty different variables from each case were specifically searched for and filled out on an Excel spreadsheet, and incidences were calculated using the number of informative reports as denominator for each variable. Altogether 166 case reports on spinal haematoma after CNB published during the years between 1994 and 2015 were collected. The annual number of case reports published during this period almost trebled compared with the two preceding decades. This trend continued even after the first guidelines on safe practice of CNBs appeared around year 2000, although more cases complied with such guidelines during the second half of the observation period (2005-2015) than during the first half. Three types of risk factors dominated: (1) Patient-related risk factors such as haemostatic and spinal disorders, (2) CNB

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...

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...

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

Decentralization and centralization: governing the activation of social assistance recipients in Europe

NARCIS (Netherlands)

Minas, R.; Wright, S.; van Berkel, H.H.A.

2012-01-01

Purpose – The purpose of this article is to examine the governance of activation in relation to the decentralization and centralization of activation for social assistance recipients in Sweden, The Netherlands and the UK. Design/methodology/approach – This paper outlines broad trends in the

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.

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...

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.

Environmental policy and the role of foreign assistance in Central- and Eastern Europe

DEFF Research Database (Denmark)

During the 1990's, a large number of international donors and financing institutions have been active in providing financial support for improving the environment in Central and Eastern Europe. One of these actors have been the Danish Government and its Environmental Support Fund for Central...... policy in their own country and to provide an assessment of the role that foreign assistance has played and could play. Covers the following countries: Czech Republic; Poland; Romania; Russia; Slovakia; Ukraine....

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 

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.

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

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.

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.

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...

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.

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

78 FR 54947 - Waiver of Restriction on Assistance to the Central Government of Afghanistan

Science.gov (United States)

2013-09-06

... DEPARTMENT OF STATE [Public Notice 8452] Waiver of Restriction on Assistance to the Central Government of Afghanistan Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... prior year Acts with respect to Afghanistan and I hereby waive this restriction. This determination and...

76 FR 36167 - Waiver of Restriction on Assistance to the Central Government of Afghanistan

Science.gov (United States)

2011-06-21

... DEPARTMENT OF STATE [Public Notice: 7506] Waiver of Restriction on Assistance to the Central Government of Afghanistan Pursuant to Section 7086(c)(2) of the Department of State, Foreign Operations, and... respect to Afghanistan, and I hereby waive such restriction. This determination shall be reported to the...

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...

78 FR 76698 - Waiver of Restriction on Assistance to the Central Government of Somalia

Science.gov (United States)

2013-12-18

... DEPARTMENT OF STATE [Public Notice 8559] Waiver of Restriction on Assistance to the Central Government of Somalia Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... prior year Acts with respect to Somalia and I hereby waive this restriction. This determination and the...

78 FR 46672 - Waiver of Restriction on Assistance to the Central Government of Ukraine

Science.gov (United States)

2013-08-01

... DEPARTMENT OF STATE [Public Notice 8401] Waiver of Restriction on Assistance to the Central Government of Ukraine Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... prior year Acts with respect to Ukraine and I hereby waive this restriction. This determination and the...

78 FR 16356 - Waiver of Restriction on Assistance to the Central Government of Somalia

Science.gov (United States)

2013-03-14

... DEPARTMENT OF STATE [Public Notice 8227] Waiver of Restriction on Assistance to the Central Government of Somalia Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Somalia, and I...

78 FR 23625 - Waiver of Restriction on Assistance to the Central Government of Yemen

Science.gov (United States)

2013-04-19

... DEPARTMENT OF STATE [Public Notice 8279] Waiver of Restriction on Assistance to the Central Government of Yemen Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Yemen and I...

78 FR 56767 - Waiver of Restriction on Assistance to the Central Government of Yemen

Science.gov (United States)

2013-09-13

... DEPARTMENT OF STATE [Public Notice 8466] Waiver of Restriction on Assistance to the Central Government of Yemen Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... States to waive the requirements of Section 7031(b)(1) of the Act with respect to Yemen, and I hereby...

78 FR 17745 - Waiver of Restriction on Assistance to the Central Government of Cambodia

Science.gov (United States)

2013-03-22

... DEPARTMENT OF STATE [Public Notice 8245] Waiver of Restriction on Assistance to the Central Government of Cambodia Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Cambodia and I...

78 FR 56767 - Waiver of Restriction on Assistance to the Central Government of Lebanon

Science.gov (United States)

2013-09-13

... DEPARTMENT OF STATE [Public Notice 8469] Waiver of Restriction on Assistance to the Central Government of Lebanon Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Lebanon, and I...

78 FR 23625 - Waiver of Restriction on Assistance to the Central Government of Lebanon

Science.gov (United States)

2013-04-19

... DEPARTMENT OF STATE [Public Notice 8282] Waiver of Restriction on Assistance to the Central Government of Lebanon Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Lebanon and I...

78 FR 16029 - Waiver of Restriction on Assistance to the Central Government of Angola

Science.gov (United States)

2013-03-13

... DEPARTMENT OF STATE [Public Notice 8230] Waiver of Restriction on Assistance to the Central Government of Angola Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Angola and I...

76 FR 61134 - Waiver of Restriction on Assistance to the Central Government of Angola

Science.gov (United States)

2011-10-03

... DEPARTMENT OF STATE [Public Notice: 7920] Waiver of Restriction on Assistance to the Central Government of Angola Pursuant to Section 7086(c)(2) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7086(c)(1) of the Act with respect to Angola and I...

Central composite rotatable design for investigation of microwave-assisted extraction of ginger (Zingiber officinale)

Science.gov (United States)

Fadzilah, R. Hanum; Sobhana, B. Arianto; Mahfud, M.

2015-12-01

Microwave-assisted extraction technique was employed to extract essential oil from ginger. The optimal condition for microwave assisted extraction of ginger were determined by resposnse surface methodology. A central composite rotatable design was applied to evaluate the effects of three independent variables. The variables is were microwave power 400 - 800W as X1, feed solvent ratio of 0.33 -0.467 as X2 and feed size 1 cm, 0.25 cm and less than 0.2 cm as X3. The correlation analysis of mathematical modelling indicated that quadratic polynomial could be employed to optimize microwave assisted extraction of ginger. The optimal conditions to obtain highest yield of essential oil were : microwave power 597,163 W : feed solvent ratio and size of feed less than 0.2 cm.

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.

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....

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.

78 FR 56767 - Waiver of Restriction on Assistance to the Central Government of Saudi Arabia

Science.gov (United States)

2013-09-13

... DEPARTMENT OF STATE [Public Notice 8471] Waiver of Restriction on Assistance to the Central Government of Saudi Arabia Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... year Acts with respect to Saudi Arabia, and I hereby waive this restriction. This determination and the...

78 FR 23625 - Waiver of Restriction on Assistance to the Central Government of Saudi Arabia

Science.gov (United States)

2013-04-19

... DEPARTMENT OF STATE [Public Notice 8281] Waiver of Restriction on Assistance to the Central Government of Saudi Arabia Pursuant to Section 7031(b)(3) of the Department of State, Foreign Operations, and... United States to waive the requirements of Section 7031(b)(1) of the Act with respect to Saudi Arabia...

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...

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...

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.

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

Functional neuroanatomy of the central noradrenergic system.

Science.gov (United States)

Szabadi, Elemer

2013-08-01

The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions ('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep disturbance.

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...

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.

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 ...

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.

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...

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...

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.

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...

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.

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

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

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.)

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....

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.

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...

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....

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.

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.

Predicting Hybrid Performances for Quality Traits through Genomic-Assisted Approaches in Central European Wheat

KAUST Repository

Liu, Guozheng

2016-07-06

Bread-making quality traits are central targets for wheat breeding. The objectives of our study were to (1) examine the presence of major effect QTLs for quality traits in a Central European elite wheat population, (2) explore the optimal strategy for predicting the hybrid performance for wheat quality traits, and (3) investigate the effects of marker density and the composition and size of the training population on the accuracy of prediction of hybrid performance. In total 135 inbred lines of Central European bread wheat (Triticum aestivum L.) and 1,604 hybrids derived from them were evaluated for seven quality traits in up to six environments. The 135 parental lines were genotyped using a 90k single-nucleotide polymorphism array. Genome-wide association mapping initially suggested presence of several quantitative trait loci (QTLs), but cross-validation rather indicated the absence of major effect QTLs for all quality traits except of 1000-kernel weight. Genomic selection substantially outperformed marker-assisted selection in predicting hybrid performance. A resampling study revealed that increasing the effective population size in the estimation set of hybrids is relevant to boost the accuracy of prediction for an unrelated test population.

Predicting Hybrid Performances for Quality Traits through Genomic-Assisted Approaches in Central European Wheat.

Directory of Open Access Journals (Sweden)

Guozheng Liu

Full Text Available Bread-making quality traits are central targets for wheat breeding. The objectives of our study were to (1 examine the presence of major effect QTLs for quality traits in a Central European elite wheat population, (2 explore the optimal strategy for predicting the hybrid performance for wheat quality traits, and (3 investigate the effects of marker density and the composition and size of the training population on the accuracy of prediction of hybrid performance. In total 135 inbred lines of Central European bread wheat (Triticum aestivum L. and 1,604 hybrids derived from them were evaluated for seven quality traits in up to six environments. The 135 parental lines were genotyped using a 90k single-nucleotide polymorphism array. Genome-wide association mapping initially suggested presence of several quantitative trait loci (QTLs, but cross-validation rather indicated the absence of major effect QTLs for all quality traits except of 1000-kernel weight. Genomic selection substantially outperformed marker-assisted selection in predicting hybrid performance. A resampling study revealed that increasing the effective population size in the estimation set of hybrids is relevant to boost the accuracy of prediction for an unrelated test population.

Predicting Hybrid Performances for Quality Traits through Genomic-Assisted Approaches in Central European Wheat

KAUST Repository

Liu, Guozheng; Zhao, Yusheng; Gowda, Manje; Longin, C. Friedrich H.; Reif, Jochen C.; Mette, Michael F.

2016-01-01

Bread-making quality traits are central targets for wheat breeding. The objectives of our study were to (1) examine the presence of major effect QTLs for quality traits in a Central European elite wheat population, (2) explore the optimal strategy for predicting the hybrid performance for wheat quality traits, and (3) investigate the effects of marker density and the composition and size of the training population on the accuracy of prediction of hybrid performance. In total 135 inbred lines of Central European bread wheat (Triticum aestivum L.) and 1,604 hybrids derived from them were evaluated for seven quality traits in up to six environments. The 135 parental lines were genotyped using a 90k single-nucleotide polymorphism array. Genome-wide association mapping initially suggested presence of several quantitative trait loci (QTLs), but cross-validation rather indicated the absence of major effect QTLs for all quality traits except of 1000-kernel weight. Genomic selection substantially outperformed marker-assisted selection in predicting hybrid performance. A resampling study revealed that increasing the effective population size in the estimation set of hybrids is relevant to boost the accuracy of prediction for an unrelated test population.

Predicting Hybrid Performances for Quality Traits through Genomic-Assisted Approaches in Central European Wheat

Science.gov (United States)

Liu, Guozheng; Zhao, Yusheng; Gowda, Manje; Longin, C. Friedrich H.; Reif, Jochen C.; Mette, Michael F.

2016-01-01

Bread-making quality traits are central targets for wheat breeding. The objectives of our study were to (1) examine the presence of major effect QTLs for quality traits in a Central European elite wheat population, (2) explore the optimal strategy for predicting the hybrid performance for wheat quality traits, and (3) investigate the effects of marker density and the composition and size of the training population on the accuracy of prediction of hybrid performance. In total 135 inbred lines of Central European bread wheat (Triticum aestivum L.) and 1,604 hybrids derived from them were evaluated for seven quality traits in up to six environments. The 135 parental lines were genotyped using a 90k single-nucleotide polymorphism array. Genome-wide association mapping initially suggested presence of several quantitative trait loci (QTLs), but cross-validation rather indicated the absence of major effect QTLs for all quality traits except of 1000-kernel weight. Genomic selection substantially outperformed marker-assisted selection in predicting hybrid performance. A resampling study revealed that increasing the effective population size in the estimation set of hybrids is relevant to boost the accuracy of prediction for an unrelated test population. PMID:27383841

The presumed central nervous system effects of rocuronium in a neonate and its reversal with sugammadex.

Science.gov (United States)

Langley, Ross J; McFadzean, Jillian; McCormack, Jon

2016-01-01

We describe a 2-day-old male infant who received rocuronium as part of general anesthesia for a tracheal esophageal fistula repair. Postoperatively, he had prolonged central and peripheral neuromuscular blockade despite cessation of the rocuronium infusion several hours previously. This case discusses the presumed central nervous system effects of rocuronium in a neonate and its effective reversal with sugammadex. © 2015 John Wiley & Sons Ltd.

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...

Literature review of the usefulness of the ilioinguinal and iliohypogastric blockade as part of multimodal management of postoperative analgesia

International Nuclear Information System (INIS)

Freeman Brooks, Katia Maurenia

2012-01-01

An specialized literature review was realized for the practice of anesthesiology, revealing the usefulness of blockings of ilioinguinal and iliohypogastric nerves to control pain or postoperative analgesia. Pain and acute postoperative pain are defined. Also, the different techniques or pharmacological options for treating and controlling postoperative pain are determined. For example, systemic opioid and non-opioid analgesics, regional analgesic techniques (neuraxial and peripheral). The use of ultrasound is described as technical support to regional anesthesia and nerve block guided by images [es

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

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.

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.

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.

Assistive technology in occupational therapy practice with a child with degenerative disease of the central nervous system

Directory of Open Access Journals (Sweden)

Tácia Caroline de Lima Rodrigues

2015-07-01

Full Text Available This paper aims to report the effects of the interventions, using the resource of assistive technology, carried out with a child with degenerative disease of the central nervous system at his home. This is a study case, which was conducted in seven meetings, addressing the child and his caregivers during a process of evaluation, preparation of assistive devices, family orientation, and evaluation of the family environment repercussion. The results showed that the child presents significant motor, cognitive, and psychosocial impairments, resulting in difficulties in performing activities of daily living, communication, and play. Adjustments were proposed to facilitate the child’s involvement and alleviate family difficulties on equipment and environments, such as wheelchair, bedroom, bathroom, orthosis, toys and communication. Finally, it was possible to note that the assistive technology resources were used according to the child’s needs and his own reality, and that the domiciliary visits contributed positively to the family’s life because they facilitated the child’s care, despite the limitations faced.

Foreign Assistance: Treasury's Technical Assistance Program

National Research Council Canada - National Science Library

Ford, Jess

1999-01-01

After the collapse of communism in Central Europe and the dissolution of the Soviet Union, the United States developed programs of technical assistance to help countries transition to market economies and democracy...

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.

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...

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.

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.

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

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.

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

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....

Transport and interaction blockade of cold bosonic atoms in a triple-well potential

International Nuclear Information System (INIS)

Schlagheck, P; Malet, F; Cremon, J C; Reimann, S M

2010-01-01

We theoretically investigate the transport properties of cold bosonic atoms in a quasi-one-dimensional (1D) triple-well potential that consists of two large outer wells, which act as microscopic source and drain reservoirs, and a small inner well, which represents a quantum-dot-like scattering region. Bias and gate 'voltages' introduce a time-dependent tilt of the triple-well configuration, and are used to shift the energetic level of the inner well with respect to the outer ones. By means of exact diagonalization considering a total number of six atoms in the triple-well potential, we find diamond-like structures for the occurrence of single-atom transport in the parameter space spanned by the bias and gate voltages. We discuss the analogy with Coulomb blockade in electronic quantum dots, and point out how one can infer the interaction energy in the central well from the distance between the diamonds.

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

Science.gov (United States)

Kiyatkin, E A

2010-05-05

Although pharmacological blockade of both dopamine (DA) and opiate receptors has an inhibiting effect on appetitive motivated behaviors, it is still unclear which physiological mechanisms affected by these treatments underlie the behavioral deficit. To clarify this issue, we examined how pharmacological blockade of either DA (SCH23390+eticlopride at 0.2 mg/kg each) or opioid receptors (naloxone 1 mg/kg) affects motor activity and temperature fluctuations in the nucleus accumbens (NAcc), temporal muscle, and facial skin associated with motivated Coca-Cola drinking behavior in rats. In drug-free conditions, presentation of a cup containing 5 ml of Coca-Cola induced locomotor activation and rapid NAcc temperature increases, which both transiently decreased during drinking, and phasically increased again after the cup was emptied. Muscle temperatures followed this pattern, but increases were weaker and more delayed than those in the NAcc. Skin temperature rapidly dropped after cup presentation, remained at low levels during consumption, and slowly restored during post-consumption behavioral activation. By itself, DA receptor blockade induced robust decrease in spontaneous locomotion, moderate increases in brain and muscle temperatures, and a relative increase in skin temperatures, suggesting metabolic activation coupled with adynamia. Following this treatment (approximately 180 min), motor activation to cup presentation and Coca-Cola consumption were absent, but rats showed NAcc and muscle temperature increases following cup presentation comparable to control. Therefore, DA receptor blockade does not affect significantly central and peripheral autonomic responses to appetitive stimuli, but eliminates their behavior-activating effects, thus disrupting appetitive behavior and blocking consumption. Naloxone alone slightly decreased brain and muscle temperatures and increased skin temperatures, pointing at the enhanced heat loss and possible minor inhibition of basal

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...

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.

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.

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.

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...

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.

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.

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.

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

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)

Neurally adjusted ventilatory assist (NAVA) mode as an adjunct diagnostic tool in congenital central hypoventilation syndrome.

Science.gov (United States)

Rahmani, Aiman; Ur Rehman, Naveed; Chedid, Fares

2013-02-01

A full term female newborn was admitted to the neonatal intensive care unit (NICU) for continuous observation of apnea. Infant was noted to have apnea while asleep requiring intubation and mechanical ventilation. A video EEG was performed which demonstrated normal awake background without any seizure activity. Neurally adjusted ventilatory assist (NAVA) demonstrated the absence of electrical activity of the diaphragm (Edi) when the patient was in quiet phase of sleep. This finding on NAVA monitor raised the suspicion of central hypoventilation syndrome (CCHS) which was confirmed by genetic identification of the PHOX2B mutation.

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...

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....

Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine

NARCIS (Netherlands)

Vranken, Jan H.; Troost, Dirk; de Haan, Peter; Pennings, Fritz A.; van der Vegt, Marinus H.; Dijkgraaf, Marcel G. W.; Hollmann, Markus W.

2006-01-01

BACKGROUND: Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central

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.

Denmark's environmental assistance to Central and Eastern Europe 1991-1996

DEFF Research Database (Denmark)

Andersen, Mikael Skou

Denmark’s Environmental Assistance to Eastern Europe 1991-1996, an assessment of project achievements, environmental policy performance and the role of foreign assistance. Main report October 1998 by Mikael Skou Andersen, Aarhus University in cooperation with PLS Consult and KPMG: The report...... is a summary and synthesis of the results of the external evaluation of the Danish Environmental Support Fund for Eastern Europe (DESF) initiated by the Danish Environmental Protection Agency (DEPA) in 1997. It provides the principles for environmental assistance in the period 1991-96 and contains...... activities and improvements in the existing framework for Danish environmental assistance to Eastern Europe....

The effects of calcium channel blockade on agouti-induced obesity

Energy Technology Data Exchange (ETDEWEB)

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

1996-12-01

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

Impact of endothelin blockade on acute exercise-induced changes in blood flow and endothelial function in type 2 diabetes mellitus.

Science.gov (United States)

Schreuder, Tim H A; van Lotringen, Jaap H; Hopman, Maria T E; Thijssen, Dick H J

2014-09-01

Positive vascular effects of exercise training are mediated by acute increases in blood flow. Type 2 diabetes patients show attenuated exercise-induced increases in blood flow, possibly mediated by the endothelin pathway, preventing an optimal stimulus for vascular adaptation. We examined the impact of endothelin receptor blockade (bosentan) on exercise-induced blood flow in the brachial artery and on pre- and postexercise endothelial function in type 2 diabetes patients (n = 9, 60 ± 7 years old) and control subjects (n = 10, 60 ± 5 years old). Subjects reported twice to the laboratory to perform hand-grip exercise in the presence of endothelin receptor blockade or placebo. We examined brachial artery endothelial function (via flow-mediated dilatation) before and after exercise, as well as blood flow during exercise. Endothelin receptor blockade resulted in a larger increase in blood flow during exercise in type 2 diabetes patients (P = 0.046), but not in control subjects (P = 0.309). Exercise increased shear rate across the exercise protocol, unaffected by endothelin receptor blockade. Exercise did not alter brachial artery diameter in either group, but endothelin receptor blockade resulted in a larger brachial artery diameter in type 2 diabetes patients (P = 0.033). Exercise significantly increased brachial artery flow-mediated dilatation in both groups, unaffected by endothelin receptor blockade. Endothelin receptor blockade increased exercise-induced brachial artery blood flow in type 2 diabetes patients, but not in control subjects. Despite this effect of endothelin receptor blockade on blood flow, we found no impact on baseline or post-exercise endothelial function in type 2 diabetes patients or control subjects, possibly related to normalization of the shear stimulus during exercise. The successful increase in blood flow during exercise in type 2 diabetes patients through endothelin receptor blockade may have beneficial effects in

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.

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....

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

Science.gov (United States)

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

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....

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....

Neurally adjusted ventilatory assist (NAVA) mode as an adjunct diagnostic tool in congenital central hypoventilation syndrome

International Nuclear Information System (INIS)

Rahmani, A.; Rehman, N.U.; Chedid, F.

2013-01-01

A full term female newborn was admitted to the neonatal intensive care unit (NICU) for continuous observation of apnea. Infant was noted to have apnea while asleep requiring intubation and mechanical ventilation. A video EEG was performed which demonstrated normal awake background without any seizure activity. Neurally adjusted ventilatory assist (NAVA) demonstrated the absence of electrical activity of the diaphragm (Edi) when the patient was in quiet phase of sleep. This finding on NAVA monitor raised the suspicion of central hypoventilation syndrome (CCHS) which was confirmed by genetic identification of the PHOX2B mutation. (author)

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.

NMDA receptor blockade alters the intracellular distribution of neuronal nitric oxide synthase in the superficial layers of the rat superior colliculus

Directory of Open Access Journals (Sweden)

R.E. de Bittencourt-Navarrete

2009-02-01

Full Text Available Nitric oxide (NO is a molecular messenger involved in several events of synaptic plasticity in the central nervous system. Ca2+ influx through the N-methyl-D-aspartate receptor (NMDAR triggers the synthesis of NO by activating the enzyme neuronal nitric oxide synthase (nNOS in postsynaptic densities. Therefore, NMDAR and nNOS are part of the intricate scenario of postsynaptic densities. In the present study, we hypothesized that the intracellular distribution of nNOS in the neurons of superior colliculus (SC superficial layers is an NMDAR activity-dependent process. We used osmotic minipumps to promote chronic blockade of the receptors with the pharmacological agent MK-801 in the SC of 7 adult rats. The effective blockade of NMDAR was assessed by changes in the protein level of the immediate early gene NGFI-A, which is a well-known NMDAR activity-dependent expressing transcription factor. Upon chronic infusion of MK-801, a decrease of 47% in the number of cells expressing NGFI-A was observed in the SC of treated animals. Additionally, the filled dendritic extent by the histochemical product of nicotinamide adenine di-nucleotide phosphate diaphorase was reduced by 45% when compared to the contralateral SC of the same animals and by 64% when compared to the SC of control animals. We conclude that the proper intracellular localization of nNOS in the retinorecipient layers of SC depends on NMDAR activation. These results are consistent with the view that the participation of NO in the physiological and plastic events of the central nervous system might be closely related to an NMDAR activity-dependent function.

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...

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.

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

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

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 ...

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 ...

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.

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

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

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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.

Central vs. peripheral neuraxial sympathetic control of porcine ventricular electrophysiology

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Yamakawa, Kentaro; Howard-Quijano, Kimberly; Zhou, Wei; Rajendran, Pradeep; Yagishita, Daigo; Vaseghi, Marmar; Ajijola, Olujimi A.; Armour, J. Andrew; Shivkumar, Kalyanam; Ardell, Jeffrey L.

2015-01-01

Sympathoexcitation is associated with ventricular arrhythmogenesis. The aim of this study was to determine the role of thoracic dorsal root afferent neural inputs to the spinal cord in modulating ventricular sympathetic control of normal heart electrophysiology. We hypothesize that dorsal root afferent input tonically modulates basal and evoked efferent sympathetic control of the heart. A 56-electrode sock placed on the epicardial ventricle in anesthetized Yorkshire pigs (n = 17) recorded electrophysiological function, as well as activation recovery interval (ARI) and dispersion in ARI, at baseline conditions and during stellate ganglion electrical stimulation. Measures were compared between intact states and sequential unilateral T1–T4 dorsal root transection (DRTx), ipsilateral ventral root transection (VRTx), and contralateral dorsal and ventral root transections (DVRTx). Left or right DRTx decreased global basal ARI [Lt.DRTx: 369 ± 12 to 319 ± 13 ms (P < 0.01) and Rt.DRTx: 388 ± 19 to 356 ± 15 ms (P < 0.01)]. Subsequent unilateral VRTx followed by contralateral DRx+VRTx induced no further change. In intact states, left and right stellate ganglion stimulation shortened ARIs (6 ± 2% vs. 17 ± 3%), while increasing dispersion (+139% vs. +88%). There was no difference in magnitude of ARI or dispersion change with stellate stimulation following spinal root transections. Interruption of thoracic spinal afferent signaling results in enhanced basal cardiac sympathoexcitability without diminishing the sympathetic response to stellate ganglion stimulation. This suggests spinal dorsal root transection releases spinal cord-mediated tonic inhibitory control of efferent sympathetic tone, while maintaining intrathoracic cardiocentric neural networks. PMID:26661096

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...

Integrated molecular analysis of tumor biopsies on sequential CTLA-4 and PD-1 blockade reveals markers of response and resistance

Science.gov (United States)

Roh, Whijae; Chen, Pei-Ling; Reuben, Alexandre; Spencer, Christine N.; Prieto, Peter A.; Miller, John P.; Gopalakrishnan, Vancheswaran; Wang, Feng; Cooper, Zachary A.; Reddy, Sangeetha M.; Gumbs, Curtis; Little, Latasha; Chang, Qing; Chen, Wei-Shen; Wani, Khalida; Petaccia De Macedo, Mariana; Chen, Eveline; Austin-Breneman, Jacob L.; Jiang, Hong; Roszik, Jason; Tetzlaff, Michael T.; Davies, Michael A.; Gershenwald, Jeffrey E.; Tawbi, Hussein; Lazar, Alexander J.; Hwu, Patrick; Hwu, Wen-Jen; Diab, Adi; Glitza, Isabella C.; Patel, Sapna P.; Woodman, Scott E.; Amaria, Rodabe N.; Prieto, Victor G.; Hu, Jianhua; Sharma, Padmanee; Allison, James P.; Chin, Lynda; Zhang, Jianhua; Wargo, Jennifer A.; Futreal, P. Andrew

2018-01-01

Immune checkpoint blockade produces clinical benefit in many patients. However better biomarkers of response are still needed, and mechanisms of resistance remain incompletely understood. To address this, we recently studied a cohort of melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen-4 (CTLA-4) followed by programmed death receptor-1 (PD-1), and identified immune markers of response and resistance. Building on these studies, we performed deep molecular profiling including T-cell receptor sequencing (TCR-seq) and whole exome sequencing (WES) within the same cohort, and demonstrated that a more clonal T cell repertoire was predictive of response to PD-1 but not CTLA-4 blockade. Analysis of copy number alterations identified a higher burden of copy number loss in non-responders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was non-redundant, suggesting the potential utility of a combinatorial biomarker to optimize patient care with checkpoint blockade therapy. PMID:28251903

A central neural circuit for itch sensation.

Science.gov (United States)

Mu, Di; Deng, Juan; Liu, Ke-Fei; Wu, Zhen-Yu; Shi, Yu-Feng; Guo, Wei-Min; Mao, Qun-Quan; Liu, Xing-Jun; Li, Hui; Sun, Yan-Gang

2017-08-18

Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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

Cannabinoid Receptor Signaling in Central Regulation of Feeding Behavior: A Mini-Review

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Marco Koch

2017-05-01

Full Text Available Cannabinoids are lipid messengers that modulate a variety of physiological processes and modify the generation of specific behaviors. In this regard, the cannabinoid receptor type 1 (CB1 represents the most relevant target molecule of cannabinoids so far. One main function of central CB1 signaling is to maintain whole body energy homeostasis. Thus, cannabinoids functionally interact with classical neurotransmitters in neural networks that control energy metabolism and feeding behavior. The promotion of CB1 signaling can increase appetite and stimulate feeding, while blockade of CB1 suppresses hunger and induces hypophagia. However, in order to treat overeating, pharmacological blockade of CB1 by the inverse agonist rimonabant not only suppressed feeding but also resulted in psychiatric side effects. Therefore, research within the last decade focused on deciphering the underlying cellular and molecular mechanisms of central cannabinoid signaling that control feeding and other behaviors, with the overall aim still being the identification of specific targets to develop safe pharmacological interventions for the treatment of obesity. Today, many studies unraveled the subcellular localization of CB1 and the function of cannabinoids in neurons and glial cells within circumscribed brain regions that represent integral parts of neural circuitries controlling feeding behavior. Here, these novel experimental findings will be summarized and recent advances in understanding the mechanisms of CB1-dependent cannabinoid signaling being relevant for central regulation of feeding behavior will be highlighted. Finally, presumed alternative pathways of cannabinoids that are not driven by CB1 activation but also contributing to control of feeding behavior will be introduced.

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...

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/.

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.

[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.

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

Comparison of rocuronium-induced neuromuscular blockade in second trimester pregnant women and non-pregnant women.

Science.gov (United States)

Jun, I J; Jun, J; Kim, E M; Lee, K Y; Kim, N; Chung, M H; Choi, Y R; Choi, E M

2018-05-01

This study set out to compare the onset and duration of rocuronium-induced neuromuscular blockade in second trimester pregnant women and non-pregnant women receiving general anesthesia. Forty-seven pregnant (Group P) and forty-seven non-pregnant (Group C) women were enrolled. Anesthesia was induced with propofol 2.0 mg/kg and rocuronium 0.6 mg/kg, and neuromuscular blockade was assessed with an accelerometric sensor using train-of-four stimulation (TOF-Watch® SX). Tracheal intubation was performed at maximum depression of the first twitch (T1) and anesthesia was maintained with sevoflurane 1.5-2.5% and 50% oxygen in air. We recorded the times to maximum T1 depression and 5% and 25% T1 recovery, as well as the mean arterial pressure and heart rate at baseline, injection of rocuronium, intubation, and 5% and 25% T1 recovery. The onset of rocuronium-induced neuromuscular blockade (time to maximum T1 depression) did not differ significantly between the groups. The duration (time to 25% T1 recovery) was significantly longer in Group P than in Group C (45.7 ± 12.9 min vs 40.6 ± 10.4 min, P rocuronium-induced neuromuscular blockade did not significantly differ in onset but lasted significantly longer in second trimester pregnant women compared with non-pregnant women. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phantom limb pain: a case of maladaptive CNS plasticity?

DEFF Research Database (Denmark)

Flor, Herta; Nikolajsen, Lone; Jensen, Troels Staehelin

2006-01-01

might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human...

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.

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.

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...

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

Directory of Open Access Journals (Sweden)

Roderick J Tan

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

TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm.

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Lareyre, Fabien; Clément, Marc; Raffort, Juliette; Pohlod, Stefanie; Patel, Meghana; Esposito, Bruno; Master, Leanne; Finigan, Alison; Vandestienne, Marie; Stergiopulos, Nikolaos; Taleb, Soraya; Trachet, Bram; Mallat, Ziad

2017-11-01

Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets. © 2017 American Heart Association, Inc.

Anatomy of the Spinal Meninges.

Science.gov (United States)

Sakka, Laurent; Gabrillargues, Jean; Coll, Guillaume

2016-06-01

The spinal meninges have received less attention than the cranial meninges in the literature, although several points remain debatable and poorly understood, like their phylogenesis, their development, and their interactions with the spinal cord. Their constancy among the chordates shows their crucial importance in central nervous system homeostasis and suggests a role far beyond mechanical protection of the neuraxis. This work provides an extensive study of the spinal meninges, from an overview of their phylogenesis and embryology to a descriptive and topographic anatomy with clinical implications. It examines their involvement in spinal cord development, functioning, and repair. This work is a review of the literature using PubMed as a search engine on Medline. The stages followed by the meninges along the phylogenesis could not be easily compared with their development in vertebrates for methodological aspects and convergence processes throughout evolution. The distinction between arachnoid and pia mater appeared controversial. Several points of descriptive anatomy remain debatable: the functional organization of the arterial network, and the venous and lymphatic drainages, considered differently by classical anatomic and neuroradiological approaches. Spinal meninges are involved in neurodevelopment and neurorepair producing neural stem cells and morphogens, in cerebrospinal fluid dynamics and neuraxis functioning by the synthesis of active molecules, and the elimination of waste products of central nervous system metabolism. The spinal meninges should be considered as dynamic functional formations evolving over a lifetime, with ultrastructural features and functional interactions with the neuraxis remaining not fully understood.

VEGF blockade inhibits angiogenesis and reepithelialization of endometrium.

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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.

Central and peripheral mechanisms underlying gastric distention inhibitory reflex responses in hypercapnic-acidotic rats.

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Tjen-A-Looi, Stephanie C; Hsiao, An-Fu; Longhurst, John C

2011-03-01

We have observed that in chloralose-anesthetized animals, gastric distension (GD) typically increases blood pressure (BP) under normoxic normocapnic conditions. However, we recently noted repeatable decreases in BP and heart rate (HR) in hypercapnic-acidotic rats in response to GD. The neural pathways, central processing, and autonomic effector mechanisms involved in this cardiovascular reflex response are unknown. We hypothesized that GD-induced decrease in BP and HR reflex responses are mediated during both withdrawal of sympathetic tone and increased parasympathetic activity, involving the rostral (rVLM) and caudal ventrolateral medulla (cVLM) and the nucleus ambiguus (NA). Rats anesthetized with ketamine and xylazine or α-chloralose were ventilated and monitored for HR and BP changes. The extent of cardiovascular inhibition was related to the extent of hypercapnia and acidosis. Repeated GD with both anesthetics induced consistent falls in BP and HR. The hemodynamic inhibitory response was reduced after blockade of the celiac ganglia or the intraabdominal vagal nerves with lidocaine, suggesting that the decreased BP and HR responses were mediated by both sympathetic and parasympathetic afferents. Blockade of the NA decreased the bradycardia response. Microinjection of kainic acid into the cVLM reduced the inhibitory BP response, whereas depolarization blockade of the rVLM decreased both BP and HR inhibitory responses. Blockade of GABA(A) receptors in the rVLM also reduced the BP and HR reflex responses. Atropine methyl bromide completely blocked the reflex bradycardia, and atenolol blocked the negative chronotropic response. Finally, α(1)-adrenergic blockade with prazosin reversed the depressor. Thus, in the setting of hypercapnic-acidosis, a sympathoinhibitory cardiovascular response is mediated, in part, by splanchnic nerves and is processed through the rVLM and cVLM. Additionally, a vagal excitatory reflex, which involves the NA, facilitates the GD

Effect of acute aerobic exercise and histamine receptor blockade on arterial stiffness in African Americans and Caucasians.

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Yan, Huimin; Ranadive, Sushant M; Lane-Cordova, Abbi D; Kappus, Rebecca M; Behun, Michael A; Cook, Marc D; Woods, Jeffrey A; Wilund, Kenneth R; Baynard, Tracy; Halliwill, John R; Fernhall, Bo

2017-02-01

African Americans (AA) exhibit exaggerated central blood pressure (BP) and arterial stiffness measured by pulse wave velocity (PWV) in response to an acute bout of maximal exercise compared with Caucasians (CA). However, whether potential racial differences exist in central BP, elastic, or muscular arterial distensibility after submaximal aerobic exercise remains unknown. Histamine receptor activation mediates sustained postexercise hyperemia in CA but the effect on arterial stiffness is unknown. This study sought to determine the effects of an acute bout of aerobic exercise on central BP and arterial stiffness and the role of histamine receptors, in AA and CA. Forty-nine (22 AA, 27 CA) young and healthy subjects completed the study. Subjects were randomly assigned to take either histamine receptor antagonist or control placebo. Central blood BP and arterial stiffness measurements were obtained at baseline, and at 30, 60, and 90 min after 45 min of moderate treadmill exercise. AA exhibited greater central diastolic BP, elevated brachial PWV, and local carotid arterial stiffness after an acute bout of submaximal exercise compared with CA, which may contribute to their higher risk of cardiovascular disease. Unexpectedly, histamine receptor blockade did not affect central BP or PWV in AA or CA after exercise, but it may play a role in mediating local carotid arterial stiffness. Furthermore, histamine may mediate postexercise carotid arterial dilation in CA but not in AA. These observations provide evidence that young and healthy AA exhibit an exaggerated hemodynamic response to exercise and attenuated vasodilator response compared with CA. NEW & NOTEWORTHY African Americans are at greater risk for developing cardiovascular disease than Caucasians. We are the first to show that young and healthy African Americans exhibit greater central blood pressure, elevated brachial stiffness, and local carotid arterial stiffness following an acute bout of submaximal exercise

The renin–angiotensin–aldosterone system blockade in patients with advanced diabetic kidney disease

Directory of Open Access Journals (Sweden)

Sheila Bermejo

2018-03-01

Full Text Available Background and objectives: Diabetic kidney disease is the leading cause of end-stage chronic kidney disease (CKD. The renin–angiotensin–aldosterone system (RAAS blockade has been shown to slow the progression of diabetic kidney disease. Our objectives were: to study the percentage of patients with diabetic kidney disease treated with RAAS blockade, to determine its renal function, safety profile and assess whether its administration is associated with increased progression of CKD after 3 years of follow-up. Materials and methods: Retrospective study. 197 diabetic kidney disease patients were included and divided into three groups according to the treatment: patients who had never received RAAS blockade (non-RAAS blockade, patients who at some point had received RAAS blockade (inconstant-RAAS blockade and patients who received RAAS blockade (constant-RAAS blockade. Clinical characteristics and analytical variables such as renal function, electrolytes, glycosylated hemoglobin and glomerular filtration rate according to CKD-EPI and MDRD formulas were assessed. We also studied their clinical course (baseline, 1 and 3 years follow-up in terms of treatment group, survival, risk factors and renal prognosis. Results: Non-RAAS blockade patients had worse renal function and older age (p < 0.05 at baseline compared to RAAS blockade patients. Patients who received RAAS blockade were not found to have greater toxicity or chronic kidney disease progression and no differences in renal prognosis were identified. Mortality was higher in non-RAAS blockade patients, older patients and patients with worse renal function (p < 0.05. In the multivariate analysis, older age and worse renal function were risk factors for mortality. Conclusions: Treatment with RAAS blockade is more common in diabetic kidney disease patients with eGFR ≥ 30 ml/min/1.73 m2. In our study, there were no differences in the evolution of renal function

Recommendations on the use of deep neuromuscular blockade by anaesthesiologists and surgeons. AQUILES (Anestesia QUIrúrgica para Lograr Eficiencia y Seguridad) Consensus.

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Errando-Oyonarte, C L; Moreno-Sanz, C; Vila-Caral, P; Ruiz de Adana-Belbel, J C; Vázquez-Alonso, E; Ramírez-Rodríguez, J M; Veiga-Ruiz, G; Guasch-Arévalo, E; Lora-Tamayo D'Ocón, J I

2017-02-01

Neuromuscular blockade enables airway management, ventilation and surgical procedures. However there is no national consensus on its routine clinical use. The objective was to establish the degree of agreement among anaesthesiologists and general surgeons on the clinical use of neuromuscular blockade in order to make recommendations to improve its use during surgical procedures. Multidisciplinary consensus study in Spain. Anaesthesiologists experts in neuromuscular blockade management (n=65) and general surgeons (n=36) were included. Delphi methodology was selected. A survey with 17 final questions developed by a dedicated scientific committee was designed. The experts answered the successive questions in two waves. The survey included questions on: type of surgery, type of patient, benefits/harm during and after surgery, impact of objective neuromuscular monitoring and use of reversal drugs, viability of a multidisciplinary and efficient approach to the whole surgical procedure, focussing on the level of neuromuscular blockade. Five recommendations were agreed: 1) deep neuromuscular blockade is very appropriate for abdominal surgery (degree of agreement 94.1%), 2) and in obese patients (76.2%); 3) deep neuromuscular blockade maintenance until end of surgery might be beneficial in terms of clinical aspects, such as as immobility or better surgical access (86.1 to 72.3%); 4) quantitative monitoring and reversal drugs availability is recommended (89.1%); finally 5) anaesthesiologists/surgeons joint protocols are recommended. Collaboration among anaesthesiologists and surgeons has enabled some general recommendations to be established on deep neuromuscular blockade use during abdominal surgery. Copyright © 2016 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

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.

α2-adrenergic blockade mimics the enhancing effect of chronic stress on breast cancer progression

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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

Peculiarities of surgical treatment of gastrointestinal tract combined congenital malformations in newborns

Directory of Open Access Journals (Sweden)

М. О. Makarova

2017-04-01

Full Text Available Congenital gastrointestinal (GI malformations make up 21–25 % of all congenital anomalies and require surgical correction in the neonatal period. The aim was to analyze the methods of operative treatment of hard composite congenital gastrointestinal malformations in infants. Materials and Methods: There were 13 newborns with gastroschisis, omphalocele and esophageal atresia combined with intestinal atresia, anal atresia and also with congenital heart defects in our study. Results. We have designed new preoperative care strategies for the newborns. All combined GI defects were corrected in one step. In gastroschisis and omphalocele in combination with small intestine atresia we made a plastic of anterior abdominal wall, bowel segment resection and anastomosis end-to-end. In esophageal atresia and atresia of the anus direct esophago-esophagoanastomosis was applied with suturing of tracheoesophageal fistula, also in two patients proctoplasty by Pena 2 was carried out, and in one patient with high anal atresia colostomy was applied, which was closed in the age of 6 months. In case of esophageal atresia combined with small intestine atresia direct esophago-esophagoanastomosis with tracheoesophageal fistula suturing was carried out, and resection of the bowel segment with anastomosis end-to-end was applied. In a patient with a combination of esophageal atresia and duodenal obstruction esophagoplasty and closure of tracheoesophageal fistula with anastomosis by Kimur was made. Preference was given to the combined anesthesia with neuraxial blockade. Postoperative care included prolonged artificial lung ventilation, anesthesia, parenteral nutrition, antibacterial and antifungal medicines. Conclusions. One-step correction of the congenital GI malformations in newborns is effective and it gives opportunity to achieve the best results with a single surgical intervention. Extremely important links of the combined GI defects therapy is timely and balanced

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.

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

Pattern of Nerve Blocks for Upper Limb Surgery at the University of ...

African Journals Online (AJOL)

Background: Central and peripheral neural blockade techniques are popular for lower and upper limb surgeries respectively. Lower limb surgery is amenable to central neural blockade techniques, anatomical and physiological imperatives makes peripheral neural blockade more suited for upper limb surgeries. We looked ...

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.)

Localized CD47 blockade enhances immunotherapy for murine melanoma.

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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.

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....

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...

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...

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

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.

Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs.

Science.gov (United States)

Ivy, D Dunbar; Lee, Dong-Seok; Rairigh, Robyn L; Parker, Thomas A; Abman, Steven H

2004-01-01

Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown. To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO2 (100%) in near-term fetal sheep. Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO2 ventilation (p <0.001 vs. control for each FiO2 concentration). PVR progressively decreased during mechanical ventilation with low and high FiO2 in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p <0.001). We conclude that selective ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.

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.

α-blockade, apoptosis, and prostate shrinkage: how are they related?

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Chłosta, Piotr; Drewa, Tomasz; Kaplan, Steven

2013-01-01

The α1-adrenoreceptor antagonists, such as terazosin and doxazosin, induce prostate programmed cell death (apoptosis) within prostate epithelial and stromal cells in vitro. This treatment should cause prostate volume decrease, However, this has never been observed in clinical conditions. The aim of this paper is to review the disconnect between these two processes. PubMed and DOAJ were searched for papers related to prostate, apoptosis, and stem cell death. The following key words were used: prostate, benign prostate hyperplasia, programmed cell death, apoptosis, cell death, α1-adrenoreceptor antagonist, α-blockade, prostate epithelium, prostate stroma, stem cells, progenitors, and in vitro models. We have shown how discoveries related to stem cells can influence our understanding of α-blockade treatment for BPH patients. Prostate epithelial and mesenchymal compartments have stem (progenitors) and differentiating cells. These compartments are described in relation to experimental in vitro and in vivo settings. Apoptosis is observed within prostate tissue, but this effect has no clinical significance and cannot lead to prostate shrinkage. In part, this is due to stem cells that are responsible for prostate tissue regeneration and are resistant to apoptosis triggered by α1-receptor antagonists.

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

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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.

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....

Central Methysergide Prevents Renal Sympathoinhibition and Bradycardia during Hypotensive Hemorrhage

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Veelken, Roland; Johnson, Kim; Scrogin, Karie E.

1998-01-01

Central methysergide prevents renal sympathoinhibition and bradycardia during hypotensive hemorrhage. Mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were measured in conscious rats during either hemorrhage or cardiopulmonary receptor stimulation with phenylbiguanide (PBG) after intracerebroventricular injection of the 5-HT1/5-HT2-receptor antagonist, methysergide (40 microg). Progressive hemorrhage caused an initial rise (109 +/- 33%) followed by a fall in RSNA (-60 +/- 7%) and a fall in HR (-126 +/- 7 beats/min). Methysergide delayed the hypotension and prevented both the sympathoinhibitory and bradycardic responses to hemorrhage. Systemic 5-HT3-receptor blockade did not influence responses to hemorrhage. The PBG infusion caused transient depressor(-25 +/- 6 mmHg), bradycardic (-176 +/- 40 beats/min), and renal sympathostimulatory (182 +/-47% baseline) responses that were not affected by central methysergide (-20 +/- 6 mmHg, -162 +/- 18 beats/min, 227 +/- 46% baseline). These data indicate that a central serotonergic receptor-mediated component contributes to the sympathoinhibitory and bradycardic responses to hypotensive hemorrhage in conscious rats. Furthermore, the same central 5-HT-receptor populations involved in reflex responses to hypotensive hemorrhage probably do not mediate the sympathoinhibitory response to cardiopulmonary chemosensitive 5-HT3 receptors.

Should we add clonidine to local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature.

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McCartney, Colin J L; Duggan, Edel; Apatu, Emma

2007-01-01

Although clonidine has been shown to prolong analgesia in central neuraxial blocks, its use in peripheral nerve blocks remains controversial. We performed a systematic review of the current literature to determine the benefit of adding clonidine to peripheral nerve blocks. A systematic, qualitative review of double-blind randomized controlled trials on the benefit of clonidine as an adjunct to peripheral nerve block was performed. Studies were identified by searching PubMed (www.ncbi.nlm.nih.gov/entrez) and EMBASE (www.embase.com) databases (July 1991 to October 2006) for terms related to clonidine as an adjunct to peripheral nerve blocks. Studies were classified as supportive if the use of clonidine demonstrated reduced pain and total analgesic consumption, or prolonged block duration versus negative if no difference was found. Twenty-seven studies were identified that met the inclusion criteria. Five studies included a systemic control group. The total number of patients reviewed was 1,385. The dose of clonidine varied from 30 to 300 mug. Overall 15 studies supported the use of clonidine as an adjunct to peripheral nerve blocks with 12 studies failing to show a benefit. Based on qualitative analysis, clonidine appeared to prolong analgesia when added to intermediate-acting local anesthetics for axillary and peribulbar blocks. Clonidine improves duration of analgesia and anesthesia when used as an adjunct to intermediate-acting local anesthetics for some peripheral nerve blocks. Side-effects appear to be limited at doses up to 150 mug. Evidence is lacking for the use of clonidine as an adjunct to local anesthetics for continuous catheter techniques. Further research is required to examine the peripheral analgesic mechanism of clonidine.

Effects of Mineralocorticoid Receptors Blockade on FearMemory Reconsolidation in Rats

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Abbas Ali Vafaei

2011-08-01

Full Text Available Reconsolidation memory is defined as a process in which the retrieval of a previously consolidated memory returns to a labile state which is then subject to stabilization. Previous studies have shown that mineralocorticoid receptors (MRs modulate distinct phases of learning and memory, which display a high concentration and distinct distribution in the hippocampus. Moreover, we found no studies that examined the role of hippocampal MRs in fear memory reconsolidation. Here, we investigated the effect of MRs blockade on fear memory reconsolidation in rats. Additionally, to test whether blockade of protein synthesis would disrupt fear memory reconsolidation in our paradigm, we tested the effect of cycloheximide, an inhibitor of protein synthesis after memory reactivation. Results indicated that systemic as well as intra-hippocampal administrations of the MR antagonist spironolactone immediately following memory reactivation did not affect on post-retrieval long-term memory. Cycloheximide given after the reactivation treatment produced a strong impairment that persisted over test sessions. These findings indicate that MRs are not required for reconsolidation of fear-based memory.

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

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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

Multibit C_kNOT 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....

alpha-MSH in systemic inflammation. Central and peripheral actions.

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Catania, A; Delgado, R; Airaghi, L; Cutuli, M; Garofalo, L; Carlin, A; Demitri, M T; Lipton, J M

1999-10-20

Until recently, inflammation was believed to arise from events taking place exclusively in the periphery. However, it is now clear that central neurogenic influences can either enhance or modulate peripheral inflammation. Therefore, it should be possible to improve treatment of inflammation by use of antiinflammatory agents that reduce peripheral host responses and inhibit proinflammatory signals in the central nervous system (CNS). One such strategy could be based on alpha-melanocyte stimulating hormone (alpha-MSH). Increases in circulating TNF-alpha and nitric oxide (NO), induced by intraperitoneal administration of endotoxin in mice, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Increase in lung myeloperoxidase (MPO) activity was significantly less in lungs of mice treated with central alpha-MSH. Proinflammatory agents induced by endotoxin were significantly greater after blockade of central alpha-MSH. The results suggest that antiinflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of proinflammatory mediators. alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro. Combined central and peripheral influences can be beneficial in treatment of sepsis.

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

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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...

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

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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

Blockades of mitogen-activated protein kinase and calcineurin both change fibre-type markers in skeletal muscle culture

DEFF Research Database (Denmark)

Higginson, James; Wackerhage, Henning; Woods, Niall

2002-01-01

A and mitogen-activated protein kinase kinase (MEK1/2) blockade with U0126 upon myosin heavy chain (MHC) isoform mRNA levels and activities of metabolic enzymes after 1 day, 3 days and 7 days of treatment in primary cultures of spontaneously twitching rat skeletal muscle. U0126 treatment significantly decreased......Activation of either the calcineurin or the extracellular signal-regulated kinase (ERK1/2) pathway increases the percentage of slow fibres in vivo suggesting that both pathways can regulate fibre phenotypes in skeletal muscle. We investigated the effect of calcineurin blockade with cyclosporin...

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

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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.

The Impact of Renin-Angiotensin System Blockade on Renal Outcomes and Mortality in Pre-Dialysis Patients with Advanced Chronic Kidney Disease.

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Oh, Yun Jung; Kim, Sun Moon; Shin, Byung Chul; Kim, Hyun Lee; Chung, Jong Hoon; Kim, Ae Jin; Ro, Han; Chang, Jae Hyun; Lee, Hyun Hee; Chung, Wookyung; Lee, Chungsik; Jung, Ji Yong

2017-01-01

Renin-angiotensin-system (RAS) blockade is thought to slow renal progression in patients with chronic kidney disease (CKD). However, it remains uncertain if the habitual use of RAS inhibitors affects renal progression and outcomes in pre-dialysis patients with advanced CKD. In this multicenter retrospective cohort study, we identified 2,076 pre-dialysis patients with advanced CKD (stage 4 or 5) from a total of 33,722 CKD patients. RAS blockade users were paired with non-users for analyses using inverse probability of treatment-weighted (IPTW) and propensity score (PS) matching. The outcomes were renal death, all-cause mortality, hospitalization for hyperkalemia, and interactive factors as composite outcomes. RAS blockade users showed an increased risk of renal death in PS-matched analysis (hazard ratio [HR], 1.381; 95% CI, 1.071-1.781; P = 0.013), which was in agreement with the results of IPTW analysis (HR, 1.298; 95% CI, 1.123-1.500; P renal outcome without improving all-cause mortality. Further studies are warranted to determine whether withholding RAS blockade may lead to better outcomes in these patients.

Sulfur passivation of semi-insulating GaAs: Transition from Coulomb blockade to weak localization regime

Energy Technology Data Exchange (ETDEWEB)

Bagraev, N. T., E-mail: Bagraev@mail.ioffe.ru [Ioffe Institute (Russian Federation); Chaikina, E. I. [Centro de Investigacion Cientifica y de Educacion Superior de Ensenada, Division de Fisica Aplicada (Mexico); Danilovskii, E. Yu.; Gets, D. S.; Klyachkin, L. E.; L’vova, T. V.; Malyarenko, A. M. [Ioffe Institute (Russian Federation)

2016-04-15

The sulfur passivation of the semi-insulating GaAs bulk (SI GaAs) grown in an excess phase of arsenic is used to observe the transition from the Coulomb blockade to the weak localization regime at room temperature. The I–V characteristics of the SI GaAs device reveal nonlinear behavior that appears to be evidence of the Coulomb blockade process as well as the Coulomb oscillations. The sulfur passivation of the SI GaAs device surface results in enormous transformation of the I–V characteristics that demonstrate the strong increase of the resistance and Coulomb blockade regime is replaced by the electron tunneling processes. The results obtained are analyzed within frameworks of disordering SI GaAs surface that is caused by inhomogeneous distribution of the donor and acceptor anti-site defects which affects the conditions of quantum- mechanical tunneling. Weak localization processes caused by the preservation of the Fermi level pinning are demonstrated by measuring the negative magnetoresistance in weak magnetic fields at room temperature. Finally, the studies of the magnetoresistance at higher magnetic fields reveal the h/2e Aharonov–Altshuler–Spivak oscillations with the complicated behavior due to possible statistical mismatch of the interference paths in the presence of different microdefects.

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

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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.

Angiotensin II type 1 receptor blockade by telmisartan prevents stress-induced impairment of memory via HPA axis deactivation and up-regulation of brain-derived neurotrophic factor gene expression.

Science.gov (United States)

Wincewicz, D; Juchniewicz, A; Waszkiewicz, N; Braszko, J J

2016-09-01

Physical and psychological aspects of chronic stress continue to be a persistent clinical problem for which new pharmacological treatment strategies are aggressively sought. By the results of our previous work it has been demonstrated that telmisartan (TLM), an angiotensin type 1 receptor (AT1) blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor gamma (PPARγ), alleviates stress-induced cognitive decline. Understanding of mechanistic background of this phenomenon is hampered by both dual binding sites of TLM and limited data on the consequences of central AT1 blockade and PPARγ activation. Therefore, a critical need exists for progress in the characterization of this target for pro-cognitive drug discovery. An unusual ability of novel ARBs to exert various PPARγ binding activities is commonly being viewed as predominant over angiotensin blockade in terms of neuroprotection. Here we aimed to verify this hypothesis using an animal model of chronic psychological stress (Wistar rats restrained 2.5h daily for 21days) with simultaneous oral administration of TLM (1mg/kg), GW9662 - PPARγ receptor antagonist (0.5mg/kg), or both in combination, followed by a battery of behavioral tests (open field, elevated plus maze, inhibitory avoidance - IA, object recognition - OR), quantitative determination of serum corticosterone (CORT) and evaluation of brain-derived neurotrophic factor (BDNF) gene expression in the medial prefrontal cortex (mPFC) and hippocampus (HIP). Stressed animals displayed decreased recall of the IA behavior (pBDNF in the mPFC (paxis deactivation associated with changes in primarily cortical gene expression. This study confirms the dual activities of TLM that controls hypertension and cognition through AT1 blockade. Copyright © 2016 Elsevier Inc. All rights reserved.

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

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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

Interaction Between the Central and Peripheral Effects of Insulin in Controlling Hepatic Glucose Metabolism in the Conscious Dog

Science.gov (United States)

Ramnanan, Christopher J.; Kraft, Guillaume; Smith, Marta S.; Farmer, Ben; Neal, Doss; Williams, Phillip E.; Lautz, Margaret; Farmer, Tiffany; Donahue, E. Patrick; Cherrington, Alan D.; Edgerton, Dale S.

2013-01-01

The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model. PMID:23011594

Blockade of the Naloxone-induced Aversion in Morphine-conditioned Wistar Rats by L-Arginine Intra-central Amygdala

Directory of Open Access Journals (Sweden)

Mahnaz Rahimpour

2011-03-01

Full Text Available AbstractObjective(sSingle injection of naloxone, a selective antagonist of morphine, prior to the drug conditioning testing was used to investigate on morphine dependence.Materials and MethodsConditioning to morphine (2.5-10 mg/kg, s.c. was established in adult male Wistar rats (weighing 200-250 g using an unbiased procedure. Nitric oxide agents were microinjected into the central amygdala prior to naloxone-paired place conditioning testing.ResultsThe results showed that morphine produced a significant dose-dependent place preference in animals. Naloxone (0.1-0.4 mg/kg, i.p. injections pre-testing of the response to morphine (7.5 mg/kg, s.c. caused a significant aversion at the higher doses (0.4 mg/kg, i.p.. This response was reversed by microinjection of L-arginine (0.3-3 µg/rat, intra-central amygdala prior to naloxone on the day of the testing. The response to L-arginine was blocked by pre-injection of NG-nitro-L-arginine methyl ester (L-NAME (intra-central amygdala.ConclusionA single injection of naloxone on the test day of morphine place conditioning may simply reveal the occurrence of morphine dependence in rats, and that the nitric oxide in the central amygdala most likely plays a key role in this phenomenon.

CT-guided stellate ganglion blockade vs. radiofrequency neurolysis in the management of refractory type I complex regional pain syndrome of the upper limb

Energy Technology Data Exchange (ETDEWEB)

Kastler, Adrian [University Hospital CHU Gabriel Montpied, Radiology Department, Clermont-Ferrand (France); Franche Comte University, I4S Laboratory-EA 4268-IFR 133, Besancon (France); CHU Clermont-Ferrand, Hopital Gabriel Montpied, Clermont-Ferrand (France); Aubry, Sebastien; Kastler, Bruno [University Hospital CHU Jean Minjoz, Radiology and Interventional Pain Unit, Besancon (France); Franche Comte University, I4S Laboratory-EA 4268-IFR 133, Besancon (France); Sailley, Nicolas; Michalakis, Demosthene [University Hospital CHU Jean Minjoz, Radiology and Interventional Pain Unit, Besancon (France); Siliman, Gaye [University Hospital CHU St Jacques, Clinical Investigation Center, Besancon (France); Gory, Guillaume [Franche Comte University, I4S Laboratory-EA 4268-IFR 133, Besancon (France); Lajoie, Jean-Louis [University Hospital CHU Jean Minjoz, Pain evaluation and Management Unit, Besancon (France)

2013-05-15

To describe and evaluate the feasibility and efficacy of CT-guided radiofrequency neurolysis (RFN) vs. local blockade of the stellate ganglion in the management of chronic refractory type I complex regional pain syndrome (CRPS) of the upper limb. Sixty-seven patients were included in this retrospective study between 2000 and 2011. All suffered from chronic upper limb type I CRPS refractory to conventional pain therapies. Thirty-three patients underwent stellate ganglion blockade and 34 benefited from radiofrequency neurolysis of the stellate ganglion. CT guidance was used in both groups. The procedure was considered effective when pain relief was {>=}50 %, lasting for at least 2 years. Thirty-nine women (58.2 %) and 28 men (41.8 %) with a mean age of 49.5 years were included in the study. Univariate analysis performed on the blockade and RFN groups showed a significantly (P < 0.0001) higher success rate in the RFN group (67.6 %, 23/34) compared with the blockade group (21.2 %, 7/33) with an odds ratio of 7.76. CT-guided radiofrequency neurolysis of the stellate ganglion is a safe and successful treatment of chronic refractory type I CRPS of the upper limb. It appears to be more effective than stellate ganglion blockade. (orig.)

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

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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

Tapping into the Forest Management Assistance Programs

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John L. Greene; Terry K. Haines

1998-01-01

Use of federal and state forest management assistance programs can enable nonindustial private forest owners to reduce their management expenses and practice better stewardship. This paper summarizes six federal and twelve state assistance programs available to owners in the North Central states. It also describes how to calculate the amount of a government...

Israel’s Blockade of Gaza, the Mavi Marmara Incident, and Its Aftermath

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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

Development of Phantom Limb Pain after Femoral Nerve Block

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Sadiah Siddiqui

2014-01-01

Full Text Available Historically, phantom limb pain (PLP develops in 50–80% of amputees and may arise within days following an amputation for reasons presently not well understood. Our case involves a 29-year-old male with previous surgical amputation who develops PLP after the performance of a femoral nerve block. Although there have been documented cases of reactivation of PLP in amputees after neuraxial technique, there have been no reported events associated with femoral nerve blockade. We base our discussion on the theory that symptoms of phantom limb pain are of neuropathic origin and attempt to elaborate the link between regional anesthesia and PLP. Further investigation and understanding of PLP itself will hopefully uncover a relationship between peripheral nerve blocks targeting an affected limb and the subsequent development of this phenomenon, allowing physicians to take appropriate steps in prevention and treatment.

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

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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.

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.

Evaluation of spinal anesthesia blockade time with 0.5% hyperbaric bupivacaine, with or without sufentanil, in chronic opioid users: a randomized clinical trial.

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Sadeghi, Mostafa; Yekta, Reza Atef; Azimaraghi, Omid; Barzin, Gilda; Movafegh, Ali

2016-01-01

The primary outcome of this study was to evaluate the effect of adding sufentanil to hyperbaric bupivacaine on duration of sensory blockade of spinal anesthesia in chronic opioid users in comparison with non-addicts. Sixty patients scheduled for orthopedic surgery under spinal anesthesia were allocated into four groups: group 1 (no history of opium use who received intrathecal hyperbaric bupivacaine along with 1mL saline as placebo); group 2 (no history of opium use who received intrathecal bupivacaine along with 1mL sufentanil [5μg]); group 3 (positive history of opium use who received intrathecal bupivacaine along with 1mL saline as placebo) and group 4 (positive history of opium use who received intrathecal bupivacaine along with 1mL sufentanil [5μg]). The onset time and duration of sensory and motor blockade were measured. The duration of sensory blockade in group 3 was 120±23.1min which was significantly less than other groups (G1=148±28.7, G2=144±26.4, G4=139±24.7, p=0.007). The duration of motor blockade in group 3 was 145±30.0min which was significantly less than other groups (G1=164±36.0, G2=174±26.8, G4=174±24.9, p=0.03). Addition of 5μg intrathecal sufentanil to hyperbaric bupivacaine in chronic opioid users lengthened the sensory and motor duration of blockade to be equivalent to blockade measured in non-addicts. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

Anisotropic Pauli Spin Blockade of Holes in a GaAs Double Quantum Dot

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Wang, Qingwen; Klochan, Oleh; Hung, Jo-Tzu; Culcer, Dimitrie; Farrer, Ian; Ritchie, David; Hamilton, Alex

Electrically defined semiconductor quantum dots are appealing systems for spin manipulation and quantum information processing. Thanks to the weak hyperfine interaction and the strong spin-orbit interaction, heavy-holes in GaAs are promising candidates for all-electrical spin manipulation. However, making stable quantum dots in GaAs has only become possible recently, mainly because of difficulties in device fabrication and device stability. Here we present electrical transport measurements of heavy-holes in a lateral double quantum dot based on a GaAs /AlxGa1 - x As heterostructure. We observe clear Pauli spin blockade and show that the lifting of the spin blockade by an external magnetic field is extremely anisotropic. Numerical calculations of heavy-hole transport through a double quantum dot in the presence of strong spin-orbit interaction demonstrate quantitative agreement with experimental results, which indicates that the observed anisotropy can be explained by the anisotropic hole g-factor and the surface Dresselhaus spin-orbit coupling.

Robot assistant versus human or another robot assistant in patients undergoing laparoscopic cholecystectomy.

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Gurusamy, Kurinchi Selvan; Samraj, Kumarakrishnan; Fusai, Giuseppe; Davidson, Brian R

2012-09-12

The role of a robotic assistant in laparoscopic cholecystectomy is controversial. While some trials have shown distinct advantages of a robotic assistant over a human assistant others have not, and it is unclear which robotic assistant is best. The aims of this review are to assess the benefits and harms of a robot assistant versus human assistant or versus another robot assistant in laparoscopic cholecystectomy, and to assess whether the robot can substitute the human assistant. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (until February 2012) for identifying the randomised clinical trials. Only randomised clinical trials (irrespective of language, blinding, or publication status) comparing robot assistants versus human assistants in laparoscopic cholecystectomy were considered for the review. Randomised clinical trials comparing different types of robot assistants were also considered for the review. Two authors independently identified the trials for inclusion and independently extracted the data. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI) using the fixed-effect and the random-effects models based on intention-to-treat analysis, when possible, using Review Manager 5. We included six trials with 560 patients. One trial involving 129 patients did not state the number of patients randomised to the two groups. In the remaining five trials 431 patients were randomised, 212 to the robot assistant group and 219 to the human assistant group. All the trials were at high risk of bias. Mortality and morbidity were reported in only one trial with 40 patients. There was no mortality or morbidity in either group. Mortality and morbidity were not reported in the remaining trials. Quality of life or the proportion of patients who were discharged as day-patient laparoscopic cholecystectomy patients were not reported in any

Myostatin deficiency but not anti-myostatin blockade induces marked proteomic changes in mouse skeletal muscle.

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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.

Central-Approach Surgical Repair of Coarctation of the Aorta with a Back-up Left Ventricular Assist Device for an Infant Presenting with Severe Left Ventricular Dysfunction

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Tae Hoon Kim

2015-12-01

Full Text Available A two-month-old infant presented with coarctation of the aorta, severe left ventricular dysfunction, and moderate to severe mitral regurgitation. Through median sternotomy, the aortic arch was repaired under cardiopulmonary bypass and regional cerebral perfusion. The patient was postoperatively supported with a left ventricular assist device for five days. Left ventricular function gradually improved, eventually recovering with the concomitant regression of mitral regurgitation. Prompt surgical repair of coarctation of the aorta is indicated for patients with severe left ventricular dysfunction. A central approach for surgical repair with a back-up left ventricular assist device is a safe and effective treatment strategy for these patients.

Central-Approach Surgical Repair of Coarctation of the Aorta with a Back-up Left Ventricular Assist Device for an Infant Presenting with Severe Left Ventricular Dysfunction.

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Kim, Tae Hoon; Shin, Yu Rim; Kim, Young Sam; Kim, Do Jung; Kim, Hyohyun; Shin, Hong Ju; Htut, Aung Thein; Park, Han Ki

2015-12-01

A two-month-old infant presented with coarctation of the aorta, severe left ventricular dysfunction, and moderate to severe mitral regurgitation. Through median sternotomy, the aortic arch was repaired under cardiopulmonary bypass and regional cerebral perfusion. The patient was postoperatively supported with a left ventricular assist device for five days. Left ventricular function gradually improved, eventually recovering with the concomitant regression of mitral regurgitation. Prompt surgical repair of coarctation of the aorta is indicated for patients with severe left ventricular dysfunction. A central approach for surgical repair with a back-up left ventricular assist device is a safe and effective treatment strategy for these patients.

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase.

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Sharma, Rajni; Di Dalmazi, Giulia; Caturegli, Patrizio

2016-08-01

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2(h4) mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. NOD-H2(h4) mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment. This study

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Science.gov (United States)

Sharma, Rajni; Di Dalmazi, Giulia

2016-01-01

Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. Methods: NOD-H2h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory

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

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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.

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.

First-principles investigation of quantum transport through an endohedral N@C60 in the Coulomb blockade regime.

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Yu, Zhizhou; Chen, Jian; Zhang, Lei; Wang, Jian

2013-12-11

We report an investigation of Coulomb blockade transport through an endohedral N@C60 weakly coupled with aluminum leads, employing the first-principles method combined with the Keldysh non-equilibrium Green's function derived from the equation of motion beyond the Hartree-Fock approximation. The differential conductance characteristics of the molecular device are calculated within the Coulomb blockade regime, which shows the Coulomb diamond as observed experimentally. When the gate voltage is less than that of the degeneracy point, there are two peaks in the differential conductance with an excited state induced by the change of the exchange interaction between the spin of C60 and the encapsulated nitrogen atom due to the transition from N@C(1-)(60) to N@C(2-)(60), while for a gate voltage larger than that of the degeneracy point, no excited state is available due to the quenching of exchange energy. As a result, there is only one Coulomb blockade peak in the differential conductance from the electron tunneling through the highest energy level below the Fermi level. Our first-principles results are in good agreement with experimental data obtained by an endohedral N@C60 molecular device.

Dissipation-induced dipole blockade and antiblockade in driven Rydberg systems

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Young, Jeremy T.; Boulier, Thomas; Magnan, Eric; Goldschmidt, Elizabeth A.; Wilson, Ryan M.; Rolston, Steven L.; Porto, James V.; Gorshkov, Alexey V.

2018-02-01

We study theoretically and experimentally the competing blockade and antiblockade effects induced by spontaneously generated contaminant Rydberg atoms in driven Rydberg systems. These contaminant atoms provide a source of strong dipole-dipole interactions and play a crucial role in the system's behavior. We study this problem theoretically using two different approaches. The first is a cumulant expansion approximation, in which we ignore third-order and higher connected correlations. Using this approach for the case of resonant drive, a many-body blockade radius picture arises, and we find qualitative agreement with previous experimental results. We further predict that as the atomic density is increased, the Rydberg population's dependence on Rabi frequency will transition from quadratic to linear dependence at lower Rabi frequencies. We study this behavior experimentally by observing this crossover at two different atomic densities. We confirm that the larger density system has a smaller crossover Rabi frequency than the smaller density system. The second theoretical approach is a set of phenomenological inhomogeneous rate equations. We compare the results of our rate-equation model to the experimental observations [E. A. Goldschmidt et al., Phys. Rev. Lett. 116, 113001 (2016), 10.1103/PhysRevLett.116.113001] and find that these rate equations provide quantitatively good scaling behavior of the steady-state Rydberg population for both resonant and off-resonant drives.

The effect of adhesion molecule blockade on pulmonary reperfusion injury.

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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.

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

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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.

Physician-assisted dying: thoughts drawn from Albert Camus' writing.

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Bozzaro, Claudia

2018-03-20

Physician-assisted dying (assisted suicide and euthanasia) is currently an intensely discussed topic in several countries. Despite differences in legislation and application, countries with end-of-life laws have similar eligibility criteria for assistance in dying: individuals must be in a hopeless situation and experience unbearable suffering. Hopelessness, as a basic aspect of the human condition, is a central topic in Albert Camus' philosophical work The Myth of Sisyphus, which addresses the question of suicide. Suffering in the face of a hopeless situation, and the way doctors approach this suffering, is the topic of his novel The Plague, which describes the story of a city confronted with a plague epidemic. In this paper, I draw philosophical and ethical conclusions about physician-assisted dying based on an analysis of central concepts in the work of Camus-specifically, those treated in The Myth of Sisyphus and The Plague. On the basis of my interpretation of Camus' work, I argue that hopelessness and unbearable suffering are useless as eligibility criteria for physician-assisted dying, given that they do not sufficiently elucidate where the line should be drawn between patients who should to be eligible for assistance and those who should not.

International assistance to upgrade the safety of Soviet-designed nuclear power plants. Selected activities in Eastern and Central Europe and the countries of the former Soviet Union

International Nuclear Information System (INIS)

Gillen, V.

1993-12-01

The overview is merely a snapshot of nuclear safety activities to assist the countries of Eastern and Central Europe and the former Soviet Union. While many other activities are planned or ongoing, this publication is meant to provide a general overview of the world community's commitment to improving the safety of Soviet-designed nuclear reactors

Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

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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.

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

Adrenergic blockade does not abolish elevated glucose turnover during bacterial infection

International Nuclear Information System (INIS)

Hargrove, D.M.; Bagby, G.J.; Lang, C.H.; Spitzer, J.J.

1988-01-01

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

Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte- stimulating hormone.

Science.gov (United States)

Delgado Hernàndez, R; Demitri, M T; Carlin, A; Meazza, C; Villa, P; Ghezzi, P; Lipton, J M; Catania, A

1999-01-01

The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central alpha-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-alpha and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central alpha-MSH. Intraperitoneal administration of the small dose of alpha-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central alpha-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central alpha-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation.

THE EFFECTS OF ACUTE AND CHRONIC STRESS ON ERYTHROCYTE DYNAMIC IN COMBINATION WITH ß–ADRENERGIC RECEPTORS BLOCKADE IN RATS

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Lucian Hritcu

2005-08-01

Full Text Available : 3 consecutive days propranolol hydrochloride administration (5 mg/kg b.w., subcutaneous injections under acute and chronic stress conditions causes changes of peripheral erythrocyte distribution in rats. The effects of acute stress and its combination with ȕ-adrenergic receptor blockade on erythrocyte dynamic were more pregnant beside the effects of chronic stress and its combination with ȕ-adrenergic receptor blockade, respectively. ȕ-adrenergic mechanisms were shown to be involved in regulation of erythrocyte dynamic in acute and chronic stress response.

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

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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.

Connexin Hemichannel Blockade Is Neuroprotective after Asphyxia in Preterm Fetal Sheep

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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...

Femoral Nerve Injury Following a Lumbar Plexus Blockade

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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.

Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation

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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.

Sugammadex to reverse neuromuscular blockade in a child with a past history of cardiac transplantation.

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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.

Analgesia/anesthesia for external cephalic version.

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Weiniger, Carolyn F

2013-06-01

Professional society guidelines recommend that women with breech presentation be delivered surgically due to a higher incidence of fetal risks compared with vaginal delivery. An alternative is attempted external cephalic version, which if successful, enables attempted vaginal delivery. Attitudes towards external cephalic version (ECV) will be considered in this review, along with pain relief methods and their impact on ECV success rates. Articles suggest that ECV is infrequently offered, due to both physician and patient factors. Success of ECV is higher in multiparous women, complete breech, posterior placenta, or smaller fetus. Preterm ECV performance does not increase vaginal delivery rates. Neuraxial techniques (spinal or epidural) significantly increase ECV success rates, as do moxibustion and hypnosis. Four reviews summarized studies considering ECV and neuraxial techniques. These reviews suggest that neuraxial techniques using high (surgical) doses of local anesthetic are efficacious compared with control groups not using anesthesia, whereas techniques using low-doses are not. Low-dose versus high-dose neuraxial analgesia/anesthesia has not been directly compared in a single study. Based on currently available data, the rate of cephalic presentation is not increased using neuraxial techniques, but vaginal delivery rates are higher. ECV appears to be a low-risk procedure. The logistics of routine ECV and provision of optimal neuraxial techniques for successful ECV require additional research. Safety aspects of neuraxial anesthesia for ECV require further investigation.

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)....

Fear memory in a neurodevelopmental model of schizophrenia based on the postnatal blockade of NMDA receptors.

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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.

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy

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Junyu Long

2017-08-01

Full Text Available Abstract Gastrointestinal (GI malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

PD-1/PD-L blockade in gastrointestinal cancers: lessons learned and the road toward precision immunotherapy.

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Long, Junyu; Lin, Jianzhen; Wang, Anqiang; Wu, Liangcai; Zheng, Yongchang; Yang, Xiaobo; Wan, Xueshuai; Xu, Haifeng; Chen, Shuguang; Zhao, Haitao

2017-08-03

Gastrointestinal (GI) malignancies are the most prevalent tumors worldwide, with increasing incidence and mortality. Although surgical resection, chemotherapy, radiotherapy, and molecular targeted therapy have led to significant advances in the treatment of GI cancer patients, overall survival is still low. Therefore, alternative strategies must be identified to improve patient outcomes. In the tumor microenvironment, tumor cells can escape the host immune response through the interaction of PD-1 and PD-L, which inhibits the function of T cells and tumor-infiltrating lymphocytes while increasing the function of immunosuppressive T regulatory cells. The use of an anti-PD-1/PD-L blockade enables reprogramming of the immune system to efficiently identify and kill tumor cells. In recent years, the efficacy of PD-1/PD-L blockade has been demonstrated in many tumors, and this treatment is expected to be a pan-immunotherapy for tumors. Here, we review the signaling pathway underlying the dysregulation of PD-1/PD-L in tumors, summarize the current clinical data for PD-1/PD-L inhibitors in GI malignancies, and discuss road toward precision immunotherapy in relation to PD-1/PD-L blockade. The preliminary data for PD-1/PD-L inhibitors are encouraging, and the precision immunotherapy of PD-1/PD-L inhibitors will be a viable and pivotal clinical strategy for GI cancer therapy.

Complex Regional Pain Syndrome Revived by Epileptic Seizure Then Disappeared Soon during Treatment with Regional Intravenous Nerve Blockade: A Case Report

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Masahiko Sumitani

2011-01-01

Full Text Available We present a case of complex regional pain syndrome (CRPS, in which symptoms, including burning pain and severe allodynia, were alleviated by using a regional intravenous nerve blockade (Bier block combined with physiotherapy, but reappeared following an epileptic seizure. Symptoms disappeared again following control of epileptic discharges, as revealed by single-photon emission computed tomography (SPECT and electroencephalography (EEG results. Although systemic toxicity of a local anesthetic applied by Bier block was suspected as a cause of the first seizure, the patient did not present any other toxic symptoms, and seizures repeatedly occurred after Bier block cessation; the patient was then diagnosed as having temporal symptomatic epilepsy. This case suggests that symptoms of CRPS may be sustained by abnormal brain conditions, and our findings contribute to the understanding of how the central nervous system participates in maintaining pain and allodynia associated with CRPS.

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

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

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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

Room-temperature current blockade in atomically defined single-cluster junctions

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Lovat, Giacomo; Choi, Bonnie; Paley, Daniel W.; Steigerwald, Michael L.; Venkataraman, Latha; Roy, Xavier

2017-11-01

Fabricating nanoscopic devices capable of manipulating and processing single units of charge is an essential step towards creating functional devices where quantum effects dominate transport characteristics. The archetypal single-electron transistor comprises a small conducting or semiconducting island separated from two metallic reservoirs by insulating barriers. By enabling the transfer of a well-defined number of charge carriers between the island and the reservoirs, such a device may enable discrete single-electron operations. Here, we describe a single-molecule junction comprising a redox-active, atomically precise cobalt chalcogenide cluster wired between two nanoscopic electrodes. We observe current blockade at room temperature in thousands of single-cluster junctions. Below a threshold voltage, charge transfer across the junction is suppressed. The device is turned on when the temporary occupation of the core states by a transiting carrier is energetically enabled, resulting in a sequential tunnelling process and an increase in current by a factor of ∼600. We perform in situ and ex situ cyclic voltammetry as well as density functional theory calculations to unveil a two-step process mediated by an orbital localized on the core of the cluster in which charge carriers reside before tunnelling to the collector reservoir. As the bias window of the junction is opened wide enough to include one of the cluster frontier orbitals, the current blockade is lifted and charge carriers can tunnel sequentially across the junction.

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

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

2015-12-01

In healthy humans, tests of the hypothesis that lactic acid, PGE2, or ATP plays a role in evoking the exercise pressor reflex proved controversial. The findings in humans resembled ours in decerebrate rats that individual blockade of the receptors to lactic acid, PGE2, and ATP had only small effects on the exercise pressor reflex provided that the muscles were freely perfused. This similarity between humans and rats prompted us to test the hypothesis that in rats with freely perfused muscles combined receptor blockade is required to attenuate the exercise pressor reflex. We first compared the reflex before and after injecting either PPADS (10 mg/kg), a P2X receptor antagonist, APETx2 (100 μg/kg), an activating acid-sensing ion channel 3 (ASIC) channel antagonist, or L161982 (2 μg/kg), an EP4 receptor antagonist, into the arterial supply of the hindlimb of decerebrated rats. We then examined the effects of combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the exercise pressor reflex using the same doses, intra-arterial route, and time course of antagonist injections as those used for individual blockade. We found that neither PPADS (n = 5), APETx2 (n = 6), nor L161982 (n = 6) attenuated the reflex. In contrast, combined blockade of these receptors (n = 7) attenuated the peak (↓27%, P reflex. Combined blockade injected intravenously had no effect on the reflex. We conclude that combined blockade of P2X receptors, ASIC3 channels, and EP4 receptors on the endings of thin fiber muscle afferents is required to attenuate the exercise pressor reflex in rats with freely perfused hindlimbs. Copyright © 2015 the American Physiological Society.

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)....

Neonatal blockade of GABA-A receptors alters behavioral and physiological phenotypes in adult mice.

Science.gov (United States)

Salari, Ali-Akbar; Amani, Mohammad

2017-04-01

Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

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Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

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...

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,

13 CFR 120.1710 - Central servicing of the Program.

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2010-01-01

... 13 Business Credit and Assistance 1 2010-01-01 2010-01-01 false Central servicing of the Program. 120.1710 Section 120.1710 Business Credit and Assistance SMALL BUSINESS ADMINISTRATION BUSINESS LOANS Establishment of SBA Secondary Market Guarantee Program for First Lien Position 504 Loan Pools § 120.1710...

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

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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

Hemodynamic and tissue oxygenation responses to exercise and beta-adrenergic blockade in patients with hyperthyroidism.

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Monachini, Maristela C; Lage, Silvia G; Ran, Miguel A N; Cardoso, Rita H A; Medeiros, Caio; Caramelli, Bruno; Sposito, Andrei C; Ramires, José A F

2004-07-01

Exercise-induced dyspnea is a frequent feature in patients with hyperthyroidism. Data from clinical studies to elucidate the origin of this symptom are lacking. In the current study, we examined the hemodynamic and oxygenation responses to exercise and beta-adrenergic blockade in patients with hyperthyroidism and their relationship with dyspnea. Hemodynamic studies were performed under resting conditions and after isotonic exercise in 15 patients with hyperthyroidism and 11 control subjects. Exercise was applied using a bicycle ergometer, with progressive loads. In the hyperthyroid group, measurements were repeated at rest and during supine exercise after administering 15 mg of intravenous metoprolol. End-diastolic pulmonary artery pressure and cardiac index were higher in the hyperthyroid group than in controls (18.6 +/- 5.3 vs. 11.2 +/- 4.9 mmHg; p = 0.02, and 6.0 +/- 1.7 vs. 2.8 +/- 0.5 l/min/m2; p = 0.0001, respectively). After exercise, there was an increase in end-diastolic pulmonary artery pressure in the hyperthyroid group (18.6 +/- 5.3 to 25.5 +/- 9.9 mmHg; p = 0.02), revealing impaired cardiocirculatory reserve. Pulmonary arteriolar resistance increased significantly in parallel with end-diastolic pulmonary artery pressure after drug administration, suggesting an inadequate cardiovascular response after beta blockade in patients with hyperthyroidism. We observed that functional left ventricular reserve is impaired in patients with hyperthyroidism, suggesting an explanation for the frequent symptom of dyspnea and impaired exercise tolerance. Moreover, we also suggest that beta-adrenergic blockade may adversely affect cardiovascular function in patients with hyperthyroidism.

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

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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

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.

Effect of lung-protective ventilation-induced respiratory acidosis on the duration of neuromuscular blockade by rocuronium.

Science.gov (United States)

Taguchi, Shinya; Ono, Kazumi; Hidaka, Hidekuni; Koyama, Yusuke

2016-12-01

The purpose of this study was to elucidate whether lung-protective ventilation-induced respiratory acidosis increased the duration of neuromuscular blockade by rocuronium. A total of 72 patients were enrolled. After the induction of general anesthesia, rocuronium 0.6 mg/kg real body weight was administered. Tidal volume and positive end-expiratory pressure were randomly assigned as either 10 ml/kg predicted body weight and 0 cmH 2 O (group S) or 6 ml/kg and 5 cmH 2 O (group L), respectively. Respiratory rate was started at 10/min. Neuromuscular blockade was monitored by acceleromyography at the adductor pollicis with train-of-four stimulation. The time from the initial bolus injection of rocuronium to first recovery of the first twitch was defined as DUR1. Immediately, rocuronium 0.15 mg/kg was administered. The time from first recovery of the first twitch to second recovery of the first twitch was defined as DUR2. We also measured arterial pH (pH1 and pH2, respectively). Data from 66 patients (33 each in groups L and S) were eventually available. pH1 and pH2 were significantly lower in group L compared with group S [pH1: 7.308 (7.288-7.334) vs. 7.439 (7.423-7.466); p respiratory acidosis increased the duration of neuromuscular blockade by rocuronium.

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Science.gov (United States)

Lingis, Melissa; Richards, Elaine M.

2011-01-01

During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus. PMID:21205934

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.

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.

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

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

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.

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.

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.

Negative Pressure Pulmonary Edema after Reversing Rocuronium-Induced Neuromuscular Blockade by Sugammadex

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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.

Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T.

Science.gov (United States)

Yoon, Dok Hyun; Osborn, Mark J; Tolar, Jakub; Kim, Chong Jai

2018-01-24

Chimeric antigen receptor (CAR) T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade.

Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts: Combination or Built-In CAR-T

Directory of Open Access Journals (Sweden)

Dok Hyun Yoon

2018-01-01

Full Text Available Chimeric antigen receptor (CAR T cell therapy represents the first U.S. Food and Drug Administration approved gene therapy and these engineered cells function with unprecedented efficacy in the treatment of refractory CD19 positive hematologic malignancies. CAR translation to solid tumors is also being actively investigated; however, efficacy to date has been variable due to tumor-evolved mechanisms that inhibit local immune cell activity. To bolster the potency of CAR-T cells, modulation of the immunosuppressive tumor microenvironment with immune-checkpoint blockade is a promising strategy. The impact of this approach on hematological malignancies is in its infancy, and in this review we discuss CAR-T cells and their synergy with immune-checkpoint blockade.

Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis

DEFF Research Database (Denmark)

Köhler, Ralf; Wulff, Heike; Eichler, Ines

2003-01-01

hyperplasia was accompanied by decreased neointimal cell content, with no change in the rate of apoptosis or collagen content. CONCLUSIONS: The switch toward IKCa1 expression may promote excessive neointimal VSMC proliferation. Blockade of IKCa1 could therefore represent a new therapeutic strategy to prevent...

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....

Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy : a randomised clinical trial

NARCIS (Netherlands)

Kwakernaak, Arjan J.; Krikken, Jan A.; Binnenmars, S. Heleen; Visser, Folkert W.; Hemmelder, Marc H.; Woittiez, Arend-Jan; Groen, Henk; Laverman, Gozewijn D.; Navis, Gerjan

Background Reduction of dietary sodium intake or diuretic treatment increases renin-angiotensin-aldosterone system (RAAS) blockade efficacy in non-diabetic nephropathy. We aimed to investigate the effect of sodium restriction and the diuretic hydrochlorothiazide, separately and in combination, added

Food assistance is associated with improved body mass index, food security and attendance at clinic in an HIV program in central Haiti: a prospective observational cohort study

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Ivers Louise C

2010-08-01

Full Text Available Abstract Background Few data are available to guide programmatic solutions to the overlapping problems of undernutrition and HIV infection. We evaluated the impact of food assistance on patient outcomes in a comprehensive HIV program in central Haiti in a prospective observational cohort study. Methods Adults with HIV infection were eligible for monthly food rations if they had any one of: tuberculosis, body mass index (BMI 2, CD4 cell count 3 (in the prior 3 months or severe socio-economic conditions. A total of 600 individuals (300 eligible and 300 ineligible for food assistance were interviewed before rations were distributed, at 6 months and at 12 months. Data collected included demographics, BMI and food insecurity score (range 0 - 20. Results At 6- and 12-month time-points, 488 and 340 subjects were eligible for analysis. Multivariable analysis demonstrated that at 6 months, food security significantly improved in those who received food assistance versus who did not (-3.55 vs -0.16; P Conclusions Food assistance was associated with improved food security, increased BMI, and improved adherence to clinic visits at 6 and 12 months among people living with HIV in Haiti and should be part of routine care where HIV and food insecurity overlap.

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...

Value of the addition of Amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade

NARCIS (Netherlands)

Dunselman, PHJM; Bouwens, LHM; Herweijer, AH; Bernink, PJLM

1998-01-01

Anginal patients who remain symptomatic despite optimally dosed beta blockade may also be given dihydropyridine calcium antagonists. This treatment regimen was examined in a double-blind parallel, randomized, controlled study in 147 patients with angina and positive bicycle exercise tests despite

Unexpected High Sensory Blockade during Continuous Spinal Anesthesiology (CSA in an Elderly Patient

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R. Ketelaars

2012-01-01

Full Text Available A 98-year-old woman presented for a hemiarthroplasty of the left hip. Because of her age and cardiac and pulmonary co-existing diseases we decided to provide adequate regional anesthesia by continuous spinal anesthesia. Fragmented doses of isobaric bupivacaine 0.5% were administered through a system consisting of a spinal catheter connected to an antimicrobial filter. After an uneventful surgical procedure, prior to removal of the catheter, this system was flushed with 10 mL of normal saline in order to try to prevent post-dural-puncture headache. After arrival at the postanesthesia care unit and fifteen minutes after removal of the catheter the patient suffered an unexpected high thoracic sensory blockade and hypotension requiring treatment. The continuous spinal anesthesia technique can be used in selected cases to be able to administer local anesthetic agents in a slow and controlled manner to reach the desired effect. The risk of post-dural-puncture headache using this technique in elderly patients is very low and therefore precludes the need to try to prevent it. We have described a potentially dangerous complication of flushing a bupivacaine-filled system into the spinal canal of an elderly patient resulting in an undesirable high sensory blockade.

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

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...

Blockade of vascular adhesion protein-1 inhibits lymphocyte infiltration in rat liver allograft rejection.

Science.gov (United States)

Martelius, Timi; Salaspuro, Ville; Salmi, Marko; Krogerus, Leena; Höckerstedt, Krister; Jalkanen, Sirpa; Lautenschlager, Irmeli

2004-12-01

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174-5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 +/- 1.0 and 2.4 +/- 1.0 corrected increment units, respectively) compared to control (6.6 +/- 1.0) (P VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection.

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

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.

Costimulation blockade and regulatory T-cells in a non-human primate model of kidney allograft transplantation

NARCIS (Netherlands)

Haanstra, Krista Geraldine

2008-01-01

Successful tolerance induction therapies in rodents are for the most part unsuccessful in larger primates. Costimulation blockade by anti-CD40 or anti-CD40 + anti-CD86 in the life-supporting kidney allograft model in the rhesus monkey prevented graft rejection during treatment but did not induce

[Comparative study of the central nervous system effect of the beta receptor blockaders pindolol and bisoprolol].

Science.gov (United States)

Görtelmeyer, R; Klingmann, I

1985-01-01

In a total of 36 volunteers with cardiac hyperreaction, investigations were carried out on the effect of bisoprolol (designated tradename: Concor), pindolol and placebo on central nervous functions with the aid of a reaction test, spiral aftereffect, tremor test and mood and sleep questionnaires. In the randomized double-blind study performed with 3 independent groups the volunteers received placebo, 2 X daily 10 mg of pindolol or 1 X daily 10 mg of bisoprolol for a period of 14 days. Bisoprolol is a new highly beta 1-selective adrenoceptor blocker with moderate lipophilia and without intrinsic sympathomimetic activity (ISA). When compared to placebo neither of the beta-adrenoceptor blockers induced any significant changes in mood, vigilance, tremor and reaction times. Moreover, under bisoprolol no negative effect on sleep quality or feeling refreshed after sleep was determined. Under pindolol, on the other hand, a significant impairment of sleep quality was observed after acute dosage and a decrease in feeling refreshed after sleep, continuing up to day 14 of treatment. It is presumed that, as bisoprolol and pindolol have comparable lipophilia, the different intensity with which the two preparations act on the central nervous system is connected with the ISA of pindolol. In the selected doses bisoprolol had a stronger effect on diastolic blood pressure and heart rate than pindolol and placebo.

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice.

Science.gov (United States)

Araújo, Wedson F; Naves, Marcelo A; Ravanini, Juliana N; Schor, Nestor; Teixeira, Vicente P C

2015-09-01

Renal cell carcinoma (RCC) is the most frequent type of cancer among renal neoplasms in adults and responds poorly to radiotherapy and chemotherapy. There is evidence that blockade of the renin-angiotensin system (RAS) might have antineoplastic effects. The aim of this study was to investigate the effects of RAS blockade on RCC in a murine model. Murine renal cancer cells (Renca) were injected (1 × 10(5)) into the subcapsular space of the left kidney of BALB/c mice (8 wk of age). The animals were divided into 4 groups: a control group (no treatment), angiotensin-receptor blockers group (losartan 100mg/kg/d), angiotensin-converting enzyme inhibitor group (captopril 10mg/kg/d), and angiotensin-receptor blockers +angiotensin-converting enzyme inhibitor group (losartan 100mg/kg/d +captopril 10mg/kg/d). The animals received the drugs by gavage for 21 days after inoculation, beginning 2 days before tumor induction, and were then euthanized. After killing the animals, the kidneys and lungs were removed, weighed, and processed for histopathological and immunohistochemical analyses. Angiogenesis and vascular microvessels were assessed with the antibodies anti-vascular endothelial growth factor and anti-CD34. Angiotensin II-inoculated animals developed renal tumors. Treated animals presented smaller tumors, regardless of the therapeutic regimen, and far fewer lung metastases in both quantity and dimension compared with the controls. The expression of vascular endothelial growth factor and CD34 were significantly decreased in renal tumors of treated animals compared with the controls. Our findings suggest that blockade of RAS decreases tumor proliferation and metastatic capacity of RCC in this experimental model. Copyright © 2015 Elsevier Inc. All rights reserved.

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

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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.

Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events.

Science.gov (United States)

Läubli, Heinz; Balmelli, Catharina; Kaufmann, Lukas; Stanczak, Michal; Syedbasha, Mohammedyaseen; Vogt, Dominik; Hertig, Astrid; Müller, Beat; Gautschi, Oliver; Stenner, Frank; Zippelius, Alfred; Egli, Adrian; Rothschild, Sacha I

2018-05-22

Immune checkpoint inhibiting antibodies were introduced into routine clinical practice for cancer patients. Checkpoint blockade has led to durable remissions in some patients, but may also induce immune-related adverse events (irAEs). Lung cancer patients show an increased risk for complications, when infected with influenza viruses. Therefore, vaccination is recommended. However, the efficacy and safety of influenza vaccination during checkpoint blockade and its influence on irAEs is unclear. Similarly, the influence of vaccinations on T cell-mediated immune reactions in patients during PD-1 blockade remains poorly defined. We vaccinated 23 lung cancer patients and 11 age-matched healthy controls using a trivalent inactivated influenza vaccine to investigate vaccine-induced immunity and safety during checkpoint blockade. We did not observe significant differences between patients and healthy controls in vaccine-induced antibody titers against all three viral antigens. Influenza vaccination resulted in protective titers in more than 60% of patients/participants. In cancer patients, the post-vaccine frequency of irAEs was 52.2% with a median time to occurrence of 3.2 months after vaccination. Six of 23 patients (26.1%) showed severe grade 3/4 irAEs. This frequency of irAEs might be higher than the rate previously published in the literature and the rate observed in a non-study population at our institution (all grades 25.5%, grade 3/4 9.8%). Although this is a non-randomized trial with a limited number of patients, the increased rate of immunological toxicity is concerning. This finding should be studied in a larger patient population.

PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro.

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Lina Quan

Full Text Available Epstein-Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL is an aggressive malignancy that is largely resistant to current therapeutic regimens, and is an attractive target for immune-based therapies. Anti-programmed death-1 (PD-1 antibodies showed encouraging anti-tumor effects in both preclinical models and advanced solid and hematological malignancies, but its efficacy against EBV+DLBCL is unknown. Herein, we performed experiments using co-culture system with T cells and lymphoma cell lines including EBV+DLBCL and EBV-DLBCL [including germinal center B-cell like (GCB-DLBCL and non-GCB-DLBCL] in vitro. We show that lymphoma cells augmented the expression of PD-1 on T cells, decreased the proliferation of T cells, and altered the secretion of multiple cytokines. However, through PD-1 blockade, these functions could be largely restored. Notbaly, the effect of PD-1 blockade on antitumor immunity was more effective in EBV+DLBCL than that in EBV-DLBCL in vitro. These results suggest that T-cell exhaustion and immune escape in microenvironment is one of the mechanisms underlying DLBCL; and PD-1 blockade could present as a efficacious immunotherapeutic treatment for EBV+DLBCL.

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

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

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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.

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.

Muscle-type nicotinic receptor blockade by diethylamine, the hydrophilic moiety of lidocaine

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Armando eAlberola-Die

2016-02-01

Full Text Available Lidocaine bears in its structure both an aromatic ring and a terminal amine, which can be protonated at physiological pH, linked by an amide group. Since lidocaine causes multiple inhibitory actions on nicotinic acetylcholine receptors (nAChRs, this work was aimed to determine the inhibitory effects of diethylamine (DEA, a small molecule resembling the hydrophilic moiety of lidocaine, on Torpedo marmorata nAChRs microtransplanted to Xenopus oocytes. Similarly to lidocaine, DEA reversibly blocked acetylcholine-elicited currents (IACh in a dose-dependent manner (IC50 close to 70 μM, but unlike lidocaine, DEA did not affect IACh desensitization. IACh inhibition by DEA was more pronounced at negative potentials, suggesting an open-channel blockade of nAChRs, although roughly 30% inhibition persisted at positive potentials, indicating additional binding sites outside the pore. DEA block of nAChRs in the resting state (closed channel was confirmed by the enhanced IACh inhibition when pre-applying DEA before its co-application with ACh, as compared with solely DEA and ACh co-application. Virtual docking assays provide a plausible explanation to the experimental observations in terms of the involvement of different sets of drug binding sites. So, at the nAChR transmembrane (TM domain, DEA and lidocaine shared binding sites within the channel pore, giving support to their open-channel blockade; besides, lidocaine, but not DEA, interacted with residues at cavities among the M1, M2, M3 and M4 segments of each subunit and also at intersubunit crevices. At the extracellular (EC domain, DEA and lidocaine binding sites were broadly distributed, which aids to explain the closed channel blockade observed. Interestingly, some DEA clusters were located at the α-γ interphase of the EC domain, in a cavity near the orthosteric binding site pocket; by contrast, lidocaine contacted with all α-subunit loops conforming the ACh binding site, both in α-γ and �

P2Y12 Receptor Localizes in the Renal Collecting Duct and Its Blockade Augments Arginine Vasopressin Action and Alleviates Nephrogenic Diabetes Insipidus.

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Zhang, Yue; Peti-Peterdi, Janos; Müller, Christa E; Carlson, Noel G; Baqi, Younis; Strasburg, David L; Heiney, Kristina M; Villanueva, Karie; Kohan, Donald E; Kishore, Bellamkonda K

2015-12-01

P2Y12 receptor (P2Y12-R) signaling is mediated through Gi, ultimately reducing cellular cAMP levels. Because cAMP is a central modulator of arginine vasopressin (AVP)-induced water transport in the renal collecting duct (CD), we hypothesized that if expressed in the CD, P2Y12-R may play a role in renal handling of water in health and in nephrogenic diabetes insipidus. We found P2Y12-R mRNA expression in rat kidney, and immunolocalized its protein and aquaporin-2 (AQP2) in CD principal cells. Administration of clopidogrel bisulfate, an irreversible inhibitor of P2Y12-R, significantly increased urine concentration and AQP2 protein in the kidneys of Sprague-Dawley rats. Notably, clopidogrel did not alter urine concentration in Brattleboro rats that lack AVP. Clopidogrel administration also significantly ameliorated lithium-induced polyuria, improved urine concentrating ability and AQP2 protein abundance, and reversed the lithium-induced increase in free-water excretion, without decreasing blood or kidney tissue lithium levels. Clopidogrel administration also augmented the lithium-induced increase in urinary AVP excretion and suppressed the lithium-induced increase in urinary nitrates/nitrites (nitric oxide production) and 8-isoprostane (oxidative stress). Furthermore, selective blockade of P2Y12-R by the reversible antagonist PSB-0739 in primary cultures of rat inner medullary CD cells potentiated the expression of AQP2 and AQP3 mRNA, and cAMP production induced by dDAVP (desmopressin). In conclusion, pharmacologic blockade of renal P2Y12-R increases urinary concentrating ability by augmenting the effect of AVP on the kidney and ameliorates lithium-induced NDI by potentiating the action of AVP on the CD. This strategy may offer a novel and effective therapy for lithium-induced NDI. Copyright © 2015 by the American Society of Nephrology.

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

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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

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

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)

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.

Anti-PD-L1 Treatment Induced Central Diabetes Insipidus.

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Zhao, Chen; Tella, Sri Harsha; Del Rivero, Jaydira; Kommalapati, Anuhya; Ebenuwa, Ifechukwude; Gulley, James; Strauss, Julius; Brownell, Isaac

2018-02-01

Immune checkpoint inhibitors, including anti-programmed cell death protein 1 (PD-1), anti-programmed cell death protein ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti-CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti-PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient's symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. To our knowledge, this is the first report of central DI associated with anti-PD-L1 immunotherapy. The patient's endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality. Copyright © 2017 Endocrine Society

Distribution of transplanted human mesenchymal stem cells from Wharton’s Jelly in the central nervous systems of the EAE rats

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Kovalchuk M. V.

2015-10-01

Full Text Available Human Wharton’s Jelly MSCs (hWJ-MSCs have a considerable advantage and potential in treating the central nervous system diseases and can be a new alternative treatment of Multiple Sclerosis (MS. Aim. To study the persistence and distribution of hWJ-MSCs along the neuraxis following transplantation in central nervous system of rats with experimental autoimmune encephalomyelitis (EAE, the animal model of MS. Methods. Isolation and cultivation of hWJ-MSCs in vitro. Immunological phenotyping by flow cytometry. EAE induction. Intrathecal (suboccipital injection of MSCs into CNS of SCH-induced EAE rats. Persistence of hWJ-MSCs in the CNS of hWJ-MSCs -treated rats was detected through detection of the human alpha-satellite DNA in the tissue sections and the cerebrospinal fluid (CSF by PCR at days 2, 3, 4 and 5 Results. PCR-assays for alpha-satellite sequences revealed that Human DNA was detected during 5 days following intrathecal injection at the peak of disease in the treated rats. It has been demonstrated that the human DNA was traced in CSF and various segments of a spinal cord. Conclusions. The data obtained suggest that intrathecally delivered hWJ-MSCs, with time, can migrate through the CSF from the injection site to various segments of CNS and persist therein during the first week of post transplantation, which was performed at the EAE disease peak in the xenogeneic setting without immunosuppression. hWJ-MSCs may be considered as a delivery cell source of therapeutic molecules for CNS inflammatory diseases.

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

Reducing risk of spinal haematoma from spinal and epidural pain procedures.

Science.gov (United States)

Breivik, Harald; Norum, Hilde; Fenger-Eriksen, Christian; Alahuhta, Seppo; Vigfússon, Gísli; Thomas, Owain; Lagerkranser, Michael

2018-04-25

Central neuraxial blocks (CNB: epidural, spinal and their combinations) and other spinal pain procedures can cause serious harm to the spinal cord in patients on antihaemostatic drugs or who have other risk-factors for bleeding in the spinal canal. The purpose of this narrative review is to provide a practise advisory on how to reduce risk of spinal cord injury from spinal haematoma (SH) during CNBs and other spinal pain procedures. Scandinavian guidelines from 2010 are part of the background for this practise advisory. We searched recent guidelines, PubMed (MEDLINE), SCOPUS and EMBASE for new and relevant randomised controlled trials (RCT), case-reports and original articles concerning benefits of neuraxial blocks, risks of SH due to anti-haemostatic drugs, patient-related risk factors, especially renal impairment with delayed excretion of antihaemostatic drugs, and specific risk factors related to the neuraxial pain procedures. Epidural and spinal analgesic techniques, as well as their combination provide superior analgesia and reduce the risk of postoperative and obstetric morbidity and mortality. Spinal pain procedure can be highly effective for cancer patients, less so for chronic non-cancer patients. We did not identify any RCT with SH as outcome. We evaluated risks and recommend precautions for SH when patients are treated with antiplatelet, anticoagulant, or fibrinolytic drugs, when patients' comorbidities may increase risks, and when procedure-specific risk factors are present. Inserting and withdrawing epidural catheters appear to have similar risks for initiating a SH. Invasive neuraxial pain procedures, e.g. spinal cord stimulation, have higher risks of bleeding than traditional neuraxial blocks. We recommend robust monitoring routines and treatment protocol to ensure early diagnosis and effective treatment of SH should this rare but potentially serious complication occur. When neuraxial analgesia is considered for a patient on anti

Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

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Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.

1984-02-01

In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of /sup 201/Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and /sup 201/Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of /sup 201/Tl uptake in non-occluded endocardium. Uptake of /sup 201/Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties.

Metabolic consequences of beta-adrenergic receptor blockade for the acutely ischemic dog myocardium

International Nuclear Information System (INIS)

Westera, G.; Hollander, W. den; Wall, E.E. van der; Eenige, M.J. van; Scholtalbers, S.; Visser, F.C.; Roos, J.P.

1984-01-01

In an experimental study in 50 dogs the myocardial uptake of free fatty acids (FFAs) after beta-blockade was determined using radioiodinated heptadecanoic acid as a metabolic tracer. All 4 beta-blockers used (metoprolol, timolol, propranolol and pindolol) lowered the uptake of FFAs in the normal canine heart. Uptake of FFAs was also diminished after coronary artery occlusion per se, but administration of beta-blockers exerted little additional influence on the uptake of FFAs. This observation was qualitatively parallelled by the uptake of 201 Tl in concomitant experiments. Plasma FFA levels were increased by pindolol (non-selective with intrinsic sympathomimetic activity), not changed by metoprolol (a cardioselective betablocking agent) and lowered by timolol and propranolol (both non-selective compounds). The extent of ischemic tissue, as reflected by uptake of iodoheptadecanoic acid and 201 Tl, was diminished by metoprolol but not by other beta-blockers. Regional distribution of both tracers, as shown in the endo-epicardial uptake ratios, was hardly influenced by beta-blockade, except for a small increase of 201 Tl uptake in non-occluded endocardium. Uptake of 201 Tl as well as of iodoheptadecanoic acid in the ischemic area was increased by metoprolol, timolol and propranolol and decreased by pindolol. We conclude that beta-blocking agents confer different effects on myocardial uptake and metabolism of FFAs which might possibly be related to their different inherent properties. (orig.) [de

Graft-versus-host disease is enhanced by selective CD73 blockade in mice.

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Long Wang

Full Text Available CD73 functions as an ecto-5'-nucleotidase to produce extracellular adenosine that has anti-inflammatory and immunosuppressive activity. We here demonstrate that CD73 helps control graft-versus-host disease (GVHD in mouse models. Survival of wild-type (WT recipients of either allogeneic donor naïve CD73 knock-out (KO or WT T cells was similar suggesting that donor naïve T cell CD73 did not contribute to GVHD. By contrast, donor CD73 KO CD4(+CD25(+ regulatory T cells (Treg had significantly impaired ability to mitigate GVHD mortality compared to WT Treg, suggesting that CD73 on Treg is critical for GVHD protection. However, compared to donor CD73, recipient CD73 is more effective in limiting GVHD. Pharmacological blockade of A2A receptor exacerbated GVHD in WT recipients, but not in CD73 KO recipients, suggesting that A2 receptor signaling is primarily implicated in CD73-mediated GVHD protection. Moreover, pharmacological blockade of CD73 enzymatic activity induced stronger alloreactive T cell activity, worsened GVHD and enhanced the graft-versus-leukemia (GVL effect. These findings suggest that both donor and recipient CD73 protects against GVHD but also limits GVL effects. Thus, either enhancing or blocking CD73 activity has great potential clinical application in allogeneic bone marrow transplants.

Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

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Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

2013-04-19

Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

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

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Elena eNosyreva

2014-12-01

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

HTLV-1 specific CD8+ T cell function augmented by blockade of 2B4/CD48 interaction in HTLV-1 infection.

Directory of Open Access Journals (Sweden)

Chibueze Chioma Ezinne

Full Text Available CD8+ T cell response is important in the response to viral infections; this response though is regulated by inhibitory receptors. Expression of inhibitory receptors has been positively correlated with CD8+ T cell exhaustion; the consequent effect of simultaneous blockade of these inhibitory receptors on CD8+ T cell response in viral infections have been studied, however, the role of individual blockade of receptor-ligand pair is unclear. 2B4/CD48 interaction is involved in CD8+T cell regulation, its signal transducer SAP (signaling lymphocyte activation molecule (SLAM-associated protein is required for stimulatory function of 2B4/CD244 on lymphocytes hence, we analyzed 2B4/CD244 (natural killer cell receptor and SAP (signaling lymphocyte activation molecule(SLAM-associated protein on total CD8+ and HTLV-1 specific CD8+T cells in HTLV-1 infection and the effect of blockade of interaction with ligand CD48 on HTLV-1 specific CD8+ T cell function. We observed a high expression of 2B4/CD244 on CD8+ T cells relative to uninfected and further upregulation on HTLV-1 specific CD8+ T cells. 2B4+ CD8+ T cells exhibited more of an effector and terminally differentiated memory phenotype. Blockade of 2B4/CD48 interaction resulted in improvement in function via perforin expression and degranulation as measured by CD107a surface mobilization on HTLV-1 specific CD8+ T cells. In the light of these findings, we thus propose an inhibitory role for 2B4/CD48 interaction on CD8+T cell function.

Our experience with facial nerve monitoring in vestibular schwannoma surgery under partial neuromuscular blockade.

Science.gov (United States)

Vega-Céliz, Jorge; Amilibia-Cabeza, Emili; Prades-Martí, José; Miró-Castillo, Nuria; Pérez-Grau, Marta; Pintanel Rius, Teresa; Roca-Ribas Serdà, Francesc

2015-01-01

Facial nerve monitoring is fundamental in the preservation of the facial nerve in vestibular schwannoma surgery. Our objective was to analyse the usefulness of facial nerve monitoring under partial neuromuscular blockade. This was a retrospective analysis of 69 patients operated in a tertiary hospital. We monitored 100% of the cases. In 75% of the cases, we could measure an electromyographic response after tumour resection. In 17 cases, there was an absence of electromyographic response. Fifteen of them had an anatomic lesion with loss of continuity of the facial nerve and, in 2 cases, there was a lesion with preservation of the nerve. Preoperative facial palsy (29% 7%; P=.0349), large tumour size (88 vs. 38%; P=.0276), and a non-functional audition (88 vs. 51%; P=.0276) were significantly related with an absence of electromyographic response. Facial nerve monitoring under neuromuscular blockade is possible and safe in patients without previous facial palsy. If the patient had an electromyographic response after tumour excision, they developed better facial function in the postoperative period and after a year of follow up. Copyright © 2014 Elsevier España, S.L.U. and Sociedad Española de Otorrinolaringología y Patología Cérvico-Facial. All rights reserved.

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

Synergistic effects of low-intensity exercise conditioning and β-blockade on cardiovascular and autonomic adaptation in pre- and postmenopausal women with hypertension.

Science.gov (United States)

Goldie, Catherine L; Brown, C Ann; Hains, Sylvia M J; Parlow, Joel L; Birtwhistle, Richard

2013-10-01

The effects of a 12-week low-intensity exercise conditioning program (walking) on blood pressure (BP), heart rate (HR), rate-pressure product (RPP), and cardiac autonomic function were measured in 40 sedentary women with hypertension. Women were assigned to either an exercise group (n = 20) or a control group (n = 20), matched for β-blockade treatment. They underwent testing at the beginning and at the end of the 12-week study period in three conditions: supine rest, standing, and low-intensity steady state exercise. The exercise group participated in a 12-week, low-intensity walking program, while the control group continued with usual sedentary activity. Compared with the control group, women in the exercise group showed reductions in systolic and diastolic BP and RPP (i.e., the estimated cardiac workload). β-Blockers increased baroreflex sensitivity and lowered BP and HR in all participants; however, those in the exercise group showed the effects of both treatments: a greater reduction in HR and RPP. The combination of exercise training and β-blockade produces cardiac and autonomic adaptations that are not observed with either treatment alone, suggesting that β-blockade enhances the conditioning effects of low-intensity exercise in women with hypertension.

75 FR 55671 - Financial Assistance Use of Universal Identifier and Central Contractor Registration

Science.gov (United States)

2010-09-14

... of Universal Identifier and Central Contractor Registration AGENCY: Office of Federal Financial...) numbers and maintain current registrations in the Central Contractor Registration (CCR) database. An... CONTRACTOR REGISTRATION Sec. Subpart A--General 25.100 Purposes of this part. 25.105 Types of awards to which...

Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial.

Directory of Open Access Journals (Sweden)

Lisa C Lindesmith

2015-03-01

Full Text Available Human noroviruses (NoVs are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP candidate vaccine in human volunteers.Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4 were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated.Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential

Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade

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Sinda Bigenzahn

2016-01-01

Full Text Available Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT with costimulation blockade (CB, but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 (H2b mice received nonmyeloablative total body irradiation (3 Gy, costimulation blockade (anti-CD40L mAb and CTLA4Ig, and 2×107 bone marrow cells (BMC from either of three donor strains: Balb/c (H2d (MHC plus multiple minor histocompatibility antigen (mHAg mismatched, B10.D2 (H2d or B10.A (H2a (both MHC mismatched, but mHAg matched. Macrochimerism was followed over time by flow cytometry and tolerance was tested by skin grafting. 20 of 21 recipients of B10.D2 BMC but only 13 of 18 of Balb/c BMC and 13 of 20 of B10.A BMC developed stable long-term multilineage chimerism (p<0.05 for each donor strain versus B10.D2. Significantly superior donor skin graft survival was observed in successfully established long-term chimeras after mHAg matched BMT compared to mHAg mismatched BMT (p<0.05. Both minor and major antigen disparities pose a substantial barrier for the induction of chimerism while the maintenance of tolerance after nonmyeloablative BMT and costimulation blockade is negatively influenced by minor antigen disparities.

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

DEFF Research Database (Denmark)

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

2014-01-01

-guided blockade of the lumbar plexus. The objective was to investigate whether the suprasacral technique is equally effective for anaesthesia of the terminal lumbar plexus nerves compared with a lumbar plexus block, and more effective for anaesthesia of the lumbosacral trunk. Twenty volunteers were included...

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.

Microwave assisted one-pot synthesis of benzothiazole and ...

Indian Academy of Sciences (India)

Dr.P.T.P

1. Microwave assisted one-pot synthesis of benzothiazole and benzoxazole libraries as analgesic agents. C PRAVEEN a. , A NANDAKUMAR a. , P DHEENKUMAR b. , D MURALIDHARAN a and P T. PERUMAL a,. * a. Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600020,. Tamilnadu ...

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

Raman Spectroscopy Differentiates Each Tissue From the Skin to the Spinal Cord: A Novel Method for Epidural Needle Placement?

Science.gov (United States)

Anderson, T. Anthony; Kang, Jeon Woong; Gubin, Tatyana; Dasari, Ramachandra R.; So, Peter T. C.

2016-01-01

BACKGROUND Neuraxial anesthesia and epidural steroid injection techniques require precise anatomical targeting to ensure successful and safe analgesia. Previous studies suggest that only some of the tissues encountered during these procedures can be identified by spectroscopic methods, and no previous study has investigated the use of Raman, diffuse reflectance, and fluorescence spectroscopies. The authors hypothesized that real-time needle-tip spectroscopy may aid epidural needle placement and tested the ability of spectroscopy to distinguish each of the tissues in the path of neuraxial needles. METHODS For comparison of detection methods, the spectra of individual, dissected ex vivo paravertebral and neuraxial porcine tissues were collected using Raman spectroscopy (RS), diffuse reflectance spectroscopy (DRS), and fluorescence spectroscopy (FS). Real-time spectral guidance was tested using a 2 mm inner diameter fiber optic probe-in-needle device. Raman spectra were collected during the needle’s passage through intact paravertebral and neuraxial porcine tissue and analyzed afterward. The RS tissue signatures were verified as mapping to individual tissue layers using histochemical staining and widefield microscopy. RESULTS Raman spectroscopy revealed a unique spectrum for all ex vivo paravertebral and neuraxial tissue layers; DRS and FS spectra were not distinct for all tissues. Moreover, when accounting for the expected order of tissues, real-time Raman spectra recorded during needle insertion also permitted identification of each paravertebral and neuraxial porcine tissue. CONCLUSIONS This study demonstrates Raman spectroscopy can distinguish the tissues encountered during epidural needle insertion. This technology may prove useful during needle placement by providing evidence of its anatomical localization. PMID:27466032

Coulomb blockade threshold in finite one-dimensional arrays of small tunnel junctions

International Nuclear Information System (INIS)

Lien, Nguyen V.; Dat, Nguyen T.; Nam, Nguyen H.

2001-11-01

The current-voltage characteristics of one-dimensional tunnel junction arrays are simulated using the semiclassical and full capacitance matrix description. The threshold voltage V th of the Coulomb blockade (CB) is evaluated and analyzed in detail as a function of the gate capacitance C 0 , the array length N, the temperature, and the degree of disorder. The disordered effect is found to be essential, while the long range interaction included in the full capacitance matrix calculations, when decreasing V th , weakly affects the qualitative behaviour of the CB for the V th (C 0 ) - and the V th (N)-dependences. (author)

Tissue polypeptide-specific antigen (TPS) determinations before and during intermittent maximal androgen blockade in patients with metastatic prostatic carcinoma

NARCIS (Netherlands)

Kil, P. J. M.; Goldschmidt, H. M. J.; Wieggers, B. J. A.; Kariakine, O. B.; Studer, U. E.; Whelan, P.; Hetherington, J.; de Reijke, Th M.; Hoekstra, J. W.; Collette, L.

2003-01-01

To evaluate the prognostic significance of serially measured tissue polypeptide-specific antigen (TPS) levels in patients with metastatic prostatic carcinoma treated with intermittent maximal androgen blockade (MAB). To determine its value with respect to predicting response to treatment and time to

Why physician-assisted suicide perpetuates the idolatory of medicine.

Science.gov (United States)

Cherry, Mark J

2003-01-01

Adequate response to physician-assisted suicide and euthanasia depends on fundamental philosophical and theological issues, including the character of an appropriate philosophically and theologically anchored anthropology, where the central element of traditional Christian anthropology is that humans are created to worship God. As I will argue, Christian morality and moral epistemology must be nested within and understood through this background Christian anthropology. As a result, I will argue that physician-assisted suicide and euthanasia can only be one-sidedly and inadequately appreciated through rational appeal to central values, such as "human dignity" and "self determination", or through "sola scriptura" biblical interpretation, or individual judgments of conscience. Adequately addressing physician-assisted suicide and euthanasia will depend on a more fundamental spiritual-therapeutic approach. This cluster of moral, epistemological, anthropological, and bioethical claims will be explored by drawing on the texts of St. Basil the Great, St. Maximos the Confessor, and St. Isaac the Syrian. Their reflections on medicine, the human good, and its relationship to worship, spiritual therapy, and God will be used as a basis to indicate a broader philosophical perspective, which will be needed to avoid a one-sided, incomplete approach to the challenges of physician-assisted suicide and euthanasia. Medical morality, I argue, is best understood within categories that transcend the right, the good, the just, and the virtuous; namely, the holy.

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...

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.

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.

Educational Research Network for West and Central Africa ...

International Development Research Centre (IDRC) Digital Library (Canada)

This grant will assist the Educational Research Network for West and Central Africa (ERNWACA) by providing funding for succession planning, recruiting a regional coordinator (to be based in Mali) and strengthening the Network's capacity to mobilize resources with a view to long-term sustainability.

Blockade of Ca2+-activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

DEFF Research Database (Denmark)

Madsen, Lars Siim; Christophersen, Palle; Olesen, Søren-Peter

2005-01-01

Voltage- and Ca(2+)-dependent K(+) channels in the membrane of both T and B lymphocytes are important for the cellular immune response. In the current issue of the European Journal of Immunology, Reich et al. demonstrate that selective blockade of the intermediate-conductance Ca(2+)-activated K(+...

Arranging for personal assistance services and assistive technology at work. A report of the rehabilitation research and training center on personal assistance services.

Science.gov (United States)

Stoddard, Susan; Kraus, Lewis

2006-01-01

For an employee with a disability, reasonable accommodation can make the difference in finding work, maintaining employment, and succeeding on the job. Today, employers and employees alike are more aware that appropriate accommodation, including workplace personal assistance services (PAS) as well as assistive technology, improves an employee's ability to succeed. While assistive technology is in widespread use as an accommodation, workplace personal assistance is less understood. The goal of the study was to learn more about how workplace PAS and AT are arranged for in the workplace, and the issues that arise. Structured phone interviews were conducted with 20 workplace PAS users, 21 employers familiar with workplace PAS, and 19 employment organizations. Interview transcripts are the basis for the qualitative analysis of findings. Requirements for personal assistance accommodations focus on task-related needs. Personal care needs at work are not included in the Americans with Disabilities act but may be needed by the employee. Employers and PAS users have developed many creative ways to address PAS need. Organizations can construct an approach that fits the needs, abilities, and constraints of each organization. The interview respondents have identified a number of practices that are succeeding, including establishment of policies for arranging for PAS; centralization of accommodation budgets to remove work unit disincentives; and providing a shared personal assistant for interpreting or for task-related and personal care tasks. A number of important research questions remain. What is the extent of the need for PAS in the workplace? Will an expanded PAS supply increase the employment opportunities for people with disabilities? Will better models of workplace PAS be adopted by employers?

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...

Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function.

Science.gov (United States)

Garrett, Joan T; Sutton, Cammie R; Kuba, María Gabriela; Cook, Rebecca S; Arteaga, Carlos L

2013-02-01

Dual blockade of HER2 with trastuzumab and lapatinib or with pertuzumab is a superior treatment approach compared with single-agent HER2 inhibitors. However, many HER2-overexpressing breast cancers still escape from this combinatorial approach. Inhibition of HER2 and downstream phosphoinositide 3-kinase (PI3K)/AKT causes a transcriptional and posttranslational upregulation of HER3 which, in turn, counteracts the antitumor action of the HER2-directed therapies. We hypothesized that suppression of HER3 would synergize with dual blockade of HER2 in breast cancer cells sensitive and refractory to HER2 antagonists. Inhibition of HER2/HER3 in HER2(+) breast cancer cell lines was evaluated by Western blotting. We analyzed drug-induced apoptosis and two- and three-dimensional growth in vitro. Growth inhibition of PI3K was examined in vivo in xenografts treated with combinations of trastuzumab, lapatinib, and the HER3-neutralizing monoclonal antibody U3-1287. Treatment with U3-1287 blocked the upregulation of total and phosphorylated HER3 that followed treatment with lapatinib and trastuzumab and, in turn, enhanced the antitumor action of the combination against trastuzumab-sensitive and -resistant cells. Mice bearing HER2(+) xenografts treated with lapatinib, trastuzumab, and U3-1287 exhibited fewer recurrences and better survival than mice treated with lapatinib and trastuzumab. Dual blockade of HER2 with trastuzumab and lapatinib does not eliminate the compensatory upregulation of HER3. Therapeutic inhibitors of HER3 should be considered as part of multidrug combinations aimed at completely and rapidly disabling the HER2 network in HER2-overexpressing breast cancers.

N-cadherin and integrin blockade inhibit arteriolar myogenic reactivity but not pressure-induced increases in intracellular Ca2+

Directory of Open Access Journals (Sweden)

Teresa Y. Jackson

2010-12-01

Full Text Available The vascular myogenic response is characterized by arterial constriction in response to an increase in intraluminal pressure and dilatation to a decrease in pressure. This mechanism is important for the regulation of blood flow, capillary pressure and arterial pressure. The identity of the mechanosensory mechanism(s for this response is incompletely understood but has been shown to include the integrins as cell-extracellular matrix receptors. The possibility that a cell-cell adhesion receptor is involved has not been studied. Thus, we tested the hypothesis that N-cadherin, a cell-cell adhesion molecule in vascular smooth muscle cells (VSMCs, was important for myogenic responsiveness. The purpose of this study was to investigate:
1. whether cadherin inhibition blocks myogenic responses to increases in intraluminal pressure and 2. the effect of the cadherin or integrin blockade on pressure-induced changes in [Ca2+]i. Cadherin blockade was tested in isolated rat cremaster arterioles on myogenic responses to acute pressure steps from 60 – 100 mmHg and changes in VSMC Ca2+ were measured using fura-2. In the presence of a synthetic cadherin inhibitory peptide or a function blocking antibody, myogenic responses were inhibited. In contrast, during N-cadherin blockade, pressure-induced changes in [Ca2+]i were not altered. Similarly, vessels treated with function-blocking β1- or β3-integrin antibodies maintained pressure-induced [Ca2+]i responses despite inhibition of myogenic constriction. Collectively, these data suggest that both cadherins and integrins play a fundamental role in mediating myogenic constriction but argue against their direct involvement in mediating pressure-induced [Ca2+]i increases.

Combined blockade of ADP receptors and PI3-kinase p110β fully prevents platelet and leukocyte activation during hypothermic extracorporeal circulation.

Directory of Open Access Journals (Sweden)

Stefanie Krajewski

Full Text Available Extracorporeal circulation (ECC and hypothermia are used to maintain stable circulatory parameters and improve the ischemia tolerance of patients in cardiac surgery. However, ECC and hypothermia induce activation mechanisms in platelets and leukocytes, which are mediated by the platelet agonist ADP and the phosphoinositide-3-kinase (PI3K p110β. Under clinical conditions these processes are associated with life-threatening complications including thromboembolism and inflammation. This study analyzes effects of ADP receptor P(2Y(12 and P(2Y(1 blockade and PI3K p110β inhibition on platelets and granulocytes during hypothermic ECC. Human blood was treated with the P(2Y(12 antagonist 2-MeSAMP, the P(2Y(1 antagonist MRS2179, the PI3K p110β inhibitor TGX-221, combinations thereof, or PBS and propylene glycol (controls. Under static in vitro conditions a concentration-dependent effect regarding the inhibition of ADP-induced platelet activation was found using 2-MeSAMP or TGX-221. Further inhibition of ADP-mediated effects was achieved with MRS2179. Next, blood was circulated in an ex vivo ECC model at 28°C for 30 minutes and various platelet and granulocyte markers were investigated using flow cytometry, ELISA and platelet count analysis. GPIIb/IIIa activation induced by hypothermic ECC was inhibited using TGX-221 alone or in combination with P(2Y blockers (p<0.05, while no effect of hypothermic ECC or antiplatelet agents on GPIIb/IIIa and GPIbα expression and von Willebrand factor binding was observed. Sole P(2Y and PI3K blockade or a combination thereof inhibited P-selectin expression on platelets and platelet-derived microparticles during hypothermic ECC (p<0.05. P(2Y blockade alone or combined with TGX-221 prevented ECC-induced platelet-granulocyte aggregate formation (p<0.05. Platelet adhesion to the ECC surface, platelet loss and Mac-1 expression on granulocytes were inhibited by combined P(2Y and PI3K blockade (p<0.05. Combined blockade of P

Energy sector developments in Central America and the Caribbean

International Nuclear Information System (INIS)

Perez, J.

1997-01-01

Energy sector developments in Central America and the Caribbean were discussed. Central America is composed of six small countries whose total population is 32 million. The Caribbean population is 20.5 million. Central America is generally poor in hydrocarbon reserves but the geological prospects in several of the countries are encouraging. The oil and petroleum products supply and demand picture, the main characteristics of the hydrocarbon market, structure of the oil industry, hydrocarbon market reforms, pricing issues and recent trend towards reforms in the electric power industry in Central America were discussed. An overview of the Inter-American Development Bank's (IDB) effort to provide technical assistance and loans to strengthen the energy sector development in Central America and the Caribbean was also given. 17 refs., 2 tabs., 23 figs

Plasticity within the Central Nervous System: A Case Report

Directory of Open Access Journals (Sweden)

Jun Hozumi

2011-01-01

Full Text Available Neural blockades are considered an alternative to pharmacotherapy for neuropathic pain although these blockades elicit limited effects. We encountered a patient with postbrachial plexus avulsion injury pain, which was refractory to conventional treatments but disappeared temporarily with the administration of the local anesthetic lidocaine around the left mandibular molar tooth during dental treatments. This analgesic effect on neuropathic pain by oral local anesthesia was reproducible. Under conditions of neuropathic pain, cerebral somatotopic reorganization in the sensorimotor cortices of the brain has been observed. Either expansion or shrinkage of the somatotopic representation of a deafferentated body part correlates with the degree of neuropathic pain. In our case, administration of an oral local anesthetic shrank the somatotopic representation of the mouth, which is next to the upper limb representation and thereby expanded the upper limb representation in a normal manner. Consequently, oral local anesthesia improved the pain in the upper limb. This case suggests that pain alleviation through neural plasticity within the brain is related to neural blockade.

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.

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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.

Employee assistance programs: a worldwide perspective.

Science.gov (United States)

Burgess, K M; O'Donnell, W J; Bennett, A A; von Vietinghoff-Scheel, K

1997-08-01

Once limited to U.S. corporations, employee assistance programs (EAPs) are now spreading around the world. The authors review global EAP trends and identify similarities and differences among EAPs in North America, Europe, Central and South America, the Asia-Pacific region, and the Caribbean. Through affiliations between international professional associations and services to multinational corporations, the EAP field is quietly creating globalized behavioral health services.

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�

Observation of the Photon-Blockade Breakdown Phase Transition

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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.

Organochlorine pesticides in follicular fluid of women undergoing assisted reproductive technologies from central China

International Nuclear Information System (INIS)

Zhu, Yindi; Huang, Bo; Li, Qing X.; Wang, Jun

2015-01-01

Female infertility rates have increased by approximately 4% since the 1980s. There is evidence of adverse effects on female fertility in relation to exposure of chemical pollution in recent years. Follicular fluid samples were collected from 127 woman patients (aged 20–35) who underwent assisted reproductive technologies (ART) and had no records indicating occupational exposure to OCPs. Seventeen OCPs were analyzed in this study. The results showed that methoxychlor was dominant, accounted for 13.4% of total OCPs with a mean concentration of 167.9 ± 33.9 ng/g lipid weight (lw), followed by heptachlor-epoxide, hexachlorocyclohexanes, endrin and DDT. The concentrations of OCPs in the follicular fluid samples in the present study were moderate in comparison with those reported from developed or industrialized countries. All these pollutants can accumulate in different tissues of human body through diet, drinking water and respiration. No correlation between patient age and OCP concentrations was observed in this study. - Highlights: • 17 OCPs in follicular fluid samples from 127 woman patients were analyzed. • Methoxychlor was the most dominant, constituting 13.4% of total OCPs with a mean concentration of 168 ng/g lw. • The concentrations of DDT and HCHs were lower than those in human breast milk from Russia and Iran and blood from India. • DDTs and HCHs in the samples would be mainly from historical usage. • The correlation between patient ages and concentrations of OCPs was weak. - OCPs at median concentrations of 460.0–2927.2 ng/g lipid weight in follicular fluids of central China have physiological effects.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms.

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Blake, M G; Krawczyk, M C; Baratti, C M; Boccia, M M

2014-01-01

Central cholinergic system is critically involved in all known memory processes. Endogenous acetylcholine release by cholinergic neurons is necessary for modulation of acquisition, encoding, consolidation, reconsolidation, extinction, retrieval and expression. Experiments from our laboratory are mainly focused on elucidating the mechanisms by which acetylcholine modulates memory processes. Blockade of hippocampal alpha-7-nicotinic receptors (α7-nAChRs) with the antagonist methyllycaconitine impairs memory reconsolidation. However, the administration of a α7-nAChR agonist (choline) produce a paradoxical modulation, causing memory enhancement in mice trained with a weak footshock, but memory impairment in animals trained with a strong footshock. All these effects are long-lasting, and depend on the age of the memory trace. This review summarizes and discusses some of our recent findings, particularly regarding the involvement of α7-nAChRs on memory reconsolidation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial

DEFF Research Database (Denmark)

Juul, Anne Benedicte; Wetterslev, Jørn; Gluud, Christian

2006-01-01

Objectives To evaluate the long term effects of perioperative blockade on mortality and cardiac morbidity in patients with diabetes undergoing major non-cardiac surgery. Design Randomised placebo controlled and blinded multicentre trial. Analyses were by intention to treat. Setting University...

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

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.

Circadian rhythm disruption by a novel running wheel: Roles of exercise and arousal in blockade of the luteinizing hormone surge

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Duncan, Marilyn J.; Franklin, Kathleen M.; Peng, Xiaoli; Yun, Christopher; Legan, Sandra J.

2014-01-01

Exposure of proestrous Syrian hamsters to a new room, cage, and novel running wheel blocks the luteinizing hormone (LH) surge until the next day in ~75% of hamsters (Legan et al, 2010) [1]. The studies described here tested the hypotheses that 1) exercise and/or 2) orexinergic neurotransmission mediate novel wheel blockade of the LH surge and circadian phase advances. Female hamsters were exposed to a 14L:10D photoperiod and activity rhythms were monitored with infra-red detectors. In Expt. 1, to test the effect of exercise, hamsters received jugular cannulae and on the next day, proestrus (Day 1), shortly before zeitgeber time 5 (ZT 5, 7 hours before lights-off) the hamsters were transported to the laboratory. After obtaining a blood sample at ZT 5, the hamsters were transferred to a new cage with a novel wheel that was either freely rotating (unlocked), or locked until ZT 9, and exposed to constant darkness (DD). Blood samples were collected hourly for 2 days from ZT 5–11 under red light for determination of plasma LH levels by radioimmunoassay. Running rhythms were monitored continuously for the next 10–14 days. The locked wheels were as effective as unlocked wheels in blocking LH surges (no Day 1 LH surge in 6/9 versus 8/8 hamsters, P>0.05) and phase advances in the activity rhythms did not differ between the groups (P= 0.28), suggesting that intense exercise is not essential for novel wheel blockade and phase advance of the proestrous LH surge. Expt. 2 tested whether orexin neurotransmission is essential for these effects. Hamsters were treated the same as in Expt. 1 except they were injected (i.p.) at ZT 4.5 and 5 with either the orexin 1 receptor antagonist SB334867 (15 mg/kg per injection) or vehicle (25% DMSO in 2-hydroxypropyl-beta-cyclodextrin (HCD). SB-334867 inhibited novel wheel blockade of the LH surge (surges blocked in 2/6 SB334867-injected animals versus 16/18 vehicle-injected animals, Pwheel running and circadian phase shifts, indicating that

Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently

NARCIS (Netherlands)

de Waard, Vivian; Bot, Ilze; de Jager, Saskia C. A.; Talib, Sara; Egashira, Kensuke; de Vries, Margreet R.; Quax, Paul H. A.; Biessen, Erik A. L.; van Berkel, Theo J. C.

2010-01-01

Objective: CCR2, the receptor for monocyte chemoattractant protein 1 (MCP1), is involved in atherosclerosis and abdominal aortic aneurysms (AAAs). Here, we explored the potential beneficial blockade of the MCP1/CCR2 pathway. Methods: We applied an AAA model in aging apolipoprotein E deficient mice

Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs

International Nuclear Information System (INIS)

Farde, L.; Wiesel, F.A.; Halldin, C.; Sedvall, G.

1988-01-01

Using positron emission tomography and the carbon 11-labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11-raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline

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.

Central neuraxial opioid analgesia after caesarean section: comparison of epidural diamorphine and intrathecal morphine.

Science.gov (United States)

Caranza, R; Jeyapalan, I; Buggy, D J

1999-04-01

In a prospective, randomized, double-blind study in 55 women undergoing elective caesarean section under spinal anaesthesia, we compared epidural diamorphine 3 mg (2 distinct boluses, group ED) with single-dose intrathecal morphine 0.2 mg (group SM), in terms of analgesic efficacy, patient satisfaction and side-effects at 2, 3, 4, 8, 12, 16, 24 and 28 h postoperatively. There were no significant differences between groups in pain (assessed by 100 mm visual analogue scale), incidence of pruritus, sedation or respiratory depression measured by continuous pulse oximetry. However, time to first request for supplementary oral analgesia was longer in SM than in ED (mean +/- SD: 22.3+/-12.0 h vs. 13.8+/-6.5 h, P=0.04). The incidence of nausea or vomiting was significantly higher in SM than ED (73% vs. 41%, P=0.01). In ED, the mean +/- SD time to requirement of the second bolus was 6.7+/-3.2 h. There was a high level of satisfaction in both groups. We conclude that two boluses of epidural diamorphine 3 mg and single-dose intrathecal morphine 0.2 mg provide satisfactory analgesia after caesarean section, but spinal morphine was associated with both delayed requirement for supplementary analgesia and a higher incidence of nausea and vomiting.

Sugammadex to reverse neuromuscular blockade and provide optimal conditions for motor-evoked potential monitoring

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Mehdi Trifa

2017-01-01

Full Text Available Sugammadex is a novel pharmacologic agent, which reverses neuromuscular blockade (NMB via a mechanism that differs completely from acetylcholinesterase inhibitors. By encapsulating rocuronium, sugammadex can provide recovery of neuromuscular function even when there is a profound degree of NMB. We report anecdotal experience with the use of sugammadex to reverse NMB to facilitate intraoperative neurophysiological monitoring (motor evoked potentials in an adolescent with scoliosis during posterior spinal fusion. Its potential application in this unique clinical scenario is discussed, and potential dosing schemes are reviewed.

Blockade of Rennin-Angiotensin system blunts the fibrotic response in experimental acute pyelonephritis

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Singal A

2005-01-01

Full Text Available Aim: To study the impact of Renin-Angiotensin system blockade in experimental acute pyelonephritis, induced by a novel surgical approach via dorsal lumbotomy incision. Materials and Methods : 45 Adult female WISTAR rats aged 8-12 weeks, underwent direct inoculation of 0.1 ml of E.coli suspension into the parenchyma of the surgically exposed kidney. 3 groups of rats were studied: Group A - treated with antibiotics only; Group B- Captopril and antibiotics and Group C- Losartan and antibiotics. Changes of acute inflammation, parenchymal destruction and scarring were compared between the groups on histopathological sections. Kruskal-Wallis test was used for statistical analysis. Results : Changes consistent with acute pyelonephritis were seen in all the kidneys. Mean% scar area in Group A, Group B and Group C was 37.08±1.79, 24.40±1.88 and 24.68±1.32% respectively at end of six weeks. Mean tubular density in Group A, B and C was 17.26±1.92, 47.18±3.00 and 47.00±5.08-tubules/lac mm2 respectively. The differences between the control and the treated animals were significant, though the results did not differ between the losartan and captopril treated rats. Conclusions : Dorsal lumbotomy approach to the kidney provides a good exposure of the kidney. Induction of acute pyelonephritis by direct inoculation of bacteria into renal cortex produced a consistent scar at 6 weeks. Blockade of renin angiotensin system by either captopril or losartan decreased the renal scar area by almost 1/3 at 6 weeks.

The effect of vagal nerve blockade using electrical impulses on glucose metabolism in nondiabetic subjects

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Sathananthan M

2014-07-01

Full Text Available Matheni Sathananthan,1 Sayeed Ikramuddin,2 James M Swain,3,6 Meera Shah,1 Francesca Piccinini,4 Chiara Dalla Man,4 Claudio Cobelli,4 Robert A Rizza,1 Michael Camilleri,5 Adrian Vella1 1Division of Endocrinology, Diabetes and Metabolism, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Division of General Surgery, University of Minnesota, Minneapolis, MN, USA; 3Division of General Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA; 4Department of Information Engineering, University of Padua, Padua, Italy; 5Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 6Scottsdale Healthcare Bariatric Center, Scottsdale, AZ, USA Purpose: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans. Patients and methods: We utilized a randomized, cross-over study design where participants were studied after 2 weeks of activation or inactivation of vagal nerve blockade (VNB. Seven obese subjects with impaired fasting glucose previously enrolled in a long-term study to examine the effect of VNB on weight took part. We used a standardized triple-tracer mixed meal to enable measurement of the rate of meal appearance, endogenous glucose production, and glucose disappearance. The 550 kcal meal was also labeled with 111In-diethylene triamine pentaacetic acid (DTPA to measure gastrointestinal transit. Insulin action and ß-cell responsivity indices were estimated using the minimal model. Results: Integrated glucose, insulin, and glucagon concentrations did not differ between study days. This was also reflected in a lack of effect on β-cell responsivity and insulin action. Furthermore, fasting and postprandial endogenous glucose production, integrated meal appearance, and glucose

Transport, atom blockade, and output coupling in a Tonks-Girardeau gas

International Nuclear Information System (INIS)

Rutherford, L.; McCann, J. F.; Goold, J.; Busch, Th.

2011-01-01

Recent experiments have demonstrated how quantum-mechanical impurities can be created within strongly correlated quantum gases and used to probe the coherence properties of these systems [S. Palzer, C. Zipkes, C. Sias, and M. Koehl, Phys. Rev. Lett. 103, 150601 (2009).]. Here we present a phenomenological model to simulate such an output coupler for a Tonks-Girardeau gas that shows qualitative agreement with the experimental results for atom transport and output coupling. Our model allows us to explore nonequilibrium transport phenomena in ultracold quantum gases and leads us to predict a regime of atom blockade, where the impurity component becomes localized in the parent cloud despite the presence of gravity. We show that this provides a stable mixed-species quantum gas in the strongly correlated limit.

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...

Combining G-CSF with a blockade of adhesion strongly improves the reconstitutive capacity of mobilized hematopoietic progenitor cells.

Science.gov (United States)

Christ, O; Kronenwett, R; Haas, R; Zöller, M

2001-03-01

Mobilization of hematopoietic progenitor cells is achieved mainly by application of growth factors and, more recently, by blockade of adhesion. In this report, we describe the advantages of a combined treatment with granulocyte colony-stimulating factor (G-CSF) and anti-VLA4 (CD49d)/anti-CD44 as compared to treatment with the individual components. Mobilization by intravenous injection of anti-CD44, anti-VLA4, or G-CSF was controlled in spleen and bone marrow with regard to frequencies of multipotential colony-forming unit (C-CFU), marrow repopulating ability, long-term reconstitution, recovery of myelopoiesis, and regain of immunocompetence. Mobilization by anti-CD44 had a strong effect on expansion of early progenitor cells in the bone marrow, while the recovery in the spleen was poor. In anti-CD49d-mobilized noncommitted and committed progenitors, progenitor expansion was less pronounced, but settlement in the spleen was quite efficient. Thus, anti-CD44 and anti-CD49d differently influenced mobilization. Accordingly, mobilization and recovery after transfer were improved by combining anti-CD44 with anti-CD49d treatment. Mobilization by G-CSF was most efficient with respect to recovery of progenitor cells in the spleen. However, when transferring G-CSF-mobilized cells, regain of immunocompetence was strongly delayed. This disadvantage could be overridden when progenitor cells were mobilized via blockade of adhesion and when expansion of these mobilized progenitor cells was supported by low-dose G-CSF only during the last 24 hours before transfer. Mobilization of pluripotent progenitor cells via antibody blockade of CD44 or CD49d or via G-CSF relies on distinct mechanisms. Therefore, the reconstitutive capacity of a transplant can be significantly improved by mobilization regimens combining antibody with low-dose G-CSF treatment.

The Central Simulation Committee (CSC): a model for centralization and standardization of simulation-based medical education in the U.S. Army healthcare system.

Science.gov (United States)

Deering, Shad; Sawyer, Taylor; Mikita, Jeffrey; Maurer, Douglas; Roth, Bernard J

2012-07-01

In this report, we describe the organizational framework, operations and current status of the Central Simulation Committee (CSC). The CSC was established in 2007 with the goals of standardizing simulation-based training in Army graduate medical education programs, assisting in redeployment training of physicians returning from war, and improving patient safety within the Army Medical Department. Presently, the CSC oversees 10 Simulation Centers, controls over 21,000 sq ft of simulation center space, and provides specialty-specific training in 14 medical specialties. In the past 2 years, CSC Simulation Centers have trained over 50,000 Army medical students, residents, physician assistants, nurses, Soldiers and DoD civilian medical personnel. We hope this report provides simulation educators within the military, and our civilian simulation colleagues, with insight into the workings of our organization and provides an example of centralized support and oversight of simulation-based medical education.

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....

Robot-assisted bronchoplasty using continuous barbed sutures.

Science.gov (United States)

Sarsam, Omar Matthieu; Dunning, Joel; Pochulu, Bruno; Baste, Jean-Marc

2018-01-01

We describe in this article our bronchoplastic robot-assisted techniques. This consists of using continuous barbed sutures. Our aim is to show the feasibility and the interest of using robotics and this kind of suture material for complex bronchial procedures. We report four cases in France and the UK, two wedge bronchoplasties and two sleeve bronchoplasties for central pulmonary tumors.

Renal Kallikrein Activation and Renoprotection after Dual Blockade of Renin-Angiotensin System in Diet-Induced Diabetic Nephropathy

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Xia Zou

2015-01-01

Full Text Available Purpose. The objective of this study is to investigate the effect of dual blockage of renin-angiotensin system (RAS on renal kallikrein expression and inflammatory response in diabetic nephropathy (DN. Methods. Rats were randomly divided into 5 groups with 10 rats in each group: normal control; DN model induced by high fat and high sucrose diets; and DN treated with either benazepril 10 mg/kg/d, irbesartan 30 mg/kg/d, or both. After 8-week treatment, we examined changes in the kidney histopathology, function and immunohistochemical stain of kallikrein, macrophage marker CD68, and profibrotic markers transforming growth factor- (TGF- β and α-smooth muscle action (SMA. Results. DN rats showed enlarged kidneys with glomerulosclerosis, interstitial chronic inflammation and fibrosis, and proteinuria. All the pathological damage and functional impairments were improved after the RAS blockades (all P<0.05. Compared with monotherapy, combined treatment further alleviated the kidney impairments in parallel to increased tubular immunoreactivity for kallikrein and decreased immunopositive cells for CD68, TGF-β, and α-SMA. Conclusion. The renoprotective effects of the dual RAS blockade in diabetic nephropathy may be attributed to improved tubular kallikrein expression and interstitial inflammatory response.

Transversus Abdominis Plane Blockade as Part of a Multimodal Postoperative Analgesia Plan in Patients Undergoing Radical Cystectomy.

Science.gov (United States)

Matulewicz, Richard S; Patel, Mehul; Jordan, Brian J; Morano, Jacqueline; Frainey, Brendan; Bhanji, Yasin; Bux, Mahreen; Nader, Antoun; Kundu, Shilajit D; Meeks, Joshua J

2018-04-26

Radical cystectomy (RC) is a morbid procedure with frequent complications that may benefit from implementation of an enhanced recovery after surgery (ERAS) protocol. To examine the benefits of a multimodal analgesic plan that uses continuous transversus abdominis plane (TAP) blockade as part of an ERAS protocol after RC. A retrospective comparison of consecutive patients undergoing RC over a 4-year period was conducted. Patients were designated as having surgery either before or after implementation of an ERAS protocol. A major component of the ERAS protocol was a multi-modal analgesia plan with TAP blockade. Patient demographics, comorbidities, operative details, and outcomes, including days to flatus, bowel movement (BM), narcotic usage, and length of stay (LOS) were compared. In total, 171 patients were included: 100 pre-ERAS and 71 ERAS. There were no differences in age, smoking status, operative approach, or diversion type. The patients in the ERAS cohort were less likely to be male, had a higher median BMI, and more likely to have received neoadjuvant chemotherapy. Total and early postoperative narcotic use were lower in the ERAS cohort: 89 vs. 336 mg ( p  RC pain management.

Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon.

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Darci R Smith

2017-01-01

Full Text Available Animal models are needed to better understand the pathogenic mechanisms of Zika virus (ZIKV and to evaluate candidate medical countermeasures. Adult mice infected with ZIKV develop a transient viremia, but do not demonstrate signs of morbidity or mortality. Mice deficient in type I or a combination of type I and type II interferon (IFN responses are highly susceptible to ZIKV infection; however, the absence of a competent immune system limits their usefulness for studying medical countermeasures. Here we employ a murine model for ZIKV using wild-type C57BL/6 mice treated with an antibody to disrupt type I IFN signaling to study ZIKV pathogenesis. We observed 40% mortality in antibody treated mice exposed to ZIKV subcutaneously whereas mice exposed by intraperitoneal inoculation were highly susceptible incurring 100% mortality. Mice infected by both exposure routes experienced weight loss, high viremia, and severe neuropathologic changes. The most significant histopathological findings occurred in the central nervous system where lesions represent an acute to subacute encephalitis/encephalomyelitis that is characterized by neuronal death, astrogliosis, microgliosis, scattered necrotic cellular debris, and inflammatory cell infiltrates. This model of ZIKV pathogenesis will be valuable for evaluating medical countermeasures and the pathogenic mechanisms of ZIKV because it allows immune responses to be elicited in immunologically competent mice with IFN I blockade only induced at the time of infection.

Gold Nanoparticles on Functionalized Silicon Substrate under Coulomb Blockade Regime: An Experimental and Theoretical Investigation.

Science.gov (United States)

Pluchery, Olivier; Caillard, Louis; Dollfus, Philippe; Chabal, Yves J

2018-01-18

Single charge electronics offer a way for disruptive technology in nanoelectronics. Coulomb blockade is a realistic way for controlling the electric current through a device with the accuracy of one electron. In such devices the current exhibits a step-like increase upon bias which reflects the discrete nature of the fundamental charge. We have assembled a double tunnel junction on an oxide-free silicon substrate that exhibits Coulomb staircase characteristics using gold nanoparticles (AuNPs) as Coulomb islands. The first tunnel junction is an insulating layer made of a grafted organic monolayer (GOM) developed for this purpose. The GOM also serves for attaching AuNPs covalently. The second tunnel junction is made by the tip of an STM. We show that this device exhibits reproducible Coulomb blockade I-V curves at 40 K in vacuum. We also show that depending on the doping of the silicon substrate, the whole Coulomb staircase can be adjusted. We have developed a simulation approach based on the orthodox theory that was completed by calculating the bias dependent tunnel barriers and by including an accurate calculation of the band bending. This model accounts for the experimental data and the doping dependence of Coulomb oscillations. This study opens new perspectives toward designing new kind of single electron transistors (SET) based on this dependence of the Coulomb staircase with the charge carrier concentration.

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.

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.

Blockade of Vascular Adhesion Protein-1 Inhibits Lymphocyte Infiltration in Rat Liver Allograft Rejection

OpenAIRE

Martelius, Timi; Salaspuro, Ville; Salmi, Marko; Krogerus, Leena; Höckerstedt, Krister; Jalkanen, Sirpa; Lautenschlager, Irmeli

2004-01-01

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174–5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/gro...

Counting statistics of transport through Coulomb blockade nanostructures: High-order cumulants and non-Markovian effects

DEFF Research Database (Denmark)

Flindt, Christian; Novotny, Tomás; Braggio, Alessandro

2010-01-01

Recent experimental progress has made it possible to detect in real-time single electrons tunneling through Coulomb blockade nanostructures, thereby allowing for precise measurements of the statistical distribution of the number of transferred charges, the so-called full counting statistics...... interactions. Our recursive method can treat systems with many states as well as non-Markovian dynamics. We illustrate our approach with three examples of current experimental relevance: bunching transport through a two-level quantum dot, transport through a nanoelectromechanical system with dynamical Franck...

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...

Oscillations-free PID control of anesthetic drug delivery in neuromuscular blockade.

Science.gov (United States)

Medvedev, Alexander; Zhusubaliyev, Zhanybai T; Rosén, Olov; Silva, Margarida M

2016-07-25

The PID-control of drug delivery or the neuromuscular blockade (NMB) in closed-loop anesthesia is considered. The NMB system dynamics portrayed by a Wiener model can exhibit sustained nonlinear oscillations under realistic PID gains and for physiologically feasible values of the model parameters. Such oscillations, also repeatedly observed in clinical trials, lead to under- and over-dosing of the administered drug and undermine patient safety. This paper proposes a tuning policy for the proportional PID gain that via bifurcation analysis ensures oscillations-free performance of the control loop. Online estimates of the Wiener model parameters are needed for the controller implementation and monitoring of the closed-loop proximity to oscillation. The nonlinear dynamics of the PID-controlled NMB system are studied by bifurcation analysis. A database of patient models estimated under PID-controlled neuromuscular blockade during general anesthesia is utilized, along with the corresponding clinical measurements. The performance of three recursive algorithms is compared in the application at hand: an extended Kalman filter, a conventional particle filter (PF), and a PF making use of an orthonormal basis to estimate the probability density function from the particle set. It is shown that with a time-varying proportional PID gain, the type of equilibria of the closed-loop system remains the same as in the case of constant controller gains. The recovery time and frequency of oscillations are also evaluated in simulation over the database of patient models. Nonlinear identification techniques based on model linearization yield biased parameter estimates and thus introduce superfluous uncertainty. The bias and variance of the estimated models are related to the computational complexity of the identification algorithms, highlighting the superiority of the PFs in this safety-critical application. The study demonstrates feasibility of the proposed oscillation-free control

Enresa's Participation in the Technical Assistance Programmes to the Eastern European Countries

International Nuclear Information System (INIS)

Beceiro, A. R.; Vico, E.

2000-01-01

This article briefly describes the participation of ENRESA in the technical assistance programmes to the Central and Eastern European countries (PHARE) and to the New Independent States (TACIS) as well as in the co-operation programmes all of them established by the European Commission. It is worth to point out the active role of ENRESA within the European Consortium CASSIOPEE, formed in 1993 by the six radioactive waste management companies in existence in the European Union at that time. CASSIOPEE was created to assist the European Commission in the area of radioactive waste management of the PHARE and TACIS technical assistance programmes. (Author)

The use of β-blockade to control heart rate during whole body hyperthermia (WBH): A toxicity study in the dog

International Nuclear Information System (INIS)

Robins, H.I.; Hugander, A.; Besozzi, M.; Grossman, J.

1987-01-01

Radionuclide ventriculography as well as invasive hemodynamic monitoring was used to study the cardiovascular changes in the dog during 42 0 C WBH, i.e., heart rate, blood pressure, cardiac output, stroke volume and ejection fraction. WBH was delivered by a radiant heat device (RHD). Results obtained agree qualitatively and quantitatively with changes observed in WBH-RHD studies done in pigs and humans. The authors elected to study the effect of propranolol in dogs during 42 0 C WBH in order to evaluate this drug's potential use in human cancer patients who are ineligible for WBH because of coronary artery disease. The results show that the level of β-blockade needed to control heart rate during WBH produces acute cardiovascular decompensation. The authors believe these results represent a contraindication to drug-induced β-blockade during RHD-WBH. Beyond its clinical implications for human cancer patients, this experience with the dog as an animal model for WBH recommends its use for further physiological and pharmacological studies

Response surface methodology (RSM) modeling of microwave-assisted extraction of natural dye from Swietenia mahagony: A comparation between Box-Behnken and central composite design method

Science.gov (United States)

Kusuma, Heri Septya; Sudrajat, Robby Ginanjar Margo; Susanto, David Febrilliant; Gala, Selfina; Mahfud, Mahfud

2015-12-01

The increasing demand of non-toxic and environmentally friendly dyes, colorants that come from natural source have risen as an alternative of sintetic poisonous dyes. In this research natural dye from S. mahagony was extracted using microwave-assisted extraction method under different operating condition such as extraction time (10-30min), plant material to solvent ratio (0.03-0.05g/mL) and microwave power level (100-380 watt). Box-Behnken method and central composite design (CCD) method is widely used for modeling response surface methodology (RSM), both methods show good prediction performance. In this study response surface methodology was performed to optimize the process, both methods were performed by the help Statgraphics Centurion 16 to evaluate the effects of different operating parameters. Finally, both methods were statistically compared by root mean square error (RMSE) and absolute average deviation (AAD) based on validation data set. Further, result suggests that CCD has better performance as compared to Box-Behnken method. The maximum yield obtained for Box-Behnken is 3.7647% (380 watt, 0.0339g/mL, 28.8899min) and 3.7506% (379.986 watt, 0.0378g/mL, 30min) for central composite design method.

Thirty-five years of assisted reproductive technologies in Israel

Directory of Open Access Journals (Sweden)

Daphna Birenbaum-Carmeli

2016-06-01

Full Text Available Israel is known as a pronatalist country. Whether due to the Biblical commandment to ‘be fruitful and multiply’ or the traumas of the Holocaust and perennial wars, reproduction is a central life goal for most Israelis. Israeli women bear substantially more children than their counterparts in industrialized countries and view child-rearing as a key life accomplishment. These personal world-view and real-life individual quests take place in a context of equally pronatalist state policies and religious openness to assisted reproductive technologies. In this paper, I outline 35 years of assisted reproductive technologies in Israel by tracing a principal axis in the development of three major technologies of assisted reproduction: the proliferation of IVF-ICSI; the globalization of gamete donation; and the privatization of surrogacy. The paper is based on a policy analysis as well as various studies of assisted reproductive technologies, conducted in Israel over this period.

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...

Multiple logic functions from extended blockade region in a silicon quantum-dot transistor

International Nuclear Information System (INIS)

Lee, Youngmin; Lee, Sejoon; Im, Hyunsik; Hiramoto, Toshiro

2015-01-01

We demonstrate multiple logic-functions at room temperature on a unit device of the Si single electron transistor (SET). Owing to the formation of the multi-dot system, the device exhibits the enhanced Coulomb blockade characteristics (e.g., large peak-to-valley current ratio ∼200) that can improve the reliability of the SET-based logic circuits. The SET displays a unique feature useful for the logic applications; namely, the Coulomb oscillation peaks are systematically shifted by changing either of only the gate or the drain voltage. This enables the SET to act as a multi-functional one-transistor logic gate with AND, OR, NAND, and XOR functions

Multiple logic functions from extended blockade region in a silicon quantum-dot transistor

Energy Technology Data Exchange (ETDEWEB)

Lee, Youngmin; Lee, Sejoon, E-mail: sejoon@dongguk.edu; Im, Hyunsik [Department of Semiconductor Science, Dongguk University-Seoul, Seoul 100-715 (Korea, Republic of); Hiramoto, Toshiro [Institute of Industrial Science, University of Tokyo, Tokyo 153-8505 (Japan)

2015-02-14

We demonstrate multiple logic-functions at room temperature on a unit device of the Si single electron transistor (SET). Owing to the formation of the multi-dot system, the device exhibits the enhanced Coulomb blockade characteristics (e.g., large peak-to-valley current ratio ∼200) that can improve the reliability of the SET-based logic circuits. The SET displays a unique feature useful for the logic applications; namely, the Coulomb oscillation peaks are systematically shifted by changing either of only the gate or the drain voltage. This enables the SET to act as a multi-functional one-transistor logic gate with AND, OR, NAND, and XOR functions.

Optimization of microwave-assisted extraction of polysaccharide from Psidium guajava L. fruits.

Science.gov (United States)

Amutha Gnana Arasi, Michael Antony Samy; Gopal Rao, Manchineela; Bagyalakshmi, Janardanan

2016-10-01

This study deals with the optimization of microwave assisted extraction of polysaccharide from Psidium guajava L. fruit using Response surface methodology. To evaluate the effect of three independent variables, Water to plant material ratio, microwave power used for extraction and Irradiation time, central composite design has been employed. The yield is considered as dependent variable. The design model estimated the optimum yield of 6.81677% at 200W microwave power level, 3:1 water to plant material ratio and 20min of irradiation time. Three factors three levels Central composite design coupled with RSM was used to model the extraction process. ANOVA was performed to find the significance of the model. The polysaccharide extracted using microwave assisted extraction process was analyzed using FTIR Spectroscopy. Copyright © 2016 Elsevier B.V. All rights reserved.

Vellozia flavicans Mart. ex Schult. hydroalcoholic extract inhibits the neuromuscular blockade induced by Bothrops jararacussu venom.

Science.gov (United States)

Tribuiani, Natália; da Silva, Alexandro Mateus; Ferraz, Miriéle Cristina; Silva, Magali Glauzer; Bentes, Ana Paula Guerreiro; Graziano, Talita Signoreti; dos Santos, Marcio Galdino; Cogo, José Carlos; Varanda, Eliana Aparecida; Groppo, Francisco Carlos; Cogo, Karina; Oshima-Franco, Yoko

2014-02-08

Snakebite is a significant public health issue in tropical countries. In Brazil, some of the most common snake envenomations are from Bothrops. Bothrops bites trigger local and systemic effects including edema, pain, erythema, cyanosis, infections, and necrosis. Vellozia flavicans is a plant from the Brazilian "cerrado" (savanna) that is popularly used as an anti-inflammatory medicine. Since inflammation develops quickly after Bothrops bites, which can lead to infection, the aim of the present study was to observe possible anti-snake venom and antimicrobial activities of V. flavicans (Vf). The chromatographic profile of the main constituents from the Vf leaf hydroalcoholic extract was obtained by thin-layer chromatography (TLC). The anti-snake venom activity was measured by Vf's ability to neutralize the in vitro neuromuscular blockade caused by Bothrops jararacussu venom (Bjssu) in a mouse phrenic nerve-diaphragm model (PND). After a 20 min incubation, preparations of PND were added to Tyrode's solution (control); Vf (0.2, 0.5, 1, and 2 mg/mL); 40 μg/mL Bjssu; pre-incubation for 30 min with Bjssu and 1 mg/mL Vf; and a Bjssu pretreated preparation (for 10 min) followed by 1 mg/mL Vf. Myographic recording was performed, and the contractile responses were recorded. The antimicrobial activity (minimum inhibitory concentration [MIC] and minimum bactericidal concentration [MBC]) was obtained for Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Enterococcus faecalis, using gentamicin and vancomycin as positive controls. TLC analysis yielded several compounds from Vf, such as flavonoids (quercetin) and phenolic acids (chlorogenic acid). Bjssu completely blocked the contractile responses of PND preparations, while Vf preserved 97% (±10%) of the contractile responses when incubated with Bjssu. In the PND pretreated with Bjssu, Vf was able to inhibit the neuromuscular blockade progress. MIC and MBC of Vf ranged from 2.5 to 5.0 mg/mL for P. aeruginosa

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

International Nuclear Information System (INIS)

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

2016-01-01

Macroautophagy, or autophagy, is a cellular response in which unnecessary cytoplasmic components, including lipids and organelles, are self-degraded. Recent studies closely related autophagy to activation of hepatic stellate cells (HSCs), a process critical in the pathogenesis of liver fibrosis. During HSC activation, cytoplasmic lipid droplets (LDs) are degraded as autophagic cargo, and then cells express fibrogenic genes. Thus, inhibition of autophagy in HSCs is a potential therapeutic approach for attenuating liver fibrosis. We found that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from Stephania tetrandra, induced lipid accumulation, a phenotype associated with quiescent HSCs, through blockade of autophagy in the rat-derived HSC line HSC-T6. Tetrandrine inhibited autophagic flux without affecting lysosomal function. A phenotypic comparison using siRNA knockdown suggested that tetrandrine may target regulators, involved in fusion between autophagosomes and lysosomes (e.g., syntaxin 17). Moreover, perilipin 1, an LD-coated protein, co-localized specifically with LC3, a marker protein for autophagosomes, in tetrandrine-treated HSC-T6 cells. This suggests a potential role for perilipin 1 in autophagy-mediated LD degradation in HSCs. Our results identified tetrandrine as a potential tool for prevention and treatment of HSC activation. - Highlights: • Autophagy is closely related to lipid degradation in hepatic stellate cells. • Tetrandrine (Tet) causes lipid accumulation via blockade of autophagy in HSC-T6 cells. • Tet blocked autophagy without affecting lysosomal function unlike bafilomycin A_1. • Perilipin 1 was specifically co-localized with LC3 in Tet-treated cells. • Perilipin 1 may play potential roles in autophagy-mediated lipid degradation.

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

Energy Technology Data Exchange (ETDEWEB)

Miyamae, Yusaku, E-mail: ymiyamae@lif.kyoto-u.ac.jp [Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan); Nishito, Yukina; Nakai, Naomi [Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan); Nagumo, Yoko; Usui, Takeo [Faculty of Life and Environmental Sciences, University of Tsukuba, Tennodai, Tsukuba, Ibaraki 305-8572 (Japan); Masuda, Seiji; Kambe, Taiho [Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan); Nagao, Masaya, E-mail: mnagao@kais.kyoto-u.ac.jp [Graduate School of Biostudies, Kyoto University, Oiwakecho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502 (Japan)

2016-08-12

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

CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis.

Science.gov (United States)

Ramonell, Kimberly M; Zhang, Wenxiao; Hadley, Annette; Chen, Ching-Wen; Fay, Katherine T; Lyons, John D; Klingensmith, Nathan J; McConnell, Kevin W; Coopersmith, Craig M; Ford, Mandy L

2017-01-01

Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.

CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis.

Directory of Open Access Journals (Sweden)

Kimberly M Ramonell

Full Text Available Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.

CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

International Nuclear Information System (INIS)

Datir, A.; Connell, D.

2010-01-01

Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

CT-guided injection for ganglion impar blockade: a radiological approach to the management of coccydynia

Energy Technology Data Exchange (ETDEWEB)

Datir, A., E-mail: apdatir@gmail.co [Jackson Memorial Hospital, Miami, FL (United States); Connell, D. [Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex (United Kingdom)

2010-01-15

Aim: To evaluate the role of computed tomography (CT) in needle placement for ganglion impar blocks, and to determine the efficacy of CT-guided ganglion impar blocks in the management of coccydynia. Materials and methods: The results of ganglion impar blockade in eight patients with coccydynia secondary to trauma or unknown cause were reviewed. The diagnosis of coccydynia was based on clinical history, location of pain, and response to previous diagnostic and therapeutic procedures. The eight patients were treated with CT-guided ganglion impar blocks to manage their coccyx pain after conservative procedures, including oral medication and cushions, failed to provide relief. All patients were subjected to ganglion impar blocks under a thin-section CT-guided technique for needle placement, using a mixture of bupivacaine and triamcinolone. The patients were followed-up for a period of 6-months. Results: Eight patients were treated in this study with a total of 11 injections. A technical success of 100% was achieved in all cases with accurate needle placement without any complications and all the patients tolerated the procedure well. Out of eight, three patients (37%) had complete relief of pain on the follow-up intervals up to 6 months. Three out of eight patients (37%), had partial relief of symptoms and a second repeat injection was given at the 3 month interval of the follow-up period. At the end of the 6-month follow-up period, six out of eight patients (75%) experienced symptomatic relief (four complete relief and two partial relief) without any additional resort to conventional pain management. Twenty-five percent (two out of eight) did not have any symptomatic improvement. The mean visual analogue score (VAS) pre-procedure was 8 (range 6-10) and had decreased to 2 (range 0-5) in six out of eight patients. Conclusion: CT can be used as an imaging method to identify the ganglion and guide the needle in ganglion impar blockade. The advantages of CT

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.

Molecular mechanism of PD-1/PD-L1 blockade via anti-PD-L1 antibodies atezolizumab and durvalumab.

Science.gov (United States)

Lee, Hyun Tae; Lee, Ju Yeon; Lim, Heejin; Lee, Sang Hyung; Moon, Yu Jeong; Pyo, Hyo Jeong; Ryu, Seong Eon; Shin, Woori; Heo, Yong-Seok

2017-07-17

In 2016 and 2017, monoclonal antibodies targeting PD-L1, including atezolizumab, durvalumab, and avelumab, were approved by the FDA for the treatment of multiple advanced cancers. And many other anti-PD-L1 antibodies are under clinical trials. Recently, the crystal structures of PD-L1 in complex with BMS-936559 and avelumab have been determined, revealing details of the antigen-antibody interactions. However, it is still unknown how atezolizumab and durvalumab specifically recognize PD-L1, although this is important for investigating novel binding sites on PD-L1 targeted by other therapeutic antibodies for the design and improvement of anti-PD-L1 agents. Here, we report the crystal structures of PD-L1 in complex with atezolizumab and durvalumab to elucidate the precise epitopes involved and the structural basis for PD-1/PD-L1 blockade by these antibodies. A comprehensive comparison of PD-L1 interactions with anti-PD-L1 antibodies provides a better understanding of the mechanism of PD-L1 blockade as well as new insights into the rational design of improved anti-PD-L1 therapeutics.

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.

Anesthesia and fast-track in video-assisted thoracic surgery (VATS): from evidence to practice.

Science.gov (United States)

Umari, Marzia; Falini, Stefano; Segat, Matteo; Zuliani, Michele; Crisman, Marco; Comuzzi, Lucia; Pagos, Francesco; Lovadina, Stefano; Lucangelo, Umberto

2018-03-01

In thoracic surgery, the introduction of video-assisted thoracoscopic techniques has allowed the development of fast-track protocols, with shorter hospital lengths of stay and improved outcomes. The perioperative management needs to be optimized accordingly, with the goal of reducing postoperative complications and speeding recovery times. Premedication performed in the operative room should be wisely administered because often linked to late discharge from the post-anesthesia care unit (PACU). Inhalatory anesthesia, when possible, should be preferred based on protective effects on postoperative lung inflammation. Deep neuromuscular blockade should be pursued and carefully monitored, and an appropriate reversal administered before extubation. Management of one-lung ventilation (OLV) needs to be optimized to prevent not only intraoperative hypoxemia but also postoperative acute lung injury (ALI): protective ventilation strategies are therefore to be implemented. Locoregional techniques should be favored over intravenous analgesia: the thoracic epidural, the paravertebral block (PVB), the intercostal nerve block (ICNB), and the serratus anterior plane block (SAPB) are thoroughly reviewed and the most common dosages are reported. Fluid therapy needs to be administered critically, to avoid both overload and cardiovascular compromisation. All these practices are analyzed singularly with the aid of the most recent evidences aimed at the best patient care. Finally, a few notes on some of the latest trends in research are presented, such as non-intubated video-assisted thoracoscopic surgery (VATS) and intravenous lidocaine.

Cardiovascular and endocrine response to hemorrhage after α1-blockade in lambs and ewes

International Nuclear Information System (INIS)

Block, S.M.; Rose, J.C.; Ernest, J.M.; Flowe, K.; South, S.; Zimmerman, C.

1987-01-01

To evaluate the role of the α 1 -adrenergic system in the response to hemorrhage during development, lambs and adult sheep were chronically catheterized and hemorrhaged after pretreatment with prazosin or vehicle. The adults became markedly more hypotensive after α 1 -blockade and hemorrhage than after vehicle and hemorrhage, whereas the lambs were no more hypotensive when hemorrhaged after prazosin. In the adults and the lambs hemorrhage produced elevations in plasma renin activity and arginine vasopressin measured by radioimmunoassay. However, after prazosin, the adults had a far greater increase in arginine vasopressin levels than after vehicle treatment

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

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...

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.

Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations

DEFF Research Database (Denmark)

Silkoff, Philip E; Flavin, Susan; Gordon, Robert

2017-01-01

BACKGROUND: Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. OBJECTIVE: We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157......, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. RESULTS: In asthmatic patients (n = 63) CNTO3157 provided......: In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought...

A randomized, dose-response study of sugammadex given for the reversal of deep rocuronium- or vecuronium-induced neuromuscular blockade under sevoflurane anesthesia

DEFF Research Database (Denmark)

Duvaldestin, Philippe; Kuizenga, Karel; Saldien, Vera

2010-01-01

Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a dose-response relationship with sugammadex for reversal of neuromuscular...

A Randomized, Dose-Response Study of Sugammadex Given for the Reversal of Deep Rocuronium- or Vecuronium-Induced Neuromuscular Blockade Under Sevoflurane Anesthesia

NARCIS (Netherlands)

Duvaldestin, Philippe; Kuizenga, Karel; Saldien, Vera; Claudius, Casper; Servin, Frederique; Klein, Jan; Debaene, Bertrand; Heeringa, Marten

BACKGROUND: Sugammadex is the first of a new class of selective muscle relaxant binding drugs developed for the rapid and complete reversal of neuromuscular blockade induced by rocuronium and vecuronium. Many studies have demonstrated a close-response relationship with sugammadex for reversal of

Relationship between evaluation by quantitative fatty acid myocardial scintigraphy and response to {beta}-blockade therapy in patients with dilated cardiomyopathy

Energy Technology Data Exchange (ETDEWEB)

Ito, Tatsuo; Hoshida, Shiro; Nishino, Masami; Aoi, Toshiyuki; Egami, Yasuyuki; Takeda, Toshihiro; Kawabata, Masayoshi; Tanouchi, Jun; Yamada, Yoshio; Kamada, Takenobu [Div. of Cardiology, Osaka Rosai Hospital (Japan)

2001-12-01

Predicting the effect of {beta}-blockade therapy on the clinical outcome of patients with dilated cardiomyopathy (DCM) is difficult prior to the initiation of therapy. Myocardial fatty acid metabolism has been shown to be impaired in patients with DCM. We examined whether the extent of myocardial injury, as assessed by iodine-123 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) myocardial scintigraphy, is related to the response of patients with DCM to {beta}-blockade therapy. Thirty-seven patients with DCM were examined using BMIPP myocardial scintigraphy before and after 6 months of treatment with metoprolol. Myocardial BMIPP uptake (%BM uptake) was estimated quantitatively as a percentage of the total injected count ratio. The left ventricular end-diastolic and end-systolic dimensions (LVDd, LVDs) and ejection fraction (LVEF) were also evaluated. The patients were divided into two groups according to their functional improvement (>10% elevation of LVEF) after 6 months of metoprolol therapy. Twenty-eight patients responded to the therapy, while nine did not. Prior to the therapy, no significant differences in LVDd, LVDs or LVEF were observed between the responders and non-responders. However, the %BM uptake was significantly lower in the non-responders than in the responders (1.0%{+-}0.2% vs 2.1%{+-}0.5%, P<0.001). The %BM uptake could be used to distinguish the responders from the non-responders with a sensitivity of 0.93 and a specificity of 1.00 at a threshold value of 1.4. After the metoprolol therapy, the %BM uptake improved significantly in the responders (2.5%{+-}0.5%, P<0.01) but did not change in the non-responders. These results indicate that myocardial BMIPP uptake could predict the response of DCM patients to {beta}-blockade therapy. (orig.)

Decentralization and centralization in a federal system: the case of democratic Brazil

Directory of Open Access Journals (Sweden)

Maria Hermínia Tavares de Almeida

2006-01-01

Full Text Available This paper discusses the contradictory impulses towards decentralization and centralization in Brazil during the 1990s and early 2000s. After discussing the analytical issues related to the specific nature of decentralization in federal systems, the paper examines two sets of policy issues: those regulating the fiscal relations between national and sub-national governments and those redefining responsibilities for social services provision (basic education, health care, social assistance. Against conventional academic wisdom, it sustains that although there has been some re-centralization of fiscal decisions and of targeted income transfer programs, a clear re-centralization tendency cannot be siad to exist. Decentralization and centralization trends coexist propelled by different forces, with different motives and different outcomes.

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.

Central bronchial carcinoid: Management of a case and anesthetic perspectives

Directory of Open Access Journals (Sweden)

D Goswami

2016-01-01

Full Text Available Obstructing lesions of the central airways present with a variety of symptoms and are often associated with pneumonia or asthma-like states. Anesthesia to these patients often presents challenges right from the preoperative stabilization of underlying lung condition, mask ventilation in the supine position to maintaining oxygenation and ventilation in the intraoperative and postoperative period. We present here a case of a young woman with a central bronchial tumor with significant airway obstruction with potential for major bleeding and subsequent anesthetic management without lung sacrificing measures and cardiopulmonary bypass assistance.

Health and health services in Central America.

Science.gov (United States)

Garfield, R M; Rodriguez, P F

1985-08-16

Despite rapid economic growth since World War II, health conditions improved only slowly in most of Central America. This is a result of poor medical, social, and economic infrastructure, income maldistribution, and the poor utilization of health investments. The economic crisis of the 1980s and civil strife have further endangered health in the region. Life expectancy has fallen among men in El Salvador and civil strife has become the most common cause of death in Guatemala, Nicaragua, and El Salvador. Large-scale US assistance has done little to improve conditions, and refugees continue to pour into North America. It is estimated that there are more than a million refugees within Central America, while a million have fled to the United States. Costa Rica and Nicaragua are partial exceptions to this dismal health picture. An effective approach to the many health problems in Central America will require joint planning and cooperation among all countries in the region.

An action-learning model to assist Circuit Teams to support School ...

African Journals Online (AJOL)

We report on the construction of a theoretical model to assist Circuit Teams to support School Management Teams of underperforming high schools towards whole-school development in which these improvement plans play a central role. We followed an action research design, employing qualitative data generation and ...

Teacher's Guide to SERAPHIM Software V. Chemistry: The Central Science.

Science.gov (United States)

Bogner, Donna J.

Designed to assist chemistry teachers in selecting appropriate software programs, this publication is the fifth in a series of six teacher's guides from Project SERAPHIM, a program sponsored by the National Science Foundation. This guide is keyed to the chapters of the text "Chemistry: The Central Science." Program suggestions are…

Safe and easy power injection of contrast material through a central line

International Nuclear Information System (INIS)

Rogalla, P.; Meiri, N.; Hamm, M.B.; Thoeni, R.F.; Goldberg, H.I.

1998-01-01

Power-assisted injection of contrast material into an antecubital vein is commonly used in CT and has been proven superior to manual injection. Power-assisted injection through a central line bares the risk of rupturing the line because manual control over the pressure applied by the power injector is lacking. We present a simple safety device which allows manual control of the pressure by means of an interposed three-way stopcock combined with a small syringe for pressure equalization. (orig.)

Adrenaline reveals the torsadogenic effect of combined blockade of potassium channels in anaesthetized guinea pigs.

Science.gov (United States)

Michael, G; Kane, K A; Coker, S J

2008-08-01

Torsade de pointes (TdP) can be induced in several species by a reduction in cardiac repolarizing capacity. The aim of this study was to assess whether combined I(Kr) and I(Ks) blockade could induce TdP in anaesthetized guinea pigs and whether short-term variability (STV) or triangulation of action potentials could predict TdP. Experiments were performed in open-chest, pentobarbital-anaesthetized, adrenaline-stimulated male Dunkin Hartley guinea pigs, which received three consecutive i.v. infusions of either vehicle, the I(Kr) blocker E-4031 (3, 10 and 30 nmol kg(-1) min(-1)), the I(Ks) blocker HMR1556 (75, 250, 750 nmol kg(-1) min(-1)) or E-4031 and HMR1556 combined. Phenylephrine-stimulated guinea pigs were also treated with the K(+) channel blockers in combination. Arterial blood pressure, ECGs and epicardial monophasic action potential (MAP) were recorded. TdP was observed in 75% of adrenaline-stimulated guinea pigs given the K(+) channel blockers in combination, but was not observed in guinea pigs treated with either I(K) blocker alone, or in phenylephrine-stimulated guinea pigs. Salvos and ventricular tachycardia occurred with adrenaline but not with phenylephrine. No changes in STV or triangulation of the MAP signals were observed before TdP. Combined blockade of both I(Kr) and I(Ks) plus the addition of adrenaline were required to induce TdP in anaesthetized guinea pigs. This suggests that there must be sufficient depletion of repolarization reserve and an appropriate trigger for TdP to occur.

NOTES ON THE PALM FLORA OF CENTRAL SUMATRA

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John Dransfield

2014-01-01

Full Text Available In July and August 1972, I spent five weeks on an expedition to study rattans and other palms in the provinces of Jambi and West Sumatra. This central area of Sumatra was chosen because expeditions have already been made to South Sumatra in February 1971 and March 1972 and to North Sumatra and Aceh with the Kyoto University Expedition in August 1971, and therefore collections made in this central area would link up collections from the south and north and would hence add considerably to our knowledge of the palm flora of this rich island. After advice from the Department of Nature Conservation in Jambi and from Dr. M. Jacobs in Rijksherbarium (Leiden had been considered, it was decided to work westwards from Berbak Nature Reserve on the east coast near Nipah Panjang, to the Bukit Barisan, the main range of Sumatra, to Gunung Kerinci Nature Reserve and G. Tujuh near Sungai Penuh and from there, across the western part of the Bukit Barisan to Padang and Bukittinggi. From Bukittinggi it was planned to visit the Kafflesia arnoldii Nature Reserve at Batang Palupuh, and then return to Jambi by way of Muara Tebo and Muara Tembesi, where reputedly there still exists lowland forest. By more or less confining our collecting activities to the normally neglected Palmae it was hoped that within the time available a large area could be covered reasonably, and a palm transect for central Sumatra made. Two assistants from Bogor accompanied me to help in the difficult task of collecting rattans: Dedy Darnaedi (Herbarium Bogoriense and Abdul Hanan (Kebun Raya. These assistants were also given individual collecting assignments as part of a scheme for training assistants in field botany. Dedy was to collect Pteridophyta and Hanan to collect material for growing in the Kebun Raya. Soetrisno Soewoko, head of Nature Conservation in Jambi accompanied us throughout tha expedition.

Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment.

Science.gov (United States)

Hardcastle, Jayson; Mills, Lisa; Malo, Courtney S; Jin, Fang; Kurokawa, Cheyne; Geekiyanage, Hirosha; Schroeder, Mark; Sarkaria, Jann; Johnson, Aaron J; Galanis, Evanthia

2017-04-01

Glioblastoma (GBM) is the most common primary malignant brain tumor and has a dismal prognosis. Measles virus (MV) therapy of GBM is a promising strategy due to preclinical efficacy, excellent clinical safety, and its ability to evoke antitumor pro-inflammatory responses. We hypothesized that combining anti- programmed cell death protein 1 (anti-PD-1) blockade and MV therapy can overcome immunosuppression and enhance immune effector cell responses against GBM, thus improving therapeutic outcome. In vitro assays of MV infection of glioma cells and infected glioma cells with mouse microglia ± aPD-1 blockade were established to assess damage associated molecular pattern (DAMP) molecule production, migration, and pro-inflammatory effects. C57BL/6 or athymic mice bearing syngeneic orthotopic GL261 gliomas were treated with MV, aPD-1, and combination treatment. T2* weighted immune cell-specific MRI and fluorescence activated cell sorting (FACS) analysis of treated mouse brains was used to examine adaptive immune responses following therapy. In vitro, MV infection induced human GBM cell secretion of DAMP (high-mobility group protein 1, heat shock protein 90) and upregulated programmed cell death ligand 1 (PD-L1). MV infection of GL261 murine glioma cells resulted in a pro-inflammatory response and increased migration of BV2 microglia. In vivo, MV+aPD-1 therapy synergistically enhanced survival of C57BL/6 mice bearing syngeneic orthotopic GL261 gliomas. MRI showed increased inflammatory cell influx into the brains of mice treated with MV+aPD-1; FACS analysis confirmed increased T-cell influx predominantly consisting of activated CD8+ T cells. This report demonstrates that oncolytic measles virotherapy in combination with aPD-1 blockade significantly improves survival outcome in a syngeneic GBM model and supports the potential of clinical/translational strategies combining MV with αPD-1 therapy in GBM treatment. © The Author(s) 2016. Published by Oxford University Press

Central extracorporeal membrane oxygenation requiring pulmonary arterial venting after near-drowning.

Science.gov (United States)

Kimura, Mitsutoshi; Kinoshita, Osamu; Fujimoto, Yoshifumi; Murakami, Arata; Shindo, Takahiro; Kashiwa, Koichi; Ono, Minoru

2014-02-01

Extracorporeal membrane oxygenation (ECMO) is an effective respiratory and circulatory support in patients in refractory cardiogenic shock or cardiac arrest. Peripheral ECMO sometimes requires left heart drainage; however, few reports state that pulmonary arterial (PA) venting is required during ECMO support. We present a case of a 14-year-old boy who required PA venting during ECMO support after resuscitation from near-drowning in freshwater. A biventricular assist device with an oxygenator implantation was intended on day 1; however, we were unable to proceed because of increasing of pulmonary vascular resistance from the acute lung injury. Central ECMO with PA venting was then performed. On day 13, central ECMO was converted to biventricular assist device with an oxygenator, which was removed on day 16. This case suggests that PA venting during ECMO support may be necessary in some cases of respiratory and circulatory failure with high pulmonary vascular resistance after near-drowning.

Pulkovskij martirolog: sotrudniki i aspiranty GAO - zhertvy vojny i blokady %t Pulkovo book of martyrs: staff members and graduate students of the main observatory as victum of the war and blockade

Science.gov (United States)

Zhukov, V. Yu.; Soboleva, T. V.

The tragedy of war and the blockade of Leningrad did not fail to have its impact on Pulkovo and its inhabitants. Many of the latter did not survive to witness the Victory Day, and the Astronomical Capital of the World - as the Pulkovo Observatory was called in the past - was razed to the ground. To commemorate the staff members of the USSR Academy of Sciences Main (Pulkovo) Observatory that perished in the war, a memorial board has been installed with 13 names engraved on it. Unfortunately, this figure is four times less than the Main Observatory really lost - roughly every third staff member lost his/her life in the war. The paper is the first endeavour to provide the complete and accurate list of losses that the Russian Academy of Sciences Main Observatory bore as a result of the war and blockade. Fifty-three died of hunger during the time of blockade. This mournful list includes astronomers proper as well as graduate students, technical and servicing staff members. It is not the names of Leningrad Pulkovites only that the authors of the above paper mention. Seeking to pay memorial honours to all staff members and graduate students of the Main Observatory who became victims of the war and blockade, the authors also adduce the names of staff members of the Nikolaevsk and Simeiz Branches of the Main Observatory, as well as those who worked in the Observatory before and in the very beginning of the war but were not formally its staff members at the moment they died. Making the names of the perished Pulkovites known is a tribute of commemoration to all Leningraders that were in the city during the blockade. The book of martyrs above is based on the unpublished documents of the Main Observatory Archive and the data extracted from the St. Petersburg Book of Memory, as well as other materials. The names are arranged alphabetically, and the structure of each entry is the same. The paper provides the foreword and comments.

Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg2+ and memantine under conditions of agonist exposure

Science.gov (United States)

McKay, Sean; Bengtson, C. Peter; Bading, Hilmar; Wyllie, David J.A.; Hardingham, Giles E.

2013-01-01

MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ‘pre-block’ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg2+ is also present. In the presence of Mg2+, 50% recovery from MK-801 blockade is achieved after 10′ of 100 μM NMDA, or 30′ of 15 μM NMDA exposure. In Mg2+-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg2+ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg2+ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100 μM NMDA in the presence of Mg2+ for 2.5 h triggers sufficient unblocking to kill >80% of neurons. We conclude that while synaptic MK-801 ‘pre-block’ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation. This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’. PMID:23402996

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.

Self-Organizing Wearable Device Platform for Assisting and Reminding Humans in Real Time

Directory of Open Access Journals (Sweden)

Yu Jin Park

2016-01-01

Full Text Available Most older persons would prefer “aging in my place,” that is, to remain in good health and live independently in their own home as long as possible. For assisting the independent living of older people, the ability to gather and analyze a user’s daily activity data would constitute a significant technical advance, enhancing their quality of life. However, the general approach based on centralized server has several problems such as the usage complexity, the high price of deployment and expansion, and the difficulty in identifying an individual person. To address these problems, we propose a wearable device platform for the life assistance of older persons that automatically records and analyzes their daily activity without intentional human intervention or a centralized server (i.e., cloud server. The proposed platform contains self-organizing protocols, Delay-Tolerant Messaging system, knowledge-based analysis and alerting for daily activities, and a hardware platform that provides low power consumption. We implemented a prototype smart watch, called Personal Activity Assisting and Reminding (PAAR, as a testbed for the proposed platform, and evaluated the power consumption and the service time of example scenarios.

Efficacy, safety and pharmacokinetics of sugammadex 4 mg kg-1 for reversal of deep neuromuscular blockade in patients with severe renal impairment

NARCIS (Netherlands)

Panhuizen, I. F.; Gold, S. J. A.; Buerkle, C.; Snoeck, M. M. J.; Harper, N. J. N.; Kaspers, M. J. G. H.; van den Heuvel, M. W.; Hollmann, M. W.

2015-01-01

This study evaluated efficacy and safety of sugammadex 4 mg kg(-1) for deep neuromuscular blockade (NMB) reversal in patients with severe renal impairment (creatinine clearance [CLCR] <30 ml min(-1)) vs those with normal renal function (CLCR ≥80 ml min(-1)). Sugammadex 4 mg kg(-1) was administered

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.

Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects.

Science.gov (United States)

Wofford, M R; Anderson, D C; Brown, C A; Jones, D W; Miller, M E; Hall, J E

2001-07-01

The purpose of this study was to determine the contribution of the adrenergic system in mediating hypertension in obese and lean patients. Thirteen obese, hypertensive patients with a body mass index (BMI) > or =28 kg/m2 (obese) and nine lean patients with a BMI lean) were recruited. After a 1-week washout period, participants underwent daytime ambulatory blood pressure monitoring (ABPM). Participants were then treated with the alpha-adrenergic antagonist doxazosin, titrating to 4 mg QHS in 1 week. In the next week, the beta-adrenergic antagonist atenolol was added at an initial dose of 25 mg/day and titrated to 50 mg/day within 1 week. One month after the addition of atenolol, all patients underwent a second ABPM session. There were no differences between the obese and lean subjects in baseline systolic (SBP), diastolic (DBP), or mean arterial pressures (MAP) measured by office recording or ABPM. However, obese subjects had higher heart rates than lean subjects (87.5+/-2.4 v 76.8+/-4.9 beats/min). After 1 month of treatment with the adrenergic blockers, obese patients had a significantly lower SBP (130.0+/-2.5 v 138.9+/-2.1 mm Hg, P = .02) and MAP (99.6+/-2.3 v 107.0+/-1.5 mm Hg, P = .02) than lean patients. Obese patients also tended to have a lower DBP than lean patients (84.3+/-2.5 v 90.9+/-1.6 mm Hg, P = .057), but there was no significant difference in heart rate after 1 month of adrenergic blockade. These results indicate that blood pressure is more sensitive to adrenergic blockade in obese than in lean hypertensive patients and suggest that increased sympathetic activity may be an important factor in the maintenance of hypertension in obesity.

Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12.

Science.gov (United States)

Bozeman, Erica N; He, Sara; Shafizadeh, Yalda; Selvaraj, Periasamy

2016-01-01

Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10-20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer.

Adapting Mobile Beacon-Assisted Localization in Wireless Sensor Networks

Directory of Open Access Journals (Sweden)

Wei Dong

2009-04-01

Full Text Available The ability to automatically locate sensor nodes is essential in many Wireless Sensor Network (WSN applications. To reduce the number of beacons, many mobile-assisted approaches have been proposed. Current mobile-assisted approaches for localization require special hardware or belong to centralized localization algorithms involving some deterministic approaches due to the fact that they explicitly consider the impreciseness of location estimates. In this paper, we first propose a range-free, distributed and probabilistic Mobile Beacon-assisted Localization (MBL approach for static WSNs. Then, we propose another approach based on MBL, called Adapting MBL (A-MBL, to increase the efficiency and accuracy of MBL by adapting the size of sample sets and the parameter of the dynamic model during the estimation process. Evaluation results show that the accuracy of MBL and A-MBL outperform both Mobile and Static sensor network Localization (MSL and Arrival and Departure Overlap (ADO when both of them use only a single mobile beacon for localization in static WSNs.

Adapting mobile beacon-assisted localization in wireless sensor networks.

Science.gov (United States)

Teng, Guodong; Zheng, Kougen; Dong, Wei

2009-01-01

The ability to automatically locate sensor nodes is essential in many Wireless Sensor Network (WSN) applications. To reduce the number of beacons, many mobile-assisted approaches have been proposed. Current mobile-assisted approaches for localization require special hardware or belong to centralized localization algorithms involving some deterministic approaches due to the fact that they explicitly consider the impreciseness of location estimates. In this paper, we first propose a range-free, distributed and probabilistic Mobile Beacon-assisted Localization (MBL) approach for static WSNs. Then, we propose another approach based on MBL, called Adapting MBL (A-MBL), to increase the efficiency and accuracy of MBL by adapting the size of sample sets and the parameter of the dynamic model during the estimation process. Evaluation results show that the accuracy of MBL and A-MBL outperform both Mobile and Static sensor network Localization (MSL) and Arrival and Departure Overlap (ADO) when both of them use only a single mobile beacon for localization in static WSNs.

Pauli-spin blockade in a vertical double quantum dot holding two to five electrons

International Nuclear Information System (INIS)

Kodera, T; Arakawa, Y; Tarucha, S; Ono, K; Amaha, S

2009-01-01

We use a vertical double quantum dot (QD) to study spin blockade (SB) for the two-to five-electron states. SB observed for the two- and four-electron states is both assigned to Pauli exclusion with formation of a spin triplet state, and lifted by singlet-triplet admixing due to fluctuating nuclear field. SB observed for the five-electron state is caused by combined Pauli effect and Hund's rule. We observe a hysteretic behavior of the SB leakage current for up and down sweep of magnetic field, and argue that SB and its lifting by hyperfine interaction are subtle with the spin configuration and modified depending on the inter-dot detuning and number of electrons.

Conductance Through a Redox System in the Coulomb Blockade Regime: Many-Particle Effects and Influence of Electronic Correlations

OpenAIRE

Tornow, Sabine; Zwicknagl, Gertrud

2009-01-01

We investigate the transport characteristics of a redox system weakly coupled to leads in the Coulomb blockade regime. The redox system comprises a donor and acceptor separated by an insulating bridge in a solution. It is modeled by a two-site extended Hubbard model which includes on-site and inter-site Coulomb interactions and the coupling to a bosonic bath. The current voltage characteristics is calculated at high temperatures using a rate equation approach. For high voltages exceeding the ...

Treatment planning in severe scoliosis: the role of MRI

Energy Technology Data Exchange (ETDEWEB)

Freund, M. [Dept. of Clinical Radiology, Univ. of Muenster (Germany); Dept. of Neuroradiology, Univ. of Heidelberg Medical School (Germany); Haehnel, S.; Sartor, K. [Dept. of Neuroradiology, Univ. of Heidelberg Medical School (Germany); Thomsen, M. [Dept. of Orthopaedic Surgery, University of Heidelberg, Medical School (Germany)

2001-06-01

The use of magnetic resonance imaging (MRI) in the preoperative investigation of children with idiopathic scoliosis is controversial. Syringomyelia and other intraspinal lesions may be risk factors for neurological injury during surgical correction. Our purpose was to investigate whether pathology of the neuraxis is associated with scoliosis and to detect lesions which may threaten neurological sequelae during distraction and instrumented correction. We obtained T1- and T2-weighted images of 40 children (28 girls, 12 boys), mean age 12.7 years with severe idiopathic scoliosis (Cobb angle 50-70 ) obtained in coronal, sagittal and axial planes from the posterior cranial fossa to the sacrum, and these were assessed by two neuroradiologists and an orthopaedic surgeon prior to further treatment planning. Abnormalities of the neuraxis were found in 24 patients (60 %); five (12 %) had two or more lesions. No abnormalities of the neuraxis were found in 16 patients (40 %). There were 15 patients (38 %) with intraspinal abnormalities who deteriorated clinically and nine (22 %) who showed no clinical changes. We transferred 16 patients (40 %) from the orthopaedic to the neurosurgical department for further assessment. Our results suggest that one should investigate the neuraxis with MRI before contemplating orthopaedic surgical correction of severe idiopathic scoliosis, because the findings may lead to a change of procedure. (orig.)

Selective blockade of protein kinase B protects the rat and human myocardium against ischaemic injury

Science.gov (United States)

Linares-Palomino, José; Husainy, Muhammad A; Lai, Vien K; Dickenson, John M; Galiñanes, Manuel

2010-01-01

Protein kinase B (PKB/Akt) plays a critical role in cell survival but the investigation of its involvement has been limited by the lack of specific pharmacological agents. In this study, using novel PKB inhibitors (VIII and XI), we investigated the role of PKB in cardioprotection of the rat and human myocardium, the location of PKB in relation to mitoKATP channels and p38 mitogen-activated protein kinase (p38 MAPK), and whether the manipulation of PKB can overcome the unresponsiveness to protection of the diabetic myocardium. Myocardial slices from rat left ventricle and from the right atrial appendage of patients undergoing elective cardiac surgery were subjected to 90 min ischaemia/120 min reoxygenation at 37°C. Tissue injury was assessed by creatine kinase (CK) released and determination of cell necrosis and apoptosis. The results showed that blockade of PKB activity caused significant reduction of CK release and cell death, a benefit that was as potent as ischaemic preconditioning and could be reproduced by blockade of phosphatidylinositol 3-kinase (PI-3K) with wortmannin and LY 294002. The protection was time dependent with maximal benefit seen when PKB and PI-3K were inhibited before ischaemia or during both ischaemia and reoxygenation. In addition, it was revealed that PKB is located downstream of mitoKATP channels but upstream of p38 MAPK. PKB inhibition induced a similar degree of protection in the human and rat myocardium and, importantly, it reversed the unresponsiveness to protection of the diabetic myocardium. In conclusion, inhibition of PKB plays a critical role in protection of the mammalian myocardium and may represent a clinical target for the reduction of ischaemic injury. PMID:20403980

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.

A new biomarker of hedonic eating? A preliminary investigation of cortisol and nausea responses to acute opioid blockade.

Science.gov (United States)

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

2014-03-01

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 mindfulness-based intervention to reduce stress eating. In addition, we assessed indices of hedonic-related eating, including eating behaviors (binge eating, emotional eating, external eating, restraint) and intake of sweets/desserts and carbohydrates (Block Food Frequency); interoceptive awareness (which is associated with dysregulated eating behavior); and level of adiposity at baseline. Naltrexone-induced increases in cortisol were associated with greater emotional and restrained eating and lower interoceptive awareness. Naltrexone-induced nausea was associated with binge eating and higher adiposity. Furthermore, in a small exploratory analysis, naltrexone-induced nausea predicted treatment response to the mindfulness intervention, as participants with more severe nausea at baseline maintained weight whereas those with little or no nausea responses tended to gain weight. These preliminary data suggest that naltrexone-induced cortisol release and nausea may help identify individuals who have greater underlying food reward dependence, which leads to an excessive drive to eat. Future research is needed to confirm this finding and to test if these markers of opioidergic tone might help predict success in certain types of weight management programs. Copyright © 2013 Elsevier Ltd. All rights reserved.

Preclinical evaluation of reconsolidation blockade by clonidine as a potential novel treatment for posttraumatic stress disorder.

Science.gov (United States)

Gamache, Karine; Pitman, Roger K; Nader, Karim

2012-12-01

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α₂-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.

Caudal anesthesia in a patient with peritonitis: Is it safe??

OpenAIRE

Kako, H; Hakim, M; Kundu, A; Tobias, TD

2016-01-01

Neuraxial anesthesia combined with general anesthesia has become a widely accepted method of providing effective postoperative analgesia and decreasing intraoperative anesthetic needs in the pediatric population. In clinical practice, there still appears to be hesitancy for the use of a neuraxial technique (spinal or epidural) in patients at risk for bacteremia or with an on-going systemic infection. However, evidence-based medicine lacks any data to support an increase in the risk of infecti...

Why do older people oppose physician-assisted dying? A qualitative study.

Science.gov (United States)

Malpas, Phillipa J; Wilson, Maria K R; Rae, Nicola; Johnson, Malcolm

2014-04-01

Physician-assisted dying at the end of life has become a significant issue of public discussion. While legally available in a number of countries and jurisdictions, it remains controversial and illegal in New Zealand. The study aimed to explore the reasons some healthy older New Zealanders oppose physician-assisted dying in order to inform current debate. Recorded interviews were transcribed and analysed by the authors after some edits had been made by respondents. In all, 11 older participants (over 65 years) who responded to advertisements placed in Grey Power magazines and a University of Auckland email list were interviewed for around 1 h and asked a number of open-ended questions. Four central themes opposing physician-assisted dying were identified from the interviews: one's personal experience with health care and dying and death, religious reasoning and beliefs, slippery slope worries and concern about potential abuses if physician-assisted dying were legalised. An important finding of the study suggests that how some older individuals think about physician-assisted dying is strongly influenced by their past experiences of dying and death. While some participants had witnessed good, well-managed dying and death experiences which confirmed for them the view that physician-assisted dying was unnecessary, those who had witnessed poor dying and death experiences opposed physician-assisted dying on the grounds that such practices could come to be abused by others.

Análise do discurso oficial sobre a humanização da assistência hospitalar Analysis of the official speech about humanization of the hospital assistance

Directory of Open Access Journals (Sweden)

Suely F. Deslandes

2004-01-01

Full Text Available O termo "humanização" tem sido empregado constantemente no âmbito da saúde. É a base de um amplo conjunto de iniciativas, mas não possui uma definição mais clara, geralmente designando a forma de assistência que valoriza a qualidade do cuidado do ponto de vista técnico, associada ao reconhecimento dos direitos do paciente, de sua subjetividade e cultura, além do reconhecimento do profissional. Tal conceito pretende-se norteador de uma nova práxis na produção do cuidado em saúde. Este artigo, de cunho exploratório, visa analisar o discurso do Ministério da Saúde sobre a humanização da assistência. Investigamos os sentidos e expectativas associados à idéia de humanização a partir da análise dos textos oficiais, retomando um diálogo crítico com os autores da área de saúde pública e das ciências sociais. Discutimos as idéias centrais da humanização como oposição à violência; oferta de atendimento de qualidade, articulando os avanços tecnológicos com acolhimento, melhoria das condições de trabalho do profissional, e ampliação do processo comunicacional, eixo central dos textos.The term "humanization" has been employed constantly in the health field. It is the base of a wide set of initiatives, even though the concept does not have a clear definition. Generally, it refers to a kind of assistance that gives importance to the technical quality of care, associated with recognition of patients' rights, subjectivity and culture. Such concept intends to guide a new praxis in the care production in health. This article, of exploratory mark, aims analyze the speech of the Health Department on the assistance humanization. We investigate the meanings and expectations associates to the humanization idea from the analysis of the official texts, retaking a critical dialog with the authors of the area of public health and of the social sciences. We argue the central ideas of the humanization as opposition to the violence

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

Blockade by phenoxybenzamine of the contractor response produced by agonists in the isolated ileum of the guinea-pig.

Science.gov (United States)

Cook, D A

1971-09-01

1. The effects of various concentrations of phenoxybenzamine (dibenzyline) on the contractor response of the isolated ileum of the guinea-pig were investigated. The agonists tested were histamine, 5-hydroxytryptamine (5-HT), acetycholine and potassium chloride.2. In addition, uptake of (14)C-phenoxybenzamine into the ileum was determined as a function of antagonist concentration. The uptake increases sharply at concentrations above 10(-6) g/ml, (3x10(-6)M) and was not saturable at any concentration tested.3. In the presence of low concentrations of phenoxybenzamine, the dose-response curve for histamine undergoes a parallel shift of about 0.5 log units. At higher concentrations of phenoxybenzamine the maximum response is depressed. In the case of the other agonists, the maximum response is depressed as soon as any blockade becomes apparent.4. The ease of blockade with phenoxybenzamine is 5-HT >/= histamine> acetylcholine >/= potassium chloride.5. These results do not lend support to the ;spare-receptor' hypothesis and may be better explained by the ;two-site' hypothesis of Moran & Triggle (1970).6. It may further be concluded that the successful antagonism of potassium-induced contractions in this preparation lies in the ability of phenoxybenzamine to prevent the action of released acetylcholine. In the case of the contraction induced by 5-HT, phenoxybenzamine probably interferes with the 5-HT receptor responsible for neuronal release of acetycholine.

An Informationally Structured Room for Robotic Assistance

Directory of Open Access Journals (Sweden)

Tokuo Tsuji

2015-04-01

Full Text Available The application of assistive technologies for elderly people is one of the most promising and interesting scenarios for intelligent technologies in the present and near future. Moreover, the improvement of the quality of life for the elderly is one of the first priorities in modern countries and societies. In this work, we present an informationally structured room that is aimed at supporting the daily life activities of elderly people. This room integrates different sensor modalities in a natural and non-invasive way inside the environment. The information gathered by the sensors is processed and sent to a centralized management system, which makes it available to a service robot assisting the people. One important restriction of our intelligent room is reducing as much as possible any interference with daily activities. Finally, this paper presents several experiments and situations using our intelligent environment in cooperation with our service robot.

The role of ZAP70 kinase in acute lymphoblastic leukemia infiltration into the central nervous system.

Science.gov (United States)

Alsadeq, Ameera; Fedders, Henning; Vokuhl, Christian; Belau, Nele M; Zimmermann, Martin; Wirbelauer, Tim; Spielberg, Steffi; Vossen-Gajcy, Michaela; Cario, Gunnar; Schrappe, Martin; Schewe, Denis M

2017-02-01

Central nervous system infiltration and relapse are poorly understood in childhood acute lymphoblastic leukemia. We examined the role of zeta-chain-associated protein kinase 70 in preclinical models of central nervous system leukemia and performed correlative studies in patients. Zeta-chain-associated protein kinase 70 expression in acute lymphoblastic leukemia cells was modulated using short hairpin ribonucleic acid-mediated knockdown or ectopic expression. We show that zeta-chain-associated protein kinase 70 regulates CCR7/CXCR4 via activation of extracellular signal-regulated kinases. High expression of zeta-chain-associated protein kinase 70 in acute lymphoblastic leukemia cells resulted in a higher proportion of central nervous system leukemia in xenografts as compared to zeta-chain-associated protein kinase 70 low expressing counterparts. High zeta-chain-associated protein kinase 70 also enhanced the migration potential towards CCL19/CXCL12 gradients in vitro CCR7 blockade almost abrogated homing of acute lymphoblastic leukemia cells to the central nervous system in xenografts. In 130 B-cell precursor acute lymphoblastic leukemia and 117 T-cell acute lymphoblastic leukemia patients, zeta-chain-associated protein kinase 70 and CCR7/CXCR4 expression levels were significantly correlated. Zeta-chain-associated protein kinase 70 expression correlated with central nervous system disease in B-cell precursor acute lymphoblastic leukemia, and CCR7/CXCR4 correlated with central nervous system involvement in T-cell acute lymphoblastic leukemia patients. In multivariate analysis, zeta-chain-associated protein kinase 70 expression levels in the upper third and fourth quartiles were associated with central nervous system involvement in B-cell precursor acute lymphoblastic leukemia (odds ratio=7.48, 95% confidence interval, 2.06-27.17; odds ratio=6.86, 95% confidence interval, 1.86-25.26, respectively). CCR7 expression in the upper fourth quartile correlated with central

Vanishing current hysteresis under competing nuclear spin pumping processes in a quadruplet spin-blockaded double quantum dot

Energy Technology Data Exchange (ETDEWEB)

Amaha, S., E-mail: s-amaha@riken.jp [Quantum Spin Information Project, Japan Science and Technology Agency, ICORP, 3-1, Morinosato Wakamiya, Atsugi-shi, Kanagawa 243-0198 (Japan); Quantum Functional System Research Group, RIKEN Center for Emergent Matter Science, RIKEN, 3-1 Wako-shi, Saitama 351-0198 (Japan); Hatano, T. [Quantum Spin Information Project, Japan Science and Technology Agency, ICORP, 3-1, Morinosato Wakamiya, Atsugi-shi, Kanagawa 243-0198 (Japan); Department of Physics, Tohoku University, Sendai-shi, Miyagi 980-8578 (Japan); Tarucha, S. [Quantum Spin Information Project, Japan Science and Technology Agency, ICORP, 3-1, Morinosato Wakamiya, Atsugi-shi, Kanagawa 243-0198 (Japan); Quantum Functional System Research Group, RIKEN Center for Emergent Matter Science, RIKEN, 3-1 Wako-shi, Saitama 351-0198 (Japan); Department of Applied Physics, School of Engineering, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan); Gupta, J. A.; Austing, D. G. [National Research Council of Canada, M50, Montreal Road, Ottawa, Ontario K1A 0R6 (Canada)

2015-04-27

We investigate nuclear spin pumping with five-electron quadruplet spin states in a spin-blockaded weakly coupled vertical double quantum dot device. Two types of hysteretic steps in the leakage current are observed on sweeping the magnetic field and are associated with bidirectional polarization of nuclear spin. Properties of the steps are understood in terms of bias-voltage-dependent conditions for the mixing of quadruplet and doublet spin states by the hyperfine interaction. The hysteretic steps vanish when up- and down-nuclear spin pumping processes are in close competition.

The insulin like growth factor system in cirrhosis. Relation to changes in body composition following adrenoreceptor blockade

DEFF Research Database (Denmark)

Bonefeld, Karen; Hobolth, Lise; Juul, Anders

2012-01-01

OBJECTIVE: Circulating levels of IGF-I and IGFBP-3 are low in cirrhosis and are related to liver dysfunction. Metabolic disturbances include malnutrition with altered body composition and osteopenia. Since the effects of IGF-I may be associated to changes in body composition and bone mineral...... content (BMC) in cirrhotic patients, we investigated the relations between changes in the IGF-system and body composition and the effects of long-term alpha- and beta-blockade. DESIGN: The study was designed as a combined cross-sectional and prospective randomised controlled study of 62 patients...

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

Central nervous system reactions to cervical myelography

International Nuclear Information System (INIS)

Vestergaard, A.; Dons, K.; Eskesen, V.; Kruse-Larsen, C.; Blatt Lyon, B.; Arlien Soeborg, P.; Jensen, N.O.; Praestholm, J.

1991-01-01

In a double blind prospective study of side effects to cervical myelography 38 patients were evaluated with neurologic examination, electroencephalography (EEG), brainstem evoked response (BER), somatosensory evoked responses (SSER), and continuous reaction times prior to and at 6 h and 24 h after myelography with either metrizamide or iohexol. A difference in the incidence of side effects (for example headache, dizziness, nausea, and neck pain) to the two different contrast media indicated that the inconveniences related to myelography were not only due to the spinal puncture. A contrast medium effect on the central nervous system varying from one agent to another was present. A high frequency of EEG deteriorations among patients with adverse clinical reactions and on only discrete affection upon BER indicated the reaction to be located to the cerebral cortex. Weakened tendon reflexes and reduced strength in the upper extremities were probably caused by blockade in the motor roots as SSER were normal indicating no affection of the sensory pathways. This hypothesis is in agreement with the fact the patients were in the prone position in the first phase of the investigation causing the highest concentration of contrast medium around the motor roots and the anterior part of the spinal cord. Difference in metabolic effect may explain differences in side effects of metrizamide and iohexol. (orig.)

Central nervous system reactions to cervical myelography

Energy Technology Data Exchange (ETDEWEB)

Vestergaard, A; Dons, K; Eskesen, V; Kruse-Larsen, C; Blatt Lyon, B; Arlien Soeborg, P; Jensen, N O; Praestholm, J [Hvidovre Hospital (Denmark). Depts. of Diagnostic Radiology, Neurosurgery, Neurology, and Clinical Neurophysiology

1991-09-01

In a double blind prospective study of side effects to cervical myelography 38 patients were evaluated with neurologic examination, electroencephalography (EEG), brainstem evoked response (BER), somatosensory evoked responses (SSER), and continuous reaction times prior to and at 6 h and 24 h after myelography with either metrizamide or iohexol. A difference in the incidence of side effects (for example headache, dizziness, nausea, and neck pain) to the two different contrast media indicated that the inconveniences related to myelography were not only due to the spinal puncture. A contrast medium effect on the central nervous system varying from one agent to another was present. A high frequency of EEG deteriorations among patients with adverse clinical reactions and on only discrete affection upon BER indicated the reaction to be located to the cerebral cortex. Weakened tendon reflexes and reduced strength in the upper extremities were probably caused by blockade in the motor roots as SSER were normal indicating no affection of the sensory pathways. This hypothesis is in agreement with the fact the patients were in the prone position in the first phase of the investigation causing the highest concentration of contrast medium around the motor roots and the anterior part of the spinal cord. Difference in metabolic effect may explain differences in side effects of metrizamide and iohexol. (orig.).

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.

Sugammadex for reversal of rocuronium-induced neuromuscular blockade in pediatric patients

Science.gov (United States)

Won, Young Ju; Lim, Byung Gun; Lee, Dong Kyu; Kim, Heezoo; Kong, Myoung Hoon; Lee, Il Ok

2016-01-01

Abstract Background: Previous studies have shown that sugammadex, a modified γ-cyclodextrin, is a well-tolerated agent for the reversal of neuromuscular blockade (NMB) induced by a steroidal neuromuscular blocking drug in adult patients. However, its use has not been reviewed in pediatric patients. The aim of this meta-analysis was to evaluate the efficacy and safety of sugammadex in the reversal of rocuronium-induced NMB during surgery under general anesthesia in pediatric patients. Methods: A literature search was performed using the Pubmed, EMBASE: Drugs and pharmacology, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Analysis was conducted using RevMan 5.3. Data collected from different trials were pooled; the weighted mean difference or the pooled risk ratio and the corresponding 95% confidence interval (CI) were used for analysis, and heterogeneity (I2) assessment was performed. Results: Six randomized controlled trials comparing 253 pediatric patients (age range, 2–18 years) were included in the final analysis. The mean time taken to reach a train-of-four ratio of ≥0.9 was significantly shorter in the sugammadex groups (2 and 4 mg/kg) than in the control group (neostigmine or placebo), although the heterogeneity was high. The weighted mean differences of the 2 and 4 mg/kg sugammadex groups were −7.15 (95% CI: −10.77 to −3.54; I2 = 96%; P = 0.0001) and −17.32 (95% CI: −29.31 to −5.32; I2 = 98%; P = 0.005), respectively. The extubation time in the sugammadex group was shorter than that in the control group; the weighted mean difference of the sugammadex group was −6.00 (95% CI: −11.46 to −0.53; I2 = 99%; P = 0.03). There was no significant difference between the groups in terms of the incidence of postanesthetic adverse events; the pooled risk ratio was 0.67 (95% CI: 0.27–1.71; I2 = 59%; P = 0.41). Conclusion: We suggest that sugammadex is fast and

[Therapeutic effect observation of chronic knee joint pain assisted with the central-square needling technique of the thumb-tack needles].

Science.gov (United States)

Yang, Yang; Qi, Si; Liu, Mengyue; Zhao, Yu; Li, Ning

2017-10-12

To compare the differences in the clinical therapeutic effects on chronic knee joint pain between the combination of the central-square needling technique of thumb-tack needles with the routine therapy of acupuncture, moxibustion and tuina and the routine therapy of acupuncture, moxibustion and tuina . One hundred and twenty patients of chronic knee joint pain were randomized into an observation group and a control group, 60 cases in each one. In the control group, the routine therapy of acupuncture, moxibustion and tuina was adopted. In the observation group, at the end of treatment with the routine therapy of acupuncture, moxibustion and tuina , the subcutaneous embedding therapy was followed with four thumb-tack needles at the sites 1 to 1.5 cm above, below and bilateral to the main point ( ashi point) separately, and the needles were retained for 24 h to 48 h. The treatment was given once every two days, three times a week, totally 6 times in two weeks; and the follow-up visit was done for 3 months in patients of the two groups. The visual analogue scale (VAS) score before and after each treatment, Lequesne index score before treatment and at the end of follow-up and the case numbers of proactive use of painkillers or receiving acupuncture treatment in the follow-up stage were compared and observed in the patients of the two groups. The VAS score was reduced gradually after treatment in the patients of the two groups. The differences were significant statistically after the second treatment as compared with those before the treatment in the two groups (all P 0.05). In the follow-up stage, there were 0 case in the observation group and 9 cases in the control group in terms of proactive use of painkillers ( P 0.05). The acupuncture scheme in assistance with the central-square needling technique of thumb-tack needles obviously relieves chronic knee joint pain, much better sustains the analgesic effects of acupuncture and improves patient compliance.

Differential effects of alpha-adrenoceptor blockade on essential, physiological and isoprenaline-induced tremor: evidence for a central origin of essential tremor.

OpenAIRE

Abila, B; Wilson, J F; Marshall, R W; Richens, A

1985-01-01

Intravenous thymoxamine reduced the power of essential tremor but increased that of physiological and isoprenaline-induced tremor. These findings indicate that essential and physiological tremor have dissimilar pathophysiological mechanisms. They also suggest that central adrenergic mechanisms are involved in the pathophysiology of essential tremor and that isoprenaline-induced tremor is not a good model of essential tremor. Furthermore, alpha-adrenoceptor blockers may be a useful therapy for...

Concepts of mental capacity for patients requesting assisted suicide: a qualitative analysis of expert evidence presented to the Commission on Assisted Dying.

Science.gov (United States)

Price, Annabel; McCormack, Ruaidhri; Wiseman, Theresa; Hotopf, Matthew

2014-04-22

In May 2013 a new Assisted Dying Bill was tabled in the House of Lords and is currently scheduled for a second reading in May 2014. The Bill was informed by the report of the Commission on Assisted Dying which itself was informed by evidence presented by invited experts.This study aims to explore how the experts presenting evidence to the Commission on Assisted Dying conceptualised mental capacity for patients requesting assisted suicide and examine these concepts particularly in relation to the principles of the Mental Capacity Act 2005. This study was a secondary qualitative analysis of 36 transcripts of oral evidence and 12 pieces of written evidence submitted by invited experts to the Commission on Assisted Dying using a framework approach. There was agreement on the importance of mental capacity as a central safeguard in proposed assisted dying legislation. Concepts of mental capacity, however, were inconsistent. There was a tendency towards a conceptual and clinical shift toward a presumption of incapacity. This appeared to be based on the belief that assisted suicide should only be open to those with a high degree of mental capacity to make the decision.The 'boundaries' around the definition of mental capacity appeared to be on a continuum between a circumscribed legal 'cognitive' definition of capacity (in which most applicants would be found to have capacity unless significantly cognitively impaired) and a more inclusive definition which would take into account wider concepts such as autonomy, rationality, voluntariness and decision specific factors such as motivation for decision making. Ideas presented to the Commission on Assisted Dying about mental capacity as it relates to assisted suicide were inconsistent and in a number of cases at variance with the principles of the Mental Capacity Act 2005. Further work needs to be done to establish a consensus as to what constitutes capacity for this decision and whether current legal frameworks are able to

Intelligence for Human-Assistant Planetary Surface Robots

Science.gov (United States)

Hirsh, Robert; Graham, Jeffrey; Tyree, Kimberly; Sierhuis, Maarten; Clancey, William J.

2006-01-01

The central premise in developing effective human-assistant planetary surface robots is that robotic intelligence is needed. The exact type, method, forms and/or quantity of intelligence is an open issue being explored on the ERA project, as well as others. In addition to field testing, theoretical research into this area can help provide answers on how to design future planetary robots. Many fundamental intelligence issues are discussed by Murphy [2], including (a) learning, (b) planning, (c) reasoning, (d) problem solving, (e) knowledge representation, and (f) computer vision (stereo tracking, gestures). The new "social interaction/emotional" form of intelligence that some consider critical to Human Robot Interaction (HRI) can also be addressed by human assistant planetary surface robots, as human operators feel more comfortable working with a robot when the robot is verbally (or even physically) interacting with them. Arkin [3] and Murphy are both proponents of the hybrid deliberative-reasoning/reactive-execution architecture as the best general architecture for fully realizing robot potential, and the robots discussed herein implement a design continuously progressing toward this hybrid philosophy. The remainder of this chapter will describe the challenges associated with robotic assistance to astronauts, our general research approach, the intelligence incorporated into our robots, and the results and lessons learned from over six years of testing human-assistant mobile robots in field settings relevant to planetary exploration. The chapter concludes with some key considerations for future work in this area.

Central Tolerance Blockade to Augment Checkpoint Immunotherapy in Melanoma

Science.gov (United States)

2017-09-01

expressed at higher levels in medullary thymic epithelial cells (mTECs) than in cortical thymic epithelial cells (cTECs), addition of anti-RANKL antibody...relative Aire expression by quantitative RT-PCR in cultured thymic tissue . 12-15 90% Subtask 3. Culture human thymus sections with OPG-Fc or vehicle...PCR in cultured thymic tissue . 15-18 90% ACURO approval 13-14 100% Major Task 1. Effect of concurrent anti-RANKL and checkpoint inhibitor

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

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.

Metabolic and vascular effects of tumor necrosis factor-alpha blockade with etanercept in obese patients with type 2 diabetes

DEFF Research Database (Denmark)

Dominguez, Helena; Storgaard, Heidi; Rask-Madsen, Christian

2005-01-01

OBJECTIVE: The pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-alpha blockade with etanercept could reverse vascular and metabolic...... glucose uptake remained unchanged as well. Beta-cell function tended to improve. CONCLUSION: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed....

Renin-Angiotensin System Blockade Improves Cardiac Indices in Acromegaly Patients.

Science.gov (United States)

Thomas, Julia D J; Dattani, Abhishek; Zemrak, Filip; Burchell, Thomas; Akker, Scott A; Kaplan, Felicity J L; Khoo, Bernard; Aylwin, Simon; Grossman, Ashley B; Davies, L Ceri; Korbonits, Márta

2017-06-01

Blockade of the angiotensin-renin system, with angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), has been shown to improve cardiac outcomes following myocardial infarction and delay progression of heart failure. Acromegaly is associated with a disease-specific cardiomyopathy, the pathogenesis of which is poorly understood.The cardiac indices of patients with active acromegaly with no hypertension (Group A, n=4), established hypertension not taking ACEi/ARBs (Group B, n=4) and established hypertension taking ACEi/ARBs (Group C, n=4) were compared using cardiac magnetic imaging.Patients taking ACEi/ARBs had lower end diastolic volume index (EDVi) and end systolic volume index (ESVi) than the other 2 groups ([C] 73.24 vs. [A] 97.92 vs. [B] 101.03 ml/m 2 , ANOVA p=0.034, B vs. C pAcromegaly patients on ACEi/ARBs for hypertension demonstrate improved cardiac indices compared to acromegaly patients with hypertension not taking these medications. Further studies are needed to determine if these drugs have a beneficial cardiac effect in acromegaly in the absence of demonstrable hypertension. © Georg Thieme Verlag KG Stuttgart · New York.

Varying patterns of the antihypertensive and antialbuminuric response to higher doses of renin-angiotensin-aldosterone system blockade in albuminuric hypertensive type 2 diabetes mellitus patients

DEFF Research Database (Denmark)

Weir, Matthew R; Hollenberg, Norman K; Remuzzi, Giuseppe

2011-01-01

In patients with type 2 diabetes mellitus (T2DM), blocking of the renin-angiotensin-aldosterone system (RAAS) has demonstrated efficacy in lowering blood pressure (BP) and urinary albumin excretion rate (UAER). Nonetheless, not all patients successfully respond to RAAS blockade with a reduction...

Systems thinking for assistive technology: a commentary on the GREAT summit.

Science.gov (United States)

MacLachlan, Malcolm; Scherer, Marcia

2018-05-17

The area of assistive technology has a long history of technological ingenuity and innovation. In order to ensure that the benefits of assistive technology are equitably distributed across the population and life course, it is necessary to adopt a systemic approach to the area. We describe examples of systems thinking and non-systems thinking across 10 Ps. These Ps are People (or users, as the primary beneficiaries of assistive technology), Policy, Products, Personnel, Provision (as key strategic drivers at systems level); and Procurement, Place, Pace, Promotion and Partnership (as key situational factors for systems). Together these Ps should constitute a framework for an "open" system that can evolve and adapt, that empowers users, inter-connects key components and locates these in the reality of differing contexts. The adoption of a stronger systems thinking perspective within the assistive technology field should allow for more equitable, more resilient and more sustainable assistive technology across high, middle- and low-income contexts and countries. Implications for Rehabilitation The progress of assistive technology provison has been hampered by disconnected initiatives and activities and this needs to be corrected. Systems thinking is a way of thinking about the connections between things and how these are influenced by contextual and other factors. By encouraging the providers and users of assitive technology to think more systemically we can provide a more cohesive and resilient systems. The user experience is the central component of systems thinking in assistive technologies.

Video-Assisted Thyroidectomy for Papillary Thyroid Carcinoma

Directory of Open Access Journals (Sweden)

Celestino Pio Lombardi

2010-01-01

Full Text Available Background. The results of video-assisted thyroidectomy (VAT were evaluated in a large series of patients with papillary thyroid carcinoma (PTC, especially in terms of completeness of the surgical resection and short-to-medium term recurrence. Methods. The medical records of all patients who underwent video-assisted thyroidectomy for PTC between June 1998 and May 2009 were reviewed. Results. Three hundred fifty-nine patients were included. One hundred twenty-six patients underwent concomitant central neck node removal. Final histology showed 285 pT1, 26 pT2, and 48 pT3 PTC. Lymph node metastases were found in 27 cases. Follow-up was completed in 315 patients. Mean postoperative serum thyroglobulin level off levothyroxine was 5.4 ng/mL. Post operative ultrasonography showed no residual thyroid tissue in all the patients. Mean post-operative 131I uptake was 1.7%. One patient developed lateral neck recurrence. No other recurrence was observed.

[Active euthanasia in Colombia and assisted suicide in California].

Science.gov (United States)

Julesz, Máté

2016-01-31

The institution of active euthanasia has been legal in Colombia since 2015. In California, the regulation on physician-assisted suicide will come into effect on January 1, 2016. The legal institution of active euthanasia is not accepted under the law of the United States of America, however, physician-assisted suicide is accepted in an increasing number of member states. The related regulation in Oregon is imitated in other member states. In South America, Colombia is not the first country to legalize active euthanasia: active euthanasia has been legal in Uruguay since 1932. The North American legal tradition markedly differs from the South American one and both are incompatible with the Central European rule of law. In Hungary and in most European Union countries, solely the passive form of euthanasia is legal. In the Benelux countries, the active form of euthanasia is legal because the supranational law of the European Union does not prohibit it. Notwithstanding, European Union law does not prescribe legalization of either the active form of euthanasia, or the physician-assisted suicide.

"Many Secrets Are Told around Horses": An Ethnographic Study of Equine-Assisted Psychotherapy

Science.gov (United States)

Van Tiem, Jennifer

2014-01-01

This dissertation presents an ethnography of equine-assisted psychotherapy (EAP) based on nine months of fieldwork at "Equine Healers," a non-profit organization in central Colorado that specialized in various therapeutic modalities associated with EAP. In bridging scholarly work around animals, a literature suffused with the notion of…

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.

Current Trends in Neuromuscular Blockade, Management, and Monitoring amongst Singaporean Anaesthetists

Directory of Open Access Journals (Sweden)

Wendy H. Teoh

2016-01-01

Full Text Available Introduction. This survey aimed to investigate the attitudes/practice pertaining the use, management, and monitoring of neuromuscular blockade amongst Singaporean anaesthetists. Methods. All specialist accredited anaesthetists registered with the Singapore Medical Council were invited to complete an anonymous online survey. Results. The response rate was 39.5%. Neuromuscular monitoring (NM was used routinely by only 13.1% despite the widespread availability of monitors. 82% stated residual NMB (RNMB was a significant risk factor for patient outcome, but only 24% believed NMB monitoring should be compulsory in all paralyzed patients. 63.6% of anaesthetists estimated the risk of RNMB in their own institutions to be 50% said such benefits may be able to offset the associated costs. Conclusions. There is a significant need for reeducation about RNMB, studies on local RNMB incidences, and strengthening of current monitoring practices and guidelines. Strategies are discussed. As NM monitors appear widely available and reversal of NMB standard practice, it is hopeful that Singaporean anaesthetists will change and strive for evidence-based best clinical practice to enhance patient safety.

Deutsch, Toffoli, and cnot Gates via Rydberg Blockade of Neutral Atoms

Science.gov (United States)

Shi, Xiao-Feng

2018-05-01

Universal quantum gates and quantum error correction (QEC) lie at the heart of quantum-information science. Large-scale quantum computing depends on a universal set of quantum gates, in which some gates may be easily carried out, while others are restricted to certain physical systems. There is a unique three-qubit quantum gate called the Deutsch gate [D (θ )], from which a circuit can be constructed so that any feasible quantum computing is attainable. We design an easily realizable D (θ ) by using the Rydberg blockade of neutral atoms, where θ can be tuned to any value in [0 ,π ] by adjusting the strengths of external control fields. Using similar protocols, we further show that both the Toffoli and controlled-not gates can be achieved with only three laser pulses. The Toffoli gate, being universal for classical reversible computing, is also useful for QEC, which plays an important role in quantum communication and fault-tolerant quantum computation. The possibility and speed of realizing these gates shed light on the study of quantum information with neutral atoms.

Labour analgesia and the baby: good news is no news.

Science.gov (United States)

Reynolds, Felicity

2011-01-01

When investigating different methods of maternal pain relief in labour, neonatal outcome has not always been at the forefront, or else maternal changes, such as haemodynamics, fever, length of labour, need for oxytocin or type of delivery, are taken as surrogates for neonatal outcome. It is essential to examine the actual baby and to appreciate that labour pain itself has adverse consequences for the baby. For systemic analgesia, pethidine has been most extensively studied and compared with neuraxial analgesia. It depresses fetal muscular activity, aortic blood flow, short-term heart rate variability and oxygen saturation. In the newborn it exacerbates acidosis, depresses Apgar scores, respiration, neurobehavioural score, muscle tone and suckling. Alternatives have few advantages, remifentanil being the most promising. Neuraxial analgesia is associated with better Apgar scores and variable neurobehavioural changes. Neonatal acid-base status is not only better with epidural than with systemic opioid analgesia, it is also better than with no analgesia. The effect on breast feeding has yet to be established, though it is certainly no worse than that of systemic opioid analgesia. Variations in neuraxial technique have little impact on the newborn. Widespread ignorance of the benefit to the newborn of neuraxial labour analgesia in the UK among non-anaesthetists needs to be combated. Copyright © 2010 Elsevier Ltd. All rights reserved.

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

Energy Technology Data Exchange (ETDEWEB)

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

2000-04-01

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

Preliminary trajectory design for a solar polar observatory using SEP and multiple gravity assists

NARCIS (Netherlands)

Corpaccioli, L.; Noomen, R.; De Smet, S.; Parker, J.S.; Herman, J.F.C.

2015-01-01

Satellite solar observatories have always been of central importance to heliophysics; while there have been numerous such missions, the solar poles have been extremely under-observed. This paper proposes to use low-thrust as well as multiple gravity assists to reach the enormous energies required

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

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

A Costly Lesson: Fatal Respiratory Depression Induced by Clindamycin during Postoperative Patient Controlled Analgesia.

Science.gov (United States)

Wu, Gao; Wu, Guo; Wu, Hanbin

2015-01-01

Many drugs can cause neuromuscular blockade. Clindamycin-related neuromuscular blockade is commonly reported, but fatal clindamycin-induced neuromuscular blockade is rarely reported. We describe a 47-year-old woman who initially presented with endometrial carcinoma. She underwent a laparoscopic-assisted vaginal hysterectomy (LAVH) and bilateral adnexectomy under general anesthesia, secondary to antibiotic treatment with clindamycin 1.2g in 250 mL for about 30 minutes through the peripheral intravenous route during postoperative patient controlled analgesia (PCA). She became unconscious near the end of the infusion, then, despite resuscitation attempts, she died. Clindamycin appeared to have triggered delayed respiratory depression during PCA. A combination of clindamycin and fentanyl led to her respiratory depression in the fatal case.

Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade

Science.gov (United States)

McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles

2016-01-01

As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

Sciatic and femoral nerve blockade using bupivacaine alone, or in combination with dexmedetomidine or buprenorphine in cats.

Science.gov (United States)

Evangelista, M C; Doodnaught, G M; Fantoni, D T; Steagall, P V M

2017-06-17

The aim of this study was to determine the onset and offset of antinociception after sciatic (ScN) and femoral (FN) nerve blocks. Six healthy adult cats (4.8±1.3years; 4.3±0.4 kg) were included in a randomised, crossover, blinded and controlled study. Following sedation with dexmedetomidine (25 µg/kg, intramuscular), each ScN and FN injection was performed using 0.1 ml/kg of saline (CONTROL), bupivacaine (0.46 per cent, 0.46 mg/kg; BUPI), bupivacaine and dexmedetomidine (1 µg/kg; BUPI-DEX) or bupivacaine and buprenorphine (2.5 µg/kg; BUPI-BUPRE). Atipamezole (250 µg/kg) was administered after injections. Paw withdrawal thresholds (PWT) and motor blockade were evaluated before sedation and up to 24 hours. The PWT were significantly increased at half an hour in CONTROL, from two to four hours in BUPI and BUPI-DEX when compared with baseline. Motor blockade was observed between one and three hours in treatments using bupivacaine. Ability to walk was significantly impaired in BUPI at half an hour to two hours, BUPI-DEX at one to two hours and BUPI-BUPRE at two hours. Antinociception was observed in BUPI between one and eight hours, and in BUPI-DEX and BUPI-BUPRE between one and four hours. This study could not demonstrate a benefit of administering bupivacaine with dexmedetomidine or buprenorphine in cats. Results in BUPI-DEX may have been biased by the administration of atipamezole. British Veterinary Association.

A randomized trial on mineralocorticoid receptor blockade in men: effects on stress responses, selective attention, and memory.

Science.gov (United States)

Cornelisse, Sandra; Joëls, Marian; Smeets, Tom

2011-12-01

Corticosteroids, released in high amounts after stress, exert their effects via two different receptors in the brain: glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs). GRs have a role in normalizing stress-induced effects and promoting consolidation, while MRs are thought to be important in determining the threshold for activation of the hypothalamic-pituitary-adrenal (HPA) axis. We investigated the effects of MR blockade on HPA axis responses to stress and stress-induced changes in cognitive function. In a double-blind, placebo-controlled study, 64 healthy young men received 400 mg of the MR antagonist spironolactone or placebo. After 1.5 h, they were exposed to either a Trier Social Stress Test or a non-stressful control task. Responses to stress were evaluated by hormonal, subjective, and physiological measurements. Afterwards, selective attention, working memory, and long-term memory performance were assessed. Spironolactone increased basal salivary cortisol levels as well as cortisol levels in response to stress. Furthermore, spironolactone significantly impaired selective attention, but only in the control group. The stress group receiving spironolactone showed impaired working memory performance. By contrast, long-term memory was enhanced in this group. These data support a role of MRs in the regulation of the HPA axis under basal conditions as well as in response to stress. The increased availability of cortisol after spironolactone treatment implies enhanced GR activation, which, in combination with MR blockade, presumably resulted in a decreased MR/GR activation ratio. This condition influences both selective attention and performance in various memory tasks.

Central catheter dressing in a simulator: the effects of tutor's assistance or self-learning tutorial Parche de catéter central en simulador: efecto de la presencia del tutor o del aprendizaje auto-instruccional Curativo de cateter central em simulador: efeito da presença do tutor ou da aprendizagem autoinstrucional

Directory of Open Access Journals (Sweden)

Milene Thaís Marmol

2012-12-01

Full Text Available AIMS: to compare the performance of undergraduate students concerning semi-implanted central venous catheter dressing in a simulator, with the assistance of a tutor or of a self-learning tutorial. METHOD: Randomized controlled trial. The sample consisted of 35 undergraduate nursing students, who were divided into two groups after attending an open dialogue presentation class and watching a video. One group undertook the procedure practice with a tutor and the other with the assistance of a self-learning tutorial. RESULTS: in relation to cognitive knowledge, the two groups had lower performance in the pre-test than in the post-test. The group that received assistance from a tutor performed better in the practical assessment. CONCLUSION: the simulation undertaken with the assistance of a tutor showed to be the most effective learning strategy when compared to the simulation using a self-learning tutorial. Advances in nursing simulation technology are of upmost importance and the role of the tutor in the learning process should be highlighted, taking into consideration the role this professional plays in knowledge acquisition and in the development of critical-reflexive thoughts and attitudes. (ClinicalTrials.gov Identifier: NCT 01614314.OBJETIVO: comparar el desempeño de graduandos en la realización del parche del catéter venoso central semi-implantado, en simulador, con el auxilio del tutor o de un guía auto-instruccional. MÉTODO: estudio experimental controlado hecho aleatorio. La muestra fue compuesta por 35 alumnos de Graduación en Enfermería que fueron asignados en dos grupos después de asistir a una clase expositiva dialogada y a un vídeo. Un grupo realizó el entrenamiento del procedimiento con el tutor y el otro con el auxilio de un guía auto- instruccional. RESULTADOS: con relación al conocimiento cognoscitivo, los dos grupos presentaron desempeño menor en la pre-prueba comparada al pos-prueba. El grupo con presencia del tutor

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

Science.gov (United States)

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

2011-05-01

Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Energy reforms in central and eastern Europe - The first year

International Nuclear Information System (INIS)

1991-01-01

The first stages of the energy reforms in central and eastern Europe - taking stock of the heritage of the past and conceptualizing the nature of reforms - were accomplished in 1990. While two countries - the USSR and Albania -introduced some market economy elements into central energy planning and basically maintained the latter, all other countries of central and eastern Europe opted for a replacement of central energy planning by market-oriented energy policies and practices. In those latter countries, a typical policy of market adaptation emerged consisting of a change of policies, institutions, economic instruments and relations. Differences in the conditions prevailing in the various countries resulted in the emergence of specific national ''models'' of market adaptation. The reforms, if successful, would imply: greater energy efficiency, reduced pollution, enhanced nuclear safety, a reduced impact on the climate, greater business opportunities, the closure of uneconomic capacities, a decline of coal production, a rise in unemployment; a rise of the energy trade dependence coupled with a rise of gas and oil imports; but practically no change of the net energy exports of the USSR. By the end of 1990 developed market economies agreed to co-ordinate assistance (within the ''Group of 24'') and determined the type and modalities of support. This support would enable and encourage the economies in transition to finalize reform, stimulate their practical implementation and address side effects (disinvestments, unemployment) and systematic risks (e.g. trade dependence) and opportunities (e.g. trade diversification). The business community and lending institutions would have to assess and support investments opportunities more actively. Intergovernmental organizations will play an important role in improving the conditions for business involvement. In 1990, the frameworks for energy reforms in central and eastern Europe, short term assistance, long term business